(M1530-09-57) Cocrystallization: A Strategy to Tune Surface Composition and Improve Wettability of Hydrophobic Drugs

Purpose: Potential wettability issues of upcoming small molecules, showing properties beyond the rule of 5, can negatively affect critical pharmaceutical processes such as dissolution, granulation and coating [1-3]. Use of surfactants, a commonly employed strategy, poses challenges, for example, the type and concentration of surfactants and wettability improvement vary considerably among different classes of drugs [4]. Thus, a need to explore alternative strategies to improve wettability, which are built within the drug system and not dependent on external manipulation, is critical in preformulation and formulation development. Cocrystallization is an emerging preformulation strategy to tune the physicochemical properties of pharmaceutical compounds. Cocrystals are multi-component molecular solids wherein a drug and coformer are crystallized into a single, new solid phase. Herein, we report a novel application of cocrystallization in altering surface composition and improving wettability and its correlation with coformer wettability and biopharmaceutical performance has been investigated extensively. Naringenin (NAR), a flavonoid with antioxidant and anti-inflammatory properties, was selected as a model drug. It has a log P of 2.42 and suffers from poor wettability and poor aqueous solubility, leading to low oral bioavailability.

Methods: Pure phases of 10 pharmaceutical cocrystals of NAR, including four novel cocrystals, were generated using liquid-assisted grinding (LAG) and solution-mediated slurries. Cocrystals were characterized and confirmed for reproducibility across more than 150 batches using PXRD, DSC, SCXRD, FTIR and solution-state ¹H NMR. Contact angles of cocrystal powders were measured using the sessile drop method. Powder was added to double-sided adhesive tape attached to a glass slide, and 4 μL of probe liquid (pH 5 acetate buffer and biorelevant Fed State Simulated Intestinal Fluid (FeSSIF v1)) was dispensed on the powder surface. The contact angle was calculated by measuring the slope of the tangent to the drop at the liquid−solid−vapor interface line. The work associated with processes involved during wetting, i.e., adhesion, immersion and spreadability was calculated using the modified Young’s equation [1, 5]. Particle morphology of cocrystals was determined using scanning electron microscopy. Powder dissolution studies of NAR and cocrystals were performed in a pH 5 acetate buffer and FeSSIF v1 media with a sink index of 0.09, and solution concentrations were quantified using UV-fiber optic probe. Relative Area Under the Curve (RAUC) of cocrystal dissolution with respect to NAR dissolution was employed to measure the extent of supersaturation. Cocrystal morphology and the relative facet surface area was predicted using the Bravais-Friedel-Donnay-Harker (BFDH) method implemented within the CSD Particle feature in the Mercury visualization software [6].

Results: NAR powder in contact with the acetate buffer after 10 seconds resulted in a contact angle of 102˚ ± 4.702˚, suggesting its hydrophobic nature and consistent with its poor wettability. Cocrystallization significantly improved the wettability of NAR in acetate buffer, as all cocrystals reduced the contact angle relative to pure NAR (p-value < 0.005). (Figure 1). Also, cocrystallization significantly reduced all three work processes involved in wetting. In FeSSIF, however, improved wettability of NAR cocrystals r was not observed, which can be attributed to the high surfactant concentration in FeSSIF, which uniformly reduced the contact angle across all materials. Observed contact angles (using acetate buffer) were strongly cocrystal dependent. We classified them in three groups: a) good wettability (NAR:CAF, NAR:HEX, NAR:PRO, and NAR:SUC), b) moderate wettability (NAR:NIC, NAR:INM, NAR:BET and NAR:PIC) and c) poor wettability (NAR:ASP and NAR:TMP).  In follow-on dissolution studies, poor wettability was observed in two variations, either a thin film forming at the air-liquid interface or formation of large aggregates. Cocrystals (NAR:ASP, NAR:PIC, NAR:NIC and NAR:INM ) that formed thin films showed improved supersaturation profiles during dissolution in FeSSIF compared to the acetate buffer. Analyzing our results in terms of coformer properties, we found that coformer wettability was not a strong predictor of cocrystal wettability in either acetate buffer or FeSSIF (Figure 2). Through analysis of cocrystal surface chemistry in Mercury, we found substantially higher density of hydrogen-bond acceptors and donors for NAR:SUC and NAR:PIC compared to NAR:TMP (Form I) on surfaces with respective higher relative areas (Figure 3). The combination of favorable interactions and access due to higher facet surface areas correlated with lower contact angles for NAR:SUC and NAR:PIC.

Conclusion: Pure phases of 10 NAR cocrystals were successfully generated. Substantial reduction in contact angles and work processes of NAR was observed through cocrystallization in acetate buffer. Differential wetting behavior was observed among cocrystals despite having hydrophilic coformers. Cocrystal wettability was found to be not dependent on coformer wettability, as stark differences were observed. For instance, CAF, PIC and TMP showed complete wettability; however, their respective cocrystals showed large differences in contact angle measurements. Analysis and visualization of the surface chemistry helped to understand and correlate polar and dispersive interactions with cocrystal dependent wettability. Overall, this study highlights the potential of cocrystallization as a preformulation strategy to tune surface composition and wettability of pharmaceutical compounds.

References: 1. Chibowski E, Holysz L, Szczes A. Wettability of powders. Adhesion in Pharmaceutical, Biomedical and Dental Fields. 2017:23-49.
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3. Modi SR, Dantuluri AK, Perumalla SR, Sun CC, Bansal AK. Effect of crystal habit on intrinsic dissolution behavior of celecoxib due to differential wettability. Crystal growth & design. 2014;14(10):5283-92.
4. Buckton G. Assessment of the wettability of pharmaceutical powders. Journal of adhesion science and technology. 1993;7(3):205-19.
5. Buckton G. The assessment, and pharmaceutical importance, of the solid/liquid and the solid/vapour interface: a review with respect to powders. International journal of pharmaceutics. 1988;44(1-3):1-8.
6. Parisi E, Del Duca G, Prandini E, Fraterrigo Garofalo S, Rosso C, Chierotti MR, Simone E. A Combined Experimental and Modeling Workflow to Tune Surface Properties of Organic Materials via Cocrystallization. Chemistry of Materials. 2025.

a) Contact angle measurements of NAR and cocrystals in pH 5 acetate buffer and FeSSIF v1, and b) Statistical comparison of contact angle of NAR and cocrystals in both media, wherein */**/***/**** denotes p-value <0.05 and ns denotes non-statistical difference

a) Correlation between relative area under the curve (RAUC) in dissolution profiles with contact angle measurements and b) Correlation between contact angle measurements for coformer and respective cocrystal, in pH 5 acetate buffer and FeSSIF v1

a) Surface chemistry analysis of facets with relatively high surface area, wherein H-bond acceptors are denoted by red, H-bond donors by blue, unsatisfied H-bond donors by sky blue and aromatic region with orange color, and b) Analysis of BFDH morphology and density information of different functional groups on surfaces of facets with relatively high surface area