Drug-drug salts of Naftopidil with non-steroidal anti-inflammatory drugs for potential multi-drug therapy

Drug-drug cocrystals (DDCs) are a subclass of pharmaceutical cocrystals in which both the components of a cocrystal are active drugs. DDCs are the recent advancement based on the crystal engineering approach to overcome the problems associated with conventional combination therapy. They also allow the modulation of the physicochemical properties of parent drugs. Four new drug-drug salts of Naftopidil (NFPD), a BCS class IV anti-cancer drug, were prepared by liquid-assisted grinding and solvent evaporation technique, with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as Aspirin (ASP), Tolfenamic acid (TFA), Mefenamic acid (MFA) and Niflumic acid (NIFA) as coformers. The solids obtained were characterized by Single Crystal X-Ray diffraction (SCXRD), Powder X-ray Diffraction (PXRD), Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC). Furthermore, the solubility of NFPD in the solids was determined by the shake flask method. SCXRD analysis showed that O–H···N hydrogen bond interactions found in the pure NFPD crystal structure are replaced by the N+–H···O- and O–H···O hydrogen bond interactions in the drug-drug solids. Additionally, the transfer of a proton from the carboxylic group of NSAIDs to piperazine nitrogen of NFPD is observed in all the drug-drug crystal structures, which suggests the nature of the solids as salts. NFPD-ASP salt exhibited improved solubility (33.2 µg/ml), which is eight-fold higher than the pure NFPD solubility (4.3 µg/ml). NFPD-MFA (0.6 µg/ml), NFPD-TFA (0.17 µg/ml), and NFPD-NIFA (1.35 µg/ml) showed reduced solubility than the pure NFPD. We anticipate that the current research will provide an alternate strategy to overcome the solubility issue of NFPD and provide potential candidates for designing combination therapy to treat complications in Benign Prostatic Hypertrophy (BPH), which involves pain and inflammation.