Nucleation Enhanced Crystallization of Pharmaceuticals in Continuous Flow Manufacturing to Mitigate Therapeutic Drug Shortages

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 DESCRIPTION (provided by applicant): Drug shortages negatively affect Public Health by causing treatment delays, medication errors, and by increasing healthcare costs from the need for ad hoc patient management strategies to cope with the shortage. Continuous flow crystallization, a process in which crystalline material is generated under dynamic flow conditions, requires very high concentrations (supersaturation) of the Active Pharmaceutical Ingredient (API), which can degrade the quality of the product and manufacturing process. These issues can be resolved by inducing crystallization at lower supersaturations using surface chemistry modifications. The product of this SBIR will be continuous flow crystallization modules that contain nucleation surfaces allowing for rapid scale up manufacturing of a broad spectrum of APIs in response to therapeutic drug shortages. Public Health benefits accrue from the expanded use of continuous flow crystallization and the QC efficiencies and economic savings that can offset shortages attributable to quality issues and business discontinuation shortages. The overarching innovation of combining cost effective, tunable enhanced nucleation surfaces with continuous flow crystallization represents a disruptive, scalable platform of broad relevance in responding to API and drug shortages. The long term objective is to develop nucleation enhanced continuous flow crystallization modules that are effective in managing drug shortages and in the manufacture of orphan, specialty (e.g., pediatric/geriatric), and commercially relevant APIs. The Phase I hypothesis is that enhanced nucleation surfaces can be incorporated into continuous flow crystallization to improve crystallization rates without adversely affecting the API crystal size and size distribution. The Specific Aims are: (1) For a given set of conditions, demonstrate a 10% improvement in average crystal size, size distribution, or throughput for nucleation enhanced vs. conventional flow crystallization, and (2) Develop and demonstrate a nucleation enhanced continuous flow crystallization module capable of manufacturing kilogram quantities of crystalline EGCg to overcome a current shortage of this API. Ketoconazole will also be studied if the budget and timing allow. Plans for Phase II emphasize an expansion of API targets; For example, ketoconazole; Two drugs with current shortages: dexamethasone and sufentanil citrate; And others defined in consult with NIH. DeNovX operates with a high value products and services model in a $425M600M addressable market, and the Go to Market strategy will leverage appropriate strategic partnerships with CROs, CMOs, and API equipment manufacturers.