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

Abstract

AZD9567 is a novel oral selective glucocorticoid receptor modulator drug candidate in AstraZeneca's pipeline. Three distinctive solid forms of AZD9567 were identified during early development where Form A was found to be a hydrate, and both Forms B and C are anhydrous. In this study, we present the significance of applying crystal structure assessments along with typical solid-state experimental characterizations in early stage drug development to guide solid form selection. The Form A hydrate, which is usually regarded as the preferred form in liquid formulation, is found not stable, narrowing the form selection toward Forms B and C. Anhydrous Form C has disorder depending on the temperature and is more stable than anhydrous Form B, and this is supported by a higher melting point and experimental density as well as a series of density functional theory calculations. This eventually results in the recommendation of selecting anhydrous AZD9567 Form C as the solid form to move forward for further development.

Crystallization of Elusive Polymorphs of Meloxicam Informed by Crystal Structure Prediction

“…1,2 It is therefore of no surprise that drug polymorphism, i.e., an ability of a drug molecule to exist in different crystalline forms, is still considered one of the most serious issues for pharmaceutical companies. For every new molecule, solid form screening involving a series of long and costly crystallization experiments is a prerequisite for the development of a drug product, 3,4 yet it still does not guarantee that all possible polymorphic forms will be discovered and properly characterized. 2,5,6 On our road to fully govern the process of crystallizing a desired polymorphic form, we need to recognize the relationship between the crystal structure, crystal morphology, and energetics of a given form with crystallization conditions needed for its preparation.…”

“…Despite the significant progress in crystal engineering, understanding crystallization processes of organic molecules is still far from completion. , It is therefore of no surprise that drug polymorphism, i.e., an ability of a drug molecule to exist in different crystalline forms, is still considered one of the most serious issues for pharmaceutical companies. For every new molecule, solid form screening involving a series of long and costly crystallization experiments is a prerequisite for the development of a drug product, , yet it still does not guarantee that all possible polymorphic forms will be discovered and properly characterized. ,, On our road to fully govern the process of crystallizing a desired polymorphic form, we need to recognize the relationship between the crystal structure, crystal morphology, and energetics of a given form with crystallization conditions needed for its preparation . Meanwhile, especially among pharmaceutical patents, the literature is rich in polymorphic forms, posing serious difficulties in their crystallization, including reproducing experiments disclosed in patents’ examples or experimental protocols of scientific articles (see, for example, the cases of levetiracetam, meloxicam, and curcumin form III).…”

Cocrystallization of multi-kinase inhibitor pazopanib with fenamic acids: improving dissolution and inhibiting cell migration

“…10,[12][13][14] However, polymorphs and pseudopolymorphs are undesired outcomes of crystallization experiments of any solid form which are differing in their physicochemical properties. [15][16][17][18][19][20] Polymorphism is a serious concern in drug development and is investigated under diverse conditions for a long time period. There are several examples where phase conversion occurred in the very late stage of drug development or after reaching the marketplace.…”