New thermoresistant polymorph from CO₂ recrystallization of minocycline hydrochloride

Purpose: To prepare and thoroughly characterize a new polymorph of the broad-spectrum antibiotic minocycline from its hydrochloride dehydrate salts.

Methods: The new minocycline hydrochloride polymorph was prepared by means of the antisolvent effect caused by carbon dioxide. Minocycline recrystallized as a red crystalline hydrochloride salt, starting from solutions or suspensions containing CO₂ and ethanol under defined conditions of temperature, pressure and composition.

Results: This novel polymorph (β-minocycline) revealed characteristic PXRD and FTIR patterns and a high melting point (of 247∈C) compared to the initial minocycline hydrochloride hydrates (α-minocycline). Upon dissolution the new polymorph showed full anti-microbial activity. Solid-state NMR and DSC studies evidenced the higher chemical stability and crystalline homogeneity of β-minocycline compared to the commercial chlorohydrate powders. Molecular structures of both minocyclines present relevant differences as shown by multinuclear solid-state NMR.

Conclusions: This work describes a new crystalline structure of minocycline and evidences the ability of ethanol-CO₂ system in removing water molecules from the crystalline structure of this API, at modest pressure, temperature and relatively short time (2 h), while controlling the crystal habit. This process has therefore the potential to become a consistent alternative towards the control of the solid form of APIs.