First global analysis of the GSK database of small molecule crystal structures

Abstract

Analysis of the molecular and structural features of the GSK crystal structure database and Cambridge Structural Database leads to improved reliability in hydrogen bond propensity models for pharmaceutical polymorphs.

A to Z of polymorphs related by proton transfer

“…51 Also of note is the fact that the GSD has a much larger proportion of ‘free drug’ structures (58.07%) than the DrugCSD (19.53%). 52 These results indicate a much higher fraction of molecules in the CSD are capable of tautomerism than initially identified by Cruz-Cabeza and Groom (10%). 9 Similarly, these numbers are much higher than those reported in marketed drugs (26%).…”

“…The crystallisation solvent itself can influence the tautomeric state in a single direction which may partially explain why so few hydrates or solvates form tautomeric polymorphs. 66 However, no conclusions shall be drawn on this given that hydrates and solvates are generally less commonly observed in the CSD 52,67 and the overall numbers of polymorphs related by proton transfer are small.…”

Understanding Crystal Structures to Guide Form Selection of Active Pharmaceutical Ingredients: A Case Study of AZD9567

“…18,19 The usage of crystal structures as an early tool for building solid form understanding and confidence has been shown for some APIs such as meglumine, bufexamac, cediranib maleate, or GW825964X. 18,20,21 In this paper, we aim to illustrate the importance of crystal structures to guide solid form selection of an API in its early phase development. We therefore use one of the compounds in AstraZeneca's pipelines, AZD9567.…”

“…In early phase drug development, covering preclinical, phase I and II studies, the constraints from a solid-state perspective are the limited amount of materials available for development and the limited amount of solid-state information for the drug candidates itself. , Nevertheless, the attempts to mitigate solid-state landscapes such as rapid polymorph screens, crystallization screens, and salt/cocrystal screens are conducted as early as possible, − including miniaturization and automation. , One of the outcomes of early solid-state screening work is the availability of crystal structures, determined mostly by single-crystal X-ray diffraction. Single crystals that represent the “pure” polymorphic form will unequivocally provide important information to structural aspects such as polymorphic stability assessments and any potential physicochemical properties that might cause issues during upcoming development. , The usage of crystal structures as an early tool for building solid form understanding and confidence has been shown for some APIs such as meglumine, bufexamac, cediranib maleate, or GW825964X. ,, …”

Combining Structural Rugosity and Crystal Packing Comparison: A Route to More Polymorphs?

“…Accordingly, experimental and computational methods have been extensively applied to polymorphism screening, especially in the pharmaceutical field. , The aim is to predict and identify any relevant polymorphic form for a given pharmaceutical compound and, consequently, define the experimental conditions to obtain them. In practice, polymorphism is a phenomenon influenced by several variables, and defining a general protocol is still challenging for several reasons …”