The present study was conducted to understand the mechanism behind the generation of hollow crystals. To validate the hypothesis that lamellar-structure-forming ability of a drug may contribute to hollow crystal formation, four different drugs, flufenamic acid (lyotropic lamellar), ketoprofen (temperature-dependent lyotropic lamellar), atorvastatin calcium (a calcium salt) and sodium cromoglycate (thermotropic hexagonal), were selected for the study. Crystallization results were in agreement with the hypothesis that drugs with lamellar properties (in this case flufenamic acid) are capable of forming hollow crystals. An ethanol/ethyl acetate-based solvent system allowed formation of hollow crystals of flufenamic acid, which was confirmed by optical microscopy. Flufenamic acid underwent polymorphic transformation from form I to form III during hollow crystal formation, which was confirmed by differential scanning calorimetry and powder X-ray diffraction. Polymorphic form III without hollow structure was generated to compare and evaluate the contribution of the newly generated habit to improvement of pharmaceutical attributes. Study of the dissolution of the hollow crystals showed a higher dissolution rate compared with plain flufenamic acid (form I) and polymorphic form III without hollow structure, which was attributed to the higher surface area of the hollow crystals. Similarly, at all studied compression pressures, compacted tablets of the hollow crystals demonstrated greater hardness than both plain flufenamic acid and crystals without hollow structure. In conclusion, this study is in agreement with the hypothesis that lamellar liquid crystalline drugs may possess an ability to form hollow crystals, and by virtue of their higher surface area, hollow crystals can improve pharmaceutical attributes like dissolution and compressibility.

中文翻译：

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通过多晶型转变产生空心晶体-氟苯那酸的案例研究†

进行本研究是为了了解中空晶体产生的机理。为了验证一种假设，即一种药物的层状结构形成能力可能有助于空心晶体的形成，使用了四种不同的药物，氟苯那酸（溶致性片状），酮洛芬（取决于温度的溶致性片状），阿托伐他汀钙（钙盐）和钠选择葡萄糖甘酸酯（热敏六角形）进行研究。结晶结果与以下假设相符：具有片层特性的药物（在这种情况下为氟苯那酸）能够形成空心晶体。基于乙醇/乙酸乙酯的溶剂系统允许形成氟芬那酸的中空晶体，这通过光学显微镜确认。氟苯那酸在中空晶体形成过程中经历了从晶型I到晶型III的多晶型转变，这已通过差示扫描量热法和粉末X射线衍射得到了证实。产生了没有空心结构的多晶型物III，以比较和评估新产生的习惯对改善药物特性的贡献。与无氟结构的普通氟芬那酸（I型）和多晶型III相比，对中空晶体溶解的研究显示出更高的溶解速率，这归因于中空晶体的表面积更大。类似地，在所有研究的压缩压力下，中空晶体的压实片均显示出比普通氟芬那酸和无中空结构的晶体更高的硬度。综上所述，