Advertisement

Pharmaceutical Research

, Volume 32, Issue 2, pp 549–561 | Cite as

Salt Stability - Effect of Particle Size, Relative Humidity, Temperature and Composition on Salt to Free Base Conversion

  • Yi-Ling Hsieh
  • Lynne S. TaylorEmail author
Research Paper

Abstract

Purpose

The aim of this study was to investigate how factors such as temperature, relative humidity and particle size impact the extent of disproportionation (salt to free base conversion) in powder blends of miconazole, benzocaine or sertraline mesylate salts mixed with a basic additive.

Method

Raman spectroscopy was used to quantitate the extent of disproportionation. The data was further analyzed by multivariate analysis with partial least squares (PLS) modeling.

Results

It was found that salt disproportionation was significantly influenced by % weight gain due to moisture sorption both in terms of the kinetics and the conversion extent, suggesting a solution-mediated reaction. Temperature plays an important role in impacting the value of pHmax which in turn has a significant correlation to the amount of free base formed. The particle size and drug: additive ratio were also found to influence the extent of disproportionation.

Conclusions

This study shows that the extent of salt disproportionation is influenced by multiple factors and the application of PLS modeling demonstrated the feasibility of utilizing multivariate analysis to generate a predictive model for estimating the extent of conversion and thus may serve as a tool for risk assessment.

KEY WORDS

disproportionation multivariate analysis Raman spectroscopy salt storage conditions 

Notes

Acknowledgments and Disclosures

The Dane O’Kildsig Center for Pharmaceutical Processing Research is acknowledged for providing partial funding for this project. Pfizer Inc is thanked for providing a fellowship for Yi-Ling Hsieh. Kaho Kwok is thanked for assisting with the multivariate analysis.

References

  1. 1.
    Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59(7):603–16.PubMedCrossRefGoogle Scholar
  2. 2.
    Giron D, Grant DJW. Evaluation of Solid-State Properties of Salts. In: Stahl PH, Wermuth CG, editors. Handbook of Pharmaceutical Salts: Properties, Selection and Use: Wiley, John & Sons, Incorporated; 2002.Google Scholar
  3. 3.
    Morris KR, Fakes MG, Thakur AB, Newman AW, Singh AK, Venit JJ, et al. An integrated approach to the selection of optimal salt form for a new drug candidate. Int J Pharm. 1994;105(3):209–17.CrossRefGoogle Scholar
  4. 4.
    Stephenson GA, Aburub A, Woods TA. Physical stability of salts of weak bases in the solid-state. J Pharm Sci. 2010;100(5):1607–17.PubMedCrossRefGoogle Scholar
  5. 5.
    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(12):1850–6.PubMedCrossRefGoogle Scholar
  6. 6.
    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(1–2):210–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Unger EF. Weighing benefits and risks -- the FDA’s review of prasugrel. N Engl J Med. 2009;361(10):942–5.PubMedCrossRefGoogle Scholar
  8. 8.
    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(1–2):29–39.PubMedCrossRefGoogle Scholar
  9. 9.
    Hsieh YL, Yu W, Xiang Y, Pan W, Waterman KC, Shalaev EY, et al. Impact of sertraline salt form on the oxidative stability in powder blends. Int J Pharm. 2014;461(1–2):322–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Guerrieri P, Taylor L. Role of salt and excipient properties on disproportionation in the solid-state. Pharm Res. 2009;26(8):2015–26.PubMedCrossRefGoogle Scholar
  11. 11.
    Merritt J, Viswanath S, Stephenson G. Implementing quality by design in pharmaceutical salt selection: a modeling approach to understanding disproportionation. Pharm Res. 2013;30(1):203–17.PubMedGoogle Scholar
  12. 12.
    John C, Xu W, Lupton L, Harmon P. Formulating weakly basic HCl salts: relative ability of common excipients to induce disproportionation and the unique deleterious effects of magnesium stearate. Pharm Res. 2013;30(6):1628–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Pudipeddi M, Serajuddin ATM, Grant DJW, Stahl PH. Solubility and dissolution of weak acids, bases, and salts. In: Stahl PH, Wermuth CG, editors. Handbook of pharmaceutical salts - properties, selection and use. Zürich: Verlag Helvetica Chimica Acta, Weinheim: Wiley-VCH; 2002. p.19–39.Google Scholar
  14. 14.
    Serajuddin ATM, Jarowski CI. Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical bases and their hydrochloride salts I: Phenazopyridine. J Pharm Sci. 1985;74(2):142–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Christensen NPA, Rantanen J, Cornett C, Taylor LS. Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients. Eur J Pharm Biopharm. 2012;82(2):410–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Guerrieri P, Rumondor A, Li T, Taylor L. Analysis of relationships between solid-state properties, counterion, and developability of pharmaceutical salts. AAPS PharmSciTech. 2010;11(3):1212–22.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Parshad H, Frydenvang K, Liljefors T, Larsen CS. Correlation of aqueous solubility of salts of benzylamine with experimentally and theoretically derived parameters. A multivariate data analysis approach. Int J Pharm. 2002;237(1–2):193–207.PubMedCrossRefGoogle Scholar
  18. 18.
    Tantishaiyakul V. Prediction of aqueous solubility of organic salts of diclofenac using PLS and molecular modeling. Int J Pharm. 2004;275(1–2):133–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Perrin D. The effect of temperature on pK values of organic bases. Aust J Chem. 1964;17(4):484–8.CrossRefGoogle Scholar
  20. 20.
    SIMCA-P+. 12.0 ed. Umeå, Sweden: Umetrics AB.Google Scholar
  21. 21.
    Seyer JJ, Luner PE. Determination of indomethacin crystallinity in the presence of excipients using diffuse reflectance near-infrared spectroscopy. Pharm Dev Technol. 2001;6(4):573–82.PubMedCrossRefGoogle Scholar
  22. 22.
    Patel AD, Luner PE, Kemper MS. Quantitative analysis of polymorphs in binary and multi-component powder mixtures by near-infrared reflectance spectroscopy. Int J Pharm. 2000;206(1–2):63–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Rumondor ACF, Taylor LS. Application of partial least-squares (PLS) modeling in quantifying drug crystallinity in amorphous solid dispersions. Int J Pharm. 2010;398(1–2):155–60.PubMedCrossRefGoogle Scholar
  24. 24.
    Wexler AS, Seinfeld JH. Second-generation inorganic aerosol model. Atmos Environ Part A G Top. 1991;25(12):2731–48.CrossRefGoogle Scholar
  25. 25.
    Salameh AK, Taylor LS. Deliquescence in binary mixtures. Pharm Res. 2005;22(2):318–24.PubMedCrossRefGoogle Scholar
  26. 26.
    Peters SJ, Ewing GE. Water on salt: an infrared study of adsorbed H2O on NaCl (100) under ambient conditions. J Phys Chem B. 1997;101(50):10880–6.CrossRefGoogle Scholar
  27. 27.
    Peters SJ, Ewing GE. Thin film water on NaCl (100) under ambient conditions: an infrared study. Langmuir. 1997;13(24):6345–8.CrossRefGoogle Scholar
  28. 28.
    Foster MC, Ewing GE. Adsorption of water on the NaCl (001) surface. II. An infrared study at ambient temperatures. The J of Chem Phys. 2000;112(15):6817–26.CrossRefGoogle Scholar
  29. 29.
    Luna M, Rieutord F, Melman NA, Dai Q, Salmeron M. Adsorption of water on alkali halide surfaces studied by scanning polarization force microscopy. The J of Phys Chem A. 1998;102(34):6793–800.CrossRefGoogle Scholar
  30. 30.
    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(2–3):87–95.CrossRefGoogle Scholar
  31. 31.
    Salameh AK, Taylor LS. Role of deliquescence lowering in enhancing chemical reactivity in physical mixtures. J Phys Chem B. 2006;110(20):10190–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Kwok K, Mauer LJ, Taylor LS. Kinetics of moisture-induced hydrolysis in powder blends stored at and below the deliquescence relative humidity: investigation of sucrose-citric acid mixtures. J Agric Food Chem. 2010;58(22):11716–24.PubMedCrossRefGoogle Scholar
  33. 33.
    Guerrieri P, Salameh AK, Taylor LS. Effect of small levels of impurities on the water vapor sorption behavior of ranitidine HCl. Pharm Res. 2007;24(1):147–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Salazar MR, Thompson SL, Kenneth E, Laintz K, Meyer TO, Pack RT. Degradation of a poly (ester urethane) elastomer. IV. Sorption and diffusion of water in PBX 9501 and its components. J Appl Polym Sci. 2007;105(3):1063–76.CrossRefGoogle Scholar
  35. 35.
    Baird JA, Olayo-Valles R, Rinaldi C, Taylor LS. Effect of molecular weight, temperature, and additives on the moisture sorption properties of polyethylene glycol. Journal of Pharmaceutical Sciences. 2010;99(1):154–68.PubMedCrossRefGoogle Scholar
  36. 36.
    Hancock B, Dalton C. The Effect of Temperature on Water Vapor Sorption by Some Amorphous Pharmaceutical Sugars. Pharmaceutical Development & Technology: Taylor & Francis Ltd; 1999. p. 125.Google Scholar
  37. 37.
    Oksanen CA, Zografi G. The relationship between the glass transition temperature and water vapor absorption by poly (vinylpyrrolidone). Pharm Res. 1990;7(6):654–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Eriksson L, Johansson, E., Kettaneh-Wold, N., Wold, S. Introduction to Multi- and Megavariate Data Analysis Using Projection Methods (PCA & PLS). Umetrics, Umea°, Sweden.1999.Google Scholar
  39. 39.
    Badawy SF, Gray D, Zhao F, Sun D, Schuster A, Hussain M. Formulation of solid dosage forms to overcome gastric pH interaction of the factor Xa inhibitor, BMS-561389. Pharm Res. 2006;23(5):989–96.PubMedCrossRefGoogle Scholar
  40. 40.
    Box KJ, Comer JEA. Using measured pK (A), LogP and solubility to investigate supersaturation and predict BCS class. Curr Drug Metab. 2008;9(9):869–78.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Industrial and Physical PharmacyPurdue UniversityWest LafayetteUSA
  2. 2.IrvineUSA

Personalised recommendations