Van den Mooter G, Wuyts M, Blaton N, Busson R, Grobet P, Augustijns P, Kinget R
Laboratorium voor Farmacotechnologie en Biofarmacie, Campus Gasthuisberg O+N, Herestraat 49, K.U. B-3000, Leuven, Belgium.
Eur J Pharm Sci. 2001 Jan;12(3):261-9. doi: 10.1016/s0928-0987(00)00173-1.
The glass forming properties of ketoconazole were investigated using differential scanning calorimetry (DSC), by quench cooling liquid ketoconazole from 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 recrystallise following reheating, indicating its stability; T(g) was found to be 317.5+/-0.3 K. However, the presence of a small amount of crystalline ketoconazole 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% of 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 effective in the prevention of such recrystallisation, but only if the amorphous drug 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 and 52% RH) in the presence or absence of crystals did not result in recrystallisation of the amorphous drug. Solid dispersions formed compatible blends as one single T(g) was observed, which gradually increased with increasing amounts of PVP K25, indicating the anti-plasticising property of the polymer. The values of T(g) followed the Gordon-Taylor equation, indicating no significant deviation from ideality and suggesting the absence of strong and specific drug-polymer interactions, which was further confirmed with 13C NMR 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.
采用差示扫描量热法（DSC）研究酮康唑的玻璃形成性质，将液态酮康唑从熔点（T(m)）+10℃骤冷至273.1K，随后以5K/min的速率加热至T(m)+10K。结果表明，液态酮康唑形成的玻璃在再加热后不会重结晶，表明其具有稳定性；玻璃化转变温度（T(g)）为317.5±0.3K。然而，少量结晶酮康唑的存在能够使无定形药物重新转变为结晶态：仅添加4.1%（w/w）的结晶物质就能使77.1%的玻璃态药物重新转变为结晶态，并且随着添加晶体量的增加，该值也会增加。发现聚乙烯吡咯烷酮K25（PVP K25）在防止此类重结晶方面非常有效，但前提是无定形药物要制成固体分散体，因为无定形酮康唑与聚合物的物理混合会导致前者重结晶。在有无晶体存在的情况下，将固体分散体在298.1K（相对湿度为0和52%）下储存30天，无定形药物均未发生重结晶。由于观察到单一的玻璃化转变温度（T(g)），且随着PVP K25含量的增加逐渐升高，表明形成了相容共混物，这体现了聚合物的抗增塑性能。T(g)值符合戈登-泰勒方程，表明与理想情况无显著偏差，暗示不存在强的和特定的药物-聚合物相互作用，这通过13C核磁共振和傅里叶变换红外光谱进一步得到证实。因此可以得出结论，保护作用的物理机制不是由药物-聚合物相互作用引起的，而是由于聚合物的抗增塑作用，从而增加了二元体系的粘度，降低了形成晶格所需的药物分子扩散。
