Transforming Industrial Crystallization by Sono-mechanical Manipulation of Crystal Surfaces

在化工生产中，净化是一个至关重要的过程，它确保只获得所需的产品，并有效地去除不需要的或有害的杂质。许多日常用品都是用结晶法提纯的。它是制药、精细化工、油漆、颜料和农用化学品领域的主要净化技术。英国化学工业的营业额为550亿英镑，占英国制造业价值的11%。2012年，英国制药行业的贸易顺差为55亿英镑，出口额为209亿英镑。（英国制造商按产品销售（PRODCOM） 2011年（ONS 2012年12月）和HMRC英国贸易信息2013年6月）。在结晶过程中，分子聚集在一起形成有规则的三维包装排列的晶体，称为晶格。在溶液-晶格界面通过分子识别进行纯化。在晶体表面的某些位置，杂质分子与晶格之间的不匹配是如此之大，以至于杂质被拒绝。在其他位置，晶格错配小到足以使杂质附着在晶体表面。远离晶面的杂质分子部分可能与相邻的分子差别很大，从而破坏并减缓了该晶面上的后续生长。增大结晶驱动力会导致杂质过度生长并混入产物中。典型的工业结晶的进料流含有百分之几的杂质，所以这些相互作用是非常频繁的，并有严重的后果。有时产品太不纯，必须重新结晶。晶体生长的杂质中毒增加了处理时间，大大减缓了接近平衡的速度，以至于一些产物不得不留在溶液中，在废物流中丢失。通过提高产量和加速结晶过程来提高晶体纯度和效率是欧洲化学工程结晶工作组确定的主要挑战之一（比坎斯工业结晶挑战和科学问题，2011年9月）。在结晶过程中干预去除生长晶体表面的杂质将克服这一问题，提高产品纯度和生产率，减少浪费并提供性能更好的晶体。超声波是唯一适合这项任务的，因为声音通过与存在的每个分子的相互作用在介质中传播。千赫到兆赫范围内的频率足够高，当每个分子层被添加到生长的晶体中时，就可以进行干预。所提出的机制包括增加生长晶体附近的分子运动，改善进出晶体表面的运输。由空化事件引起的高度局域扰动导致局部温度瞬间波动。当这些发生在靠近杂质附着的晶格的应变区域时，它们有利于杂质分子的释放。虽然之前已经有关于结晶的工作，但这是一个新的应用领域，将发展新的理解并导致新的工艺能力。该方法有利于批量工艺，但在连续工艺中尤其有价值，其中加速结晶将减少通常最长工艺步骤的停留时间。这对于批量加工占主导地位的制药行业具有战略意义，但出于财务、质量和可持续性原因，有强烈的动力转向连续操作。在斯特拉斯克莱德大学进行这个项目与主要的国家制造研究活动保持一致，包括EPSRC创新制造中心和连续制造和结晶博士培训中心（CMAC），以及耗资8900万英镑的斯特拉斯克莱德大学技术和创新中心（TIC）内的专用设施，旨在促进连续加工，特别是结晶。

Purification is a vital process in chemical manufacture that ensures only the desired product is obtained and unwanted or hazardous impurities are effectively removed. Many every day materials are purified by crystallization. It is the principal purification technique in the pharmaceutical, fine chemical, paint, pigment and agrochemical sectors. The UK chemical industry turnover is £55 billion or 11% of the value of UK manufacturing. The UK pharmaceutical sector generated a trade surplus of £5.5 billion in 2012 with exports of £20.9 billion. (UK Manufacturers' Sales by Product (PRODCOM) 2011 (ONS December 2012) & HMRC UK Trade Information June 2013).During crystallization molecules assemble together to form crystals with a regular 3D packing arrangement known as a lattice. Purification occurs by molecular recognition at the solution - lattice interface. At some sites on the crystal surface the mismatch between the impurity molecule and the lattice is so large that the impurity is rejected. At other sites the lattice mismatch is small enough for the impurity to attach to the crystal face. The portion of the impurity molecule facing away from the crystal face may differ so much from the adjacent molecules that it disrupts and slows the subsequent growth on that crystal face. Increasing the crystallization driving force results in the impurity being overgrown and incorporated into the product. Typical feed streams to industrial crystallizations contain several % of impurities so these interactions are very frequent and have serious consequences. Sometimes the product is so impure it has to be re-crystallized. Impurity poisoning of crystal growth increases processing time slowing the approach to equilibrium so much that some product has to be left in solution and lost in the waste stream. Improving crystal purity and increasing efficiency through improved yield and accelerating crystallization processes are amongst the major challenges identified by the European Federation of Chemical Engineering Working Party on Crystallization, (Biscans Industrial Crystallization Challenges and Scientific Issues Sept 2011).Intervening to remove impurities from the growing crystal surface during crystallization will overcome this problem increasing product purity and productivity, reducing waste and delivering crystals with improved performance. Ultrasound is uniquely suited to this task as sound propagates through media by interaction with every molecule present. Frequencies in the KHz to MHz range are high enough to intervene as each molecular layer is added to the growing crystal. The proposed mechanisms involve increased molecular motion adjacent to the growing crystal improving transport to and from the crystal faces. Highly localised perturbations caused by cavitation events lead to momentary local temperature fluctuations. When these occur close to strained regions of the lattice where impurities are attached they favour release of the impurity molecules. Although there has been previous work sonocrystallization this is a new area of application that will develop new understanding and lead to a new process capability. The approach benefits batch processes but will be especially valuable in continuous processes where accelerating crystallization will reduce residence time in what is usually the longest process step. This is strategic for the pharmaceutical sector where batch processing dominates but there is a strong drive to switch to continuous operation for financial, quality and sustainability reasons. Undertaking this project at Strathclyde University aligns it with major national manufacturing research activities including the EPSRC Centre for Innovative Manufacturing and Doctoral Training Centre in Continuous Manufacturing and Crystallisation (CMAC) and dedicated facility within the £89M University of Strathclyde Technology and Innovation Centre (TIC) designed to promote continuous processing, particularly crystallization.