Liquid-assisted grinding was employed to generate a cocrystal of adefovir dipivoxil (AD) and glutaric acid (GLU), which had not been successfully obtained through solution crystallization. The cocrystal formation was confirmed with powder X-ray diffraction, and its thermal stability and release behavior were studied through differential scanning calorimetry and dissolution experiments, respectively. The AD/GLU cocrystal was less stable than neat AD phase and the previously reported AD cocrystals with other dicarboxylic acids, such as suberic acid and succinic acid. This suggests that the intermolecular interactions of the AD/GLU cocrystal are probably weaker than the other crystal phases. The release behavior of the AD/GLU was comparable with the cocrystal with suberic acid. The current study verifies the effectiveness of the liquid-assisted grinding for the preparation of the thermodynamically less stable cocrystal phase.
Pharmaceutical cocrystallization is a useful method to regulate the physical properties of active pharmaceutical ingredients (APIs). Since the cocrystals may form in various API/coformer ratios, identification of the cocrystal composition is the critical first step of any further analysis. However, the composition identification is not always unambiguous if cocrystallization is performed in solid state with unsuccessful solution crystallization. Single melting point and some new X-ray diffraction peaks are necessary but not sufficient conditions. In the present study, the use of melting diagrams coupled with the X-ray diffraction data was tested to identify cocrystal compositions. Adefovir dipivoxil (AD) was used as a model API, and succinic acid (SUC), suberic acid (SUB), and glutaric acid (GLU) were coformers. Compositions of AD/SUC and AD/SUB had been previously identified as 2:1 and 1:1, but that of AD/GLU was not unambiguously identified because of the difficulty of solution crystallization. Melting diagrams were constructed with differential scanning calorimetry, and their interpretation was assisted by powder X-ray diffraction. The cocrystal formation was exhibited as new compositions with congruent melting in the phase diagrams. This method correctly indicated the previously known cocrystal compositions of AD/SUC and AD/SUB, and it successfully identified the AD/GLU cocrystal composition as 1:1. The current approach is a simple and useful method to assess the cocrystal compositions when the crystallization is only possible in solid state.
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