Pharmaceutical Research

, Volume 30, Issue 1, pp 203–217 | Cite as

Implementing Quality by Design in Pharmaceutical Salt Selection: A Modeling Approach to Understanding Disproportionation

  • Jeremy M. MerrittEmail author
  • Shekhar K. Viswanath
  • Gregory A. Stephenson
Research Paper



Salts of active pharmaceutical ingredients are often used to enhance solubility, dissolution rate, or take advantage of other improved solid-state properties. The selected form must be maintained during processing and shelf-life to ensure quality. We aimed to develop a model to quantify risk of disproportionation, where the salt dissociates back to the freebase form.


A mechanistic model based on thermodynamics was built to predict disproportionation. Stress testing of molecules in combination with excipients was used to benchmark model predictions. X-ray powder diffraction and solid-state NMR were used to quantify the formation of freebase experimentally.


13 pharmaceutical compounds were screened in 4 formulations containing different combinations of excipients. The test set spanned molecules which did and did not disproportionate and also formulations which did and did not induce disproportionation. Model predictions were in qualitative agreement with the experimental data, recovering trends of how disproportionation varies with humidity, formulation excipients, base pK a and solubility of the API.


The model can predict the balance between different driving forces for disproportionation with limited experimental data resulting in a tool to aid in early-phase risk assessment and formulation design with respect to disproportionation.


disproportionation microenvironmental pH model pHmax quality by design 


Acknowledgments and Disclosures

Tim Woods, Adam McFarland, John Rose, Susan Reutzel-Edens, Bob Behme, and Ron Iacocca are thanked for many fruitful discussions.

Supplementary material

11095_2012_863_MOESM1_ESM.docx (192 kb)
ESM 1 (DOCX 192 kb)


  1. 1.
    Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Del Rev. 2007;59:603–16.CrossRefGoogle Scholar
  2. 2.
    Wermuth CG, Stahl PH editors. Handbook of pharmaceutical salts: properties selection and use. Wiley-VCH; 2002 pp 1–7.Google Scholar
  3. 3.
    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
  4. 4.
    Chen LR, Wesley JA, Bhattachar S, Ruiz B, Bahash K, Babu SR. Dissolution behavior of a poorly water soluble compound in the presence of Tween 80. Pharm Res. 2003;20(5):797–801.PubMedCrossRefGoogle Scholar
  5. 5.
    Stephenson GA, Aburub A, Woods TA. Physical Stability of salts of weak bases in the solid-state. J Pharm Sci. 2011;100:1607–17.PubMedCrossRefGoogle Scholar
  6. 6.
    Guerrieri P, Taylor LS. Role of salt and excipient properties on disproportionation in the solid-state. Pharm Res. 2009;26:2015–26.PubMedCrossRefGoogle Scholar
  7. 7.
    Brittain HG. Strategy for the prediction and selection of drug substance salt forms. Pharm Technol. 2007;31:78–88.Google Scholar
  8. 8.
    Kramer SF, Flynn GL. Solubility of organic hydrochlorides. J Pharm Sci. 1972;61:1896–904.PubMedCrossRefGoogle Scholar
  9. 9.
    Bogardus JB, Blackwood RK. Solubility of doxycycline in aqueous solution. J Pharm Sci. 1979;68:188–94.PubMedCrossRefGoogle Scholar
  10. 10.
    Anderson BD, Conradi RA. Predictive relationships in the water solubility of salts of a nonsteroidal anti-inflammatory drug. J Pharm Sci. 1985;74:815–20.PubMedCrossRefGoogle Scholar
  11. 11.
    Carstensen JT. Solid state stability. In: Drug stability: principles and practices. 3rd ed. New York: Marcel Dekker; 2000 pp. 166.Google Scholar
  12. 12.
    Leeson LJ, Mattocks AM. Decomposition of aspirin in the solid-state. J Am Pharm Assoc. 1958;47:329–33.Google Scholar
  13. 13.
    Carstensen JT, Pothisiri P. Decomposition of para-aminosalicyclic acid in solid-state. J Pharm Sci. 1975;64:37–44.CrossRefGoogle Scholar
  14. 14.
    Hiatt AN, Taylor LS, Mauer LJ. Influence of simultaneous variations in temperature and relative humidity on chemical stability of two vitamin C forms and implications for shelf life models. J Agric Food Chem. 2010;58:3532–40.PubMedCrossRefGoogle Scholar
  15. 15.
    Guerrieri P, Jarring K, Taylor LS. Impact of counter ion on the chemical stability of crystalline salts of procaine. J Pharm Sci. 2010;99:3719–30.PubMedGoogle Scholar
  16. 16.
    Serajuddin ATM, Jarowski CI. Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical acids and their sodium salts. Part 2. Salicylic acid, theophylline, and benzoic acid. J Pharm Sci. 1985;74:148–54.PubMedCrossRefGoogle Scholar
  17. 17.
    Badawy SIF, Williams RC, Gilbert D. Effect of different acids on solid-state stability of an ester prodrug of an iib/iiia glycoprotein receptor antagonist. Pharm Dev Technol. 1999;4:325–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Thakur AB, Morris K, Grosso JA, Himes K, Thottathil JK, Jerzewski RL, et al. Mechanism and kinetics of metal ion-mediated degradation of fosinopril sodium. Pharm Res. 1993;10:800–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Serajuddin ATM, Rosoff M. pH-solubility profile of paverine hydrochloride and its relationship to the dissolution rate of sustained-release pellets. J Pharm Sci. 1984;73:1203–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Carstensen JT, Rhodes CT. Drug stability: principles and practices. New York: Marcel Dekker; 2000. p. 199.Google Scholar
  21. 21.
    Pudipeddi M, Zannou EA, Vasanthavada M, Dontabhaktuni A, Royce AE, Joshi 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Govindarajam 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(10):2454–68.CrossRefGoogle Scholar
  23. 23.
    Qiu Y, Chen Y, Liu L, Zhang G. Developing solid oral dosage forms: pharmaceutical theory and practice. p130.Google Scholar
  24. 24.
    Li Y, Sanzgiri YD, Chen Y. A study on moisture isotherms of formulations: the use of polynomial equations to predict the moisture isotherms of tablet products AAPS Pharm Sci Tech; 2003 4(4) Article 59.Google Scholar
  25. 25.
    Brown ME, Glass BD. Pharmaceutical applications of the Prout-Tompkins rate equation. Int J Pharm. 1999;190:129–37.PubMedCrossRefGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Jeremy M. Merritt
    • 1
    • 2
    Email author
  • Shekhar K. Viswanath
    • 1
  • Gregory A. Stephenson
    • 3
  1. 1.Chemical Product Research and DevelopmentEli Lilly and CompanyIndianapolisUSA
  2. 2.Eli Lilly & CoDC 4816, Eli Lilly and Co., Lilly Technology Center SouthIndianapolisUSA
  3. 3.Pharmaceutical Sciences Research and DevelopmentEli Lilly and CompanyIndianapolisUSA

Personalised recommendations