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Influence of the Solid Form of Siramesine Hydrochloride on its Behavior in Aqueous Environments

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Abstract

Purpose

To study the influence of solid form on the behavior of the salt siramesine hydrochloride in aqueous environments.

Methods

The solubilities and dissolution rates of siramesine hydrochloride anhydrate and monohydrate were determined at pH 3.4 and 6.4, and precipitates were examined by X-ray powder diffraction. The mechanism of anhydrate–hydrate conversion was investigated by optical microscopy, and wet massing of the anhydrate was carried out using water and 60% (v/v) ethanol separately as granulation liquids. The wet masses were analyzed using Raman microscopy.

Results

At pH 3.4 the anhydrate and monohydrate salts exhibited similar dissolution profiles. At pH 6.4 both the anhydrate and monohydrate salts formed supersaturated solutions of high apparent solubility. From the anhydrate solution, precipitation of the free base occurred, while the solution of the monohydrate salt remained in the supersaturated state. This resulted in a superior dissolution profile of the monohydrate salt. Microscopy and wet massing experiments showed that the anhydrate–hydrate conversion of siramesine hydrochloride was solution-mediated and dissolution-controlled.

Conclusion

During development of a formulation based on the anhydrate salt, the risk of processing-induced transformation to the monohydrate form as well as precipitation of the free base should be considered.

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References

  1. S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell. Solid-state chemistry of drugs, SSCI, West Lafayette, IN, 1999.

    Google Scholar 

  2. D. Giron, M. Mutz, and S. Gamier. Solid-state of pharmaceutical compounds. J. Therm. Anal. Calorim. 77:709–747 (2004). doi:10.1023/B:JTAN.0000039005.51343.33.

    Article  CAS  Google Scholar 

  3. H. L. Fung, and T. Nealon. Solvent effects on comparative dissolution of pharmaceutical solvates. Chem. Pharm. Bull. 22:454–458 (1974).

    CAS  Google Scholar 

  4. R. K. Khankari, and D. J. W. Grant. Pharmaceutical hydrates. Thermochim. Acta. 248:61–79 (1995). doi:10.1016/0040-6031(94)01952-D.

    Article  CAS  Google Scholar 

  5. E. Shefter, and T. Higuchi. Dissolution behavior of crystalline solvated and nonsolvated forms of some pharmaceuticals. J. Pharm. Sci. 52:781–791 (1963). doi:10.1002/jps.2600520815.

    Article  PubMed  CAS  Google Scholar 

  6. K. R. Morris, U. J. Griesser, C. J. Eckhardt, and J. G. Stowell. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv. Drug Delivery Rev. 48:91–114 (2001). doi:10.1016/S0169-409X(01)00100-4.

    Article  CAS  Google Scholar 

  7. A. Jørgensen, J. Rantanen, M. Karjalainen, L. Khriachtchev, E. Räsänen, and J. Yliruusi. Hydrate formation during wet granulation studied by spectroscopic methods and multivariate analysis. Pharm. Res. 19:1285–1291 (2002). doi:10.1023/A:1020621906855.

    Article  PubMed  Google Scholar 

  8. M. Otsuka, H. Hasegawa, and Y. Matsuda. Effect of polymorphic transformation during the extrusion-granulation process on the pharmaceutical properties of carbamazepine granules. Chem. Pharm. Bull. 45:894–898 (1997).

    CAS  Google Scholar 

  9. H. Wikström, P. J. Marsac, and L. S. Taylor. In-line monitoring of hydrate formation during wet granulation using Raman spectroscopy. J. Pharm. Sci. 94:209–219 (2005). doi:10.1002/jps.20241.

    Article  PubMed  CAS  Google Scholar 

  10. S. Debnath, and R. Suryanarayanan. Influence of processing-induced phase transformations on the dissolution of theophylline tablets. AAPS PharmSciTech. 5:E8 (2004).

    Article  PubMed  Google Scholar 

  11. Y. Kobayashi, S. Ito, S. Itai, and K. Yamamoto. Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate. Int. J. Pharm. 193:137–146 (2000). doi:10.1016/S0378-5173(99)00315-4.

    Article  PubMed  CAS  Google Scholar 

  12. M. Otsuka, R. Teraoka, and Y. Matsuda. Rotating-disk dissolution kinetics of nitrofurantoin anhydrate and monohydrate at various temperatures. Pharm. Res. 9:307–311 (1992). doi:10.1023/A:1015874415248.

    Article  PubMed  CAS  Google Scholar 

  13. S. Balbach, and C. Korn. Pharmaceutical evaluation of early development candidates “the 100 mg-approach”. Int. J. Pharm. 275:1–12 (2004). doi:10.1016/j.ijpharm.2004.01.034.

    Article  PubMed  CAS  Google Scholar 

  14. A. C. Williams, V. B. Cooper, L. Thomas, L. J. Griffith, C. R. Petts, and S. W. Booth. Evaluation of drug physical form during granulation, tabletting and storage. Int. J. Pharm. 275:29–39 (2004). doi:10.1016/j.ijpharm.2004.01.042.

    Article  PubMed  CAS  Google Scholar 

  15. A. T. M. Serajuddin. Salt formation to improve drug solubility. Adv. Drug Delivery Rev. 59:603–616 (2007). doi:10.1016/j.addr.2007.05.010.

    Article  CAS  Google Scholar 

  16. P. L. Gould. Salt selection for basic drugs. Int. J. Pharm. 33:201–217 (1986). doi:10.1016/0378-5173(86)90055-4.

    Article  CAS  Google Scholar 

  17. S. M. Berge, L. D. Bighley, and D. C. Monkhouse. Pharmaceutical salts. J. Pharm. Sci. 66:1–19 (1977). doi:10.1002/jps.2600660104.

    Article  PubMed  CAS  Google Scholar 

  18. J. O. Christensen, K. Schultz, B. Mollgaard, H. G. Kristensen, and A. Müllertz. Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain triacylglycerols. Eur. J. Pharm. Sci. 23:287–296 (2004). doi:10.1016/j.ejps.2004.08.003.

    Article  PubMed  CAS  Google Scholar 

  19. S. N. Bhattachar, L. A. Deschenes, and J. A. Wesley. Solubility: it’s not just for physical chemists. Drug Discov. Today. 11:1012–1018 (2006). doi:10.1016/j.drudis.2006.09.002.

    Article  PubMed  CAS  Google Scholar 

  20. M. T. Ledwidge, and O. I. Corrigan. Effects of surface active characteristics and solid state forms on the pH solubility profiles of drug-salt systems. Int. J. Pharm. 174:187–200 (1998). doi:10.1016/S0378-5173(98)00257-9.

    Article  CAS  Google Scholar 

  21. A. T. M. Serajuddin, and C. I. Jarowski. Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical acids and their sodium salts II: salicylic acid, theophylline and benzoic acid. J. Pharm. Sci. 74:148–154 (1985). doi:10.1002/jps.2600740209.

    Article  PubMed  CAS  Google Scholar 

  22. A. T. M. Serajuddin, and M. Rosoff. pH-solubility profile of papaverine hydrochloride and its relationship to the dissolution rate of its sustained release pellets. J. Pharm. Sci. 73:1203–1208 (1984). doi:10.1002/jps.2600730905.

    Article  PubMed  CAS  Google Scholar 

  23. N. Rodriguez-Hornedo, D. Lechuga-Ballesteros, and H. J. Wu. Phase transition and heterogeneous/epitaxial nucleation of hydrated and anhydrous theophylline crystals. Int. J. Pharm. 85:149–162 (1992). doi:10.1016/0378-5173(92)90144-Q.

    Article  CAS  Google Scholar 

  24. R. J. Davey, N. Blagden, S. Righini, H. Alison, and E. S. Ferrari. Nucleation control in solution mediated polymorphic phase transformations: the case of 2,6-dihydroxybenzoic acid. J. Phys. Chem. B. 106:1954–1959 (2002). doi:10.1021/jp013044i.

    Article  CAS  Google Scholar 

  25. G. L. Amidon, H. Lennernäs, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413–420 (1995). doi:10.1023/A:1016212804288.

    Article  PubMed  CAS  Google Scholar 

  26. A. F. Davis, and J. Hadgraft. Effect of supersaturation on membrane transport: 1. Hydrocortisone acetate. Int. J. Pharm. 76:1–8 (1991). doi:10.1016/0378-5173(91)90337-N.

    Article  CAS  Google Scholar 

  27. J. Kemken, A. Ziegler, and B. W. Müller. Influence of supersaturation on the pharmacodynamic effect of bupranolol after dermal administration using microemulsions as vehicle. Pharm. Res. 9:554–558 (1992). doi:10.1023/A:1015856800653.

    Article  PubMed  CAS  Google Scholar 

  28. P. Gao, M. E. Guyton, T. Huang, J. M. Bauer, K. J. Stefanski, and Q. Lu. Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations. Drug Dev. Ind. Pharm. 30:221–229 (2004). doi:10.1081/DDC-120028718.

    Article  PubMed  CAS  Google Scholar 

  29. P. T. Cardew, and R. J. Davey. The kinetics of solvent-mediated phase transformations. Proc. R. Soc. Lond. 398:415–428 (1985).

    Article  CAS  Google Scholar 

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Acknowledgements

H. Lundbeck A/S (Copenhagen, Denmark) and the Drug Research Academy (Copenhagen, Denmark) are thanked for financial support. Mogens Frost, H. Lundbeck A/S, Preformulation, is thanked for assistance with SEM micrographs and BET measurements. Furthermore, Erling Bonne Jørgensen, H. Lundbeck A/S, Preformulation, is thanked for commenting on the manuscript.

Author information

Author notes

  1. Anne Zimmermann

    Present address: NeuroSearch A/S, Preformulation, 2750, Ballerup, Denmark

  2. Lars Hovgaard

    Present address: Novo Nordisk A/S, Preformulation and Delivery, Novo Nordisk Park, 2760, Måløv, Denmark

Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen Ø, Denmark

    Anne Zimmermann, Fang Tian, Jukka Rantanen, Anette Müllertz & Lars Hovgaard

  2. H. Lundbeck A/S, Preformulation, Ottiliavej 9, 2500, Copenhagen-Valby, Denmark

    Heidi Lopez de Diego

  3. H. Lundbeck A/S, Pharmaceutical Development, Ottiliavej 9, 2500, Copenhagen-Valby, Denmark

    Michiel Ringkjøbing Elema

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  1. Anne Zimmermann
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Correspondence to Anne Zimmermann.

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Zimmermann, A., Tian, F., Lopez de Diego, H. et al. Influence of the Solid Form of Siramesine Hydrochloride on its Behavior in Aqueous Environments. Pharm Res 26, 846–854 (2009). https://doi.org/10.1007/s11095-008-9783-0

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  • DOI: https://doi.org/10.1007/s11095-008-9783-0

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