Impact of Mixed Solvent on Co-Crystal Solubility, Ternary Phase Diagram, and Crystallization Scale Up

This contribution covers the identification, understanding, and rationale of the interplay between the choice of mixed solvent on the crystallization of the co-crystal system benzoic acid and isonicotinamide (BZ:INA). A critical first step was gauging the impact of solvent choice and composition on the overall crystallization process, across a number of temperature points. This required defining the solubility and phase diagrams of the co-crystal system at specified temperatures, which reflects the cooling by crystallization profile encountered in a batch crystallization step. To this end, identifying and understanding the impact of solvent composition over a selected temperature range on the solubility of co-crystal underpins this contribution

Open questions in organic crystal polymorphism

From Springer Nature via Jisc Publications RouterHistory: received 2020-09-17, accepted 2020-09-25, registration 2020-09-30, pub-electronic 2020-10-19, online 2020-10-19, collection 2020-12Publication status: PublishedFunder: The Royal Society, Industry Fellowship in AstraZenecaPolymorphs, crystals with different structure and properties but the same molecular composition, arise from the subtle interplay between thermodynamics and kinetics during crystallisation. In this opinion piece, the authors review the latest developments in the field of polymorphism and discuss standing open questions

Knowledge-based H-bond prediction to aid experimental polymorph screening

With an ever increasing regulatory and financial emphasis on solid form screening in the pharmaceutical industry, a knowledge-based method has been developed to assess crystal stability based on hydrogen bonding. An application is illustrated for the polymorphic drug ritonavir (Norvir™). The method quickly suggests a real threat of polymorphism in this compound by quantifying the likelihood of competing H-bonds, and strongly supports the relative stability of form II over form I. For the first time, H-bond geometry data are also reported following structure redeterminations deposited recently in the Cambridge Structural Database. The method's speed and versatility are emphasized, facilitating future application in assisting solid form selection of a diverse range of compounds

Phosphine-substituted porphyrins as supramolecular building blocks

A route to alkyne-phosphine-substituted metalloporphyrins is presented. The X-ray structure of the methanol adduct of a diphenylphosphine Zn(II) porphyrin reveals solid state dimerisation accompanied by proton transfer from coordinated methanol to phosphine in a process reminiscent of carbonic anhydrase, The ability of the phosphine-substituted porphyrins to form non-covalent arrays with a Ru(II) porphyrin was explored using H-1/P-31 NMR and UV/vis spectroscopy as well as MALDI-TOF mass spectrometry

Knowledge-based model of hydrogen-bonding propensity in organic crystals

A new method is presented to predict which donors and acceptors form hydrogen bonds in a crystal structure, based on the statistical analysis of hydrogen bonds in the Cambridge Structural Database (CSD). The method is named the logit hydrogen-bonding propensity (LHP) model. The approach has a potential application in identifying both likely and unusual hydrogen bonding, which can help to rationalize stable and metastable crystalline forms, of relevance to drug development in the pharmaceutical industry. Whilst polymorph prediction techniques are widely used, the LHP model is knowledge-based and is not restricted by the computational issues of polymorph prediction, and as such may form a valuable precursor to polymorph screening. Model construction applies logistic regression, using training data obtained with a new survey method based on the CSD system. The survey categorizes the hydrogen bonds and extracts model parameter values using descriptive structural and chemical properties from three-dimensional organic crystal structures. LHP predictions from a fitted model are made using two-dimensional observables alone. In the initial cases analysed, the model is highly accurate, achieving ~ 90% correct classification of both observed hydrogen bonds and non-interacting donor-acceptor pairs. Extensive statistical validation shows the LHP model to be robust across a range of small-molecule organic crystal structures