A peculiar dehydration and solid–solid phase transition of the active pharmaceutical ingredient AZD9898 based on <i>in situ</i> single crystal-to-single crystal transformations

Pettersen, Anna; Putra, Okky Dwichandra; Light, Mark E.; Namatame, Yukiko

doi:10.1039/d0ce00276c

Cited by 8 publications

(6 citation statements)

References 41 publications

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“…Therefore, it is not surprising that water molecules can easily leave the structure as it would be thermodynamically more favorable. Similar cases are also reported in AZD9898, pyrogallol, and phloroglucinol. ,, …”

Section: Resultssupporting

confidence: 80%

“…Similar cases are also reported in AZD9898, pyrogallol, and phloroglucinol. 34,40,41 On the basis of the information above, AZD9567 Form A was not recommended for further development. The analysis shows that Form A contains a disordered structure also at low temperatures that may imply its inefficient packing and contains labile water molecules that are observed to have nonstoichiometric behavior.…”

Section: Resultsmentioning

confidence: 99%

“…During pharmaceutical development, it is also important to understand the water uptake as a function of vapor partial pressure. , To investigate this, we performed vapor sorption–desorption using DVS methods. AZD9567 Form A hydrate shows a continuous sorption–desorption behavior between 0 and 80% RH as shown in Figure (blue line).…”

Section: Resultsmentioning

confidence: 99%

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

Putra

Ottosson

Lill

et al. 2021

Crystal Growth & Design

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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.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

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

Putra

Ottosson

Lill

et al. 2021

Crystal Growth & Design

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“…[33] In this direction, several papers regarding polyalcohol and its amine derivatives have been reported in terms of their thermodynamic and crystallographic properties for advanced TES utilization. [35,[114][115][116][117][118][119][120][121] More importantly, these highly symmetric polyalcohols mainly included PE, neopentylglycol (NPG), tris(hydroxymethyl)amino methane (TRIS), pentaglycerine (PG), trimethylol propane, and 2-amino-2-methyl-1,3-propanediol (AMPL) materials. These molecules absorb a great amount of energy through reversible breaking and the formation of nearest neighbor bonds (H-bond) in the molecular crystals.…”

Section: Polyalcoholsmentioning

confidence: 99%

Emerging Solid‐to‐Solid Phase‐Change Materials for Thermal‐Energy Harvesting, Storage, and Utilization

et al. 2022

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“…In other cases, crystallinity can be preserved after water loss even if significant structural changes result from the collapse of water channels (an effect that can be reversed by exposure of crystals to humidity) . When water molecules do not perform a major structure-sustaining role, the crystal structure can remain intact, with barely any structural alterations. − In metal-ion-associated hydrates, water molecules form strong interactions with transition metals or alkali metals . The resulting hydrated crystal form can show high stability against dehydration .…”

Section: Introductionmentioning

confidence: 99%

Toward an Understanding of the Propensity for Crystalline Hydrate Formation by Molecular Compounds. Part 2

Sanii

Patyk‐Kaźmierczak

Hua

et al. 2021

Crystal Growth & Design

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The propensity of molecular organic compounds to form stoichiometric or nonstoichiometric crystalline hydrates remains a challenging aspect of crystal engineering and is of practical relevance to fields such as pharmaceutical science. In this work, we address the propensity for hydrate formation of a library of eight compounds comprised of 5-and 6-membered Nheterocyclic aromatics classified into three subgroups: linear dipyridyls, substituted Schiff bases, and tripodal molecules. Each molecular compound studied possesses strong hydrogen bond acceptors and is devoid of strong hydrogen bond donors. Four methods were used to screen for hydrate propensity using the anhydrate forms of the molecular compounds in our library: water slurry under ambient conditions, exposure to humidity, aqueous solvent drop grinding (SDG), and dynamic water vapor sorption (DVS). In addition, crystallization from mixed solvents was studied. Water slurry, aqueous SDG, and exposure to humidity were found to be the most effective methods for hydrate screening. Our study also involved a structural analysis using the Cambridge Structural Database, electrostatic potential (ESP) maps, full interaction maps (FIMs), and crystal packing motifs. The hydrate propensity of each compound studied was compared to a compound of the same type known to form a hydrate through a previous study of ours. Out of the eight newly studied compounds (herein numbered 4−11), three Schiff bases were observed to form hydrates. Three crystal structures (two hydrates and one anhydrate) were determined. Compound 6 crystallized as an isolated site hydrate in the monoclinic space group P2 1 /a, while 7 and 10 crystallized in the monoclinic space group P2 1 /c as a channel tetrahydrate and an anhydrate, respectively. Whereas we did not find any direct correlation between the number of H−bond acceptors and either hydrate propensity or the stoichiometry of the resulting hydrates, analysis of FIMs suggested that hydrates tend to form when the corresponding anhydrate structure does not facilitate intermolecular interactions.

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A peculiar dehydration and solid–solid phase transition of the active pharmaceutical ingredient AZD9898 based on in situ single crystal-to-single crystal transformations

Abstract: Isostructural dehydration from form A hydrate to form B, and solid–solid phase transition from form B to C of AZD9898 were revealed by in situ single crystal-to-single crystal transformations.

Cited by 8 publications

References 41 publications

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

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

Emerging Solid‐to‐Solid Phase‐Change Materials for Thermal‐Energy Harvesting, Storage, and Utilization

Toward an Understanding of the Propensity for Crystalline Hydrate Formation by Molecular Compounds. Part 2

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