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

Award Number: R44TR001380
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	DENOVX, LLC	3440 S DEARBORN ST # 204-S	CHICAGO	IL	60616	COOK	USA	National Center for Advancing Translational Sciences	000	3	3/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	DENOVX, LLC	3440 S DEARBORN ST # 204-S	CHICAGO	IL	60616	COOK	USA	National Center for Advancing Translational Sciences	000	3	11/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $668,775 )
2020	2020	DENOVX, LLC	651 S. SUTTON RD., STE. 300	STREAMWOOD	IL	60107	COOK	USA	National Center for Advancing Translational Sciences	000	3	3/2/2020	NON-COMPETING CONTINUATION	$668,775
														Subtotal = $668,775

Issue Date FY: 2019 ( Subtotal = $800,139 )
2019	2019	DENOVX, LLC	651 S. SUTTON RD., STE. 300	STREAMWOOD	IL	60107	COOK	USA	National Center for Advancing Translational Sciences	000	2	2/20/2019	COMPETING CONTINUATION	$800,139
														Subtotal = $800,139

Grand Total All Awards = $1,468,914

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

Award Number: R44TR001380

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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