Impact of polymer conformation on the crystal growth inhibition of a poorly water-soluble drug in aqueous solution.
Impact of polymer conformation on the crystal growth inhibition of a poorly water-soluble drug in aqueous solution.
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DOI：
10.1021/la503644m
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Taylor LS
中科院分区：
文献类型：
--
作者：
Schram CJ;Beaudoin SP;Taylor LS
水溶性差是许多新兴药物口服给药的主要障碍。只要能够抑制结晶，过饱和药物溶液就可以改善胃肠道膜的被动吸收，从而增强此类难溶性治疗药物的递送。聚合物能抑制结晶并延长过饱和度；因此，需要了解使聚合物有效的属性。 In this study, the conformation of a polymer adsorbed to a crystal surface and its impact on crystal growth inhibition were investigated.在醋酸琥珀酸羟丙甲基纤维素 (HPMCAS) 存在下，在两种不同的 pH 条件下测量难溶性药物化合物非洛地平的晶体生长速率：pH 3 和 pH 6.8。发现 HPMCAS 在 pH 为 3（低于其 pKa）时是一种效果较差的生长速率抑制剂。预计 HPMCAS 的电离态很可能会影响其在固液界面的构象。原子力显微镜 (AFM) 的进一步研究表明，在两种 pH 条件下，非洛地平吸附的 HPMCAS 构象存在显着差异。在pH 3时，HPMCAS在表面形成卷曲小球，而在pH 6.8时，HPMCAS吸附更均匀。因此，HPMCAS 在 pH 3 时有效性的降低似乎与其构象直接相关。小球的形成使许多非洛地平生长位点开放并可供生长单位附着，从而使聚合物作为生长速率抑制剂的效果降低。
Poor aqueous solubility is a major hindrance to oral delivery of many emerging drugs. Supersaturated drug solutions can improve passive absorption across the gastrointestinal tract membrane as long as crystallization can be inhibited, enhancing the delivery of such poorly soluble therapeutics. Polymers can inhibit crystallization and prolong supersaturation; therefore, it is desirable to understand the attributes which render a polymer effective. In this study, the conformation of a polymer adsorbed to a crystal surface and its impact on crystal growth inhibition were investigated. The crystal growth rate of a poorly soluble pharmaceutical compound, felodipine, was measured in the presence of hydroxypropyl methylcellulose acetate succinate (HPMCAS) at two different pH conditions: pH 3 and pH 6.8. HPMCAS was found to be a less effective growth rate inhibitor at pH 3, below its pKa. It was expected that the ionization state of HPMCAS would most likely influence its conformation at the solid–liquid interface. Further investigation with atomic force microscopy (AFM) revealed significant differences in the conformation of HPMCAS adsorbed to felodipine at the two pH conditions. At pH 3, HPMCAS formed coiled globules on the surface, whereas at pH 6.8, HPMCAS adsorbed more uniformly. Thus, it appeared that the reduced effectiveness of HPMCAS at pH 3 was directly related to its conformation. The globule formation leaves many felodipine growth sites open and available for growth units to attach, rendering the polymer less effective as a growth rate inhibitor.
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