Implementing quality by design in pharmaceutical salt selection: a modeling approach to understanding disproportionation.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Chemical Product Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46221, USA. merrittje@lilly.com
Jeremy M
JM
Merritt
Shekhar K
SK
Viswanath
Gregory A
GA
Stephenson
D005079:Excipients / Q000737:chemistry*; D006813:Humidity; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D033362:Powder Diffraction; D012492:Salts / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics; D014961:X-Ray Diffraction
D005079:Excipients; D004364:Pharmaceutical Preparations; D012492:Salts