Purpose: Cocrystal engineering has received immense prominence in pharmaceutical formulation development . The presence of coformer as an integral part of the crystal lattice in cocrystals results in significant change in the physicochemical properties. The last two decades have witnessed wide range applications of cocrystals in fine-tuning pharmaceutically important properties such as solubility, dissolution rate, hygroscopicity, stability, mechanical properties, etc . Understanding the surface properties and morphology of pharmaceutical cocrystals leads to a greater understanding of surface reactivity, which in turn can be related to stability and interactions with other solids or liquids such as water. In this study, the properties of pure API’s and cocrystals were studied by investigating the crystal structure, surface energy, solubility, and dissolution rate.
Methods: Griseofulvin (antifungal drug, GF) and Carbamazepine (anticonvulsant drug, CBZ) were chosen as model APIs. Several different cocrystal systems were studied: GF with acesulfame (ACEH); CBZ with hydroquinone (HQ), nicotinamide (NA), and aspirin (ASP). While all the CBZ cocrystals are in 1:1 molar ratio, the cocrystal of GF with ACEH is in 2:1:1 molar ratio with the third component being a water molecule . The cocrystals were prepared as described previously [2,3]. Powder X-Ray Diffraction (PXRD) was used to confirm the cocrystal identity and purity. Inverse Gas Chromatography (IGC) was then used to measure the surface energy distributions of pure API’s and cocrystals. Slurry-agitation method was used for solubility measurement and powder dissolution experiments were conducted using a Varian VK7010 dissolution apparatus.
Results: PXRD results confirmed creation of cocrystals and they were identical to the PXRD patterns reported for the model systems chosen for this study. For the CBZ-HQ materials, surface energy distribution indicated that the CBZ-HQ cocrystal had total surface energy values more similar to pure HQ than that of CBZ (Figure 1b). The CBZ-HQ physical mixture had surface energy values very similar to pure CBZ. Combined, these results indicate that the CBZ-HQ cocrystal had unique surface properties compared to the pure API and physical mixture samples. For the CBZ-NA system, surface energy profiles as measured by IGC (Figure 1a) indicated that the surface energy values for pure materials and cocrystals were similar. For the CBZ-ASP samples, the cocrystal had surface energy values more similar to CBZ, while the physical mixture was more closely related to ASP (Figure 1c). In the case of GF-ACEH system, the GF-ACEH cocrystal had surface energy values closer to GF than ACEH surfaces (Figure 2a).
Solubility experiments of the CBZ cocrystals revealed that the CBZ-ASP and CBZ-HQ cocrystals show approximately same solubility as that of pure CBZ. In contrast, the CBZ-NA cocrystal showed 3 times the solubility of CBZ (Table 1). The cocrystals with ASP and HQ also show similar initial dissolution rates as pure CBZ, while the cocrystal with NA had a lower initial dissolution rate (Figure 1d). In the case of GF, the cocrystal hydrate showed 3 times the solubility of the parent GF, which also has a significant impact on the dissolution rate which resulted in higher dissolution rate of the cocrystal than the parent GF (Figure 2b).
Conclusion: The surface properties of different cocrystal systems were investigated by IGC and compared the results with their physicochemical properties. The results indicated that most of the cocrystal samples had unique properties compared to the cocrystal constituents. The differences in surface properties and the physicochemical properties (solubility and dissolution rate) could be rationalized on the basis of crystal structures of the cocrystals and parent APIs. For example, an analysis of the crystal structure of the GF revealed its hydrophobic nature by the absence hydrogen bond donors and the presence several hydrophobic methyl groups. On the other hand, the cocrystal hydrate with ACEH makes it hydrophilic with exterior functional groups accessible for water molecules to form hydrogen bonds. Therefore, the cocrystal showed a significant improvement in solubility and dissolution rate. A similar analogy has been drawn for the cocrystals of CBZ in which the parent CBZ self-assembles in the crystal structures with dimers mediated by amide-amide dimers and weaker inter-dimer interactions, while the crystal structures of the cocrystals feature stronger intermolecular molecular interactions and confer greater stability to the crystal lattice. Thus, the unique structural features in cocrystals have a direct impact on the surface functionalities and in turn impact the surface energetics. The unique surface energy characteristics of the cocrystals could lead to desired formulation, drug delivery, or stability characteristics compared to the pure API materials.
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Armando Garcia– Surface Measurement Systems, Ltd.
Frank Thielmann– Novartis Pharma AG
Jerry Heng– Reader, Imperial College London, London, England
Srinivasulu Aitipamula– Institute of Chemical and Engineering Sciences
Jin Wang Kwek– Institute of Chemical and Engineering Sciences