Kinetics Study of Cocrystal Formation between Indomethacin and Saccharin using High-Shear Granulation with In Situ Raman Spectroscopy.

Abstract

Pharmaceutical manufacturing processes are necessary to make solid dosage formulations even in molecular complexes, such as cocrystals, with the following problems: additional pretreatment is required to make the cocrystal, and crystalline transition or decomposition during the process leads to unexpected properties in the products. In the present study for the purpose of making an indomethacin (IND) with saccharin (SAC) cocrystal product and investigation of the kinetics during the consistent process, granules were prepared using a high-shear wet granulation with in situ Raman analysis without the preprocess of cocrystal formation. The role of each initial IND crystal state (γ-form, α-form, amorphous) was explored using Raman spectroscopy with multivariate curve resolution by alternating least-squares analysis (MCR-ALS) as a chemometrics, X-ray diffraction, and tablet dissolution testing. The Raman peaks assigned to IND-SAC cocrystals increased during the granulation using ethanol as a binding solvent. Additionally, the reaction kinetics of run samples which had different IND forms were distinguished by best fitting using Avrami-Erofeev or Ginstling-Brounshtein model. The kinetic variance depended on the initial thermodynamic state of IND, because they had a different crystallization mechanism for the cocrystal. These scalable methods which can reduce the number of unit operations are required in the pharmaceutical industry.