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

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.

KEY WORDS

Antisolvent effect Minocycline Physical stability Structural characterization Supercritical CO2 

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

Notes

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.

References

  1. 1.
    Bishburg E, Bishburg K. Minocycline – an old drug for a new century: emphasis on methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii. Int J Antimicrob Agents. 2009;34:395–401.PubMedCrossRefGoogle Scholar
  2. 2.
    Huang V, Cheung CM, Kaatz GW, Rybak MJ. Evaluation of dalbavancin, tigecycline, minocycline, tetracycline, teicoplanin, and vancomycin against community-associated and multidrug-resistant hospital-associated methicillin-resistant Staphylococcus aureus. Int J Antimicrob Agents. 2010;35:25–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Torrey EF, Davis JM. Adjunct treatments for schizophrenia and bipolar disorder: what to try when you are out of ideas. Clin Schizophr Relat Psychoses. 2012;5:208–16.PubMedCrossRefGoogle Scholar
  4. 4.
    European Pharmacopoeia. 8th Ed. Strasbourg, France: Council of Europe; 2013. p. 2779.Google Scholar
  5. 5.
    Ahlneck C, Zografi G. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int J Pharm. 1990;62:87–95.CrossRefGoogle Scholar
  6. 6.
    Waterman KC, Adami RC. Accelerated aging: prediction of chemical stability of pharmaceuticals. Int J Pharm. 2005;293:101–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Mendes Z, Antunes JR, Marto S, Heggie W. Crystalline minocycline base and processes for its preparation. WO2008102161-A2; US20100286417-A1.Google Scholar
  8. 8.
    Xiurong H, Jianming G, Linschen C. Minocycline hydrochloride hydrate crystal forms and preparation method thereof. CN101693669-A.Google Scholar
  9. 9.
    Morissette SL, Almarsson O, Peterson ML, Remenar JF, Read MJ, Lemmo AV, et al. High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev. 2004;56:275–300.PubMedCrossRefGoogle Scholar
  10. 10.
    Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9:2950–67.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Childs SL, Stahly GP, Park A. The salt-cocrystal continuum: the influence of crystal structure on ionization state. Mol Pharmaceutics. 2007;4:323–38.CrossRefGoogle Scholar
  12. 12.
    Padrela L, Rodrigues MA, Velaga SP, Fernandes AC, Matos HA, Azevedo EG. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process. J Supercrit Fluids. 2010;53:156–64.CrossRefGoogle Scholar
  13. 13.
    Padrela L, Rodrigues MA, Velaga SP, Matos HA, Azevedo EG. Formation of indomethacin-saccharin cocrystals using supercritical fluid technology. Eur J Pharm Sci. 2009;38:9–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Rodrigues MA, Li J, Padrela L, Almeida AJ, Matos HA, Azevedo EG. Antisolvent effect in the production of lysozyme nano- and microparticles by supercritical fluid-assisted atomization processes. J Supercrit Fluids. 2009;48:253–60.CrossRefGoogle Scholar
  15. 15.
    Tiago JM, Padrela L, Rodrigues MA, Matos HA, Almeida AJ, Azevedo EG. Single-step co-crystallization and lipid dispersion by supercritical enhanced atomization. Cryst Growth Des. 2013;13:4940–74.CrossRefGoogle Scholar
  16. 16.
    Bettini R, Bonassi L, Castoro V, Rossi A, Zema L, Gazzaniga A, et al. Solubility and conversion of carbamazepine polymorphs in supercritical carbon dioxide. Eur J Pharm Sci. 2001;13:281–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Bettini R, Menabeni R, Tozzi R, Pranzo MB, Pasquali I, Chierotti MR, et al. Didanosine polymorphism in a supercritical antisolvent process. J Pharm Sci. 2010;99:1855–70.PubMedGoogle Scholar
  18. 18.
    Cocero MJ, Martin A, Mattea F, Varona S. Encapsulation and co-precipitation processes with supercritical fluids: fundamentals and applications. J Supercrit Fluids. 2009;47:546–55.CrossRefGoogle Scholar
  19. 19.
    Martin A, Scholle K, Mattea F, Meterc D, Cocero MJ. Production of polymorphs of ibuprofen sodium by supercritical antisolvent (SAS) precipitation. Cryst Growth Des. 2009;9:2504–11.CrossRefGoogle Scholar
  20. 20.
    Subra P, Laudani CG, Vega-Gonzalez A, Reverchon E. Precipitation and phase behavior of theophylline in solvent-supercritical CO2 mixtures. J Supercrit Fluids. 2005;35:95–105.CrossRefGoogle Scholar
  21. 21.
    Reverchon E, Torino E, Dowy S, Braeuer A, Leipertz A. Interactions of phase equilibria, jet fluid dynamics and mass transfer during supercritical antisolvent micronization. Chem Eng J. 2010;156:446–58.CrossRefGoogle Scholar
  22. 22.
    Cardoso MAT, Cabral JMS, Palavra AMF, Geraldes V. Characterization of minocycline powder micronized by a supercritical antisolvent (SAS) process. J Supercrit Fluids. 2008;47:247–58.CrossRefGoogle Scholar
  23. 23.
    Li J, Rodrigues MA, Matos HA, Azevedo EG. VLE of carbon dioxide/ethanol/water: applications to volume expansion evaluation and water removal efficiency. Ind Eng Chem Res. 2005;44:6751–9.CrossRefGoogle Scholar
  24. 24.
    Fischer K. A new method for the analytical determination of the water content of liquids and solids. Angew Chem. 1935;48:394–6.CrossRefGoogle Scholar
  25. 25.
    Bruttel P, Schlink R. Water determination by Karl Fisher titration. Metrohm Ltd: Herisau, Switzerland; 2006.Google Scholar
  26. 26.
    Hong J, Harbison GS. Magic-Angle-spinning Side-band elimination by temporary interruption of the chemical-shift. J Magn Reson Ser A. 1993;105:128–36.CrossRefGoogle Scholar
  27. 27.
    Stezwoski JJ. Chemical-structural properties of tetracycline derivatives. 1. Molecular structure and conformation of the free base derivatives. J Am Chem Soc. 1976;98:6012–8.CrossRefGoogle Scholar
  28. 28.
    Curtis RD, Wasylishen RE. A nitrogen-15 nuclear magnetic resonance study of the tetracycline antibiotics. Can J Chem. 1991;69:834–8.CrossRefGoogle Scholar
  29. 29.
    Mooibroek S, Wasylishen RE. A carbon-13 nuclear magnetic resonance study of solid tetracyclines. Can J Chem. 1987;65:357–62.CrossRefGoogle Scholar
  30. 30.
    Levy GC, Lichter RL. Nitrogen-15 nuclear magnetic resonance spectroscopy. New York: John Wiley & Sons; 1979.Google Scholar
  31. 31.
    Casy AF, Yasin A. Application of 13C nuclear magnetic resonance spectroscopy to the analysis and structural investigation of tetracycline antibiotics and their common impurities. J Pharm Biomed Anal. 1984;2:19–36.PubMedCrossRefGoogle Scholar
  32. 32.
    Casy AF, Yasin A. Stereochemical studies of tetracycline antibiotics and their common impurities by 400 MHz 1H NMR spectroscopy. Magn Reson Chem. 1985;23:767–70.CrossRefGoogle Scholar
  33. 33.
    Mannargudi B, McNally D, Reynolds W, Uetrecht J. Bioactivation of minocycline to reactive intermediates by myeloperoxidase, horseradish peroxidase, and hepatic microsomes: implications for minocycline-induced lupus and hepatitis. Drug Metab Dispos. 2009;37:1806–18.PubMedCrossRefGoogle Scholar
  34. 34.
    Mazzola EP, Melin JA, Wayland LG. 13C-NMR spectroscopy of three tetracycline antibiotics: minocycline hydrochloride, meclocycline, and rolitetracycline. J Pharm Sci. 1980;69:229–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Takeuchi Y, Imafuku Y, Nishikawa M. Reassignment of the 13C NMR spectrum of minomycin. Arkivoc. 2003; XV:2003:39–46.Google Scholar
  36. 36.
    Tatton AS, Pham TN, Vogt FG, Iuga D, Edwards AJ, Brown SP. Probing intermolecular interactions and nitrogen protonation in pharmaceuticals by novel 15 N-edited and 2D 14 N-1H solid-state NMR. Cryst Eng Comm. 2012;14:2654–9.CrossRefGoogle Scholar
  37. 37.
    Tatton AS, Pham TN, Vogt FG, Iuga D, Edwards AJ, Brown SP. Probing hydrogen bonding in cocrystals and amorphous dispersions using 14 N-1H HMQC solid-state NMR. Mol Pharm. 2013;10:999–1007.PubMedCrossRefGoogle Scholar
  38. 38.
    Bradley JP, Pickard CJ, Burley JC, Martin DR, Hughes LP, Cosgrove SD, et al. Probing intermolecular hydrogen bonding in sibenadet hydrochloride polymorphs by high-resolution 1H double-quantum solid-state NMR spectroscopy. J Pharm Sci. 2012;101:1821–30.PubMedCrossRefGoogle Scholar
  39. 39.
    Baias M, Widdifield CM, Dumez J-N, Thompson HPG, Cooper TG, Salager E, et al. Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy. Phys Chem Chem Phys. 2013;15:8069–80.PubMedCrossRefGoogle Scholar
  40. 40.
    Dudenko DV, Williams PA, Hughes CE, Antzutkin ON, Velaga SP, Brown SP, et al. Exploiting the synergy of powder X-ray diffraction and solid-state NMR spectroscopy in structure determination of organic molecular of solids. J Phys Chem C. 2013;117:12258–65.CrossRefGoogle Scholar
  41. 41.
    Rodrigues MA, Padrela L, Matos HA, Azevedo EG, Pinheiro L, Bettencourt A, Castro ML, Almeida AJ, Duarte MA. New crystalline minocycline chlorohydrate, useful for preparing composite materials, prostheses, bone cements, implants, and controlled drug delivery formulations for the treatment of bacterial infections. WO2013095169-A1; PT106063-A1; 2013.Google Scholar

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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