Differential Solution Behavior of the New API–API Co-Crystal of Tramadol–Celecoxib (CTC) versus Its Constituents and Their Combination

Abstract

Co-crystal of tramadol–celecoxib (CTC) is a novel active pharmaceutical ingredient API–API co-crystal formed by an intrinsic 1:1 molecular ratio of rac-tramadol·HCl (TRM) and celecoxib (CXB) in late-stage development for the treatment of pain. In line with previous intrinsic dissolution rate studies, we report here that the kinetic dissolution profile of CTC in hydroxypropyl methyl cellulose and buffered solutions led to a supersaturation state of CXB and a release significantly faster from CTC than from the free combination, which in turn was quite similar to the release from CXB alone. Inversely, TRM was released much more slowly from CTC than from the free combination and TRM alone. Experimental and predicted solubility–pH curves showed that the thermodynamic solubility of CTC lies in between those of TRM and CXB within the physiologically meaningful pH range. The lattice and solvation contributions to CTC aqueous solubility was studied, showing that the solvation factor is the most important, but it appears to be proportionally lower and more similar to the more soluble component, TRM. These results, together with those obtained in the hygroscopicity studies, show that CTC co-crystal structure provides a clear differential profile versus the free combination or the two APIs alone.