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The landscapes of observed and predicted three-dimensional crystal packing arrangements of small-molecule drug candidates can be complex. The possible appearance of a more thermodynamically stable solid form during drug development has led to the digital workflow of informatics-based risk assessments, named a Solid Form Health Check. Herein, we describe the use of a combined approach consisting of experiments, informatics together with energetic calculations in analysis of four competing polymorphs of PF-06282999, a myeloperoxidase (MPO) inhibitor with conformational flexibility and multiple plausible hydrogen bond networks. This combined approach offered a comprehensive understanding of the solid form structure, properties, and performance, ensuring robust solid form derisking and selection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Levofloxacin is a broad-spectrum antibiotic that exists as a hemihydrate under ambient conditions. In addition to the hemihydrate, there are three known crystalline anhydrate forms, denoted as α, β, and γ. In this study, differential scanning calorimetry (DSC), thermogravimetric analysis, Raman spectroscopy, single-crystal and powder X-ray diffraction, and solid-state NMR spectroscopy were used to investigate the transitions that occurred upon dehydration to the anhydrate as well as additional transitions that occurred to the anhydrous material upon heating/cooling. An enantiotropic conversion was observed in the DSC around 54°C corresponding to the conversion of the γ form to a new form, denoted as the δ form. Raman spectroscopy, powder X-ray diffraction, and solid-state NMR spectroscopy confirmed that a new crystalline form was being produced., (Copyright © 2012 Wiley Periodicals, Inc.)

Nonstoichiometric channel hydrates are a class of crystalline hydrates that can incorporate a range of water levels as a function of temperature and relative humidity (RH). When a nonstoichiometric channel hydrate can dehydrate to yield a physically stable isostructural crystalline lattice, it may become challenging to accurately evaluate the thermodynamic stability relationship associated with a polymorphic system using traditional methods. This work demonstrates application of a eutectic-melting method to determine the stability relationship between a nonstoichiometric channel dehydrate and an anhydrous form. A transition temperature (122°C) between the isostructural dehydrate of the nonstoichiometric channel hydrate and the anhydrous polymorph was identified, with the nonstoichiometric channel hydrate being the thermodynamically stable anhydrous form at room temperature (RT). Solid-state storage at a range of RH conditions demonstrated that the nonstoichiometric channel hydrate is also the stable form at RT above an RH of 94%. These results demonstrate that the nonstoichiometric channel hydrate is the stable form at low temperatures, independent of its hydration state. It has been demonstrated that the eutectic-melting method is applicable to the study of thermodynamic stability relationships between anhydrous forms and dehydrated channel hydrates., (Copyright © 2012 Wiley Periodicals, Inc.)

There are two major challenges in developing a solid form: (1) identifying the thermodynamically stable form and (2) determining the method used to crystallize that form. Often experiments performed to address these challenges have different objectives and use separate experimental techniques. The thermodynamically stable form is usually found on small scale, utilizing slurries or crystallizations. Subsequently, a crystallization process is developed to purge impurities and to increase yield and these experiments are typically conducted on medium to large scale (greater than 10  g). Axitinib, a research compound for the treatment of cancer, forms solvates in most solvents to which it is exposed, presenting a problem in discovering and making a desirable anhydrous phase. A method has been developed that will give the best chance of making a thermodynamic stable form of the anhydrous material, necessarily not a desolvated form. This approach relies on solvent mediated transformation (thermodynamic control), rather than crystallization or solid-to-solid phase desolvation (generally kinetic control). Experimental conditions (a desolvation window) to produce an anhydrous solid form for this compound that shows predominance for solvate formation is detailed., (Copyright © 2010 Wiley-Liss, Inc. and the American Pharmacists Association)