Process Development of a Model Solvate for Drying Research

Drying of organic solvates remains hard to scale down and fully understand, as (a) residual solvent is typically hard to remove due to high solid-phase transport resistances, and (b) precise control over crystal properties is challenging. These issues are especially relevant to the pharmaceutical sector and its stringent quality criteria. We have identified a Schiff base forming a methanol solvate (derived from <i>o</i>-vanillin and <i>para</i>-aminobenzoic acid) with chemical complexity representative of pharmaceutical active ingredients that is cost-effective and a straightforward process for its manufacture has been developed. Initial attempts to crystallize the compound resulted in the formation of a slurry with a high yield stress caused by extremely high product supersaturation. By seeding the crystallization and controlling the addition rate of the catalyzing reagent, the process was successfully scaled up into one which was both high-yielding (93% at 1 L scale) and concentrated. These changes altered the crystal morphology, with crystal growth being favored over nucleation, resulting in larger, higher aspect ratio crystals (from 8 to 20). Powder X-ray diffraction (XRD) showed that the solvated Schiff base gradually transformed into a distinct desolvated polymorph, and a quantitative method for assessing solvent content with XRD was developed. The compound is a promising candidate as a model solvate system for drying trials on account of its (a) high-aspect-ratio morphology typical of many organic products; (b) stability at room temperature, facilitating handling and analysis; (c) desolvation temperature exceeding the boiling point of methanol, separating the drying of the free solvent from the period of desolvation. In conclusion, this relatively unexplored Schiff-base was identified as a promising model solvate for studying drying under industrially relevant conditions.