(521e) Continuous Crystallization Process Development of Modafinil: A Step Towards Achieving Integrated Continuous Manufacturing

Although integrated continuous manufacturing (CM) of drug products is already a reality with multiple commercial products available¹, the integrated CM of drug substances (molecule synthesize and purification by crystallization) is generally lacking behind. Recently, we have reported a highly efficient flow synthesis of modafinil², a drug used to treat excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea, or shift work disorder.³ Modafinil is of particular interest to military and space agencies⁴. This study deals with the purification of modafinil by continuous crystallization (CC) with the ultimate goal to achieve an integrated CM of modafinil. In phase I of the CC development commercially available modafinil was used for (anti-)solvent screening (Crystal16â„¢) including polymorph screening and solid-state characterization (PXRD, DSC, TGA, optical microscopy). All solvents (neat and binary mixtures), except isopropanol, yielded the commercial form I polymorph. Batch trials (50 mL scale) with the most promising solvent methanol (solvent) and water (antisolvent) revealed that relative supersaturation <1.25 (for only cooling) and anti-solvent content < 30% v/v were critical parameters to achieve individual deagglomerated crystals. The crystallization kinetics of commercial and in-house synthesized modafinil were determined by small-scale desupersaturation curve and impurity distribution coefficient experiments followed by a process systems engineering approach that included mathematical modeling. In phase II of the CC development, the process models were used to screen the effect of the critical process parameters (e.g., temperature, solvent/antisolvent ratio, residence time, supersaturation, number of stages) on the critical quality attributes (e.g., purity, yield, crystal size). Finally, the design space of the mixed-suspension mixed-product removal crystallizer (single and multi-stages) at the optimized conditions was determined. The approach allowed to minimize experimental trial-and-error and was supported by subsequent validation experiments to confirm that crude Modafinil obtained as described in literature can be purified by CC. Ultimately, this study represents a vital step towards the realization of integrated CM of modafinil.

1. Vanhoorne, V.; Vervaet, C., Recent progress in continuous manufacturing of oral solid dosage forms. International Journal of Pharmaceutics 2020, 579.
2. Silva-Brenes, D. V.; Emmanuel, N.; López Mejías, V.; Duconge, J.; Vlaar, C.; Stelzer, T.; Monbaliu, J.-C. M., Out-smarting smart drug modafinil through flow chemistry. Green Chemistry 2022, 24 (5), 2094-2103.
3. Billiard, M.; Broughton, R., Modafinil: its discovery, the early European and North American experience in the treatment of narcolepsy and idiopathic hypersomnia, and its subsequent use in other medical conditions. Sleep Medicine 2018, 49, 69-72.
4. Thirsk, R.; Kuipers, A.; Mukai, C.; Williams, D., The space-flight environment: the International Space Station and beyond. Canadian Medical Association Journal 2009, 180 (12), 1216-1220.