(T1130-06-38) Achieving Sustained Supersaturation of Poorly Soluble Naringenin through Cocrystal Engineering

Purpose: Cocrystallization is an emerging preformulation strategy to tune the physicochemical properties of pharmaceutical compounds. Pharmaceutical cocrystals are multi-component molecular solids wherein a drug and coformer are crystallized into a single, new solid phase. Cocrystals can maintain supersaturated drug concentrations in solution, resulting in improved oral bioavailability. However, the solution behavior of most cocrystals is developed via trial-and-error experiments because the correlation of molecular properties of drug and coformers with the extent of drug supersaturation achieved is not explored extensively, and the overall promise of engineering drug product performance through cocrystallization remains quite limited [1-5]. To narrow this knowledge gap, this study was designed to determine how the magnitude and extent of supersaturation correlated with key coformer properties - solubility of coformers relative to the drug, solubility of cocrystals, eutectic concentrations, and also dissolution parameters – wettability, sink index and dissolution media. Poorly water-soluble naringenin (NAR) with low oral bioavailability was selected as a model flavonoid due to its antioxidant properties and potential treatment for a variety of chronic diseases.

Methods: Pharmaceutical cocrystals of NAR were generated by testing 54 pharmacologically safe coformers and using 4 preparation methods, such as liquid-assisted grinding (LAG) and solution-mediated slurries, with over 800 screening experiments. Cocrystals were characterized and confirmed for reproducibility across more than 150 batches using PXRD, DSC, SCXRD, FTIR and solution-state ¹H NMR. The equilibrium solubilities of NAR, coformers and cocrystals were performed at 25^oC in pH 5 acetate buffer and biorelevant Fed State Simulated Intestinal Fluid (FESSIF) media. Powder dissolution studies of NAR, physical mixtures (PMs) and cocrystals were performed in triplicate at room temperature in pH 5 acetate buffer and FESSIF media with sink index (SI) of 0.09, 0.2 and 0.7. NAR and coformer solution concentrations were quantified using either HPLC or an in-situ UV-fiber optic probe. The solid residue was analyzed using PXRD to determine whether a phase transformation occurred. Relative Area Under the Curve (RAUC) of cocrystal dissolution with respect to NAR dissolution was employed to measure the extent of supersaturation. The solubility product and solubility of cocrystals were calculated using concentrations measured at the eutectic point.

Results: Fifteen pharmaceutical cocrystals of NAR, including seven novel cocrystals with succinimide, hexamine, aspartame (ASP), and varying stoichiometries with tetramethyl pyrazine (TMP), were generated in this work (Table 1). All cocrystal dissolutions significantly showed sustained supersaturation in FESSIF compared to PMs and neat NAR, with a p-value < 0.05. A broad range of coformer:drug solubility ratios, from 100 to 100000, were obtained in acetate and FESSIF media. The solubility ratio of coformers has reduced significantly in FESSIF compared to the acetate buffer, but the trend of the solubility ratio remained the same across all coformers. NAR cocrystals with TMP and ASP showed the highest RAUC and sustained supersaturation in FESSIF dissolution studies up to 4 hours, despite having a solubility ratio of coformers in the lowest range (Figure 1). Despite maintaining the same sink index of 0.09, the acetate buffer and FESSIF media resulted in dissolution profiles with substantial differences. This is mainly due to the poor wettability of NAR cocrystals in the acetate buffer, which was substantially improved in FESSIF media, supported by a decrease in contact angle measurements. Incomplete coformer release in the acetate buffer with SI much more than 1 w.r.t coformer, hinted at wettability issues faced by cocrystals in the acetate buffer. In FESSIF with an SI of 0.09, cocrystal dissolution profiles were distinct and coformer dependent, whereas at SI of 0.7, dissolution profiles for all cocrystals showed no meaningful differences, and expectedly, no substantial supersaturation was achieved. Two types of dissolution profiles in FESSIF, i.e., spring-parachute vs moderate spring–extended parachute, were observed wherein differences in C_max, T_max and sustained supersaturation were evident (Figure 2). Cocrystals showing spring-parachute profile completely converted to NAR after 4 hours, whereas a mixture of cocrystal and NAR was obtained for cocrystals showing moderate spring–extended parachute profile. The different dissolution profiles and solid phase conversions were correlated with the solubility of cocrystals.

Conclusion: Through 800 experimental screens, fifteen pharmaceutical cocrystals of NAR, including seven novel cocrystals, were generated. Substantial supersaturation was maintained by NAR cocrystals compared to physical mixtures, resulting in improved solution behavior of NAR. Higher RAUC and sustained supersaturation were achieved with a lower solubility ratio of coformers without needing to rely only on coformers with a high solubility ratio. It is important to consider dissolution media with sufficient wettability and non-sink conditions with a sink index below 0.1 to observe the ‘real’ NAR cocrystal dissolution profile. In conclusion, understanding the interplay between drug and coformer properties to optimize the solution performance of cocrystals is critical to advance cocrystal engineering as a first-line preformulation method in pharmaceutical product development.

References: 1. Good DJ, Rodríguez-Hornedo N. Solubility advantage of pharmaceutical cocrystals. Crystal Growth and Design. 2009;9(5):2252-64.
2. Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Crystal Growth & Design. 2011;11(7):2662-79.
3. Haskins MM, Kavanagh ON, Sanii R, Khorasani S, Chen J-M, Zhang Z-Y, et al. Tuning the Pharmacokinetic Performance of Quercetin by Cocrystallization. Crystal Growth & Design. 2023;23(8):6059-66.
4. Huang S, Xu J, Peng Y, Guo M, Cai T. Facile tuning of the photoluminescence and dissolution properties of phloretin through cocrystallization. Crystal Growth & Design. 2019;19(12):6837-44.
5. Zhu B, Zhang Q, Wang J-R, Mei X. Cocrystals of baicalein with higher solubility and enhanced bioavailability. Crystal Growth & Design. 2017;17(4):1893-901.


Table. Details of naringenin cocrystals generated in this work


Figure. Influence of the solubility ratio of coformers with respect to NAR on sustained NAR supersaturation maintenance



Figure. Influence of sink index on sustained NAR supersaturation maintenance in FESSIF dissolution studies