Abstract
Purpose. The objective of this study was to compare the results of anormal saturation shake-flask method to a new potentiometricacid-base titration method for determining the intrinsic solubility and thesolubility-pH profiles of ionizable molecules, and to report thesolubility constants determined by the latter technique.
Methods. The solubility-pH profiles of twelve generic drugs (atenolol,diclofenac.Na, famotidine, flurbiprofen, furosemide,hydrochlorothiazide, ibuprofen, ketoprofen, labetolol.HCl, naproxen, phenytoin, andpropranolol.HCl), with solubilities spanning over six orders ofmagnitude, were determined both by the new pH-metric method and by atraditional approach (24 hr shaking of saturated solutions, followed byfiltration, then HPLC assaying with UV detection).
Results. The 212 separate saturation shake-flask solubilitymeasurements and those derived from 65 potentiometric titrations agreed well.The analysis produced the correlation equation:log(1/S)titration = ±0.063(± 0.032)+ 1.025(±0.011) log(1/S)shake-flask,s = 0.20, r2 = 0.978.The potentiometrically-derived intrinsic solubilities of the drugs were:atenolol 13.5 mg/mL, diclofenac.Na 0.82 μg/mL, famotidine 1.1mg/mL, flurbiprofen 10.6 μg/mL, furosemide 5.9 μg/mL,hydrochlorothiazide 0.70 mg/mL, ibuprofen 49 μg/mL, ketoprofen 118 μg/mL,labetolol.HCl 128 μg/mL, naproxen 14 μg/mL, phenytoin 19 μg/mL, andpropranolol.HCl 70 μg/mL.
Conclusions. The new potentiometric method was shown to be reliablefor determining the solubility-pH profiles of uncharged ionizable drugsubstances. Its speed compared to conventional equilibriummeasurements, its sound theoretical basis, its ability to generate the fullsolubility-pH profile from a single titration, and its dynamic range (currentlyestimated to be seven orders of magnitude) make the new pH-metricmethod an attractive addition to traditional approaches used bypreformulation and development scientists. It may be useful even todiscovery scientists in critical decision situations (such as calibratingcomputational prediction methods).
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Avdeef, A., Berger, C.M. & Brownell, C. pH-Metric Solubility. 2: Correlation Between the Acid-Base Titration and the Saturation Shake-Flask Solubility-pH Methods. Pharm Res 17, 85–89 (2000). https://doi.org/10.1023/A:1007526826979
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DOI: https://doi.org/10.1023/A:1007526826979