Mechanochemical syntheses and Cl-35 solid-state NMR characterization of fluoxetine HCl cocrystals

Fluoxetine hydrochloride, the active pharmaceutical ingredient (API) in the antidepressant Prozac (R), can form cocrystals with numerous organic acid coformers. The solvothermal syntheses of cocrystals with (i) fumaric acid, (ii) benzoic acid, and (iii) succinic acid coformers were first reported by Childs et al. in 2004. Herein, we report the novel mechanochemical syntheses of these cocrystals, and their structural characterization using a combination of powder X-ray diffraction (PXRD) and solid-state NMR (SSNMR) spectroscopy. It is demonstrated that high-purity samples of fluoxetine HCl cocrystals can be synthesized using neat grinding or liquid assisted grinding in a fraction of the time required for analogous solvothermal syntheses. Cl-35 SSNMR spectroscopy is used as a primary characterization technique of the materials, providing a spectral fingerprint and unique set of Cl-35 electric field gradient (EFG) tensor parameters for each system, due to the extreme sensitivity of the Cl-35 EFG tensor to unique hydrogen bonding arrangements about the Cl- anions. It is also demonstrated that first-principles quantum chemical calculations conducted using the DFT-D2* method, which introduces two-body semiempirical dispersion corrections, can be applied to obtain better models of the true molecular-level structures of the API salts than is possible through XRD alone, because of the ability to accurately position hydrogen atoms. The combined use of Cl-35 SSNMR spectroscopy, PXRD, and DFT-D2* calculations, may find extensive future use in NMR crystallographic refinements of numerous organic HCl salts, including HCl APIs in bulk forms, cocrystals, and dosage formulations.