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.
Highlights
Pharmaceutical crystallization plays a critical role in solid dosage forms, because the physicochemical properties of the solid forms of active pharmaceutical ingredients (APIs) are intrinsically defined by the structures of the API crystals
Adefovir dipivoxil (AD) cocrystals with SUC and suberic acid (SUB) were studied to evaluate the effectiveness of using the binary phase diagrams to assess the cocrystal compositions
X-ray diffraction (XRD) peaks of the cocrystal at 21.54◦ and 22.01◦ displayed subtle changes observed at four different compositions: pure SUC, AD/SUC
Summary
Pharmaceutical crystallization plays a critical role in solid dosage forms, because the physicochemical properties of the solid forms of active pharmaceutical ingredients (APIs) are intrinsically defined by the structures of the API crystals. Salt formation is perhaps the most well-known example, and polymorphs, solvates, hydrates, and cocrystals are the important variations of the solid forms [1,2]. Pharmaceutical cocrystallization is an emerging technology that involves strong intermolecular interactions (usually hydrogen bonding) between APIs and coformers [3,4,5]. The diverse possibilities of coformers have expanded the landscape of pharmaceutical crystallization in a new dimension. Some examples of pharmaceutical cocrystals commercially available on the market are FarxigaTM, SuglatTM, SteglatroTM, and EntrestoTM, and the cases are expected to increase steadily [10,11]. Experimental screening methods for the viable pairs of APIs/coformers are diverse, and a single method does not consider the entire range of cocrystal possibilities.
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