Mitulkumar A. Patel

Approximately 50% of solid oral dosage forms utilize salt forms of the active pharmaceutical ingredient (API). A major challenge with the salt form is its tendency to disproportionate to produce the unionized API form, decreasing the solubility and negatively impacting product stability. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties of the salt on the disproportionation reaction is unknown. Herein, various solid forms of a model salt, miconazole mesylate (MM), were evaluated for their tendency to undergo disproportionation when mixed with basic excipients, namely tribasic sodium phosphate dodecahydrate (TSPd) and croscarmellose sodium (CCS), and exposed to moderate relative humidity storage conditions. It was observed that the rate and extent of salt disproportionation were significantly different for the various solid forms of MM. As expected, the amorphous salt was highly susceptible to disproportionation, while the dihydrate salt form was resistant to conversion under the conditions tested. In addition, binary excipient blends of amorphous and anhydrous forms exhibited a reduced extent of disproportionation at a higher relative humidity storage condition. This was due to the competitive kinetics between disproportionation to the free base and conversion to the dihydrate salt form. The results of this study provide important insights into the impact of solid-state form on susceptibility to disproportionation that can be utilized for rationally designing robust pharmaceutical formulations.

While polymer induced heterogeneous nucleation (PIHn) has been shown to be a powerful tool for crystallization control and polymorph screening the factors influencing PIHn, such as solvent selection, supersaturation and method of crystallization are not well understood. Herein, we report on the use of PIHn to selectively crystallize a new and rare crystal structure of vanillin. Nearly 65 years ago, Walter McCrone postulated vanillin to be trimorphic. However, only one crystal form, Form I, had been structurally characterized to this point. Form II crystallizes in the space group Pna2₁ with four molecules in the asymmetric unit. Achiral molecules exhibiting such crystal structures account for less than 0.008% of all organic entries in the Cambridge Structural Database. Polymorphic control by PIHn was observed to be highly dependent on the method of crystallization. In the presence of poly(acrylic acid) and poly(methyl methacrylate) micro-particles the thermodynamically stable Form I was crystallized from isopropanol by quench cooling, while metastable Form II was obtained by slow evaporation. To our knowledge this is the first deliberate study to highlight the influence of crystallization method on PIHn.