Professional Documents
Culture Documents
Volker Bühler
Pharmaceutical Technology of BASF Excipients
Volker Bühler
Volker Bühler
Pharmaceutical Technology
of BASF Excipients
Foreword 6
2. M
odified-release solid dosage formes
(Tablets, pellets, granules)
2.1 Enteric film-coatings 63
2.1.1 General notes 63
2.1.2 Enteric film-coating of tablets and capsules 64
2.1.3 Enteric film-coating of pellets and crystals 66
2
2.2 Sustained-release pellets 68
2.2.1 Coating with Kollicoat® SR 30D 68
2.2.2 Coating with Kollicoat® EMM 30D 69
2.3 Sustained-release tablet 71
2.3.1 Direct compression with Kollidon® SR 71
2.3.2 Wet granulation and compression to matrix tablets 74
2.3.3 Compression of sustained-release pellets 80
2.3.4 Sustained-release film-coating of tablet cores with
Kollicoat® SR 30D 82
2.4 Plasticizers 86
2.4.1 Propylene glycol 86
2.4.2 Macrogols 87
2.5 Mucoadhesives for buccal tablets 88
4. Solutions
4.1 Solubilization for oral and topical use 97
4.1.1 Surfactants: Cremophor® RH 40, Cremophor® EL 97
4.1.2 Complex formers: Kollidon® 25 and Kollidon® 30 100
4.1.3 Poloxamers: Lutrol® F68 and Lutrol® F127 101
4.2 Solubilization for parenteral use 102
4.2.1 Complex formers: Kollidon® 12PF and Kollidon® 17PF 102
4.2.2 Surfactants: Solutol® HS15 and Cremophor® ELP 103
4.2.3 Poloxamers: Lutrol® F68 104
4.3 Thickeners 105
4.3.1 High molecular povidone: Kollidon® 90 F 105
4.3.2 Poloxamer 407: Lutrol® F 127 106
4.4 Solvents 107
4.4.1 Low molecular weight macrogols: Lutrol® E grades 107
4.4.2 Propylene glycol 107
4.5 Taste masking agents 108
4.6 Drug stabilizers for solutions 109
4.6.1 Stabilizers in injectables 109
4.6.2 Stabilizers in oral and topical solutions 110
4.6.3 D, L-alpha-Tocopherol as antioxidant 111
4.7 Enhancers of bioavailability in injectables 112
4.8 Film formers for topical aerosols 113
4.9 Lyophilization agents 114
4.10 Sustained-release agents in veterinary injectables 115
4.11 Reduction of toxicity of active ingredients 116
3
5. Suspensions
5.1 Sedimentation inhibitors for oral and topical use 119
5.1.1 Crospovidone: Kollidon® CL-M 119
5.1.2 Povidone: Kollidon® 90 F, Kollidon® 30, Kollidon® 25 122
5.1.3 Poloxamers: Lutrol® F 68, Lutrol® F 127 124
5.1.4 Surfactants: Cremophor® RH 40, Cremophor® EL 125
5.2 Redispersing agents for oral and topical use 126
5.2.1 Crospovidone: Kollidon® CL-M 126
5.2.2 Povidone: Kollidon® 90 F, Kollidon® 30 126
5.3 Sedimentation inhibitors and redispersing agents for injectables 128
5.3.1 Low molecular povidone: Kollidon® 12PF or Kollidon® 17PF128
5.3.2 Surfactant: Solutol® HS15 128
5.4 Crystallization inhibitors, solubilizers 129
5.4.1 Solvent: 1,2-Propylene glycol 129
5.4.2 Surfactants: Cremophor® RH 40, Cremophor® EL 130
5.4.3 Macrogols: Lutrol® E300, Lutrol® E400 131
5.5 Taste masking agents 132
5.5.1 Crospovidone: Kollidon® CL-M 132
5.5.2 Poloxamers: Lutrol® F 68 133
5.6 Stabilizer of active ingredients in instant granules and dry syrups 134
7. Diagnostic products
7.1 Enzym stabilizers 155
4
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.
Details and descriptions of the BASF excipients can be found in the Tech-
nical 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
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
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) 457.5 g
II. Kollidon® 30 25.0 g
Water 90.0 g
III. Magnesium stearate (Merck) 2.5 g
Kollidon® CL 10.0 g
3. Tablet properties
Weight 511 mg
Diameter 12 mm
Hardness 95 N
Disintegration 3 min
Friability 0.3 %
Dissolution, pH 7.4 (10 min) 87 %
10
Table 1.2: Gemfibrozil Tablets (600 mg)
1. Formulation
I Gemfibrozil 600 g
Corn starch 200 g
Kollidon® CL 20 g
Aerosil® 200 (Degussa) 30 g
Kollidon® VA 64 40 g
II Ethanol 96 % (or water) about 72 g
III Kollidon® CL 20 g
Macrogol 6000, powder 10 g
Talc 40 g
Magnesium stearate 8 g
3. Tablet properties
Weight 950 mg
Diameter 16 mm
Hardness 151 N
Disintegration 2 min
Friability 0.7 %
Dissolution, USP (paddle), 10 min 70 %
20 min 84 %
Solvent granulation with Kollidon ® VA 64 not only has the economic advan-
tage 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
Hardness, N
80
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 hard-
ness of aminophylline tablets
1. Formulation
I Verapamil HCI (BASF) 480 g
Microcrystalline cellulose 300 g
Kollidon® VA 64 20 g
Aerosil® 200 (Degussa) 25 g
Talc 175 g
II Water 400 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
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.
1. Formulation
I. Acetaminophen crystals 500 mg
Lactose monohydrate 50 mg
II. Kollicoat® IR or Kollidon® 90F 24 mg
Water q.s.
III. Kollidon® CL 20 mg
Magnesium stearate 6 mg
3. Tablet properties
Kollicoat® IR Kollidon® 90F
Weight 617 mg 603 mg
Diameter 12 mm 12 mm
Hardness 54 N 40 N
Disintegration time 3 min 1 min
Friability <0.1 % 2%
Proportion of capped 0 % 25 %
tablets
13
1.1.3 Binders for dry granulation (roller compaction)
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 ex-
cellent physical properties in spite of the high active concentration.
1. Formulation
I. Ascorbic acid powder (BASF) 500 mg
Kollidon® 30 30 mg
II. Sorbitol, crystalline 50 mg
Macrogol 6000, powder 37 mg
Orange flavour 3 mg
Cyclamate sodium 10 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 640 mg
Diameter 12 mm
Hardness 120 N
Disintegration 6–7 min
Friability 0.1 %
Kollidon® VA 64 Fine was specially tailored for the application in roller com-
paction 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 100 g
Ludipress® 50 g
Kollidon® VA 64 Fine 10 g
Kollidon® CL 6 g
Magnesium stearate 1 g
2. Compaction conditions
Roller compactor Gerteis Type Mini-Pactor M1114
Roll width 25 mm
Compression force 2 kN/cm
Gap width 3 mm
Tamping/feeding ration 120 %
Roll speed 2 rpm
Mesh sizes 1.25 mm
After the compaction process the obtained allopurinol granules of the formu-
lation 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.
1. Formulation
Allopurinol granules obtained by roller compaction 160 mg
Ludipress® 120 mg
Magnesium stearate 0.9 mg
3. Tablet properties
Diameter 8 mm
Weight 281 mg
Hardness 246 N
Disintegration time 9 min
Friability <0.1 %
15
1.1.4 Binders for direct compression
Compress. force 25 kN
0.8
0.7
0.6
0.5
0.4
HPMC Microcryst. Povidone Kollidon®
11000 Cellulose K 30 VA 64
Fig. 1.2: Plasticity of different dry binders mixed with 0.5% of magnesium
stearate in tablets (Plasticity = plastic energy/total energy)
16
Hardness, N
190
170 15 %
150 10 %
130 5%
110
5% 10 % 15 %
90
0% 0%
70
50
Kollidon® VA 64 Kollidon® 30
17
200 hardness at 10 kN
Hardness, N
199
hardness at 18 kN
175 hardness at 25 kN
150
145
125
18
Table 1.8: Vitamin C chewable tablets (100 mg, 500 mg, 1000 mg)
1. Formulations
Ascorbic acid, powder 42.2 %
Microcrystalline cellulose 28.3 %
(e.g. Avicel® PH101, FMC)
Sucrose, powder 13.0 %
Sucrose, crystalline 8.0 %
Kollidon® VA 64 2.4 %
Cyclamate sodium 2.4 %
Macrogol 6000, powder 2.0 %
Orange flavour + strawberry flavour (2+1) 1.2 %
Aerosil® 200 (Degussa) 0.2 %
Saccharin sodium 0.1 %
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
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.
3. Tablet properties
Content of 17ß-estradiol hemihydrate 2 mg
Diameter 6 mm
Dissolution of the granules 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 disso-
lution media was 0.1 N hydrochloric acid.
20
60
17ß-Estradiol dissolved, %
Melt extruded granules with Kollidon® VA 64
17ß-Estradiol hemihydrate alone
40
20
0
0 10 20 30 40 50 60
Time, min
21
1.2 Disintegrants for normal tablets
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.
Table 1.10 gives a overview of the general properties and functions of the
three Kollidon® CL grades normally used as disintegrants in tablets.
Kollidon® CL ++ – – +/– ++
Kollidon® CL-F + + +/– + +
Kollidon® CL-SF + ++ + ++ +/–
22
1.2.2 Standard disintegrant
Kollidon® CL
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 20 g
Corn starch 150 g
Ludipress® 50 g
Kollidon® CL 8 g
Macrogol 6000, powder 10 g
Aerosil® 200 (Degussa) 1 – 2 g
3. Tablet properties
Weight 238 mg
Diameter 8 mm
Form biplanar
Hardness 66 N
Disintegration (water) 57 sec
Friability 0.1 %
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
Dissolved drug, %
100
+ 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
25
1.2.3 Special disintegrants
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 combina-
tion 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 croscarm-
ellose or carboxymethyl starch in two different analgesic tablets. In both
formulations the disintegration and the drug dissolution is faster using
Kollidon® CL grades.
1. Composition
I. Acetaminophen cryst. 250 mg
Acetylsalicylic acid cryst. 250 mg
Caffeine cryst. 50 mg
II. Kollidon® 90 F (dissolved in 2-propanol) 17 mg
III. Magnesium stearate 5 mg
Disintegrant 27 mg
26
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 disinte-
grants 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
Acetaminophen dissolved, %
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
27
1.3 Disintegrant for fast disintegrating buccal tablets
Kollidon® CL-SF
1. Formulation
I. Loperamide-HCl (Select Chemie) 2.0 mg
Mannitol powder (Roquette) 85.5 mg
Kollidon® CL-SF 4.0 mg
II. Kollicoat® IR 3.0 mg
Water 27.0 mg
III. Kollidon® CL-SF 3.0 mg
Chocolate flavour (Symrise) 1.5 mg
Sodium stearyl fumarate (JRS Pharma) 1.0 mg
3. Tablet properties
Weight 100 mg
Diameter and form 7 mm, concave
Hardness 27 N
Disintegration in water 27 sec
Friability less than 0.2 %
Dissolution (0.01 N HCl/100 rpm) 84 % after 5 min,
94 % after 10 min
Content uniformity corresponds to Ph.Eur.
28
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.
29
1.4 Enhancers of drug release
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
Dissolved indomethacin, %
100
®
60 + Kollidon 30 1+2
40
20
Indomethacin alone
0
0 30 60 90 120
Time, min
30
1.4.3 Crospovidone as enhancer of drug release
Kollidon® CL grades
31
0.5
0.3
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 crospo-
vidone
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.
32
Dissolved drug, mg/ml
6
0
0 30 60 90 120
Time, min
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.
Cremophor® RH 40
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.
33
1.5 Direct compression agents
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.
Ludipress®
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 uni-
formity of tablets even with very low dosages of the active ingredient.
34
Hardness
250
Ludipress®
200
Phys. mixture
(like Ludipress)
150
100
50
0
0 5 10 15 20 25 30 35
Compression force, kN
1. Formulation
Aminophylline powder (BASF) 100 g
Ludipress® 150 g
Magnesium stearate 2 g
Aerosil® 200 (Degussa) 2 g
3. Tablet properties
Weight 254 mg
Diameter 8 mm
Hardness 97 N
Disintegration 10 min
Friability 0.2 %
Dissolution 10 min: 87 %
15 min: 100 %
35
1.5.3 D
irect compression of lozenges, chewable, effervescent
and sustained-release tablets
Ludipress® LCE
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.
36
Table 1.16: Acetylsalicylic acid + vitamin C effervescent tablets
(400 mg + 250 mg)
1. Formulation
Acetylsalicylic acid (Synopharm) 400 g
Ascorbic acid, crystalline (BASF) 250 g
Ludipress® LCE 600 g
Citric acid, crystalline 300 g
Sodium bicarbonate 600 g
Macrogol 4000, powder 90 g
3. Tablet properties
Weight 2251 mg
Diameter 20 mm
Hardness 145 N
Disintegration 1 min 35 sec
Friability 0.66 %
Colour white
Ludiflash®
37
180 180
Hardness, N
Disintegration times, s
Hardness
150 150
Disintegration
120 120
90 90
60 60
30 30
0 0
0 5 10 15
Compression force, kN
38
Table 1.17 shows a typical formulation of fast-disintegrating famotidine tab-
lets having a disintegration time of 27 sec and a dissolution of almost 100 %
after 3 min.
1. Formulation
Famotidine (various sources) 20 g
Ludiflash® 267 g
Aerosil® 200 (Degussa) 3 g
L-Menthol 0.9 g
Aspartame 4.5 g
Sodium stearyl fumarate 4.5 g
3. Tablet properties
Weight 300 mg
Diameter 10 mm
Hardness 51 N
Disintegration (pH 7.2) 27 sec
Friability < 0.2 %
Dissolution (5 min) about 99 %
39
1.6 Instant-release and protective coatings of tablets and capsules
1. Colouring
- Increase the patient compliance
- Identification and distinction of different types of tablets.
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.
40
1.6.2 Instant-release film-coating with Kollicoat ® IR
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
Viscosity, mPa.s
4000
3000
2000
0
®
Kollicoat IR HPMC, type HPMC, type
3 mPa.s 6 mPa.s
Fig.1.14: Viscosity of Kollicoat® IR and hypromellose (20 % in water)
41
Table 1.20 shows a typical film-coating formulation of Kollicoat ® IR for tab-
lets or capsules. The viscosity of this spray suspension is below 200 mPa.s.
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.
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.
43
■ Film-coating impossible, sticking of the cores ■ Good film-coating process, surface acceptable
■ Film-coating possible, but surface not acceptable ■ Optimal film-coating process, best surface quality
■ Film-coating impossible, sticking of the cores ■ Good film-coating process, surface acceptable
■ Film-coating possible, but surface not acceptable ■ Optimal film-coating process, best surface quality
44
1.6.3 Instant-release film-coating with Kollicoat ® IR White
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.
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
Fig. 1.17: clearlyof
Dispersion illustrate the® simple
Kollicoat redispersion
IR White in water: of Kollicoat® IR White.
On account of itsstirred
1 Slightly much water
lower viscosity,
using a magnetic IR White
Kollicoat®stirrer can
prior to be processed
addition.
in spray2 Start of addition of Kollicoat IR White. than other ready-to-use
suspensions of much higher concentration
®
instant-release
3 During formulations.
the addition This greatly ®
of Kollicoat shortens the spraying and processing
IR White.
time in4the manufacture
Final homogeneous of film-coated tablets. Suspensions with a solids
suspension.
concentration of 15 – 30% can be processed without problem.
To obtain coloured coatings, water-soluble colorants or ready-made colour
The
mixes, high
e.g. elasticity®ofDry
Sepispers Kollicoat ®
(Seppic), IR can
Whitebeensures
added that it does
directly. not crack on the
However,
tablets when they are exposed to varying humidity during
colour lakes or iron oxide pigments can also be used. They must, however, storage.
be separately dispersed in water beforehand and then homogenized before
beingThe coating
added system
to the can ®
Kollicoat beIRapplied
White on all the usual coaters, e.g. horizontal drum
suspension.
coaters, fluidized bed coaters, immersion sword coaters, and coating pans,
under
Due to the the
low usual conditions
viscosity for aqueous
of aqueous solutions.
Kollicoat ® IR White suspensions (25 %
in water: about 150 mPa.s), a much higher concentration can be used than
The following
for other commerciallyconditions haveready-made
available produced good results inmixtures.
film-coating numerousThistrials:
re-
duces the spraying time considerably and hence the overall processing costs.
Inlet air temperature: 50-80°C
46 Outlet air temperature: 30-50°C
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.
Parameter Setting
Batch size 6 kg
Inlet air temperature 60 °C
Outlet air temperature 36 °C
Core temperature 35 °C
Inlet flow rate 210 m3/h
Outlet air flow rate 410 m3/h
Spray pressure 2 bar
No. nozzles 1
Spray rate 30 g/min
Spraying time, total 35 min
Subsequent drying 4 min/60 °C
Amount applied 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 hard-
ness was observed without any influence on the disintegration or dissolution.
47
Table 1.22: Blue instant-release film-coating with Kollicoat ® IR
White for 250 kg tablets (weight 250 mg, diameter 9 mm)
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.
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 concentration of solids in the spray suspension usually lies in the range
of 15 – 20 %.
49
■ Film-coating impossible, sticking of the cores ■ Good film-coating process, surface acceptable
■ Film-coating possible, but surface not acceptable ■ Optimal film-coating process, best surface quality
■ Film-coating impossible, sticking of the cores ■ Good film-coating process, surface acceptable
■ Film-coating possible, but surface not acceptable ■ Optimal film-coating process, best surface quality
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.
50
Table 1.23: Protective white film-coating with Kollicoat ® Protect
for 6 kg of acetylsalicylic acid tablets (weight 300 mg, diameter
9 mm)
2. Procedure (Method B)
Stirr the talcum and titanium dioxide into a part of the water, homo-
genize the obtained pigment suspension in a corundum disk mill
and stirr it into the polymer solution prepared with the rest of water.
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 protec-
tive 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.
51
1.6.5 Instant-release film-coating with Kollidon ® VA 64
1000
Viscosity, mPa·s
400
®
Limit (Accela Cota )
200
0
0 3 6 9 12 15 18
Polymer concentration in water, %
52
Table 1.24: Sugar film-coating with Kollidon ® VA 64
2. Preparation
Dissolve the sucrose, Kollidon® VA 64 and macrogol 4000 in the water
and suspend the other components. Pass through a colloid mill.
Kollidon® 30 or Kollidon® VA 64
Sugar coatings are particularly susceptible to cracking when they are applied
to large batches of tablet cores that are dried rapidly. As most active ingre-
dients are hydrophobic, Kollidon® VA 64 and Kollidon® 30 are useful as ad-
ditives 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.
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: 5 s
Interval: 10 min
Drying phase (warm air): 10 min
Total coating time: 16 h
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.
54
Table 1.26: Reasons for subcoating tablet cores and the function
of Kollidon® VA 64 in this application
55
Table 1.27: Taste masking film-coating with Kollicoat ® Protect for
5 kg of pseudo-ephedrine tablets (weight 300 mg, diameter 9 mm)
Content [%]
1. Formulation of spray suspension
Kollicoat® Protect 12
Talcum 6
Titanium dioxide 2
Water 80
Total 100
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.
56
1.6.9 T
aste masking by coating of granules or crystals
before tabletting
Kollicoat® SR 30 D
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
80
Released drug, %
60
Tablets from uncoated
40 crystals
57
1.7 Colorants (pigments)
Both in tablets and in tablet coatings, iron oxide pigments are finding increas-
ing 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.
1. Formulations
I. Cyanocobalamin gelatin coated 0.1 % 50.0 g
Ludipress® 150.0 g
II. Magnesium stearate 1.5 g
Sicovit® Iron oxide Yellow 10 2.0 g
Sicovit® Iron oxide Red 30 3.0 g
3. Tablet properties
Weight 209 mg
Diameter 8 mm
Hardness 80 N
Disintegration 10 min
Friability < 0.1 %
Colour homogeneous
58
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.
1. Formulation
I. Pigment suspension:
Titanium dioxide 6 g
Talc 48 g
Sicovit® Iron Oxide Red 30 6 g
Kollidon® 30 6 g
Water 120 g
II. Polymer suspension:
Kollicoat® MAE 30DP 600 g
Propylene glycol 18 g
Water 396 g
Total I + II: 1200 g
59
60
61
62
2. M
odified-release solid dosage forms
(Tablets, pellets and granules)
2.1 Enteric film-coatings with Kollicoat ® MAE grades
140
120
100
Dissolution, mg/min
80
60
40
20
0
5.3 5.4 5.5 5.6 5.7 5.8 5.9 6 6.1
pH
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 recom-
mended 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 elonga-
tion 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-form-
ing 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
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:
Kollicoat® MAE 30 DP 495.0 g
1,2-Propylene glycol 22.3 g
Water 319.4 g
Alternative II:
Kollicoat® MAE 100 P 148.5 g
1,2-Propylene glycol 22.3 g
Water 665.9 g
II. Pigment suspension:
Titanium dioxide 4.9 g
Talc 39.6 g
Sicovit® Iron Oxide Red 30 4.9 g
Water. 103.9 g
Total (I + II): 990 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.
65
100
80
Release of active ingredient, %
60
40
Uncoated tablets
20 (Phosphate buffer only)
Coated tablets
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
Gastric juice-resistant (enteric) pellets or crystals are also produced for mar-
keting 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 compo-
sition:
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 pro-
duced 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 condi-
tions 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)
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.
67
2.2 Sustained-release coating of pellets
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
80
Release of active ingredient, %
60
40
5% coating
20 10% coating
15% coating
20% coating
0
0 4 8 12 16 20 24
Time, h
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 hypro-
mellose 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 consider-
ably less than in the case of hypromellose. The fact that talcum in concen-
trations 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 com-
bining 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
70
2.3 Sustained-release tablets
Kollidon® SR
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.
100
75
Released drug (%)
50 80 mg Kollidon® SR
120 mg Kollidon® SR
25
160 mg Kollidon® SR
0
0 4 8 12 16 20 24
Time (h)
1. Formulation of tablets
Weight [g] [%]
3. Tablet properties
Diameter 8 mm
Weight 206 mg
Hardness 195 N
Friability < 0.1 %
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.
% drug released
100
80
60
40
Medium: 0.08 N HCl (0-2 h),
20 phosphate buffer pH 6.8 (2-16 h)
0
0 2 4 6 8 12 16
hours
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 sub-
stances. 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.
1. Formulation of tablets
Weight [g] [%]
3. Tablet properties
Diameter 19.0 x 8.5 mm
Weight 928 mg
Hardness 172 N
Friability < 0.1 %
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
drug release [%]
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time [h]
73
2.3.2 S
ustained-release matrix tablets obtained by wet granulation
and compression
Kollicoat® SR 30D
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 poly-
mer 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 poly-
vinyl 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 160 mg
II. Kollicoat® SR 30D 110 mg
Triethyl citrate 3 mg
III. Microcrystalline cellulose 200 mg
Magnesium stearate 2 mg
3. Tablet properties
Weight 400 mg
Diameter 11 mm
Friability < 0.1 %
Drug release see Fig. 2.9
Drug release, %
100
80
60
0
0 4 8 12 16 20 24
Time, h
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 re-
leased a little quicker. In order to compensate for this, a little more sustained-
release 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 rec-
ommended technology for sustained-release matrix tablets.
100
80
Release of active ingredient, %
60
40
Mixing granulator
20 Fluidized bed granulation
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time, h
76
Table 2.7: Carbamazepine sustained-release matrix tablets
(200 mg)
1. Formulation
I. Carbamazepine (Sintetica) 200 g
Lactose monohydrate 148 g
Kollidon® CL-M 20 g
II. Kollicoat® SR 30 D 99 g
III. Aerosil® 200 (Degussa) 2 g
Magnesium stearate 2 g
3. Tablet properties
Weight 407 mg
Diameter 11 mm
Form biconvex
Hardness 136 N
Friability < 0.1 %
Drug, dissolved, %
100
80
60
40
Medium: 0.08 N HCl (0-2 h),
20 phosphate buffer pH 6.8 (2-16 h)
0
0 4 8 12 16 20
hours
77
Kollicoat® EMM 30D
The formulations are very similar to those of Kollicoat ® SR 30D but the
quantities of Kollicoat® EMM 30 D required for the manufacture of sustained-
release 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 com-
pression force of 18 kN.
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
The amount of Kollicoat® EMM 30D required in the theophylline sustained-
release 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 theophyl-
line (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.
100
80
Release of active ingredient, %
60
40
0
0 4 8 12 16 20 24
Time, h
As tablets are the most popular and best accepted drug form, sustained-
release 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 sustained-
release 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 tech-
nology of preparing tablets from sustained-release pellets.
80
100
80
Release of active ingredient, %
60
40
20
10% coating
20% coating
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time, h
Kollicoat® SR 30D
81
Table 2.10: Elongation at break of film formers with plasticizers
(23 °C, 54 % relative humidity)
5 kg of the metoprolol tartrate cores were coated with a red spray suspen-
sion 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 film-
coating 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 sedi-
mentation 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 43.5 %
Triacetin 0.7 %
Kollicoat® IR 3.3 %
Kollidon® 30 0.5 %
Titanium dioxide 0.5 %
Sicovit® red iron oxide 0.5 %
Talcum 3.5 %
Water 47.5 %
83
100
80
Release of active ingredient, %
60
40
Uncoated cores
4 mg coating/cm2
6 mg coating/cm2
20 10 mg coating/cm2
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time, h
84
100
80
Release of active ingredient, %
60
40
Untreated tablets
After friability testing
20 Punctured tablets
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Time, h
85
2.4 Plasticizers
MFT [°C]
25
20
15
10
0
0% 10% 15%
Propylene glycol in Kollicoat® MAE
86
2.4.2 Macrogol as plasticizer
Lutrol® E 400
Liquid and solid macrogols such as Lutrol® E 400 can also be used as plasti-
cizers, 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 concen-
trations 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 Macrogol Triethyl Triacetin
glycol citrate
Fig. 2.17: Influence of different plasticizers on the tackiness of polyvinyl
acetate.
87
2.5 Mucoadhesives for buccal tablets
Table 2.12 gives basic formulations for a mucoadhesive tablet that was de-
veloped 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.
88
89
90
3. Soft gelatin capsules
3.1 Carriers, solvents
Nifedipine and temazepam are typical examples of drugs for which macro-
gols 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 ibu-
profen, cyclosporin and vitamins.
91
3.2 Solubilizers in soft gelatin capsules
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
93
3.4 Colorants in soft gelatin capsules
Though soft gelatin capsules, unlike the hard variety, are not always coloured,
the use of colorants in this sector is not unimportant.
94
95
96
4. Solutions
4.1 Solubilization for oral and topical use
Emulsifiers (macroemulsion)
Macrogol cetostearyl ether 25 25 2 – 3 %
Macrogol lauryl ether 9 9 1 – 2 %
Macrogolglycerol hydroxystearate 7 7 3 – 6 %
Solubilizers (microemulsion)
Macrogol hydroxystearate 15 15 27 – 37 %
Polysorbate 80 20 12 – 16 %
Macrogolglycerol ricinoleate 35 35 12 – 18 %
Macrogolglycerol hydroxystearate 40 40 22 – 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.
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 appli-
cation.
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) 10.0 mg
Vitamin D 40 Mio. I.U./g 0.05 mg
Vitamin E acetate (BASF) 100.0 mg
Butylhydroxytoluene 2.0 mg
Cremophor® RH 40 4.5 g
II. Water 10.0 g
III. Sucrose 45.0 g
Methylparaben 200.0 mg
Citric acid 80.0 mg
IV. Glycerol 9.6 g
Water 25.0 g
V. Thiamine hydrochloride 15.0 mg
Riboflavin 5’-phosphate sodium 15.0 mg
Nicotinamide 55.0 mg
Pyridoxine hydrochloride 15.0 mg
Ascorbic acid, crystalline 300.0 mg
Sorbic acid 100.0 mg
1,2-Propylene glycol 5.0 g
Total amount 100 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.
99
4.1.2 Complex formers
The quantity of complexing agent required depends on the type of drug in-
volved 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. amoxi-
cillin, chloramphenicol and doxycycline), analgesics (e.g. acetaminophen
and diclofenac) and particularly iodine which forms the well known povidone-
iodine complex as water soluble disinfectant.
1. Formulation
Diclofenac sodium 1.5 g
Kollidon® 30 2.5 g
Sucrose, crystalline 40.0 g
Water 56.0 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.
100
4.1.3 Poloxamers as solubilizers
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.
1. Formulations
No. 1 (= 0.2 %) No. 2 (= 0.5 %)
I. Alpha-bisabolol, natural (BASF) 0.2 g 0.5 g
Flavour q.s. q.s.
Cremophor® RH 40 2.5 g –
Lutrol® F 127 – 5.0 g
1,2-Propylene glycol – 10.0 g
Ethanol 96 % – 30.0 g
II. Glycerol 5.0 g –
Saccharin sodium 0.1 g q.s.
Preservative q.s. –
Water 92.2 g 54.5 g
2. Procedure
Heat mixture I to about 60 °C and add slowly the warm solution II
(60 °C).
101
4.2 Solubilization for parenteral use
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 par-
enterals in Europe.
Oxytetracycline-HCl 5.70 g
Kollidon® 17 PF 10.00 g
Magnesium oxide 0.46 g
Reducing agent e.g. sodium formaldehyde sulfoxylate 0.50 g
Ethanolamine q.s. (pH)
Water for injections to 100 ml
102
4.2.2 Surfactants as parenteral solubilizers
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.
1. Formulations
No. 1 No. 2
Phytomenadione 1.0 g 2.0 g
Solutol® HS 15 6.5 g 11.0 g
Preservatives q.s q.s.
Water for injections 93.0 g 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.
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.
1. Formulation
Vitamin A propionate 2.5 Mio I.U./g (BASF) 22.0 g
Vitamin D3 40 Mio. I.U./g 0.2 g
Vitamin E acetate (BASF) 5.5 g
Butylhydroxytoluene 0.5 g
Solutol® HS 15 15.0 g
Benzyl alcohol 1.0 g
Water for injections ad 100 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 separa-
tion of the phases that may have occurred. Sterilization can also be
performed by membrane filtration under pressure.
Lutrol® F 68
104
4.3 Thickeners
Kollidon 90® F
mPa·s
10000
1000
100
10
1
0 2,5 5 10 15 %
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.
1. Formulation
I. PVP-Iodine 30/06 (BASF) 10.0 g
Sodium chloride 1.0 g
II. Lutrol® F 127 15.0 g
III. Sodium hydroxide solution, 1 molar 4.4 g
IV. Water 69.6 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)
106
4.4 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.
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.
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.
107
4.5 Taste masking agents
1. Formulation
Acetaminophen (Merck) 5.0 g
Sorbitol, crystalline 5.0 g
Cyclamate sodium 4.0 g
Strawberry flavour 0.1 g
Kollidon® 25 20.0 g
Glycerol 15.0 g
1,2-Propylene glycol 20.0 g
Water 31.0 g
2. Procedure
Dissolve first Kollidon 25 and then the other solid components in the
solvent mixture of glycerol, propylene glycol and water.
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.
108
4.6 Drug stabilizers in solutions
Kollidon® 17 PF
Table 4.10 gives the formulation for a vitamin B complex ampoule, in which
cyanocobalamin is stabilized by Kollidon ® 17 PF.
1. Formulation
I. Thiamine hydrochloride 1,100 mg
Riboflavin phosphate sodium 660 mg
Nicotinamide 4,400 mg
Pyridoxine hydrochloride 440 mg
Cyanocobalamin 880 µg
EDTA, disodium salt 20 mg
Propyl gallate 50 mg
Kollidon® 17 PF 10.0 g
II. Parabens 160 mg
Citric acid 2,270 mg
Sodium hydroxide solution, 1 molar 21.6 ml
Hydrochloric acid, 0.1 molar 72.0 ml
1,2-Propylene glycol 20.0 ml
Water for injections 86.4 ml
Total amount approx. 200 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.
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
– Interferon
– Iodine
– Isosorbide dinitrate
– Methylprednisolone
– Nitroglycerol
– Prostaglandin
– Taurolidine
– Theophylline
– Vitamins.
1,2-Propylene glycol
Vitamin content, %
100
80
60
40
20
0
Water Propylene Propylene
glycol + Water glycol
1+1
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.
1. Formulation
I. Vitamin A palmitate 1.7 Mio. I.U./g. (BASF) 1.5 g
Vitamin E acetate (BASF) 5.0 g
Cremophor® RH 40 21.0 g
DL-alpha-Tocopherol (BASF) 1.0 g
II. Preservative q.s.
Water 71.5 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.
111
4.7 Enhancers of bioavailability in injectables
70
Vitamin A, found in the liver [%]
60
50
40
30
20
10
0
Aqueous Organic Oily
emulsion solution solution
112
4.8 Film formers for topical aerosols
1. Formulation
I. PVP-Iodine 30/06 (BASF) 10 g
Kollicoat® IR 5 g
II. Ethanol 96 % 43 g
Water 42 g
2. Procedure
Dissolve the components I in the mixture II and fill in flasks for
manual pump sprays.
113
4.9 Lyophilization agents
Different grades of povidone (Kollidon ® 12PF and Kollidon® 17PF for inject-
ables 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.
1. Formulation
Amoxicillin sodium 6.25 g
Kollidon® 12 PF 7.50 g
Water for injections 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.
1. Formulation
Oxytetracycline 22.65 g
Magnesium oxide 1.92 g
Soluphor® P 40.00 g
Kollidon® 17 PF 5.00 g
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 formalde-
hyde 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.
115
4.11 Reduction of toxicity of active ingredients
1. Formulation
I. Closantel 12.0 – 20.0 g
II. Kollidon® 12 PF or Kollidon® 17 PF 9.0 – 12.0 g
Sodium hydroxide, 50 % in water 2.5 – 3.0 g
1,2-Propylene glycol approx. 60 g
III. Sodium hydrogen sulfite 0.01 – 0.04 g
Water for injections approx. 20 g
2. Procedure
Dissolve Closantel in solution II and add solution III.
Sterilize by heating to 120 °C for 20 min.
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
Kollidon® CL-M
Viscosity, mPa·s
120
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 concentra-
tions 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.
1. Formulation
Ibuprofen (BASF) 4.0 g
Kollidon® 90 F 2.0 g
Sodium citrate 2.0 g
Sucrose 25.0 g
Kollidon® CL-M 8.0 g
Water ad 100 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.
The effect on the relative sediment volume after a period of 2 weeks of vary-
ing the concentration of Kollidon® CL-M in the ibuprofen suspension de-
scribed 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
Relative sediment volume, % (14 days)
100
80
60
40
20
0
2 4 6 8 10
®
Kollidon CL-M, %
1. Formulation
I. Acetaminophen, fine powder 50 g
Sorbitol Instant (Merck) 130 g
Kollidon® CL-M 50 g
Aspartame 7 g
Orange aroma 5 g
Strawberry aroma 5 g
Sodium citrate 3 g
Citric acid 3 g
II. Kollidon® 90 F 8 g
Ethanol 96 % 50 g
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.
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.
80
60
40
20
0
0 1 2 3
®
% Kollidon 90 F
122
Table 5.3: Aciclovir oral suspension (2 % = 200 mg/10 ml)
1. Formulation
Aciclovir 2.0 g
Kollidon® CL-M 6.0 g
Kollidon® 30 3.0 g
Sorbitol, crystalline 28.0 g
Citric acid 0.5 g
Preservative q.s.
Water 60.5 g
2. Procedure
Suspend aciclovir and Kollidon® CL-M in the solution of the other
components with vigorous stirring
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
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 formu-
lation for albendazole dry syrup. The suspension prepared by the patient by
adding water contains 1 % Lutrol® F 68.
1. Formulation
I. Albendazole 4 g
Citric acid 3 g
Sodium citrate 3 g
Sorbitol, crystalline 88 g
II. Ethanol 96 % 22 g
Lutrol® F 68 2 g
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.
124
5.1.4 Surfactants as sedimentation inhibitors for oral and topical use
1. Formulation (granules)
I. Aceclofenac 1.3 g
Orange flavour 4.3 g
Sorbitol, crystalline 85.6 g
II. Lutrol® F 68 4.4 g
Cremophor® RH 40 4.4 g
Water about 50 g
125
5.2 Redispersing agents for oral and topical use
Kollidon® CL-M
5.2.2 Povidone
Kollidon® 90 F, Kollidon® 30
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 microbio-
logical stability, it may be desirable to modify the formulation to obtain an
instant syrup.
126
Table 5.6: Magaldrate suspension (10 %)
1. Formulation
Magaldrate USP 10.0 g
Kollidon® CL-M 8.0 g
Sucrose 15.0 g
Kollidon® 90 F 3.0 g
Orange flavour 1.0 g
Coconut flavour 0.05 g
Banana flavour 0.08 g
Saccharin sodium 0.02 g
Water ad 100 ml
2. Procedure
Dissolve and suspend all the solids in water under aseptic conditions.
20
15
10
0
0 1 2 3
Kollidon® 90 F, %
127
5.3 Sedimentation inhibitors and redispersing agents for injectables
Kollidon® 12 PF or Kollidon® 17 PF
1. Formulation
I. Procaine benzylpenicillin 20.0 g
Dihydrostreptomycin sulfate 20.0 g
II. Kollidon® 12 PF 0.5 g
Carboxymethyl cellulose sodium 0.5 g
Sodium citrate 0.6 g
Parabens q.s.
Water for injections ad 100 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
128
5.4 Crystallization inhibitors and solubilizers in suspensions
5.4.1 Solvent
1,2-Propylene glycol
1. Formulation
Carbamazepine (Flavine) 2.0 g
1,2-Propylene glycol 20.0 g
Kollidon® 90 F 3.0 g
Saccharin sodium 0.1 g
Sodium citrate 1.0 g
Sorbitol, crystalline 25.0 g
Kollidon® CL-M 7.0 g
Water 41.9 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.
129
5.4.2 Surfactants as solubilizers in suspensions
1. Formulation
I. Simethicone (Abil® 200, Goldschmidt) 10.0 g
Cremophor® RH 40 5.0 g
II. Kollidon® VA 64 3.0 g
Ethanol 40.0 g
III. Sorbitol, crystalline (Merck) 50.0 g
Fructose (Merck) 50.0 g
Kollidon® CL-M 50.0 g
Orange flavour (Dragoco) 0.5 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.
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
131
5.5 Taste masking agents in suspensions
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 unpleas-
ant 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 low-
dose 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
1. Formulation
I. Azithromycin dihydrate 5.0 g
Sodium citrate 5.0 g
Citric acid 2.0 g
Sucrose 60.0 g
Sodium cyclamate 0.5 g
Kollidon® CL-M 9.0 g
II. Ethanol 9.0 g
Menthol, crystalline 0.5 g
Cremophor® RH 40 0.3 g
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
1. Formulation
I. Vitamin A + D powder 250,000 + 50,000 I.U./g 200 g
CWD (BASF)
Thiamine mononitrate 26 g
Riboflavin 33 g
Nicotinamide 110 g
Pyridoxine hydrochloride 22 g
Calcium D-pantothenate 150 g
Cyanocobalamin gelatin coated 0.1 % 66 g
Ascorbic acid powder 1,150 g
Vitamin E acetate dry powder SD 50 (BASF) 210 g
Sucrose, finely ground 20,000 g
Kollidon® CL-M 5,000 g
Orange flavour 1,000 g
II. Kollidon® VA 64 2,000 g
Ethanol or isopropanol approx. 7 l
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 tempera-
ture. 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.
135
136
137
138
6 S
emisolid dosage forms (Gels, creams,
suppositories, transdermal systems)
6.1 Emulsifiers
Cremophor® A 6, Cremophor® A 25
1. Formulation
I. Cetostearyl alcohol 7.0 g
Cremophor® A 6 1.5 g
Cremophor® A 25 1.5 g
Liquid paraffin 12.0 g
Parabens 0.2 g
II. Water 67.8 – 69.7 g
III. 1,2-Propylene glycol 8.0 g
Active ingredient 0.1 – 2.0 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
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.
Viscosity, mPa·s
2500
22%
16%
2000 20%
18%
20%
18%
1500 16%
22%
1000
500
0
10 20 30 40 50 60 70 80 90
Temperature, °C
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.
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 5 g
Ethanol 96 % 10 g
1,2-Propylene glycol 10 g
II. Lutrol® F 127 15 g
III. Isopropyl myristate 1 g
Preservative q.s.
Water 59 g
2. Procedure
Dissolve II in solution III at 70 °C under vacuum, cool to 40 °C and
add solution I.
4. Remark
The function of the isopropyl myristate is to reduce the tack.
141
6.3 Solubilizers in gels, creams and suppositories
Table 6.3 shows the formulation for a mouth gel in which Cremophor® RH 40
solubilizes the insoluble active ingredient miconazole.
1. Formulation
I. Miconazole nitrate (Sigma) 2.0 g
Orange flavour 0.1 g
II. Lutrol® F 127 20.0 g
Cremophor® RH 40 10.0 g
1,2-Propylene glycol 10.0 g
III. Kollidon® 90 F 5.0 g
Saccharin sodium 0.3 g
Water 52.6 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.
142
Table 6.4: Vitamin A suppositories (150,000 I.U.)
1. Formulation
Vitamin A palmitate 1.7 Mio I.U./g (BASF) 9 g
Vitamin A palmitate 1.7 Mio I.U./g (BASF) 9 g
Butylhydroxytoluene 1 g
Cremophor® RH 40 40 g
Macrogol 1500 80 g
Macrogol 4000 50 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.
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
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.
20
15
10
Without povidone
5 Copreciptate with
povidone (1+3)
0
0 2 4 6 8 10
Hours
144
6
Relative vasoconstriction effect after 30 min after 60 min
5
0
Without With povidone, With povidone,
povidone phys. mixture coprecipitate
1+2 1+2
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.
145
6.4.2 Solvent as absorption enhancer
1,2-Propylene glycol
146
6.5 Solvents in semisolid dosage forms
Lutrol® E grades
In semisolid presentation forms, the low molecular weight and liquid macro-
gols (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.
1. Formulation
I. Tretinoin (BASF) 50.0 mg
Lutrol® E 400 5.0 g
Cremophor® RH 40 6.0 g
Butylhydroxytoluene 40 mg
II. Water 68.4 g
Dexpanthenol (BASF) 2.5 g
III. Lutrol® F 127 18.0 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.
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.
1. Formulation
I. Metronidazole 1.2 g
Lutrol® F 127 21.0 g
Lutrol® E 400 40.0 g
II. Water 37.8 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.
For this purpose, 1,2-propylene glycol is usually diluted with water to a con-
centration 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.
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.
1. Formulation
Diclofenac sodium 1 g
1,2-Propylene glycol 15 g
Miglyol® 812 (Dynamit-Nobel) 10 g
Lutrol® F 127 20 g
Water 54 g
2. Procedure
Dissolve diclofenac sodium in propylene glycol, add the mixture of wa-
ter 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.
1. Formulation
I. Acetaminophen, fine powder 50.0 g
II. Lutrol® E 400 10.0 g
Macrogol 1500 60.0 g
Macrogol 4000 80.0 g
2. Procedure
Melt the mixture II and suspend in it. Cast the melted mass into
suppository moulds.
150
6.7 Bioadhesives and film-forming agents for transdermal systems
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.
Kollicoat® EMM 30 D
151
100 – 500 µm based on in-vitro experiments. Should the percutaneous re-
sorption 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 emul-
sifiers can be added.
1.6 100 µm
1.2 200 µm
Release rate, mg · cm-2 · d-1
300 µm
0.8
400 µm
0.4
500 µm
0.0
0.5 0.75 1.0 1.25 1.5 1.75 2.0
Initial drug concentration in the film, mg/cm2
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
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
157
Excipient Ph.Eur. Monograph USP-NF Monograph
Lutrol® E 300 Macrogols Polyethylene glycols
Lutrol® E 400 Macrogols Polyethylene glycols
Lutrol® E 600 Macrogols Polyethylene glycols
Lutrol® F 127 Poloxamer 407 Poloxamer 407
Lutrol® F 68 Poloxamer 188 Poloxamer 188
Lutrol® micro 127 Poloxamer 407 Poloxamer 407
Lutrol® micro 68 Poloxamer 188 Poloxamer 188
1,2-Propylene glycol Propylene glycol Propylene glycol
Sicovit® Iron oxides – Ferric oxide
Soluphor® P Pyrrolidone –
Solutol® HS 15 Macrogol hydroxystearate 15 –
158
9 A
lphabetical index of formulations, excipients and
technologies
Formulation/Excipient/Technology Page
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
Kollicoat® EMM 30D for sustained-release matrix tablets 78 – 79
Kollicoat® EMM 30D for sustained-release pellets 69 – 70
Kollicoat® EMM 30D in transdermal systems 151 – 152
Kollicoat® IR as binder for wet granulation 13, 28
Kollicoat® IR for instant-release film-coating 40 – 44
Kollicoat® IR in aerosols 113
Kollicoat® IR White 40, 45 – 48
Kollicoat® MAE grades for enteric film-coating 59, 63 – 67
Kollicoat® Protect as film former 40, 48 – 51
Kollicoat® SR 30D for sustained-release coated tablets 81 – 85
Kollicoat® SR 30D for sustained-release matrix tablets 74 – 77, 79 – 81
Kollicoat® SR 30D for sustained-release pellets 68 – 69
Kollicoat® SR 30D for taste masking 57
Kollidon® 12 PF and Kollidon® 17 PF as suspension stabilizers 128
Kollidon® 12 PF as solubilizer 114
Kollidon® 17 PF as solubilizer 114 – 116
Kollidon® 30 and Kollidon® 25 as enzym stabilizer 155
Kollidon® 30 and Kollidon® 90F as suspension stabilizers 59, 83, 120,
122 – 123, 126 – 127, 129
Kollidon® 30, Kollidon® 25 and Kollidon® 90F as binder 9 – 15, 20 – 21
Kollidon® 30 as bioavailability enhancer 30
Kollidon® 30 and Kollidon® 25 as solubilizer 100
Kollidon® 30 for taste masking 108
Kollidon® 90 F as thickener 105
Kollidon® CL as disintegrant 22 – 23
160
Kollidon® CL grades as dissolution/bioavailability enhancers 31 – 32
Kollidon® CL-F as disintegrant 22, 26, 27
Kollidon® CL-M as bioavailability enhancer 30 – 32
Kollidon® CL-M as stabilizer of active ingredients 134 – 135
Kollidon® CL-M as suspension stabilizer 119 – 123, 126, 127
Kollidon® CL-M for taste masking 132
Kollidon® CL-SF as disintegrant 22, 26 – 29
Kollidon® SR as matrix in sustained-release tablets 71 – 73
Kollidon® VA 64 as binder 9 – 12, 14 – 21
Kollidon® VA 64 as film former in aerosols 113
Kollidon® VA 64 as bioadhesive 88, 151
Kollidon® VA 64 Fine as dry binder 16 – 21
Kollidon® VA 64 for film-coating 52 – 56
Loperamide fast-disintegrating tablets 28
Ludiflash® for fast-disintegrating tablets 34, 37 – 39
Ludipress® 15, 24, 25, 34, 35
Ludipress® LCE 34, 36 – 37
Lutrol® E 400 as plasticizer 87
Lutrol® E grades as solvents 91, 107, 147
Lutrol® F 127 as thickener and gel former 106, 140 – 141, 148 – 149
Lutrol® F 68 for taste masking 133
Lutrol® F grades as dissolution enhancers 32 – 33, 146
Lutrol® F grades as solubilizer 101, 104, 143
Lutrol® F grades as suspension stabilizer 124
Lµtrol® micro 127 32 – 33
Lµtrol® micro 68 32 – 33
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
Process-Parameter charts of Kollicoat® IR grades 43 – 44, 49 – 50
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
Sicovit® iron oxides 58 – 59, 65, 94
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
Soluphor® P 115
Solutol® HS 15 as solubilizer 103 – 104
Solutol® HS 15 as suspension stabilizer 128
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 Printed in Germany
162
163
164
Pharmaceutical Technology of BASF Excipients
June 2008; Supersedes edition of April 2004; Printed in Germany
EMP080601e-00
Volker Bühler
Pharmaceutical Technology of BASF Excipients
Volker Bühler
Volker Bühler