Comparison of the Solubilization Effect of Micronized Poloxamers,

on a poorly water-soluble model drug in capsule formulation by dry Granulation

Charles Onyiuke
BASF Corporation, Pharma Ingredients and Services, 500 White Plains Road, NY 10591
Abstract
Dry blend formulations have been the fastest and most economical methods of solid oral dosage
manufacture in the pharmaceutical industry. This study investigated the effect of micronized poloxamers
on the solubility of poorly-water soluble drugs in capsule formulation using dry blended powder.
Introduction
The ideal method of solid dosage formulation and manufacture has always been dry granulation where
the active ingredient(s) and the excipients are blended to achieve homogeneity of the mixed particles. This
is a simple, fast and economical process; but it is the most challenging method in terms of achieving a
robust formulation. The diffculty to achieve good content uniformity, inter-particle interactions, and good
choice of excipients that have similar particle sizes as that of the API (active pharmaceutical ingredients)
make this method unachievable for many formulators in the pharmaceutical industries 2,3. One of the
critical parameters in this process is the mixing time of the dry particles which need to be long enough to
enhance the blend homogeneity 5,6. This is necessary to achieve adequate drug release and stability.
Materials
Carbamazepine was obtained from BASF Corporation.
Micronized Poloxamer 188 (Lutrol F68 Micro), Poloxamer 237 (Lutrol F87 Prill), Poloxamer 338
(Lutrol F108 Prill) and Micronized Poloxamer 407 (Lutrol F127 Micro), the non-ionic surfactants of
polyoxyethylene (POE) and polyoxypropylene (POP), were obtained from BASF Corporation.
Crospovidone (Kollidon CL) was obtained from BASF Corporation.
Calcium Carbonate was obtained from Particle Dynamics.
Pro-Solv, (Silicifed Microcrystalline Cellulose (S-MCC)) was obtained from JRS Pharma LP.
Size 0 Empty Capsule Shells were obtained from Capsugel.
Poloxamers are block-copolymers consisting of
Polyoxyethylene-(POE-) and Polyoxypropylene-(POP-) units.
[POE] Unit [POP] Unit [POE] Unit
Poloxamer 188a a = ca. 79 b = ca. 28 Lutrol F 68
Poloxamer 407a a = ca. 98 b = ca. 57 Lutrol F 127
Pharmacopeia name trade name
Methods
Poloxamer 237 (Lutrol F87 Prill), and Poloxamer 338 (Lutrol F108 Prill) were micronized in-house using
Freezer/Mill 6870, SpexSample Prep. method to achieve particle size uniformity. These micronized grades
of Poloxamer 188, 237, 338, and 407 (Lutrol F68, F87, F108 and F127 respectively) with particle sizes
of 50 microns approximately; were mixed with Carbamazepine, as the model drug. Carbamazepine
was combined with each Poloxamer at 9 wt%(1:10) and 17 wt% (1:5), and blended for 20 minutes with
Calcium Carbonate 90A as fller, Kollidon CL as the super disintegrant and Silicifed Microcrystalline
Cellulose as glidant. The fnal dry granulation was flled into hard gelatin capsules, each weighing 400 mg.
The dissolution of Carbamazepine was done using Type II Dissolution Apparatus (dissolution medium:
1.0% SLS in DI water, 100 rpm, 37C). The release profle of the carbamazepine capsules was measured
using UV Detection Apparatus.
Carbamazepine Formulations with Different
Lutrol

Micro Grades in 1:5 ratios

Materials
Drug: Poloxamer Ratio ( w/w % )
(1:0) Control (1:5) (1:5) (1:5) (1:5)
Carbamazepine 5.0 5.0 5.0 5.0 5.0
Lutrol F68 Micro 0.0 25.0 0.0 0.0 0.0
Lutrol F127 Micro 0.0 0.0 25.0 0.0 0.0
Lutrol F87 Micro Prill 0.0 0.0 0.0 25.0 0.0
Lutrol F108 Micro Prill 0.0 0.0 0.0 0.0 25.0
Kollidon CL 12.5 10.5 10.5 10.5 10.5
Calcium Carbonate 69.5 59.0 59.0 59.0 59.0
Pro-Solv ( S-MCC ) 13.0 0.5 0.5 0.5 0.5
T O T A L 100.0 100.0 100.0 100.0 100.0
Table I
Carbamazepine Formulations with Different
Lutrol

Micro Grades in 1:10 ratios

Materials
Drug: Poloxamer Ratio ( w/w % )
(1:0) Control (1:10) (1:10) (1:10) (1:10)
Carbamazepine 5.0 5.0 5.0 5.0 5.0
Lutrol F68 Micro 0.0 50.0 0.0 0.0 0.0
Lutrol F127 Micro 0.0 0.0 50.0 0.0 0.0
Lutrol F87 Micro Prill 0.0 0.0 0.0 50.0 0.0
Lutrol F108 Micro Prill 0.0 0.0 0.0 0.0 50.0
Kollidon CL 12.5 5.0 5.0 5.0 5.0
Calcium Carbonate 69.5 39.0 39.0 39.0 39.0
Pro-Solv ( S-MCC ) 13.0 0.5 0.5 0.5 0.5
T O T A L 100.0 100.0 100.0 100.0 100.0
Table II
Results
0
10
20
30
40
50
60
70
80
90
100
0 15 30 45 60 120
C
a
rb
a
m
a
z
e
p
in
e
(%
R
e
le
a
s
e
d
)
Release Prole of Carbamazepine Capsule in Dry Blend
Formulation with Lutrol Micro as Solubilizer
Time (min.)
Control
F68 (1:5)
F87 (1:5)
F108 (1:5)
F127 (1:5)
Figure1. Control: Carbamazepine:Poloxamer Ratio (1:5)
0
10
20
30
40
50
60
70
80
90
100
0 15 30 45 60 120
C
a
rb
a
m
a
z
e
p
in
e
(%
R
e
le
a
s
e
d
)
Release Prole of Carbamazepine Capsule in Dry Blend
Formulation with Lutrol Micro as Solubilizer
Time (min.)
Control
F68 (1:10)
F87 (1:10)
F108 (1:10)
F127 (1:10)
Figure II. Control: Carbamazepine:Poloxamer Ratio (1:10)
Discussion
Physical mixtures of Carbamazepine and different Lutrol F micro grades in capsule formulations
increased Carbamazepine solubility relatively. The capsules from the 1:5 ratio formulations have less
solubility enhancement than those from the 1:10 ratio. In two hours, the capsules of Lutrol F68 micro
(1:10 ratio) showed a 97% drug release as compared to 92% from the Lutrol F68 micro (1:5 ratio),
formulations. This is relatively due to the 50% increase in the amount of Lutrol F68 in fgure II formulation.
In both formulations, Lutrol F127 showed a very small solubilization effect due to its known gelling
property associated with its high molecular weight. However, at 1:10 ratio, Lutrol F127 showed 75%
drug released after two hours. Lutrol F87 at 1:5 ratio, showed 75% drug release as opposed to 1:10
ratio with only about 70% drug release. Lutrol F108 showed a better drug release at 1:5 ratio, (62%) as
opposed to below 50% in the 1:10 ratio. It is desirable to increase the mixing time of the ingredients to
assure good content uniformity and most importantly enhance complexation of the drug particles with
the poloxamer molecules 3,4. The comparative study of the behavior of these Lutrol grades in a tablet
formulation is desirable 1,5.
Conclusion
Micronized grades of Lutrol

F68 and F127 improved the solubility of

carbamazepine when compared to control capsule formulation.
Carbamazepine was more soluble in micronized Lutrol

F68 than in Lutrol

F127
micro, F87 and F108 micro prill.
The small particle size of the micronized Lutrol

grades ensured optimum

ingredient miscibility and blend homogeneity.
The gelling property of Lutrol

F127 micro can be utilized in Dry Blend

formulations to provide sustained or delayed drug release
6
.
Dry blend granulation where micronized Lutrol

F68 and F127 are used to

solubilize poorly water-soluble drugs, such as Carbamazepine, is a robust and
economical method of solid dosage manufacture.
The solubilization effect of Poloxamers studied decreased from
F68 > F127 > F87 >108.
References
1. The infuence of three poly(oxyethylene)poly(oxypropylene) surface active block co-polymers on the
solubility behavior of Indomethacin. Pharma Acta Helv. 60 No. 12 (1985) 339-344
2. Kinetic studies on the stability of Indomethacin in alkaline aqueous solution containing
poly(oxyethylene)poly(oxypropylene) surface active block copolymers. Pharma Acta Helv. 60 No. 12
(1985) 345-350
3. Pluronic surfactants affecting Diazepan solubility, compatibility and adsorption from i.v. admixture
solutions. J. Parent. Sci & Tech Vol. 41 No. 3, May-June (1987) 83-87
4. Comparative study of Prill and Micronized Poloxamers Using Different Conventional Granulation
Techniques, AAPS Poster presentation 2005
5. Effect of Micronized Poloxamers on Poorly Water Soluble Drugs, AAPS 2003
6. Solubilization of selected poorly soluble Drugs in directly compressible formulations Using micronized
Poloxamers, AAPS Poster presentation 2007