Semiaqueous potentiometric determinations of apparent pKa1 values for benzothiadiazines and detection of decomposition during solubility variation with pH studies.

Apparent acidity constants obtained for various benzothiadiazine diuretics by semiaqueous potentiometric titrations gave satisfactory agreement with many values obtained by aqueous potentiometry. One suitable method for determining the acidity constants of sparingly soluble drugs, the solubility variation with pH technique, does not take into account instability problems. The preparation of decomposition products and the TLC analysis of sample solutions at various time intervals during solubility studies of methyclothiazide and bendroflumethiazide indicated that decomposition takes place during agitation and equilibration. This decomposition in buffers of pH 8 and higher was confirmed with the acidified p-dimethylaminobenzaldehyde test for primary aromatic amines.