Molecular Understanding of the Compaction Behavior of Indomethacin Polymorphs

Polymorphs enable us to gain molecular insights into the compaction behavior of pharmaceutical powders. Two polymorphs (alpha and gamma) of indomethacin (IMC) were investigated for in-die and out-of-die compaction behavior using compressibility, tabletability and compactibility (CTC) profile, stress-strain relationship, and Heckel, Kawakita and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. CTC analysis revealed that the gamma-form has increased compressibility while the a-form showed greater compactibility. The alpha-form also showed increased tabletability over the gamma-form at all the compaction pressures. Lower values of Py (Heckel parameter) and 1/b (Kawakita parameter) indicated increased deformation behavior of gamma-form. Stress strain analysis also supports the increased compressibility of gamma-form. In addition, Walker analysis showed higher compressibility coefficient (W) for alpha-form, consistent with its greater tabletability. Thus, tabletability of IMC polymorphs was governed by the compactibility of the material. Detailed examination of crystallographic data revealed that the presence of a slip plane system in the gamma-form offered it increased compressibility and deformation behavior. However, the alpha-form showed greater compactibility by virtue of closer molecular packing (higher true density). Hence, although direct correlation between tabletability and the presence of slip planes in the crystals has been reported, prediction solely based on this crystallographic feature must be avoided. The present work reiterates the influence of the crystal packing on the tabletability of the pharmaceutical polymorphs.