Melting Diagrams of Adefovir Dipivoxil and Dicarboxylic Acids: An Approach to Assess Cocrystal Compositions

Abstract

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.

Enhanced Dissolution of Naproxen by Combining Cocrystallization and Eutectic Formation

“…For example, naproxen did not form eutectics with fatty alcohols, such as octadecanol and docosanol, whereas ibuprofen with a similar molecular structure successfully formed eutectics [ 38 ]. This is one of the reasons why we explored the cocrystals of naproxen since cocrystals are likely interacting favorably with an excess amount of its constituting components to make eutectic formation successful [ 18 , 39 , 40 ].…”

Preface of the Special Issue “Pharmaceutical Crystals”

“…Besides the crystal growth, identification of the co-crystal composition is the critical step of any further analysis. An et al successfully utilized the melting diagrams for adefovir dipivoxil and dicarboxylic acids [8]. This method is powerful in assessing the co-crystal composition in solid-state crystallization.…”