Abstract
Previously, we have reported on a zwitterionic cocrystal of diclofenac acid and L-proline. However, the solubility of this multicomponent crystal was still lower than that of diclofenac sodium salt. Therefore, this study aimed to observe whether a multicomponent crystal could be produced from diclofenac sodium hydrate with the same coformer, L-proline, which was expected to improve the pharmaceutics performance. Methods involved screening, solid phase characterization, structure determination, stability, and in vitro pharmaceutical performance tests. First, a phase diagram screen was carried out to identify the molar ratio of the multicomponent crystal formation. Next, the single crystals were prepared by slow evaporation under two conditions, which yielded two forms: one was a rod-shape and the second was a flat-square form. The characterization by infrared spectroscopy, thermal analysis, and diffractometry confirmed the formation of the new phases. Finally, structural determination using single crystal X-ray diffraction analysis solved the new salt cocrystals as a stable diclofenac–sodium–proline–water (1:1:1:4) named NDPT (natrium diclofenac proline tetrahydrate), and unstable diclofenac–sodium–proline–water (1:1:1:1), named NDPM (natrium diclofenac proline monohydrate). The solubility and dissolution rate of these multicomponent crystals were superior to those of diclofenac sodium alone. The experimental results that this salt cocrystal is suitable for further development.
Highlights
Diclofenac is a well-established non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic activities [1], and is the most widely consumed NSAID in some countries
Based on the Biopharmaceutics Classification System (BCS), diclofenac is a class II compound with high permeability but low solubility, which results in limited bioavailability
NDH was used as the initial material due to its stability compared to anhydrous ND, as previously stated, to absorbed water from the environment quickly
Summary
Diclofenac is a well-established non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic activities [1], and is the most widely consumed NSAID in some countries. In Indonesia, diclofenac is one of the three most widely used NSAID drugs and represents 14.4% of all NSAIDs consumed in the country [2]. Based on the Biopharmaceutics Classification System (BCS), diclofenac is a class II compound with high permeability but low solubility, which results in limited bioavailability. The rationale behind screening for suitable coformers for pharmaceutical development of a hydrophobic drug should consider the rule of five by Lapinski, i.e., hydrogen bonding, halogen bonding (and non-covalent bonding in general), length of the carbon chain, molecular recognition points, and aqueous solubility [8,9]
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