Physical stabilisation of amorphous ketoconazole in solid dispersions withpolyvinylpyrrolidone K25

The glass forming properties of ketoconazole were investigated using differ ential scanning calorimetry (DSC), by quench cooling liquid ketoconazole fr om T-m+10 to 273.1 K, followed by subsequent heating at 5 K/min to T-m+10 K . It was shown that liquid ketoconazole forms a glass which did not recryst allise following reheating, indicating its stability; T-g was found to be 3 17.5+/-0.3 K. However, the presence of a small amount of crystalline ketoco nazole was able to convert the amorphous drug back to the crystalline state : the addition of only 4.1% (w/w) of crystalline material converted 77.1% o f the glass back to the crystalline state, and this value increased as the amount of added crystals increased. PVP K25 was found to be highly effectiv e in the prevention of such recrystallisation, but only if the amorphous dr ug was formulated in a solid dispersion, since physical mixing of amorphous ketoconazole with the polymer resulted in recrystallisation of the former compound. Storage of the solid dispersions for 30 days at 298.1 K (both 0 a nd 52% RH) in the presence or absence of crystals did not result in recryst allisation of the amorphous drug. Solid dispersions formed compatible blend s as one single T-g was observed, which gradually increased with increasing amounts of PVP K25, indicating the anti-plasticising property of the polym er. The values of T-g followed the Gordon-Taylor equation, indicating no si gnificant deviation from ideality and suggesting the absence of strong and specific drug-polymer interactions, which was further confirmed with C-13 N MR and FT-IR. It can be concluded therefore that the physical mechanism of the protective effect is not caused by drug-polymer interactions but due to the polymer anti-plasticising effect, thereby increasing the viscosity of the binary system and decreasing the diffusion of drug molecules necessary to form a lattice. (C) 2001 Elsevier Science B.V. All rights reserved.