Modelling agglomeration and breakage during agitated vacuum thermal drying

人们非常重视原料药颗粒属性在药物产品性能和可加工性方面所起的作用。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，原料药的分离步骤、过滤、洗涤，特别是干燥，还没有受到如此密集的调查。本博士学位将加深我们对颗粒状API的创建和后续破坏的理解。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干燥过程中的团聚尺寸、粒度分布和团聚强度的演变。最终目标是将测量的属性和工艺参数与结果相关联。PHD计划将首先评估描述晶体之间个别接触点的材料积聚的替代方法，建立随着溶剂蒸发而沉积材料的颈部。与这两个粒子的方法平行，学生将开发一个基于粒子大小、大小分布和晶体习性的接触强度模型。结合这两个组成部分，学生将把模型扩展到多颗粒凝聚体/颗粒，以研究强度和破坏模式。还将考虑其他研究领域的现有模型，特别是将审查土壤科学的流变学见解，并将相关方法纳入项目。考虑到颗粒的形成，将分析静态和搅拌干燥。模拟程序涉及几个关键方面：-接触颈的干燥动力学，以及对颗粒大小和溶剂性质的依赖；-在静态床中堆积颗粒以获得颗粒接触的网络；-在干燥过程中团聚的演变，产生与时间相关的颗粒尺寸分布和形状；-各种团聚的机械强度，接触颈部是破碎的薄弱环节；-开发搅拌式干燥器中团聚的随机模型，其中颗粒在整个干燥过程中由于碰撞而形成和破裂。这项工作将利用一系列分析和软件工具，导致开发具有预测能力的统计模型。将建立一个显式的模型，描述晶体之间的润湿颈部和干燥过程中驱动颈部形成和溶质传输的毛细管力，并用于预测由此产生的将颗粒保持在一起的固体桥的强度。所使用的软件包括：用于颗粒堆积的EDEM；用于团聚体机械强度的有限元工具；以及用于团聚体生长和破碎的定制蒙特卡罗程序。最后，将进行比例分析，以了解系统行为如何随时间和流程规模的变化而变化，即从桌面系统转移到生产单位。实验方案旨在补充建模方案，提供关键数据和特征，为建模提供支持，使方法得以改进。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，重点研究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、蒸气压力、粘度、界面张力和与所选原料药的润湿性的作用。干燥动力学也将被确定为操作温度、压力和气体流量的函数。为了跟踪原料药在干燥过程中的物理属性，将采用半批方法，将相同的输入材料干燥到不同的终点，然后进行表征。通过这种方式，这项工作与模型程序中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.