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

> **NIH NIH R44** · DENOVX, LLC · 2020 · $668,775

## Abstract

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 m...

## Key facts

- **NIH application ID:** 9878148
- **Project number:** 5R44TR001380-03
- **Recipient organization:** DENOVX, LLC
- **Principal Investigator:** Andrew H. Bond
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $668,775
- **Award type:** 5
- **Project period:** 2016-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878148

## Citation

> US National Institutes of Health, RePORTER application 9878148, Nucleation Enhanced Crystallization of Pharmaceuticals in Continuous Flow Manufacturing to Mitigate Therapeutic Drug Shortages (5R44TR001380-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878148. Licensed CC0.

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