Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients
Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients
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DOI：
10.1021/cg800035w
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发表时间：
2008-05-01
影响因子：
3.8
通讯作者：
Blagden, Nicholas
中科院分区：
文献类型：
--
作者：
Berry, David J.;Seaton, Colin C.;Blagden, Nicholas
通常使用高通量溶液生长进行共晶体筛选。我们报告了一种低到中等吞吐量的方法，包括熔融和溶液结晶步骤，作为鉴定共晶的一种途径。在溶液研究之前，使用Koller混合熔融法包括熔体生长步骤。这种方法可以阐明二元相图中的热力学图景，并被发现提高了整体筛选效率。作为合成子稳定性更大系统研究的一部分，选择了药学上可接受的加合物烟酰胺，并与少量活性药物成分(布洛芬(外消旋化合物(R/S)和S对映体)、芬布芬、氟比洛芬(R/S)、酮洛芬(R/S)、扑热息痛、吡拉西坦和水杨酸)进行了筛选。从屏幕上鉴定了三个新的共晶体系(布洛芬(R/S和S)和水杨酸)，并测定了它们的晶体结构。由于晶体生长不良，S-布洛芬烟酰胺共晶的结构溶液需要同步辐射。还发现了另外两个潜在的体系(芬布芬和氟比洛芬)，但还没有得到适合结构测定的晶体。为了充分验证这一晶体工程策略，需要更强的结晶动力学控制能力才能生产出相纯的单晶材料。
Co-crystal screening is routinely undertaken using high-throughput solution growth. We report a low- to medium-throughput approach, encompassing both a melt and solution crystallization step as a route to the identification of co-crystals. Prior to solution studies, a melt growth step was included utilizing the Koller mixed fusion method. This method allowed elucidation of the thermodynamic landscape within the binary phase diagram and was found to increase overall screening efficiency. The pharmaceutically acceptable adduct nicotinamide was selected and screened against a small set of active pharmaceutical ingredients (APIs) (ibuprofen (both the racemic compound (R/S) and S-enantiomer), fenbufen, flurbiprofen (R/S), ketoprofen (R/S), paracetamol, piracetam, and salicylic acid) as part of a larger systematic study of synthon stability. From the screen, three new co-crystal systems have been identified (ibuprofen (R/S and S) and salicylic acid) and their crystal structures determined. Because of poor crystal growth synchrotron radiation was required for structure solution of the S-ibuprofen nicotinamide co-crystal. Two further potential systems have also been discovered (fenbufen and flurbiprofen), but crystals suitable for structure determination have yet to be obtained. A greater ability to control crystallization kinetics is required to yield phase-pure single-crystalline material for full verification of this crystal engineering strategy.