Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
Pharm Res. 2009 Dec;26(12):2599-606. doi: 10.1007/s11095-009-9974-3. Epub 2009 Oct 6.
The objective of this study was to investigate the effects of polymer type and storage relative humidity (RH) on the crystallization kinetics of felodipine from amorphous solid dispersions.
Crystallization of the model drug felodipine from amorphous solid dispersion samples containing poly(vinyl pyrrolidone) (PVP) and hypromellose acetate succinate (HPMCAS) were evaluated. Samples at three different drug-polymer weight ratios (10, 25, and 50 wt. % polymer) were prepared and stored at six different RHs (0%, 32%, 52% or 66%, 75%, 86%, and 93%). Periodically, the fraction of the drug that had crystallized from the samples was quantified using powder X-ray diffractometry (PXRD).
Felodipine crystallization rates from PVP-containing dispersions were found to be very sensitive to changes in storage RH, while crystallization rates from HPMCAS-containing dispersions were not. PVP and HPMCAS were similar in terms of their ability to inhibit crystallization at low RH, but when the storage RH was increased to 75% or above, felodipine crystallization from PVP-containing solid dispersions proceeded much faster. It is hypothesized that this trend was caused by moisture-induced drug-polymer immiscibility in PVP-felodipine system. For PVP-containing solid dispersion samples stored at 75% RH and above, crystallization of the model drug felodipine seemed to approach a kinetic plateau, whereby a fraction of the drug still remained amorphous even after storage for 500 days or more.
The physical stability of solid dispersions as a function of RH is highly dependent on the polymer used to form the solid dispersion, with PVP-containing dispersions being much less physically stable at high RH than HPMCAS-containing dispersions.
本研究旨在考察聚合物类型和储存相对湿度（RH）对非晶态固体分散体中氨氯地平结晶动力学的影响。
评估了含有聚乙烯吡咯烷酮（PVP）和醋酸羟丙甲纤维素琥珀酸酯（HPMCAS）的模型药物氨氯地平从无定形固体分散体样品中的结晶情况。制备了三种不同药物-聚合物重量比（10、25 和 50wt%聚合物）的样品，并在六种不同的 RH（0%、32%、52%或 66%、75%、86%和 93%）下储存。定期使用粉末 X 射线衍射法（PXRD）定量测定样品中已结晶药物的分数。
发现含 PVP 分散体中氨氯地平的结晶速率对储存 RH 的变化非常敏感，而含 HPMCAS 分散体中氨氯地平的结晶速率则不然。PVP 和 HPMCAS 在低 RH 下抑制结晶的能力相似，但当储存 RH 增加到 75%或以上时，含 PVP 的固体分散体中氨氯地平的结晶速度快得多。据推测，这种趋势是由 PVP-氨氯地平体系中水分诱导的药物-聚合物不混溶性引起的。对于储存 RH 为 75%或以上的含 PVP 固体分散体样品，模型药物氨氯地平的结晶似乎接近动力学平台，即在储存 500 天或更长时间后，仍有一部分药物保持无定形态。
RH 下固体分散体的物理稳定性高度依赖于用于形成固体分散体的聚合物，与含 HPMCAS 的分散体相比，含 PVP 的分散体在高 RH 下的物理稳定性要差得多。
