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A fast and reliable empirical approach for estimating solubility of crystalline drugs in polymers for hot melt extrusion formulations.

Journal of pharmaceutical sciences (2014-03-19)
Samuel O Kyeremateng, Marieke Pudlas, Gerd H Woehrle
ABSTRACT

A novel empirical analytical approach for estimating solubility of crystalline drugs in polymers has been developed. The approach utilizes a combination of differential scanning calorimetry measurements and a reliable mathematical algorithm to construct complete solubility curve of a drug in polymer. Compared with existing methods, this novel approach reduces the required experimentation time and amount of material by approximately 80%. The predictive power and relevance of such solubility curves in development of amorphous solid dispersion (ASD) formulations are shown by applications to a number of hot-melt extrudate formulations of ibuprofen and naproxen in Soluplus. On the basis of the temperature-drug load diagrams using the solubility curves and the glass transition temperatures, physical stability of the extrudate formulations was predicted and checked by placing the formulations on real-time stability studies. An analysis of the stability samples with microscopy, thermal, and imaging techniques confirmed the predicted physical stability of the formulations. In conclusion, this study presents a fast and reliable approach for estimating solubility of crystalline drugs in polymer matrixes. This powerful approach can be applied by formulation scientists as an early and convenient tool in designing ASD formulations for maximum drug load and physical stability.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Acetaminophen, BioXtra, ≥99.0%
Sigma-Aldrich
Acetaminophen, meets USP testing specifications, 98.0-102.0%, powder
Sigma-Aldrich
Acetaminophen, analytical standard
Itraconazole, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Itraconazole, ≥98% (TLC)
Sigma-Aldrich
Naproxen, meets USP testing specifications
Sigma-Aldrich
(S)-(+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid, 98%
Supelco
Naproxen, VETRANAL®, analytical standard
Supelco
Naproxen, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Acetaminophen, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Acetaminophen solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
USP
Naproxen, United States Pharmacopeia (USP) Reference Standard
USP
Acetaminophen, United States Pharmacopeia (USP) Reference Standard
Naproxen, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Nifedipine, ≥98% (HPLC), powder
Supelco
Ibuprofen, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Ibuprofen, ≥98% (GC)
Sigma-Aldrich
Ibuprofen, meets USP testing specifications
USP
Ibuprofen, United States Pharmacopeia (USP) Reference Standard
Paracetamol, European Pharmacopoeia (EP) Reference Standard
Supelco
Nifedipine, Pharmaceutical Secondary Standard; Certified Reference Material
Ibuprofen, European Pharmacopoeia (EP) Reference Standard
Ibuprofen for peak identification, European Pharmacopoeia (EP) Reference Standard
USP
Nifedipine, United States Pharmacopeia (USP) Reference Standard
Nifedipine, European Pharmacopoeia (EP) Reference Standard
Supelco
Ibuprofen