Abstract
Solid form screening and crystal structure prediction (CSP) calculations were carried out on two related molecules, 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid (B5) and 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7). Only one anhydrate form was crystallized for B5, whereas multiple solid forms, including three neat polymorphs, were found for DB7. The crystal structure of B5 is P21/n Z′ = 1 with intramolecular hydrogen bonding, whereas Forms I and II of DB7 are conformational polymorphs with distinct Z′ = 1 P1 structures and intermolecular hydrogen bonds. A disordered structure for Form III of DB7 is proposed, based on CSP-generated structures which gave a promising match to the X-ray powder diffraction and solid state NMR data for this metastable form. The differences in the hydrogen bonding and experimental solid form landscapes of the two molecules appear to arise from the dominance of the self-assembly of the benzoisoxazolepiperazinyl an...
Highlights
Multidisciplinary solid form screening[1−3] is routinely conducted in the pharmaceutical and specialty chemicals industries to ensure that solid forms with the best compromise of physical and chemical properties are developed
We have found that having the crystal energy landscape available during the solid form screening process can be very advantageous, with the combined disciplines helping to clarify the experimental solid form landscape and suggest new experiments and calculations to be explored
The structures of B5 Form I and DB7 Forms I and II were solved by single crystal diffraction, and a disordered structure for DB7 Form III was proposed by combining powder diffraction, SSNMR, and structures on the calculated crystal energy landscape
Summary
Multidisciplinary solid form screening[1−3] is routinely conducted in the pharmaceutical and specialty chemicals industries to ensure that solid forms with the best compromise of physical and chemical properties are developed. With neither a sure fire approach nor a clear end point to finding crystal forms, a computational method for ensuring that all relevant polymorphs have been found is highly desirable To this end, studies on smaller molecules have established crystal structure prediction (CSP) as a complement to solid form screening,[7−11] helping to rationalize and unify experimental observations on polymorphs, solvates, and hydrates.[12−16] In the most recent (2010) blind test of CSP methods, the progress toward tackling larger, flexible molecules allowed a target crystal structure of a molecule large enough to be seen as a model for modern smaller drug molecules.[17] The success in predicting the crystal structure of blind test candidate benzyl-(4-(4-methyl-5-(ptolylsulfonyl)-1,3-thiazol-2-yl)phenyl)carbamate (XX)[18] has led to a series of studies in which the crystal energy landscapes of pharmaceuticals, such as olanzapine (LY170053),[19] N-[(2R)(6-chloro-5-methoxy-1H-indol-3-yl)-propyl]acetamide (melatonin agonist, LY156735),[9,10] and 6-[(5-chloro-2-([(4-chloro2-fluorophenyl)methyl]oxy)phenyl)methyl]-2-pyridinecarboxylic acid (GSK269984B),[20] have been contrasted with industrial. This shows the extent to which the pharmaceutical materials tetrahedron,[22] the relationships between the possible structures, properties, performance, and processing, is specific to a given API rather than a family, and the potential role of CSP in providing the required information
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