Morphology Design of Organic Crystals Grown from Solution

1159746这项工作由化学、生物工程、环境和运输系统(CBET)的化学和生物分离计划以及化学部的化学测量和成像计划资助。超过90%的药物产品是以颗粒形式，通常是结晶形式配制的。同样，超过70%的化学工业产品是作为固体出售的。溶液结晶是这些行业中最常见的操作，用于在室温和压力下分离和提纯固体产品。在结晶过程中，定义了物质的许多物理化学特性，包括晶体的晶型、形状和大小、化学纯度和稳定性、生物利用度、溶解度和溶解速度。因此，溶液结晶是一个非常重要的研究领域。然而，对有机晶体的物理形态的控制仍然很差，这主要是由于对基本的生长和溶解机制的了解不够充分，以及杂质、添加剂和溶剂对单个晶面生长速度的影响。这项研究的一个关键方面是开发和测试现实复杂性的非中心对称(非中心)溶质和/或杂质分子的晶体生长模型，这将为设计定义形状的晶体系统提供平台。晶体生长是一种表面控制的现象，在这种现象中，溶质分子被立体地结合到表面晶格位置，以产生表征晶体材料的大块长程有序。这种表面过程自然很容易受到其他小浓度表面活性分子存在的影响。它们可能是故意添加到结晶过程中的，也可能是作为反应副产物固有的--无论哪种方式，它们的活性都是基于它们与所需溶质的立体化学相似性，并且已知它们会对有机晶体材料的结晶造成严重破坏。50年来，这种效应的晶体生长模型一直假设吸附的不动杂质通过降低边缘的速度(溶质吸收速率)来降低晶面的垂直生长速度。具体地说，不能移动的杂质将边缘分割成一组片段，并且阻止那些长度小于或等于某一临界长度的片段的生长，从而降低边缘速度。然而，我们在这里辩称，在稀释冒名顶替者的条件下(正常情况下)，这不是预期的。相反，我们认为，在晶面上生长螺旋的第一圈期间，边缘移动的距离增加，从而降低了穿过晶面的台阶密度，并降低了晶面的垂直生长速度。研究建议测试和扩展这一新的预测模型，使其成为过程科学家和工程师的有用工具。模型测试系统将包括在对乙酰氧基乙酰苯胺杂质(溶质和杂质均为非中心)存在的情况下从水溶液中生长的扑热息痛(对乙酰氨基酚)；在存在己酸和辛酸(均为非中心)添加剂的情况下从水溶液中生长的己二酸(中心溶质)；以及与我们的工业合作伙伴合作的部分原料药系统。新的晶体生长方法的智力优势完全取决于这样一个事实，即这些模型为预测多面晶体的形状和形状演变提供了一种预测方法。这将大大减少为具有工程形状的晶体定义设计空间所需的实验次数。这项工作的更广泛影响包括(A)为来自UCSB的学生、美国各地的大学以及来自国际大学的本科生提供我的实验室的本科研究经验，(B)通过研讨会、特邀讲座以及与礼来公司、雅培实验室和其他公司的行业合作者传播研究成果，(C)通过创建和传播将提高美国制药公司生产率的软件工具来技术转让结果。

1159746DohertyThis work is funded by the Chemical and Biological Separations Program of the Chemical, Bioengineering, Environmental, and Transport Systems (CBET) and the Chemical Measurements and Imaging Program of the Chemistry Division.Over ninety percent of all pharmaceutical products are formulated in particulate, generally crystalline form. Similarly, over seventy percent of the products from the chemical industry are sold as solids. Solution crystallization is the most common operation in these industries for the separation and purification of products that are solids at room temperature and pressure. During crystallization, many physical-chemical characteristics of the substance are defined, including crystal polymorph, shape and size, chemical purity and stability, bioavailability, solubility and dissolution rate. Accordingly, solution crystallization is a very important field of research. However, control over the physical form of organic crystals has remained poor, mainly due to inadequate understanding of the basic growth and dissolution mechanisms, and the influence of impurities, additives and solvents on the growth rate of individual crystal faces. A key aspect of this research is to develop and test a crystal growth model for non-centrosymmetric (noncentric) solute and/or impurity molecules of realistic complexity, which will provide a platform for designing crystal systems of defined shape. Crystal growth is a surface-controlled phenomenon in which solute molecules are incorporated stereo-specifically into surface lattice sites in order to yield the bulk long range order that characterizes crystalline materials. Such surface processes are naturally highly susceptible to the presence of small concentrations of other surface active molecules. These may be deliberately added to a crystallization process or may be inherent as reaction by-products - either way their activity is based on their stereo-chemical similarity to the desired solute and they are known to play havoc with the crystallization of organic crystalline materials. For fifty years, crystal growth models of this effect have assumed that adsorbed immobile impurities decrease the perpendicular growth rate of a crystal face by reducing the velocity (rate of solute uptake) at an edge. Specifically, the immobile impurities partition the edge into a collection of segments and the growth of those segments whose length is less than or equal to some critical length is arrested, thus decreasing the edge velocity. However, we argue here that under dilute imposter conditions (the normal situation) this is not expected. Rather, we argue the distances travelled by edges during the first turn of a growth spiral on a crystal face are increased, thereby decreasing the density of steps across the face and reducing the perpendicular growth rate of the crystal face. Research is proposed to test and extend this new predictive model so that it becomes a useful tool for process scientists and engineers. Model test systems will include paracetamol (acetaminophen) grown from aqueous solution in the presence of p-acetoxyacetanilide impurity (solute and impurity are both noncentric); adipic acid (centric solute) grown out of aqueous solution in the presence of hexanoic acid and octanoic acid (both noncentric) additives, and selected API systems in collaboration with our industrial partners. The intellectual merit of the new approach to crystal growth rests entirely on the fact that the models provide a predictive method for anticipating the shape, and shape evolution, of faceted crystals. This will greatly reduce the number of experiments needed to define the design space for crystals with an engineered shape. The broader impacts of this work include (a) providing undergraduate research experiences in my laboratory for students from UCSB, from universities across the USA more broadly, and for undergraduates from international universities, (b) dissemination of the research results through workshops, invited lectures and with industrial collaborators at Eli Lilly, Abbott Labs, and others, (c) tech transfer of the results through the creation and dissemination of software tools that will enhance the productivity of US pharma companies.