Morphology Design of Organic Crystals Grown from Solution

溶液生长有机晶体的形貌设计

• 批准号: 1159746
• 负责人: Michael Doherty
• 金额: $ 36.18万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1159746&HistoricalAwards=false
• 关键词: Morphology; Design; Organic; Crystals; Grown

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.

1159746多尔蒂这项工作是由化学，生物工程，环境和运输系统（CBET）的化学和生物分离计划和化学部的化学测量和成像计划资助的。超过百分之九十的所有药品都是以颗粒状，通常是晶体形式配制的。同样，化学工业中70%以上的产品是以固体形式出售的。溶液结晶是这些工业中用于分离和纯化在室温和压力下为固体的产品的最常见操作。在结晶过程中，确定了物质的许多物理化学特性，包括晶体多晶型、形状和大小、化学纯度和稳定性、生物利用度、溶解度和溶出速率。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，主要是由于对基本生长和溶解机制的理解不足，以及杂质、添加剂和溶剂对单个晶面生长速率的影响。本研究的一个关键方面是开发和测试一个晶体生长模型的非中心对称（非中心）溶质和/或杂质分子的现实复杂性，这将提供一个平台，用于设计晶体系统的定义形状。晶体生长是一种表面控制的现象，其中溶质分子立体特异性地结合到表面晶格位点中，以产生表征晶体材料的本体长程有序。此类表面过程自然对低浓度其他表面活性分子的存在高度敏感。这些可以被有意地添加到结晶过程中，或者可以作为反应副产物而固有-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，并且已知它们对有机结晶材料的结晶起破坏作用。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处的速度（溶质吸收速率）来降低晶面的垂直生长速率。具体地，不动杂质将边缘划分成片段的集合，并且阻止长度小于或等于某个临界长度的那些片段的生长，从而降低边缘速度。然而，我们在这里认为，在稀释冒名顶替条件下（正常情况），这是不期望的。相反，我们认为，在第一圈的生长螺旋在晶面上的边缘所行进的距离增加，从而降低了整个面的步骤的密度，并降低了晶面的垂直生长速率。研究提出了测试和扩展这种新的预测模型，使其成为一个有用的工具，过程科学家和工程师。模型试验系统将包括在存在对乙酰氧基乙酰苯胺杂质（溶质和杂质均为非中心）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选择的API系统。晶体生长新方法的智力价值完全取决于这样一个事实，即模型提供了一种预测方法，用于预测多面晶体的形状和形状演变。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数量。这项工作的更广泛的影响包括：（a）在我的实验室为来自加州大学B的学生、来自美国各地大学的学生以及来自国际大学的本科生提供本科生研究经验;（B）通过研讨会、特邀讲座以及与礼来公司、雅培实验室等的工业合作者传播研究成果;（c）通过创造和传播软件工具，对成果进行技术转让，以提高美国制药公司的生产力。