pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties
Hsieh, Yi-Ling levbare, Grace A. Van Eerdenbrugh, Bernard Box, Karl J. Sanchez-Felix, Manuel Vincente Taylor, Lynne S. # ×
Pharmaceutical Research vol:29 issue:10 pages:2738-2753
To examine the precipitation and supersaturation behavior of ten weak bases in terms of the relationship between pH-concentration-time profiles and the solid state properties of the precipitated material.
Initially the compound was dissolved at low pH, followed by titration with base to induce precipitation. Upon precipitation, small aliquots of acid or base were added to induce slight subsaturation and supersaturation respectively and the resultant pH gradient was determined. The concentration of the unionized species was calculated as a function of time and pH using mass and charge balance equations.
Two patterns of behavior were observed in terms of the extent and duration of supersaturation arising following an increase in pH and this behavior could be rationalized based on the crystallization tendency of the compound. For compounds that did not readily crystallize, an amorphous precipitate was formed and a prolonged duration of supersaturation was observed. For compounds that precipitated to crystalline forms, the observed supersaturation was short-lived.
This study showed that supersaturation behavior has significant correlation with the solid-state properties of the precipitate and that pH-metric titration methods can be utilized to evaluate the supersaturation behavior.