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

Abstract

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

Crystallization Process Development for the Final Step of the Biocatalytic Synthesis of Islatravir: Comprehensive Crystal Engineering for a Low-Dose Drug

“…In conjunction with purity, the pure recrystallization process must consider the physical property demands for downstream formulations. Islatravir exhibits a complex crystal phase landscape with islatravir monohydrate as the thermodynamically stable form at ambient conditions . Islatravir is also a potent compound with efficacy at sub-milligram doses.…”

“…Islatravir exhibits a complex crystal phase landscape with islatravir monohydrate as the thermodynamically stable form at ambient conditions. 2 Islatravir is also a potent compound with efficacy at sub-milligram doses. Thus, the oral tablet formulations use islatravir monohydrate at low doses, requiring robust control of form and particle size.…”

Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting a 47‐Year‐Old Misunderstanding**

“…Although solution crystallization is the traditional method for polymorph screening, melt crystallization is now revealing a growing list of pharmaceutical polymorphs that cannot be obtained from solution. [3][4][5][6][7][8][9][10][11] Employing X-ray diffraction techniques is the standard approach for identifying polymorphism and since melt crystallization usually yields polycrystalline spherulites it is challenging to elucidate the structures of melt-crystallized polymorphs. Recently, we developed a general method for rapidly growing single crystals from melt microdroplets.…”

Solid-State Dehydration Mechanism of Diclofenac Sodium Salt Hydrates

“…For pharmaceutical hydrates, such property changes may affect their bioavailability and safety as pharmaceutical products. Therefore, the structural investigation of polymorphic transitions and the establishment of dehydration mechanisms of drug hydrates are both important processes in drug development [31].…”