Implementing Quality by Design in Pharmaceutical Salt Selection: A Modeling Approach to Understanding Disproportionation
- 1.6k Downloads
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 pKa 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.
KEY WORDSdisproportionation 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.
- 2.Wermuth CG, Stahl PH editors. Handbook of pharmaceutical salts: properties selection and use. Wiley-VCH; 2002 pp 1–7.Google Scholar
- 7.Brittain HG. Strategy for the prediction and selection of drug substance salt forms. Pharm Technol. 2007;31:78–88.Google Scholar
- 11.Carstensen JT. Solid state stability. In: Drug stability: principles and practices. 3rd ed. New York: Marcel Dekker; 2000 pp. 166.Google Scholar
- 12.Leeson LJ, Mattocks AM. Decomposition of aspirin in the solid-state. J Am Pharm Assoc. 1958;47:329–33.Google Scholar
- 20.Carstensen JT, Rhodes CT. Drug stability: principles and practices. New York: Marcel Dekker; 2000. p. 199.Google Scholar
- 23.Qiu Y, Chen Y, Liu L, Zhang G. Developing solid oral dosage forms: pharmaceutical theory and practice. p130.Google Scholar
- 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