Anne Nong, Claire Schleper, Abigail Martin, Mitchell Paolello, Fredrik L. Nordstrom and Gerard Capellades
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This work combines the fields of impurity rejection, solid solutions, and dyeing crystals, to provide visual evidence of those effects, and to further demonstrate how impure regions in a single crystal can present vastly different behaviors to the purified regions of the same crystal. The work revolves around four model host–guest pairs, two of them previously unreported. These include mixed crystals of acetaminophen with curcumin, sulforhodamine B, and acid fuchsin, as well as potassium sulfate dyed with acid fuchsin. Results challenge common assumptions in the study of multicomponent crystals, demonstrating how neglecting composition anisotropy may lead to misdiagnosing solid solutions as surface adsorbed impurities in impurity retention diagnostics, and how neglecting the habit-modifying effects of dissolved impurities may lead to the use of erroneous models for growth inhibition. 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引用次数: 0
摘要
作为盐类和共晶体的替代品,药用固体溶液在提高药物溶解度和溶解动力学方面越来越受到关注。在工业上,固溶体也是药物中潜在有毒杂质的夹带物。意外将加工过程中的杂质加入晶体生长的晶格中,或有意加入添加剂,都会极大地改变产品的特性。据报道,这些影响包括溶解性增强、熔点变化、多晶体稳定性改变、生长抑制和晶体习性改变等。这项工作结合了杂质剔除、固溶体和晶体染色等领域,为这些效应提供了直观的证据,并进一步证明了单晶体中的不纯区域与同一晶体的纯化区域如何呈现出截然不同的行为。这项研究围绕四对主客体模型展开,其中两对此前从未报道过。其中包括对乙酰氨基酚与姜黄素、磺胺多巴胺 B 和酸性品红的混合晶体,以及用酸性品红染色的硫酸钾。研究结果对多组分晶体研究中的常见假设提出了挑战,证明了忽视成分各向异性可能导致在杂质保留诊断中将固溶体误诊为表面吸附杂质,以及忽视溶解杂质的习性改变效应可能导致使用错误的生长抑制模型。同时,我们还提出了开发新型杂质剔除和晶体工程策略的机会,有助于各向异性晶体的生长,这些晶体的特性可在连续体中进行微调。
Impurity retention and pharmaceutical solid solutions: visualizing the effect of impurities on dissolution and growth using dyed crystals†
Pharmaceutical solid solutions are gaining increased interest as alternatives to salts and co-crystals for the enhancement of drug solubility and dissolution kinetics. Industrially, they are also responsible for the entrapment of potentially toxic impurities in drug substances. The accidental incorporation of process impurities into the lattice of a growing crystal, or the intentional incorporation of an additive, can vastly alter the product's properties. Reported effects include solubility enhancements, changes in melting point, shifting polymorph stabilities, growth inhibition, and change in crystal habit, among others. This work combines the fields of impurity rejection, solid solutions, and dyeing crystals, to provide visual evidence of those effects, and to further demonstrate how impure regions in a single crystal can present vastly different behaviors to the purified regions of the same crystal. The work revolves around four model host–guest pairs, two of them previously unreported. These include mixed crystals of acetaminophen with curcumin, sulforhodamine B, and acid fuchsin, as well as potassium sulfate dyed with acid fuchsin. Results challenge common assumptions in the study of multicomponent crystals, demonstrating how neglecting composition anisotropy may lead to misdiagnosing solid solutions as surface adsorbed impurities in impurity retention diagnostics, and how neglecting the habit-modifying effects of dissolved impurities may lead to the use of erroneous models for growth inhibition. At the same time, we present opportunities for the development of novel impurity rejection and crystal engineering strategies, aiding the growth of anisotropic crystals with properties that can be fine-tuned in continuum.