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New Thermoresistant Polymorph from CO2 Recrystallization of Minocycline Hydrochloride

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Abstract

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 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.

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.

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Abbreviations

API:

Active pharmaceutical ingredient

ASAIS:

Atomization of supercritical antisolvent induced suspensions

DSC:

Differential scanning calorimetry

FTIR:

Fourier transform infrared spectroscopy

MRSA:

Methicillin-resistant Staphylococcus aureus

Nl:

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

PR-EOS:

Peng-Robinson equation of state

PXRD:

Powder X-ray diffraction

RH:

Relative humidity

RVC:

Recrystallization visual cell

SAS:

Supercritical antisolvent

SELTICS:

Sideband elimination by temporary interruption of the chemical shift

αMH:

Form α of minocycline hydrochloride

βMH:

Form β of minocycline hydrochloride

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ACKNOWLEDGMENTS AND DISCLOSURES

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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Authors and Affiliations

  1. Centro de Química Estrutural and Department of Chemical Engineering Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal

    Miguel A. Rodrigues, João M. Tiago, Luis Padrela, Henrique A. Matos, Teresa G. Nunes & Edmundo Gomes de Azevedo

  2. Instituto de Investigação do Medicamento (i. Med.ULisboa) Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal

    Lídia Pinheiro & António J. Almeida

Authors
  1. Miguel A. Rodrigues
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  2. João M. Tiago
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  3. Luis Padrela
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  4. Henrique A. Matos
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  5. Teresa G. Nunes
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  6. Lídia Pinheiro
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  7. António J. Almeida
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  8. Edmundo Gomes de Azevedo
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Correspondence to Edmundo Gomes de Azevedo.

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Rodrigues, M.A., Tiago, J.M., Padrela, L. et al. New Thermoresistant Polymorph from CO2 Recrystallization of Minocycline Hydrochloride. Pharm Res 31, 3136–3149 (2014). https://doi.org/10.1007/s11095-014-1406-3

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  • DOI: https://doi.org/10.1007/s11095-014-1406-3

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