Development and evaluation of high-flowability spherical crystals of tofacitinib citrate Form A for direct powder...

A novel method for preparing spherical crystals of tofacitinib citrate Form A is presented in this study, alongside the determination of its single-crystal structure. Tofacitinib citrate was dissolved in a ternary solvent system of two alcohols and water at elevated temperatures, followed by cooling and the addition of a bridging agent to induce crystallization under stirring, resulting in spherical crystals of tofacitinib citrate Form A. Conventional methods for preparing tofacitinib citrate often yield uneven particle size distribution, typically necessitating a pulverization step. Subsequent wet granulation and other processing techniques into oral solid dosage forms inevitably lead to raw material loss, active dust pollution, and increased costs and processing times. This study leveraged the characteristics of spherical aggregates observed in previously reported crystallization systems and, based on experimental design, hypothesized a mechanism for sphere formation. By employing supersaturation control coupled with a spherical agglomeration method, the morphology of the crystalline product was successfully modified, yielding tofacitinib citrate spherical crystals with excellent flow properties and high bulk density. These crystals exhibit a uniform particle size distribution and good dissolution performance, meeting the requirements for direct compression into oral solid dosage forms without the need for milling. The preparation method is straightforward, facilitating the industrial production of both the active pharmaceutical ingredients and oral formulations.