Effect of pH and Buffer Capacity of Physiological Bicarbonate Buffer on Precipitation of Drugs

The purpose of this study was to investigate the effect of the pH and buffer capacity (β) of physiological bicarbonate buffer solutions (BCB) on drug precipitation. The precipitation profiles of poorly soluble drugs in BCB were evaluated by using a pH-shift precipitation test. Phosphate buffer solutions (PPB) were used for comparison. Two weakly acidic drugs (pK_a: 4.9 and 7.0) and two weakly basic drugs (pK_a: 6.1 and 8.3) were used as model drugs. The bulk phase pH value (pH_bulk) and β values were set to cover the physiological range in the small intestines (pH: 5.5 to 7.5, β: 2.2 to 17.6 mM/ΔpH). A floating lid was used to maintain the pH_bulk of BCB to avoid CO₂ loss. It was also applied to PPB to align the experimental conditions. Each drug was completely dissolved in HCl (pH 3.0, for weakly basic drugs) or NaOH (pH 11.0, for weakly acidic drugs) solutions (450 mL, 50 rpm, 37 °C). The pH_bulk value was then shifted to the neutral pH region by adding a 10-fold concentrated buffer solution (50 mL, final volume of 500 mL). The initial total drug concentration (neutral + ionized species) was set so that the concentration and supersaturation ratio of the neutral species were the same under all pH_bulk conditions. The solid forms of the precipitates were determined by powder X-ray diffraction and differential scanning calorimetry. In BCB, as pH_bulk was increased above (for weakly acidic drugs) or decreased below (for weakly basic drugs) the drug pK_a value, the precipitation of the free form solid became slower. As β was increased, drug precipitation in BCB became faster. Drug precipitation in PPB was faster than that in BCB and less affected by pH_bulk and β. In BCB, at pH_bulk at which a drug is ionizable, the surface pH of the precipitating particles can differ from pH_bulk because of the slow hydration process of CO₂. In conclusion, pH_bulk and β affected the precipitation of weakly acidic and basic drugs in BCB. As BCB is a physiological buffer in the small intestine, it should be used for precipitation studies of weakly acidic and basic drugs.