Poloxamers as Solubilizing Agents in Solid DispersionsYidan Lan, Shaukat Ali, Nigel Langley

BASF Corporation, 500 White Plains Road, Tarrytown NY, USAyidan.lan@basf.com

AbstractThe 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.

KeywordsSolid dispersion, Carbamazapine, Poloxamer 188, Poloxamer 407, Poloxamer 338, Poloxamer 237, Lutrol® F68, Lutrol® F127 , Lutrol® F87, Lutrol® F108,Solubilizer.

IntroductionEnhancing 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 emulsifiers, 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 25°C, was chosen as a model drug.

MaterialsCarbamazapine, 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 MethodsUsing solvent casting method to evaluate CBZ/ Lutrol dispersionThe 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 first 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 solidified samples were gently grounded in a mortar and sieved through a 120 mesh sieve. The resulting powders, with particle size less than 125 µm, were stored in desiccators before analysis.

In vitro dissolution studyThe dissolution of solid dispersions was performed in a USP apparatus II (Distek 2100c) with 900ml DI water at 37ºC and 100 rpm. A sample was taken from each of the six vessels through a 10 micron filter 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 10°C/min heating rate between -50ºC and 200ºC 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 2θ range of 7º ~ 45º. The step size is 0.02 second, and the dwell time is 1.2 second.

Results and DiscussionSolubilization effect of PoloxamerThe solubilization of CBZ by Poloxamers was identified 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 first 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 first 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 56.53ºC 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 first heating. When reheating after cooling, Fig. 3(c) depicted part of the CBZ re-crystallized out of F108 melt at 69.99ºC, and melted again at 126.09ºC 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 first heat and cool period.

Figure 3 (b) DSC plot of casting sample with 80% of Poloxamer F108 and 20% of CBZ during the first 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

106.21119.16

174.37

0

20

40

60

80100

120

140

160

180

200

0% 5% 10% 15% 20% 100%

CBZ (%)

Mel

ting

Poin

t (C

0)F68

CBZ

(b)

49.92 47.76 47.2 47.2 47.73

85.78106.34 116.69

174.37

0

20

40

60

80

100

120

140

160

180

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0% 5% 10% 15% 20% 100

CBZ (%)

Mel

ting

Poin

t

F87

CBZ

(c)

56.52 55.61 56.53 56.31 53.9

111.47123.68

174.37

0

20

40

60

80

100

120

140

160

180

200

0% 5% 10% 15% 20% 100%

CBZ (%)

Mel

ting

Poin

t (C

°)(C

°)

(C°)

(C°)F108

CBZ

(d)

56.03 53.53 53.72 52.85 52.99

80.0489.96

118.62

174.37

0

20

40

60

80

100

120

140

160

180

200

0% 5% 10% 15% 20% 100

CBZ (%)

Mel

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F127CBZ

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.

ConclusionThis study investigated the feasibility to use Poloxamers to enhance the solubility of the poorly soluble drug Carbamazepine. All Poloxamer solvent casting samples demonstrated significant 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 50º-56ºC 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 justified 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. O’Brien at BASF Tarrytown, NY for their analytical support, and useful discussion.