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Role of Salt and Excipient Properties on Disproportionation in the Solid-State

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Abstract

Purpose

Approximately 50% of active pharmaceutical ingredients (APIs) are manufactured and formulated as salts, due to their enhanced dissolution rates or improved solid state properties. It is essential to maintain the appropriate solid state form of the drug during processing and over the lifetime of the product. The aim of this study was to investigate the contributing factors in the process of disproportionation, whereby the salt converts back to the free form of the drug.

Methods

Infrared and Raman spectroscopy were used to detect and quantify the formation of free base in physical mixtures with excipients. The pH-solubility relationships were determined based on measured salt solubilities and properties of the free form.

Results

The mesylate salts of two model pharmaceutical compounds were found to disproportionate to the free base form when physically mixed with certain common basic excipients and exposed to moderate relative humidities. In contrast, the napsylate salts were much more resistant to disproportionation. The napsylate salts had solubilities more than 3 orders of magnitude lower than the respective mesylate salts, and showed little to no detectable formation of free base. The mesylate salts with higher solubilities showed significant levels of conversion to the free base.

Conclusions

It appears that both the solubility and pHmax (the pH of a solution where there is saturation of both ionized and unionized species) of the salts, as well as the base solubility, play important roles in determining the susceptibility of salts to disproportionate. The extent of conversion was also affected by excipient properties, including basicity, solubility, physical state and surface area.

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References

  1. Rohrs BR, Thamann TJ, Gao P, Stelzer DJ, Bergren MS, Chao RS. Tablet dissolution affected by a moisture mediated solid-state interaction between drug and disintegrant. Pharm. Res. 1999;16:1850–56.

    Article  PubMed  CAS  Google Scholar 

  2. Zannou EA, Ji Q, Joshi YM, Serajuddin ATM. Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form. Int. J. Pharm. 2007;337:210–8.

    Article  PubMed  CAS  Google Scholar 

  3. Williams AC, Cooper VB, Thomas L, Griffith LJ, Petts CR, Booth SW. Evaluation of drug physical form during granulation, tabletting and storage. Int. J. Pharm. 2004;275:29–39.

    Article  PubMed  CAS  Google Scholar 

  4. Towler CS, Li TL, Wikstrom H, Remick DM, Sanchez-Felix MV, Taylor LS. An Investigation into the Influence of Counterion on the Properties of Some Amorphous Organic Salts. Mol. Pharm. 2008;5:946–55.

    Article  PubMed  CAS  Google Scholar 

  5. Guo YS, Byrn SR, Zografi G. Effects of lyophilization on the physical characteristics and chemical stability of amorphous quinapril hydrochloride. Pharm. Res. 2000;17:930–5.

    Article  PubMed  CAS  Google Scholar 

  6. Adeyeye MC and Brittain HG (eds.). Preformulation in Solid Dosage Form Development, Informa Healthcare, 2008.

  7. Salameh AK, Taylor LS. Deliquescence in binary mixtures. Pharm. Res. 2005;22:318–24.

    Article  PubMed  CAS  Google Scholar 

  8. Box KJ, Comer JEA. Using Measured pK(a) LogP and Solubility to Investigate Supersaturation and Predict BCS Class. Curr. Drug Metab. 2008;9:869–78.

    Article  PubMed  CAS  Google Scholar 

  9. Piel G, Evrard B, Fillet M, Llabres G, Delattre L. Development of a non-surfactant parenteral formulation of miconazole by the use of cyclodextrins. Int. J. Pharm. 1998;169:15–22.

    Article  CAS  Google Scholar 

  10. Black SN, Collier EA, Davey RJ, Roberts RJ. Structure, solubility, screening, and synthesis of molecular salts. J. Pharm. Sci. 2007;96:1053–68.

    Article  PubMed  CAS  Google Scholar 

  11. Avila CM, Martinez F. Thermodynamic study of the solubility of benzocaine in some organic and aqueous solvents. J. Solution Chem. 2002;31:975–85.

    Article  CAS  Google Scholar 

  12. Zografi G, Hancock B. Water-Solid Interactions in Pharmaceutical Systems. In: Crommelin DJA, Midha KK, Nagai T, editors. Topics in Pharmaceutical Sciences. Stuttgart, Germany: Proceedings of International Congress on Pharmaceutical Sciences FIP; 1993. p. 405–19.

    Google Scholar 

  13. Sharpe SA, Celik M, Newman AW, Brittain HG. Physical characterization of the polymorphic variations of magnesium stearate and magnesium palmitate hydrate species. Struct. Chem. 1997;8(1):73–84.

    Article  CAS  Google Scholar 

  14. Skoog DA, Holler FJ, Nieman TA. Principles of Instrumental Analysis. 5th ed. Philadelphia: Saunders College Publishing; 1998.

    Google Scholar 

  15. Ross KD. Estimation of Water Activity in Intermediate Moisture Foods. Food Technol. 1975;29:26–34.

    CAS  Google Scholar 

  16. Dai DJ, Peters SJ, Ewing GE. Water-Adsorption and Dissociation on Nacl Surfaces. J. Phys. Chem. 1995;99:10299–304.

    Article  CAS  Google Scholar 

  17. Luna M, Rieutord F, Melman NA, Dai Q, Salmeron M. Adsorption of water on alkali halide surfaces studied by scanning polarization force microscopy. J. Phys. Chem. A. 1998;102:6793–800.

    Article  CAS  Google Scholar 

  18. Shindo H, Ohashi M, Baba K, Seo A. AFM observation of monatomic step movements on NaCl(001) with the help of adsorbed water. Surf. Sci. 1996;358:111–4.

    Article  Google Scholar 

  19. Shindo H, Ohashi M, Tateishi O, Seo A. Atomic force microscopic observation of step movements on NaCl(001) and NaF(001) with the help of adsorbed water. J. Chem. Soc., Faraday Trans. 1997;93:1169–74.

    Article  CAS  Google Scholar 

  20. Verdaguer A, Sacha GM, Luna M, Ogletree DF and Salmeron M. Initial stages of water adsorption on NaCl (100) studied by scanning polarization force microscopy. J. Chem. Phy. 123: (2005).

  21. Kramer SF and Flynn GL. Solubility of Organic Hydrochlorides. J. Pharm. Sci.. 61:1896-& (1972).

    Google Scholar 

  22. Bogardus JB, Blackwood RK. Solubility of Doxycycline in Aqueous-Solution. J. Pharm. Sci. 1979;68:188–94.

    Article  PubMed  CAS  Google Scholar 

  23. Serajuddin ATM. Salt formation to improve drug solubility. Adv. Drug Delivery Rev. 2007;59:603–16.

    Article  CAS  Google Scholar 

  24. Stahl PH, Wemuth CG. Handbook of Pharmaceutical Salts. New York: Wiley-VCH; 2002.

    Google Scholar 

  25. Govindarajan R, Zinchuk A, Hancock B, Shalaev E, Suryanarayanan R. Ionization states in the microenvironment of solid dosage forms: Effect of formulation variables and processing. Pharm. Res. 2006;23:2454–68.

    Article  PubMed  CAS  Google Scholar 

  26. Pudipeddi M, Zannou EA, Vasanthavada M, Dontabhaktuni A, Royce AE, Josh YM, et al. Measurement of surface pH of pharmaceutical solids: A critical evaluation of indicator dye-sorption method and its comparison with slurry pH method. J. Pharm. Sci. 2008;97:1831–42.

    Article  PubMed  CAS  Google Scholar 

  27. Dulin WA. Degradation of bisoprolol fumarate in tablets formulated with dicalcium phosphate. Drug Dev. Ind. Pharm. 1995;21:393–409.

    Article  CAS  Google Scholar 

  28. Glombitza BW, Oelkrug D, Schmidt PC. Surface-acidity of solid pharmaceutical excipients 1. Determination of the surface-acidity. Eur. J. Pharm. Biopharm. 1994;40:289–93.

    CAS  Google Scholar 

  29. Glombitza BW, Schmidt PC. Surface-acidity of solid pharmaceutical excipients 2. Effect of the surface-acidity on the decomposition rate of acetylsalicylic acid. Eur. J. Pharm. Biopharm. 1995;41:114–9.

    CAS  Google Scholar 

  30. Hussain MSH, York P, Timmins P. A study of the formation of magnesium stearate film on sodium-chloride using energy-dispersive x-ray-analysis. Int. J. Pharm. 1988;42:89–95.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors acknowledge AstraZeneca R&D Lund Sweden for funding this research. Dr. Kjell Jarring is sincerely thanked for helpful discussions. Aansh jarmarwala is thanked for his help in collecting spectra.

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA

    Peter Guerrieri & Lynne S. Taylor

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  1. Peter Guerrieri
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  2. Lynne S. Taylor
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Correspondence to Lynne S. Taylor.

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Guerrieri, P., Taylor, L.S. Role of Salt and Excipient Properties on Disproportionation in the Solid-State. Pharm Res 26, 2015–2026 (2009). https://doi.org/10.1007/s11095-009-9918-y

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