Yamamoto Hibiki, Sugano Kiyohiko
Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan.
Mol Pharm. 2025 Mar 3;22(3):1318-1328. doi: 10.1021/acs.molpharmaceut.4c00996. Epub 2025 Feb 2.
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 (p: 4.9 and 7.0) and two weakly basic drugs (p: 6.1 and 8.3) were used as model drugs. The bulk phase pH value (pH) 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 of BCB to avoid CO 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 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 conditions. The solid forms of the precipitates were determined by powder X-ray diffraction and differential scanning calorimetry. In BCB, as pH was increased above (for weakly acidic drugs) or decreased below (for weakly basic drugs) the drug p 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 and β. In BCB, at pH at which a drug is ionizable, the surface pH of the precipitating particles can differ from pH because of the slow hydration process of CO. In conclusion, pH 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.
本研究的目的是考察生理碳酸氢盐缓冲溶液（BCB）的pH值和缓冲容量（β）对药物沉淀的影响。采用pH值变化沉淀试验评估难溶性药物在BCB中的沉淀情况。使用磷酸盐缓冲溶液（PPB）作为对照。选用两种弱酸性药物（pKa：4.9和7.0）和两种弱碱性药物（pKa：6.1和8.3）作为模型药物。将本体相pH值（pH）和β值设定在小肠生理范围内（pH：5.5至7.5，β：2.2至17.6 mM/ΔpH）。使用浮动盖维持BCB的pH值以避免CO2损失。也将其应用于PPB以统一实验条件。每种药物完全溶解于HCl（pH 3.0，用于弱碱性药物）或NaOH（pH 11.0，用于弱酸性药物）溶液中（450 mL，50 rpm，37 °C）。然后通过加入10倍浓缩缓冲溶液（50 mL，最终体积500 mL）将pH值转变至中性pH区域。设定初始总药物浓度（中性+离子化形式），使得在所有pH条件下中性形式的浓度和过饱和度相同。通过粉末X射线衍射和差示扫描量热法确定沉淀物的固体形式。在BCB中，当pH值高于（对于弱酸性药物）或低于（对于弱碱性药物）药物的pKa值时，游离形式固体的沉淀变得更慢。随着β值增加，BCB中药物沉淀变得更快。PPB中的药物沉淀比BCB中的更快，且受pH值和β值的影响更小。在BCB中，在药物可离子化的pH值下，由于CO2的水合过程缓慢，沉淀颗粒的表面pH值可能与本体相pH值不同。总之，pH值和β值影响了BCB中弱酸性和弱碱性药物的沉淀。由于BCB是小肠中的生理缓冲液，它应用于弱酸性和弱碱性药物的沉淀研究。
