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Komplett Pharmaceutical Technology PDF
Komplett Pharmaceutical Technology PDF
EMP080601e-00
June 2008; Supersedes edition of April 2004; Printed in Germany
Volker Bhler
Volker Bhler
Pharmaceutical Technology of BASF Excipients
Volker Bhler
Pharmaceutical
Technology
of BASF Excipients
Pharma Ingredients & Services.
Welcome to more opportunities.
Volker Bhler
Pharmaceutical Technology
of BASF Excipients
Contents
Page
Foreword
1.1
1.2
1.3
1.4
1.5
1.6
1.7
Binders
1.1.1 General notes
1.1.2 Binders for wet granulation
1.1.3 Dry granulation (roller compaction)
1.1.4 Direct compression
1.1.5 Melt extrusion
Disintegrants for normal tablets
1.2.1 General notes
1.2.2 Standard disintegrant: Kollidon CL
1.2.3 Special disintegrants: Kollidon CL-F, Kollidon CL-SF
Disintegrant for fast disintegrating buccal tablets
Enhancers of drug release
1.4.1 General notes
1.4.2 Povidone: Soluble Kollidon grades
1.4.3 Crospovidone: Kollidon CL grades
1.4.4 Poloxamers
1.4.5 Solubilizers: Cremophor RH 40
Direct compression agents
1.5.1 General notes
1.5.2 Normal tablets with Ludipress
1.5.3 Lozenges, chewable, effervescent and sustained-release
tablets with Ludipress LCE
1.5.4 Fast disintegrating tablets with Ludiflash
Instant-release and protective coatings of tablets and capsules
1.6.1 General notes
1.6.2 Instant-release film-coating with Kollicoat IR
1.6.3 Instant-release film-coating with Kollicoat IR White
1.6.4 Protective film-coating with Kollicoat Protect
1.6.5 Instant-release film-coating with Kollidon VA 64
1.6.6 Traditional sugar coating
1.6.7 Subcoatings of tablet cores
1.6.8 Taste masking by coatings of tablets
1.6.9 Taste masking by coatings of granules or crystals before
tabletting
Colorants (pigments)
9
9
9
14
16
20
22
22
23
26
28
30
30
30
31
32
33
34
34
34
36
37
40
40
41
45
48
52
53
54
55
57
58
2. M
odified-release solid dosage formes
(Tablets, pellets, granules)
2.1
Enteric film-coatings
2.1.1 General notes
2.1.2 Enteric film-coating of tablets and capsules
2.1.3 Enteric film-coating of pellets and crystals
63
63
64
66
2.2
2.3
2.4
2.5
Sustained-release pellets
2.2.1 Coating with Kollicoat SR 30D
2.2.2 Coating with Kollicoat EMM 30D
Sustained-release tablet
2.3.1 Direct compression with Kollidon SR
2.3.2 Wet granulation and compression to matrix tablets
2.3.3 Compression of sustained-release pellets
2.3.4 Sustained-release film-coating of tablet cores with
Kollicoat SR 30D
Plasticizers
2.4.1 Propylene glycol
2.4.2 Macrogols
Mucoadhesives for buccal tablets
3.
3.1
3.2
3.3
3.4
Carriers, solvents
Solubilizers
Antioxidants
Colorants
4.
Solutions
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
4.10
4.11
68
68
69
71
71
74
80
82
86
86
87
88
91
92
93
94
97
97
100
101
102
102
103
104
105
105
106
107
107
107
108
109
109
110
111
112
113
114
115
116
5.
Suspensions
5.1
5.2
5.3
5.4
5.5
5.6
6.
6.1
6.2
6.3
6.4
6.5
6.6
6.7
7.
Diagnostic products
7.1
Enzym stabilizers
139
140
142
144
144
146
146
147
147
148
150
151
151
151
155
157
9.
159
Alphabetical index
Foreword
This book describes the wide range of applications and functions of the
excipients manufactured by BASF SE for the pharmaceutical industry.
The spectrum of applications is remarkably broad, as can already be seen
from the list of contents. It covers many fields of application in solid dosage
forms such as instant-release and controlled-release tablets, applications
in liquid dosage forms as solutions, suspensions and dry syrups, as well
as many functions in semisolid dosage forms.
In addition to the applications given here, there are a number of minor
speciality areas of lesser importance.
Details and descriptions of the BASF excipients can be found in the Technical Informations for the products concerned and in the books Kollidon,
Polyvinylpyrrolidone excipients for the pharmaceutical industry and
Kollicoat Grades, Functional Polymers for the Pharmaceutical Industry.
Both books are available on request at BASF SE.
Most of the formulations given here have been taken form the Generic Drug
Formulations compendium also available on request.
The 3rd edition was actualized and revised by the inclusion of new excipients
such as Kollicoat IR grades, Kollidon CL-F, Kollidon CL-SF, Kollidon
VA 64 Fine and Ludiflash, by the inclusion of new technologies such as
melt extrusion and of several new formulations.
Wet granulation
Dry granulation (roller compaction)
Melt extrusion
Direct compression
Kollicoat IR would also be capable of acting as a binder in the wet granulation technology.
Direct compression excipients that contain a binder, such as Ludipress
grades or Ludiflash play an increasingly important role in the production
of generic products.
The sustained-release matrix bases Kollidon SR and Kollicoat SR 30D
also demonstrate strong binding properties in tablets.
1.1.2 Binders for wet granulation
Kollidon 25, Kollidon 30, Kollidon 90 F, Kollidon VA 64
The three grades of povidone, Kollidon 25, Kollidon 30 and Kollidon 90 F,
as well as copovidone (Kollidon VA 64) are very suitable for wet granulation,
whether the granulation of the active ingredient with a binder solution or the
granulation of a mixture of the active ingredient and binder with the solvent
only (usually water). The most widely used methods of wet granulation are
the following:
Quantities of 25% of the tablet weight are required in the case of Kollidon
25, Kollidon 30 and Kollidon VA 64, but only 13% 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.
457.5
25.0
90.0
2.5
10.0
g
g
g
g
g
511
12
95
3
0.3
87
mg
mm
N
min
%
%
10
Formulation
Gemfibrozil
600
Corn starch
200
20
Kollidon CL
30
Aerosil 200 (Degussa)
40
Kollidon VA 64
Ethanol 96% (or water) about 72
20
Kollidon CL
Macrogol 6000, powder
10
Talc
40
Magnesium stearate
8
g
g
g
g
g
g
g
g
g
g
950
16
151
2
0.7
70
84
mg
mm
N
min
%
%
%
Solvent granulation with Kollidon VA 64 not only has the economic advantage that it is not necessary to dissolve the binder. It is particularly suitable
if the capacity of the powder to be granulated is too small for the quantity
of solvent that would be necessary to dissolve the binder.
11
80
Hardness, N
75
70
Kollidon VA64
65
60
Kollidon 30
55
50
12
14
18
22
26
30
34
38
Amount of water, ml
Aminophylline 100 g, Starch 100 g, Kollidon 6 g, Mg stearate 1.5 g
Fig. 1.1: Solvent granulation: Influence of the amount of water on the hardness of aminophylline tablets
Kollidon 25, Kollidon 30, Kollidon 90 F and Kollidon VA 64 can also
be used to produce pellets and granules by wet granulation. The spheronization of a verapamil drug pellet formulation is described in Table 1.3 as
an example.
Table 1.3: Verapamil spheronized pellets (48%)
1.
I
II
Formulation
Verapamil HCI (BASF)
Microcrystalline cellulose
Kollidon VA 64
Aerosil 200 (Degussa)
Talc
Water
480
300
20
25
175
400
g
g
g
g
g
g
2. Procedure
Granulate the mixture (I) in a Diosna granulator with water (II) and
pass the moist granules through a sieve of 1.5 mm. Pelletize in a
spheronizer at a speed of 300400 rpm. Dry the pellets in a fluidized
bed and pass over a 0.7 mm sieve to remove the fines.
12
Formulation
Acetaminophen crystals
Lactose monohydrate
Kollicoat IR or Kollidon 90F
Water
Kollidon CL
Magnesium stearate
500
50
24
q.s.
20
6
mg
mg
mg
mg
mg
Kollicoat IR
617 mg
12 mm
54 N
3 min
<0.1 %
0 %
Kollidon 90F
603 mg
12 mm
40 N
1 min
2%
25 %
13
500
30
50
37
3
10
mg
mg
mg
mg
mg
mg
2. Procedure
Pass mixture I through a roller compactor, mix with the components II
and press to tablets with low to medium compression force
3. Tablet properties
Weight
Diameter
Hardness
Disintegration
Friability
640
12
120
67
0.1
mg
mm
N
min
%
Kollidon VA 64 Fine was specially tailored for the application in roller compaction and is the material of choice in terms of particle size distribution
and particle shape for this application. Due to the particle size it is able to
cover a big surface area and to form numerous bridges in the tablet structure
that lead to hard tablets with a reduced friability.
The formulations of allopurinol granules and tablets shown in Tables 1.6 and
1.7 are typical examples for a formulation using this technique with about
3.5 % of Kollidon VA 64 Fine in the final tablets.
14
100
50
10
6
1
g
g
g
g
g
After the compaction process the obtained allopurinol granules of the formulation of Table 1.6 were blended for 10 minutes with the tabletting excipients
Ludipress and magnesium stearate mentioned in Table 1.7 and pressed to
tablets of about 100 mg of active ingredient.
Table 1.7: Allopurinol tablets prepared with compacted allopurinol
granules from Table 1.6
1.
Formulation
Allopurinol granules obtained by roller compaction 160 mg
120 mg
Ludipress
Magnesium stearate
0.9 mg
Tablet properties
Diameter
Weight
Hardness
Disintegration time
Friability
8
281
246
9
<0.1
mm
mg
N
min
%
15
Plasticity
Compress. force 18 kN
0.8
0.7
0.6
0.5
0.4
HPMC
11000
Microcryst.
Cellulose
Povidone
K 30
Kollidon
VA 64
Fig. 1.2: Plasticity of different dry binders mixed with 0.5% of magnesium
stearate in tablets (Plasticity = plastic energy/total energy)
Kollidon VA 64 grades have a more irregular particle structure than Kollidon
25 or Kollidon 30. The finer particle size of Kollidon VA 64 Fine and the
structure are the principal explanations why Kollidon VA 64 grades give
harder tablets in the direct compression that povidone (see Fig. 1.3) although
in the binder solution granulation there is no difference.
Kollidon VA 64 and Kollidon VA 64 Fine can be used as dry binders
together with all fillers and practically all active ingredients. A mixture with
microcrystalline cellulose has been found to be a particularly effective
combination. The usual concentration of Kollidon VA 64 grades used in
the direct compression of tablets is 2 8 %, though this can be increased
considerably, as, unlike many other binders like povidone, its binding effect
continues to increase with the concentration even beyond 5 %, which is
reflected in the tablet hardness. Fig. 1.3 illustrates this effect in ascorbic
acid tablets.
16
Hardness, N
190
170
15 %
150
10 %
5%
130
110
90
5%
0%
10 %
15 %
0%
70
50
Kollidon VA 64
Kollidon 30
17
Hardness, N
200
hardness at 10 kN
hardness at 18 kN
hardness at 25 kN
199
175
150
145
125
100
107
75
71
50
25
0
102
88
86
64
58
48
38
35
21
without
Binder
21
Kollidon
VA 64
82
82
59
Kollidon
VA 64 Fine
Povidone
K 30
24
HPMC
6 mPas
HPC
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 %
2.4 %
Kollidon VA 64
Cyclamate sodium
2.4 %
Macrogol 6000, powder
2.0 %
Orange flavour + strawberry flavour (2+1) 1.2 %
0.2 %
Aerosil 200 (Degussa)
Saccharin sodium
0.1 %
19
10.0 %
50.0 %
40.0 %
8.3
45.6
45.6
0.5
3. Tablet properties
Content of 17-estradiol hemihydrate
Diameter
Dissolution of the granules
%
%
%
%
2 mg
6 mm
see Fig. 1.5
Fig. 1.5 shows the almost 20-fold increase of the dissolution for the melt
extruded 17-estradiol granules produced with Kollidon VA 64. The dissolution media was 0.1 N hydrochloric acid.
20
17-Estradiol dissolved, %
60
Melt extruded granules with Kollidon VA 64
17-Estradiol hemihydrate alone
40
20
0
0
10
20
30
40
50
60
Time, min
21
Kollidon
Kollidon
Kollidon
Kollidon
CL:
CL-F:
CL-SF:
CL-M:
90
20
10
3
130
40
30
10
m
m
m
m
Kollidon CL is the usual disintegrant for normal tablets, Kollidon CL-F and
Kollidon CL-SF can be used as disintegrants for special cases and the
micronized type Kollidon CL-M is mainly applied as stabilizer in liquid dosage
forms like suspensions, instant drink granules and dry syrups.
Crospovidone is referred to as one of the super disintegrants in the literature
but it is also an excellent agent for the enhancement of the drug release
(see Section 1.4.3). The Kollidon CL grades can be used for all tabletting
technologies like granulation, direct compression etc..
Table 1.10 gives a overview of the general properties and functions of the
three Kollidon CL grades normally used as disintegrants in tablets.
Table 1.10: Comparison of general properties of Kollidon CL
grades used as disintegrants
Product
Disintegration Mouthfeel Smooth tablet Adsorption
Drug
power
surface
of granulation dissolution
liquid
Kollidon CL
Kollidon CL-F
Kollidon CL-SF
22
++
+
+
+
++
+/
+
+/
+
++
++
+
+/
23
20
150
50
8
10
1 2
g
g
g
g
g
g
238 mg
8 mm
biplanar
66 N
57 sec
0.1 %
24
100
Dissolved drug, %
+ 3 % Kollidon CL
80
60
40
20
Without Kollidon CL
0
0
10
20
30
40
50
60
Time, min
Disintegration time of both formulations: max. 4 min
25
250
250
50
17
5
27
mg
mg
mg
mg
mg
mg
26
Acetaminophen dissolved, %
100
80
60
40
Kollidon CL
Kollidon CL-F
Kollidon CL-SF
20
Croscarmellose
Caroxymethyl starch
0
0
10
20
30
40
50
60
Time, min
27
2.0
85.5
4.0
3.0
27.0
3.0
1.5
1.0
mg
mg
mg
mg
mg
mg
mg
mg
28
100 mg
7 mm, concave
27 N
27 sec
less than 0.2 %
84 % after 5 min,
94 % after 10 min
corresponds to Ph.Eur.
Due to its interesting properties Kollidon CL-SF also forms a part of a new
direct compression agent (Ludiflash) developed as direct compression
agent for the production of fast disintegrating buccal tablets (see Section
1.5.4). It is a preparation of mannitol, Kollidon CL-SF and polyvinyl acetate.
Furthermore Kollidon CL-SF shows the strongest ability of all Kollidon CL
grades to adsorb water or ethanol.
29
80
+ Kollidon 30 1+2
60
40
20
Indomethacin alone
0
0
30
60
90
120
Time, min
30
31
0.5
Medroxyprogesterone acetate
+ crospovidone (1 + 6)
0.4
0.3
0.2
Medroxyprogesterone acetate
alone
0.1
0
0
30
60
90
120
Time, min
32
0
0
30
60
90
Time, min
120
33
Type of tablet
Normal tablets
Ludipress
Ludipress LCE Lozenges, chewable tablets, effervescent tablets
sustained-release tablets
Fast disintegrating buccal tablets
Ludiflash
34
250
Hardness
Ludipress
200
Phys. mixture
(like Ludipress)
150
100
50
0
0
10
15
20
25
30
Compression force, kN
35
100
150
2
2
g
g
g
g
mg
mm
N
min
%
%
%
35
1.5.3 D
irect compression of lozenges, chewable, effervescent
and sustained-release tablets
Ludipress LCE
Ludipress LCE is a direct compression agent based on 96.5% lactose
monohydrate and 3.5% of Kollidon 30 as binder. It does not contain any
disintegrant and is therefore suitable for all tablets of slow disintegration
(lozenges, chewable and sustained-release tablets) or which contains an
other system of disintegration like effervescent tablets.
Beside of the function as filler, flowability agent and binder Ludipress LCE
can be suitable as pore former in sustained-release matrix tablets of insoluble
active ingredients to adjust its release.
Both Ludipress grades have a particle structure (see Fig. 1.12) that gives
them excellent flow properties, and their concentration in tablets is often
fairly high, they are also effective flow improvers.
36
400
250
600
300
600
90
g
g
g
g
g
g
2251 mg
20 mm
145 N
1 min 35 sec
0.66 %
white
37
Hardness
150
Disintegration
150
120
120
90
90
60
60
30
30
Disintegration times, s
Hardness, N
180
180
0
0
10
15
Compression force, kN
38
Table 1.17 shows a typical formulation of fast-disintegrating famotidine tablets having a disintegration time of 27 sec and a dissolution of almost 100 %
after 3 min.
20
267
3
0.9
4.5
4.5
g
g
g
g
g
g
300
10
51
27
< 0.2
about 99
mg
mm
N
sec
%
%
39
Type
Main function/application
Polymer
Kollicoat IR
Kollicoat IR White
Ready to mix
preparation
Polymer mixture
Kollicoat Protect
Polymer
Kollidon VA 64
40
Viscosity, mPa.s
Fig. 1.14 shows the viscosity of 20% solutions in water of Kollicoat IR and
two hypromellose types used for instant-release film-coating. The viscosity
of Kollicoat IR solution is much lower than the usual limit of 250 mPa.s to
pass well the nozzle of about 0.8 mm.
5000
4000
3000
2000
1000
0
Usual limit
of the nozzle
Kollicoat IR
HPMC, type
3 mPa.s
HPMC, type
6 mPa.s
41
Table 1.20 shows a typical film-coating formulation of Kollicoat IR for tablets or capsules. The viscosity of this spray suspension is below 200 mPa.s.
Proportion [%]
20.8
55.0
7.2
3.0
1.5
12.5
2. Procedure
Stirr the talc and the pigments vigorously into the water, homogenize
the obtained suspension in a corundum disk mill and stirr it into the
polymer solution.
3. Coating conditions (Accela cota 24, Manesty)
Inlet air temperature
60 C
Outlet air temperature
40 C
Cores temperature
35 C
Air flow
180 m3/h
Spray pressure
3 bar
Spray rate
30 g/min
Spraying time
20 min
Final drying
4 min, 60 C
Quantity applied
3 mg polymer/cm2
The tablets of propranolol or caffeine coated with the formulation given in
Table 1.20 had got a smooth and brillant surface without any polishing.
All other physical properties like hardness, friability, disintegration and dissolution were not changed in a significant manner by the coating and after
the storage at different conditions.
In the pharmaceutical industry today the question of production cost, including
that of coatings, is constantly being raised. In the case of the pure material
costs the difference between coating with Kollicoat IR grades and hypromellose is so small that it can be practically neglected for comparative purposes. However, production costs are a different matter.
42
With Kollicoat IR, the production of the polymer solution is simpler, and
hence a little cheaper, than is the case with hypromellose; however, the
decisive cost factor is the film-coating process and this is practically entirely
dependent on the solid concentration of the spray suspension. In the case
of Kollicoat IR, this concentration is about 20% and hence substantially
higher than in the case of hypromellose (about 12%). This means that the
spray time, and hence the cost, can be considerably reduced. In addition,
the temperatures that can be achieved with cores comprising the Kollicoat
IR grades are substantially higher than with hypromellose.
In order to demonstrate this, extensive comparison studies were done in
an Accela-Cota 24 (Manesty) to develop Process-Parameter-Charts.
The influence of product temperature and processing time on the aspect of
the coated tablets and the processing behaviour were detemined.
Four groups of results were classified in these studies:
- Class 1 (red area): The film-coating process is not possible with the
chosen settings. Cores stick to the drum or are overwetted.
- Class 2 (orange area): The film-coating process is principly possible,
but the surface of the coated tablets is not acceptable.
- Class 3 (light green area): The film-coating process is possible and
the surface of the coated tablets is acceptable.
- Class 4 (dark green area): The film-coating process is possible and
the surface of the coated tablets is optimal.
The Process-Parameter-Charts of Kollicoat IR and HPMC (3 mPa.s) shown
in Fig.1.15 and Fig. 1.16 demonstrate clearly that a very robust process
with short process times (about 50 min) can be achieved with Kollicoat IR.
Since in the case of HPMC (3 mPa.s) the green areas are much more limited the minimal process time is much longer (at least about 100 min) and
the transfer from a pilot to production scale is not so easy. In the case of
HPMC (6 mPa.s) the process time is even longer than for HPMC (3 mPa.s).
43
44
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
The figures
clearlyof
illustrate
the simple
redispersion
Fig. 1.17:
Dispersion
Kollicoat
IR White
in water: of Kollicoat IR White.
IR White
can
processed
On account
of itsstirred
much water
lower viscosity,
Kollicoatstirrer
1 Slightly
using a magnetic
prior
to be
addition.
in spray
suspensions
of
much
higher
concentration
2 Start of addition of Kollicoat IR White. than other ready-to-use
instant-release
greatly
shortens
the spraying and processing
IR White.
3 During formulations.
the addition This
of Kollicoat
time in4the
manufacture
of film-coated
tablets. Suspensions with a solids
Final
homogeneous
suspension.
concentration of 15 30% can be processed without problem.
To obtain coloured coatings, water-soluble colorants or ready-made colour
The
high
elasticityofDry
Kollicoat
IR can
White
it does
not crack on the
(Seppic),
beensures
added that
directly.
However,
mixes,
e.g.
Sepispers
tablets
when
they
are
exposed
to
varying
humidity
during
storage.
colour lakes or iron oxide pigments can also be used. They must, however,
be separately dispersed in water beforehand and then homogenized before
coating
system
can
beIRapplied
all the usual coaters, e.g. horizontal drum
White on
suspension.
beingThe
added
to the
Kollicoat
coaters, fluidized bed coaters, immersion sword coaters, and coating pans,
IR White suspensions (25%
under
conditions
for aqueous
solutions.
Due to
the the
low usual
viscosity
of aqueous
Kollicoat
in water: about 150 mPa.s), a much higher concentration can be used than
The following
conditions
haveready-made
produced good
results inmixtures.
numerousThis
trials:
for other
commercially
available
film-coating
reduces the spraying time considerably and hence the overall processing costs.
Inlet air temperature:
50-80C
Outlet
air
temperature:
30-50C
46
Atomizing pressure:
2-4 bar
Temperature of spray suspension:
20-70C
Table 1.21: Machine settings for the white film-coating of acetylsalicylic acid cores with Kollicoat IR White (Accela Cota 24")
Parameter
Setting
6 kg
60 C
36 C
35 C
210 m3/h
410 m3/h
2 bar
1
30 g/min
35 min
4 min/60 C
5 mg solid/cm2
Batch size
Inlet air temperature
Outlet air temperature
Core temperature
Inlet flow rate
Outlet air flow rate
Spray pressure
No. nozzles
Spray rate
Spraying time, total
Subsequent drying
Amount applied
The physical properties of the acetylsalicylic acid tablets were not changed
significantly by the coating process. Only a slight increase of the tablet hardness was observed without any influence on the disintegration or dissolution.
For the coloured film-coating of cores with Kollicoat IR White a typical
formulation of the spray suspension and the machine settings are given
in Table 1.22 for the scale of 250 kg of cores. This particular production
run is somewhat more complex than for a simple white suspension as the
insoluble indigotin-aluminium colour lake first has to be suspended and
homogenized (e.g. using a high-speed mixer) before being added to the
Kollicoat IR White suspension.
47
Proportion [%]
18.8
60.6
1.2
19.4
2. Procedure
Stirr the colour lake vigorously into the water, homogenize the
obtained suspension in a corundum disk mill and stirr it into
the polymer suspension.
3. Coating conditions (Driacoater 900, Driam)
Inlet air temperature
70 C
Outlet air temperature
45 C
Cores temperature
47 C
Air flow
4600 m3/h
Spray pressure
4 bar
No. nozzles
6
Spray rate
700 g/min
Spraying time
60 min
Final drying
5 min, 60 C
Quantity applied
3 % solids
48
49
Weight [g]
Proportion [%]
125.40
52.25
31.35
836.00
1045.00
12
5
3
80
100
2. Procedure (Method B)
Stirr the talcum and titanium dioxide into a part of the water, homogenize the obtained pigment suspension in a corundum disk mill
and stirr it into the polymer solution prepared with the rest of water.
3. Coating conditions (Accela Cota 24, Manesty)
Inlet air temperature
60 C
Outlet air temperature
36 C
Cores temperature
35 C
Inlet air flow
210 m3/h
Outlet air flow
410 m3/h
Spray pressure
2 bar
No. nozzles
1
Spray rate
30 g/min
Spraying time
35 min
Final drying
4 min, 60 C
Quantity applied
5 mg solids/cm2
The coated acetylsalicylic acid tablets obtained had a white, glossy coating
that covered the engravings on the tablet surface excellently. The physical
properties of acetylsalicylic acid tablets were hardly affected by the protective coating; however, there was an small increase in hardness. The release
curve is also practically identical to that of identical cores coated with
Kollicoat IR.
Hydrolysis of acetylsalicylic acid in the tablets coated with Kollicoat Protect
was investigated over a period of 6 months under various storage conditions
(25 C/60% and 30 C/70% relative humidity). In the case of the Kollicoat
Protect coating, a significant smaller amount of free salicylic acid was determined than with a coating of Kollicoat IR White or without any coating.
To obtain coloured film-coatings with Kollicoat Protect the same formulation
as given in Table 1.23 could be used adding an iron oxide or a colour lake
to the pigment suspension.
51
Viscosity, mPas
1000
800
Hypromellose alone
Hypromellose +
Kollidon VA 64 (4+6)
600
400
200
0
12
15
18
52
5.0
1.2
45
36
0.8
15
2.0
50
4
kg
kg
C
C
mm
rpm
bar
min
mg/cm2
53
5
10
10
16
s
min
min
h
54
Table 1.26: Reasons for subcoating tablet cores and the function
of Kollidon VA 64 in this application
Reasons for subcoating
tablet cores
Function of Kollidon VA 64
Presence of high-performance
disintegrants
Improvement in adhesion of
subsequent coatings by hydrophilization of the surface
Content [%]
12
6
2
80
100
C
C
C
m3/h
bar
g/min
min, 60 C
mg solids/cm2
The effect of taste masking was tested subjectively; a tablet was placed in
the mouth and the time noted for the first bitter taste to occur. The results
shown in Table 1.28 show that a coating of 20 mg/cm 2 is adequate to mask
the taste for more than one minute.
Table 1.28: Taste masking effect of Kollicoat Protect on
pseudoephedrine tablets
Amount of coating used
56
Without coating
10 mg/cm2
15 mg/cm2
20 mg/cm2
sec.
sec.
sec.
sec.
1.6.9 T
aste masking by coating of granules or crystals
before tabletting
Kollicoat SR 30 D
The alternative to the coating of tablets of active ingredients with an unpleasant taste is the coating of the crystals or granules of such active substance
before tabletting. For this purpose the film-former Kollicoat SR 30 D could
be used. As this polyvinyl acetate polymer is insoluble in water, the optimum
quantity and the composition of the formulation must be determined very
carefully, to minimize the delay in drug release, though this delay can be
reduced to some extent by adding hydrophilic polymers (e.g. Kollidon 30)
or surfactants.
Acetaminophen crystals, for example, have a bitter taste, but if 300 g of
these crystals are coated with an dispersion of 150 g Kollicoat SR 30 D
and 33.7 g Kollidon 30 in 210 g water in a fluidized bed granulator until
the resulting granules are coated with 15% polyvinyl acetate and 11%
Kollidon 30, the bitter taste is masked for more than 2 minutes.
Even after these acetaminophen granules are compressed into tablets with
a little of microcrystalline cellulose, drug release is not much slower than
from the uncoated substance (Fig. 1.21). Similar results were obtained with
ibuprofen.
100
Released drug, %
80
60
Tablets from uncoated
crystals
40
20
0
0
10
20
30
min
40
50
60
57
50.0
150.0
1.5
2.0
3.0
g
g
g
g
g
58
209 mg
8 mm
80 N
10 min
< 0.1 %
homogeneous
g
g
g
g
g
g
g
g
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
2.1.1 General notes
The copolymer products Kollicoat MAE 30 DP and Kollicoat MAE 100 P
based on methacrylic acid and ethylacrylate only dissolve at pH values of
5.5 and above, and are used for enteric film-coatings for tablets, pellets,
granules and capsules. Both the aqueous dispersion, Kollicoat MAE 30 DP
and the powder, Kollicoat MAE 100 P can be processed easily in water,
are impermeable to protons, ions and water, and have low hygroscopicity.
It is not necessary to cure the tablets or capsules after coating.
The dissolution in water in dependence of the pH is identical for both Kollicoat
MAE grades. It is shown in Fig. 2.1 that the dissolution starts at ph 5.5.
140
120
Dissolution, mg/min
100
80
60
40
20
0
5.3
5.4
5.5
5.6
5.7
5.8
5.9
6.1
pH
more compatible with other excipients and less sensitive about shearing
forces in comparison with the commercial dispersion Kollicoat MAE 30DP
which is not partly neutralized.
As the Kollicoat MAE copolymer has a very low plasticity, always it is recommended to add a plasticizer like 1,2-propylene glycol or triethyl citrate. Fig. 2.2
shows the influence of different triethyl citrate concentrations on the elongation at break of this polymer. Most coating formulations with Kollicoat MAE
grades given in this book contains about 15% of 1,2-propylene glycol as
plasticizer. The influence of 1,2-propylene glycol on the minimum film-forming temperature (MFT) of Kollicoat MAE is shown in Section 2.4.1.
Elongation at break, %
14
12
10
8
6
4
2
0
10%
15%
20%
Triethyl citrate in the Kollicoat MAE polymer
Fig. 2.2: Influence of triethyl citrate on the elongation of the Kollicoat MAE
copolymer
2.1.2 Enteric film-coating of tablets and capsules
To obtain enteric tablets that meet the requirements of the pharmacopoeias
(insoluble for 2 h at pH 1 and readily soluble at pH 6.8), the tablet cores
should generally be coated with a amount of 3 6 mg solids/cm 2.
A typical formulation of acetylsalicylic acid tablets coated with Kollicoat
MAE grades and the machine settings for an Accela Cota 24 (Manesty)
are given in Table 2.1. In this formulation, the 495 g of Kollicoat MAE 30
DP can be replaced directly with the equivalent quantity of 148.5 g of the
powder product, Kollicoat MAE 100 P plus the missing quantity of water
contributed by the polymer dispersion.
64
g
g
g
g
g
g
g
g
g
g
g
2. Procedure
I. Mix 1,2-propylene glycol with water and stir in Kollicoat MAE
30DP or suspend Kollicoat MAE 100 P in 665 g of water, stir
for 2 3 hours and add the propylene glycol.
II. Suspend the pigments and talc in 103 g of well stirred water
and homogenize in a disk mill or in a colloid mill.
Add the pigment suspension II to the well stirred polymer suspension I.
Stir the spray suspension obtained throughout the coating process.
3. Coating conditions (Accela Cota 24, Manesty)
Inlet air temperature
50 C
Outlet air temperature
37 C
Core temperature
32 C
Spray rate
40 g/min
Spray pressure
2.0 bar
Spraying time (continuous)
30 min
Quantity of solids applied
3 4 mg/cm2
3 mg of solids/cm2 of the spray formulation as described in Table 2.1 were
sprayed onto 5 kg of cores. Subsequently, the release of active ingredient
from the coated tablets was determined after 2 hours of immersion in synthetic gastric juice and then in synthetic intestinal fluid and compared with
that of uncoated cores in synthetic intestinal fluid only. Fig 2.3 shows that
the tablets were fully gastric juice-resistant and that active ingredient release
from the tablets after changing the medium was almost as fast as from the
uncoated cores.
65
100
0.1 N HCI
80
60
40
Uncoated tablets
(Phosphate buffer only)
Coated tablets
20
0
30
60
90
120
10
15
20
25
30
35 40
Time, min
Fig. 2.3: Release of acetylsalicylic acid from tablets coated with Kollicoat
MAE grades compared with uncoated cores
Kollicoat MAE 100 P can also be applied in the form of a non-aqueous
system, i.e. a solution in organic solvents such as a mixture of ethanol
or 2-propanol and acetone.
2.1.3 Enteric coating of pellets and crystals
Gastric juice-resistant (enteric) pellets or crystals are also produced for marketing as hard gelatine capsules; these are filled into the capsules. The main
difference in comparison to the enteric coating of tablets is the needed total
amount of gastroresistent polymer. This is explained by the higher surface of
pellets and even higher surface of crystals. In the case of crystals the weight
increase can be until 30% of solids. In the following example of diclofenac
pellets about 20% of coating solids was applied. For this application test,
uncoated diclofenac drug pellets were produced with the following composition:
Sodium diclofenac 10%, Kollidon VA64 2.5%, microcrystalline cellulose
43.7%, lactose monohydrate 43.7%. The pellets, rendered spherical, had
a diameter of 0.8 1.2 mm.
The spray suspensions containing both Kollicoat MAE grades were produced in the composition shown in Table 2.2 with a solid content of 22 %
and a polymer content of 15 %. The indicated amounts and coating conditions were designed for coating 5 kg of pellets in a Kugelcoater of Httlin.
66
g
g
g
g
g
g
g
g
g
g
g
2. Procedur
I. Mix 1,2-propylene glycol with water and stir in Kollicoat MAE
30DP or suspend Kollicoat MAE 100 P in water, stir for
2 3 hours and add the propylene glycol.
II. Suspend the pigments and talc in the well stirred solution of
Kollidon 30 and homogenize in a disk mill or in a colloid mill.
Add the pigment suspension II to the well stirred polymer suspension I.
Stir the spray suspension obtained throughout the coating process.
3. Coating conditions (Kugelcoater HKC 5 TJ, Httlin)
Inlet air temperature
60
Outlet air temperature
32-35
Spray rate
45
Spraying time (continuous)
100
Quantity of solids applied
3
C
C
g/min
min
mg/ cm2
67
800 g
68
100
80
60
40
5% coating
10% coating
15% coating
20% coating
20
12
16
20
24
Time, h
effect is not so strongly reduced but its influence on tackiness is considerably less than in the case of hypromellose. The fact that talcum in concentrations normally used has practically no effect on the sustained-release
effect explains why it is the most widely used anti-tack agent. The effect of
talcum can be enhanced in the case of Kollicoat EMM 30D films by combining with simethicon.
Microcryst.
Cellulose
Hypromellose
Talc
(+ simethicone)
Concentration of antiadhesive
Sustained release effect
Tackiness
Fig. 2.5: Effect of some anti-tack agents in pellet coating formulations with
Kollicoat EMM 30 D
Kollicoat EMM 30 D is processed for the sustained-release pellet coating
by the same methods as Kollicoat SR 30 D. Plasticizers are never required.
Also for this application drug pellets or drug layered nonpareilles can be used.
70
100
75
50
80 mg Kollidon SR
120 mg Kollidon SR
25
160 mg Kollidon SR
0
0
12
16
20
24
Time (h)
Weight [g]
[%]
100.0
100.0
3.4
3.4
48.4
48.4
1.6
1.6
8
206
195
< 0.1
mm
mg
N
%
The release profile of diclofenac sodium of the tablets of Table 2.4 was not
completely 24 hours as shown in Fig. 2.7. The main reason was the relative
fine particle size of the active ingredient used in this formulation.
100
% drug released
80
60
40
Medium: 0.08 N HCl (0-2 h),
phosphate buffer pH 6.8 (2-16 h)
20
0
0
6
hours
12
16
72
Weight [g]
[%]
500
200
225
3
53.9
21.6
24.2
0.3
19.0 x 8.5
928
172
< 0.1
mm
mg
N
%
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
80
60
40
20
0
0
10
12
14
16
18
20
22
24
time [h]
2.3.2 S
ustained-release matrix tablets obtained by wet granulation
and compression
Kollicoat SR 30D
In contrast to Kollidon SR, Kollicoat SR 30D is an aqueous dispersion of
27% polyvinyl acetate and 2.7% Kollidon 30. It is intended not for direct
compression, but for wet granulation of sustained-release matrix tablets or
for film-coatings. In the case of sustained-release tablets, the minimum
quantity of matrix former required is generally much less than with Kollidon
SR, as it does not contain 20% of the pore former Kollidon 30.
In this technology, the active ingredient, with or without filler, is granulated
with Kollicoat SR 30D and, subsequent to the addition of further excipients
like extragranular fillers and/or lubricants, compressed to matrix tablets with
controlled-release properties. When using standard amounts of polyvinyl
acetate of 5 30% in the granules, a matrix structure is formed on compression that encloses the particles of active ingredient. Subsequent to
penetration of gastric juice or intestinal fluid into the matrix, the active ingredient is slowly dissolved; it then diffuses through the matrix at a controlled
speed.
Like in the case of Kollidon SR the drug release of tablets produced with
Kollicoat SR 30D is completely independent on the pH and on the ionic
strength of the dissolution medium. An other important property of this polymer is its plasticity which avoids any influence of the tabletting compression
force on the drug release. This is demonstrated in Fig. 2.9 by means of
a tablet of the active ingredient propranolol hydrochloride. The dissolution of
propranolol-HCl before tabletting and after tabletting applying low, medium
and high compression forces did not show any significant difference.
The needed amount of Kollicoat SR 30 D for the sustained release of
20 24 hours depends mainly on the solubility of the active ingredient.
Its particle size also can have an influence but it is not so strong as in the
case of direct compression with Kollidon SR. The usual amounts of polyvinyl acetate in the granules lies in the range of 5 15% for sparingly soluble
or insoluble active ingredients and 15 30% for soluble or very soluble
active substances. Table 2.6 shows as a typical example of a soluble active
ingredient that for propranolol hydrochloride only about 16% of polyvinyl
acetate are required in the granules as a proportion of the active ingredient
which represents about 8% of the finished tablet.
74
160
110
3
200
2
mg
mg
mg
mg
mg
400 mg
11 mm
< 0.1 %
see Fig. 2.9
The sustained release of the propranolol-HCl tablets of Table 2.6 is demonstrated in Fig. 2.9. There is neither an influence of the tabletting process
nor an influence of the compression force in the range of 5 to 25 kN. The
granules before tabletting gave almost the same release profile as the final
tablets.
100
Drug release, %
80
60
40
20
0
0
12
16
20
Time, h
24
Fig. 2.9: Influence of the compression forces on the release of propranololHCl matrix tablets (formulation see Table 2.6)
75
100
80
60
40
Mixing granulator
Fluidized bed granulation
20
10
12
14
16
18
20
22 24
Time, h
Fig. 2.10: Influence of granulation technology on the release of propranololHCl sustained-release matrix tablets with Kollicoat SR 30D
The next example of a sustained-release matrix tablet with Kollicoat SR
30D is given in Table 2.7 and based on the insoluble active ingredient
carbamazepine. In this case about 7% polyvinyl acetate is used in the
granules and final tablets.
76
200
148
20
99
2
2
g
g
g
g
g
g
407 mg
11 mm
biconvex
136 N
< 0.1 %
100
Drug, dissolved, %
80
60
40
Medium: 0.08 N HCl (0-2 h),
phosphate buffer pH 6.8 (2-16 h)
20
0
0
12
16
20
hours
77
No. 2
(7.5 %)
400 mg
340 mg
200 mg
(= 60 mg solids)
4 mg
4 mg
808 mg
2. Granulation settings
(fluidized bed granulator, top-spray method)
Inlet air temperature
55 C
Outlet air temperature:
22 27 C
Nozzle diameter
0.8 mm
Spray rate
Approx. 10 g/ml
Spray pressure
2 bar
78
808 mg
The amount of Kollicoat EMM 30D required in the theophylline sustainedrelease tablets is very low due to the insolubility of theophylline if no pore
former is used. As can be seen in Fig 2.12, for the particle size of theophylline (powder, BASF) used, the amount of solid Kollicoat EMM of 5%,
based on the weight of granulate, would be just right for release of active
ingredient over a period of 24 h. This amount should if at all possible not
be smaller as it might prevent the formation of the right matrix structure.
100
80
60
40
20
12
16
20
24
Time, h
If the same pellets are coated using the identical amount of Kollicoat SR
film instead of ethyl acetate containing only 10% instead of 25% of triethyl
acetate plasticizer and if these are subsequently compressed in the same
way and formulation to tablets the release effect is not reduced as a result
of the mechanical stress of compression.
Electron microscopic photos showed that the pellets in this case were not
destroyed but only deformed. For this reason, Kollicoat SR 30D and also
Kollicoat EMM 30D can be regarded as excellent film formers for the technology of preparing tablets from sustained-release pellets.
The sustained-release pellets can be compressed to tablets with various
fillers; however, release is not always uniform as the pores and dissolution
speeds tend to vary. Based on experience gained, the differences are not
very great. Strongly swelling or strongly hydrophilic excipients such as micronized crospovidone (e.g. Kollidon CL-M) accelerate release. In the case of
sparingly soluble active ingredients such as theophylline or carbamazepine,
hydrophilic fillers like lactose monohydrate in pure or granule form
(Ludipress LCE) or even Kollidon CL-M are perhaps more suitable.
For readily soluble active ingredients, microcrystalline cellulose could be the
substance of choice.
To demonstrate this application of Kollicoat SR 30D the ambroxol sustainedrelease pellets as described in Section 2.2.1, with coatings of 10 and 20%
solids, were compressed to biplanar tablets using direct tabletting technology
in the formulation given in Table 2.9.
Table 2.9: Formulation of ambroxol-HCl sustained-release tablets from pellets with Kollicoat SR 30D
250.0 g
250.0 g
2.5 g
400 mg
10 mm
about 100 N
80
100
80
60
40
20
10% coating
20% coating
10
12
14
16
18
20
22 24
Time, h
81
Elongation at break
5% triacetin
10% propylene glycol
Kollicoat SR 30D
188%
300%
5.4%
5.7%
< 2.0%
< 2.0%
Ammonium methylacrylate
co-polymer
82
43.5
0.7
3.3
0.5
0.5
0.5
3.5
47.5
%
%
%
%
%
%
%
%
83
100
80
60
40
Uncoated cores
4 mg coating/cm2
6 mg coating/cm2
10 mg coating/cm2
20
10
12
14
16
18
20
22 24
Time, h
84
100
80
60
40
20
Untreated tablets
After friability testing
Punctured tablets
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Time, h
85
2.4 Plasticizers
2.4.1 Propylene glycol
1,2-Propylene glycol is nowhere near as effective a plasticizer as other
traditional compounds such as triethyl citrate, but its adverse effect on drug
release is less. This is particularly important with tablet coatings that dissolve
in gastric juice and tablet coatings that do not. Furthermore 1,2-propylene
glycol has no negative influence on the tackeniss of the coating (see Fig. 2.17).
In concentrations of 10 15% as a proportion of the film-forming agent,
1,2-propylene glycol considerably reduces the minimum film-forming temperature (MFT). Fig. 2.16 shows the effect of adding 1,2-propylene glycol
to Kollicoat MAE.
MFT [C]
25
20
15
10
5
0
0%
10%
15%
86
2
Tacky
Non-tacky
1
Without
Propylene
glycol
Macrogol
Triethyl
citrate
Triacetin
87
No. 1
q.s.
76 g
4 g
19 g
15 g
1 g
No. 2
q.s.
76 g
4g
19 g
10 g
1g
88
89
90
91
92
93
94
95
96
4. Solutions
4.1 Solubilization for oral and topical use
4.1.1 Surfactants as solubilizers
Cremophor RH 40, Cremophor EL
The preparation of a microemulsion with the aid of non-ionic solubilizers is
a traditional method of solubilizing active ingredients of low solubility. In this
method, they are incorporated in the surfactant micelles which are so small
that they cannot be seen with
the naked eye.
The comparison of different non-ionic ethoxylated surfactants in Table 4.1
shows that the formation of a clear microemulsion or of a turbid macroemulsion does not depend on the degree of ethoxylation (ethylene units per
molecule) but appearantly on the content of the free macrogol. All tested
surfactants having a content of free macrogol lower than 6% are emulsifiers.
All non-ionic solubilizers like macrogolglycerol hydroxystearate 40 or macrogolglycerol ricinoleate 35 (Cremophor RH 40 or Cremophor EL) contain
more than 12% of free macrogol. An indirect proof of this theory was given
by the extraction of the free macrogol from a solubilizer like Cremophor
RH40 or Solutol HS15. After such elimination of the free macrogol part
the solubilizing properties of the product are lost. The explanation is the
formation of mixed micelles which have a stronger solubilization effect than
normal micelles particularly if the free macrogol is combined with glycerol
or sorbitol.
Degree of
Content of
ethoxylation free macrogol
(EO units
per molecule)
Emulsifiers (macroemulsion)
Macrogol cetostearyl ether 25
Macrogol lauryl ether 9
Macrogolglycerol hydroxystearate 7
25
9
7
Solubilizers (microemulsion)
Macrogol hydroxystearate 15
Polysorbate 80
Macrogolglycerol ricinoleate 35
Macrogolglycerol hydroxystearate 40
15
20
35
40
2 3%
1 2%
3 6%
27
12
12
22
37%
16%
18%
28%
97
98
10.0
0.05
100.0
2.0
4.5
10.0
45.0
200.0
80.0
9.6
25.0
15.0
15.0
55.0
15.0
300.0
100.0
5.0
100
mg
mg
mg
mg
g
g
g
mg
mg
g
g
mg
mg
mg
mg
mg
mg
g
g
2. Procedure
Heat I and II separately to about 60 C and slowly add I to II with
thorough stirring to obtain a clear solution. Dissolve III in the hot
solution IV to obtain a clear solution. Mix the cool solutions I/II, III/IV
and V and adjust the pH value to 4.0 4.2. Purge the solution with
nitrogen for 10 min and fill into bottles under nitrogen.
3. Chemical stability (20 25 C; HPLC methods)
(9 months)
(12 months)
Vitamin A
86%
73%
Vitamin B1
88%
83%
Vitamin B2
96%
92%
Vitamin C
78%
77%
99
1.5
2.5
40.0
56.0
g
g
g
g
2. Procedure
Dissolve diclofenac sodium in the aqueous solution of the auxiliaries.
3. Physical stability
No crystallization had occurred after storage for 2 weeks at 6 C.
A further example is the formulation an acetaminophen solution with
Kollidon 25 given in Section 4.5.
100
No. 1 (= 0.2%)
0.2 g
q.s.
2.5 g
5.0 g
0.1 g
q.s.
92.2 g
No. 2 (= 0.5%)
0.5 g
q.s.
5.0 g
10.0 g
30.0 g
q.s.
54.5 g
2. Procedure
Heat mixture I to about 60 C and add slowly the warm solution II
(60 C).
3. Properties of the solutions
Clear, colourless liquid with a low viscosity.
101
5.70
10.00
0.46
0.50
q.s.
to 100
g
g
g
g
(pH)
ml
A further example of a formulation in which Kollidon 17 PF acts as a solubilizer is a retard ampoule for veterinary use in Section 4.10.
102
No. 1
1.0 g
6.5 g
q.s
93.0 g
No. 2
2.0 g
11.0 g
q.s.
87.0 g
2. Procedure
Dissolve phytomenadione in Solutol HS 15 heated to about 60 C
and slowly add the warm water. The solution can be sterilized by
heating to 120 C or by filtering.
3. Properties of the solutions
A clear colourless solution of low viscosity is obtained.
4. Physical stability (Formulation No. 1)
After storage for 12 weeks at 20 C and 40 C, the heat-sterilized
solution did not show any change in appearance.
103
Table 4.7 shows the formulation for one of the widely marketed veterinary
ampoules with highly dosed vitamins A, D and E. This formulation gives a
milky emulsion with very good physical and chemical stability. An indication
of the bioavailability of the vitamins can be derived from results for a similar
formulation in Section 4.7.
22.0
0.2
5.5
0.5
15.0
1.0
ad 100
g
g
g
g
g
g
ml
2. Procedure
Mix the vitamins, Solutol HS 15, butylhydroxytoluene and benzyl
alcoholat approx. 60 C, and then add the water (60 C) slowly and
with vigorous stirring. After the ampoules have been heat-sterilized,
they should be shaken briefly while still hot, to eliminate any separation of the phases that may have occurred. Sterilization can also be
performed by membrane filtration under pressure.
3. Properties of the solution
Appearance: milky, pale yellow emulsion.
Viscosity: less than 20 mPas
4. Physical stability (2025 C, protected from light)
No change in appearance in 2 years.
5. Chemical stability of vitamin A
Room temperature: 9% loss after 1 year, 16% loss after 2 years.
6 C:
About 10% loss after 2 years.
104
4.3 Thickeners
4.3.1 High molecular povidone
Kollidon 90 F
Kollidon 90 F having a high weight-average molecular weight of more than
106 is used occasionally as a thickener in oral and topical solutions, even
though rather higher concentrations are required than would be the case
with some cellulose derivatives.
Fig. 4.1 shows the variation in viscosity of aqueous solutions of Kollidon
90 F as a function of concentration.
When Kollidon 90 F is used in aqueous solutions, it is recommended to
add an antioxidant, e.g. 0.5% cysteine, to stabilize the colour of the solution.
mPas
10000
1000
100
10
2,5
Kollidon
10
15
90 F in water (20 25 C)
105
10.0
1.0
15.0
4.4
69.6
g
g
g
g
g
2. Procedure
Dissolve the solids (I) in water (IV), cool to about 6 C, dissolve Lutrol
F 127 (II) in this and adjust the pH value with the sodium hydroxide
solution (III)
3. Properties of the gelling solution
Viscosity at room temperature
Viscosity on the skin (3537 C)
pH (20% in water)
4. Stability (14 days, 52 C)
pH (20% in water)
Loss of available iodine
106
viscous solution
gel
4.8
2.5
9.7 %
4.4 Solvents
4.4.1 Low molecular weight macrogols: Lutrol E grades
The low-molecular-weight macrogols Lutrol E 300, Lutrol E 400 and
Lutrol E 600 are used in liquid oral and topical preparations mainly as
solvents.
They are frequently used in syrups, drops, sprays, and topical solutions with
the following active ingredients:
Acetaminophen
Clotrimazole, miconazole
Isosorbide dinitrate
Nifedipine
Nitrazepam, diazepam
Nitrofural.
Low molecular weight liquid macrogols e.g. Lutrol E 300 and Lutro E 400
are occasionally used also in parenterals as solvents. In such cases, they
are often combined with nonionic solubilizers or with 1,2-propylene glycol.
The use of macrogols as solvents in injectables is not restricted to particular
groups of active substances, though diclofenac sodium, etoposide, ibuprofen
and nifedipine represent typical examples.
4.4.2 Propylene glycol
1,2-Propylene glycol is one of the few organic solvents that is still relatively
widely used in pharmaceutical formulations. In contrast to ethanol, this also
applies to preparations for oral administration.
Examples of formulations of oral solutions with 1,2-propylene glycol are
given in Tables 4.2, 4.4 and 4.9.
Also in injectables for human use 1,2-propylene glycol is almost the only
organic solvent that is still relatively frequently used. In such cases, it is
occasionally used in combination with solubilizers or with liquid macrogols.
As with the low molecular weight macrogols, its use is not restricted to any
particular active substances, but the most important groups are probably
analgesics e.g. diclofenac and piroxicam, corticoids, vitamins, and sedatives
such as diazepam and digitalis glycosides.
Typical formulations containing 1,2-propylene glycol for ampoules are given
in Tables 4.10 (vitamin B complex) and 4.15 (closantel).
1,2-Propylene glycol in concentrations above 15% has a useful side effect
in that it kills microbes.
107
5.0
5.0
4.0
0.1
20.0
15.0
20.0
31.0
g
g
g
g
g
g
g
g
2. Procedure
Dissolve first Kollidon 25 and then the other solid components in the
solvent mixture of glycerol, propylene glycol and water.
3. Properties of the solution
Clear solution of moderate viscosity with only a slightly bitter taste.
4. Physical stability
The solution remained clear for more than 1 week at 6 C and for
more than 3 months at 25 C and 40 C. The colour of the solution
changed only slightly over 3 months at 25 C and 40 C.
5. Chemical stability (HPLC)
No loss of acetaminophen was found after 3 months at 40 C.
To avoid undesirable yellowing in aqueous solutions containing Kollidon 25
or Kollidon 30, it is recommended to add a stabilizer e.g. 0.5% cysteine or
0.1% sodium hydrogen sulphite.
108
1,100
660
4,400
440
880
20
50
10.0
160
2,270
21.6
72.0
20.0
86.4
approx. 200
mg
mg
mg
mg
g
mg
mg
g
mg
mg
ml
ml
ml
ml
ml
2. Procedure
Dissolve mixture I in the buffer solution II, purge with nitrogen for
5 min, filter through a 0.2 m membrane filter and fill the clear
yellow solution into ampoules of 2 ml under nitrogen. The pH is
about 4.
3. Stability (20 25 C, dark)
The following losses of vitamins were determined by HPLC:
Vitamin
B1
B2
Nicotinamide
B6
B12
9 months
8 %
6 %
0 %
9 %
13 %
12 months
11 %
10 %
0%
9%
not tested
Without Kollidon 17 PF the loss of vitamin B12 after 9 months was > 50%.
109
Interferon
Iodine
Isosorbide dinitrate
Methylprednisolone
Nitroglycerol
Prostaglandin
Taurolidine
Theophylline
Vitamins.
1,2-Propylene glycol
1,2-Propylene glycol is used mainly as a solvent, but it can also stabilize
certain active ingredients. The best known example is vitamin C. Results
can be found in the literature such as those in Fig. 4.2 which show that
1,2-propylene glycol has a very strong positive effect on the stability of
ascorbic acid solutions. Without 1,2-propylene glycol, the vitamin loss after
240 days is 81% and with 50% 1,2-propylene glycol it is less than 10%
after the same storage time.
Vitamin content, %
100
80
60
40
20
0
Water
Propylene
glycol + Water
1+1
Propylene
glycol
Fig. 4.2 : Influence of the solvent on the stability of ascorbic acid solutions
(240 days, 22 C)
110
1.5
5.0
21.0
1.0
q.s.
71.5
g
g
g
g
g
2. Procedure
Mix the vitamins with Cremophor RH 40 (and DL-alpha-tocopherol)
at 60 C and then add solution II (at 37 C) slowly, with stirring.
3. Properties of the solutions
Clear, yellow, viscous liquids.
111
70
60
50
40
30
20
10
0
Aqueous
emulsion
Organic
solution
Oily
solution
112
10
5
43
42
g
g
g
g
2. Procedure
Dissolve the components I in the mixture II and fill in flasks for
manual pump sprays.
3. Properties of the solutions
Aspect
Viscosity
Drying on the skin
Chemical stability (1 year, rt)
113
6.25 g
7.50 g
ad 100.00 ml
2. Procedure
Dissolve the active ingredient in the well stirred solution of Kollidon 12
PF in water, freeze-dry, then fill 500-mg-portions of the dry lyophilizate
into ampoules.
3. Administration
Prior to administration, mix the dry content of an ampoule with 1.9 ml
of water for injections to give a clear injection solution.
114
115
12.0 20.0
9.0 12.0
2.5 3.0
approx. 60
0.01 0.04
approx. 20
g
g
g
g
g
g
2. Procedure
Dissolve Closantel in solution II and add solution III.
Sterilize by heating to 120 C for 20 min.
3. Properties of the solution
Clear yellow solution
4. Remarks
The function of Kollidon 12 PF or Kollidon 17 PF is to greatly
reduce the local side-effects (e.g. formation of oedemas) and to
increase the retention time in the tissue.
116
117
118
5. S
uspensions
(Ready-to-use suspensions, dry syrups,
instant drink granules)
5.1 Sedimentation inhibitors for oral and topical use
5.1.1 Micronized crospovidone
Kollidon CL-M
One of the greatest problems in the development of formulations for suspensions is the prevention of sedimentation over the necessary period.
Thickeners such as cellulose derivatives are traditionally used as sedimentation inhibitors to increase the relative sediment volume. However, these
substances have the major disadvantage that by increasing the viscosity,
they make it more difficult to shake up the preparation. An alternative that
gives the same effect, but without increasing the viscosity, is therefore
preferable. Kollidon CL-M provides this alternative as a result of its special
physical properties such as its low bulk density, its small particle size, its
relatively high specific surface area and the low viscosity of aqueous suspension of the substance. Furthermore, Kollidon CL-M does not reduce
the zeta potential of the active substance particles and sterically holds
them apart.
120
Viscosity, mPas
100
80
60
40
20
0
0
10
Fig. 5.1: Dynamic viscosity of amoxicillin dry syrup suspensions with different
amounts of Kollidon CL-M
119
As can be seen from Fig. 5.1, oral amoxicillin suspensions with concentrations of Kollidon CL-M up to 10% can be prepared without exceeding
a viscosity of 80 mPas. As the usual concentrations cover a range of
5 to 8% Kollidon CL-M (6% in the case of the amoxicillin dry syrup), the
change in viscosity is hardly visible. The suspensions were prepared by
shaking amoxicillin dry syrups (amoxicillin trihydrate 5 g, sodium citrate 5 g,
citric acid 2 g, sodium gluconate 5 g, sorbitol 40 g, Kollidon CL-M 0 10 g,
flavours 2 g, saccharin sodium 0.4 g) with the amount of water to fill up to
the volume of 100 ml.
A other typical formulation for a low-viscosity oral suspension is the ibuprofen
suspension given in Table 5.1.
Most of the suspension formulations containing Kollidon CL-M as a sedimentation inhibitor, such as that in Table 5.1, contain a series of further excipients that also help to stabilize the suspension. These include Kollidon
90 F, sucrose and sorbitol as well as an ionic component such as sodium
citrate, that also increases the sediment volume.
4.0
2.0
2.0
25.0
8.0
ad 100
g
g
g
g
g
ml
2. Procedure
Dissolve sucrose, Kollidon 90 F and sodium citrate in about 40 ml
of water, suspend Kollidon CL-M and ibuprofen in this solution by
stirring and add the rest of the water.
3. Physical properties of the suspension
After 1 day
Milky white
94%
Very easy
Low
Homogeneous
Color
Relative sediment volume
Redispersibility
Viscosity
Aspect
Milky white
100%
Not necessary
Low
Homogeneous
The effect on the relative sediment volume after a period of 2 weeks of varying the concentration of Kollidon CL-M in the ibuprofen suspension described in Table 5.1 is shown in Fig. 5.2. The small sedimentation obtained
with the use of 8% of Kollidon CL-M can still be regarded as good, as the
low viscosity of the formulation makes redispersion easy.
120
100
80
60
40
20
0
10
Kollidon CL-M, %
50
130
50
7
5
5
3
3
8
50
g
g
g
g
g
g
g
g
g
g
121
100
80
60
40
20
0
0
% Kollidon 90 F
122
2.0
6.0
3.0
28.0
0.5
q.s.
60.5
g
g
g
g
g
g
2. Procedure
Suspend aciclovir and Kollidon CL-M in the solution of the other
components with vigorous stirring
3. Properties of the solution
Color
Relative sediment volume after 14 days
Redispersibility after 14 days
white
96%
easy
Apart from their use in ready-to-use suspensions, instant drink granules and
dry syrups, Kollidon 25 and Kollidon 30 can also be used to stabilize the
pigment and spray suspensions that are used for coatings. Typical examples
of this application are given in Sections 1.7 and 2.1.3.
123
4
3
3
88
22
2
g
g
g
g
g
g
124
1.3
4.3
85.6
4.4
4.4
about 50
g
g
g
g
g
g
125
126
10.0
8.0
15.0
3.0
1.0
0.05
0.08
0.02
ad 100
g
g
g
g
g
g
g
g
ml
2. Procedure
Dissolve and suspend all the solids in water under aseptic conditions.
3. Properties of the suspension
No sedimentation after 24 hours
Very easy to redisperse after more than 2 weeks
20
15
10
3
Kollidon 90 F, %
127
20.0
20.0
0.5
0.5
0.6
q.s.
ad 100
g
g
g
g
g
ml
2. Procedure
Prepare solution II, suspend the components I in the well stirred
solution II and pass through a colloid mill.
3. Properties
A white homogeneous suspension is obtained.
5.3.2 S
urfactants as sedimentation inhibitors and redispersing
agents for injectables
Solutol HS 15
Just as Cremophor RH 40 can be recommended as a sedimentation inhibitor and redispersing agent in oral suspensions (Section 5.1.4), macrogol
hydroxystearate 15 (= Solutol HS 15) is suitable for use in parenteral suspensions for the same purpose.
It gives solutions of low viscosity in water, even at high concentrations of
up to 30%.
128
2.0
20.0
3.0
0.1
1.0
25.0
7.0
41.9
g
g
g
g
g
g
g
g
2. Procedure
Stir the mixture of carbamazepine and 1,2-propylene glycol for at
least 2 hours, add Kollidon 90 F, saccharin, sodium citrate and the
water and stir again until these components are dissolved. Dissolve
sorbitol in this mixture and add Kollidon CL-M to the well stirred
suspension to obtain a homogeneous suspension.
3. Properties of the suspension
After 1 day After 1 month (RT)
Colour
Milky white
Milky white
Relative sedimentation volume
100%
98%
Redispersibility
Not needed
Very easy
Structure of the sediment Very fine particles, Very fine particles,
no crystals
no crystals
Viscosity
Very low
Very low
129
10.0
5.0
3.0
40.0
50.0
50.0
50.0
0.5
g
g
g
g
g
g
g
g
2. Procedure
Introduce solution II into the mixture I, granulate the powder mixture III
with the well stirred mixture I/II, dry and pass through a 1 mm sieve.
Fill 1 g or 2 g portions into sachets.
3. Properties of the granules
Free-flowing white granules;
98% coarser than 50 m;
Easily dispersing in water; no physical separation within 30 min.
4. Administration
Disperse the contents of one sachet (1 g = 60 mg simethicone or
2 g = 120 mg simethicone) in about 100 ml of drinking water.
130
5.4.3 Macrogols
Lutrol E 400, Lutrol E 600
Macrogols of low molecular weight are also used in parenteral suspensions,
and particularly in crystal suspensions. This is of interest for drugs such as
corticoids, e.g. methylprednisolone or triamcinolone and hormone derivatives, e.g. medroxyprogesterone.
131
5.0
5.0
2.0
60.0
0.5
9.0
9.0
0.5
0.3
g
g
g
g
g
g
g
g
g
132
133
200 g
26
33
110
22
150
66
1,150
210
20,000
5,000
1,000
2,000
approx. 7
g
g
g
g
g
g
g
g
g
g
g
g
l
134
135
136
137
138
6 S
emisolid dosage forms (Gels, creams,
suppositories, transdermal systems)
6.1 Emulsifiers
Cremophor A 6, Cremophor A 25
The two macrogol cetostearyl ethers Cremophor A 6 and Cremophor A 25
are excellent emulsifiers for the manufacture of pharmaceutical and cosmetic
creams.
Even relatively small concentrations of these two Cremophor A grades suffice to form a stable emulsion. The best results are obtained by combining
the two products, as has been done in the formulation for a cream base
shown in Table 6.1. This formulation is suitable for a wide range of active
ingredients; they are dissolved in 1,2-propylene glycol prior to incorporation
in the cream base. Typical examples of substances that have been tested in
this formulation are betamethasone, bifonazole, clotrimazole, hydrocortisone
and miconazole.
7.0
1.5
1.5
12.0
0.2
67.8 69.7
8.0
0.1 2.0
g
g
g
g
g
g
g
g
2. Procedure
Heat mixture I and the water II separately to about 80 C. Add the
water II to the solution of mixture I with vigorous stirring. Heat III until
the active ingredient has dissolved, mix with I/II and continue to stir
while cooling to room temperature.
3. Properties
White cream
4. Physical stability
No change in appearance was observed after 6 weeks at 45 C.
139
2500
Viscosity, mPas
22%
16%
20%
18%
2000
20%
18%
16%
22%
1500
1000
500
0
10
20
30
40
50
60
70
80
90
Temperature, C
5
10
10
15
1
q.s.
59
g
g
g
g
g
g
2. Procedure
Dissolve II in solution III at 70 C under vacuum, cool to 40 C and
add solution I.
3. Properties of the gel
A colourless clear gel is obtained.
4. Remark
The function of the isopropyl myristate is to reduce the tack.
141
2.0
0.1
20.0
10.0
10.0
5.0
0.3
52.6
g
g
g
g
g
g
g
g
2. Procedure
Dissolve I in the melted mixture II. Heat solution III to 90 C and mix
slowly with I/II. Once the air bubbles have escaped, allow to cool to
room temperature.
3. Properties of the gel
A clear, colourless, soft gel was obtained, with an orange flavour and
a slightly bitter aftertaste.
However, solubilizers are also used in suppositories to homogeneously
dissolve lipophilic active substances in a hydrophilic matrix, or to improve
their absorption.
Table 6.4 shows an example of the use of Cremophor RH40 in vitamin A
suppositories.
142
9
9
1
40
80
50
g
g
g
g
g
g
2. Procedure
Dissolve butylhydroxytoluene in the warm vitamin A, add Cremophor
RH 40 and mix with the molten macrogols.
Fill into moulds of suppositories to obtain the weight of 2 g.
3. Properties of the gel
Weight
Colour
Drop point
Macrogol 1500
Disintegration in water
2.0 g
Homogeneously yellow
54 C
80 g
22 min (emulsion)
Poloxamers 188 and 407 (Lutrol F 68 and Lutrol F 127) can also be used
as solubilizers in semisolid dosage forms just as in oral forms (see also
Section 4.1.3).
143
25
20
15
10
Without povidone
5
0
Copreciptate with
povidone (1+3)
0
10
Hours
144
6
after 30 min
after 60 min
5
4
3
2
1
0
Without
povidone
With povidone,
phys. mixture
1+2
With povidone,
coprecipitate
1+2
145
146
50.0
5.0
6.0
40
68.4
2.5
18.0
mg
g
g
mg
g
g
g
2. Procedure
Add II slowly to the clear solution I at about 40 C. Heat to about 50 C
and dissolve about 4 g of III in I/II. Cool to about 6 C and dissolve
the rest of III. Maintain at this temperature until the air bubbles have
escaped.
3. Properties of the gel
A clear yellowish gel was obtained.
4. Chemical stability (12 months, 23 C, dark)
Tretinoin: 96%
Dexpanthenol: 100%
5. Remark
It is important to protect the gel from light to avoid the isomerization
and degradation of tretinoin.
147
Table 6.6 gives the formulation for a metronidazole vaginal gel that contains
40% Lutrol E 400 as an example for the use of this product as a solvent
for the active ingredient.
1.2
21.0
40.0
37.8
g
g
g
g
2. Procedure
Heat mixture I to 70 80 C and slowly add the water heated to about
70 C. Maintain the temperature until the air bubbles have disappeared.
3. Properties of the gel
A clear colourless gel is obtained.
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
15
10
20
54
g
g
g
g
g
2. Procedure
Dissolve diclofenac sodium in propylene glycol, add the mixture of water and Miglyol 812. Dissolve Lutrol F 127 in this well stirred mixture
at 4 6 C (or at > 70 C). Maintain the temperature until the air bubbles
have escaped.
3. Properties
White, turbid gel-cream.
149
50.0
10.0
60.0
80.0
g
g
g
g
2. Procedure
Melt the mixture II and suspend in it. Cast the melted mass into
suppository moulds.
3. Properties of the suppositories
Weight
2.0 g
Solubility in water
readily soluble
Color
colourless
150
100 500 m based on in-vitro experiments. Should the percutaneous resorption be slower than the release from the matrix film, the skin becomes
the speed-determining factor for bioavailability. Should release from the
matrix film be too slow, resorption enhancers such as pore formers or emulsifiers can be added.
1.6
100 m
1.2
200 m
300 m
0.8
400 m
0.4
0.0
500 m
0.5
0.75
1.0
1.25
1.5
1.75
2.0
152
153
154
7 Diagnostic products
7.1 Enzym stabilizers
Kollidon 25, Kollidon 30
In diagnostic and similar preparations that are used as reagents, povidone
(e. g. Kollidon 25 or Kollidon 30) can also be used to stabilize enzymes,
in addition to the fields of application in solid and liquid dosage forms given
in the previous sections.
The complexation of enzymes is described in detail in many publications in
the scientific literature. Table 7.1 shows a selection of enzymes that can be
stabilized with povidone.
155
Note
The data submitted in this publication are based on our current knowledge
and experience. They do not constitute a guarantee in the legal sense of
the term and, in view of the manifold factors that may affect processing
and application, do not relieve those to whom we supply our products
from the responsibility of carrying out their own tests and experiments.
Any relevant patent rights and existing legislation and regulations must be
observed.
156
8 L
ist of BASF pharmaceutical excipients and their
pharmacopoeial monographs
Excipient
alpha-Tocopherol
Cremophor A 6
Cremophor A 25
Cremophor EL
Cremophor ELP
Cremophor RH 40
Kollicoat EMM 30D
Kollicoat IR
Ph.Eur. Monograph
Tocopherol, all-rac-alpha
Macrogol cetostearyl ether 6
Macrogol cetostearyl ether 25
Macrogolglycerol ricinoleate 35
Macrogolglycerol ricinoleate 35
Macrogolglycerol hydroxystearate 40
Polyacrylate dispersion 30 per cent
Macrogol Polyvinyl alcohol grafted copolymer (published draft)
Kollicoat IR White
Macrogol Polyvinyl alcohol grafted
Kollicoat Protect
copolymer
+ Poly(vinyl alcohol)
Kollicoat MAE 100P Methacrylic acid Ethacrylate
copolymer 1:1 (Type B)
Kollicoat MAE 30DP Methacrylic acid Ethacrylate
copolymer 1:1 dispersion 30 per cent
Poly(vinyl acetate) dispersion 30 per
Kollicoat SR 30D
cent
Povidone (nominal K-value 12)
Kollidon 12 PF
Povidone (nominal K-value 17)
Kollidon 17 PF
Povidone (nominal K-value 25)
Kollidon 25
Povidone (nominal K-value 30)
Kollidon 30
Povidone (nominal K-value 90)
Kollidon 90 F
Crospovidone (Type A)
Kollidon CL
Crospovidone (Type B)
Kollidon CL-S
Crospovidone (Type B)
Kollidon CL-SF
Crospovidone (Type B)
Kollidon CL-M
Poly(vinyl acetate) dispersion
Kollidon SR
30 percent
+ Povidone
Copovidone
Kollidon VA 64
Kollidon VA 64 Fine Copovidone
Lactose monohydrate
Ludipress
+Povidone
+ Crospovidone
Lactose monohydrate
Ludipress LCE
+ Povidone
Mannitol
Ludiflash
+ Crospovidone
+ Poly(vinyl acetate) dispersion 30 %
USP-NF Monograph
Vitamin E
Methacrlyic acid
copolymer
Methacrlyic acid
copolymer dispersion
Copovidone
Copovidone
Lactose monohydrate
+ Povidone
+ Crospovidone
Lactose monohydrate
+ Povidone
157
Excipient
Ph.Eur. Monograph
USP-NF Monograph
Lutrol E 300
Lutrol E 400
Lutrol E 600
Lutrol F 127
Lutrol F 68
Lutrol micro 127
Lutrol micro 68
1,2-Propylene glycol
Sicovit Iron oxides
Soluphor P
Solutol HS 15
Macrogols
Macrogols
Macrogols
Poloxamer 407
Poloxamer 188
Poloxamer 407
Poloxamer 188
Propylene glycol
Pyrrolidone
Macrogol hydroxystearate 15
Polyethylene glycols
Polyethylene glycols
Polyethylene glycols
Poloxamer 407
Poloxamer 188
Poloxamer 407
Poloxamer 188
Propylene glycol
Ferric oxide
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
78 79
Kollicoat EMM 30D for sustained-release matrix tablets
69 70
Kollicoat EMM 30D for sustained-release pellets
151 152
Kollicoat EMM 30D in transdermal systems
13, 28
Kollicoat IR as binder for wet granulation
40 44
Kollicoat IR for instant-release film-coating
113
Kollicoat IR in aerosols
40, 45 48
Kollicoat IR White
59, 63 67
Kollicoat MAE grades for enteric film-coating
40, 48 51
Kollicoat Protect as film former
81 85
Kollicoat SR 30D for sustained-release coated tablets
74 77, 79 81
Kollicoat SR 30D for sustained-release matrix tablets
68 69
Kollicoat SR 30D for sustained-release pellets
57
Kollicoat SR 30D for taste masking
128
Kollidon 12 PF and Kollidon 17 PF as suspension stabilizers
114
Kollidon 12 PF as solubilizer
114 116
Kollidon 17 PF as solubilizer
155
Kollidon 30 and Kollidon 25 as enzym stabilizer
59, 83, 120,
Kollidon 30 and Kollidon 90F as suspension stabilizers
122 123, 126 127, 129
9 15, 20 21
Kollidon 30, Kollidon 25 and Kollidon 90F as binder
30
Kollidon 30 as bioavailability enhancer
100
Kollidon 30 and Kollidon 25 as solubilizer
108
Kollidon 30 for taste masking
105
Kollidon 90 F as thickener
22 23
Kollidon CL as disintegrant
160
Redispersibility of suspensions
126 128
Roller compaction
14 15
Sedimentation inhibition
119 125, 128
58 59, 65, 94
Sicovit iron oxides
Simethicone instant granules
130
Solubilization in oral dosage forms
97 101
Solubilization in parenteral dosage forms
102 104
Solubilization in topical dosage forms
97 101
115
Soluphor P
103 104
Solutol HS 15 as solubilizer
128
Solutol HS 15 as suspension stabilizer
Solvent granulation
12
Stabilization of active ingredients
93, 109 111, 134 135
Stabilization of enzyms
155
Stabilization of oral suspensions
119 125
Stabilization of parenteral suspensions
128
Subcoating of tablets
54 55
Sugar coating formulation
54
Sugar coating of tablets
53 54
Sugar film-coating formulation of tablets
53
Sustained release in injectables
115
Sustained release in matrix tablets
71 81
Sustained release in pellets
68 70
Sustained-release film-coating of tablets
81 85
Taste masking by coating of crystals
57
Taste masking by tablet coating
55 56
Taste masking in liquids
108, 132 133
Theophylline sustained-release tablets
73, 78 79
Thickening
105 106
Toxicity reduction
116
Transdermal system
151 152
Tretinoin + dexpanthenol gel
147
Trituration
30 32
Verapamil speronized pellets (instant-release)
12
Vitamin A + D3 + E aqueous injectable emulsion (vet.)
104
Vitamin A + E drops
111
Vitamin A suppositories
143
Vitamin B complex injectable solution
109
Vitamin B12 coloured tablets
58
Vitamin C chewable tablets
19
Vitamin C tablets
14
Vitamin K1 injectable solution
103
Wet granulation
9 13
MEFM 11011 e
June 2008
Supersedes edition of April 2004
162
Printed in Germany
163
164
EMP080601e-00
June 2008; Supersedes edition of April 2004; Printed in Germany
Volker Bhler
Volker Bhler
Pharmaceutical Technology of BASF Excipients
Volker Bhler
Pharmaceutical
Technology
of BASF Excipients
Pharma Ingredients & Services.
Welcome to more opportunities.