School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Mol Pharm. 2012 Oct 1;9(10):2844-55. doi: 10.1021/mp300135h. Epub 2012 Aug 27.
The applicability of the computational docking approach was investigated to create a novel method for quick additive screening to inhibit the crystallization taking place in amorphous drugs. Surface energy and attachment energy were utilized to recognize the morphologically most important crystal faces. The surfaces (100), (001), and (010) were identified as target faces, and the estimated free energies of binding of additives on these surfaces were computationally determined. The molecule of the crystallizing compound was included in the group of the modeled additives as the reference and for the validation of the approach. Additives having a lower estimated free energy of binding than the reference molecule itself were considered as potential crystallization inhibitors. Salicylamide, salicylic acid, and sulfanilamide with computationally prescreened additives were melt-quenched, and the nucleation and crystal growth rates were subsequently monitored by polarized light microscopy. As a result, computationally screened additives decelerated the nucleation and crystal growth rates of the studied drugs while the pure drugs crystallized too fast to be measured. The use of a computational approach enabled fast and cost-effective additive selection to retard nucleation and crystal growth, thus facilitating the production of amorphous binary small molecular compounds with stabilized disordered structures.
研究了计算对接方法的适用性，以创建一种新的快速添加剂筛选方法，抑制无定形药物中的结晶。利用表面能和附着能来识别形态上最重要的晶体面。确定了表面（100）、（001）和（010）为目标面，并计算确定了添加剂在这些表面上的结合自由能。将结晶化合物的分子包含在建模添加剂组中作为参考，并验证该方法。将结合自由能估计值低于参考分子本身的添加剂视为潜在的结晶抑制剂。对具有经计算预筛选的添加剂的柳氮磺胺吡啶、水杨酸和磺胺嘧啶进行熔融淬火，并随后通过偏光显微镜监测成核和晶体生长速率。结果表明，计算筛选的添加剂可降低研究药物的成核和晶体生长速率，而纯药物结晶速度太快而无法测量。使用计算方法能够快速有效地选择添加剂来延迟成核和晶体生长，从而促进具有稳定无序结构的无定形二元小分子化合物的生产。
