Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS, 38655, USA.
Arch Pharm Res. 2015;38(5):839-48. doi: 10.1007/s12272-014-0471-9. Epub 2014 Sep 13.
Clarithromycin (CAM) is known to be poorly water-soluble and acid-labile drug. Various alkalizers such as MgO, Na2CO3, Na2HPO4 and NaHCO3 were utilized to modulate the microenvironmental pH (pHM) and to improve the low stability and solubility of CAM in a crystalline-solid dispersion system (CSD). Polyvinylpyrrolidone (PVP K-30) and hydroxypropylmethylcellulose (HPMC) 4000-based CSDs containing alkalizers were prepared by cosolvent precipitation followed by evaporation process. The dried-CSDs mixed with microcrystalline cellulose, 2% croscarmellose sodium, and 1% magnesium stearate was then directly compressed into tablet. A dissolution test was carried out in 900 mL of pH 5.0 buffer solutions at 37 °C with a 50 rpm paddle speed. pHM, surface morphology, and structural behaviors were investigated. The dissolution rates of CAM in CSD containing alkalizers were improved. The drug in CSD remained crystalline as observed by differential scanning calorimetry and powder X-ray diffraction. Scanning electron microscopy revealed nearly identical images regardless of the sorts and amounts of carriers. PVP-based CSD tablet without alkalizer showed greater drug release, while HPMC-based CSD tablet without alkalizer retarded drug release due to its greater swelling capability. However, when the alkalizers were added in CSD tablet, the drug release was sharply increased. NaHCO3 induced the most rapid drug release while MgO retarded drug dissolution. Alkalizers in CSD also could maintain the pHM of the tablet above pH 5 under acidic conditions. The use of pH modifiers in CSDs could provide a useful method to improve the dissolution rate and stability of CAM via modulation of pHM without changing drug crystallinity.
克拉霉素（CAM）是一种水溶性差、酸不稳定的药物。各种堿化剂，如 MgO、Na2CO3、Na2HPO4 和 NaHCO3，被用于调节微环境 pH（pHM），并改善 CAM 在晶态分散系统（CSD）中的低稳定性和溶解度。含有堿化剂的聚乙烯吡咯烷酮（PVP K-30）和羟丙基甲基纤维素（HPMC）4000 基 CSD 通过共溶剂沉淀后蒸发过程制备。干燥的 CSD 与微晶纤维素、2%交联羧甲基纤维素钠和 1%硬脂酸镁混合，然后直接压片。在 37°C 下，以 50 rpm 桨速在 900 mL pH 5.0 缓冲溶液中进行溶出试验。研究了 pHM、表面形貌和结构行为。含有堿化剂的 CSD 中 CAM 的溶出速率得到提高。差示扫描量热法和粉末 X 射线衍射观察到 CSD 中的药物仍保持结晶状态。扫描电子显微镜显示，无论载体的种类和数量如何，图像几乎相同。不含堿化剂的 PVP 基 CSD 片显示出更大的药物释放，而不含堿化剂的 HPMC 基 CSD 片由于其更大的溶胀能力而延迟药物释放。然而，当 CSD 中加入堿化剂时，药物释放迅速增加。NaHCO3 诱导药物释放最快，而 MgO 则延缓药物溶解。CSD 中的堿化剂也可以在酸性条件下将片剂的 pHM 维持在 pH5 以上。在 CSD 中使用 pH 调节剂可以通过调节 pHM 来提高 CAM 的溶解速率和稳定性，而不改变药物结晶度，这是一种有用的方法。
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