Poloxamers as Solubilizing Agents in Solid Dispersions

Yidan Lan, Shaukat Ali, Nigel Langley

BASF Corporation, 500 White Plains Road, Tarrytown NY, USA
yidan.lan@basf.com
Abstract
The solubilizing effect of four poloxamers in solid dispersion of a model drug Carbamazepine (CBZ) was
studied using the solvent casting method. The dissolution rate of CBZ was enhanced by increasing the
poloxamer concentration for all poloxamers. Solid state evidence showed the solubilizing effect was
attributed to the homogenous dispersion of the crystalline drug in polymeric carriers. This work provided
useful information for further study on Hot Melt Extrusion.
Keywords
Solid dispersion, Carbamazapine, Poloxamer 188, Poloxamer 407, Poloxamer 338, Poloxamer 237, Lutrol
F68, Lutrol F127 , Lutrol F87, Lutrol F108,Solubilizer.
Introduction
Enhancing the solubility and bioavailability of poorly soluble drug remains a major challenge in
pharmaceutical research. The recent trend is to utilize solid dispersion/solution, either in amorphous or
crystalline forms, to improve solubility of these compounds. Several polymeric carriers, such as PVP1,
PVPVA2, HPMCAS3, and Soluplus4 have attracted considerable attention to form solid dispersion with APIs.
Poloxamers, a group of block copolymer nonionic surfactants, are widely used as emulsifers, wetting
agents, and suspension stabilizers in liquid, oral, topical, and parenteral dosage forms. It has been reported
that Poloxamer 188 and 407 can also act as solubilizing agents and plasticizers,5,6 for enhancing the
solubility and bioavailability of sparingly soluble drugs in solid dosage forms.
This study was focused on exploring the solubilizing effect of four Poloxamer grades7, especially the newer
USP grade Poloxamers 237 and 338. Carbamazapine, a BCS class II drug with a solubility of 17.7 mg/L in
water at 25C, was chosen as a model drug.
Materials
Carbamazapine, Lutrol F68, Lutrol F127, Lutrol F87, and Lutrol F108 (BASF brand name of Poloxamer
188, 407, 237, and 338) were obtained from BASF, Ludwigshafen, Germany. All other ingredients were of
analytical grade and were used as received.
Experimental Methods
Using solvent casting method to evaluate
CBZ/ Lutrol dispersion
The solid dispersion of carbamazepine with Poloxamers grade (Lutrol F grade) at different drug load
(5%, 10%, 15%and 20%w/w) were prepared by the solvent casting technique. CBZ was frst dissolved in
methanol (99%) before adding the appropriate weight of Poloxamer. The solution was then transferred to
a Petri dish, and dried in a vacuum drying oven at room temperature for 24 hours. The solidifed samples
were gently grounded in a mortar and sieved through a 120 mesh sieve. The resulting powders, with
particle size less than 125 m, were stored in desiccators before analysis.
In vitro dissolution study
The dissolution of solid dispersions was performed in a USP apparatus II (Distek 2100c) with 900ml DI
water at 37C and 100 rpm. A sample was taken from each of the six vessels through a 10 micron flter
at predetermined time intervals. Sample analysis was conducted at 286 nm using a UV spectrometer
(Shimadzu, UV160U).
Differential scanning calorimetry (DSC) and
powder x-ray diffraction (PXRD)
The thermal analysis was examined by Differential Scanning Calorimeter (DSC) (Universal V4, 5A TA
Instruments) at 10C/min heating rate between -50C and 200C with heat-cool-heat cycles.
Powder X-Ray Diffraction was performed using a Rigaku Ultima IV system with a D/tex ultra detector at 40
kV and 44mA over a 2 range of 7 ~ 45. The step size is 0.02 second, and the dwell time is 1.2 second.
Results and Discussion
Solubilization effect of Poloxamer
The solubilization of CBZ by Poloxamers was identifed in dissolution test (Fig. 1). Casting samples from all
Poloxamer grades showed more than two fold of improvement on CBZ release.
The dissolution rate was characterized by the percentage of CBZ released in the frst 60 minutes in Fig. 2,
which illustrates the rate pattern based on different CBZ contents as well as different Lutrol grades. It has
been found that the dissolution rate was directly proportional to the concentration of Poloxamer. The higher
Poloxamer level, (or the lower CBZ loading), the faster the release. In order to study the role of Poloxamers
in CBZ solubilizing, DSC and XRD tests were conducted.
Figure 1 The CBZ release from neat CBZ crystal and solvent casting samples consisted of 5%CBZ and 95%Lutrol F
grades.
Figure 1 Dissolution rate of CBZ in the frst 60 minutes
Solid state characterization
All DSC thermograms from CBZ-Lutrol solvent casting samples have a very similar pattern. Figure 3(a),
(b) and (c) illustrated an example of these curves, where 10%or 20%of CBZ was casted by Lutrol F108.
In Fig. 3(a), the only melting point shown up at 56.53C was from F68, while the melting point of CBZ
vanished, which indicated CBZ and Lutrol F 108 were miscible when the CBZ concentration was 10%.
As CBZ increased to 20%, two melting points for F108 and CBZ were detected in Fig. 3(b) during the frst
heating. When reheating after cooling, Fig. 3(c) depicted part of the CBZ re-crystallized out of F108 melt
at 69.99C, and melted again at 126.09C with a broad melting range. This melting and re-crystallization
phenomenon was observed in all casting samples, subjecting the dispersion of CBZ crystals in Lutrol
grades after solvent casting.
Figure 4 demonstrated the extrapolated onset melting points of all samples. Both Carbamazepine and
Lutrol F grades were depressed from their original melting points because of the existence of the other
component in the dispersion. The 5%CBZ samples from all Lutrol grades have only one meting point close
to the corresponding Lutrol melting point, which suggested a complete dispersion of CBZ in Lutrol. As CBZ
percentage increased to 10%, only the F108 casting sample had one melting point. When CBZ levels were
greater than 15%, there were always two melting points in the DSC curves corresponding to the depressed
CBZ and Lutrol melting points in the broadened melting ranges.
Figure 3(a) DSC plot of casting sample
with 90%of Poloxamer F108 and 10%
of CBZ during the frst heat and cool
period.
Figure 3 (b) DSC plot of casting sample
with 80%of Poloxamer F108 and 20%
of CBZ during the frst heat and cool
period.
Figure 3 (c) DSC plot of casting sample
with 80%of Poloxamer F108 and 20%
of CBZ during the second heating
period.
(a)
52.14 50.13 51.29 50.1 49.95
65.53
106.21
119.16
174.37
0
20
40
60
80
100
120
140
160
180
200
0% 5% 10% 15% 20% 100%
CBZ (%)
M
eltin
g
P
o
in
t (C
0) F68
CBZ
(b)
49.92 47.76 47.2 47.2 47.73
85.78
106.34
116.69
174.37
0
20
40
60
80
100
120
140
160
180
200
0% 5% 10% 15% 20% 100
CBZ(%)
M
e
ltin
g
P
o
in
t
F87
CBZ
(c)
56.52 55.61 56.53 56.31 53.9
111.47
123.68
174.37
0
20
40
60
80
100
120
140
160
180
200
0% 5% 10% 15% 20% 100%
CBZ (%)
M
e
ltin
g
P
o
in
t (C
)
(C
)
(C
)
(C
) F108
CBZ
(d)
56.03 53.53 53.72 52.85 52.99
80.04
89.96
118.62
174.37
0
20
40
60
80
100
120
140
160
180
200
0% 5% 10% 15% 20% 100
CBZ(%)
M
e
ltin
g
P
o
in
t
F127
CBZ
Figure 4 The extrapolated onset melting points of casting samples in DSC heating period (a) Lutrol F68 casting sample,
(b) Lutrol F87 casting sample, (c) Lutrol F108 casting sample, (d) Lutrol F127 casting sample
Figure 5 X-ray diffraction patterns of solvent casting Lutrol F grade samples with 5%, 10%, 15%and 20%of
Carbamazepine.
Conclusion
This study investigated the feasibility to use Poloxamers to enhance the solubility
of the poorly soluble drug Carbamazepine. All Poloxamer solvent casting samples
demonstrated signifcant enhancement on solubility. Thermo analysis results
indicated that the melting endotherm of CBZ decreased with the increase of
poloxamer ratio. The melting peak of CBZ vanished, and only a single endotherm
was shown at 50-56C when poloxamer ratios reached 90%-95%, suggesting
a complete solid dispersion of CBZ in Poloxamers. Solid state observation from
XRD study showed the decrease of crystallinity in lower CBZ level samples, which
justifed the increase of dissolution rate. These results indicate that poloxamers are
effective solubilizing agents.
References
1. K. Khougaz et al., J. Pharm. Sci., Vol. 89, No. 10, 1325-1334, (2000)
2. J.C. DiNunzio et al., Eu. Journal of Pharma. Biopharm. Vol.74, 340-351 (2010)
3. Z.Dong et al., AAPS PharmSciTech, Vol. 9 No. 3 (2008)
4. S. Ali et al. CRS 2010 conf. Poster 555 (2010)
5. Y. Chen et al., Int. J. Pharm. 286, 69-80 (2004)
6. C.Rouchotas et al., Int. J. Pharm. 195, 1-6 (2000)
7. Lutrol L and Lutrol F Grades, Technical Information, BASF (2010)
Acknowledgements
The authors are thankful to R. Burke, Y. Yiao, and R. OBrien at BASF Tarrytown, NY for their analytical
support, and useful discussion.