Tran Phuong Ha Lien, Tran Huyen Thi Thanh, Lee Beom-Jin
National Research Lab. for Bioavailability Control, College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea.
J Control Release. 2008 Jul 2;129(1):59-65. doi: 10.1016/j.jconrel.2008.04.001. Epub 2008 Apr 13.
The present work is an original evaluation of the microenvironmental pH (pH(M)) and crystallinity of an ionizable drug in order to enhance its dissolution using alkalizers in polyethylene glycol 6000 (PEG 6000) based solid dispersions (SDs). Telmisartan (TEL) was chosen as a model drug due to its poor and pH-dependent water solubility. The nine alkalizers used to modify the pH of TEL were MgO, NaOH, KOH, Na2CO3, NaHCO, bentonite, Na2HPO4, K2HPO4 and arginine. MgO, NaOH, KOH and Na2CO3 in the SD system significantly increased the drug dissolution rate in intestinal fluid (pH 6.8) and water. Modulation of pH(M) was clearly observed as a function of time at different fractional dimensions of tablet. Structural change in drug crystallinity to an amorphous form was also a contributing factor based on differential scanning calorimetry (DSC) thermograms and powder X-ray diffraction (PXRD) patterns. The drug frequency of the CO band decreased and the O-H broad band in the Fourier transform infrared (FTIR) spectra disappeared when these alkalizers were added. It was evident that the alkalizers in PEG 6000 based SDs synergistically enhanced dissolution of TEL not only by modulating pH(M) but also by changing drug crystallinity to an amorphous form via molecular interactions.
本研究是对一种可电离药物的微环境pH值（pH(M)）和结晶度进行的原创性评估，目的是在基于聚乙二醇6000（PEG 6000）的固体分散体（SDs）中使用碱化剂来提高其溶出度。由于替米沙坦（TEL）水溶性差且依赖于pH值，因此选择其作为模型药物。用于调节TEL pH值的九种碱化剂分别为氧化镁、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、膨润土、磷酸氢二钠、磷酸氢二钾和精氨酸。SD系统中的氧化镁、氢氧化钠、氢氧化钾和碳酸钠显著提高了药物在肠液（pH 6.8）和水中的溶出速率。在片剂的不同分数维下，可清楚观察到pH(M)随时间的变化。基于差示扫描量热法（DSC）热谱图和粉末X射线衍射（PXRD）图谱，药物结晶度向无定形形式的结构变化也是一个促成因素。当加入这些碱化剂时，傅里叶变换红外光谱（FTIR）中CO带的药物频率降低，O-H宽带消失。显然，基于PEG 6000的SDs中的碱化剂不仅通过调节pH(M)，而且通过分子相互作用将药物结晶度转变为无定形形式协同增强了TEL的溶出度。
