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

PROJECT SUMMARY DeNovX and its collaborators in the Myerson Group at MIT are developing innovative approaches to improve crystallization of active pharmaceutical ingredients (APIs) and proteins. The goal of this Phase II grant is to expand the use of continuous flow crystallization using enhanced nucleation surfaces to the manufacture of small molecule therapeutics to improve efficiencies, economics, and drug product quality. Continuous flow manufacturing offers many process benefits, but requires high supersaturation ratios that limit application. These limitations can be overcome by facilitating nucleation at lower supersaturation using DeNovX’s surface energy modifications to reduce the thermodynamic and kinetic barriers to nucleation. Public Health benefits accrue from the expanded use of continuous flow crystallization, which offers a 20-50+% reduction in manufacturing costs by replacing capital intensive batch reactors with hood-sized flow crystallization modules. Results from rigorously replicated and controlled studies of different solutes, solvent systems, and hydrodynamic conditions in Phase I provide a high confidence POC supporting development of nucleation enhanced continuous flow crystallization. The product will be small footprint, multi-kg-scalable, and disposable modules that are useful for manufacture of a variety of therapeutic APIs. The tunable surface energies that enhance crystal nucleation are a key innovation in DeNovX’s patented platform technologies. The Phase II hypothesis is that enhanced nucleation surfaces can meaningfully expand the use of continuous flow crystallization to bring manufacturing cost efficiencies to more therapeutic APIs. Specific Aim 1: Conduct controlled, replicate, and statistically significant batch antisolvent crystallization studies to advance the understanding of which surface energy modifications most improve crystal nucleation for ≥ 30 therapeutic APIs selected from the FDA Orange Book. Specific Aim 2: Design and manufacture 30 β-prototype nucleation enhanced continuous flow crystallization modules as consumable products having chemically inert fluid contact surfaces, 1-4 antisolvent injection points, and universal pump connections. Modules will target a fit in a standard 6’ fume hood. Subsequently manufacture 12 pilot units capable of producing ≥ 5 kg of crystalline API per day with ≥ 85% of bulk crystalline material within defined structure, morphology, and size specifications for the chosen API. Specific Aim 3: Identify ≥ 15 API candidates from Aim 1 with suitable nucleation thermodynamics and kinetics and investigate in replicate in the β-prototype nucleation enhanced continuous flow crystallization modules. Data will include purity; crystal structure, size, and morphology characteristics; production yield; etc. Specific Aim 4: Execute ≥ 4 pilot demonstrations of nucleation enhanced continuous flow crystallization of therapeutic APIs for pharmaceutical companies, CROs, CMOs, or generics manufacturers. It is expected that the demonstrations of nucleation enhanced continuous flow crystallization will show improved process economics and quality characteristics for therapeutic APIs.Project Narrative: Relevance to Public Health Research Quality control failures, recalls, and 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 issues. A positive impact to Public Health will derive from the proposed application of continuous flow crystallization, which is a pharmaceutical manufacturing technique that can reduce manufacturing costs while improving product quality.