Islatravir Case Study for Enhanced Screening of Thermodynamically Stable Crystalline Anhydrate Phases in Pharmaceutical Process Development by Hot Melt Extrusion

• DOI: 10.1021/acs.molpharmaceut.0c00316
• Publication Date: 2020-06-08T22:48:47Z
• Authors: Daniel Skomski; Richard J. Varsolona; Yongchao Su; Jingtao Zhang; Ryan Teller; Seth P. Forster; Stephanie Elizabe...; Wei Xu
• Keywords: Hot Temperature; Calorimetry, Differential Scanning; Deoxyadenosines; Polymers; Chemistry, Pharmaceutical; Drug Compounding; Hot Melt Extrusion Technology; 02 engineering and technology; 01 natural sciences; 0104 chemical sciences; 3. Good health; Drug Development; Pharmaceutical Preparations; Solubility; X-Ray Diffraction; Thermodynamics; 0210 nano-technology

The emergence of new active pharmaceutical ingredient (API) polymorphs in development presents significant risks. Even with thorough polymorph screening, pathways toward alternate crystal phases can present themselves over the course formulation development; thus, further improvements phase screening methods are needed. Herein, a case study is presented thermodynamically stable crystalline HIV drug Islatravir (MK-8591, EFdA) that was not isolated from initial screening. In total, five identified: one monohydrate and four anhydrate phases. phase, form IV, unexpectedly discovered during hot melt extrusion (HME) process polymeric implant product formulations while probing extreme manufacturing conditions (elevated shear forces). X-ray diffraction (XRD), differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR) were utilized as principal tools to identify polymorph. result suggests HME introduces may allow these necessarily captured by routine Subsequent investigations identified procedures generate without equipment use special thermal procedures. It found for hydrate rate water loss well entrapment heating vessel play crucial role conversions into different polymorphs. Further, polymer involved also plays critical conversion, likely coating API microparticles thereby altering conversion kinetics. Strategies herein mimic changes manufacture hold promise identification forms earlier stages development.