Department of Pharmacy, Uppsala University, BMC P.O. Box 580, Husargatan 3, 75123 Uppsala, Sweden.
Kulliyyah of Pharmacy, International Islamic University Malaysia, Jalan Istana, Bandar Indera Mahkota, 25200 Kuantan Pahang, Malaysia.
Molecules. 2019 Jul 27;24(15):2731. doi: 10.3390/molecules24152731.
This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (C), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their C and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its C and AUC by 50%, with C being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.
本研究探讨了物理老化和/或结晶对无定形活性药物成分（APIs）过饱和度潜力和结晶动力学的影响。喷雾干燥的完全无定形的吲达帕胺、美托拉宗、格列本脲、氢化可的松、氢氯噻嗪、酮康唑和磺胺噻唑被用作模型 APIs。用于评估过饱和度潜力和结晶动力学的参数是最大过饱和度浓度（C）、曲线下面积（AUC）和结晶速率常数（k）。将这些参数与新鲜喷雾干燥和老化/结晶的样品进行比较。老化样品在 75%相对湿度下储存 168 天（6 个月）或直至完全结晶，以先到者为准。通过差示扫描量热法、拉曼光谱和粉末 X 射线衍射监测固态变化。使用相对于热力学溶解度的十倍过饱和度比使用 µDISS Profiler 研究过饱和度潜力和结晶动力学。与新鲜喷雾干燥的样品相比，物理老化的吲达帕胺和美托拉宗以及最小结晶的格列本脲和氢化可的松在 C 和 AUC 方面没有显著差异。结晶含量为 23%的酮康唑将其 C 和 AUC 降低了 50%，C 与结晶溶解度相同。在储存过程中保持完全无定形的两种化合物之一的老化美托拉宗的 AUC 显著提高，同时结晶动力学显著降低。从无定形化角度来看，格列本脲在过饱和度潜力方面的改善最大。该研究还表明，除了储存期间的固态结晶外，溶解过程中的结晶及其相应途径可能会严重影响完全无定形 APIs 的过饱和度潜力。
