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 form even in cocrystal formation. In an effort to reduce the number of unit operations, high-shear wet granulation with cocrystallization system was proposed. In the present study, indomethacin-saccharin was chosen as a model compound, and the cocrystal formation kinetics was investigated during the consistent process. The role of each initial indomethacin crystal state (γ-form, α-form, or amorphous) for the kinetics was explored using in situ Raman spectroscopy with multivariate curve resolution by alternating least-squares analysis as a chemometrics. Obtained granules were characterized by X-ray diffraction and tablet dissolution testing. The Raman peaks assigned to indomethacin-saccharin cocrystal were increased with granulation when ethanol was used as a binding solvent. In addition, the reaction kinetics of run samples which had different indomethacin forms was distinguished by best fitting using Avrami-Erofeev or Ginstling-Brounshtein model. The kinetic variance depended on the initial thermodynamic state of indomethacin because they had a different crystallization mechanism for the cocrystal. The scalable and feasible granulation method is required in the pharmaceutical industry.

Keywords: Raman spectroscopy; chemometrics; cocrystal; continuous processing; crystal engineering; crystal structure; crystallization; granulation; kinetics; process analytical technology.