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.

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

“…The pellet surface is 0.5 cm 2 , and calculated IDR is in mg/(s·cm 2 ). Reprinted with permission from ref . Copyright 2019 American Chemical Society.…”

Novel Pharmaceutical Cocrystal of Apalutamide, a Nonsteroidal Antiandrogen Drug: Synthesis, Crystal Structure, Dissolution, Stress, and Excipient Compatibility

“…30,31 Further, E-58425, an investigationed novel cocrystal form of celecoxib and tramadol, has very recently been approved by the US-FDA. 32,33 Apalutamide (APA), a second-generation nonsteroidal antiandrogen drug, has been approved by the US-FDA in Feb 2018 and by EMA in Jan 2019 to treat non-metastatic castration-resistant prostate cancer (CRPC). 34,35 The innovator, Aragon pharmaceuticals, and Sloan Kettering developed the product and launched it under the brand name Erleda.…”

Exploring the molecular landscape of multicomponent crystals formed by naproxen drug and acridines

“…For instance, the cocrystal of tramadol–celecoxib proved to have a much better biopharmacological profile than their free combination or the two APIs alone. 8 With these premises, the structural properties of cocrystals involving naproxen and acridines were explored to understand when cocrystals can be obtained, if different stoichiometric ratios are possible and which are the interactions driving their crystal packing. Naproxen (IUPAC name: (2 S )-2-(6-methoxy-2-naphthyl) propanoic acid) is a commonly used nonsteroidal anti-inflammatory drug (NSAID) because it has a wide range of applications.…”