Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
Mol Pharm. 2010 Oct 4;7(5):1406-18. doi: 10.1021/mp1000197. Epub 2010 May 20.
The crystallization of amorphous drugs during dissolution is a type of solution mediated phase transformation that can reduce the bioavailability enhancement one hoped to gain from the amorphous state. The goal of this study was to explore the effects of processing on the dissolution performance of amorphous indomethacin. The amorphous solids were prepared by four techniques, quench cooling the melted solid, cryogrinding γ indomethacin amorphous for 1 or 3 h and quench cooling the solid followed by 1 h of cryogrinding. Dissolution results assessed in a flow-through intrinsic dissolution apparatus reveal decreases in the dissolution rate of amorphous indomethacin during the experimental time frame indicating that a solution mediated phase transformation has occurred. The amorphous solids prepared by melt quenching and melt quenching followed by cryogrinding showed a significant dissolution rate advantage over the γ form of indomethacin. In contrast, indomethacin that was cryoground amorphous for 1 or 3 h did not show any dissolution rate advantage over the crystalline material. Transformation was confirmed by in situ Raman microscopy and polarized light microscopy with differences seen in the nature of the crystals apparent on the surface of the dissolving solid. A portion of the melt quenched amorphous sample was annealed at 25 °C and 0% relative humidity to induce partial crystallization of γ indomethacin. As crystallinity increased, the dissolution rate decreased. The transformation time of partially amorphous indomethacin was not dependent on the level of crystallinity present, indicating only a small fraction of crystalline material needs to be present to affect the kinetics of crystallization. The solution mediated phase transformation of amorphous indomethacin is affected by the processing method even though all solids were confirmed amorphous by polarized light microscopy and X-ray diffraction. Dissolution may distinguish differences in amorphous solids that other methods cannot discern.
无定形药物在溶解过程中的结晶是一种溶液介导的相转变，可能会降低人们从无定形状态获得的生物利用度增强效果。本研究的目的是探索加工对无定形吲哚美辛溶解性能的影响。通过四种技术制备无定形固体：熔融固体淬火冷却、γ 吲哚美辛无定形研磨 1 或 3 小时以及淬火冷却后研磨 1 小时。在流动式内在溶解仪中评估的溶解结果表明，无定形吲哚美辛的溶解速率在实验时间内降低，表明发生了溶液介导的相转变。通过熔融淬火和熔融淬火后研磨制备的无定形固体在溶解速率方面明显优于 γ 形式的吲哚美辛。相比之下，研磨 1 或 3 小时的无定形吲哚美辛没有显示出比结晶材料更快的溶解速率。通过原位拉曼显微镜和偏光显微镜证实了转变的发生，在溶解固体表面可以看到晶体性质的差异。一部分熔融淬火的无定形样品在 25°C 和 0%相对湿度下退火，以诱导 γ 吲哚美辛的部分结晶。随着结晶度的增加，溶解速率降低。部分无定形吲哚美辛的转变时间与存在的结晶度无关，表明只需要存在一小部分结晶材料就会影响结晶动力学。无定形吲哚美辛的溶液介导相转变受加工方法的影响，尽管偏光显微镜和 X 射线衍射均证实所有固体均为无定形。溶解可能会区分其他方法无法区分的无定形固体之间的差异。
