Solid State Pharmaceutics Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
Department of Chemistry, Indian Institute of Technology (IIT), Gandhinagar, Palaj, Gujarat 382355, India.
J Pharm Sci. 2024 Jul;113(7):1844-1853. doi: 10.1016/j.xphs.2024.02.001. Epub 2024 Feb 8.
The solid-state properties of active pharmaceutical ingredient (API) have significant impact on its dissolution performance. In the present study, two different crystal habits viz. rod and plate shape of form I of FEN were evaluated for dissolution profile using USP Type 2 and Type 4 apparatuses. Molecular basis of differential dissolution performance of different crystal habits was investigated. Rod (FEN-R) and plate (FEN-P) shaped crystal habits of Form I of FEN were generated using anti-solvent crystallization method. Despite the same polymorphic form and similar particle size distribution, FEN-P demonstrated higher dissolution performance than FEN-R. Crystal face indexation and electrostatic potential (ESP) map provided information on differential relative abundance of various facets and their molecular environment. In FEN-R, the dominant facet (001) is hydrophobic due to the exposure of chlorophenyl moiety. Whereas, in FEN-P the dominant facet (01-1) was hydrophilic due to the presence of chlorine and ester carbonyl groups. Deeper insight on the impact of different facets on dissolution behavior was obtained by energy framework analysis by unveiling strength of intermolecular interactions along various crystallographic facets. Moreover, type 4 apparatus provided higher discriminatory ability over USP Type 2 apparatus, in probing the crystal habit induced differential dissolution performance of FEN. The findings of this study emphasize that crystal habit should be considered as an important critical material attribute (CMA) during formulation development of FEN and due considerations should be given to the selection of the appropriate dissolution testing set-up for establishing in vitro-in vivo correlation.
活性药物成分（API）的固态性质对其溶解性能有重大影响。在本研究中，使用 USP 类型 2 和 4 仪器评估了两种不同的晶体形态，即 I 型 FEN 的棒状和片状，以评估其溶解曲线。研究了不同晶体形态差异溶解性能的分子基础。使用反溶剂结晶法生成 I 型 FEN 的棒状（FEN-R）和板状（FEN-P）晶体形态。尽管具有相同的多晶型形式和相似的粒度分布，但 FEN-P 表现出比 FEN-R 更高的溶解性能。晶体面指数和静电势（ESP）图提供了有关不同晶面相对丰度及其分子环境的信息。在 FEN-R 中，由于氯苯基部分的暴露，主导晶面（001）是疏水性的。而在 FEN-P 中，由于氯和酯羰基的存在，主导晶面（01-1）是亲水性的。通过揭示沿各种晶体学晶面的分子间相互作用强度，通过能量框架分析更深入地了解了不同晶面对溶解行为的影响。此外，与 USP 类型 2 仪器相比，类型 4 仪器在探测 FEN 的晶体形态引起的差异溶解性能方面提供了更高的辨别能力。这项研究的结果强调，在 FEN 的配方开发过程中，应将晶体形态视为重要的关键材料属性（CMA），并应考虑选择适当的溶解试验装置，以建立体内外相关性。
