# Multiplexed Nucleation Approaches for Enhanced High Throughput Screening of Co-Crystals

> **NIH NIH R44** · DENOVX, LLC · 2020 · $1,078,661

## Abstract

PROJECT SUMMARY
DeNovX’s technologies improve crystallization of active pharmaceutical ingredients (APIs) and proteins. Over
70% of APIs exhibit poor H2O solubility and bioavailability that contribute to drug failures. Co-crystallization
mates an API with a supramolecular heterosynthon and is a crystal engineering approach to creating H2O
soluble API compositions, but it is not yet reproducible for high throughput screening (HTS). A punch/die in an
HTS format and a hydraulic press can be used for compressive mechanocrystallization to give reproducible
shear forces adequate to form co-crystals. Phase I demonstrated a high confidence POC with a 48 well format
for HTS mechanocrystallization of an API co-crystal and gave excellent reproducibility in a continuous variation
study. A comparison of the solvent drop grinding benchmark with compressive mechanocrystallization showed
that the latter can be conducted in 81% less time with 60% less material while yielding 25% more sample for
analysis. Through subawards to Stanford’s Synchrotron Radiation Lightsource (SSRL) and Argonne’s
Advanced Photon Source (APS), Phase II will integrate HTS mechanocrystallization with synchrotron powder
X-ray diffraction (PXRD) analysis to give unparalleled minor constituent identification, quantitation, structure,
and throughput. Specific Aim 1: Conduct replicate (n ≥ 6) studies of compressive mechanocrystallization using
α-prototypes to identify variables most impacting API co-crystallization. Examine two benchmarks and ≥ 14
co-crystals from the acidic, basic, and neutral API classes matched appropriately to heterosynthons having
complementary H-bonding behavior. Collect synchrotron PXRD by subawards to SSRL and APS. Specific Aim
2: Test ≥ 6 compressive mechanocrystallization ꞵ-prototypes that can serve as consumable sample holders for
PXRD analyses of APIs and co-crystals. Four prototypes to be compatible with synchrotron PXRD and two
lower multiplexed formats suitable for laboratory PXRD. API co-crystal samples in multiplexed holders to give
synchrotron PXRD compositions within ±3σ of averages for n ≥ 6 continuous variation studies. Specific Aim 3:
Conduct high throughput synchrotron PXRD data collection to demonstrate limit of detection ≤ 0.2% (w/w) for
minor constituent API phases in a continuous variation study using 𝛾-prototype mechanocrystallization sample
holders. Concurrently demonstrate PXRD pattern acquisition rates ≤ 90 s per sample while retaining data
quality. Specific Aim 4: Demonstrate neat and solvent sparse compressive mechanocrystallization HTS of
co-crystals with synchrotron PXRD at SSRL/APS for each of ≥ 6 high impact API targets relevant to
pharmaceutical companies and NIH. Identify new co-crystal phases and preparative conditions enabling
solubility/permeability studies by stakeholders. Reproducible tools for HTS mechanocrystallization of APIs and
co-crystals will benefit Public Health by creating new or repurposed API compositions exhibiting superi...

## Key facts

- **NIH application ID:** 10081479
- **Project number:** 2R44GM116285-02
- **Recipient organization:** DENOVX, LLC
- **Principal Investigator:** Andrew H. Bond
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,078,661
- **Award type:** 2
- **Project period:** 2016-05-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10081479

## Citation

> US National Institutes of Health, RePORTER application 10081479, Multiplexed Nucleation Approaches for Enhanced High Throughput Screening of Co-Crystals (2R44GM116285-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10081479. Licensed CC0.

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