(M1130-09-51) Engineered Cocrystals to Improve Solution Behavior of Poorly Soluble NAR

Purpose: Pharmaceutical cocrystals are multi-component molecular solids wherein a drug and coformer are crystallized into a single, new solid phase. Cocrystals demonstrate a clear capacity to maintain supersaturated drug concentrations in solution which has been shown to  correlate with improved oral bioavailability. To engineer improved solubility in cocrystals, the conventional logic is to use a coformer with a solubility at a minimum of 10 times that of the drug’s. [1,2]. However, variation in dissolution profiles of cocrystals despite using highly soluble coformer was observed in many cases [3-5]. Thus, the solution behavior of most cocrystals is developed via trial-and-error experiments, and the overall promise of engineering drug product performance through cocrystallization remains quite limited. A challenge is connecting the molecular properties of drug and coformers with the extent of drug supersaturation achieved has not been explored extensively. To narrow this knowledge gap, this study was designed to determine how the magnitude and extent of supersaturation of a model low solubility compound correlated with two key coformer properties:  solubility relative to the drug and solution complexation.  Herein, a total of 12 cocrystals of naringenin (NAR), a poorly soluble flavonoid, and potential treatment for a variety of diseases are reported with varying solution behaviors.

Methods: A series of pharmaceutical cocrystals of NAR were produced with pharmacologically safe coformers of varying aqueous solubilities. Cocrystals were generated using liquid-assisted grinding (LAG) and solution-mediated slurries with equimolar and non-equimolar stoichiometric ratios of NAR:coformer. Cocrystals were characterized and confirmed for reproducibility across batches using PXRD, DSC and solution-state 1H NMR. The equilibrium solubilities of NAR and coformers were performed at 25^oC in pH 5 acetate buffer.Powder dissolution profiles of NAR, each NAR:coformer physical mixture (PM) and NAR cocrystals with powder equivalent to 10 mg NAR (n = 3) were carried out in pH 5 acetate buffer at 25^oC with a sink index of 0.03 and 150 rpm agitation using a rotary shaker. Before all dissolution studies, each sample was sieved using a sonic sifter to control for particle size with fractions captured 150-250 μm used for dissolution studies. The concentration was quantified using HPLC and solid residue was analyzed using PXRD to determine whether a phase transformation occurred. Solution complexation between NAR and coformer was determined by adding excess NAR to 20 mL of pH 5 acetate buffer and increasing concentrations of coformer up to just below its solubility. The slope of the plot of NAR and coformer solution concentration was used to calculate the complexation constant (Kc).

Results: The pure cocrystal phases of different stoichiometric ratios of NAR: nicotinamide, NAR: isonicotinamide, NAR: betaine, NAR: caffeine, NAR: tetramethyl pyrazine, NAR: picolinic acid, NAR: succinimide and NAR: proline were generated. Ethyl acetate-based slurries were found to have a higher success rate of generating pure cocrystal. The equilibrium solubilities of NAR and coformers showed that NAR cocrystals span a broad range of coformer: drug solubility ratios from 100 to 100000 (Table 1). Such a wide range in coformer solubilities was helpful in determining the desired coformer solubility range for maintaining supersaturation. Representative powder dissolution profiles of NAR: succinimide and NAR: caffeine cocrystals in non-sink conditions achieved and maintained NAR concentrations three times higher relative to pure NAR and respective physical mixtures for up to four hours (Figure 1). Interestingly, the solid residue after dissolution studies was found to be NAR for NAR: succinimide cocrystal whereas a mixture of two cocrystal polymorphs for NAR: caffeine. The solution complexation studies showed negligible solution complexation between NAR and coformer for both NAR: succinimide and NAR: caffeine systems.

Conclusion: Twelve pharmaceutical cocrystals of NAR, including five previously unreported cocrystals, were generated in the pure phase in this work. Cocrystallization is a promising strategy to improve the performance of NAR, a weakly ionizable compound with poor aqueous solubility and low bioavailability. Overall, how coformer properties (coformer: drug solubility ratio, solution complexation, and ionization state) impacted drug supersaturation was investigated for a series of NAR cocrystals. Interestingly, we observed similar solution behaviors for two different NAR cocrystals despite a large difference in solubility ratios for coformers, different phases for solid residues and modest differences in solution complexation. In conclusion, understanding the interplay between drug and coformers properties to optimize the solution performance of cocrystals is critical to advance cocrystal engineering as a first-line preformulation method in pharmaceutical product development.

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Table 1. Equilibrium solubilities of NAR and coformers measured at 25oC in pH 5 acetate buffer.

Figure 1. Powder dissolution profiles of NAR, NAR: succinimide (SUC) PM (1:1), NAR:SUC cocrystal, NAR: CAF PM (1:1) and NAR: caffeine cocrystal in pH 5 acetate buffer with sink index of 0.03 at 25oC stirred at 150 rpm.