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Pharmaceutical Technology of BASF Excipients
EMP080601e-­00
June 2008; Supersedes edition of April 2004; Printed in Germany
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Volker Bühler
Volker Bühler
Pharmaceutical Technology of BASF Excipients
Volker Bühler
Pharmaceutical
Technology
of BASF Excipients
Pharma Ingredients & Services.
Welcome to more opportunities.
Volker Bühler
Pharmaceutical Technology
of BASF Excipients
3rd revised edition
June 2008
Contents
Page
Foreword
6
1. I nstant-release solid dosage forms
(Tablets, pellets, granules)
1.1
1.2
1.3
1.4
1.5
1.6
1.7
Binders
1.1.1 General notes
1.1.2 Binders for wet granulation
1.1.3 Dry granulation (roller compaction)
1.1.4 Direct compression
1.1.5 Melt extrusion
Disintegrants for normal tablets
1.2.1 General notes
1.2.2 Standard disintegrant: Kollidon® CL
1.2.3 Special disintegrants: Kollidon® CL-F, Kollidon® CL-SF
Disintegrant for fast disintegrating buccal tablets
Enhancers of drug release
1.4.1 General notes
1.4.2 Povidone: Soluble Kollidon® grades
1.4.3 Crospovidone: Kollidon® CL grades
1.4.4 Poloxamers
1.4.5 Solubilizers: Cremophor® RH 40
Direct compression agents
1.5.1 General notes
1.5.2 Normal tablets with Ludipress®
1.5.3Lozenges, chewable, effervescent and sustained-release
tablets with Ludipress® LCE
1.5.4 Fast disintegrating tablets with Ludiflash ®
Instant-release and protective coatings of tablets and capsules
1.6.1 General notes
1.6.2 Instant-release film-coating with Kollicoat ® IR
1.6.3 Instant-release film-coating with Kollicoat ® IR White
1.6.4 Protective film-coating with Kollicoat ® Protect
1.6.5 Instant-release film-coating with Kollidon ® VA 64
1.6.6 Traditional sugar coating
1.6.7 Subcoatings of tablet cores
1.6.8 Taste masking by coatings of tablets
1.6.9Taste masking by coatings of granules or crystals before
tabletting
Colorants (pigments)
9
9
9
14
16
20
22
22
23
26
28
30
30
30
31
32
33
34
34
34
36
37
40
40
41
45
48
52
53
54
55
57
58
2. M
odified-release solid dosage formes
(Tablets, pellets, granules)
2.1
2
Enteric film-coatings
2.1.1 General notes
2.1.2 Enteric film-coating of tablets and capsules
2.1.3 Enteric film-coating of pellets and crystals
63
63
64
66
2.2
2.5
Sustained-release pellets
2.2.1 Coating with Kollicoat® SR 30D
2.2.2 Coating with Kollicoat® EMM 30D
Sustained-release tablet
2.3.1 Direct compression with Kollidon® SR
2.3.2 Wet granulation and compression to matrix tablets
2.3.3 Compression of sustained-release pellets
2.3.4Sustained-release film-coating of tablet cores with
Kollicoat® SR 30D
Plasticizers
2.4.1 Propylene glycol
2.4.2 Macrogols
Mucoadhesives for buccal tablets
3.
Soft gelatin capsules
3.1
3.2
3.3
3.4
Carriers, solvents
Solubilizers
Antioxidants
Colorants
4.
Solutions
2.3
2.4
4.1
Solubilization for oral and topical use
4.1.1 Surfactants: Cremophor® RH 40, Cremophor® EL
4.1.2 Complex formers: Kollidon® 25 and Kollidon® 30
4.1.3 Poloxamers: Lutrol® F68 and Lutrol® F127
4.2
Solubilization for parenteral use
4.2.1 Complex formers: Kollidon® 12PF and Kollidon® 17PF
4.2.2 Surfactants: Solutol® HS15 and Cremophor® ELP
4.2.3 Poloxamers: Lutrol® F68
4.3
Thickeners
4.3.1 High molecular povidone: Kollidon® 90 F
4.3.2 Poloxamer 407: Lutrol® F 127
4.4
Solvents
4.4.1 Low molecular weight macrogols: Lutrol® E grades
4.4.2 Propylene glycol
4.5
Taste masking agents
4.6
Drug stabilizers for solutions
4.6.1 Stabilizers in injectables
4.6.2 Stabilizers in oral and topical solutions
4.6.3 D, L-alpha-Tocopherol as antioxidant
4.7
Enhancers of bioavailability in injectables
4.8
Film formers for topical aerosols
4.9
Lyophilization agents
4.10 Sustained-release agents in veterinary injectables
4.11 Reduction of toxicity of active ingredients
68
68
69
71
71
74
80
82
86
86
87
88
91
92
93
94
97
97
100
101
102
102
103
104
105
105
106
107
107
107
108
109
109
110
111
112
113
114
115
116
3
5.
Suspensions
5.1
5.6
Sedimentation inhibitors for oral and topical use
119
119
5.1.1 Crospovidone: Kollidon® CL-M
122
5.1.2 Povidone: Kollidon® 90 F, Kollidon® 30, Kollidon® 25
124
5.1.3 Poloxamers: Lutrol® F 68, Lutrol® F 127
125
5.1.4 Surfactants: Cremophor® RH 40, Cremophor® EL
Redispersing agents for oral and topical use
126
126
5.2.1 Crospovidone: Kollidon® CL-M
126
5.2.2 Povidone: Kollidon® 90 F, Kollidon® 30
Sedimentation inhibitors and redispersing agents for injectables 128
5.3.1Low molecular povidone: Kollidon® 12PF or Kollidon® 17PF128
128
5.3.2 Surfactant: Solutol® HS15
Crystallization inhibitors, solubilizers
129
5.4.1 Solvent: 1,2-Propylene glycol
129
130
5.4.2 Surfactants: Cremophor® RH 40, Cremophor® EL
131
5.4.3 Macrogols: Lutrol® E300, Lutrol® E400
Taste masking agents
132
132
5.5.1 Crospovidone: Kollidon® CL-M
133
5.5.2 Poloxamers: Lutrol® F 68
Stabilizer of active ingredients in instant granules and dry syrups 134
6.
Semisolid dosage forms
6.1
6.2
6.3
6.4
Emulsifiers: Cremophor® A grades
Gel forming agents: Lutrol® F 127
Solubilizers: Cremophor® RH 40, Lutrol® F grades
Absorption enhancers
6.4.1Complex formers: Kollidon® 25, Kollidon® 30,
Kollidon® CL-M
6.4.2 Solvent: 1,2-Propylene glycol
6.4.3 Solubilizers: Cremophor® RH 40, Lutrol® F 68
Solvents
6.5.1 Liquid macrogols: Lutrol® E grades
6.5.2 Propylene glycol
Carriers for suppositories and ovulae
Bioadhesives, film-forming agents for transdermal systems
6.7.1 Povidone and copovidone
6.7.2 Polyacrylate
5.2
5.3
5.4
5.5
6.5
6.6
6.7
7.
Diagnostic products
7.1
Enzym stabilizers
139
140
142
144
144
146
146
147
147
148
150
151
151
151
155
8.List of BASF pharmaceutical excipients
and their pharmacopoeial monographs
157
9.
159
4
Alphabetical index
5
Foreword
This book describes the wide range of applications and functions of the
excipients manufactured by BASF SE for the pharmaceutical industry.
The spectrum of applications is remarkably broad, as can already be seen
from the list of contents. It covers many fields of application in solid dosage
forms such as instant-release and controlled-release tablets, applications
in liquid dosage forms as solutions, suspensions and dry syrups, as well
as many functions in semisolid dosage forms.
In addition to the applications given here, there are a number of minor
speciality areas of lesser importance.
Details and descriptions of the BASF excipients can be found in the Technical Informations for the products concerned and in the books “Kollidon®,
Polyvinylpyrrolidone excipients for the pharmaceutical industry” and
“Kollicoat® Grades, Functional Polymers for the Pharmaceutical Industry”.
Both books are available on request at BASF SE.
Most of the formulations given here have been taken form the Generic Drug
Formulations compendium also available on request.
The 3rd edition was actualized and revised by the inclusion of new excipients
such as Kollicoat® IR grades, Kollidon® CL-F, Kollidon® CL-SF, Kollidon®
VA 64 Fine and Ludiflash®, by the inclusion of new technologies such as
melt extrusion and of several new formulations.
6
7
8
1. I nstant-release solid dosage forms
(Tablets, granules, pellets)
1.1 Binders
1.1.1 General notes
Among the most important binders for the manufacture of tablets, granules
and pellets are povidone (e.g. Kollidon® 30) and copovidone (e.g. Kollidon®
VA 64). They can be used in practically all the usual granulation and tabletting
processes:
-
Wet granulation
Dry granulation (roller compaction)
Melt extrusion
Direct compression
Kollicoat® IR would also be capable of acting as a binder in the wet granulation technology.
Direct compression excipients that contain a binder, such as Ludipress ®
grades or Ludiflash®‚ play an increasingly important role in the production
of generic products.
The sustained-release matrix bases Kollidon ® SR and Kollicoat® SR 30D
also demonstrate strong binding properties in tablets.
1.1.2 Binders for wet granulation
Kollidon® 25, Kollidon® 30, Kollidon® 90 F, Kollidon® VA 64
The three grades of povidone, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F,
as well as copovidone (Kollidon® VA 64) are very suitable for wet granulation,
whether the granulation of the active ingredient with a binder solution or the
granulation of a mixture of the active ingredient and binder with the solvent
only (usually water). The most widely used methods of wet granulation are
the following:
–
–
–
–
Traditional mixer granulation and drying on hurdles
Mixer granulation with fluidized bed drying
Fluidized bed granulation
Extrusion
Quantities of 2–5% of the tablet weight are required in the case of Kollidon ®
25, Kollidon® 30 and Kollidon® VA 64, but only 1–3 % in the case of
Kollidon® 90 F. This difference is due to the higher molecular weight of
Kollidon® 90 F which gives it greater binding power.
The formulation for naproxen tablets in Table 1.1 is a typical example in which
an active substance is granulated with a binder solution, but without a filler.
9
Table 1.1: Naproxen Tablets (450 mg)
1. Formulation
I. Naproxen (Syntex)
II. Kollidon® 30
Water
III. Magnesium stearate (Merck)
Kollidon® CL
457.5
25.0
90.0
2.5
10.0
g
g
g
g
g
2. Procedure (binder solution granulation)
Granulate mixture I with solution II pass through a 0.8 mm sieve,
add III and press to tablets with low compression force.
3. Tablet properties
Weight
Diameter
Hardness
Disintegration
Friability
Dissolution, pH 7.4 (10 min)
511
12
95
3
0.3
87
mg
mm
N
min
%
%
The formulation for gemfibrozil tablets is an example for solvent granulation
(Table 1.2). It would be possible to replace the ethanol in this formulation
with water, though the optimum quantity would have to be determined.
Particularly with solvent granulation, the quantity of solvent (e.g. water)
strongly influences the properties of the tablets obtained. Also, the physical
properties of the binder, in particular its particle structure and size, have a
significant effect on the hardness of the tablets. This is illustrated in Fig. 1.1
for aminophylline tablets, the granules for which contained the same quantity
of two different binders (6 g Kollidon® 30 and 6 g Kollidon® VA 64), but
were made with different quantities of water. Until about 30 ml of water
Kollidon® 30 is more sensitive to the amount of water used in granulation
than Kollidon® VA 64. With the latter, adequate tablet hardness is obtained
with relatively small quantities of liquid.
10
Table 1.2: Gemfibrozil Tablets (600 mg)
1. Formulation
I
Gemfibrozil
600
Corn starch
200
20
Kollidon® CL
30
Aerosil® 200 (Degussa)
40
Kollidon® VA 64
II Ethanol 96 % (or water) about 72
20
III Kollidon® CL
Macrogol 6000, powder
10
Talc
40
Magnesium stearate
8
g
g
g
g
g
g
g
g
g
g
2. Procedure (solvent granulation)
Granulate mixture I with ethanol II, dry, pass through a 0.8 mm sieve
and mix with the components III. Press with high compression force
(e.‑g. 28 kN) to tablets
3. Tablet properties
Weight
Diameter
Hardness
Disintegration
Friability
Dissolution, USP (paddle),
10 min
20 min
950
16
151
2
0.7
70
84
mg
mm
N
min
%
%
%
Solvent granulation with Kollidon ® VA 64 not only has the economic advantage that it is not necessary to dissolve the binder. It is particularly suitable
if the capacity of the powder to be granulated is too small for the quantity
of solvent that would be necessary to dissolve the binder.
11
80
Hardness, N
75
70
Kollidon® VA64
65
60
Kollidon® 30
55
50
12
14
18
22
26
30
34
38
Amount of water, ml
Aminophylline 100 g, Starch 100 g, Kollidon® 6 g, Mg stearate 1.5 g
Fig. 1.1: Solvent granulation: Influence of the amount of water on the hardness of aminophylline tablets
Kollidon® 25, Kollidon® 30, Kollidon® 90 F and Kollidon® VA 64 can also
be used to produce pellets and granules by wet granulation. The spheronization of a verapamil drug pellet formulation is described in Table 1.3 as
an example.
Table 1.3: Verapamil spheronized pellets (48 %)
1. Formulation
I
Verapamil HCI (BASF)
Microcrystalline cellulose
Kollidon® VA 64
Aerosil® 200 (Degussa)
Talc
II Water
480
300
20
25
175
400
g
g
g
g
g
g
2. Procedure
Granulate the mixture (I) in a Diosna granulator with water (II) and
pass the moist granules through a sieve of 1.5 mm. Pelletize in a
spheronizer at a speed of 300–400 rpm. Dry the pellets in a fluidized
bed and pass over a 0.7 mm sieve to remove the fines.
12
Kollicoat® IR in wet granulation
The instant-release film-coating polymer Kollicoat® IR (polyvinyl alcohol grafted
onto polyethylene glycol, see Section 1.6.2) also can be used as an excellent
binder in the wet granulation using a binder solution. This plastic polymer is
very soluble in water and alcohol, does not form any peroxides during storage
and gives good physical tablet properties. Particularly the plasticity of this
binder is of strong interest.
In Table 1.4 the comparison of Kollicoat® IR with the strong binder Kollidon®
90 F is shown using a very sensitive and difficult formulation of 500 mg
acetaminophen in a 610 mg tablet. Kollicoat ® IR gave the hardest and best
tablets. Kollidon® 30 did not work in this formulation and also in the case of
Kollidon® 90 F a certain part of the tablets showed a capping effect. Due to
its high plasticity Kollicoat® IR gave tablets without any capping. The granules
produced with Kollidon® 90 F were coarser but newertheless the flowability
of the granules of Kollicoat® IR was better.
Table 1.4: Acetaminophen tablets (500 mg) produced with
Kollicoat® IR or Kollidon® 90F as binder
1. Formulation
I. Acetaminophen crystals
Lactose monohydrate
II. Kollicoat® IR or Kollidon® 90F
Water
III. Kollidon® CL
Magnesium stearate
500
50
24
q.s.
20
6
mg
mg
mg
mg
mg
2. Procedure (wet granulation)
Granulate the dry mixture I with the solution II, dry, mix with III and
press to tablets with high compression force (about 20 kN) on a
rotary press
3. Tablet properties
Weight
Diameter
Hardness
Disintegration time
Friability
Proportion of capped
tablets
Kollicoat® IR
617 mg
12 mm
54 N
3 min
<0.1 %
0%
Kollidon® 90F
603 mg
12 mm
40 N
1 min
2%
25 %
A further formulation example with Kollicoat ® IR as binder is shown in
Section 1.3.
13
1.1.3 Binders for dry granulation (roller compaction)
Kollidon® 25, Kollidon® 30, Kollidon® VA 64,
Kollidon® VA 64 Fine
Kollidon® 25, Kollidon® 30, Kollidon® VA 64 and Kollidon® VA 64 Fine can
also be used in compaction processes. The Kollidon ® VA 64 grades are
particularly suitable for this application because of their higher plasticity.
The quantities required are usually the same as those for wet granulation:
2 – 6 % weight, in the tablet. Table 1.5 shows a typical formulation with 4.7
% Kollidon® 30 for this application for a high-dose vitamin C tablet with excellent physical properties in spite of the high active concentration.
Table 1.5: Vitamin C Tablets (500 mg) obtained by roller
compaction with Kollidon® 30
1. Formulation
I. Ascorbic acid powder (BASF)
Kollidon® 30
II. Sorbitol, crystalline
Macrogol 6000, powder
Orange flavour
Cyclamate sodium
500
30
50
37
3
10
mg
mg
mg
mg
mg
mg
2. Procedure
Pass mixture I through a roller compactor, mix with the components II
and press to tablets with low to medium compression force
3. Tablet properties
Weight
Diameter
Hardness
Disintegration
Friability
640
12
120
6–7
0.1
mg
mm
N
min
%
Kollidon® VA 64 Fine was specially tailored for the application in roller compaction and is the material of choice in terms of particle size distribution
and particle shape for this application. Due to the particle size it is able to
cover a big surface area and to form numerous bridges in the tablet structure
that lead to hard tablets with a reduced friability.
The formulations of allopurinol granules and tablets shown in Tables 1.6 and
1.7 are typical examples for a formulation using this technique with about
3.5 % of Kollidon® VA 64 Fine in the final tablets.
14
Table 1.6: Allopurinol granules obtained by roller compaction
with Kollidon® VA 64 Fine
1. Formulation
Allopurinol
Ludipress®
Kollidon® VA 64 Fine
Kollidon® CL
Magnesium stearate
2. Compaction conditions
Roller compactor
Roll width
Compression force
Gap width
Tamping/feeding ration
Roll speed
Mesh sizes
100
50
10
6
1
g
g
g
g
g
Gerteis Type Mini-Pactor M1114
25 mm
2 kN/cm
3 mm
120 %
2 rpm
1.25 mm
After the compaction process the obtained allopurinol granules of the formulation of Table 1.6 were blended for 10 minutes with the tabletting excipients
Ludipress® and magnesium stearate mentioned in Table 1.7 and pressed to
tablets of about 100 mg of active ingredient.
Table 1.7: Allopurinol tablets prepared with compacted allopurinol
granules from Table 1.6
1. Formulation
Allopurinol granules obtained by roller compaction 160 mg
120 mg
Ludipress®
Magnesium stearate
0.9 mg
2. Procedure (Direct compression)
Mix the components and press with the compression force of about
16 kN on a rotary press to tablets of the following properties:
3. Tablet properties
Diameter
Weight
Hardness
Disintegration time
Friability
8
281
246
9
<0.1
mm
mg
N
min
%
15
1.1.4 Binders for direct compression
Kollidon® VA 64, Kollidon® VA 64 Fine
Plasticity
Copovidone is widely used as a binder in direct compression. It has a
higher plasticity than other binders, a low hygroscopicity, a low glass transition temperature, and it gives hard tablets, making it the best dry binder
available. Fig. 1.2 shows the comparison of the plasticity of different dry
binders pressed to tablets with 0.5 % of magnesium stearate. It is interesting that not only the absolute plasticity is higher in the case of copovidone
but also there is almost no influence of the compression force on the plasticity.
1.0
Compress. force 25 kN
0.9
Compress. force 18 kN
0.8
0.7
0.6
0.5
0.4
HPMC
11000
Microcryst.
Cellulose
Povidone
K 30
Kollidon®
VA 64
Fig. 1.2: Plasticity of different dry binders mixed with 0.5% of magnesium
stearate in tablets (Plasticity = plastic energy/total energy)
Kollidon® VA 64 grades have a more irregular particle structure than Kollidon®
25 or Kollidon® 30. The finer particle size of Kollidon ® VA 64 Fine and the
structure are the principal explanations why Kollidon ® VA 64 grades give
harder tablets in the direct compression that povidone (see Fig. 1.3) although
in the binder solution granulation there is no difference.
Kollidon® VA 64 and Kollidon® VA 64 Fine can be used as dry binders
together with all fillers and practically all active ingredients. A mixture with
microcrystalline cellulose has been found to be a particularly effective
combination. The usual concentration of Kollidon ® VA 64 grades used in
the direct compression of tablets is 2 – 8 %, though this can be increased
considerably, as, unlike many other binders like povidone, its binding effect
continues to increase with the concentration even beyond 5 %, which is
reflected in the tablet hardness. Fig. 1.3 illustrates this effect in ascorbic
acid tablets.
16
Hardness, N
190
170
15 %
150
10 %
5%
130
110
90
5%
0%
10 %
15 %
0%
70
50
Kollidon® VA 64
Kollidon® 30
Fig. 1.3: influence of the dry binder concentration on the hardness of
vitamin C tablets (40 % ascorbic acid pressed with Ludipress ® + Kollidon®)
It is normally difficult to produce tablets with ascorbic acid by direct compression, but they can be produced much more readily using Kollidon ®
VA 64. When this dry binder is added, the hardness of the tablets increases
and the friability decreases much more than after the addition of Kollidon ®
30 or hypromellose which had no effect on the hardness in such formulation.
For the comparison of several dry binders including Kollidon ® VA 64 Fine
and hypromellose (HPMC) a formulation of acetylsalicylic acid tablets was
used (Composition: acetylsalicylic acid 500 mg, microcrystalline celullose
200 mg, dry binder 60 mg, Kollidon® CL 25 mg, magnesium stearate 3 mg).
Fig. 1.4 demonstrates that the dry binding effect of Kollidon ® VA 64 Fine is
much higher than the effect of all other binders including normal Kollidon ®
VA 64. The hardness of the tablets produced with Kollidon ® VA 64 Fine was
about the double in comparison with the hardness of the tablets obtained
with povidone K30, hypromellose (HPMC) or hydroxpropyl cellulose (HPC).
17
Hardness, N
200
hardness at 10 kN
hardness at 18 kN
hardness at 25 kN
199
175
150
145
125
100
107
75
71
50
25
0
102
88
86
64
58
48
38
35
21
without
Binder
21
Kollidon®
VA 64
82
82
59
Kollidon®
VA 64 Fine
Povidone
K 30
24
HPMC
6 mPas
HPC
Fig. 1.4: Hardness of acetylsalicylic acid tablets (500 mg) obtained by
direct compression with different dry binders
The combination of Kollidon® VA 64 with sucrose and microcrystalline cellulose is mentioned for vitamin C chewable tablets in the commentary to the
German Standard Generic Formulations („Standardzulassungen für Fertigarzneimittel“ published by Deutscher Apothekerverlag, 1988).
Table 1.8 shows the recommended formulation and the properties of these
chewable tablets reproduced in the laboratory with the dosages of 100 mg,
500 mg and 1000 mg of ascorbic acid.
18
Table 1.8: Vitamin C chewable tablets (100 mg, 500 mg, 1000 mg)
1. Formulations
Ascorbic acid, powder
Microcrystalline cellulose
(e.g. Avicel® PH101, FMC)
Sucrose, powder
Sucrose, crystalline
Kollidon® VA 64
Cyclamate sodium
Macrogol 6000, powder
Orange flavour + strawberry flavour (2+1)
Aerosil® 200 (Degussa)
Saccharin sodium
42.2 %
28.3 %
13.0
8.0
2.4
2.4
2.0
1.2
0.2
0.1
%
%
%
%
%
%
%
%
2. Procedure (direct compression)
Pass all components through a 0.8 mm sieve, mix and press with
medium to high compression force.
3. Tablet properties
Vitamin C content/tablet
100 mg
500 mg
1000 mg
Weight
250 mg
1250 mg
2500 mg
Diameter
8 mm
15 mm
20 mm
Form
biplanar
biplanar
biplanar
Hardness
157 N
>100 N
>150 N
Disintegration (water)
15 min
>15 min
14 min
Friability
<-0.1 %
0.8 %
0.6 %
19
1.1.5 Binders for melt extrusion
Kollidon® VA 64, Kollidon® VA 64 Fine, Kollidon® 30
The most important newer technology for the application of Kolldion ® VA 64
or Kollidon® 30 as binder and matrix former is the melt extrusion. In this
technology they also can be combined with surfactants. A drug containing
Kollidon® VA 64 and the anti-HIV protease inhibitors lopinavir and ritonavir
was the first co-formulated pharmaceutical compound to be successfully
tabletted using a proprietary melt extrusion process. The melt extrusion
appears to have overcome the poor solubility and negligible oral bioavailability of previous formulations of lopanavir/ritonavir. Similar results of
dissolution increase were publishes with lacidipine and indomethacin melt
extruded with copovidone.
A typical example of an estradiol tablet was taken from the literature. Table
1.9 shows the formulations of the granules obtained by melt extrusion and
the final tablets produced with these granules. Kollidon ® VA 64 grades have
the advantage of their higher plasticity in comparison with other polymers
like povidone or macrogol.
Table 1.9: Estradiol tablets produced by melt extrusion
1. Formulation of the granules (melt extrusion)
17ß-Estradiol hemihydrate
Kollidon® VA 64
Gelucire® 44/14 (Gattefossé)
10.0 %
50.0 %
40.0 %
2. Formulation of the tablets (direct compression)
17ß-Estradiol hemihydrate melt extruded granules
Microcrystalline cellulose
Corn starch
Magnesium stearate
8.3
45.6
45.6
0.5
3. Tablet properties
Content of 17ß-estradiol hemihydrate
Diameter
Dissolution of the granules
%
%
%
%
2 mg
6 mm
see Fig. 1.5
Fig. 1.5 shows the almost 20-fold increase of the dissolution for the melt
extruded 17ß-estradiol granules produced with Kollidon ® VA 64. The dissolution media was 0.1 N hydrochloric acid.
20
17ß-Estradiol dissolved, %
60
Melt extruded granules with Kollidon® VA 64
17ß-Estradiol hemihydrate alone
40
20
0
0
10
20
30
40
50
60
Time, min
Fig. 1.5: Dissolution of 17ß-estradiol hemihydrate granules obtained by
melt extrusion with Kollidon® VA 64
21
1.2 Disintegrants for normal tablets
1.2.1 General notes
The crospovidone grades, Kollidon® CL, Kollidon® CL-F, Kollidon® CL-SF
and Kollidon® CL-M differ mainly in their particle size. One of the possible
methods for the determination of the particle size distribution is the laser
light diffraction measurement (e.g. in a Malvern Mastersizer, Malvern Instruments). By this method the following typical values of the volume average
diameter D[4.3] were found:
-
Kollidon®
Kollidon®
Kollidon®
Kollidon®
CL:
CL-F:
CL-SF:
CL-M:
90
20
10
3
– 130
– 40
– 30
– 10
µm
µm
µm
µm
Kollidon® CL is the usual disintegrant for normal tablets, Kollidon ® CL-F and
Kollidon® CL-SF can be used as disintegrants for special cases and the
micronized type Kollidon® CL-M is mainly applied as stabilizer in liquid dosage
forms like suspensions, instant drink granules and dry syrups.
Crospovidone is referred to as one of the “super disintegrants” in the literature
but it is also an excellent agent for the enhancement of the drug release
(see Section 1.4.3). The Kollidon® CL grades can be used for all tabletting
technologies like granulation, direct compression etc..
Table 1.10 gives a overview of the general properties and functions of the
three Kollidon® CL grades normally used as disintegrants in tablets.
Table 1.10: Comparison of general properties of Kollidon ® CL
grades used as disintegrants
Product
Disintegration Mouthfeel Smooth tablet
power
surface
Kollidon® CL
Kollidon® CL-F
Kollidon® CL-SF
22
++
+
+
–
+
++
–
+/–
+
Adsorption
of granulation
liquid
Drug
dissolution
+/–
+
++
++
+
+/–
1.2.2 Standard disintegrant
Kollidon® CL
Kollidon® CL is used as the standard disintegrant for all kind of different
tablet formulations. Since many years the pharmaceutical industries know
quite well the performance of the material. Main reasons for taking this
disintegrant is the strongest disintegration power with benefits especially in
large tablets. It has advantages compared to other disintegrants which are
based on a different chemistry due to disintegration and dissolution speed.
The particle size of Kollidon® CL must be regarded as a compromise:
although even coarser particles provide a slightly better disintegration effect
than Kollidon® CL, the latter probably gives tablets whose surface finish
is less affected by humidity than tablets made with a coarser crospovidone
which does not contain the fine fraction that makes up the major portion of
Kollidon® CL. But it must be stated that the differences of few minutes of
the disintegration time of a tablet normally have no significant influence on
the dissolution of the active ingredient.
In the wet granulation process, Kollidon® CL can be incorporated after
granulation, or in the intragranular use, as its swelling action is completely
reversible. In difficult cases, it is recommended to add some of the Kollidon ®
CL before granulation, and some after. This has been done with the formulation of a gemfibrozil tablet shown in Table 1.2, as the active substance
has a relatively low melting point and can therefore sinter together on compression. If part of the Kollidon® CL were not added before granulation, the
disintegration time of the resulting tablets would be much longer.
Obviously, Kollidon® CL is also very suitable for use in formulations for direct
compression. Typical examples are those for a piroxicam tablet in Table 1.11
and an acetylsalicylic acid tablet in Fig. 1.6.
23
Table 1.11: Piroxicam tablets (20 mg)
1. Formulations
Piroxicam
Corn starch
Ludipress®
Kollidon® CL
Macrogol 6000, powder
Aerosil® 200 (Degussa)
20
150
50
8
10
1–2
g
g
g
g
g
g
2. Procedure (direct compression)
Mix all components, pass through a 0.8 mm sieve and press with low
to medium compression force.
3. Tablet properties
Weight
Diameter
Form
Hardness
Disintegration (water)
Friability
238 mg
8 mm
biplanar
66 N
57 sec
0.1 %
The rapid disintegration of a tablet is by no means a guarantee that the active
substance is dissolved and made bioavailable quickly. Thus, the drug dissolution is a much more important criterion than its disintegration time. Kollidon ®
CL is often very effective in this respect, as can be seen from Fig. 1.6 which
contains data for acetylsalicylic acid tablets made by direct compression.
Although both tablets, with and without Kollidon ® CL, disintegrate within
about 4 minutes, the difference in drug release remain considerable even
after 60 minutes.
Table 1.12 and also Fig. 1.7 in the next Section 1.2.3 show the comparison
of disintegration and dissolution of analgesic tablets caused by Kollidon ® CL
grades and other disintegrants.
24
100
Dissolved drug, %
+ 3 % Kollidon® CL
80
60
40
20
Without Kollidon® CL
0
0
10
20
30
40
50
60
Time, min
Disintegration time of both formulations: max. 4 min
Fig. 1.6: Influence of Kollidon® CL on the dissolution of acetylsalicylic acid
tablets (Acetylsalicylic acid 400 mg, Ludipress ® 99 mg, stearic acid 1 mg)
The direct compression agent Ludipress® contains 3.5% Kollidon® CL.
Therefore usually it also acts as a disintegrant. The disintegrant effect is
adequate, if the content of Ludipress® in the tablet is high enough.
However, if tablets made with Ludipress® are found to disintegrate too
slowly, it is recommended to add Kollidon ® CL to the formulation.
Such a formulation for acetylsalicylic acid tablets is given in Fig. 1.6.
25
1.2.3 Special disintegrants
Kollidon® CL-F, Kollidon® CL-SF
Kollidon® CL-F has a strong disintegration power although the particles are
finer compared with Kollidon® CL. Tablets containing Kollidon® CL-F do not
tend to form rough surfaces after storage under humid conditions. Therefore
it is a perfect alternative to Kollidon® CL when formulators are looking for
a disintegrant with short disintegration time and fast dissolution in combination with a smooth tablet surface. With Kollidon ® CL rough surfaced tablets
might occur with very hygroscopic formulations packed in a multidose
packaging. This sensitivity increases with a decreased size of the tablet.
As a consequence Kollidon® CL-F (or Kollidon® CL-SF) should be taken for
the development of small tablets.
Furthermore Kollidon® CL-F and even more Kollidon® CL-SF are able to
adsorb large amounts of liquid (see Table 1.10). This behaviour can be
beneficial when large amounts of granulation liquid have to be used for wet
granulation (e.g. for dissolving the active ingredient in the granulation solvent).
Table 1.12 and Fig. 1.7 show the comparison of the three Kollidon ® CL
grades normally used as disintegrants with other substances like croscarmellose or carboxymethyl starch in two different analgesic tablets. In both
formulations the disintegration and the drug dissolution is faster using
Kollidon® CL grades.
Table 1.12: Comparison of disintegrants in analgesic tablets
1. Composition
I. Acetaminophen cryst.
Acetylsalicylic acid cryst.
Caffeine cryst.
II. Kollidon® 90 F (dissolved in 2-propanol)
III. Magnesium stearate
Disintegrant
250
250
50
17
5
27
mg
mg
mg
mg
mg
mg
2. Procedure (wet granulation)
Granulate Mixture I with Solution II, sieve through a 1000 µm
sieve, dry and mix 10 min with III and press on a rotary tablet
press with a high compression force of 18 kN.
3. Disintegration times of the tablets in synthetic gastric juice
Disintegrant
None
Kollidon® CL
Kollidon® CL-F
Kollidon® CL-SF
Croscarmellose
Carboxymethyl starch
26
Min
> 60
9
11
9
23
34
Acetaminophen dissolved, %
Apart from the enhancement of the tablet disintegration it is even more
important that the dissolution of the active ingredient is increased as well
to achieve a fast resorption of the drug. Fig. 1.7 shows an example of
dissolution data of an acetaminophen tablet with 2.7 % of different disintegrants including three Kollidon® CL grades. In some formulations there is
no significant difference of the dissolution between the disintegrants, in
other formulations the difference is strong. But allways the increase of the
dissolution in comparison with the tablets without disintegrant is enormous.
100
80
60
40
Kollidon® CL
Kollidon® CL-F
Kollidon® CL-SF
20
Croscarmellose
Caroxymethyl starch
0
0
10
20
30
40
50
60
Time, min
Fig. 1.7: Dissolution of an acetaminophen tablet (2.7 % disintegrant)
27
1.3 Disintegrant for fast disintegrating buccal tablets
Kollidon® CL-SF
Kollidon® CL-SF is the finest crospovidone grade for disintegration and it
has a good disintegration power and less surface defects of the tablets
after humid storage. This grade is perfect for fast disintegrating tablets
(e.g. Flash tabs®) since it gives a very smooth cream-like mouth feel superior
to the other Kollidon® CL types. For this kind of tablets – first of all of analgesics – a “superdisintegrant” like crospovidone is used to obtain a disintegration within much less than one minute. A typical example mentioned in
the literature is ibuprofen. Table 1.13 illustrates the practical use of Kollidon ®
CL-SF in a formulation of fast disintegrating buccal tablets of loperamide.
The disintegration time of these tablets is 27 sec.
Table 1.13: Fast disintegrating buccal loperamide tablets with
Kollidon® CL-SF
1. Formulation
I. Loperamide-HCl (Select Chemie)
Mannitol powder (Roquette)
Kollidon® CL-SF
II. Kollicoat® IR
Water
III. Kollidon® CL-SF
Chocolate flavour (Symrise)
Sodium stearyl fumarate (JRS Pharma)
2.0
85.5
4.0
3.0
27.0
3.0
1.5
1.0
mg
mg
mg
mg
mg
mg
mg
mg
2. Procedure (wet granulation)
Granulate mixture I with binder solution II in a fluidized bed granulator (inlet air temperature 40 – 45 °C, outlet air temperature 30 °C,
atomizing pressure 0.5 bar), mix with the components III, pass
through a 0.8 mm sieve, blend and press on a rotary press with
low compression force (about 4 kN).
3. Tablet properties
Weight
Diameter and form
Hardness
Disintegration in water
Friability
Dissolution (0.01 N HCl/100 rpm)
Content uniformity
28
100 mg
7 mm, concave
27 N
27 sec
less than 0.2 %
84 % after 5 min,
94 % after 10 min
corresponds to Ph.Eur.
Due to its interesting properties Kollidon ® CL-SF also forms a part of a new
direct compression agent (Ludiflash®) developed as direct compression
agent for the production of fast disintegrating buccal tablets (see Section
1.5.4). It is a preparation of mannitol, Kollidon ® CL-SF and polyvinyl acetate.
Furthermore Kollidon® CL-SF shows the strongest ability of all Kollidon ® CL
grades to adsorb water or ethanol.
29
1.4 Enhancers of drug release
1.4.1 General notes
One problem with many of the active ingredients used today is their poor
solubility in water and their limited bioavailability in solid dosage forms. If
the usual concentration of a tablet disintegrant like crospovidone does not
solve the problem an other method must be found. The simplest means of
improving the bioavailability of a drug is to enhance its dissolution by adding
complex formers or solubilizing agents, such as povidone, crospovidone,
poloxamers or surfactants. In many cases it may be sufficient to produce
a physical mixture or a trituration of the active ingredient with the solubilizer
or complex former.
1.4.2 Povidone
Soluble Kollidon® grades
Povidone, e.g. Kollidon® 25 or Kollidon® 30 has no disintegrant effect whatsoever, but it can be used to improve the dissolution of many drugs by
forming a soluble complex with them. To this end, as with Kollidon ® CL,
it is necessary to prepare an intimate mixture of povidone and drug by
comilling, or mixing (or coprecipitation or coextrusion) that contains an
excess of Kollidon® 25 or Kollidon® 30. Fig. 1.8 shows a typical example
of a physical mixture with indomethacin in the ratio 1+2. After 30 min the
dissolution of the active ingredient was about 10 times enhanced by the
presence of Kollidon® 30.
Dissolved indomethacin, %
100
+ Kollidon® CL-M 1+2
80
®
+ Kollidon 30 1+2
60
40
20
Indomethacin alone
0
0
30
60
90
120
Time, min
Fig. 1.8: Enhancement of the dissolution of indomethcin by mixing with
Kollidon® 30 or Kollidon® CL-M in the ratio 1+ 2
30
1.4.3 Crospovidone as enhancer of drug release
Kollidon® CL grades
The rapid disintegration of a tablet is by no means a guarantee that the
active substance is released and made bioavailable quickly. Thus, the drug
release rate of a tablet is a much more important criterion than its disintegration time. Kollidon® CL is often very effective in this respect, as can be
seen from Fig. 1.6 (Section 1.2.2) which contains data for acetylsalicylic
acid tablets made by direct compression.
But in difficult cases of insoluble active ingredients where drug release still
proves inadequate, higher concentrations of crospovidone can be used
to solubilize the active ingredient by complex formation as it is well known
in the case of povidone. Then, the active substance should be mixed or
comilled (or perhaps coevaporated) with one of the Kollidon ® CL grades
before addition to the other ingredients. The complex formed between
the active ingredient and crospovidone in these intimate mixtures increases
the dissolution and bioavailability of the drug.
Such preparations generally require an excess of crospovidone, typically
2 to 6 parts per 1 part of active ingredient. With active substances that are
used in low dosages, such as hormone derivatives, this presents no problems.
A typical enhancement of the drug dissolution is shown in Fig. 1.8 in the
case of the example of a physical mixture of indomethacin and Kollidon ®
CL-M (or Kollidon® 30) in the ratio 1+2. A very high increase of the drug
release was observed within the tested period of 2 hours.
A typical example of this application from the literature is a tablet formulation
of medroxyprogesterone. Fig. 1.9 shows the influence of a trituration of this
active ingredient with crospovidone on the dissolution of the tablet.
31
Drug, dissolved, mg/ml
0.5
Medroxyprogesterone acetate
+ crospovidone (1 + 6)
0.4
0.3
0.2
Medroxyprogesterone acetate
alone
0.1
0
0
30
60
90
120
Time, min
Fig. 1.9: Dissolution of medroxyprogesterone acetate from tablets made
from a trituration with Kollidon® CL, compared with tablets without crospovidone
1.4.4 Poloxamers as enhancers of drug release
Lutrol® F 68, Lutrol® F 127, Lµtrol® micro 68, Lµtrol® micro 127
Like Kollidon® 25 and Kollidon® 30 the poloxamers 188 and 407 in the
normal particle size (Lutrol® F 68, Lutrol® F 127) or in the milled form
(Lµtrol® micro 68, Lµtrol® micro 127) can be used in tablets and capsules
to improve the drug release.
Fig. 1.10 shows the influence of Lutrol® F 68 on the dissolution of digitoxin
in a physical mixture 1+9. The dissolution of the active ingredient could be
doubled by this combination. Preparing a coprecipitate with the same ratio
the dissolution of digitoxin reached until more than 11 µg/ml after 120 min.
32
Dissolved drug, mg/ml
6
Digitoxin + Poloxamer 188 (1+9)
Digitoxin alone
4
2
0
0
30
60
90
Time, min
120
Fig. 1.10: Influence of Lutrol® F 68 on the dissolution of digitoxin
Because of the large particle size of the standard grades Lutrol ® F 68 and
Lutrol® F 127 it is recommended to use a preparation of the poloxamer with
the active ingredient obtained by comilling, coextrusion or coprecipitation
before tabletting. It must be noted that the comilling procedure is only possible
if the mill is cooled, as the Lutrol® F grades have a melting point in the
50 – 60 °C range.
If only a physical mixture of the active ingredient with Lutrol® F will be applied
(e.g. for the direct compression technology), it would be preferable to use
the milled products Lµtrol® micro 68 and Lµtrol® micro 127 instead of the
standard grades.
1.4.5 Solubilizer as enhancer of drug release
Cremophor® RH 40
In recent years, Cremophor® RH 40, the nonionic solubilizer macrogol glycerol
hydroxystearate 40, has increasingly been used in solid drug forms to improve
drug release. Unlike most other solubilizers, this product is almost odourles
and tasteless in water, which is an advantage in this application.
In wet granulation, a small amount (usually less than 1% of the weight of the
finished tablets) of Cremophor® RH 40 is dissolved in the granulating fluid
or the binder solution, before starting the granulation.
This is of particular interest in the case of lipophilic or strongly hydrophobic
drugs that can be solubilized as micelles.
33
1.5 Direct compression agents
1.5.1 General notes
The direct compression of tablets is of increasing interest particularly for
generic preparations. Since the majority of the active ingredients don’t have
the needed physical properties for the direct compression (flowability, particle
size and particle structure) a direct compression agent can solve this problem.
In the product range of BASF excipients there are direct compression agents
for different types of tablets as shown in Table 1.14. All these products act
as flowability agent, filler, binder and enhancer of the content uniformity
of tablets. Furthermore the standard grade Ludipress ® and also Ludiflash®
contain crospovidone as disintegrant.
Table 1.14: Direct compression agents of BASF
Product
Type of tablet
Normal tablets
Ludipress®
Ludipress® LCELozenges, chewable tablets, effervescent tablets
sustained-release tablets
Fast disintegrating buccal tablets
Ludiflash®
1.5.2 Direct compression of normal tablets
Ludipress®
Ludipress® is a direct compression agent based on lactose monohydrate as
filler and it contains 3.5 % of Kollidon® 30 as a binder and 3.5 % of Kollidon®
CL as disintegrant.
Fig. 1.11 shows the comparison of Ludipress ® and a physical mixture of the
same components in identical proportions like in Ludipress®. This Figure gives
one of the important justifications of the commercialization of Ludipress ® since
the tablet hardness is much higher in comparison to the physical mixture.
Ludipress® is suited above all for normal tablets with a low to medium dosage
of active ingredients. The irregular structure of the particles of the Ludipress ®
grades illustrated in Fig. 1.12 (Section 1.5.3) explains the good content uniformity of tablets even with very low dosages of the active ingredient.
34
250
Hardness
Ludipress®
200
Phys. mixture
(like Ludipress)
150
100
50
0
0
5
10
15
20
25
30
Compression force, kN
35
Fig. 1.11: Hardness of placebo tablets manufactured with Ludipress ® or
with an iIdentical physical mixture like Ludipress ®
Table 1.15 shows a typical direct compression formulation of aminophyllline
tablets as a example of the many available guide formulations containing
Ludipress®.
Table 1.15: Aminophylline tablets (100 mg)
1. Formulation
Aminophylline powder (BASF)
Ludipress®
Magnesium stearate
Aerosil® 200 (Degussa)
100
150
2
2
g
g
g
g
2. Procedure (direct compression)
Mix all components, sieve and press on a rotary press to tablets with
low compression force.
3. Tablet properties
Weight
254
Diameter
8
Hardness
97
Disintegration
10
Friability
0.2
Dissolution
10 min: 87
15 min: 100
mg
mm
N
min
%
%
%
35
1.5.3 D
irect compression of lozenges, chewable, effervescent
and sustained-release tablets
Ludipress® LCE
Ludipress® LCE is a direct compression agent based on 96.5 % lactose
monohydrate and 3.5 % of Kollidon® 30 as binder. It does not contain any
disintegrant and is therefore suitable for all tablets of slow disintegration
(lozenges, chewable and sustained-release tablets) or which contains an
other system of disintegration like effervescent tablets.
Beside of the function as filler, flowability agent and binder Ludipress ® LCE
can be suitable as pore former in sustained-release matrix tablets of insoluble
active ingredients to adjust its release.
Both Ludipress® grades have a particle structure (see Fig. 1.12) that gives
them excellent flow properties, and their concentration in tablets is often
fairly high, they are also effective flow improvers.
Fig. 1.12: Particle structure of the Ludipress ® grades
Table 1.16 shows a typical direct compression formulation of acetylsalicylic
acid + vitamin C effervescent tablets as an example of the many available
guide formulations containing Ludipress ® LCE.
36
Table 1.16: Acetylsalicylic acid + vitamin C effervescent tablets
(400 mg + 250 mg)
1. Formulation
Acetylsalicylic acid (Synopharm)
Ascorbic acid, crystalline (BASF)
Ludipress® LCE
Citric acid, crystalline
Sodium bicarbonate
Macrogol 4000, powder
400
250
600
300
600
90
g
g
g
g
g
g
2. Procedure (direct compression)
Pass all components through a 0.8 mm sieve, mix and press with
high compression force.
3. Tablet properties
Weight
Diameter
Hardness
Disintegration
Friability
Colour
2251
20
145
1 min 35
0.66
white
mg
mm
N
sec
%
1.5.4 Direct compression of fast-disintegrating buccal tablets
Ludiflash®
Ludiflash® is a formulation of about 90 % D-mannitol, 5 % Kollidon® CL-SF
and about 5 % polyvinyl acetate obtained by granulation with Kollicoat ® SR
30D.
It is suitable for direct compression manufacturing of fast disintegrating tablets
particularly for buccal administration having the functions of filler, disintegrant,
flowability agent and binder. But it could also be used for such fast disintegrating tablets produced by wet granulation.
When placebo tablets of Ludiflash® were produced using different compression forces a linear influence of the compression force on tablet hardness
and disintegration could be demonstrated (see Fig. 1.13).
37
Hardness
150
Disintegration
150
120
120
90
90
60
60
30
30
Disintegration times, s
Hardness, N
180
180
0
0
0
5
10
15
Compression force, kN
Fig. 1.13: Influence of compression force on the hardness and disintegration
of Ludiflash® placebo tablets
If the disintegration is not fast enough because the amount of Ludiflash ® in
the formulation must be small it would be recommended to add an additional
amount of Kollidon® CL-SF.
Detailed test revealed magnesium stearate and sodium stearyl fumarate to
be appropriate lubricants for fast disintegration buccal tablets based on
Ludiflash®.
38
Table 1.17 shows a typical formulation of fast-disintegrating famotidine tablets having a disintegration time of 27 sec and a dissolution of almost 100 %
after 3 min.
Table 1.17: Famotidine fast-disintegrating buccal tablets (20 mg)
1. Formulation
Famotidine (various sources)
Ludiflash®
Aerosil® 200 (Degussa)
L-Menthol
Aspartame
Sodium stearyl fumarate
20
267
3
0.9
4.5
4.5
g
g
g
g
g
g
2. Procedure (direct compression)
Mix all components, pass through a 0.8 mm sieve and press with a
compression force of about 10 kN and a rotation speed of 40 rpm.
3. Tablet properties
Weight
Diameter
Hardness
Disintegration (pH 7.2)
Friability
Dissolution (5 min)
300
10
51
27
< 0.2
about 99
mg
mm
N
sec
%
%
39
1.6 Instant-release and protective coatings of tablets and capsules
1.6.1 General notes
Instant-release coatings can be a subcoating (see Section 1.6.7), a final
film-coating or a traditional sugar coating of tablets or capsules. Final instantrelease coatings usually are applied to tablets or capsules with one or several
of the purposes mentioned in Table 1.18.
Table 1.18: Important purposes of final instant-release coatings
1. Colouring
- Increase the patient compliance
- Identification and distinction of different types of tablets.
2. Protection of the active ingredient
- Against oxidation or hydrolysis
- Reduction of chemical interactions between active ingredients
(e.g. antibiotics, vitamin combinations).
3. Masking the smell and taste of the active ingredient
In the product range of BASF excipients there are four different film-coating
substances or preparations suitable for instant-release film-coatings (Table
1.19). Most of they are based on the grafted copolymer Kollicoat ® IR.
Table 1.19: Polymers or preparations for instant-release coatings
in the BASF product range
Product
Type
Main function/application
Polymer
Kollicoat® IR
Coloured coatings, protective
coatings
Kollicoat® IR White
White coatings, protective
coatings
Ready to mix
preparation
Polymer mixture
Kollicoat® Protect
Protection, white or coloured
coatings, taste masking
Polymer
Kollidon® VA 64
Coloured coatings, protection
(combination with sugar or
HPMC)
40
1.6.2 Instant-release film-coating with Kollicoat ® IR
Kollicoat® IR powder comprises polyethylene glycol and polyvinyl alcohol
bound in the ratio of 25:75. A polyethylene glycol chain forms a base onto
which side chains of polyvinyl alcohol are grafted. The mean molecular
weight is approximately 45,000.
It can be considered as the ideal film former for instant-release film-coatings, since it is very plastic, very soluble in water, has no significant viscosity
even in a concentration of 20 % and very low tackiness. Therefore high
concentrated spray solutions can be applied and no plasticizer is needed.
Smooth tablet coatings are obtained and nether polishing nor curing is
needed.
Viscosity, mPa.s
Fig. 1.14 shows the viscosity of 20 % solutions in water of Kollicoat® IR and
two hypromellose types used for instant-release film-coating. The viscosity
of Kollicoat® IR solution is much lower than the usual limit of 250 mPa.s to
pass well the nozzle of about 0.8 mm.
5000
4000
3000
2000
1000
0
Usual limit
of the nozzle
®
Kollicoat IR
HPMC, type
3 mPa.s
HPMC, type
6 mPa.s
Fig.1.14: Viscosity of Kollicoat® IR and hypromellose (20 % in water)
The manufacture of a spray suspension of Kollicoat ® IR for coating tablets
and capsules is straightforward; it is also quicker than with most other filmforming agents. The suspension can be prepared using a number of methods;
the recommended method is described below:
Suspend the pigments and talcum in part of the water and homogenize until
fine and lump-free. Dissolve the Kollicoat ® IR in the rest of the water. Add
the homogenized pigment suspension to the Kollicoat ® IR solution. Pass
the suspension through a sieve (e.g. 200 µm) in order to remove any pigment that may have agglomerated and that would block the spray nozzle.
Frequently, a simpler method is also possible: suspend the pigments in the
total amount of water, homogenize and then stir in the Kollicoat ® IR, stirring
for 5 min until dissolved.
Generally, the stirring speed should not be too high in order to prevent or
minimize foaming.
41
Table 1.20 shows a typical film-coating formulation of Kollicoat ® IR for tablets or capsules. The viscosity of this spray suspension is below 200 mPa.s.
Table 1.20: Instant-release film-coating formulation with
Kollicoat® IR for 5 kg tablets (weight 330 mg, diameter 9 mm)
Weight [g]
1. Formulation
Polymer solution:
108.2
Kollicoat® IR
Water
286.0
Pigment suspension:
Talc
37.5
Titanium dioxide
15.6
7.8
Sicovit® Iron oxide red
Water
65.0
Proportion [%]
20.8
55.0
7.2
3.0
1.5
12.5
2. Procedure
Stirr the talc and the pigments vigorously into the water, homogenize
the obtained suspension in a corundum disk mill and stirr it into the
polymer solution.
3. Coating conditions (Accela cota® 24’’, Manesty)
Inlet air temperature
60 °C
Outlet air temperature
40 °C
Cores temperature
35 °C
Air flow
180 m3/h
Spray pressure
3 bar
Spray rate
30 g/min
Spraying time
20 min
Final drying
4 min, 60 °C
Quantity applied
3 mg polymer/cm2
The tablets of propranolol or caffeine coated with the formulation given in
Table 1.20 had got a smooth and brillant surface without any polishing.
All other physical properties like hardness, friability, disintegration and dissolution were not changed in a significant manner by the coating and after
the storage at different conditions.
In the pharmaceutical industry today the question of production cost, including
that of coatings, is constantly being raised. In the case of the pure material
costs the difference between coating with Kollicoat ® IR grades and hypromellose is so small that it can be practically neglected for comparative purposes. However, production costs are a different matter.
42
With Kollicoat® IR, the production of the polymer solution is simpler, and
hence a little cheaper, than is the case with hypromellose; however, the
decisive cost factor is the film-coating process and this is practically entirely
dependent on the solid concentration of the spray suspension. In the case
of Kollicoat® IR, this concentration is about 20 % and hence substantially
higher than in the case of hypromellose (about 12 %). This means that the
spray time, and hence the cost, can be considerably reduced. In addition,
the temperatures that can be achieved with cores comprising the Kollicoat ®
IR grades are substantially higher than with hypromellose.
In order to demonstrate this, extensive comparison studies were done in
an Accela-Cota® 24’’ (Manesty) to develop “Process-Parameter-Charts”.
The influence of product temperature and processing time on the aspect of
the coated tablets and the processing behaviour were detemined.
Four groups of results were classified in these studies:
- Class 1 (red area): The film-coating process is not possible with the
chosen settings. Cores stick to the drum or are overwetted.
- Class 2 (orange area): The film-coating process is principly possible,
but the surface of the coated tablets is not acceptable.
- Class 3 (light green area): The film-coating process is possible and
the surface of the coated tablets is acceptable.
- Class 4 (dark green area): The film-coating process is possible and
the surface of the coated tablets is optimal.
The Process-Parameter-Charts of Kollicoat® IR and HPMC (3 mPa.s) shown
in Fig.1.15 and Fig. 1.16 demonstrate clearly that a very robust process
with short process times (about 50 min) can be achieved with Kollicoat ® IR.
Since in the case of HPMC (3 mPa.s) the green areas are much more limited the minimal process time is much longer (at least about 100 min) and
the transfer from a pilot to production scale is not so easy. In the case of
HPMC (6 mPa.s) the process time is even longer than for HPMC (3 mPa.s).
43
■ Film-coating impossible, sticking of the cores
■ Film-coating possible, but surface not acceptable
■ Good film-coating process, surface acceptable
■ Optimal film-coating process, best surface quality
Fig. 1.15: Influence of process time and temperature on the film-coating
with a Kollicoat® IR formulation (Process-Parameter-Chart)
■ Film-coating impossible, sticking of the cores
■ Film-coating possible, but surface not acceptable
■ Good film-coating process, surface acceptable
■ Optimal film-coating process, best surface quality
Fig. 1.16: Influence of process time and temperature on the film-coating
with a HPMC (3 mPa.s) formulation (Process-Parameter-Chart)
To test the scale-up of Kollicoat® IR coatings a formulation similar to the red
film-coating formulation described in Table 1.20 was produced on propranololHCl cores in various batch sizes from 5 kg to 250 kg of cores. It was found
that the most important parameter to be considered for the scale-up is the
relative spray rate. If a relative spray rate of 2.8 g/min was applied for 1 kg
of cores, no significant differences of the coated tablets could be observed
in this study.
44
1.6.3 Instant-release film-coating with Kollicoat ® IR White
Kollicoat® IR White is a ready-made mixture based on film-forming agent
Kollicoat® IR and is for immediate use (Composition: 61 % Kollicoat ® IR,
7 % Kollidon® VA 64, 14 % titanium dioxide, 16 % kaolin, 2 % sodium lauryl
sulphate). It is mainly intended for use in white tablets; however, other pigments can be added for colour if required. It has all the advantages of film
former Kollicoat® IR, e.g. rapid dissolution in water, a high degree of adhesion also on lipophilic surfaces, its enormous plasticity and its low viscosity
in water.
With Kollicoat® IR White, a white, readily soluble coating is obtained. It can
be used to mask taste, to facilitate swallowing tablets or to improve the stability of the active ingredient by decreasing contact with oxygen and moisture.
Due to the very high flexibility of Kollicoat ® IR, Kollicoat® IR White requires
no additional plasticizer. In addition, the flexibility prevents the coating from
cracking during storage, especially if the relative humidity varies. Even if the
cores contain a swelling disintegrant such as crospovidone (Kollidon ® CL
grades), the coating retains its strength during storage – also if the storage
conditions may not be ideal.
The manufacture of a spray suspension of Kollicoat ® IR White for film-coating tablets and capsules is both easy and quick. The following method is
recommended:
Stir the required amount of water well. The stirring speed must be such that
little or, better, no foam is produced. Add Kollicoat ® IR White slowly but
continuously. Continue stirring for a further 10 – 15 minutes; the white
spraying suspension is then ready for use (see Fig 1.17).
45
Stir Kollicoat® IR White into water and redisperse. The mixer speed should be
adjusted so that little or no foam is produced. After stirring for 15 min, Kollicoat®
IR White is ready for further processing.
1
2
3
4
The figures
clearlyof
illustrate
the® simple
redispersion
Fig. 1.17:
Dispersion
Kollicoat
IR White
in water: of Kollicoat® IR White.
IR White
can
processed
On account
of itsstirred
much water
lower viscosity,
Kollicoat®stirrer
1 Slightly
using a magnetic
prior
to be
addition.
®
in spray
suspensions
of
much
higher
concentration
2 Start of addition of Kollicoat IR White. than other ready-to-use
instant-release
greatly ®
shortens
the spraying and processing
IR White.
3 During formulations.
the addition This
of Kollicoat
time in4the
manufacture
of film-coated
tablets. Suspensions with a solids
Final
homogeneous
suspension.
concentration of 15 – 30% can be processed without problem.
To obtain coloured coatings, water-soluble colorants or ready-made colour
®
The
high
elasticity®ofDry
Kollicoat
IR can
White
it does
not crack on the
(Seppic),
beensures
added that
directly.
However,
mixes,
e.g.
Sepispers
tablets
when
they
are
exposed
to
varying
humidity
during
storage.
colour lakes or iron oxide pigments can also be used. They must, however,
be separately dispersed in water beforehand and then homogenized before
coating
system
can ®
beIRapplied
all the usual coaters, e.g. horizontal drum
White on
suspension.
beingThe
added
to the
Kollicoat
coaters, fluidized bed coaters, immersion sword coaters, and coating pans,
® IR White suspensions (25 %
under
conditions
for aqueous
solutions.
Due to
the the
low usual
viscosity
of aqueous
Kollicoat
in water: about 150 mPa.s), a much higher concentration can be used than
The following
conditions
haveready-made
produced good
results inmixtures.
numerousThis
trials:
for other
commercially
available
film-coating
reduces the spraying time considerably and hence the overall processing costs.
Inlet air temperature:
50-80°C
Outlet
air
temperature:
30-50°C
46
Atomizing pressure:
2-4 bar
Temperature of spray suspension:
20-70°C
Spray suspensions containing 20 – 25 % of solids can be prepared with ease
at room temperature as their viscosity is always below the critical limit of
250 mPa.s.
Like in the case of Kollicoat® IR a very robust process with short process
times can be achieved with Kollicoat® IR White.
For the white film-coating of cores usually 20 % of Kollicoat® IR White is
suspended in water and stirred for further 15 minutes. For the coating of
6 kg of acetylsalicilic acid cores the machine settings of the Accela Cota ®
24" (Manesty) are summarized in Table 1.21 as a typical example. Although
the inlet air temperature was relatively low at 60 °C and the spraying pressure was only 2 bar, the entire spraying process took only 35 minutes.
Table 1.21: Machine settings for the white film-coating of acetylsalicylic acid cores with Kollicoat® IR White (Accela Cota® 24")
Parameter
Setting
Batch size
Inlet air temperature
Outlet air temperature
Core temperature
Inlet flow rate
Outlet air flow rate
Spray pressure
No. nozzles
Spray rate
Spraying time, total
Subsequent drying
Amount applied
6 kg
60 °C
36 °C
35 °C
210 m3/h
410 m3/h
2 bar
1
30 g/min
35 min
4 min/60 °C
5 mg solid/cm2
The physical properties of the acetylsalicylic acid tablets were not changed
significantly by the coating process. Only a slight increase of the tablet hardness was observed without any influence on the disintegration or dissolution.
For the coloured film-coating of cores with Kollicoat ® IR White a typical
formulation of the spray suspension and the machine settings are given
in Table 1.22 for the scale of 250 kg of cores. This particular production
run is somewhat more complex than for a simple white suspension as the
insoluble indigotin-aluminium colour lake first has to be suspended and
homogenized (e.g. using a high-speed mixer) before being added to the
Kollicoat® IR White suspension.
47
Table 1.22: Blue instant-release film-coating with Kollicoat ® IR
White for 250 kg tablets (weight 250 mg, diameter 9 mm)
Weight [kg]
1. Formulation
Polymer suspension:
7.76
Kollicoat® IR White
Water
25.0
Colour lake suspension:
Indigotin colour lake E 132
0.495
Water
8.0
Proportion [%]
18.8
60.6
1.2
19.4
2. Procedure
Stirr the colour lake vigorously into the water, homogenize the
obtained suspension in a corundum disk mill and stirr it into
the polymer suspension.
3. Coating conditions (Driacoater® 900, Driam)
Inlet air temperature
70 °C
Outlet air temperature
45 °C
Cores temperature
47 °C
Air flow
4600 m3/h
Spray pressure
4 bar
No. nozzles
6
Spray rate
700 g/min
Spraying time
60 min
Final drying
5 min, 60 °C
Quantity applied
3 % solids
1.6.4 Protective film-coating with Kollicoat ® Protect
Kollicoat® Protect is a mixture of the film-forming polymers Kollicoat ® IR and
polyvinyl alcohol in the ratio 6:4. It is designed for white and coloured tablet
and capsule film-coatings. Due to its very low permeability with respect
to oxygen and water, its primary application is as a protective film against
oxidation and hydrolysis of the active ingredient. In addition, it can be used
to mask taste, to facilitate the swallowing of tablets, to improve their appearance or as subcoating.
It possesses all the advantages of Kollicoat® IR, e.g. rapid dissolution in water,
a high degree of adhesion, also on lipophilic surfaces, enormous flexibility
and low viscosity in water (20 % in water: about 230 mPa.s).
48
Kollicoat® Protect allows smooth and rapidly dissolving coatings to be
produced. Due to its high degree of flexibility, coating formulations using
Kollicoat® Protect do not require the addition of a plasticizer. In addition,
the flexibility prevents the coating from cracking during storage, especially if
the relative humidity varies. Even if the cores contain a swelling disintegrant
such as crospovidone (Kollidon® CL grades), the coating retains its strength
during storage – also if the storage conditions may not be ideal.
The manufacture of a polymer solution of Kollicoat ® Protect for film-coating
tablets and capsules is both straightforward and quick. However, at certain
stirring speeds foam may form. The formation of foam can be best prevented
or at least reduced by adding 0.1 % of a 30 % simethicon emulsion or
0.75 % Labrasol® (Gattefossé). Normally, one of the following two methods
can be used:
A) Spray solution containing a water-soluble colorant:
Stir Kollicoat® Protect and the soluble colorant into the required amount of
water. Set the stirring speed so that as little foam as possible is generated.
Continue stirring for a further 30 min. If necessary, add an anti-foaming
agent beforehand.
B) Spray suspension with white and/or coloured pigment or colour lake:
Stir Kollicoat® Protect into the required amount of water to obtain the polymer solution. Set the stirring speed so that as little foam as possible is
generated. Continue to stir for a further 30 min.
To prepare the pigment suspension, stir the insoluble components, e.g.
talcum powder, titanium dioxide, iron oxide or colour lake into the required
amount of water and homogenize in a high-speed stirrer or corundum disk
mill. Stir the pigment suspension into the polymer solution to make the spray
suspension. Stir continuously during the entire spraying process. A typical
example of this method is demonstrated in Table 1.23.
The concentration of solids in the spray suspension usually lies in the range
of 15 – 20 %.
The Process-Parameter-Charts of formulations of Kollicoat ® Protect and of
polyvinyl alcohol shown in Fig.1.18 and Fig. 1.19 demonstrate clearly the
strong advantages of the polmer combination Kollicoat ® Protect against the
polyvinyl alcohol alone. A very robust process with short process times
(about 90 min) can be achieved with the Kollicoat ® Protect formulation.
Since in the case of the polyvinyl alcohol formulation the green areas are
strongly limited the minimal process time is very much longer, the inlet-air
temperature much higher and the transfer from a pilot to production scale
is more difficult.
49
■ Film-coating impossible, sticking of the cores
■ Film-coating possible, but surface not acceptable
■ Good film-coating process, surface acceptable
■ Optimal film-coating process, best surface quality
Fig. 1.18: Influence of process time and temperature on the film-coating
with a Kollicoat® Protect formulation (Process-Parameter-Chart)
■ Film-coating impossible, sticking of the cores
■ Film-coating possible, but surface not acceptable
■ Good film-coating process, surface acceptable
■ Optimal film-coating process, best surface quality
Fig. 1.19: Influence of process time and temperature on the film-coating
with a polyvinyl alcohol formulation (Process-Parameter-Chart)
For a typical formulation acetylsalicylic acid (100 mg) was selected as active
ingredient for this particular application because of its high sensitivity to
hydrolysis. In this way, the protective effect of Kollicoat ® Protect can best
be shown.
The 20 % suspension was prepared as described in general method B. The
composition and the machine settings is shown in Table 1.23. The formulation
was designed for the coating of 6 kg of cores.
50
Table 1.23: Protective white film-coating with Kollicoat ® Protect
for 6 kg of acetylsalicylic acid tablets (weight 300 mg, diameter
9 mm)
1.Formulation
(spray suspension)
Kollicoat® Protect
Talcum
Titanium dioxide
Water
Total
Weight [g]
Proportion [%]
125.40
52.25
31.35
836.00
1045.00
12
5
3
80
100
2. Procedure (Method B)
Stirr the talcum and titanium dioxide into a part of the water, homogenize the obtained pigment suspension in a corundum disk mill
and stirr it into the polymer solution prepared with the rest of water.
3. Coating conditions (Accela Cota® 24’’, Manesty)
Inlet air temperature
60 °C
Outlet air temperature
36 °C
Cores temperature
35 °C
Inlet air flow
210 m3/h
Outlet air flow
410 m3/h
Spray pressure
2 bar
No. nozzles
1
Spray rate
30 g/min
Spraying time
35 min
Final drying
4 min, 60 °C
Quantity applied
5 mg solids/cm2
The coated acetylsalicylic acid tablets obtained had a white, glossy coating
that covered the engravings on the tablet surface excellently. The physical
properties of acetylsalicylic acid tablets were hardly affected by the protective coating; however, there was an small increase in hardness. The release
curve is also practically identical to that of identical cores coated with
Kollicoat® IR.
Hydrolysis of acetylsalicylic acid in the tablets coated with Kollicoat ® Protect
was investigated over a period of 6 months under various storage conditions
(25 °C/60 % and 30 °C/70 % relative humidity). In the case of the Kollicoat ®
Protect coating, a significant smaller amount of free salicylic acid was determined than with a coating of Kollicoat® IR White or without any coating.
To obtain coloured film-coatings with Kollicoat® Protect the same formulation
as given in Table 1.23 could be used adding an iron oxide or a colour lake
to the pigment suspension.
51
1.6.5 Instant-release film-coating with Kollidon ® VA 64
Kollidon® VA 64 is used in water-soluble tablet coatings to improve stability
or organoleptic properties, particularly in conjunction with other film-forming
agents. A typical example is the combination with hypromellose (HPMC),
in which the use of Kollidon® VA 64 saves not only material costs but also
processing costs, as it reduces the viscosity of the spray suspension. This
allows the use of a higher concentration, which saves time. The effect of
reducing the viscosity is shown in Fig. 1.20.
Viscosity, mPa·s
Kollidon® VA 64 can also be used together with other film-forming agents
such as polyvinyl alcohol, hydroxypropyl cellulose (HPC), ethyl cellulose or
sucrose in the manufacture of soluble tablet coatings.
1000
800
Hypromellose alone
Hypromellose +
®
Kollidon VA 64 (4+6)
600
400
®
Limit (Accela Cota )
200
0
0
3
6
9
12
15
18
Polymer concentration in water, %
Fig. 1.20: Viscosity of hypromellose (+ Kollidon ® VA 64) coating solutions
The combination with sugar in Table 1.24 is an intersting formulation for
film-coatings. In this case, the film-forming and plastic properties of Kollidon ®
VA 64 are combined with the protective and taste masking properties of
sugar. Kollidon® VA 64 not only acts as a film-forming agent, it also acts
as a crystallization inhibitor that prevents the sugar from crystallizing during
spraying and on the tablets. The coating can be applied in any thickness
desired.
52
Table 1.24: Sugar film-coating with Kollidon ® VA 64
1.Formulation of the spray suspension
Sucrose
200 g
50 g
Kollidon® VA 64
Titanium dioxide
30 g
15 g
Sicovit® Iron oxide
Macrogol 4000
40 g
Talc
50 g
Water
ad 1200 g
2. Preparation
Dissolve the sucrose, Kollidon® VA 64 and macrogol 4000 in the water
and suspend the other components. Pass through a colloid mill.
3. Coating conditions (Accela Cota® 24)
Batch size (tablet cores)
Amount of coating suspension
Inlet air temperature
Outlet air temperature
Nozzle
Coating pan speed
Spray pressure
Spraying time (continuous)
Quantity of film former applied
5.0
1.2
45
36
0.8
15
2.0
50
4
kg
kg
°C
°C
mm
rpm
bar
min
mg/cm2
1.6.6 Traditional sugar coating
Kollidon® 30 or Kollidon® VA 64
Kollidon® 30 and Kollidon® VA 64 are also used in traditional sugar coating,
as they reduce the rate of crystallization of the sugar, which in turn makes
it possible to automate the coating process. Typically, about 10 % Kollidon®
(as a proportion of the sucrose) is used.
Sugar coatings are particularly susceptible to cracking when they are applied
to large batches of tablet cores that are dried rapidly. As most active ingredients are hydrophobic, Kollidon® VA 64 and Kollidon® 30 are useful as additives to prevent the tablet coating peeling during manufacture. Particularly
when soluble dyes are used, Kollidon® VA 64 and Kollidon® 30 are useful
in achieving an even distribution of the dye and preventing its migration, as
well as increasing the capacity of the coating suspension for the dye.
53
Apart from its use in manual sugar coating, Kollidon ® VA 64 or Kollidon® 30
makes it possible to automate the traditional sugar coating process.
Table 1.25 gives a suitable formulation.
Table 1.25: Spray suspension for automatic sugar coating
1.Formulation of the coating suspension
Sucrose
76 g
8 g
Kollidon® 30
Titanium dioxide
9 g
Calcium carbonate
9 g
Talc
29 g
Colorant/pigment (e.g. Sicovit ® iron oxide) q.s.
Glycerol
4 g
Water
63 g
2. Procedure
40 kg of tablet cores with a weight of 420 mg were sprayed with
25 kg of the above suspension in a conventional coating pan
under the following conditions:
3. Coating conditions
Spray phase:
Interval:
Drying phase (warm air):
Total coating time:
5
10
10
16
s
min
min
h
1.6.7 Subcoating of tablet cores
Kollidon® VA 64 (Kollidon® 30)
Kollidon® VA 64, which is much less hygroscopic and more plastic than
povidone, is more suitable and more widely used for subcoating tablet
cores or capsules than Kollidon® 30 or Kollidon® 25.
In this application, it is used either to form a moisture barrier around the
tablet core or capsule to prevent the entry of water during subsequent
processing, or as an adhesion promoter to give tablet cores and capsules
a hydrophilic surface for subsequent film-coating or sugar coating. The
most important reasons for the application of a subcoating and for the
functions of Kollidon® VA 64 are summarized in Table 1.26.
54
Table 1.26: Reasons for subcoating tablet cores and the function
of Kollidon® VA 64 in this application
Reasons for subcoating
tablet cores
Function of Kollidon® VA 64
Instability of the active
ingredient towards water
(hydrolysis)
Formation of a barrier layer on
the surface and in the pores
Chemical interactions between
the active ingredients
(e.g. vitamins)
Formation of a barrier layer on
the surface and in the pores
Presence of high-performance
disintegrants
Formation of a barrier layer on
the surface and in the pores
Hydrophobic surface of the
tablet core or capsule
Dust formation (friability
of the tablet cores)
Improvement in adhesion of
subsequent coatings by hydrophilization of the surface
Loose particles are bound to
the surface of the tablet core
Kollidon® VA 64 (or Kollidon® 30) is usually sprayed onto the cores as a
10 % solution in alcohol (e.g. ethanol or 2-propanol) during few minutes
until an adequate thickeness is achieved.
1.6.8 Taste masking by coating of tablets
Kollidon® VA 64, Kollicoat® Protect, Kollicoat® IR
A film-coating containing Kollidon® VA 64 and sucrose is one of the simplest
and most effective means of masking the unpleasant taste of tablets without
compromizing drug release. An example of such a coating is given in
Section 1.6.5.
This applies in even more to Kollicoat® Protect. To demonstrate this application pseudo-ephedrine tablets were used. Pseudo-ephedrine hydrochloride is an active ingredient with a bitter taste; this is very much enhanced
by its very good solubility. For this reason, it is suitable for use as a test
substance in experiments designed to mask taste as it is immediately
tasted if the tablets remain uncoated.
Using direct compression technology, tablet cores containing 90 mg of
active ingredient were produced (weight 300 mg, diameter 9 mm). 5 kg of
these cores were coated with a white spray suspension of Kollicoat ® Protect
in an Accela Cota® 24’’ (Manesty) coating machine. Coatings of 10, 15 and
20 mg/cm2 were obtained. The formulation for the spray suspension, the
spraying conditions and the machine settings are summarized in Table 1.27.
The spraying time was able to be considerably shortened due to the higher
spraying rate used.
55
Table 1.27: Taste masking film-coating with Kollicoat ® Protect for
5 kg of pseudo-ephedrine tablets (weight 300 mg, diameter 9 mm)
1.Formulation of spray suspension
Kollicoat® Protect
Talcum
Titanium dioxide
Water
Total
Content [%]
12
6
2
80
100
2. Coating conditions (Accela Cota® 24’’, Manesty)
Inlet air temperature
60
Outlet air temperature
37
Cores temperature
32
Air flow
389
Spray pressure
2
Spray rate
24-26
Final drying
3
Quantity applied
10, 15 and 20
°C
°C
°C
m3/h
bar
g/min
min, 60 °C
mg solids/cm2
The effect of taste masking was tested subjectively; a tablet was placed in
the mouth and the time noted for the first bitter taste to occur. The results
shown in Table 1.28 show that a coating of 20 mg/cm 2 is adequate to mask
the taste for more than one minute.
Table 1.28: Taste masking effect of Kollicoat ® Protect on
pseudoephedrine tablets
Amount of coating used
Without coating
10 mg/cm2
15 mg/cm2
20 mg/cm2
56
Time to occurrence of bitter taste
<1
14 – 24
46 – 47
78
sec.
sec.
sec.
sec.
1.6.9 T
aste masking by coating of granules or crystals
before tabletting
Kollicoat® SR 30 D
The alternative to the coating of tablets of active ingredients with an unpleasant taste is the coating of the crystals or granules of such active substance
before tabletting. For this purpose the film-former Kollicoat ® SR 30 D could
be used. As this polyvinyl acetate polymer is insoluble in water, the optimum
quantity and the composition of the formulation must be determined very
carefully, to minimize the delay in drug release, though this delay can be
reduced to some extent by adding hydrophilic polymers (e.g. Kollidon ® 30)
or surfactants.
Acetaminophen crystals, for example, have a bitter taste, but if 300 g of
these crystals are coated with an dispersion of 150 g Kollicoat ® SR 30 D
and 33.7 g Kollidon® 30 in 210 g water in a fluidized bed granulator until
the resulting granules are coated with 15% polyvinyl acetate and 11 %
Kollidon® 30, the bitter taste is masked for more than 2 minutes.
Even after these acetaminophen granules are compressed into tablets with
a little of microcrystalline cellulose, drug release is not much slower than
from the uncoated substance (Fig. 1.21). Similar results were obtained with
ibuprofen.
100
Released drug, %
80
60
Tablets from uncoated
crystals
40
Tablets from coated
crystals
(15% PVAc + 11% PVP)
20
0
0
10
20
30
min
40
50
60
Fig. 1.21: Release of taste masked acetaminophen tablets (from crystals
coated with Kollicoat® SR 30 D + Kollidon® 30)
57
1.7 Colorants (pigments)
Sicovit® iron oxides
Both in tablets and in tablet coatings, iron oxide pigments are finding increasing favour over the lakes of organic dyes, even though the colours that can
be achieved are not quite as brilliant. Usually, one or two iron oxide pigments
are combined with titanium dioxide to obtain the desired shade.
If the tablets are to be made by direct compression, it is recommended to
first mix the pigments with the lubricant (e.g. magnesium stearate), and
to use this mixture as a lubricant. This ensures that the pigments are homogeneously distributed throughout the tablets. Table 1.29 shows a typical
example of this application in the formulation for a vitamin B12 tablet.
Table 1.29: Coloured vitamin B12 tablets (50 µg)
1.Formulations
I.Cyanocobalamin gelatin coated 0.1 %
Ludipress®
II.Magnesium stearate
Sicovit® Iron oxide Yellow 10
Sicovit® Iron oxide Red 30
50.0
150.0
1.5
2.0
3.0
g
g
g
g
g
2. Procedure (direct compression)
Prepare premix II, add to mixture I, pass through a 0.5 mm sieve
and press with low compression force.
3. Tablet properties
Weight
Diameter
Hardness
Disintegration
Friability
Colour
58
209 mg
8 mm
80 N
10 min
< 0.1 %
homogeneous
Coating pigment suspensions are best stabilized with Kollidon ® 25 or
Kollidon® 30, as the example of a spray suspension formulation for
couloured enteric film-coating shows in Table 1.30.
Table 1.30: Enteric film-coating of tablets with Sicovit ® Iron
Oxide Red 30 (for 5 kg tablet cores, 9 mm diameter)
1.Formulation
I. Pigment suspension:
Titanium dioxide
6
Talc
48
6
Sicovit® Iron Oxide Red 30
6
Kollidon® 30
Water
120
II. Polymer suspension:
600
Kollicoat® MAE 30DP
Propylene glycol
18
Water
396
Total I + II:
1200
g
g
g
g
g
g
g
g
g
2. Preparation of the spray suspension
I.Suspend the pigments and talc in the thoroughly stirred solution of
Kollidon® 30 and homogenize in a disk mill or in a colloid mill.
II.Separately suspend Kollicoat® MAE 30DP in the solution of propylene glycol.
Add pigment suspension I to the thoroughly stirred polymer suspension II.
Keep the suspension stirred throughout the coating process.
59
60
61
62
2. M
odified-release solid dosage forms
(Tablets, pellets and granules)
2.1 Enteric film-coatings with Kollicoat ® MAE grades
2.1.1 General notes
The copolymer products Kollicoat® MAE 30 DP and Kollicoat® MAE 100 P
based on methacrylic acid and ethylacrylate only dissolve at pH values of
5.5 and above, and are used for enteric film-coatings for tablets, pellets,
granules and capsules. Both the aqueous dispersion, Kollicoat ® MAE 30 DP
and the powder, Kollicoat® MAE 100 P can be processed easily in water,
are impermeable to protons, ions and water, and have low hygroscopicity.
It is not necessary to cure the tablets or capsules after coating.
The dissolution in water in dependence of the pH is identical for both Kollicoat ®
MAE grades. It is shown in Fig. 2.1 that the dissolution starts at ph 5.5.
140
120
Dissolution, mg/min
100
80
60
40
20
0
5.3
5.4
5.5
5.6
5.7
5.8
5.9
6
6.1
pH
Fig. 2.1: Dissolution of Kollicoat® MAE grades in aqueous medium as a
function of pH
The powder Kollicoat® MAE 100P is partly neutralized. Therefore it is possible
to produce the polymer dispersion for manufacturing by stirring this powder
into water without the addition of any alcaline substance. A further advantage
of Kollicoat® MAE 100P is that the dispersion obtained by this manner is
63
more compatible with other excipients and less sensitive about shearing
forces in comparison with the commercial dispersion Kollicoat ® MAE 30DP
which is not partly neutralized.
As the Kollicoat® MAE copolymer has a very low plasticity, always it is recommended to add a plasticizer like 1,2-propylene glycol or triethyl citrate. Fig. 2.2
shows the influence of different triethyl citrate concentrations on the elongation at break of this polymer. Most coating formulations with Kollicoat ® MAE
grades given in this book contains about 15 % of 1,2-propylene glycol as
plasticizer. The influence of 1,2-propylene glycol on the minimum film-forming temperature (MFT) of Kollicoat® MAE is shown in Section 2.4.1.
Elongation at break, %
14
12
10
8
6
4
2
0
10%
15%
20%
Triethyl citrate in the Kollicoat® MAE polymer
Fig. 2.2: Influence of triethyl citrate on the elongation of the Kollicoat ® MAE
copolymer
2.1.2 Enteric film-coating of tablets and capsules
To obtain enteric tablets that meet the requirements of the pharmacopoeias
(insoluble for 2 h at pH 1 and readily soluble at pH 6.8), the tablet cores
should generally be coated with a amount of 3 – 6 mg solids/cm 2.
A typical formulation of acetylsalicylic acid tablets coated with Kollicoat ®
MAE grades and the machine settings for an Accela Cota ® 24’’ (Manesty)
are given in Table 2.1. In this formulation, the 495 g of Kollicoat ® MAE 30
DP can be replaced directly with the equivalent quantity of 148.5 g of the
powder product, Kollicoat® MAE 100 P plus the missing quantity of water
contributed by the polymer dispersion.
64
Table 2.1: Enteric film-coating of acetylsalicylic acid tablets
(for 5 kg of cores, 300 mg weight, 9 mm diameter)
1.Formulation
I. Polymer suspension:
Alternative I:
495.0
Kollicoat® MAE 30 DP
1,2-Propylene glycol
22.3
Water
319.4
Alternative II:
148.5
Kollicoat® MAE 100 P
1,2-Propylene glycol
22.3
Water
665.9
II. Pigment suspension:
Titanium dioxide
4.9
Talc
39.6
4.9
Sicovit® Iron Oxide Red 30
Water.
103.9
Total (I + II):
990
g
g
g
g
g
g
g
g
g
g
g
2. Procedure
I.Mix 1,2-propylene glycol with water and stir in Kollicoat ® MAE
30DP or suspend Kollicoat® MAE 100 P in 665 g of water, stir
for 2 – 3 hours and add the propylene glycol.
II.Suspend the pigments and talc in 103 g of well stirred water
and homogenize in a disk mill or in a colloid mill.
Add the pigment suspension II to the well stirred polymer suspension I.
Stir the spray suspension obtained throughout the coating process.
3. Coating conditions (Accela Cota® 24’’, Manesty)
Inlet air temperature
50 °C
Outlet air temperature
37 °C
Core temperature
32 °C
Spray rate
40 g/min
Spray pressure
2.0 bar
Spraying time (continuous)
30 min
Quantity of solids applied
3 – 4 mg/cm2
3 mg of solids/cm2 of the spray formulation as described in Table 2.1 were
sprayed onto 5 kg of cores. Subsequently, the release of active ingredient
from the coated tablets was determined after 2 hours of immersion in synthetic gastric juice and then in synthetic intestinal fluid and compared with
that of uncoated cores in synthetic intestinal fluid only. Fig 2.3 shows that
the tablets were fully gastric juice-resistant and that active ingredient release
from the tablets after changing the medium was almost as fast as from the
uncoated cores.
65
100
Release of active ingredient, %
0.1 N HCI
Phosphate buffer pH 6.8
80
60
40
Uncoated tablets
(Phosphate buffer only)
Coated tablets
20
0
30
60
90
120
5
10
15
20
25
30
35 40
Time, min
Fig. 2.3: Release of acetylsalicylic acid from tablets coated with Kollicoat ®
MAE grades compared with uncoated cores
Kollicoat® MAE 100 P can also be applied in the form of a non-aqueous
system, i.e. a solution in organic solvents such as a mixture of ethanol
or 2-propanol and acetone.
2.1.3 Enteric coating of pellets and crystals
Gastric juice-resistant (enteric) pellets or crystals are also produced for marketing as hard gelatine capsules; these are filled into the capsules. The main
difference in comparison to the enteric coating of tablets is the needed total
amount of gastroresistent polymer. This is explained by the higher surface of
pellets and even higher surface of crystals. In the case of crystals the weight
increase can be until 30 % of solids. In the following example of diclofenac
pellets about 20 % of coating solids was applied. For this application test,
uncoated diclofenac drug pellets were produced with the following composition:
Sodium diclofenac 10 %, Kollidon® VA64 2.5 %, microcrystalline cellulose
43.7 %, lactose monohydrate 43.7 %. The pellets, rendered spherical, had
a diameter of 0.8 – 1.2 mm.
The spray suspensions containing both Kollicoat ® MAE grades were produced in the composition shown in Table 2.2 with a solid content of 22 %
and a polymer content of 15 %. The indicated amounts and coating conditions were designed for coating 5 kg of pellets in a Kugelcoater of Hüttlin.
66
Table 2.2: Enteric film-coating of diclofenac drug pellets
(for 5 kg of pellets)
1.Formulation of spray suspension
I. Polymer suspension:
Alternative I:
2250.0
Kollicoat® MAE 30 DP
1,2-Propylene glycol
67.5
Water
1435.0
Alternative II:
675.0
Kollicoat® MAE 100 P
1,2-Propylene glycol
67.5
Water
3010.5
II. Pigment suspension:
Titanium dioxide
45.5
Talc
180.0
22.5
Kollidon® 30
Water.
500.0
Total (I + II):
4500.0
g
g
g
g
g
g
g
g
g
g
g
2. Procedur
I.Mix 1,2-propylene glycol with water and stir in Kollicoat ® MAE
30DP or suspend Kollicoat® MAE 100 P in water, stir for
2 – 3 hours and add the propylene glycol.
II.Suspend the pigments and talc in the well stirred solution of
Kollidon® 30 and homogenize in a disk mill or in a colloid mill.
Add the pigment suspension II to the well stirred polymer suspension I.
Stir the spray suspension obtained throughout the coating process.
3. Coating conditions (Kugelcoater HKC 5 TJ, Hüttlin)
Inlet air temperature
60
Outlet air temperature
32-35
Spray rate
45
Spraying time (continuous)
100
Quantity of solids applied
3
°C
°C
g/min
min
mg/ cm2
The release of the enteric sodium diclofenac pellets produced according to
Table 2.2 was tested by placing the coated pellets in artificial gastric juice
for a period of 2 hours and subsequently in artificial intestinal fluid. During
the first 2 hours (pH 1) no drug release was observed and during the following 55 min almost 100 % of diclofenac sodium were dissolved.
67
2.2 Sustained-release coating of pellets
2.2.1 Pellet film-coating with Kollicoat ® SR 30D
Plasticity, a low minimum film-forming temperature and an absence of tack
make Kollicoat® SR 30 D (30 % dispersion of polyvinyl acetate and Kollidon®
30 in the ratio 9:1 in water) an excellent film-forming agent for sustainedrelease pellets. For this application drug pellets or drug layered nonpareilles
can be used.
In the unlikely event that a plasticizer is required, 5 – 10 % 1,2-propylene
glycol is quite adequate. The pellets obtained can be marketed as such or
filled into hard gelatin capsules.
The formulation for ambroxol sustained-release pellets in Table 2.3 is a typical
example of this application of Kollicoat® SR 30 D on drug layered nonpareilles
which were produced by coating commercially available placebo pellets
with a coating of the active ingredient ambroxol hydrochloride and Kollicoat ®
IR or HPMC 2910.
800 g of these drug layered nonpareilles were film coated with 5, 10, 15
and 20 % of a colourless film coating in a fluidized bed granulator GPCG1
(Glatt) using a process according to Wurster and the amounts and spraying
conditions listed in Table 2.3.
To prepare the spray suspension, plasticizer triethyl acetate was mixed with
water and Kollicoat® SR 30D stirred in. Separately, talcum was suspended
in water and homogenized with a high-speed stirrer. The talcum suspension
was then stirred into the polymer suspension. During the entire spraying
process the spray suspension thus obtained was continuously stirred.
Table 2.3: Sustained-release coating of ambroxol-HCl pellets
1.Formulation of colourless spray suspension
533 g
I. Kollicoat® SR 30 D
Tritethyl citrate
16 g
Water
433 g
II. Talcum
56 g
Water
100 g
2. Uncoated pellets (batch size)
800 g
3. Coating conditions (Fluidized bed granulator Glatt CPCG1)
Inlet air temperature
50 – 55 °C
Outlet air temperature
29 – 32 °C
Pellet temperature
35 – 40 °C
Spray pressure
1.2 bar
Amount of inlet air
90 m3/h
Spray nozzle
1.2 mm
Spraying time
220 min
Subsequent drying
15 min/40 °C
Coating amount applied
5 – 20 % solids
68
Measurement of the release of active ingredient ambroxol-HCl from the pellets
was carried out under the following conditions: 0 – 24 h in phosphate buffer
pH 7.4 at 37 °C and 100 rpm. Active ingredient release was measured
using coating amounts between 5 and 20 %. Fig. 2.4 shows that between
15 and 20 % coating there is no strong difference and that in this case
a coating of about 10 % would be appropriate for active ingredient release
over a period of 24 h.
100
Release of active ingredient, %
80
60
40
5% coating
10% coating
15% coating
20% coating
20
0
0
4
8
12
16
20
24
Time, h
Fig. 2.4: Release of sustained-release ambroxol-HCl pellets
2.2.2 Pellet film-coating with Kollicoat® EMM 30D
Kollicoat® EMM 30D is the 30 % aqueous dispersion of polyacrylate (ethyl
acrylate – methyl methacrylate 2:1 copolymer) for sustained-release dosage
forms that also features high plasticity and a good retarding effect.
The one disadvantage of Kollicoat® EMM 30D as a film former is its tackiness.
For this reason, practically all formulations must include an anti-tack agent.
The most widely used agent of this type is talcum; however, microcrystalline
cellulose (MCC), hypromellose and simethicon are also suitable. However,
MCC and hypromellose have some influence on the sustained-release effect
of the polymer. This is schematically illustrated in Fig. 2.5. In the case of hypromellose 2910, type 3 mPa.s (HPMC), this side-effect is strongest; for, as fast
as the tackiness decreases with increase in concentration, the more the
sustained-release effect of Kollicoat® EMM decreases due to its pore forming
effect. In the case of microcrystalline cellulose (MCC), the sustained-release
69
effect is not so strongly reduced but its influence on tackiness is considerably less than in the case of hypromellose. The fact that talcum in concentrations normally used has practically no effect on the sustained-release
effect explains why it is the most widely used anti-tack agent. The effect of
talcum can be enhanced in the case of Kollicoat® EMM 30D films by combining with simethicon.
Microcryst.
Cellulose
Hypromellose
Talc
(+ simethicone)
Concentration of antiadhesive
Sustained release effect
Tackiness
Fig. 2.5: Effect of some anti-tack agents in pellet coating formulations with
Kollicoat® EMM 30 D
Kollicoat® EMM 30 D is processed for the sustained-release pellet coating
by the same methods as Kollicoat® SR 30 D. Plasticizers are never required.
Also for this application drug pellets or drug layered nonpareilles can be used.
70
2.3 Sustained-release tablets
2.3.1 Direct compression
Kollidon® SR
Kollidon® SR is the spray-dried form of polyvinyl acetate stabilized by the
addition of 19 % Kollidon® 30, and is a free-flowing powder. This makes
it ideal for direct compression. When it is compressed, it forms a matrix
structure from which the active ingredient is released gradually. The Kollidon ®
30 also forms pores in this matrix from which the active ingredient is released
mainly by diffusion. Other excipients that swell or dissolve in water such
as lactose monohydrate, Ludipress® LCE or Kollidon® CL-M can also be
considered as pore-formers.
The quantity of Kollidon® SR required to extend drug release over a period
of 20 – 24 hours depends mainly on the particle size and the solubility of
the active ingredient. For a soluble active ingredient more than the double
concentration of Kollidon® SR would needed in the tablet in comparison
with a slightly soluble active ingredient. The usual amount of Kollidon ® SR
lies in the range of 20 – 50 % of the weight of the tablets. The smallest
quantity required to form an adequate matrix usually is about 15 %, even if
the active ingredient is insoluble (e.g. theophylline) and present in a low
dosage. It is usually necessary to include a hydrophilic component such as
lactose or a pore-former such as Kollidon® CL or Kollidon® 30 with insoluble
active substances.
The following concentrations of Kollidon ® SR in the tablets can be taken as
a guide in most cases:
– Soluble drugs:
40 – 60 %
– Less soluble drugs:
30 – 40 %
– Sparingly soluble drugs:
15 – 30 %
On the other hand the variation of the quantity of Kollidon ® SR in the tablet
can be used for the adjustment of the release profile of the tablet of a given
active ingredient. Fig. 2.6 shows the effect of using different quantities of
Kollidon® SR on the release of caffeine, a soluble active ingredient.
Released drug (%)
100
75
50
80 mg Kollidon® SR
120 mg Kollidon® SR
25
160 mg Kollidon® SR
0
0
4
8
12
16
20
24
Time (h)
Fig. 2.6: Influence of the amount of Kollidon ® SR on the release of caffeine
sustained-release matrix tablets (Caffeine 160 mg, Kollidon® SR 80 – 160 mg,
Aerosil® 200 (Degussa) 3.4 mg, magnesium stearate 1.6 mg)
71
To demonstrate the application of Kollidon® SR in a sustained-release matrix
tablet of a soluble active ingredient obtained by direct compression diclofenac sodium was selected. Table 2.4 shows the formulation for 100 mg
active ingredient. It contains almost 50 % Kollidon® SR.
Table 2.4 Formulation of diclofenac sodium sustained-release
matrix tablets with Kollidon® SR
1.Formulation of tablets
Diclofenac sodium (Irotec)
Kollidon® SR
Aerosil® 200 (Degussa)
Magnesium stearate
Weight [g]
[%]
100.0
100.0
3.4
3.4
48.4
48.4
1.6
1.6
2. Manufacture (Direct compression)
Pass all ingredients through a sieve, mix for 10 min and press on
a rotary press with a medium compression force.
3. Tablet properties
Diameter
Weight
Hardness
Friability
8
206
195
< 0.1
mm
mg
N
%
The release profile of diclofenac sodium of the tablets of Table 2.4 was not
completely 24 hours as shown in Fig. 2.7. The main reason was the relative
fine particle size of the active ingredient used in this formulation.
100
% drug released
80
60
40
Medium: 0.08 N HCl (0-2 h),
phosphate buffer pH 6.8 (2-16 h)
20
0
0
2
4
6
hours
8
12
16
Fig. 2.7: Diclofenac sustained-release matrix tablets (Direct compression)
72
Since the needed concentration of Kollidon ® SR is relatively high for soluble
active ingredients it would be even more suitable for less soluble active substances. Table 2.5 shows an example of theophylline sustained-release
matrix tablets with 21 % Kollidon® SR. This concentration could be lower by
reduction of the amount of the pore former Ludipress® LCE in the formulation.
Table 2.5 Formulation of theophylline sustained-release matrix
tablets with Kollidon® SR
1.Formulation of tablets
Weight [g]
[%]
500
200
225
3
53.9
21.6
24.2
0.3
Theophylline gran. (BASF)
Kollidon® SR
Ludipress® LCE
Magnesium stearate
2. Manufacture (Direct compression)
Pass all ingredients through a sieve, mix for 10 min and press on
a rotary press with a compression force of about 11 kN.
3. Tablet properties
Diameter
Weight
Hardness
Friability
19.0 x 8.5
928
172
< 0.1
mm
mg
N
%
drug release [%]
Fig. 2.8 shows that the release of the theophylline tablets of Table 2.5 is
even more extended than 24 hours. Therefore the concentration of Kollidon ®
SR could be reduced to obtain an release profile of about 24 hours.
100
medium: 0.08 N HCI (0-2 h)
phosphate buffer pH 6.8 (2-16 h)
80
60
40
20
0
0
2
4
6
8
10
12
14
16
18
20
22
24
time [h]
Fig. 2.8: Release of theophylline sustained-release tablets with Kollidon ® SR
(Formulation see Table 2.5)
73
2.3.2 S
ustained-release matrix tablets obtained by wet granulation
and compression
Kollicoat® SR 30D
In contrast to Kollidon® SR, Kollicoat® SR 30D is an aqueous dispersion of
27 % polyvinyl acetate and 2.7 % Kollidon® 30. It is intended not for direct
compression, but for wet granulation of sustained-release matrix tablets or
for film-coatings. In the case of sustained-release tablets, the minimum
quantity of matrix former required is generally much less than with Kollidon ®
SR, as it does not contain 20 % of the pore former Kollidon® 30.
In this technology, the active ingredient, with or without filler, is granulated
with Kollicoat® SR 30D and, subsequent to the addition of further excipients
like extragranular fillers and/or lubricants, compressed to matrix tablets with
controlled-release properties. When using standard amounts of polyvinyl
acetate of 5 – 30 % in the granules, a matrix structure is formed on compression that encloses the particles of active ingredient. Subsequent to
penetration of gastric juice or intestinal fluid into the matrix, the active ingredient is slowly dissolved; it then diffuses through the matrix at a controlled
speed.
Like in the case of Kollidon® SR the drug release of tablets produced with
Kollicoat® SR 30D is completely independent on the pH and on the ionic
strength of the dissolution medium. An other important property of this polymer is its plasticity which avoids any influence of the tabletting compression
force on the drug release. This is demonstrated in Fig. 2.9 by means of
a tablet of the active ingredient propranolol hydrochloride. The dissolution of
propranolol-HCl before tabletting and after tabletting applying low, medium
and high compression forces did not show any significant difference.
The needed amount of Kollicoat® SR 30 D for the sustained release of
20 –24 hours depends mainly on the solubility of the active ingredient.
Its particle size also can have an influence but it is not so strong as in the
case of direct compression with Kollidon ® SR. The usual amounts of polyvinyl acetate in the granules lies in the range of 5 – 15 % for sparingly soluble
or insoluble active ingredients and 15 – 30 % for soluble or very soluble
active substances. Table 2.6 shows as a typical example of a soluble active
ingredient that for propranolol hydrochloride only about 16 % of polyvinyl
acetate are required in the granules as a proportion of the active ingredient
which represents about 8 % of the finished tablet.
74
Table 2.6: Sustained-release matrix tablets of propranolol
hydrochloride (160 mg)
1.Formulation
I. Propranolol-HCl
II. Kollicoat® SR 30D
Triethyl citrate
III. Microcrystalline cellulose
Magnesium stearate
160
110
3
200
2
mg
mg
mg
mg
mg
2. Procedure (wet granulation in a fluidized bed system)
Granulate I with the mixture II in the fluidized bed (inlet temperature
about 55 °C, outlet temperature about 30 °C), mix with the
components III and press with low compression force.
3. Tablet properties
Weight
Diameter
Friability
Drug release
400 mg
11 mm
< 0.1 %
see Fig. 2.9
The sustained release of the propranolol-HCl tablets of Table 2.6 is demonstrated in Fig. 2.9. There is neither an influence of the tabletting process
nor an influence of the compression force in the range of 5 to 25 kN. The
granules before tabletting gave almost the same release profile as the final
tablets.
100
Drug release, %
80
60
40
Granules before tabletting
Compression force 5 kN
Compression force 15 kN
Compression force 25 kN
20
0
0
4
8
12
16
20
Time, h
24
Fig. 2.9: Influence of the compression forces on the release of propranololHCl matrix tablets (formulation see Table 2.6)
75
In a similar formulation of propranolol hydrochloride as given in Table 2.6
the influence of the granulation technology was investigated, the parameters
selected being tablet hardness and release of the active ingredient. It was
found that the traditional mixer granulation produces tablets of considerably
less hardness than with fluidized bed granulation. Fig 2.10 shows that the
sustained-release effect with fluidized bed granulation is somewhat greater,
i.e. with traditional mixer granulation the active ingredient propranolol is released a little quicker. In order to compensate for this, a little more sustainedrelease polymer is required in order to achieve the same effect as with
fluidized bed granulation.
In other examples such influence of the granulation technology on the drug
release was even stronger. Therefore, fluidized bed granulation is the recommended technology for sustained-release matrix tablets.
Release of active ingredient, %
100
80
60
40
Mixing granulator
Fluidized bed granulation
20
0
0
2
4
6
8
10
12
14
16
18
20
22 24
Time, h
Fig. 2.10: Influence of granulation technology on the release of propranololHCl sustained-release matrix tablets with Kollicoat ® SR 30D
The next example of a sustained-release matrix tablet with Kollicoat ® SR
30D is given in Table 2.7 and based on the insoluble active ingredient
carbamazepine. In this case about 7 % polyvinyl acetate is used in the
granules and final tablets.
76
Table 2.7: Carbamazepine sustained-release matrix tablets
(200 mg)
1.Formulation
I. Carbamazepine (Sintetica)
Lactose monohydrate
Kollidon® CL-M
II. Kollicoat® SR 30 D
III. Aerosil® 200 (Degussa)
Magnesium stearate
200
148
20
99
2
2
g
g
g
g
g
g
2. Procedure of wet granulation in Aeromatic Strea-1™ (Niro)
Granulate mixture I with Kollicoat® SR 30 D (II) in a top spray
fluidized bed, mix with the components of III and press with
medium compression force
3. Tablet properties
Weight
Diameter
Form
Hardness
Friability
407 mg
11 mm
biconvex
136 N
< 0.1 %
The carbamazepine in the tablets formulated as described in Table 2.7 is
released over a period of 16 hours (see Fig. 2.11). If the pore former Kollidon ®
CL-M is not included in this formulation the release of the active ingredient
after 16 hours would be only about 40 %. Therefore this is a typical example
of function and need of a pore former in sustained-release matrix tablets of
insoluble active ingredients.
100
Drug, dissolved, %
80
60
40
Medium: 0.08 N HCl (0-2 h),
phosphate buffer pH 6.8 (2-16 h)
20
0
0
4
8
12
16
20
hours
Fig. 2.11: Release of carbamazepine controlled-release matrix tablets with
Kollicoat® SR 30 D
77
Kollicoat® EMM 30D
Kollicoat® EMM 30 D is an aqueous dispersion of polyacrylate (copolymer
of ethylacrylate and methyl methacrylate 2+1) and is used in much the
same manner as Kollicoat® SR 30 D. It is essential to reduce the greater
tack of Kollicoat® EMM 30 D by adding an antiadhesive (for details see
Section 2.2.2).
The formulations are very similar to those of Kollicoat ® SR 30D but the
quantities of Kollicoat® EMM 30 D required for the manufacture of sustainedrelease matrix tablets via wet granulation often can be somewhat less than
those for Kollicoat® SR 30 D, as its sustained-release effect is greater.
Generally a plasticizer never is needed for formulations of Kollicoat ® EMM
30D because its plasticity is very high.
One of the goals of the theophylline tablet formulation given in Table 2.8
was to demonstrate how, by varying the amount of Kollicoat ® EMM polymer,
the release profile of the active ingredient can be influenced.
The active ingredient theophylline was mixed with a filler/pore former and
this mixture sprayed with 5.0 and 7.5 % solid Kollicoat® EMM, based on the
weight of granulate, directly in an Aeromatic Strea-1™ (Niro) fluidized bed
granulator. The dry granules were mixed with magnesium stearate lubricant
and flowability agent Aerosil® 200 (Degussa) for 10 minutes and then sieved.
The mixture was compressed to 19 x 8.5 mm oblong tablets of approx.
800 mg weight with an active ingredient of approx. 400 mg using a compression force of 18 kN.
Table 2.8: Formulations and granulation conditions
for theophylline sustained-release matrix tablets
1.Formulations
No. 1
(5.0 %)
I Theophylline powder (BASF)
400 mg
Lactose monohydrate
360 mg
133 mg
II Kollicoat® EMM 30 D
(= 40 mg solids)
III Magnesium stearate
4 mg
4 mg
Aerosil® 200 (Degussa)
Tablet weight
No. 2
(7.5 %)
400 mg
340 mg
200 mg
(= 60 mg solids)
4 mg
4 mg
808 mg
2.Granulation settings
(fluidized bed granulator, “top-spray” method)
Inlet air temperature
55 °C
Outlet air temperature:
22 – 27 °C
Nozzle diameter
0.8 mm
Spray rate
Approx. 10 g/ml
Spray pressure
2 bar
78
808 mg
The amount of Kollicoat® EMM 30D required in the theophylline sustainedrelease tablets is very low due to the insolubility of theophylline if no pore
former is used. As can be seen in Fig 2.12, for the particle size of theophylline (powder, BASF) used, the amount of solid Kollicoat ® EMM of 5 %,
based on the weight of granulate, would be just right for release of active
ingredient over a period of 24 h. This amount should if at all possible not
be smaller as it might prevent the formation of the right matrix structure.
Release of active ingredient, %
100
80
60
40
20
0
5% Kollicoat EMM polymer
7.5% Kollicoat EMM polymer
0
4
8
12
16
20
24
Time, h
Fig. 2.12: Influence of the amount of Kollicoat ® EMM on the release of
theophylline sustained-release matrix tablets
2.3.3 Compression of sustained-release pellets to tablets
Kollicoat® SR 30D, Kollicoat® EMM 30D
As tablets are the most popular and best accepted drug form, sustainedrelease pellets can also be compressed to tablets instead of being filled
into hard gelatine capsules. However, in the case of pellet compression,
the plasticity of the coating is even more important as these rounded particles
have to be deformed even more in order to produce tablets with a sustainedrelease matrix and no hollow spaces.
Thus, it is not possible to compress sustained-release pellets coated with
the popular ethyl cellulose to tablets. Even if 25 % triethyl acetate was added
as plasticizer to the ethyl cellulose, the release profile was significantly altered
due to the mechanical stress of compression. The loss of sustained-release
effect brought about by compression is disproportionately high and hence
unacceptable in practice.
79
If the same pellets are coated using the identical amount of Kollicoat ® SR
film instead of ethyl acetate containing only 10 % instead of 25 % of triethyl
acetate plasticizer and if these are subsequently compressed in the same
way and formulation to tablets the release effect is not reduced as a result
of the mechanical stress of compression.
Electron microscopic photos showed that the pellets in this case were not
destroyed but only deformed. For this reason, Kollicoat ® SR 30D and also
Kollicoat® EMM 30D can be regarded as excellent film formers for the technology of preparing tablets from sustained-release pellets.
The sustained-release pellets can be compressed to tablets with various
fillers; however, release is not always uniform as the pores and dissolution
speeds tend to vary. Based on experience gained, the differences are not
very great. Strongly swelling or strongly hydrophilic excipients such as micronized crospovidone (e.g. Kollidon® CL-M) accelerate release. In the case of
sparingly soluble active ingredients such as theophylline or carbamazepine,
hydrophilic fillers like lactose monohydrate in pure or granule form
(Ludipress® LCE) or even Kollidon® CL-M are perhaps more suitable.
For readily soluble active ingredients, microcrystalline cellulose could be the
substance of choice.
To demonstrate this application of Kollicoat® SR 30D the ambroxol sustainedrelease pellets as described in Section 2.2.1, with coatings of 10 and 20 %
solids, were compressed to biplanar tablets using direct tabletting technology
in the formulation given in Table 2.9.
Table 2.9: Formulation of ambroxol-HCl sustained-release tablets from pellets with Kollicoat® SR 30D
Table 2.9: Formulation of ambroxol-HCl sustained-release tablets
from pellets with Kollicoat® SR 30D
1.Formulation (direct compression)
Ambroxol-HCl sustained-release pellets with
Kollicoat® SR 30D (as described in Section 2.2.1)
Microcrystalline cellulose
Magnesium stearate
2.Tablet properties (compression force: 15 kN
Weight
Diameter
Hardness
250.0 g
250.0 g
2.5 g
400 mg
10 mm
about 100 N
The release of ambroxol-HCl from the sustained-release tablets produced
according to Table 2.9 was not quite as linear as the sustained-release
pellets prior to compression (c.f. Section 2.2.1); however, they produced
release of active ingredient over a period of 24 h. The curve of the tablets
made from pellets with 20 % coating was somewhat flatter than that with
10 % (Fig. 2.13).
80
Release of active ingredient, %
100
80
60
40
20
0
10% coating
20% coating
0
2
4
6
8
10
12
14
16
18
20
22 24
Time, h
Fig. 2.13: Release of ambroxol-HCl sustained-release tablets produced from
pellets with 10 and 20 % Kollicoat® SR coating
2.3.4 Sustained-release film-coating of tablet cores
Kollicoat® SR 30D
Normally, the manufacture of sustained-release tablets by coating instantrelease tablet cores with a sustained-release coating is avoided; this is
because the risk is too high of the active ingredient being released too
quickly due to incomplete coating or, especially, damage to the coating.
Using the example of sustained-release tablets containing metoprolol tartrate,
propranolol hydrochloride or pseudo-ephedrine hydrochloride, it was,
however, proven that this particular risk can be excluded in the case of
Kollicoat® SR 30D as a film former. In this way, a very simple system for
achieving sustained release is possible. This is mainly due to the plasticity
and elasticity of Kollicoat® SR films, which enable the films to self-repair
damage so that release remains unaffected. In addition, the film will not
rupture should the core begin to swell during storage or during release
of the active ingredient. To demonstrate this effect, Table 2.10 shows the
elongation at break of isolated films containing 5 % triacetin and 10 %
1,2-propylene glycol as plasticizers in comparison with other sustainedrelease film formers ethyl cellulose and ammonium methacrylate co-polymer.
The differences are so great that the surprising results obtained with Kollicoat ®
SR 30D become understandable.
81
Table 2.10: Elongation at break of film formers with plasticizers
(23 °C, 54 % relative humidity)
Sustained release
film former
Elongation at break
5 % triacetin
10 % propylene glycol
Kollicoat® SR 30D
188 %
300 %
Ethyl cellulose dispersion
5.4 %
5.7 %
< 2.0 %
< 2.0 %
Ammonium methylacrylate
co-polymer
In the coating formulation of metoprolol sustained-release tablets given in
Table 2.11, the two co-polymers Kollicoat ® SR 30D and Kollicoat® IR were
combined in a ratio of 4:1 in order to increase the elasticity of the film.
Experiments carried out with similar formulations containing propranolol-HCl
and pseudo-ephedrine-HCl showed that the release profile could be altered
by varying the ratio. The higher the proportion of soluble polymer Kollicoat ®
IR, the more quickly the active ingredient was released.
To produce the instant-release tablet cores, 4 kg of metoprolol tartrate
were granulated with an aqueous solution of 100 g Kollidon ® 30 as binder,
dried, sieved and mixed for 10 minutes with the other excipients (3200 g
dicalcium phosphate, 80 g talcum, 60 g Aerosil® 200 (Degussa) and 80 g
magnesium stearate). The mixture was then compressed to biconvex cores
with a weight of approx. 390 mg.
5 kg of the metoprolol tartrate cores were coated with a red spray suspension of Kollicoat® SR 30D in an Accela Cota® 24’’ (Manesty). Table 2.11
lists the formulation of the spray suspension and the conditions of the filmcoating process.
To prepare the spray suspension, the pigments iron oxide and titanium dioxide
were suspended with talcum in an aqueous solution of Kollidon ® 30 and
Kollicoat® IR and homogenized. The pigment suspension was stirred into
the separately prepared aqueous mixture of triacetin and Kollicoat ® SR 30D.
Kollidon® 30 in this case served as a suspension stabilizer to prevent sedimentation and agglomeration of the pigments. Kollicoat ® IR is a very flexible
film former that can also function as a pore former.
82
Table 2.11: Red spray suspension and spraying conditions for
sustained-release film-coating of metoprolol cores
1.Spray suspension
Kollicoat® SR 30D
Triacetin
Kollicoat® IR
Kollidon® 30
Titanium dioxide
Sicovit® red iron oxide
Talcum
Water
43.5
0.7
3.3
0.5
0.5
0.5
3.5
47.5
%
%
%
%
%
%
%
%
2.Coating parameters (Accela Cota® 24’’, Manesty)
Batch size
5 kg
Inlet air temperature
50 °C
Tablet core temperature
35 °C
Spray pressure
2.0 bar
Spray rate
22 g/min
Amount applied (solid)
4, 6 and 10 mg/cm2
The release of metoprolol tartrate was determined at three different applied
amounts of coating. Measurement took place under the following conditions:
0 – 2 h in 0.08 M hydrochloric acid, 2 – 24 h in phosphate buffer of pH 6.8,
37 °C and 50 rpm.
Fig. 2.14 shows that, for release over a period of 24 h, a coating of 10 mg
solid per cm2 of tablet surface is appropriate. The S-curve is brought about
by the fact that it takes some time for the water to penetrate the film and
for the active ingredient to begin to dissolve before diffusing through the film
to the exterior. The thicker the film, the stronger the affect achieved.
83
Release of active ingredient, %
100
80
60
40
Uncoated cores
4 mg coating/cm2
6 mg coating/cm2
10 mg coating/cm2
20
0
0
2
4
6
8
10
12
14
16
18
20
22 24
Time, h
Fig. 2.14: Release of metoprolol tartrate from sustained-release tablets
as a function of coating thickness of Kollicoat ® SR 30D
In order to investigate the sensitivity of the coating to mechanical stress and
damage, two methods were selected that could well be described as being
drastic in nature. In the first method – a friability test – the coated tablets
were subjected to 500 revolutions in a friability apparatus with a falling
height of 15 cm; thereafter, they were allowed to fall 20 times from a height
of 1.5 m onto a stone floor. In the second method, the tablets were punctured with a needle in such a way that the coating was completely penetrated.
Subsequent to both methods, the influence of release of active ingredient
was determined. The results obtained were surprising, to say the least.
In comparison with untreated tablets, not the slightest difference in release
was observed (Fig 2.15).
In the case of the punctured tablets, there must be some sort of mechanism
whereby the damage is repaired. In this case, it is the high degree of plasticity
that exists in the aqueous test medium that then, due to the swelling of the
coating, closes off the holes.
84
Release of active ingredient, %
100
80
60
40
20
0
Untreated tablets
After friability testing
Punctured tablets
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Time, h
Fig. 2.15: Influence of mechanical stress and damage to the coating of
metoprolol sustained-release film tablets on the release of active ingredient
85
2.4 Plasticizers
2.4.1 Propylene glycol
1,2-Propylene glycol is nowhere near as effective a plasticizer as other
traditional compounds such as triethyl citrate, but its adverse effect on drug
release is less. This is particularly important with tablet coatings that dissolve
in gastric juice and tablet coatings that do not. Furthermore 1,2-propylene
glycol has no negative influence on the tackeniss of the coating (see Fig. 2.17).
In concentrations of 10 – 15 % as a proportion of the film-forming agent,
1,2-propylene glycol considerably reduces the minimum film-forming temperature (MFT). Fig. 2.16 shows the effect of adding 1,2-propylene glycol
to Kollicoat® MAE.
MFT [°C]
25
20
15
10
5
0
0%
10%
15%
Propylene glycol in Kollicoat® MAE
Fig. 2.16: Influence of 1,2-propylene glycol on the minimum film-forming
temperature of Kollicoat® MAE
Typical examples of applications of 1,2-propylene glycol in formulations for
tablet coatings are given in the Section of enteric coatings with Kollicoat ®
MAE grades.
86
2.4.2 Macrogol as plasticizer
Lutrol® E 400
Liquid and solid macrogols such as Lutrol® E 400 can also be used as plasticizers, though relatively large quantities of some 20 %, as a proportion of
the film-forming agent, are required.
The tackiness of films is an important property in the practical application of
polymer coating. In the case of Kollicoat® SR 30D films, this was investigated
using the Hoessel method. Simultaneously, the influence of various concentrations of the plasticizers macrogol, 1,2-propylene glycol, triethyl citrate
and triacetin was determined. The results of this investigation are shown in
Fig. 2.17, where it can be seen that macrogol and 1,2-propylene glycol
have no negative influence on the tackiness. However, in the case of the
other two plasticizers at a concentration of 10 %, based on the polymer, the
tackiness, also perceptible by the finger test, exceeded the limit of 1.3.
4
PVAc without plastic
5% Plasticizer in PVA
3
10% Plasticizer in PVA
2
Tacky
Non-tacky
1
0
Without
Propylene
glycol
Macrogol
Triethyl
citrate
Triacetin
Fig. 2.17: Influence of different plasticizers on the tackiness of polyvinyl
acetate.
87
2.5 Mucoadhesives for buccal tablets
Kollidon® VA 64, Kollidon® 30, Kollidon® 90 F
Both povidone (e.g. Kollidon® 30 or Kollidon® 90 F) and particularly copovidone (Kollidon® VA 64) are suitable for use as mucoadhesives in buccal
tablets.
Mucoadhesive buccal tablets containing povidone or copovidone are typically
used to administer such drugs as flurbiprofen, hormones, nicotine, morphine
and verapamil.
Table 2.12 gives basic formulations for a mucoadhesive tablet that was developed for morphine sulphate (20 mg). In this formulations, Kollidon ® VA 64
was found to be far superior to Kollidon® 30 or Kollidon® 90 F, particularly
as the mucoadhesive strength of the tablets made with it was many times
higher.
Table 2.12: Mucoadhesive buccal tablet with Kollidon ® VA 64
(basic formulations)
1.Formulations
I. Active ingredient (e.g. morphine sulphate)
Lactose monohydrate
Carbopol® 934 (Goodrich)
Carbopol® 980/981 1+1 (Goodrich)
Kollidon® VA 64
II. Ethanol 96 %
III. Magnesium stearate
No. 1
q.s.
76 g
4g
–
19 g
15 g
1g
No. 2
q.s.
76 g
–
4g
19 g
10 g
1g
2.Procedure (wet granulation)
Vigorously mix the components in I, granulate mixture I with ethanol
II, pass through a 0.8 mm sieve, dry, sieve again through a 0.5 mm
sieve, mix with the component III and press into tablets using
medium compression force.
3.Tablet properties (Formulations No. 1 and No. 2)
Diameter
8 mm
Weight
200 mg
Hardness
> 180 N
Disintegration
> 30 min
Friability
< 0.1 %
4.Mucoadhesive strength (in vitro)
One drop of human saliva was placed on a glass plate and a tablet
was placed on this drop. After 7 min the force (N) was measured
needed to pull the tablet off the glass plate perpendicularly:
Formulation No. 1:
about 7 N
Formulation No. 2:
about 3 N
88
89
90
3. Soft gelatin capsules
3.1 Carriers, solvents
Lutrol® E 300, Lutrol® E 400, Lutrol® E 600
Macrogols, usually in the form of liquid or semisolid mixtures, are used as
carriers and solvents in soft gelatin capsules. Macrogols, e.g. mixtures of
the Lutrol® E grades, have the advantage over the normally used oils that
they are hydrophylic and therefore tend to enhance the bioavailability of the
embedded or dissolved drug.
Nifedipine and temazepam are typical examples of drugs for which macrogols can be used as a carrier in soft gelatin capsules.
1,2-Propylene glycol
Apart from glycerol, the most widely used solvent in soft gelatin capsules,
it is also possible to use anhydrous 1,2-propylene glycol alone or, as is
often done, in combination with glycerol. Typical examples of drugs with
which 1,2-propylene glycol can be used in soft gelatin capsules are ibuprofen, cyclosporin and vitamins.
91
3.2 Solubilizers in soft gelatin capsules
Cremophor® RH 40, Cremophor® EL
Macrogolglycerol ricinoleate 35 and macrogolglycerol hydroxystearate 40
(Cremophor® EL and Cremophor® RH 40) are used as nonionic solubilizers
in soft gelatin capsules to solubilize the active ingredient or to improve the
release and bioavailability of active substances (see also Section 1.4.5).
Because of the good miscibility and solubility of these solubilizers, their use
does not depend on the carrier. This can be a vegetable oil or a specific
triglyceride made from a vegetable oil (e.g. for vitamin capsules), or it can
consist of macrogol, glycerol and/or 1,2-propylene glycol (e.g. for ibuprofen,
cyclosporin or vitamin capsules).
92
3.3 Antioxidants in soft gelatin capsules
alpha-Tocopherol
The fat-soluble antioxidants ascorbyl palmitate and alpha-tocopherol are
used in soft gelatin capsules to stabilize oxidation-sensitive active ingredients.
The quantity of alpha-tocopherol used usually lies in the range of 0.5 – 2.0 %.
Typical examples of this application of alpha-tocopherol are in capsules
containing vitamins, carotenoids, omega fatty acids, isotretinoin and cyclosporin. This use is concentrated on capsules in which the carriers are
vegetable oils and fatty acid glycerides.
93
3.4 Colorants in soft gelatin capsules
Sicovit® Iron oxides
Though soft gelatin capsules, unlike the hard variety, are not always coloured,
the use of colorants in this sector is not unimportant.
As in the case of tablets, (see Sections 1 and 2) pigments are increasingly
used for this dosage form. The iron oxide and titanium oxide pigments are
the most widely applied.
94
95
96
4. Solutions
4.1 Solubilization for oral and topical use
4.1.1 Surfactants as solubilizers
Cremophor® RH 40, Cremophor® EL
The preparation of a microemulsion with the aid of non-ionic solubilizers is
a traditional method of solubilizing active ingredients of low solubility. In this
method, they are incorporated in the surfactant micelles which are so small
that they cannot be seen with
the naked eye.
The comparison of different non-ionic ethoxylated surfactants in Table 4.1
shows that the formation of a clear microemulsion or of a turbid macroemulsion does not depend on the degree of ethoxylation (ethylene units per
molecule) but appearantly on the content of the free macrogol. All tested
surfactants having a content of free macrogol lower than 6 % are emulsifiers.
All non-ionic solubilizers like macrogolglycerol hydroxystearate 40 or macrogolglycerol ricinoleate 35 (Cremophor ® RH 40 or Cremophor® EL) contain
more than 12 % of free macrogol. An indirect proof of this theory was given
by the extraction of the free macrogol from a solubilizer like Cremophor ®
RH40 or Solutol® HS15. After such elimination of the free macrogol part
the solubilizing properties of the product are lost. The explanation is the
formation of mixed micelles which have a stronger solubilization effect than
normal micelles particularly if the free macrogol is combined with glycerol
or sorbitol.
Table 4.1: Degree of ethoxylation and content of free macrogol in
some surfactants
Surfactant
Degree of
ethoxylation
(EO units
per molecule)
Emulsifiers (macroemulsion)
Macrogol cetostearyl ether 25
Macrogol lauryl ether 9
Macrogolglycerol hydroxystearate 7
25
9
7
Solubilizers (microemulsion)
Macrogol hydroxystearate 15
Polysorbate 80
Macrogolglycerol ricinoleate 35
Macrogolglycerol hydroxystearate 40
15
20
35
40
Content of
free macrogol
2 – 3%
1 – 2%
3 – 6%
27
12
12
22
–
–
–
–
37 %
16 %
18 %
28 %
97
The two products Cremophor® RH 40 and Cremophor® EL are excellent
solubilizers for the oral and topical use. This applies particularly to Cremophor ®
RH 40 as its odour and taste in aqueous solutions is very low.
The principle of solubilization in a microemulsion is useful for lipophilic and
strongly hydrophobic substances. Typical examples are the fat-soluble
vitamins A, D, E and K1, antimycotics such as miconazole, ethereal oils and
constituents of these, fragrance oils, buccal antiseptics such as hexeditine
and certain drugs such as ciclosporin, simethicone and tramadol.
In addition, many topical and buccal cleansing and antiseptic solutions also
contain Cremophor® RH 40 as it acts as a detergent at the point of application.
As a typical example of a buccal application of Cremophor ® RH 40, Table
4.4 (Formulation No. 1) gives a formulation for a mouth-wash containing
alpha-bisabolol, the active principal of camomile.
As an example of oral applications of Cremophor ® RH 40, Table 4.2 gives a
formulation for a multivitamin syrup and Table 4.11 a formulation for vitamin
A + E drops.
The two formulations in Tables 4.2 and 4.4 demonstrate that the solubilizer
must always be heated with the lipophilic active before this mixture is mixed
into the hot water as the continuous phase.
98
Table 4.2: Multivitamin syrup (1 – 2 RDA/20 ml)
1.Formulation
I. Vitamin A palmitate 1.7 Mio. I.U./g (BASF)
Vitamin D 40 Mio. I.U./g
Vitamin E acetate (BASF)
Butylhydroxytoluene
Cremophor® RH 40
II. Water
III. Sucrose
Methylparaben
Citric acid
IV. Glycerol
Water
V. Thiamine hydrochloride
Riboflavin 5’-phosphate sodium
Nicotinamide
Pyridoxine hydrochloride
Ascorbic acid, crystalline
Sorbic acid
1,2-Propylene glycol
Total amount
10.0
0.05
100.0
2.0
4.5
10.0
45.0
200.0
80.0
9.6
25.0
15.0
15.0
55.0
15.0
300.0
100.0
5.0
100
mg
mg
mg
mg
g
g
g
mg
mg
g
g
mg
mg
mg
mg
mg
mg
g
g
2.Procedure
Heat I and II separately to about 60 °C and slowly add I to II with
thorough stirring to obtain a clear solution. Dissolve III in the hot
solution IV to obtain a clear solution. Mix the cool solutions I/II, III/IV
and V and adjust the pH value to 4.0 – 4.2. Purge the solution with
nitrogen for 10 min and fill into bottles under nitrogen.
3.Chemical stability (20 – 25 °C; HPLC methods)
(9 months)
(12 months)
Vitamin A
86 %
73 %
Vitamin B1
88 %
83 %
Vitamin B2
96 %
92 %
Vitamin C
78 %
77 %
99
4.1.2 Complex formers
Kollidon® 25, Kollidon® 30
One means of preparing an aqueous solution of a substance that is insoluble
in water without using an organic solvent is to convert it into a soluble complex, e.g. with povidone. Kollidon® 25 and Kollidon® 30 can be used for this
purpose in formulations for oral and topical administrations.
The quantity of complexing agent required depends on the type of drug involved and its concentration. It also depends to some extent on the grade
of povidone employed: The higher the molecular weight, the greater is the
solubilizing effect.
Important drugs with which this effect is used include antibiotics (e.g. amoxicillin, chloramphenicol and doxycycline), analgesics (e.g. acetaminophen
and diclofenac) and particularly iodine which forms the well known povidoneiodine complex as water soluble disinfectant.
Table 4.3 describes an oral solution of a diclofenac complex with
Kollidon® 30 as a typical example.
Table 4.3: Diclofenac oral solution (1.5 %)
1.Formulation
Diclofenac sodium
Kollidon® 30
Sucrose, crystalline
Water
1.5
2.5
40.0
56.0
g
g
g
g
2.Procedure
Dissolve diclofenac sodium in the aqueous solution of the auxiliaries.
3.Physical stability
No crystallization had occurred after storage for 2 weeks at 6 °C.
A further example is the formulation an acetaminophen solution with
Kollidon® 25 given in Section 4.5.
100
4.1.3 Poloxamers as solubilizers
Lutrol® F 68, Lutrol® F 127
Poloxamers 188 and 407 (Lutrol® F 68 and Lutrol® F 127) are also used as
solubilizers in oral and topical preparations. Lutrol ® F 68 is used primarily
in oral preparations, while Lutrol® F 127 is preferred for topical and buccal
applications.
Formulation No. 2 in Table 4.4 shows an application of Lutrol ® F 127 in
a mouth wash, in which it serves mainly as a solubilizer, even though it is
combined with ethanol and 1,2-propylene glycol as well.
Table 4.4: alpha-Bisabolol mouth wash solutions (0.2 % and 0.5 %)
1.Formulations
I. Alpha-bisabolol, natural (BASF)
Flavour
Cremophor® RH 40
Lutrol® F 127
1,2-Propylene glycol
Ethanol 96 %
II. Glycerol
Saccharin sodium
Preservative
Water
No. 1 (= 0.2 %)
0.2 g
q.s.
2.5 g
–
–
–
5.0 g
0.1 g
q.s.
92.2 g
No. 2 (= 0.5 %)
0.5 g
q.s.
–
5.0 g
10.0 g
30.0 g
–
q.s.
–
54.5 g
2.Procedure
Heat mixture I to about 60 °C and add slowly the warm solution II
(60 °C).
3.Properties of the solutions
Clear, colourless liquid with a low viscosity.
101
4.2 Solubilization for parenteral use
4.2.1 Complex formers
Kollidon® 12 PF, Kollidon® 17 PF
As an increasing number of active ingredients are inadequately soluble in
water, and organic solvents are hardly used any more, solubilizers are finding
increasing use in injectables.
As already described in Section 4.1, a number of products and mechanisms
are suitable for this purpose. In the case of the low molecular weight povidone grades, Kollidon® 12 PF and Kollidon® 17 PF the principle involved
is that of the formation of a soluble complex between the substance and
povidone.
Only povidone grades with a K-value of less than 18, which corresponds to
an weight-average molecular weight of about 11,000, may be used for parenterals in Europe.
The most important groups of active ingredients in human and veterinary
ampoules for which these two grades of Kollidon ® have been used up to
now to improve solubility are antibiotics, e.g. doxycycline, oxytetracycline
and rifampicin as well as further anti-infectives. However, a number of other
active substances e.g. certain analgesics and antiseptics can also be solubilized with povidone.
Table 4.5 shows as an example of this application the composition of an
aqueous oxytetracycline hydrochloride ampoule with Kollidon ® 17 PF for
veterinary administration.
Table 4.5: Composition of a commercial oxytetracycline injectable
solution for veterinary administration
Oxytetracycline-HCl
Kollidon® 17 PF
Magnesium oxide
Reducing agent e.g. sodium formaldehyde sulfoxylate
Ethanolamine
Water for injections
5.70
10.00
0.46
0.50
q.s.
to 100
g
g
g
g
(pH)
ml
A further example of a formulation in which Kollidon ® 17 PF acts as a solubilizer is a retard ampoule for veterinary use in Section 4.10.
102
4.2.2 Surfactants as parenteral solubilizers
Solutol® HS 15, Cremophor® EL and Cremophor® ELP
As in the case with oral solutions (see Section 4.1), nonionic surfactants are
also used as solubilizers in parenteral preparations. However, because of
side effects such as the release of histamine, their suitability for use in an
injectable formulation must be carefully checked. The only solubilizer that
did not trigger the release of histamine in an animal trial was macrogol
hydroxystearate 15 (Solutol® HS 15), so that this product can be particularly
recommended for parenterals. Though Cremophor ® EL is still relatively
widely used particularly in veterinary formulations, it must now be declared
on the package in Germany.
Solutol® HS 15 and Cremophor® EL are frequently used to solubilize lipophilic
substances, in particular vitamins and liponic acid. But they can also be
used to solubilize other hydrophobic substances e.g. diazepam, ibuprofen,
paclitaxel, propanidid etc. A special purified grade, Cremophor ® ELP is
available for paclitaxel.
Table 4.6 shows the formulation for a vitamin K1 ampoule as an example of
an injection solution for human use.
Table 4.6: Vitamin K1 (= phytomenadione) injectable solution
(10 mg and 20 mg/ml)
1.Formulations
Phytomenadione
Solutol® HS 15
Preservatives
Water for injections
No. 1
1.0 g
6.5 g
q.s
93.0 g
No. 2
2.0 g
11.0 g
q.s.
87.0 g
2.Procedure
Dissolve phytomenadione in Solutol® HS 15 heated to about 60 °C
and slowly add the warm water. The solution can be sterilized by
heating to 120 °C or by filtering.
3.Properties of the solutions
A clear colourless solution of low viscosity is obtained.
4.Physical stability (Formulation No. 1)
After storage for 12 weeks at 20 °C and 40 °C, the heat-sterilized
solution did not show any change in appearance.
103
Table 4.7 shows the formulation for one of the widely marketed veterinary
ampoules with highly dosed vitamins A, D and E. This formulation gives a
milky emulsion with very good physical and chemical stability. An indication
of the bioavailability of the vitamins can be derived from results for a similar
formulation in Section 4.7.
Table 4.7: Vitamin A + Vitamin D3 + Vitamin E Aqueous Injectable
Emulsion for Cattle (500,000 I.U. + 75,000 I.U. + 50 mg/ml)
1.Formulation
Vitamin A propionate 2.5 Mio I.U./g (BASF)
Vitamin D3 40 Mio. I.U./g
Vitamin E acetate (BASF)
Butylhydroxytoluene
Solutol® HS 15
Benzyl alcohol
Water for injections
22.0
0.2
5.5
0.5
15.0
1.0
ad 100
g
g
g
g
g
g
ml
2.Procedure
Mix the vitamins, Solutol® HS 15, butylhydroxytoluene and benzyl
alcoholat approx. 60 °C, and then add the water (60 °C) slowly and
with vigorous stirring. After the ampoules have been heat-sterilized,
they should be shaken briefly while still hot, to eliminate any separation of the phases that may have occurred. Sterilization can also be
performed by membrane filtration under pressure.
3.Properties of the solution
Appearance: milky, pale yellow emulsion.
Viscosity: less than 20 mPa·s
4.Physical stability (20–25 °C, protected from light)
No change in appearance in 2 years.
5.Chemical stability of vitamin A
Room temperature: 9 % loss after 1 year, 16 % loss after 2 years.
6 °C:
About 10 % loss after 2 years.
4.2.3 Poloxamer 188 as parenteral solubilizer
Lutrol® F 68
Lutrol® F 68 is the only poloxamer that is used in parenterals. As in oral
and topical solutions, it can also serve as a parenteral solubilizer (see
Section 4.1.3).
104
4.3 Thickeners
4.3.1 High molecular povidone
Kollidon 90® F
Kollidon® 90 F having a high weight-average molecular weight of more than
106 is used occasionally as a thickener in oral and topical solutions, even
though rather higher concentrations are required than would be the case
with some cellulose derivatives.
Fig. 4.1 shows the variation in viscosity of aqueous solutions of Kollidon ®
90 F as a function of concentration.
When Kollidon® 90 F is used in aqueous solutions, it is recommended to
add an antioxidant, e.g. 0.5 % cysteine, to stabilize the colour of the solution.
mPa·s
10000
1000
100
10
1
0
2,5
Fig. 4.1: Dynamic viscosity of
Kollidon ®
5
10
15
%
90 F in water (20 – 25 °C)
105
4.3.2 Poloxamer 407 as thickener
Lutrol® F 127
The poloxamer Lutrol® F 127 is also used as a thickener. The special feature
of this product is that the thickening effect depends on the temperature, as
is explained in detail in Section 6.2.
Table 4.8 shows a formulation for an antiseptic solution with povidone-iodine
as the active ingredient. This thermo-gelling antiseptic is liquid at room
temperature, but when it is applied to the warm skin or mucous membranes,
the Lutrol® F 127 it contains causes its viscosity to increase to such an extent that it thickens to a gel with good adhesion. This feature is of particular
interest in the treatment of burns.
Table 4.8: Povidone-iodine thermo-gelling solution (10 %)
1.Formulation
I. PVP-Iodine 30/06 (BASF)
Sodium chloride
II. Lutrol® F 127
III. Sodium hydroxide solution, 1 molar
IV. Water
10.0
1.0
15.0
4.4
69.6
g
g
g
g
g
2.Procedure
Dissolve the solids (I) in water (IV), cool to about 6 °C, dissolve Lutrol ®
F 127 (II) in this and adjust the pH value with the sodium hydroxide
solution (III)
3.Properties of the gelling solution
Viscosity at room temperature
Viscosity on the skin (35–37 °C)
pH (20% in water)
4.Stability (14 days, 52 °C)
pH (20% in water)
Loss of available iodine
106
viscous solution
gel
4.8
2.5
9.7 %
4.4 Solvents
4.4.1 Low molecular weight macrogols: Lutrol ® E grades
The low-molecular-weight macrogols Lutrol ® E 300, Lutrol® E 400 and
Lutrol® E 600 are used in liquid oral and topical preparations mainly as
solvents.
They are frequently used in syrups, drops, sprays, and topical solutions with
the following active ingredients:
–
–
–
–
–
–
Acetaminophen
Clotrimazole, miconazole
Isosorbide dinitrate
Nifedipine
Nitrazepam, diazepam
Nitrofural.
Low molecular weight liquid macrogols e.g. Lutrol ® E 300 and Lutro® E 400
are occasionally used also in parenterals as solvents. In such cases, they
are often combined with nonionic solubilizers or with 1,2-propylene glycol.
The use of macrogols as solvents in injectables is not restricted to particular
groups of active substances, though diclofenac sodium, etoposide, ibuprofen
and nifedipine represent typical examples.
4.4.2 Propylene glycol
1,2-Propylene glycol is one of the few organic solvents that is still relatively
widely used in pharmaceutical formulations. In contrast to ethanol, this also
applies to preparations for oral administration.
Examples of formulations of oral solutions with 1,2-propylene glycol are
given in Tables 4.2, 4.4 and 4.9.
Also in injectables for human use 1,2-propylene glycol is almost the only
organic solvent that is still relatively frequently used. In such cases, it is
occasionally used in combination with solubilizers or with liquid macrogols.
As with the low molecular weight macrogols, its use is not restricted to any
particular active substances, but the most important groups are probably
analgesics e.g. diclofenac and piroxicam, corticoids, vitamins, and sedatives
such as diazepam and digitalis glycosides.
Typical formulations containing 1,2-propylene glycol for ampoules are given
in Tables 4.10 (vitamin B complex) and 4.15 (closantel).
1,2-Propylene glycol in concentrations above 15% has a useful side effect
in that it kills microbes.
107
4.5 Taste masking agents
Kollidon® 25, Kollidon® 30
Povidone is capable of masking the unpleasant taste of some drugs to a
certain extent, through the formation of a water-soluble complex. Kollidon ®
25 and Kollidon® 30 are particularly suitable for this purpose in oral solutions.
Typical examples of active ingredients, some of which are described in the
literature, whose unpleasant taste can be masked with povidone, include
guaifenesin, acetaminophen, trimethoprim and vitamin B formulations.
This effect is demonstrated by the formulation in Table 4.9 for an acetaminophen solution, in which the bitter taste of the drug is almost completely
masked by Kollidon® 25.
Table 4.9: Acetaminophen solution (5 % = 500 mg/10 g)
1.Formulation
Acetaminophen (Merck)
Sorbitol, crystalline
Cyclamate sodium
Strawberry flavour
Kollidon® 25
Glycerol
1,2-Propylene glycol
Water
5.0
5.0
4.0
0.1
20.0
15.0
20.0
31.0
g
g
g
g
g
g
g
g
2.Procedure
Dissolve first Kollidon 25 and then the other solid components in the
solvent mixture of glycerol, propylene glycol and water.
3.Properties of the solution
Clear solution of moderate viscosity with only a slightly bitter taste.
4.Physical stability
The solution remained clear for more than 1 week at 6 °C and for
more than 3 months at 25 °C and 40 °C. The colour of the solution
changed only slightly over 3 months at 25 °C and 40 °C.
5.Chemical stability (HPLC)
No loss of acetaminophen was found after 3 months at 40 °C.
To avoid undesirable yellowing in aqueous solutions containing Kollidon ® 25
or Kollidon® 30, it is recommended to add a stabilizer e.g. 0.5 % cysteine or
0.1 % sodium hydrogen sulphite.
108
4.6 Drug stabilizers in solutions
4.6.1 Stabilizers of active ingredients in injectables
Kollidon® 17 PF
Low molecular weight povidone, e.g. Kollidon® 17 PF can be used to stabilize
active ingredients in parenteral preparations. The mechanism of this effect
has not been elucidated, but it may involve the formation of a complex.
Concrete examples of the utilization of this stabilizing effect of Kollidon ® 17 PF
are found above all in the field of vitamins and taurolidine.
Table 4.10 gives the formulation for a vitamin B complex ampoule, in which
cyanocobalamin is stabilized by Kollidon ® 17 PF.
Table 4.10: Vitamin B complex injectable solution
1.Formulation
I. Thiamine hydrochloride
Riboflavin phosphate sodium
Nicotinamide
Pyridoxine hydrochloride
Cyanocobalamin
EDTA, disodium salt
Propyl gallate
Kollidon® 17 PF
II. Parabens
Citric acid
Sodium hydroxide solution, 1 molar
Hydrochloric acid, 0.1 molar
1,2-Propylene glycol
Water for injections
Total amount
1,100
660
4,400
440
880
20
50
10.0
160
2,270
21.6
72.0
20.0
86.4
approx. 200
mg
mg
mg
mg
µg
mg
mg
g
mg
mg
ml
ml
ml
ml
ml
2.Procedure
Dissolve mixture I in the buffer solution II, purge with nitrogen for
5 min, filter through a 0.2 µm membrane filter and fill the clear
yellow solution into ampoules of 2 ml under nitrogen. The pH is
about 4.
3.Stability (20 – 25 °C, dark)
The following losses of vitamins were determined by HPLC:
Vitamin
B1
B2
Nicotinamide
B6
B12
9 months
8%
6%
0%
9%
13 %
12 months
11 %
10 %
0%
9%
not tested
Without Kollidon® 17 PF the loss of vitamin B12 after 9 months was > 50 %.
109
4.6.2 Stabilizers of active ingredients in oral and topical solutions
Kollidon® 25, Kollidon® 30
Kollidon® 25 and Kollidon® 30 also stabilize a number of active ingredients
in aqueous oral, buccal or topical solutions. Typical active ingredients that
can be mentioned and are described in the literature in this connection are:
–
–
–
–
–
–
–
–
–
Interferon
Iodine
Isosorbide dinitrate
Methylprednisolone
Nitroglycerol
Prostaglandin
Taurolidine
Theophylline
Vitamins.
1,2-Propylene glycol
1,2-Propylene glycol is used mainly as a solvent, but it can also stabilize
certain active ingredients. The best known example is vitamin C. Results
can be found in the literature such as those in Fig. 4.2 which show that
1,2-propylene glycol has a very strong positive effect on the stability of
ascorbic acid solutions. Without 1,2-propylene glycol, the vitamin loss after
240 days is 81 % and with 50 % 1,2-propylene glycol it is less than 10 %
after the same storage time.
Vitamin content, %
100
80
60
40
20
0
Water
Propylene
glycol + Water
1+1
Propylene
glycol
Fig. 4.2 : Influence of the solvent on the stability of ascorbic acid solutions
(240 days, 22 °C)
110
The good stability of the vitamins B1 to B6 in the vitamin B complex ampoule
in Table 4.10 is most likely also due to the 1,2-propylene glycol content in
the formulation.
4.6.3 D,L-alpha-Tocopherol as antioxidant
The antioxidant D,L-alpha-tocopherol is particularly suitable for stabilizing
lipophilic substances in oily solutions and aqueous microemulsions
(= solubilizates). Vitamins A and D, and the essential fatty acids are the
main substances concerned here.
The quantities of alpha-tocopherol required are rather higher than those of
other antioxidants such as butylhydroxytoluene, but alpha-tocopherol is also
approved worldwide for use in food.
A typical example of a vitamin formulation with alpha-tocopherol as an antioxidant is given in Table 4.11 for vitamin A + E drops.
Table 4.11: Vitamin A + Vitamin E drops (25,000 I.U. + 50 mg/ml)
1.Formulation
I. Vitamin A palmitate 1.7 Mio. I.U./g. (BASF)
Vitamin E acetate (BASF)
Cremophor® RH 40
DL-alpha-Tocopherol (BASF)
II. Preservative
Water
1.5
5.0
21.0
1.0
q.s.
71.5
g
g
g
g
g
2.Procedure
Mix the vitamins with Cremophor® RH 40 (and DL-alpha-tocopherol)
at 60 °C and then add solution II (at 37 °C) slowly, with stirring.
3.Properties of the solutions
Clear, yellow, viscous liquids.
111
4.7 Enhancers of bioavailability in injectables
Solutol® HS 15, Cremophor® EL
The use of nonionic solubilizers as a means of improving the bioavailability
of active ingredients in injectables is of interest above all for lipophilic substances such as vitamins.
Fig. 4.3 compares the bioavailability of an aqueous emulsion formulation
similar to that in Table 4.7 with that of other commercially available formulations based on vegetable oils or organic solvents.
Vitamin A, found in the liver [%]
70
60
50
40
30
20
10
0
Aqueous
emulsion
Organic
solution
Oily
solution
Fig. 4.3: Bioavailability of Vitamin A in injectables after 7 days
(intramuscular application in broilers)
112
4.8 Film formers for topical aerosols
Kollicoat® IR, Kollidon® VA 64
The two film formers Kollicoat® IR and Kollidon® VA 64 described in the
Section 1.6 for soluble tablet coatings are also suitable for topical aerosols.
A typical formulation of an antiseptic wound spray with Kollicoat ® IR is given
in Table 4.12. This formulation was developed for the use as a manual pump
spray but it would also be possible to add propellents and fill it in usefull
aerosol cans.
Table 4.12: Antiseptic povidone-iodine wound spray
1.Formulation
I. PVP-Iodine 30/06 (BASF)
Kollicoat® IR
II. Ethanol 96 %
Water
10
5
43
42
g
g
g
g
2.Procedure
Dissolve the components I in the mixture II and fill in flasks for
manual pump sprays.
3.Properties of the solutions
Aspect
Viscosity
Drying on the skin
Chemical stability (1 year, rt)
brown, clear solution
low
fast, it forms a washable film
less than 10 % loss of iodine
The main application field of Kollidon® VA 64 in aerosols actually is a topical
veterinary spray of fipronil against parasits of dogs and cats.
113
4.9 Lyophilization agents
Kollidon® 12PF, Kollidon® 17PF, Kollidon® 25, Kollidon® 30
Different grades of povidone (Kollidon ® 12PF and Kollidon® 17PF for injectables and Kollidon® 25 and Kollidon® 30 for oral and topical preparations)
can also be used as lyophilizing agents. They act as a binder in the same
way as mannitol, holding the powder together during the freeze-drying
process and preventing splashing, and also as a solubilizer or suspension
stabilizer that facilitates reconstitution with the solvent prior to use by the
patient.
Table 4.13 shows the formulation for an amoxicillin lyophilizate with Kollidon ®
12 PF, taken from an old patent granted in 1979.
Table 4.13: Amoxicillin lyophylizate for injection (250 mg)
1.Formulation
Amoxicillin sodium
Kollidon® 12 PF
Water for injections
6.25 g
7.50 g
ad 100.00 ml
2.Procedure
Dissolve the active ingredient in the well stirred solution of Kollidon 12
PF in water, freeze-dry, then fill 500-mg-portions of the dry lyophilizate
into ampoules.
3.Administration
Prior to administration, mix the dry content of an ampoule with 1.9 ml
of water for injections to give a clear injection solution.
114
4.10 Sustained-release agents in veterinary parenteral solutions
Soluphor® P
There are very few sustained-release agents for parenteral use as almost all
polymers are either degraded too rapidly, or eliminated too soon if they have
a low molecular weight, or are eliminated much too slowly if they have a high
molecular weight.
In the field of veterinary medicine, 2-pyrrolidone (Soluphor ® P) has been
used successfully for many years to achieve this effect in intramuscular
injectable solutions, though at 30 – 50 %, the concentration required is
relatively high.
Table 4.14 shows, as a typical example, a formulation for an oxytetracycline
sustained-release ampoule, taken from an old patent from 1976.
Table 4.14: Oxytetracycline sustained-release injectable solution
for veterinary i.m. administration (2.2 g/10 ml)
1.Formulation
Oxytetracycline
22.65 g
Magnesium oxide
1.92 g
40.00 g
Soluphor® P
5.00 g
Kollidon® 17 PF
Sodium formaldehyde sulfoxylate
0.44 g
2-Aminoethanol
3.84 g
Water for injections
q.s. ad 100.00 ml
2.Procedure
Mix the water and the Soluphor® P, and dissolve the Kollidon® 17 PF
in the mixture. Heat the solution to 75 °C. Add the sodium formaldehyde sulfoxylate and stir until dissolved. After the magnesium oxide
has been suspended, slowly stir in the oxytetracycline until a clear
solution is obtained. After the solution has cooled, adjust to pH 8.5
with aminoethanol.
3.Remarks
High quality oxytetracycline and a complete absence of oxygen during
the manufacture and packaging of the solution are essential to obtain
a solution with acceptable chemical stability.
The reducing agent selected e.g. sodium formaldehyde sulfoxylate
must meet the regulations of the country in which it is to be used.
115
4.11 Reduction of toxicity of active ingredients
Kollidon® 12 PF, Kollidon® 17 PF
The reduction of the local toxicity of some active ingredients by complexation
with povidone is utilized not only in topical solutions with iodine, but also in
parenterals.
The best-known example of such a drug is oxytetracycline, whose local
irritating effect at the point of injection can be reduced by adding Kollidon ®
17 PF. Another example is the closantel veterinary ampoule described in
Table 4.15 in which the addition of Kollidon ® 17 PF has been demonstrated
to reduce the size of the oedema that appears around the point of injection
by 80 %.
Table 4.15: Closantel veterinary injectable solution
(12 – 20 g/100 ml)
1.Formulation
I. Closantel
II. Kollidon® 12 PF or Kollidon® 17 PF
Sodium hydroxide, 50 % in water
1,2-Propylene glycol
III. Sodium hydrogen sulfite
Water for injections
12.0 –
9.0 –
2.5 –
approx.
0.01 –
approx.
20.0
12.0
3.0
60
0.04
20
g
g
g
g
g
g
2.Procedure
Dissolve Closantel in solution II and add solution III.
Sterilize by heating to 120 °C for 20 min.
3.Properties of the solution
Clear yellow solution
4.Remarks
The function of Kollidon® 12 PF or Kollidon® 17 PF is to greatly
reduce the local side-effects (e.g. formation of oedemas) and to
increase the retention time in the tissue.
116
117
118
5. S
uspensions
(Ready-to-use suspensions, dry syrups,
instant drink granules)
5.1 Sedimentation inhibitors for oral and topical use
5.1.1 Micronized crospovidone
Kollidon® CL-M
One of the greatest problems in the development of formulations for suspensions is the prevention of sedimentation over the necessary period.
Thickeners such as cellulose derivatives are traditionally used as sedimentation inhibitors to increase the relative sediment volume. However, these
substances have the major disadvantage that by increasing the viscosity,
they make it more difficult to shake up the preparation. An alternative that
gives the same effect, but without increasing the viscosity, is therefore
preferable. Kollidon® CL-M provides this alternative as a result of its special
physical properties such as its low bulk density, its small particle size, its
relatively high specific surface area and the low viscosity of aqueous suspension of the substance. Furthermore, Kollidon ® CL-M does not reduce
the zeta potential of the active substance particles and sterically holds
them apart.
120
Viscosity, mPa·s
100
80
60
40
20
0
0
2
4
6
8
10
Kollidon® CL-M, g/100 ml
Fig. 5.1: Dynamic viscosity of amoxicillin dry syrup suspensions with different
amounts of Kollidon® CL-M
119
As can be seen from Fig. 5.1, oral amoxicillin suspensions with concentrations of Kollidon® CL-M up to 10 % can be prepared without exceeding
a viscosity of 80 mPa·s. As the usual concentrations cover a range of
5 to 8 % Kollidon® CL-M (6 % in the case of the amoxicillin dry syrup), the
change in viscosity is hardly visible. The suspensions were prepared by
shaking amoxicillin dry syrups (amoxicillin trihydrate 5 g, sodium citrate 5 g,
citric acid 2 g, sodium gluconate 5 g, sorbitol 40 g, Kollidon® CL-M 0 – 10 g,
flavours 2 g, saccharin sodium 0.4 g) with the amount of water to fill up to
the volume of 100 ml.
A other typical formulation for a low-viscosity oral suspension is the ibuprofen
suspension given in Table 5.1.
Most of the suspension formulations containing Kollidon ® CL-M as a sedimentation inhibitor, such as that in Table 5.1, contain a series of further excipients that also help to stabilize the suspension. These include Kollidon ®
90 F, sucrose and sorbitol as well as an ionic component such as sodium
citrate, that also increases the sediment volume.
Table 5.1: Ibuprofen oral suspension (4 % = 200 mg/5 ml)
1.Formulation
Ibuprofen (BASF)
Kollidon® 90 F
Sodium citrate
Sucrose
Kollidon® CL-M
Water
4.0
2.0
2.0
25.0
8.0
ad 100
g
g
g
g
g
ml
2.Procedure
Dissolve sucrose, Kollidon® 90 F and sodium citrate in about 40 ml
of water, suspend Kollidon® CL-M and ibuprofen in this solution by
stirring and add the rest of the water.
3.Physical properties of the suspension
After 1 day
Color
Relative sediment volume
Redispersibility
Viscosity
Aspect
Milky white
100 %
Not necessary
Low
Homogeneous
After 1 month (RT)
Milky white
94 %
Very easy
Low
Homogeneous
The effect on the relative sediment volume after a period of 2 weeks of varying the concentration of Kollidon® CL-M in the ibuprofen suspension described in Table 5.1 is shown in Fig. 5.2. The small sedimentation obtained
with the use of 8 % of Kollidon® CL-M can still be regarded as good, as the
low viscosity of the formulation makes redispersion easy.
120
100
Relative sediment volume, % (14 days)
80
60
40
20
0
2
4
6
10
8
®
Kollidon CL-M, %
Fig. 5.2: Influence of the amount of Kollidon ® CL-M on the sedimentation
of an ibuprofen suspension (Formulation see Table 5.1)
Table 5.2 contains a formulation for acetaminophen instant drink granules
as an example of a suspension that is prepared as required by the patient
himself. These granules for suspension in water also contain sodium citrate
and citric acid as further sedimentation inhibitors. As further benefits,
Kollidon® CL-M completely masks the bitter taste of the active substance
and stabilizes its content in the granules.
Table 5.2: Acetaminophen instant drink granules
(250 mg or 500 mg)
1.Formulation
I. Acetaminophen, fine powder
Sorbitol Instant (Merck)
Kollidon® CL-M
Aspartame
Orange aroma
Strawberry aroma
Sodium citrate
Citric acid
II. Kollidon® 90 F
Ethanol 96 %
50
130
50
7
5
5
3
3
8
50
g
g
g
g
g
g
g
g
g
g
2.Procedure (wet granulation)
Granulate mixture I with solution II, and pass through a 0.8 mm sieve.
Fill 1.3 g or 2.6 g of the free flowing granules in sachets corresponding
to 250 mg or 500 mg of acetaminophen.
3.Administration form
Suspend the content of one sachet in a glass of water.
The milky suspension has a sweet and fruity taste.
121
The use of Kollidon® CL-M as a suspension stabilizer is not limited to aqueous
systems. It also stabilizes suspensions in organic solvents such as paraffin.
Simethicone oil can also be incorporated as active ingredient in homo-geneous instant drink granules with the aid of Kollidon ® CL-M (see Table 5.9).
5.1.2 Povidone as sedimentation inhibitor for oral and topical use
Kollidon® 90 F, Kollidon® 30
Like Kollidon® CL-M, soluble polymers can also act as sedimentation inhibitors,
since, above a certain molecular weight, they do not alter the zeta potential
of the active ingredient particles.
Of the range of soluble povidones, Kollidon ® 90 F and Kollidon® 30 should
be mentioned for this application in oral and topical suspensions. Fig. 5.3
shows the effect of Kollidon® 90 F on the relative sediment volume of a oral
carbamazepine suspension (Formulation: carbamazepine 2 %, Kollidon® CL-M
7 %, 1,2-propylene glycol 10 %, water 78 – 81 %). It can be seen clearly that
even small quantities of Kollidon® 90 F are effective in reducing sedimentation.
100
Relative sediment volume after 2 days
80
60
40
20
0
0
1
2
3
®
% Kollidon 90 F
Fig. 5.3: Influence of Kollidon® 90 F on the sedimention of a carbamazepine
suspension
In some formulations, Kollidon® 30 has proved superior to Kollidon® 90 F.
This is not only because of the lower viscosity of its solutions. The sediment
formed by the oral aciclovir suspension in Table 5.3 with Kollidon ® 90 F was
too compact. However, 3 % Kollidon® 30 was determined as the optimum
for minimum sedimentation and easy redispersibility in combination with
Kollidon® CL-M.
122
Table 5.3: Aciclovir oral suspension (2 % = 200 mg/10 ml)
1.Formulation
Aciclovir
Kollidon® CL-M
Kollidon® 30
Sorbitol, crystalline
Citric acid
Preservative
Water
2.0
6.0
3.0
28.0
0.5
q.s.
60.5
g
g
g
g
g
g
2.Procedure
Suspend aciclovir and Kollidon® CL-M in the solution of the other
components with vigorous stirring
3.Properties of the solution
Color
Relative sediment volume after 14 days
Redispersibility after 14 days
white
96 %
easy
Apart from their use in ready-to-use suspensions, instant drink granules and
dry syrups, Kollidon® 25 and Kollidon® 30 can also be used to stabilize the
pigment and spray suspensions that are used for coatings. Typical examples
of this application are given in Sections 1.7 and 2.1.3.
123
5.1.3 Poloxamers as sedimentation inhibitors for oral and topical use
Lutrol® F 68, Lutrol® F 127
The two poloxamers 188 and 407 (= Lutrol® F 68 and Lutrol® F 127) can
also influence the sediment volume of a suspension. Table 5.4 gives a formulation for albendazole dry syrup. The suspension prepared by the patient by
adding water contains 1 % Lutrol® F 68.
Table 5.4: Albendazole dry syrup (200 mg/10 ml)
1.Formulation
I. Albendazole
Citric acid
Sodium citrate
Sorbitol, crystalline
II. Ethanol 96 %
Lutrol® F 68
4
3
3
88
22
2
g
g
g
g
g
g
2.Procedure (wet granulation)
Granulate mixture I with solution II, pass through a 0.8 mm screen,
dry and sieve again. Fill 50 g of the granules into a 100-ml flask.
3.Administration form
Fill the flask containing 50 g of granules with water to the 100-ml
mark. The suspension obtained has no bitter taste.
A further formulation with Lutrol® F 68 is shown in Table 5.5 in the form of
aceclofenac instant granules.
Lutrol® F 127 is recommended more for use in topical suspensions.
The use of poloxamers in suspensions is not restricted to aqueous systems.
They can also be used to stabilize oily suspensions e.g. of antibiotics in
vegetable oils.
124
5.1.4 Surfactants as sedimentation inhibitors for oral and topical use
Cremophor® RH 40, Cremophor® EL
Surfactants such as macrogolglycerol hydroxystearate 40 (= Cremophor ®
RH 40) increase the wettability of the solid particles in a suspension and
reduce the surface tension of the continuous phase. This prevents, among
other things, the flotation of the particles and reduces aggregate formation,
which increases the sediment volume.
Often even very small quantities of Cremophor ® RH 40 suffice to achieve
a stabilizing effect in a suspension. For example, calculation shows that the
suspension prepared by the patient in a glass of water of 3.9 g of the aceclofenac instant granules described in Table 5.5 contains only 0.1 – 0.2 %
Cremophor® RH 40.
Since magrogolglycerol ricinoleate (= Cremophor ® EL) has a bitter taste like
polysorbate it is less suitable for oral dosage forms but usefull for topical
forms like Cremophor® RH 40 too.
Table 5.5: Aceclofenac instant granules (50 mg)
1.Formulation (granules)
I. Aceclofenac
Orange flavour
Sorbitol, crystalline
II. Lutrol® F 68
Cremophor® RH 40
Water
1.3
4.3
85.6
4.4
4.4
about 50
g
g
g
g
g
g
2.Procedure (wet granulation)
Granulate mixture I with solution II, pass through a 0.8 mm screen,
dry and sieve again.
Fill 3.9 g in sachets corresponding to 50 mg aceclofenac.
3.Properties of the granules
Free flowing, water dispersing granules having almost no bitter taste.
The ability of Cremophor® RH 40 to improve the wettability of solid particles
in a suspension is also used in suspensions for the sugar-coating and for
film-coating of tablets.
125
5.2 Redispersing agents for oral and topical use
5.2.1 Micronized crospovidone
Kollidon® CL-M
Kollidon® CL-M not only improves the physical stability of a suspension by
slowing sedimentation and increasing the sediment volume, it also improves
its redispersibility through steric separation of the drug particles and above
all through its low viscosity. A clear distinction between the two functions of
the low bulk density product Kollidon® CL-M cannot be recognized. Tables
5.1 – 5.3, 5.6 and 5.8 – 5.10 contain typical examples of formulations in
which Kollidon® CL-M is used also as a redispersing agent.
5.2.2 Povidone
Kollidon® 90 F, Kollidon® 30
Povidone (e.g. Kollidon® 90 F or Kollidon® 30) dissolves in the continuous
phase of a suspension as a polymer, separating the drug particles without
lowering their zeta potential. Just as with Kollidon® CL-M, these two products
can act as redispersing agents by increasing the sediment volume.
Table 5.3 shows a formulation in which Kollidon® 30 is used for this purpose
in an aciclovir suspension.
Kollidon® 90 F has the same function in the formulation for the magaldrate
suspension shown in Table 5.6. Because of possible problems with microbiological stability, it may be desirable to modify the formulation to obtain an
instant syrup.
If the concentration of Kollidon® 90 F in the antacid suspension in Table 5.6
is varied, a significant change in the redispersibility of the suspension can
be observed. Fig. 5.4 illustrates this effect, showing the number of inversions
of the bottle required to obtain a homogeneous suspension, each 180° motion
taking 2 seconds. It can be seen clearly that 3 % Kollidon® 90 F is the
optimum concentration for ready redispersibility.
126
Table 5.6: Magaldrate suspension (10 %)
1.Formulation
Magaldrate USP
Kollidon® CL-M
Sucrose
Kollidon® 90 F
Orange flavour
Coconut flavour
Banana flavour
Saccharin sodium
Water
10.0
8.0
15.0
3.0
1.0
0.05
0.08
0.02
ad 100
g
g
g
g
g
g
g
g
ml
2.Procedure
Dissolve and suspend all the solids in water under aseptic conditions.
3.Properties of the suspension
No sedimentation after 24 hours
Very easy to redisperse after more than 2 weeks
Number of shakings needed
for reconstitution after 1 week
25
20
15
10
5
0
0
1
2
3
Kollidon® 90 F, %
Fig. 5.4: Influence of Kollidon® 90 F on the redispersibility of a magaldrate
suspension (Formulation see Table 5.6)
127
5.3 Sedimentation inhibitors and redispersing agents for injectables
5.3.1 Low molecular povidone
Kollidon® 12 PF or Kollidon® 17 PF
In the same way as Kollidon® 30 and Kollidon® 90 F can be used in oral
suspensions (Section 5.1.2), the two low molecular weight povidone grades,
Kollidon® 12 PF and Kollidon® 17 PF are suitable for use in parenteral suspensions. Because of their low viscosity, they are usefull in injectables as
sedimentation inhibitors and redispersing agents.
Typical examples of commercialized parenteral drug formulations in which
low molecular weight povidone is used as a suspension stabilizer include
benzylpenicillin, fluspirilen, methylprednisolon and streptomycin preparations.
Table 5.7 shows a formulation for a parenteral antibiotic suspension with
Kollidon® 12 PF.
Table 5.7: Benzylpenicillin + dihydrostreptomycin injectable
suspension (200,000 units + 200 mg/ml)
1.Formulation
I. Procaine benzylpenicillin
Dihydrostreptomycin sulfate
II. Kollidon® 12 PF
Carboxymethyl cellulose sodium
Sodium citrate
Parabens
Water for injections
20.0
20.0
0.5
0.5
0.6
q.s.
ad 100
g
g
g
g
g
ml
2.Procedure
Prepare solution II, suspend the components I in the well stirred
solution II and pass through a colloid mill.
3.Properties
A white homogeneous suspension is obtained.
5.3.2 S
urfactants as sedimentation inhibitors and redispersing
agents for injectables
Solutol® HS 15
Just as Cremophor® RH 40 can be recommended as a sedimentation inhibitor and redispersing agent in oral suspensions (Section 5.1.4), macrogol
hydroxystearate 15 (= Solutol® HS 15) is suitable for use in parenteral suspensions for the same purpose.
It gives solutions of low viscosity in water, even at high concentrations of
up to 30 %.
128
5.4 Crystallization inhibitors and solubilizers in suspensions
5.4.1 Solvent
1,2-Propylene glycol
In some suspensions, it is important to ensure that the relatively small proportion of dissolved active ingredient does not crystallize out, as this could
change the physical properties of the suspension and its stability.
1,2-Propylene glycol is a solvent that can prevent such crystallization.
The formulation for a carbamazepine suspension in Table 5.8 is a typical
example. In the presence of water, the small proportion of dissolved carbamazepine has a tendency to change into the hydrate which, however, is
less soluble and can therefore crystallize out as needles. The addition of
20 % 1,2-propylene glycol prevents this phenomenon.
Table 5.8: Carbamazepine oral suspension (2 %)
1.Formulation
Carbamazepine (Flavine)
1,2-Propylene glycol
Kollidon® 90 F
Saccharin sodium
Sodium citrate
Sorbitol, crystalline
Kollidon® CL-M
Water
2.0
20.0
3.0
0.1
1.0
25.0
7.0
41.9
g
g
g
g
g
g
g
g
2.Procedure
Stir the mixture of carbamazepine and 1,2-propylene glycol for at
least 2 hours, add Kollidon® 90 F, saccharin, sodium citrate and the
water and stir again until these components are dissolved. Dissolve
sorbitol in this mixture and add Kollidon ® CL-M to the well stirred
suspension to obtain a homogeneous suspension.
3.Properties of the suspension
After 1 day After 1 month (RT)
Colour
Milky white
Milky white
Relative sedimentation volume
100 %
98 %
Redispersibility
Not needed
Very easy
Structure of the sediment Very fine particles, Very fine particles,
no crystals
no crystals
Viscosity
Very low
Very low
129
5.4.2 Surfactants as solubilizers in suspensions
Cremophor® RH 40, Cremophor® EL
The solubilizers macrogolglycerol ricinoleate 35, macrogolglycerol hydroxystearate 40 and macrogol hydroxystearate 15 (Cremophor ® EL and Cremophor® RH40 for oral use and Solutol® HS15 for injectables) solubilize the
active ingredients not only in solutions but also in suspensions. Here, they
act in a similar manner to 1,2-propylene glycol in preventing the dissolved
part of the active ingredient from recrystallizing, stabilizing the physical
properties of the suspension.
The solubilizing effect of Cremophor® RH 40 is also used in oral and topical
suspensions for incorporating lipophilic drugs, fragrances and flavours (e.g.
menthol in Table 5.10). The formulation for simethicone instant granules in
Table 5.9 is a typical example for the solubilization and emulsification of
an active ingredient. In this case, a milk-like combination of emulsion and
suspension is obtained as soon as the patient adds the granules to water.
Table 5.9: Simethicone instant granules (60 mg and 120 mg)
1.Formulation
I. Simethicone (Abil® 200, Goldschmidt)
Cremophor® RH 40
II. Kollidon® VA 64
Ethanol
III. Sorbitol, crystalline (Merck)
Fructose (Merck)
Kollidon® CL-M
Orange flavour (Dragoco)
10.0
5.0
3.0
40.0
50.0
50.0
50.0
0.5
g
g
g
g
g
g
g
g
2.Procedure
Introduce solution II into the mixture I, granulate the powder mixture III
with the well stirred mixture I/II, dry and pass through a 1 mm sieve.
Fill 1 g or 2 g portions into sachets.
3.Properties of the granules
– Free-flowing white granules;
– 98 % coarser than 50 µm;
– Easily dispersing in water; no physical separation within 30 min.
4.Administration
Disperse the contents of one sachet (1 g = 60 mg simethicone or
2 g = 120 mg simethicone) in about 100 ml of drinking water.
130
5.4.3 Macrogols
Lutrol® E 400, Lutrol® E 600
Macrogols of low molecular weight are also used in parenteral suspensions,
and particularly in crystal suspensions. This is of interest for drugs such as
corticoids, e.g. methylprednisolone or triamcinolone and hormone derivatives, e.g. medroxyprogesterone.
131
5.5 Taste masking agents in suspensions
5.5.1 Micronized crospovidone
Kollidon® CL-M
Kollidon® CL-M not only improves the physical stability and redispersibility
of oral suspensions, it is also able to mask partly or completely the unpleasant taste of a series of active ingredients. The mechanism of this effect is
unknown, but it has been found with most formulations that a relatively
large quantity of Kollidon® CL-M is required in relation to the drug. In lowdose preparations, this presents no problems, but in high dose preparations
such as acetaminophen chewable tablets, it can be costly, and difficult to
obtain a workable formulation.
Kollidon® CL-M has proved particularly suitable for taste masking in instant
drink granules and dry syrups. Typical examples of this application are the
formulations for acetaminophen instant granules and azithromycin dry syrup
in Tables 5.2 and 5.10
Table 5.10: Azithromycin dry syrup (5 % = 500 mg/10 ml)
1.Formulation
I. Azithromycin dihydrate
Sodium citrate
Citric acid
Sucrose
Sodium cyclamate
Kollidon® CL-M
II. Ethanol
Menthol, crystalline
Cremophor® RH 40
5.0
5.0
2.0
60.0
0.5
9.0
9.0
0.5
0.3
g
g
g
g
g
g
g
g
g
2.Procedure (wet granulation)
Mixture I is granulated with solution II. The granules obtained are
passed through a 1.0 mm sieve and dried at room temperature.
Fill 83 g of the granules into a 100 ml flask.
3.Administration form
Shake 83 g of the granules with drinking water and fill the flask to the
100 ml mark. The suspension obtained has practically no bitter taste.
132
5.5.2 Poloxamer for taste masking
Lutrol F® 68
Poloxamer 188 (= Lutrol® F 68) not only acts to prevent sedimentation in oral
suspensions, it can also partly or completely mask the unpleasant taste of
a number of drugs.
The formulations for an albendazole dry syrup (Table 5.4) and aceclofenac
instant granules (Table 5.5) are typical examples of this effect.
133
5.6 Stabilizer of active ingredients in instant granules and dry syrups
Kollidon® CL-M
Reducing the susceptibility of active ingredients to oxidation and hydrolysis
contributes greatly to improving the stability of a preparation.
Owing to its enormous water-binding capacity and high surface, micronized
crospovidone Kollidon® CL-M acts as a strong desiccant in solid dosage
forms such as instant granules and dry syrups. As a result, it is able to
stabilize drugs that are susceptible to hydrolysis, and prevent chemical
reactions such as interactions between vitamins, and their oxidation.
Table 5.11: Multivitamin instant granules (2 – 4 RDA of vitamins)
1.Formulation
I. Vitamin A + D powder 250,000 + 50,000 I.U./g
CWD (BASF)
Thiamine mononitrate
Riboflavin
Nicotinamide
Pyridoxine hydrochloride
Calcium D-pantothenate
Cyanocobalamin gelatin coated 0.1 %
Ascorbic acid powder
Vitamin E acetate dry powder SD 50 (BASF)
Sucrose, finely ground
Kollidon® CL-M
Orange flavour
II. Kollidon® VA 64
Ethanol or isopropanol
200 g
26
33
110
22
150
66
1,150
210
20,000
5,000
1,000
2,000
approx. 7
g
g
g
g
g
g
g
g
g
g
g
g
l
2.Procedure (wet granulation, fluidized bed)
Pass mixture through a 0.8 mm sieve and granulate with solution II.
Fill 6 – 12 g of the free flowing granules into sachets.
3.Administration
Suspend 6 –12 g (= 1 sachet) in a glass of water corresponding
to 2 – 4 RDA of vitamins. The uniform, yellow suspension obtained
shows no sedimentation over a period of some hours.
4.Chemical stability
After storage of the granules for 1 year at room temperature, the
following vitamin contents were measured by HPLC:
Vitamin C:
94 %
All other vitamins:
> 95 %
134
The multivitamin instant granules in Table 5.11 represent an example of this
application. With the exception of vitamin C, none of the vitamins showed
any statistical loss after storage of the granules for 1 year at room temperature. Even the loss of vitamin C was only 9 %. When the same granules
were produced without Kollidon® CL-M, the losses of some vitamins were
considerable.
The acetaminophen instant granules described in Table 5.2 are a further
example of this application of Kollidon® CL-M. In an accelerated storage
test at 60 °C over 2 months, the granules were found to have not lost any
of their potency at all.
135
136
137
138
6 S
emisolid dosage forms (Gels, creams,
suppositories, transdermal systems)
6.1 Emulsifiers
Cremophor® A 6, Cremophor® A 25
The two macrogol cetostearyl ethers Cremophor® A 6 and Cremophor® A 25
are excellent emulsifiers for the manufacture of pharmaceutical and cosmetic
creams.
Even relatively small concentrations of these two Cremophor ® A grades suffice to form a stable emulsion. The best results are obtained by combining
the two products, as has been done in the formulation for a cream base
shown in Table 6.1. This formulation is suitable for a wide range of active
ingredients; they are dissolved in 1,2-propylene glycol prior to incorporation
in the cream base. Typical examples of substances that have been tested in
this formulation are betamethasone, bifonazole, clotrimazole, hydrocortisone
and miconazole.
Table 6.1: Cream base for different active ingredients
1.Formulation
I. Cetostearyl alcohol
Cremophor® A 6
Cremophor® A 25
Liquid paraffin
Parabens
II. Water
III. 1,2-Propylene glycol
Active ingredient
7.0
1.5
1.5
12.0
0.2
67.8 – 69.7
8.0
0.1 – 2.0
g
g
g
g
g
g
g
g
2.Procedure
Heat mixture I and the water II separately to about 80 °C. Add the
water II to the solution of mixture I with vigorous stirring. Heat III until
the active ingredient has dissolved, mix with I/II and continue to stir
while cooling to room temperature.
3.Properties
White cream
4.Physical stability
No change in appearance was observed after 6 weeks at 45 °C.
139
6.2 Poloxamer as gel forming agent
Lutrol® F 127
Poloxamer 407 (= Lutrol® F 127) is a gel former with special properties.
Firstly, the gels it gives are stable over a relatively wide pH range of 4–8,
and secondly, the gel formation is thermoreversible. However, it must be
mentioned that the concentrations required are quite high, and that the
gels obtained are slightly tacky.
The thermoreversibility of the gel is shown in Fig. 6.1. It has a gel structure
between 25 °C and 70 – 80 °C, and is liquid outside this range.
2500
Viscosity, mPa·s
22%
16%
20%
18%
2000
20%
18%
16%
22%
1500
1000
500
0
10
20
30
40
50
60
70
80
90
Temperature, °C
Fig. 6.1: Viscosity of gels of Lutrol® F 127 in water (Brookfield viscosimeter,
rotation 250 rpm)
The curves in Fig. 6.1 show that a concentration of at least 18 % Lutrol® F
127 is required in aqueous solutions without other additives to obtain a gel
at room temperature. There are various means of modifying these curves.
The pH has only a minor effect on the position of the curves within the
recommended limits of pH 4 – 7. However, the concentration of a number
of ions has a definite effect. The addition of 0.9 % sodium or potassium
chloride extends the curves to the right by some 10 °C, while higher
concentrations, e.g. 5 % of the same ions shifts the whole curves to the
left by 10 – 15 °C.
A formulation that takes advantage of this thermoreversibility is the thermogelling PVP-iodine solution presented in Section 4.3.2 that turns into a gel
when it is applied to the skin.
The formulation for a topical ibuprofen gel that has the desired gel structure
even at room temperature is given in Table 6.2. Further formulations with
Lutrol® F 127 as a gel former in transparent gels and in a gel cream are
given in Tables 6.3 and 6.5 – 6.7.
140
Table 6.2: Ibuprofen gel (5 %)
1.Formulation
I. Ibuprofen
Ethanol 96 %
1,2-Propylene glycol
II. Lutrol® F 127
III. Isopropyl myristate
Preservative
Water
5
10
10
15
1
q.s.
59
g
g
g
g
g
g
2.Procedure
Dissolve II in solution III at 70 °C under vacuum, cool to 40 °C and
add solution I.
3.Properties of the gel
A colourless clear gel is obtained.
4.Remark
The function of the isopropyl myristate is to reduce the tack.
141
6.3 Solubilizers in gels, creams and suppositories
Cremophor® RH 40 and Lutrol® F grades
Nonionic surfactants are also required in semisolid dosage forms to solubilize
the active ingredient. This applies in particular to transparent gels, but is
also important for creams in which the active principle must be in a dissolved or solubilized form, and not in crystalline form, for good absorption.
Because of its weak odour and good solubilizing power, macrogolglycerol
hydroxystearate 40 (= Cremophor® RH 40) is particularly suitable for this
purpose.
Table 6.3 shows the formulation for a mouth gel in which Cremophor® RH 40
solubilizes the insoluble active ingredient miconazole.
Table 6.3: Miconazole mouth gel (2%)
1.Formulation
I. Miconazole nitrate (Sigma)
Orange flavour
II. Lutrol® F 127
Cremophor® RH 40
1,2-Propylene glycol
III. Kollidon® 90 F
Saccharin sodium
Water
2.0
0.1
20.0
10.0
10.0
5.0
0.3
52.6
g
g
g
g
g
g
g
g
2.Procedure
Dissolve I in the melted mixture II. Heat solution III to 90 °C and mix
slowly with I/II. Once the air bubbles have escaped, allow to cool to
room temperature.
3.Properties of the gel
A clear, colourless, soft gel was obtained, with an orange flavour and
a slightly bitter aftertaste.
However, solubilizers are also used in suppositories to homogeneously
dissolve lipophilic active substances in a hydrophilic matrix, or to improve
their absorption.
Table 6.4 shows an example of the use of Cremophor ® RH40 in vitamin A
suppositories.
142
Table 6.4: Vitamin A suppositories (150,000 I.U.)
1.Formulation
Vitamin A palmitate 1.7 Mio I.U./g (BASF)
Vitamin A palmitate 1.7 Mio I.U./g (BASF)
Butylhydroxytoluene
Cremophor® RH 40
Macrogol 1500
Macrogol 4000
9
9
1
40
80
50
g
g
g
g
g
g
2.Procedure
Dissolve butylhydroxytoluene in the warm vitamin A, add Cremophor ®
RH 40 and mix with the molten macrogols.
Fill into moulds of suppositories to obtain the weight of 2 g.
3.Properties of the gel
Weight
Colour
Drop point
Macrogol 1500
Disintegration in water
2.0 g
Homogeneously yellow
54 °C
80 g
22 min (emulsion)
Poloxamers 188 and 407 (Lutrol® F 68 and Lutrol® F 127) can also be used
as solubilizers in semisolid dosage forms just as in oral forms (see also
Section 4.1.3).
143
6.4 Absorption enhancers in semisolid dosage forms
6.4.1 Complex formers
Kollidon® 25, Kollidon® 30, Kollidon® CL-M
In semisolid dosage forms such as suppositories, creams and transdermal
systems, medium molecular weight povidone (Kollidon ® 25, Kollidon® 30)
can be used to accelerate absorption and bioavailability.
Fig. 6.2 shows the effect of povidone on the release of phenobarbital from
suppositories in rabbits. In the first 2 hours, the blood level increases by
a factor of 3 as a result of the use of a coprecipitate of phenobarbital and
povidone, and even after 6 hours, the blood level is still twice as high as
without povidone.
25
Blood level, mg/µl
20
15
10
Without povidone
5
0
Copreciptate with
povidone (1+3)
0
2
4
6
8
10
Hours
Fig. 6.2: Absorption of phenobarbital from suppositories in rabbits
The effect that povidone can have in a formulation on the percutaneous
absorption of hydrocortisone acetate is demonstrated in Fig. 6.3. Here, the
absorption through human skin was increased several times, particularly
after 60 min, and particularly if a coprecipitate of the drug and povidone
was used.
144
Relative vasoconstriction effect
6
after 30 min
after 60 min
5
4
3
2
1
0
Without
povidone
With povidone,
phys. mixture
1+2
With povidone,
coprecipitate
1+2
Fig. 6.3: Percutaneous effect of hydrocortisone acetate on the human skin
Just as the use of povidone (e.g. Kollidon ® 30) in traditional topical dosage
forms e.g. creams to accelerate percutaneous absorption, its use for the
same purpose in transdermal systems is also possible. Descriptions of its
use with a number of drugs, for example bromhexine, captopril, diclofenac,
flurbiprofen, isosorbide dinitrate, nitroglycerin and propranolol can be found
in the pharmaceutical literature.
The micronized grade of crospovidone, Kollidon ® CL-M can also be used to
achieve a similar absorption-accelerating effect in transdermal systems. The
effect derives from the formation of a complex with the active ingredient like
in the case of povidone, as already described for oral preparations in Sections
1.4.2 and 1.4.3. A typical example of a drug to which this effect is applied
is estradiol.
145
6.4.2 Solvent as absorption enhancer
1,2-Propylene glycol
The solvent 1,2-propylene glycol has also the function as a percutaneous
absorption enhancer in semisolid dosage forms such as gels and creams
(see also Section 6.5).
This effect is described in numerous publications. Typical formulations are
gels with clotrimazole and triamcinolone. The concentration of 1,2-propylene glycol can range from 5 % to 40 %.
6.4.3 Solubilizers as absorption enhancers
Cremophor® RH 40, Lutrol® F 68
As these two substances are used to improve solubility in semisolid presentation forms (see Section 6.3), it is highly likely that they will also improve
the absorption of the solubilized active ingredients via the skin and mucous
membranes in these dosage forms.
146
6.5 Solvents in semisolid dosage forms
6.5.1 Liquid macrogols
Lutrol® E grades
In semisolid presentation forms, the low molecular weight and liquid macrogols (Lutrol® E 300, Lutrol® E 400 and Lutrol® E 600) are used as solvents
or cosolvents in the solubilization process (see also Section 4.4.1), particularly
in gels and creams.
As an example for the use of Lutrol® E 400 as a cosolvent in the solubilization
of an insoluble active substance with Cremophor ® RH 40, the formulation of
a tretinoin + dexpanthenol gel is presented in Table 6.5.
Table 6.5: Tretinoin + dexpanthenol gel (50 mg + 2,500 mg/100 g)
1.Formulation
I. Tretinoin (BASF)
Lutrol® E 400
Cremophor® RH 40
Butylhydroxytoluene
II. Water
Dexpanthenol (BASF)
III. Lutrol® F 127
50.0
5.0
6.0
40
68.4
2.5
18.0
mg
g
g
mg
g
g
g
2.Procedure
Add II slowly to the clear solution I at about 40 °C. Heat to about 50 °C
and dissolve about 4 g of III in I/II. Cool to about 6 °C and dissolve
the rest of III. Maintain at this temperature until the air bubbles have
escaped.
3.Properties of the gel
A clear yellowish gel was obtained.
4.Chemical stability (12 months, 23 °C, dark)
Tretinoin: 96 %
Dexpanthenol: 100 %
5.Remark
It is important to protect the gel from light to avoid the isomerization
and degradation of tretinoin.
147
Table 6.6 gives the formulation for a metronidazole vaginal gel that contains
40 % Lutrol® E 400 as an example for the use of this product as a solvent
for the active ingredient.
Table 6.6: Metronidazole vaginal gel (1.2%)
1.Formulation
I. Metronidazole
Lutrol® F 127
Lutrol® E 400
II. Water
1.2
21.0
40.0
37.8
g
g
g
g
2.Procedure
Heat mixture I to 70 – 80 °C and slowly add the water heated to about
70 °C. Maintain the temperature until the air bubbles have disappeared.
3.Properties of the gel
A clear colourless gel is obtained.
6.5.2 Propylene glycol
Just as in liquid dosage forms, 1,2-propylene glycol is also used in semisolid
forms to dissolve the active ingredient. With gels, this is important particularly
for their appearance. However, with both creams and gels, it is important
both for the absorption (see Section 6.4) and for the feel of the product
when it is spread on the skin that the active ingredient should be in the
dissolved form. A product that contains crystals is not at all pleasant to spread
on the skin.
For this purpose, 1,2-propylene glycol is usually diluted with water to a concentration of 5 to 25 %. Above a concentration of 15 % 1,2-propylene glycol,
one can also take advantage of its properties as a preservative.
Table 6.1 shows a typical formulation for a cream base for a wide range of
active substances in which these are dissolved in 8 % 1,2-propylene glycol.
Table 6.2 presents a transparent ibuprofen gel that contains, in addition to
ethanol, 10 % 1,2-propylene glycol as a solvent for the active substance.
148
Table 6.7 gives the formulation for a diclofenac gel cream that contains
15 % 1,2-propylene glycol as a solvent for the active ingredient.
Table 6.7: Diclofenac gel-cream (1%)
1.Formulation
Diclofenac sodium
1,2-Propylene glycol
Miglyol® 812 (Dynamit-Nobel)
Lutrol® F 127
Water
1
15
10
20
54
g
g
g
g
g
2.Procedure
Dissolve diclofenac sodium in propylene glycol, add the mixture of water and Miglyol® 812. Dissolve Lutrol® F 127 in this well stirred mixture
at 4 – 6 °C (or at > 70 °C). Maintain the temperature until the air bubbles
have escaped.
3.Properties
White, turbid gel-cream.
149
6.6 Carriers for suppositories and ovulae
Lutrol® E grades
The base for most suppositories is usually a solid mixture of fats, but often
a blend of different macrogols is also used. This is particularly the case with
vaginal ovulae.
Macrogols have the advantage that they are soluble in water, so that it is no
longer essential that the suppositories should melt at body temperature.
Also, the bioavailability of a drug can be much better from a hydrophilic
macrogol matrix than from a lipophilic carrier.
Usually, two or three grades of macrogol are mixed for this purpose, e.g.
Lutrol® E 400 or Lutrol® E 600 with solid macrogols. Typical examples of
drugs that are used in these mixtures include diphenhydramine, indomethacin,
metronidazole, acetaminophen and povidone-iodine.
Table 6.8 shows a formulation for acetaminophen suppositories.
Table 6.8: Acetaminophen suppositories (500 mg)
1.Formulation
I. Acetaminophen, fine powder
II. Lutrol® E 400
Macrogol 1500
Macrogol 4000
50.0
10.0
60.0
80.0
g
g
g
g
2.Procedure
Melt the mixture II and suspend in it. Cast the melted mass into
suppository moulds.
3.Properties of the suppositories
Weight
2.0 g
Solubility in water
readily soluble
Color
colourless
150
6.7 Bioadhesives and film-forming agents for transdermal systems
6.7.1 Povidone and copovidone
Kollidon® 30, Kollidon® 90 F, Kollidon® VA 64
Because of their excellent adhesive and film-forming properties, both povidone (e.g. Kollidon® 25, Kollidon® 30 or Kollidon® 90 F) and copovidone
(Kollidon® VA 64) are eminently suitable for use as bioadhesives and filmforming agents in transdermal and transmucosal systems, in much the
same way as described in Section 2.5 for buccal tablets for transmucosal
absorption. In many cases, povidone is also able to accelerate drug penetration (see Section 6.4.1).
The literature gives the following examples of active substances that have
been tested with povidone in this application: captopril, diclofenac, dilthiazem,
ephedrine, flurbiprofen, indomethacin, isosorbide dinitrate, promethazine,
testosterone and verapamil.
As Kollidon® VA 64 is less hygroscopic and has greater plasticity, it is often
preferable to the better-known povidone. Here too, a number of examples
of its use can be found in the literature.
6.7.2 Polyacrylate as carrier film
Kollicoat® EMM 30 D
This polyacrylic dispersion (ethyl acrylate-methyl methacrylate copolymer 2:1)
also produces films with good adhesion to the skin and can be used in
transdermal therapeutic systems (TTS).
A transdermal therapeutic system comprises various layers, a carrier film, a
matrix film containing a reservoir of active ingredient and a removable cover
film, e.g. made of aluminium. Sometimes, an intermediate adhesive layer
can be inserted between the active ingredient matrix film and the cover film
in order to improve adhesion to the skin.
As Kollicoat® EMM 30D forms neutral, adhesive and insoluble polyacrylate
films that swell in water and are to some extent permeable to water and
active ingredients, it is excellently suited to applications in TTS as an active
ingredient matrix layer. As it also contains no functional groups, there is
normally no interaction with active ingredient groups. A further advantage of
the aqueous dispersion Kollicoat® EMM 30D is that organic solvents need
not be used. In a similar way to matrix tablets, a high concentration of
active ingredient can be used.
The speed of active ingredient release from polyacrylate films is dependent
on the solubility of the active ingredient and, especially, on its concentration
in the polymer and the thickness of the polymer layer. Fig. 6.4 shows the
correlation between concentration and matrix film thickness for initial active
ingredient concentrations of 0.5 – 2.0 mg/cm 3 and film thicknesses of
151
Release rate, mg · cm-2 · d-1
100 – 500 µm based on in-vitro experiments. Should the percutaneous resorption be slower than the release from the matrix film, the skin becomes
the speed-determining factor for bioavailability. Should release from the
matrix film be too slow, resorption enhancers such as pore formers or emulsifiers can be added.
1.6
100 µm
1.2
200 µm
300 µm
0.8
400 µm
0.4
0.0
500 µm
0.5
0.75
1.0
1.25
1.5
1.75
2.0
Initial drug concentration in the film, mg/cm2
Fig. 6.4: Active ingredient release from polyacrylate films in transdermal
systems as a function of film thickness (100 – 500 µm) and active ingredient
concentration in the film
For the manufacture of matrix film containing active ingredient, the active
ingredient is suspended or dissolved in dilute aqueous Kollicoat ® EMM 30D.
If required, the viscosity can be adjusted by adding a thickener such as
Aerosil® 200 (Degussa). Alternatively, other excipients such as emulsifiers
can be added. Plasticizers are not required. The continuous manufacture
of TTS usually takes place using the so-called blade coating process. The
dispersion of active ingredient and Kollicoat ® EMM 30D is applied to the
carrier film as a product layer and dried. It is then applied to the film side
of the matrix and covered with a film (e.g. aluminium). Using this process,
matrix films up to 0.5 mm thickness can be applied.
152
153
154
7 Diagnostic products
7.1 Enzym stabilizers
Kollidon® 25, Kollidon® 30
In diagnostic and similar preparations that are used as reagents, povidone
(e. g. Kollidon® 25 or Kollidon® 30) can also be used to stabilize enzymes,
in addition to the fields of application in solid and liquid dosage forms given
in the previous sections.
The complexation of enzymes is described in detail in many publications in
the scientific literature. Table 7.1 shows a selection of enzymes that can be
stabilized with povidone.
Table 7.1: Enzymes that can be stabilized with povidone
(selection)
Asparaginase
Beta-Interferon
Catalase
Dehydrogenase
Ferrochelatase
Galactosidase
Glucose oxidase
Hyaluronidase
Peroxidase
Phenolase
Prostaglandin E
Pyruvate carboxylase
Transaminase
Urease
155
Note
The data submitted in this publication are based on our current knowledge
and experience. They do not constitute a guarantee in the legal sense of
the term and, in view of the manifold factors that may affect processing
and application, do not relieve those to whom we supply our products
from the responsibility of carrying out their own tests and experiments.
Any relevant patent rights and existing legislation and regulations must be
observed.
156
8 L
ist of BASF pharmaceutical excipients and their
pharmacopoeial monographs
Excipient
alpha-Tocopherol
Cremophor® A 6
Cremophor® A 25
Cremophor® EL
Cremophor® ELP
Cremophor® RH 40
Kollicoat® EMM 30D
Kollicoat® IR
Ph.Eur. Monograph
Tocopherol, all-rac-alpha
Macrogol cetostearyl ether 6
Macrogol cetostearyl ether 25
Macrogolglycerol ricinoleate 35
Macrogolglycerol ricinoleate 35
Macrogolglycerol hydroxystearate 40
Polyacrylate dispersion 30 per cent
Macrogol Polyvinyl alcohol grafted copolymer (published draft)
–
Kollicoat® IR White
Macrogol Polyvinyl alcohol grafted
Kollicoat® Protect
copolymer
+ Poly(vinyl alcohol)
Kollicoat® MAE 100P Methacrylic acid – Ethacrylate
copolymer 1:1 (Type B)
Kollicoat® MAE 30DP Methacrylic acid – Ethacrylate
copolymer 1:1 dispersion 30 per cent
Poly(vinyl acetate) dispersion 30 per
Kollicoat® SR 30D
cent
Povidone (nominal K-value 12)
Kollidon® 12 PF
Povidone (nominal K-value 17)
Kollidon® 17 PF
Povidone (nominal K-value 25)
Kollidon® 25
Povidone (nominal K-value 30)
Kollidon® 30
Povidone (nominal K-value 90)
Kollidon® 90 F
Crospovidone (Type A)
Kollidon® CL
Crospovidone (Type B)
Kollidon® CL-S
Crospovidone (Type B)
Kollidon® CL-SF
Crospovidone (Type B)
Kollidon® CL-M
Poly(vinyl acetate) dispersion
Kollidon® SR
30 percent
+ Povidone
Copovidone
Kollidon® VA 64
Kollidon® VA 64 Fine Copovidone
Lactose monohydrate
Ludipress®
+Povidone
+ Crospovidone
Lactose monohydrate
Ludipress® LCE
+ Povidone
Mannitol
Ludiflash®
+ Crospovidone
+ Poly(vinyl acetate) dispersion 30 %
USP-NF Monograph
Vitamin E
–
–
Polyoxyl castor oil
Polyoxyl castor oil
Polyoxyl hydrogenated castor oil
–
–
–
Methacrlyic acid
copolymer
Methacrlyic acid
copolymer dispersion
–
Povidone (nominal K-value 12)
Povidone (nominal K-value 17)
Povidone (nominal K-value 25)
Povidone (nominal K-value 30)
Povidone (nominal K-value 90)
Crospovidone
Crospovidone
Crospovidone
Crospovidone
–
Copovidone
Copovidone
Lactose monohydrate
+ Povidone
+ Crospovidone
Lactose monohydrate
+ Povidone
157
Excipient
Ph.Eur. Monograph
USP-NF Monograph
Lutrol® E 300
Lutrol® E 400
Lutrol® E 600
Lutrol® F 127
Lutrol® F 68
Lutrol® micro 127
Lutrol® micro 68
1,2-Propylene glycol
Sicovit® Iron oxides
Soluphor® P
Solutol® HS 15
Macrogols
Macrogols
Macrogols
Poloxamer 407
Poloxamer 188
Poloxamer 407
Poloxamer 188
Propylene glycol
–
Pyrrolidone
Macrogol hydroxystearate 15
Polyethylene glycols
Polyethylene glycols
Polyethylene glycols
Poloxamer 407
Poloxamer 188
Poloxamer 407
Poloxamer 188
Propylene glycol
Ferric oxide
–
–
For all excipients Technical Informations and particularly the books
“Kollidon®, Polyvinylpyrrolidone excipients for the pharmaceutical industry“,
9th edition, and “Kollicoat® grades, Functional Polymers for the Pharmaceutical Industry” are available. Most of these informations can be found
under www.pharma-solutions.basf.com.
158
9 A
lphabetical index of formulations, excipients and
technologies
Formulation/Excipient/Technology
Page
Aceclofenac instant granules
125
Acetaminophen + acetylsalicylic acid + caffeine tablets
26
Acetaminophen instant granules
121
Acetaminophen solution
108
Acetaminophen suppositories
150
Acetaminophen tablets
13, 27
Acetylsalicylic acid + vitamin C effervescent tablets
37
Acetylsalicylic acid tablets
25
Aciclovir oral suspension
123
Adhesive buccal tablets (basic formulation)
88
Aerosols
113
Albendazol dry syrup
124
Allopurinol granules (roller compaction)
15
Allopurinol tablets
15
Alpha-Bisabolol mouth wash solution
101
Alpha-Tocopherol as antioxidant
93, 111
Ambroxol sustained-release pellets
68 – 69
Ambroxol sustained-release tablets
80 – 81
Aminophylline tablets
35
Amoxicillin dry syrup
120
Amoxicillin lyophylisate for injection
114
Antioxidant effect
93, 111
Anti-tack agents
70
Azithromycin dry syrup
132
Basic cream for different active ingredients
139
Benzylpenicillin + streptomycin injectable suspension
128
Binder for direct compression
16 – 19
Binder for dry granulation (roller compaction)
14 – 15
Binder for melt extrusion
20 – 21
Binder for wet granulation
9 – 13
Bioadhesion
88, 151 – 152
Bioavailability enhancement
30 – 33, 112, 144, 146
Carbamazepine oral suspension
129
Carbamazepine sustained-release tablets
77
Closantel veterinary injectable solution
116
Coevaporation
31
Compaction see roller compaction
Complex formation
30 – 32, 100, 144 – 145
Coprecipitation
30
139
Cremophor® A grades as emulsifiers
97 – 98, 103
Cremophor® EL as solubilizer
103
Cremophor® ELP
33
Cremophor® RH 40 as dissolution/bioavailability enhancer
92, 97 – 99, 111, 142 – 143, 147
Cremophor® RH 40 as solubilizer
125, 130
Cremophor® RH 40 as suspension stabilizer
Crystallization Inhibition in suspensions
129 – 131
159
Diclofenac gel-cream
149
Diclofenac oral solution
100
Diclofenac sustained-release tablets
72
Direct compression agents
34 – 39
Disintegrant for buccal tablets
28 – 29
Disintegrant for normal tablets
22 – 25
Dissolution enhancers
30 – 33
Dry granulation (roller compaction)
14 – 15
Emulsification
139
Enteric coating of granules or pellets
66 – 67
Enteric film-coating formulation
59, 65, 67
Enteric film-coating of tablets
63 – 66
Estradiol tablets (melt extrusion)
20 – 21
Famotidine fast-disintegrating tablets
39
Fast-disintegrating buccal tablets
28 – 29, 37 – 39
Film-coating of pellets (sustained-release)
68 – 70
Film-coating of tablets (instant-release)
40 – 56
Film-coating of tablets (sustained-release)
81 – 85
Film-coating of tablets and crystals (enteric)
63 – 67
Fluidized bed granulation
9, 75 – 76
Free macrogol in solubilizers
97
Gel forming
140 – 141, 148
Gemfibrozil tablets
10
Ibuprofen gel
141
Ibuprofen oral suspension
120 –121
Instant-release film-coating formulation
42
Instant-release film-coating of tablets and capsules
40 – 54
78 – 79
Kollicoat® EMM 30D for sustained-release matrix tablets
69 – 70
Kollicoat® EMM 30D for sustained-release pellets
151 – 152
Kollicoat® EMM 30D in transdermal systems
13, 28
Kollicoat® IR as binder for wet granulation
40 – 44
Kollicoat® IR for instant-release film-coating
113
Kollicoat® IR in aerosols
40, 45 – 48
Kollicoat® IR White
59, 63 – 67
Kollicoat® MAE grades for enteric film-coating
40, 48 – 51
Kollicoat® Protect as film former
81 – 85
Kollicoat® SR 30D for sustained-release coated tablets
74 – 77, 79 – 81
Kollicoat® SR 30D for sustained-release matrix tablets
68 – 69
Kollicoat® SR 30D for sustained-release pellets
57
Kollicoat® SR 30D for taste masking
128
Kollidon® 12 PF and Kollidon® 17 PF as suspension stabilizers
114
Kollidon® 12 PF as solubilizer
114 – 116
Kollidon® 17 PF as solubilizer
155
Kollidon® 30 and Kollidon® 25 as enzym stabilizer
59, 83, 120,
Kollidon® 30 and Kollidon® 90F as suspension stabilizers
122 – 123, 126 – 127, 129
9 – 15, 20 – 21
Kollidon® 30, Kollidon® 25 and Kollidon® 90F as binder
30
Kollidon® 30 as bioavailability enhancer
100
Kollidon® 30 and Kollidon® 25 as solubilizer
108
Kollidon® 30 for taste masking
105
Kollidon® 90 F as thickener
22 – 23
Kollidon® CL as disintegrant
160
Kollidon® CL grades as dissolution/bioavailability enhancers
31 – 32
22, 26, 27
Kollidon® CL-F as disintegrant
30 – 32
Kollidon® CL-M as bioavailability enhancer
134 – 135
Kollidon® CL-M as stabilizer of active ingredients
119 – 123, 126, 127
Kollidon® CL-M as suspension stabilizer
132
Kollidon® CL-M for taste masking
22, 26 – 29
Kollidon® CL-SF as disintegrant
71 – 73
Kollidon® SR as matrix in sustained-release tablets
9 – 12, 14 – 21
Kollidon® VA 64 as binder
113
Kollidon® VA 64 as film former in aerosols
88, 151
Kollidon® VA 64 as bioadhesive
16 – 21
Kollidon® VA 64 Fine as dry binder
52 – 56
Kollidon® VA 64 for film-coating
Loperamide fast-disintegrating tablets
28
34, 37 – 39
Ludiflash® for fast-disintegrating tablets
15, 24, 25, 34, 35
Ludipress®
34, 36 – 37
Ludipress® LCE
87
Lutrol® E 400 as plasticizer
91, 107, 147
Lutrol® E grades as solvents
106, 140 – 141, 148 – 149
Lutrol® F 127 as thickener and gel former
133
Lutrol® F 68 for taste masking
32 – 33, 146
Lutrol® F grades as dissolution enhancers
101, 104, 143
Lutrol® F grades as solubilizer
124
Lutrol® F grades as suspension stabilizer
32 – 33
Lµtrol® micro 127
32 – 33
Lµtrol® micro 68
Lyophylization
114
Magaltrate oral suspension
127
Melt extrusion
20 – 21
Metronidazole vaginal gel
148
Metroprolol sustained-release coated tablets
83 – 85
Miconazole mouth gel
142
Morphine sulphate mucoadhesive tablets
88
Mucoadhesion
88
Multivitamin instant granules
134
Multivitamin syrup
99
Naproxen tablets
10
Oxytetracyclin veterinary injectable
102
Oxytetracycline sustained-release injectable (vet.)
115
Pigment
58 – 59, 94
Piroxicam tablets
24
Plastizicer
64, 86 – 87
Povidone-Iodine thermo-gelling solution
106
Povidone-Iodine wound spray
113
43 – 44, 49 – 50
Process-Parameter charts of Kollicoat® IR grades
Propranolol sustained-release tablets
75 – 76
Propylene glycol as plasticizer
59, 65, 67, 86
Propylene glycol as solvent or crystallization inhibitor
91, 107, 116, 129,
148 – 149
Propylene glycol as stabilizer of active ingredients
109 – 111
Protective film-coating formulation
51
Protective film-coating of tablets and capsules
40, 48 – 51
161
Redispersibility of suspensions
126 – 128
Roller compaction
14 – 15
Sedimentation inhibition
119 – 125, 128
58 – 59, 65, 94
Sicovit® iron oxides
Simethicone instant granules
130
Solubilization in oral dosage forms
97 – 101
Solubilization in parenteral dosage forms
102 – 104
Solubilization in topical dosage forms
97 – 101
115
Soluphor® P
103 – 104
Solutol® HS 15 as solubilizer
128
Solutol® HS 15 as suspension stabilizer
Solvent granulation
12
Stabilization of active ingredients
93, 109 – 111, 134 – 135
Stabilization of enzyms
155
Stabilization of oral suspensions
119 – 125
Stabilization of parenteral suspensions
128
Subcoating of tablets
54 – 55
Sugar coating formulation
54
Sugar coating of tablets
53 – 54
Sugar film-coating formulation of tablets
53
Sustained release in injectables
115
Sustained release in matrix tablets
71 – 81
Sustained release in pellets
68 – 70
Sustained-release film-coating of tablets
81 – 85
Taste masking by coating of crystals
57
Taste masking by tablet coating
55 – 56
Taste masking in liquids
108, 132 – 133
Theophylline sustained-release tablets
73, 78 – 79
Thickening
105 – 106
Toxicity reduction
116
Transdermal system
151 – 152
Tretinoin + dexpanthenol gel
147
Trituration
30 – 32
Verapamil speronized pellets (instant-release)
12
Vitamin A + D3 + E aqueous injectable emulsion (vet.)
104
Vitamin A + E drops
111
Vitamin A suppositories
143
Vitamin B complex injectable solution
109
Vitamin B12 coloured tablets
58
Vitamin C chewable tablets
19
Vitamin C tablets
14
Vitamin K1 injectable solution
103
Wet granulation
9 – 13
MEFM 11011 e
June 2008
Supersedes edition of April 2004
162
Printed in Germany
163
164
Pharmaceutical Technology of BASF Excipients
EMP080601e-­00
June 2008; Supersedes edition of April 2004; Printed in Germany
BASF combines cGMP-­quality manufacturing with dependable, timely delivery.
You benefit from unsurpassed technical expertise and customer-­driven innovation –
plus a customer-­service team dedicated to giving you personal advice and
assistance.
Join forces with BASF – for sustainable success through partnership
www.pharma-ingredients.basf.com
Volker Bühler
Volker Bühler
Pharmaceutical Technology of BASF Excipients
Volker Bühler
Pharmaceutical
Technology
of BASF Excipients
Pharma Ingredients & Services.
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