The solubility advantage of amorphous solid dispersions (ASDs) is contingent upon supersaturation being generated and maintained. If crystals are present within an ASD, these crystals directly result in lost solubility advantage, and may also seed crystal growth leading to desupersaturation. The goal of this study was to evaluate the impact of residual crystals on ASD supersaturation profiles. Indomethacin-copovidone (PVPVA) ASDs with different levels of residual crystallinity were manufactured by hot melt extrusion (HME). PVPVA at 5 and 50 µg/mL was found to be a highly effective nucleation and crystal growth inhibitor of indomethacin at high supersaturation. Evidence of polymer adsorption onto indomethacin crystals was observed by atomic force microscopy and scanning electron microscopy. HME ASDs containing 0-25% residual crystallinity demonstrated lost solubility advantage, along with minimal desupersaturation during non-sink dissolution testing. While bulk seeds did not properly represent the impact of residual crystals, extensive polymer adsorption onto residual seed crystals resulted in poisoned crystal growth, limiting the potential dissolution performance consequences. Several risk factors related to the presence of residual crystallinity were identified: polymeric crystal growth inhibition effectiveness, seed properties, and supersaturation conditions.

中文翻译：

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含有残余结晶度的无定形固体分散体：种子性质和聚合物吸附对溶解性能的影响。

无定形固体分散体 (ASD) 的溶解度优势取决于过饱和的产生和维持。如果晶体存在于 ASD 中，这些晶体会直接导致溶解度优势的丧失，并且还可能导致晶种生长导致去过饱和。本研究的目的是评估残余晶体对 ASD 过饱和曲线的影响。通过热熔挤出 (HME) 制造具有不同残留结晶度水平的吲哚美辛-共聚维酮 (PVPVA) ASD。发现 5 和 50 µg/mL 的 PVVPA 在高过饱和度下是一种高效的消炎痛成核和晶体生长抑制剂。通过原子力显微镜和扫描电子显微镜观察到聚合物吸附到吲哚美辛晶体上的证据。含有 0-25% 残余结晶度的 HME ASD 表现出溶解度优势的丧失，以及在非汇溶出测试期间的去过饱和度最小。虽然散装晶种不能正确代表残留晶体的影响，但残留晶种上的大量聚合物吸附会导致有毒的晶体生长，从而限制了潜在的溶解性能后果。确定了与残留结晶度存在相关的几个风险因素：聚合物晶体生长抑制效果、晶种特性和过饱和条件。限制潜在的溶解性能后果。确定了与残留结晶度存在相关的几个风险因素：聚合物晶体生长抑制效果、晶种特性和过饱和条件。限制潜在的溶解性能后果。确定了与残留结晶度存在相关的几个风险因素：聚合物晶体生长抑制效果、晶种特性和过饱和条件。