The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement
The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement
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DOI：
10.1016/j.ijpharm.2014.01.005
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发表时间：
2014-04-10
影响因子：
5.8
通讯作者：
Moribe, Kunikazu
中科院分区：
文献类型：
--
作者：
Ueda, Keisuke;Higashi, Kenjirou;Moribe, Kunikazu
采用不同形式的羟丙基甲基纤维素乙酸琥珀酸酯（HPMCAS）对水溶液中药物结晶的抑制作用进行了评价。HPMCAS抑制卡马西平（CBZ）、硝苯地平（NIF）、甲氧胺酸和地塞米松的结晶。对药物结晶的抑制主要来源于药物与HPMCAS分子水平的疏水相互作用。琥珀酰取代基比较低的HPMCAS对药物结晶有较强的抑制作用。pH值对结晶的抑制作用有一定的影响，在较高的pH值下，琥珀酰电离产生的HPMCAS的亲水性会抑制CBZ的结晶。通过1h - h -1核磁共振和弛豫时间测量，评价了CBZ在HPMCAS溶液中的分子迁移率。在HPMCAS溶液中，CBZ的迁移率被强烈抑制，对CBZ的结晶有强烈的抑制作用。CBZ在HPMCAS溶液中的迁移率抑制是由于CBZ与HPMCAS分子间相互作用导致结晶抑制。采用NIF/HPMCAS固体分散体评价HPMCAS对药物溶出率的影响。采用琥珀基取代比较高的HPMCAS可提高NIF的溶出率。(C) 2014 Elsevier B.V.版权所有
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-H-1 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. (C) 2014 Elsevier B.V. All rights reserved.