Crystallization inhibition in solid dispersions of MK-0591 and poly(vinylpyrrolidone) polymers.
The effects of poly(vinylpyrrolidone) (PVP) molecular weight, composition, and content on the crystallization of a model drug, MK-0591 (Form I), were investigated. Solid dispersions of crystalline MK-0591 with PVP homopolymers of different molecular weights (2500-1 x 10(6) g/mol) and with a copolymer containing poly(vinyl acetate) (PVA), (PVP/VA, 60:40, 5.8 x 10(4) g/mol) were prepared by the solvent method. MK-0591 in the solid dispersions was found to be X-ray amorphous. One glass transition temperature (T(g)) was observed suggesting drug-polymer miscibility. The T(g) values were higher than predicted by the Gordon-Taylor equation, indicating drug-polymer interactions. The extent of crystallization inhibition increased with PVP molecular weight and, for a comparable PVP molecular weight, the homopolymer was more effective in the crystallization inhibition of the drug than the copolymer. The first onset temperature of crystallization (T(c)(obs)) increased with polymer content. The T(c)(obs) values (normalized to polymer content) were a function of the difference between the T(g) of the polymer and drug. For PVP K-90, K-30, and K-17 dispersions, the T(c)(obs) values increased proportionally to the T(g) of the dispersions. However, for PVP K-12 and PVP/VA, the increase in T(c)(obs) values corresponded to a small decrease in the T(g) values of the dispersions. This result suggests that additional factors other than the reduction in mobility affect the crystallization behavior of MK-0591 in the solid dispersions, such as specific interactions. By Fourier transform-infrared spectroscopy, changes in the carbonyl-stretching band of PVP in the solid dispersions were observed. The existence of an ion-dipole interaction between COO(-)Na(+) of the drug and the cyclic amide group of PVP was postulated.
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Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Canada, H9H 4P8. karine.khougaz@merck.com
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D003460:Crystallization; D004347:Drug Interactions; D007211:Indoles / Q000737:chemistry*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry*; D010592:Pharmaceutic Aids / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D013696:Temperature
D007211:Indoles; D016859:Lipoxygenase Inhibitors; D010592:Pharmaceutic Aids; D011108:Polymers; D011804:Quinolines; C078266:MK 0591; D011205:Povidone