Category: Formulation and Quality
Purpose: Although pharmaceutical cocrystals have emerged as a useful strategy for enhancing the solubility, dissolution, and 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 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, such as pH or the presence of additives. 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 additives 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.
Methods: 1:1 Danazol – vanillin cocrystal (DNZ-VAN) was prepared by reaction crystallization method at room temperature. Cocrystal and danazol (DNZ) drug solubilities were measured under equilibrium conditions (eutectic point for cocrystal) at 37 ± 1 °C in pH 6.5 phosphate buffer with known additive concentrations. SA values for each media were calculated as the ratio of cocrystal solubility to drug solubility. Solubilization power (SPdrug = Sdrug,T/Sdrug,aq) values were calculated as the ratio of drug solubility in the presence of additive(s) to aqueous drug solubility. Cocrystal and drug powder dissolution studies in pH 6.5 phosphate buffer with and without additives were conducted using overhead stirring at 100 rpm for 2 hours at 37 ± 1 °C. Solution concentrations of DNZ and VAN were analyzed by high performance liquid chromatography (HPLC), and solid phases were characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Photomicrographs of dissolution aliquots were taken via bright field inverted microscopy using a Leica DMi8 microscope.
Results: DNZ-VAN was found to have an aqueous SA (SAaq) of 183 at pH 6.5. Cocrystal solubility was found to predictably increase in the presence of solubilizing additives, while SA was found to predictably decrease from 183 according to log(SA) = log(SAaq) – 0.5 log(SPdrug). SA represents both the thermodynamically possible drug supersaturation that a cocrystal may generate and the driving force for cocrystal conversion. Solubilizing additives and concentrations were chosen based on the SA – SP diagram to predictably modulate SA to more kinetically achievable values. The thermodynamic function of additives was determined by comparing DNZ-VAN and DNZ powder dissolution results in the presence of different additives at SA values of 2, 12, and 55. While SA = 55 represents the highest thermodynamically possible supersaturation and yielded the highest maximum supersaturation (σmax = Cmax/Sdrug) of 12, it also represents the highest driving force for conversion, which resulted in a relative area under the curve (RAUC = AUCcocrystal/AUCdrug) value of only 2.0. SA = 2 greatly modulated the thermodynamically possible supersaturation such that the highest observed supersaturation was 0.5 at 2 hours, but also represented more kinetically sustainable concentrations and yielded an RAUC value of 14. Kinetic effects on DSP were examined by studying three different additive combinations at similar SA values of 12 – 13. The σmax values ranged from 3.3 – 7.3 in these systems, but the ability to sustain supersaturation and prevent nucleation and growth greatly varied with different additives, as the RAUC values ranged from 1.3 – 16. Dissolution aliquots were observed via microscope to visually examine the different kinetic effects of the additives. Nucleation was inhibited with the additives that resulted in the highest σmax and RAUC values, nucleation was delayed and growth was inhibited with the additives that yielded the middle values, and neither were inhibited nor delayed with the additives corresponding to the lowest values.
Conclusion: Design of cocrystal delivery systems that can generate both thermodynamically possible and kinetically achievable supersaturation in the gastrointestinal tract is essential for cocrystals to be a viable strategy to enhance the bioavailability of poorly soluble drugs. SA is a meaningful thermodynamic parameter to assess the potential for cocrystal conversions and can be predictably modulated through knowledge of additive SP. σmax and RAUC are useful parameters for determining the kinetic functionality of additives to modulate or inhibit nucleation and growth. 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 utilize both the thermodynamic and kinetic control of additives on DSP behavior.