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Physical characterization of drug:polymer dispersion behavior in polyethylene glycol 4000 solid dispersions using a suite of complementary analytical techniques.

Journal of pharmaceutical sciences (2014-05-16)
Dipy M Vasa, Namita Dalal, Jeffrey M Katz, Rahul Roopwani, Akshata Nevrekar, Harshil Patel, Ira S Buckner, Peter L D Wildfong
ABSTRACT

Fifteen model drugs were quenched from 3:1 (w/w) mixtures with polyethylene glycol 4000 (PEG4000). The resulting solids were characterized using powder X-ray diffraction (PXRD), analysis of pair distribution function-transformed PXRD data (where appropriate), hot-stage polarized light microscopy, and differential scanning calorimetry (DSC). Drug/polymer dispersion behavior was classified using the data from each technique, independent of the others, and limitations to single-method characterization of PEG-based systems are highlighted. The data from all characterization techniques were collectively used to classify dispersion behavior, which was compared with single-technique characterization. Of the 15 combinations, only six resulted in solids whose dispersion behavior was consistently described using each standalone technique. The other nine were misclassified using at least one standalone technique, mainly because the phase behavior was ambiguously interpreted when only the data from one technique were considered. The data indicated that a suite of complementary techniques provided better classifications of the phase behavior. Of all the quenched solids, only cimetidine was fully dispersed in PEG4000, suggesting that it solidified from a completely miscible mixture of molten drug and polymer that did not phase separate upon cooling. In contrast, ibuprofen and PEG4000 completely recrystallized during preparation, whereas the remaining 13 drugs were partially dispersed in PEG4000 at this composition.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Indomethacin, meets USP testing specifications
Sigma-Aldrich
Griseofulvin, from Penicillium griseofulvum, 97.0-102.0%
Sigma-Aldrich
Sulfanilamide, puriss. p.a., ≥99% (calc. to the dried substance)
Supelco
Sulfanilamide, VETRANAL®, analytical standard
Sigma-Aldrich
Cimetidine
Sigma-Aldrich
Sulfanilamide, ≥98%
Sigma-Aldrich
Nifedipine, ≥98% (HPLC), powder
Sigma-Aldrich
Indomethacin, 98.5-100.5% (in accordance with EP)
Supelco
Cimetidine, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Sulfanilamide melting point standard, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Indomethacin, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Nifedipine, Pharmaceutical Secondary Standard; Certified Reference Material
Indomethacin, European Pharmacopoeia (EP) Reference Standard
USP
Griseofulvin, United States Pharmacopeia (USP) Reference Standard
Supelco
Griseofulvin, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Sulfanilamide, Vetec, reagent grade, 97%
USP
Cimetidine, United States Pharmacopeia (USP) Reference Standard
USP
Indomethacin, United States Pharmacopeia (USP) Reference Standard
Sulfanilamide, European Pharmacopoeia (EP) Reference Standard
USP
Sulfanilamide Melting Point Standard, United States Pharmacopeia (USP) Reference Standard
Nifedipine, European Pharmacopoeia (EP) Reference Standard
USP
Nifedipine, United States Pharmacopeia (USP) Reference Standard
Cimetidine, European Pharmacopoeia (EP) Reference Standard
USP
Sulfanilamide, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Melatonin, powder, ≥98% (TLC)
Sigma-Aldrich
Terfenadine
Supelco
Chlorpropamide, analytical standard, ≥97%
USP
Melatonin, United States Pharmacopeia (USP) Reference Standard
Cimetidine for peak identification, European Pharmacopoeia (EP) Reference Standard
Cimetidine for system suitability, European Pharmacopoeia (EP) Reference Standard