Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Int J Pharm. 2014 Apr 10;464(1-2):205-13. doi: 10.1016/j.ijpharm.2014.01.005. Epub 2014 Jan 17.
The inhibitory effect on drug crystallization in aqueous solution was evaluated using various forms of hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS suppressed crystallization of carbamazepine (CBZ), nifedipine (NIF), mefenamic acid, and dexamethasone. The inhibition of drug crystallization mainly derived from molecular level hydrophobic interactions between the drug and HPMCAS. HPMCAS with a lower succinoyl substituent ratio strongly suppressed drug crystallization. The inhibition of crystallization was affected by pH, with the CBZ crystallization being inhibited at a higher pH due to the hydrophilization of HPMCAS derived from succinoyl ionization. The molecular mobility of CBZ in an HPMCAS solution was evaluated by 1D-(1)H NMR and relaxation time measurements. CBZ mobility was strongly suppressed in the HPMCAS solutions where strong inhibitory effects on CBZ crystallization were observed. The mobility suppression of CBZ in the HPMCAS solution was derived from intermolecular interactions between CBZ and HPMCAS leading to an inhibition of crystallization. The effect of HPMCAS on the drug dissolution rate was evaluated using an NIF/HPMCAS solid dispersion. The dissolution rate of NIF was increased when HPMCAS with a higher succinoyl substituent ratio was used.
采用各种形式的羟丙甲纤维素醋酸琥珀酸酯（HPMCAS）评价其在水溶液中对药物结晶的抑制作用。HPMCAS 抑制了卡马西平（CBZ）、硝苯地平（NIF）、甲芬那酸和地塞米松的结晶。药物结晶的抑制主要源于药物与 HPMCAS 之间的分子水平疏水相互作用。取代度较低的 HPMCAS 强烈抑制药物结晶。结晶抑制受 pH 值的影响，由于琥珀酰化电离导致 HPMCAS 的亲水化，在较高 pH 值下抑制 CBZ 结晶。通过 1D-（1）H NMR 和弛豫时间测量评估 CBZ 在 HPMCAS 溶液中的分子迁移率。在观察到对 CBZ 结晶有强烈抑制作用的 HPMCAS 溶液中，CBZ 的迁移率受到强烈抑制。CBZ 在 HPMCAS 溶液中的迁移率抑制源于 CBZ 和 HPMCAS 之间的分子间相互作用，从而抑制结晶。采用 NIF/HPMCAS 固体分散体评价 HPMCAS 对药物溶出速率的影响。当使用取代度较高的 HPMCAS 时，NIF 的溶出速率增加。
