Rutgers Chemical and Biochemical Engineering, Piscataway, NJ 08854, United States.
Eur J Pharm Sci. 2011 Apr 18;42(5):452-61. doi: 10.1016/j.ejps.2011.01.009. Epub 2011 Feb 1.
It is currently of great interest to the pharmaceutical industry to control the size and agglomeration of nano- and micro-particles for the enhancement of drug delivery. Typically, surfactants and polymers are used as additives to interact with and stabilize the growing crystal surface, thus controlling size and agglomeration; however, selection is traditionally done empirically or using heuristics. The objective of this study was to use molecular dynamic simulations to investigate and predict additive interactions, and thus, evaluate the stabilization potential of individual and multiple additives on the surface of the model drug fenofibrate. Non-ionic surfactant Tween 80, anionic surfactant sodium dodecyl sulfate (SDS), and polymers hydroxypropyl methylcellulose (HPMC) and Pullulan were evaluated individually on three distinct crystal surfaces [(001), (010), (100)], as well as in surfactant-polymer combinations. HPMC was determined to have the strongest interaction with the surfaces of the fenofibrate crystal, and therefore, was predicted to be the most effective individual additive. A mixture of HPMC with SDS was determined to be the most effective mixture of additives, and more effective than HPMC alone, indicating a synergistic effect. The predictions of mixed additives indicated a relative order of effectiveness as follows: HPMC-SDS>HPMC-Tween 80>Pullulan-Tween 80>Pullulan-SDS. The simulations were subsequently validated by an anti-solvent crystallization of fenofibrate where it was found that HPMC individually, and a mixture of HPMC-SDS, produced the smallest and most stable crystals, as measured by laser diffraction; this, in combination with measurements of the crystal growth rate in the presence and absence of additives confirmed the results of the simulations.
目前，控制纳米和微米颗粒的大小和团聚以增强药物传递是制药行业的一大关注点。通常，表面活性剂和聚合物被用作添加剂与生长的晶体表面相互作用并稳定它，从而控制大小和团聚；然而，传统上是通过经验或启发式方法进行选择。本研究的目的是使用分子动力学模拟来研究和预测添加剂的相互作用，从而评估单个和多种添加剂对模型药物非诺贝特表面的稳定潜力。非离子表面活性剂吐温 80、阴离子表面活性剂十二烷基硫酸钠 (SDS) 和聚合物羟丙基甲基纤维素 (HPMC) 和普鲁兰分别在三个不同的晶体表面[(001)、(010)、(100)]以及表面活性剂-聚合物组合上进行了评估。HPMC 被确定与非诺贝特晶体表面具有最强的相互作用，因此被预测为最有效的单一添加剂。HPMC 与 SDS 的混合物被确定为最有效的添加剂混合物，并且比单独的 HPMC 更有效，表明存在协同效应。混合添加剂的预测表明相对有效性顺序如下：HPMC-SDS>HPMC-吐温 80>Pullulan-吐温 80>Pullulan-SDS。随后通过非诺贝特的反溶剂结晶对模拟进行了验证，发现 HPMC 单独使用以及 HPMC-SDS 的混合物产生了最小和最稳定的晶体，这可以通过激光衍射来衡量；这与添加剂存在和不存在时晶体生长速率的测量相结合，证实了模拟的结果。
