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Developing a robust crystallization process for an active pharmaceutical ingredient (API) molecule with a complex polymorphic profile can present a significant challenge. The presented case illustrates an unusual crystallization development problem where a polymorphically complex API has the additional obstacles of poor solubility in standard crystallization solvents as well as a propensity for forming solvates. After early polymorph screening of this candidate highlighted the potential for a complex solid form profile, a variety of experimental approaches was utilized to determine the low-energy polymorph and characterize the various solvates formed. Characterization of the API crystallization process identified a critical solvent composition range for the transformation from a metastable solvate form to the desired polymorph. During subsequent crystallization process development studies, a new lower-energy polymorph was discovered. Examination of the crystal structures led to a rationale for the formation of solvates and the existence of a new lower-energy form.

The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.

A complex relationship between chain length and the concentration dependence of polymer self-diffusion, D p(c)/D p(0), is revealed from analysis of polystyrene (PS) and oligostyrene self-diffusion in solution. Pulsed-field-gradient NMR measurements of PS self-diffusion in styrene and toluene were compared with literature results for PS self-diffusion in benzene, tetrahydrafuran, toluene, and carbon tetrachloride. An empirical relationship was used to correlate D p(c)/D p(0) to the concentration dependence of solvent self-diffusion, D s(c)/D s(0):  D p(c)/D p(0) = [D s(c)/D s(0)]β where β quantifies the relationship between chain length and the concentration dependence of D p. (This power law, with a chain-length-independent β, may be justified from Vrentas−Duda free volume theory.) Accounting for differences in the free volume contribution of the solvent species, β values obtained in the five solvents can be normalized to a single solvent, styrene, revealing universality in the relationship between chain length and the concentration dependence of PS self-diffusion in solution. A strong dependence of β on chain length was observed for oligomers, increasing from 1.0 for styrene (1-unit chain) to ∼2.3 for a 20-unit chain. For unentangled PS, β is nearly chain-length-independent, ranging from 2.5 to 3.4 for chain lengths of ∼55 to ∼1000 units. For longer chains, there is a sharp rise in β with increasing chain length, consistent with entanglement effects. The β values for PS correspond with those from analysis of limited poly(methyl methacrylate) self-diffusion data, supporting the notion that polymers with similar glass transitions and critical chain lengths for entanglement should exhibit similar impact of chain length on the concentration dependence of D p in solution.

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