A Combined Experimental and Modeling Workflow to Tune Surface Properties of Organic Materials via Cocrystallization

Abstract

Cocrystallization is a specific crystal engineering strategy widely used to enhance the dissolution rate or bioavailability of active pharmaceutical ingredients. In this work, we demonstrate how cocrystallization can also be used to tune surface properties of crystalline particles, such as facet-specific surface chemistry, polarity, and wettability. As a model system, we have isolated a cocrystal of quercetin (Que) with imidazole (Im). Que is widely recognized for its potential antioxidative and antibacterial properties and other potentially beneficial therapeutic effects. Surface chemistry is a property that can affect ease of manufacturability (e.g., flowability) and storage stability (e.g., tendency to agglomerate) for particulate materials; here, we used cocrystallization to modify this property for Que particles. The screening of suitable coformers was first performed in silico using a method based on molecular complementarity and hydrogen bond (H-bond) propensity scores. Experiments were conducted using the identified coformers via slurrying in different solvents. The cocrystal was identified and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Raman spectroscopy, and solid-state nuclear magnetic resonance (SSNMR). The Que-Im crystal structure was solved by single-crystal X-ray diffraction (SXRD) and characterized computationally, using the attachment energy model, and experimentally by contact angle measurements. Structural and vibrational analyses showed a major modification in intermolecular interactions of Que-Im compared to pure Que polymorphs. The contribution of the H-bond and π-π stacking interactions to the crystal energy is similar, but the crystal morphology exposes a predominant facet growing via van der Waals interactions. As a result, Que-Im is more hydrophobic than the dihydrate (QDH) and dimethyl sulfoxide (QDMSO) solvate forms. The shift in the average water droplet contact angle from 38.8 ± 1.0° (QDMSO), 48.0 ± 3.2° (QDH) to 78.5 ± 3.9° (Que-Im) is strong evidence of a marked decrease in hydrophilicity of the target compound.

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Molecular diagram of a) quercetin (Que) and b) imidazole (Im) with atom numbering.

1. Computational and Experimental Workflow

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(Left) Comparison of the X-ray powder patterns of Que-Im and the starting materials QDH and Im. (Right) Comparison of the Raman spectra of Que-Im and the starting materials QDH and Im. Cocrystal (black), QDH (purple), and Im (red).

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(Left) DSC comparisons of Que-Im (black), QDH (violet), and Im (red). (Right) TGA and DSC comparison of the Que-Im cocrystal. The thermal analysis was carried out under a N₂ flux at 50 mL/min, with a heating rate of 10 °C/min.

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Solubility data of QDH, Que-Im, and imidazole collected in IPA. The van’t Hoff plots are represented by the lines, where x is the component molar fraction.

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¹⁵N (40.56 MHz) CPMAS spectra of Que-Im and Im acquired with a spinning speed of 9 kHz at room temperature. The red and blue arrows highlight the shifts of the signals on passing from pure Im to Que-Im cocrystal.

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(Left) Optical microscope image of Que-Im crystallization. (Right) Molecular structure of Que-Im. Ellipsoids are drawn at 50% probability level.

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Crystal packing of Que-Im, viewed along the c-axis (a) and the a-axis (b). The molecules are colored by symmetry equivalence, and the H-bonding and π–π stacking interactions are drawn with black dashed lines.

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Principal synthons in Que-Im. Que1 (green), Que2 (blue), and Im (red). The interactions are highlighted with dashed black lines.

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A 2 × 2 representation of the Que-Im facets. Surface topology and rugosity comparison for Que-Im: average plane (green), the region above the average plane (yellow and red), and the region below the average plane (blue). The projected areas of the six facets (001), (−101), (−11–1), (−110), (01–1), and (010) are 49, 59, 62, 61, 57, and 59 nm². The terminations of the facets are shown in a side view for each facet. The atom properties are represented as HBDs (blue), HBAs (red), and aromatic bonds (orange).

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A 2 × 2 representation of the QDH facets. Surface topology and rugosity comparison for QDH: the average plane (green), region above the average plane (yellow), and region below the average plane (blue). The projected areas of the five facets (00–1), (01–1), (0–10), (100), and (1–10) are 78, 77, 50, 44, and 43 nm².The terminations of the facets are shown in the top and side views for each facet. The atom properties are represented as HBDs (blue), HBAs (red), and aromatic bonds (orange).

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A 2 × 2 representation of the QDMSO facets. Surface topology and rugosity comparison for QDMSO: the average plane (green), the region above the average plane (yellow), and the region below the average plane (blue). The terminations of the facets are shown in the top and side views for each facet. The atom properties are represented as HBDs (blue), HBAs (red), and aromatic bonds (orange).

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SEM images of (A) QDH, (B) QDMSO, and (C, D) Que-Im crystals. Facet orientations are depicted with white labels and arrows.

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Contact angle measurements of Que-Im (left), QDH (center), and QDMSO (right).