Thermodynamic and Mathematical Relationships for Predicting Cocrystal Stability and Controlling Dissolution - Supersaturation - Precipitation Behavior

Abstract

Although pharmaceutical cocrystals have emerged as a useful strategy for enhancing the solubility, dissolution, and oral bioavailability of poorly water-soluble drugs, their development has thus far been marked by a lack of critical understanding of their solution behavior and the underlying solution interactions that govern drug supersaturation and exposure. This has led to empirical, time-consuming approaches with inadequate methods to control cocrystal behavior, leaving cocrystals as appearing overly risky and a largely untapped drug development strategy. However, changes in cocrystal solubility and thermodynamic stability have been shown to be readily predictable as a function of changing solution conditions. The purpose of this research is (1) to develop a quantitative, mechanistic-based approach through which known relationships between cocrystal solubility advantage (SA = Scocrystal / Sdrug) and solution conditions such as pH, surfactant concentration, or excess coformer concentration can be used to fine-tune cocrystal inherent supersaturation, and (2) to modulate nucleation by selecting additives that will exhibit thermodynamic and kinetic control over the dissolution-supersaturation-precipitation (DSP) behavior of cocrystal systems. The effects of changing solution conditions on SA and corresponding DSP behavior were studied for cocrystals of three different poorly water-soluble drugs: lamotrigine, danazol, and posaconazole. Cocrystals with highly soluble coformers were found to have SA values orders of magnitude higher than parent drug in aqueous conditions, which left them at high risk for rapid solution-mediated conversion during previously reported in vitro and in vivo dissolution studies. For cocrystals with ionizable components, aqueous solubility was found to predictably change with pH, with some cocrystals exhibiting a transition point pHmax at which cocrystal and drug solubilities were equal and above or below which their relative stabilities were inverted. Cocrystal SA was found to predictably decrease in the presence of additives with increasing drug solubilization power (SPD = Sdrug,T / Sdrug,aq). The SA - SP relationship provided a mechanistic basis to fine-tune SA (thermodynamic supersaturation limit) below critical supersaturation (kinetic supersaturation limit) which, combined with precipitation and growth inhibitors, promoted sustained supersaturation. Drug dose/solubility ratio (D0(D) = Cdose / Sdrug) was found to be an important parameter to define the potential fraction dose dissolved by the cocrystal as well as the risk of dose-limited supersaturation or undersaturation if SA was dialed too low. Finally, excess coformer concentration was also shown to predictably modulate cocrystal SA according to the solubility product Ksp, which allowed the cocrystal to sustain supersaturation and maintain a quasi-equilibrium at concentrations near the eutectic point. Design of cocrystal delivery systems that can generate both thermodynamically possible and kinetically sustainable supersaturation in the gastrointestinal tract is essential for cocrystals to be a viable strategy to enhance the oral bioavailability of poorly soluble drugs. Although cocrystals may appear to be risky due to their vulnerability to conversion to less soluble forms, their development can be successfully streamlined through rational, mechanistic approaches that are cognizant of solubility transition points and utilize both the thermodynamic and kinetic control of additives on DSP behavior.