Modelling agglomeration and breakage during agitated vacuum thermal drying

非常重视API颗粒属性在制剂性能和可加工性中的作用。在将晶体结构与结晶工艺设计联系起来方面取得了重大进展。然而，尚未对API分离步骤、过滤、洗涤和特别是干燥进行如此密集的研究。这个博士学位将加深我们对颗粒API的创建和随后的破坏的理解。研究的目的是了解和模拟干燥过程中发生的团聚过程，以及这些过程如何影响团聚体尺寸的演变;尺寸分布;干燥过程中的团聚体强度。最终目标是将测量属性和工艺参数与结果相关联。博士课程将从评估替代方法开始，以描述在溶剂蒸发时晶体之间建立沉积材料颈部的各个接触点处的材料积累。与此同时，学生将根据颗粒尺寸、尺寸分布和晶体习性建立接触强度模型。结合这两个组件，学生将模型扩展到多颗粒团聚体/颗粒，以研究强度和破碎模式。其他研究领域的现有模型也将被考虑，特别是来自土壤科学的流变学见解将被审查，相关方法将被纳入该项目。关于颗粒的形成，静态和搅拌干燥将被分析。模拟方案涉及若干关键方面：-接触颈的干燥动力学，以及对颗粒尺寸和溶剂性质的依赖性;-颗粒在静态床中的堆积，以获得颗粒接触的网络;-附聚物随着干燥的进行而演变，产生随时间变化的颗粒尺寸分布和形状;-各种附聚物的机械强度，接触颈提供破裂的弱点;- 在搅拌干燥器中，颗粒在干燥过程中由于碰撞而形成和破碎，因此开发了团聚的随机模型。这项工作将利用一系列分析和软件工具，从而开发具有预测能力的统计模型。一个明确的模型之间的湿颈晶体和毛细管力驱动两个颈部形成和溶质运输过程中干燥将建立和用于预测所产生的固体桥保持颗粒在一起的强度。将采用的软件包括：颗粒堆积的EDEM;团聚体机械强度的有限元工具;以及团聚体生长和破碎的定制Monte Carlo代码。最后，将进行缩放分析，以了解系统行为如何随着时间和过程规模而变化，即从桌面系统转移到生产单元时。实验方案旨在补充建模方案，提供关键数据和表征，为建模提供支持，从而改进方法。我们将首先使用我们定制的滤饼干燥设备，在一系列高度受限的实验中，专注于特定溶剂含量下的静态干燥。将研究温度、在所选溶剂中的溶解度、溶剂性质、沸点、蒸汽压、粘度、界面张力和润湿性对所选API的作用。干燥动力学也将被确定为操作温度、压力和气体流速的函数。为了跟踪干燥过程中API的物理属性，将采用半批方法，其中将相同的输入材料干燥至不同的终点，然后进行表征。通过这种方式，这项工作与建模程序的预测进行了直接比较。

Much emphasis has been placed on the role API particle attributes play in both drug product performance and processability. Significant progress has been made in linking crystal structure with crystallization process design. However, the API isolation steps, filtration, washing and especially drying have not been subject to such intense investigation. This PhD will deepen our understanding of the creation and subsequent breakage of granular APIs. The research objective is to understand and model the agglomeration processes which occur during drying and how these influence the evolution of: agglomerate size; size distribution; and agglomerate strength during drying. The ultimate objective being to correlate measured attributes and process parameters with outcomes.The PhD program will start with an evaluation of alternative approaches to describe the build-up of material at individual points of contact between crystals establishing necks of deposited material as the solvent evaporates. In parallel to this two particle approach the student will develop a model for contact strength based on particle size, size distribution and crystal habit. Combining these two components the student will extend the model to multi-particle agglomerates / granules to investigate strength and breakage mode. Existing models from other fields of research will also be considered, in particular rheological insights from soil science will be reviewed and relevant approaches will be incorporated into the project.Concerning the formation of granules, both static and agitated drying will be analysed. The modelling programme involves a number of key aspects:- The drying kinetics of contact necks, and the dependence on particle size as well as solvent properties;- The packing of particles in a static bed to obtain a network of particle contacts;- The evolution of agglomerates as the drying proceeds, yielding time-dependent granule size distributions and shapes;- The mechanical strength of the various agglomerates, with contact necks providing weak points for breakage;- The development of stochastic models for agglomeration in agitated dryers, where the granules form and break due to collisions throughout the drying process.The work will utilise a range of analysis and software tools, leading to the development of statistical models with predictive capabilities. An explicit model of the wetted neck between crystals and the capillary forces driving both neck formation and solute transport during drying will be built and used to predict the strength of the resulting solid bridge holding particles together. The software to be employed includes: EDEM for particle packing; Finite Element tools for mechanical strength of the agglomerates; and bespoke Monte Carlo codes for agglomerate growth and fragmentation. Finally, scaling analyses will be performed to understand how the system behaviour changes over time and over process scale, i.e. when moving from the desk-top systems to production units. The experimental programme is designed to complement the modelling one, providing key data and characterisation that feeds into the modelling enabling a refinement of the methodology. We will first focus on static drying at specific solvent contents in a series of highly constrained experiments, using our bespoke filter cake drying apparatus. The role of temperature, solubility in the selected solvent, solvent properties, boiling point, vapour pressure, viscosity, interfacial tension and wettability with respect to the chosen API will be investigated. Drying kinetics will also be determined as a function of operating temperature, pressure and gas flow rate. In order to track the physical attributes of the API during drying a semi batch approach will be taken in which the same input material is dried to different end points then characterised. In this way, the work makes direct comparison to the predictions from the modelling programme.