Tuning surface chemistry via cocrystallization improves wettability of a hydrophobic flavonoid

Cocrystallization is an emerging strategy in preformulation and early solid-form discovery to rationally engineer material properties that facilitate drug product development. Despite the development of a broad library of cocrystals to address poor drug solubility, stability, and processability, relatively few studies have explored cocrystallization as an approach to overcome poor wettability. Herein, sessile drop contact angle goniometry using an acetate buffer (pH 5) probe was employed to quantify the powder wettability of naringenin (NAR), a hydrophobic, poorly soluble flavonoid, and three NAR cocrystals with picolinic acid (PIC), succinimide (SUC), and isonicotinamide (INM). NAR exhibited a large contact angle (102.3°), consistent with its hydrophobic character, whereas all NAR cocrystals showed significantly reduced contact angles in a coformer-dependent manner: NAR:PIC (46.8°), NAR:INM (36.4°), and NAR:SUC (15.5°). To gain mechanistic insight into cocrystal-dependent wettability, a complementary approach was employed blending (i) surface free energy calculations, (ii) analysis of surface chemistry and hydrogen-bonding interaction density derived from single-crystal structures, and (iii) X-ray photoelectron spectroscopy (XPS) for surface-sensitive chemical analysis. Surface analysis-derived hydrophilicity indices were used to assess wettability trends, and several potential sources of variability are considered when interpreting their correlation with measured contact angles. However, this study provides the first evidence that cocrystallization can improve drug wettability in a cocrystal-dependent manner. These findings demonstrate that cocrystallization enables tuning of surface hydrophobicity, while underscoring the need for further studies to establish clear guidelines for coformer selection to achieve tailored wettability by material design.