Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions

TY - JOUR

T1 - Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions

AU - Löbmann, Korbinian

AU - Strachan, Clare

AU - Grohganz, Holger

AU - Rades, Thomas

AU - Korhonen, Ossi

AU - Laitinen, Riikka

N1 - Copyright © 2012 Elsevier B.V. All rights reserved.

PY - 2012/5

Y1 - 2012/5

N2 - The objective of this study was to prepare a co-amorphous drug/drug combination between two BCS class II drugs, simvastatin (SVS) and glipizide (GPZ). This pharmacologically relevant combination of two drugs could produce a promising candidate for formulations intended for combination therapy of metabolic disorders. The co-amorphous SVS-GPZ mixtures (molar ratios 2:1, 1:1 and 1:2) were prepared by mechanical activation (ball milling or cryomilling) and characterized with respect to their thermal properties, possible molecular interactions, dissolution properties and physical stability, and compared to the behaviour of pure amorphous forms and their physical mixtures. It was found that even though a molecular mixture was achieved with all SVS-GPZ mixture ratios, no molecular interactions between the drugs could be detected. By formation of co-amorphous single-phase mixtures, only the dissolution rate of GPZ could be improved. The co-amorphous mixtures showed improved stability compared to the pure amorphous forms and the amorphous physical mixtures. It was concluded that this was attributable to the molecular level mixing of SVS with GPZ upon milling, and GPZ is acting as an anti-plasticizer in these mixtures.

AB - The objective of this study was to prepare a co-amorphous drug/drug combination between two BCS class II drugs, simvastatin (SVS) and glipizide (GPZ). This pharmacologically relevant combination of two drugs could produce a promising candidate for formulations intended for combination therapy of metabolic disorders. The co-amorphous SVS-GPZ mixtures (molar ratios 2:1, 1:1 and 1:2) were prepared by mechanical activation (ball milling or cryomilling) and characterized with respect to their thermal properties, possible molecular interactions, dissolution properties and physical stability, and compared to the behaviour of pure amorphous forms and their physical mixtures. It was found that even though a molecular mixture was achieved with all SVS-GPZ mixture ratios, no molecular interactions between the drugs could be detected. By formation of co-amorphous single-phase mixtures, only the dissolution rate of GPZ could be improved. The co-amorphous mixtures showed improved stability compared to the pure amorphous forms and the amorphous physical mixtures. It was concluded that this was attributable to the molecular level mixing of SVS with GPZ upon milling, and GPZ is acting as an anti-plasticizer in these mixtures.

KW - Drug Combinations

KW - Drug Compounding

KW - Drug Incompatibility

KW - Drug Stability

KW - Glipizide

KW - Hypoglycemic Agents

KW - Hypolipidemic Agents

KW - Simvastatin

KW - Solubility

U2 - 10.1016/j.ejpb.2012.02.004

DO - 10.1016/j.ejpb.2012.02.004

M3 - Journal article

C2 - 22353489

SN - 0939-6411

VL - 81

SP - 159

EP - 169

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

IS - 1

ER -