Olanzapine Form IV: Discovery of a New Polymorphic Form Enabled by Computed Crystal Energy Landscapes

Abstract

Olanzapine is a polymorphic drug molecule that has been extensively studied, with over 60 structures reported in the Cambridge Structural Database. All anhydrous and solvated forms of olanzapine known to date contain the SC0 dimer packing motif. In this study, a new screening approach was adopted involving heat-induced forced crystallization from a polymer-based molecular dispersion of olanzapine. Simultaneous differential scanning calorimetry-powder X-ray diffraction (DSC-PXRD) was used to heat the amorphous dispersion and to identify a novel physical form from diffraction and heat flow data. Comparison of the diffraction data with those from a computed crystal energy landscape allowed the crystal structure to be determined. The result was the discovery of a new polymorph, form IV, which does not use the SC0 motif. Hence, while dimer formation is the dominant process that defines crystal packing for olanzapine formed from solution, it seems that molecularly dispersing the drug in a polymeric matrix permits crystallization of alternative motifs. Having identified form IV, it proved possible to scale up the synthesis and demonstrate its enhanced dissolution properties over form I.

Crystal forms in pharmaceutical applications: olanzapine, a gift to crystal chemistry that keeps on giving

“…Alas, some publications (Tiwari et al, 2007), as well as patent claims to a new OZPN form III, overlooked or ignored our 2003 report identifying a third polymorph (III) in mixture with form II, and while the existence of form III was recognized in a 2011 publication reporting a newly discovered form IV (Thakuria & Nangia, 2011), excellent agreement between the PXRD pattern simulated from the single-crystal structure disclosed in this report and the experimental powder pattern of form II quickly disproved the claim of a new polymorph. Only recently has a fourth OZPN polymorph, form IV, been confirmed (Askin et al, 2019), and as will be discussed later, its discovery would wait many years for the right heterogeneous nucleation experiment to be conducted.…”

“…With a growing number of reports of predicted crystal structures having later been found (Braun et al, 2014(Braun et al, , 2016Arlin et al, 2011;Neumann et al, 2015) and the potential to crystallize a more stable polymorph, many attempts, all unsuccessful, were made to target nondimer structures of OZPN (Bhardwaj et al, 2013). Eventually, a fourth polymorph (IV), not based on OZPN dimers, would be discovered using a novel screening approach: heat-induced crystallization from an amorphous polyvinylpyrrolidone (PVP) based molecular dispersion (Askin et al, 2019). The prediction of more stable OZPN crystal structures prompted further exploration of crystallization conditions which ultimately led to the discovery of form IV.…”

Mechanistic In Situ and Ex Situ Studies of Phase Transformations in Molecular Co‐Crystals

“…[7] Most recently,w e employed the DSC-XRD platform with crystal structure prediction work and were able to identify and solvet he structure of an ew polymorph of olanzapine. [8] Herein, we extendt he DSC-XRD approach to explore the fabrication of co-crystals by thermalm ethods. Understanding these processes is important, becausef or industriala pplications co-crystals are most likely to be preparedu sing hot melt extrusion (HME), ac ontinuous manufacturinga pproach which appliesh eat energy to an intimate mixture of the co-formers to generateaco-crystal.…”

“…This approach has led to enhanced understanding of phase transitions in glutaric acid and sulfathiazole, [5] carbamazepine and dihydrocarbamazapine, [6] and paracetamol [7] . Most recently, we employed the DSC‐XRD platform with crystal structure prediction work and were able to identify and solve the structure of a new polymorph of olanzapine [8] …”

A novel ammonium pentaborate – poly(ethylene-glycol) templated polymer-inclusion compound

“…The polymer may form an intrinsic part of a co-crystal structure 1 or it may simply act as a template for crystal growth in the synthesis of new polymorphs. 2 Alternatively, the polymer may act as a template for the formation of novel supramolecular structures. To the best of our knowledge, the ammonium pentaborate -poly(ethylene-glycol) templated polymer-inclusion compound reported here is the only boratebased inclusion compound to host organic guest molecules.…”