Crystal Structure Analysis and Pharmaceutical Properties of Amide Salts Consisting of Paracetamol/Sulfonic Acids as Solid Forms Prepared by Grinding

In this study, we coground paracetamol (APAP), a neutral drug, and the sulfonic acids 1,2-ethanedisulfonic acid dihydrate (EDSA), p-toluenesulfonic acid hydrate (TOSA), and 2-naphthalenesulfonic acid monohydrate (NASA) to prepare crystalline complexes. As a result of cogrinding, we identified two complexes for EDSA and NASA, respectively, and one complex for TOSA. The single-crystal structure analysis of APAP-TOSA and APAP-NASAs revealed that these complexes were amide salts because the sulfonyl group of the sulfonic acids was deprotonated and the free proton was bound to the amide carbonyl group of APAP. However, single crystals of APAP-EDSAs could not be obtained because a complex of p-aminophenol, which is an acid degradant of APAP, only formed with EDSA in precipitation. From these results, the grinding was suitable for screening new complexes with sulfonic acids. Moreover, we performed counter materials exchange reactions to evaluate the stability of the amide salts during the formulation process by identifying the preferentially formed complexes. The amide salt was preferentially generated during cogrinding, indicating that amide salts are relatively stable in the formulation process. Furthermore, APAP-TOSA monohydrate has better tabletability in comparison to to previously reported cocrystals. These findings suggest that the APAP-TOSA amide salt was a pharmaceutically more useful solid form in comparison to cocrystals containing APAP.