Pharmaceutical Research

, Volume 31, Issue 11, pp 3136–3149 | Cite as

New Thermoresistant Polymorph from CO2 Recrystallization of Minocycline Hydrochloride

  • Miguel A. Rodrigues
  • João M. Tiago
  • Luis Padrela
  • Henrique A. Matos
  • Teresa G. Nunes
  • Lídia Pinheiro
  • António J. Almeida
  • Edmundo Gomes de Azevedo
Research Paper



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


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.


This novel polymorph (β-minocycline) revealed characteristic PXRD and FTIR patterns and a high melting point (of 247 ºC) 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.


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.


Antisolvent effect Minocycline Physical stability Structural characterization Supercritical CO2 



Active pharmaceutical ingredient


Atomization of supercritical antisolvent induced suspensions


Differential scanning calorimetry


Fourier transform infrared spectroscopy


Methicillin-resistant Staphylococcus aureus


Normal liter (mass of 1 l of gas at 1 atm and 20°C)


Peng-Robinson equation of state


Powder X-ray diffraction


Relative humidity


Recrystallization visual cell


Supercritical antisolvent


Sideband elimination by temporary interruption of the chemical shift


Form α of minocycline hydrochloride


Form β of minocycline hydrochloride



We thank Dr. William Heggie and Dr. Zita Mendes from Hovione FarmaCiencia SA (Loures, Portugal) for the fruitful discussions and Professor Aida Duarte for the invaluable help at Microbiology Laboratory of FFUL (Lisbon, Portugal). For financial support, the authors are grateful to Fundação para a Ciência e Tecnologia (FCT), Lisbon (Grants SFRH/BD/39836/2007 and PTDC/EQUFTT/099912/2008, Strategic Project PEst-OE/SAU/UI4013/2011, project RECI/QEQ-QIN/0189/2012) and “Infra-estruturas de C&T” for the funding of the upgrade of the solid-state NMR spectrometer.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Miguel A. Rodrigues
    • 1
  • João M. Tiago
    • 1
  • Luis Padrela
    • 1
  • Henrique A. Matos
    • 1
  • Teresa G. Nunes
    • 1
  • Lídia Pinheiro
    • 2
  • António J. Almeida
    • 2
  • Edmundo Gomes de Azevedo
    • 1
  1. 1.Centro de Química Estrutural and Department of Chemical Engineering Instituto Superior TécnicoUniversidade de LisboaLisboaPortugal
  2. 2.Instituto de Investigação do Medicamento (i. Med.ULisboa) Faculdade de FarmáciaUniversidade de LisboaLisboaPortugal

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