Selective manipulation of crystal shape by combined crystallization, milling, and dissolution stages - An approach for robust process design

Solid formulations are nowadays extremely important in everyday life, especially concerning food and pharmaceutical products. Particularly in the latter case, the size and shape of the active pharmaceutical ingredients play a major role in determining their properties, both in terms of processability and bioavailability. For this reason, the interest in the crystallization community is driven nowadays more and more towards the identification of solutions to control the morphology of the particles during crystallization processes. Currently, the use of additives and antisolvents, as well as milling the particles after crystallization, are techniques commonly applied in industry. In order to avoid chemical impurities and fines in the final products, processes involving temperature cycles, eventually combined with a feedback controller, have also proved to be an interesting alternative. In this work, a new technique based on the combination of crystallization, milling and dissolution is proposed to control the shape of crystals. The crystallization stage is used to recover the solute from solution, while milling is used to break particles lengthwise, therefore reducing their length and leading to more equant shaped crystals. The fines formed during rupture are subsequently removed by dissolving them and the three stages are repeated for the desired number of cycles. The approach used for a successful process design is thoroughly explained. First of all, it is necessary to develop devices to reliably and accurately measure multidimensional particle size and shape distributions. This is fundamental for a precise characterization of the basic phenomena occurring during the different stages. To this aim, the flow-through cell, an in-house built device, is used to monitor and measure populations of crystals and characterize them in terms of length and width; on top of that, a hot-stage microscope is used to investigate phenomena at the single particle scale. The experimental observation is used to develop a mathematical model, based on population balance equations. This model allows to describe phenomena typically occurring during crystallization processes, such as breakage and nucleation, hence allowing for an accurate prediction of experimental outcomes. The mathematical model developed proves to be a reliable tool for the investigation of the feasibility of the proposed process. After the identification of process variables, particular focus is placed on the effect of the amount of mass dissolved, the milling intensity and the number of cycles performed, by considering and comparing both average properties and the whole particle size and shape distributions. A parametric analysis is used to identify general process trends and possible tradeoffs, as well as close-to-optimality conditions. To conclude, a comparison with a single crystallization stage and cooling crystallization followed by milling is carried out, highlighting benefits and limitations of the new process on the alternatives proposed

Optimization and Feedback Control of the Size and Shape Evolution of Elongated Crystals in Suspension

The purification and the solidification of substances is of interest in a large number of applications in the fine chemical, pharmaceutical, and food industries. Batch crystallization from solution is often applied to fulfill this task. The macroscopic shapes of the crystals obtained in this way are governed by the principles of crystallography, and thus they exhibit a compound-specific diversity. Still, the shape and also the size of these solids can be influenced by the choice of the process operating conditions, for instance, by varying the driving force or by applying mechanical action. Since the particle size and shape distribution (PSSD) is widely accepted to be a central attribute of the obtained solid powder, the ability to engineer crystalline particles to a desirable size and shape is of great interest regardless of the application. The main purpose of this thesis is to develop, to implement, and to evaluate---both in simulation and in experiments---optimization and feedback control algorithms aimed at the manipulation of particle size and shape during batch crystallization processes. The presented methodologies are mainly concerned with elongated (or needle-like) crystals, since particles of this type often cause problems in the pharmaceutical industry. The main challenges encountered during the development of these methodologies are their high requirements with respect to online size and shape monitoring abilities, the limited predictive capabilities of currently available crystal shape evolution models, and the often encountered lack of physical actuators to alter the crystal shape. In particular, the following results have been achieved: - Model-based path planning methodologies have been developed for studying computationally the possible size and shape transitions of single crystals undergoing temperature cycling. - Feedback control laws for driving the average particle dimensions of ensembles of elongated crystals to target regions during growth-dominated batch cooling crystallization have been conceived and successfully validated. - A feedback controller for the targeted length reduction of elongated particles using wet milling has been designed and tested. - A multidimensional kinetic model for the dissolution of an elongated organic compound has been identified from experimental data. Furthermore, a simple feedback law for the controlled operation of dissolution stages has been implemented. - The feedback controllers developed for wet milling and dissolution have been integrated and combined with a simple controlled growth stage to operate a multistage process for the systematic PSSD modification in a fully automated, controlled, and thus robust manner. In particular, a significant and repeatable shape transformation from elongated to more equant particles has been realized in lab-scale experiments. From a control systems engineering point of view, the results collected in this thesis simply represent yet another example of the potential of feedback control. From a crystallization perspective, however, the developed control and operating strategies represent a novel and robust approach to crystallizing compounds that form elongated particles. The key benefits of these strategies are that most of them do not require kinetic models to operate the process and that they can mitigate considerably undesirable batch-to-batch variations in terms of selected properties of the product PSSD

An Alternative Approach to Estimate Solute Concentration: Exploiting the Information Embedded in the Solid Phase

ISSN:1948-718

Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. III. Wet Milling

Several operating and control strategies with the purpose of manipulating the size and shape of crystals exhibiting needle-like morphology are presented using an ex situ wet mill as the actuator. A model-based operating policy and different model-free controllers are discussed. These controllers were coupled with an online particle size and shape monitoring tool. First, the attainable region in the size and shape space for a wet milling operation was evaluated in a simulation framework using a multidimensional population balance model describing the breakage phenomenon. Second, the operating and control strategies were tested experimentally in a lab-scale setup using two different milling configurations and two different compounds, namely, β l-glutamic acid and γ d-mannitol. The goal of the experiments was to drive various seed populations of the two compounds to several target average lengths in the size and shape space. It was observed that the model-based operating policy, run without any feedback action, was not able to achieve this goal for arbitrary seed populations. The model-free controllers incorporating feedback were able to do so without relying on any multidimensional breakage model. These controllers enable the robust operation of wet milling stages in complex crystal size and shape modification processes.ISSN:1528-7483ISSN:1528-750

Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. IV. Modeling and Control of Dissolution

Several two-dimensional dissolution rate models for the needle-like compound β l-glutamic acid (BLGA) in water are obtained by first conducting a series of lab-scale experiments and then applying the maximum likelihood parameter estimation technique within a population balance framework. Among these models, a reasonable choice consists of expressions for the dissolution rates along both particles dimensions that are linear in the driving force and yield a constant value of 12 for the ratio of the dissolution rate along the length of the needles to that along their width. The insights gained from this model are applied to discuss the potential of cyclic processes aimed at modifying the size and the shape of BLGA crystals. Furthermore, a model-free feedback control law with the goal to dissolve a given fraction of the overall solid volume initially suspended in a batch system is presented. This controller is tested in a simulation framework making use of the identified dissolution kinetics. It is also validated experimentally by using BLGA and another compound forming needle-like crystals, vanillin. The results demonstrate its effectiveness and its general applicability, making it suitable for the controlled operation of dissolution stages in cyclic size and shape modification processes.ISSN:1528-7483ISSN:1528-750

Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. I. Concepts and Simulation Studies

Two feedback control approaches for influencing the evolution of the average particle dimensions of populations of needle-like crystals in growth-dominated batch cooling crystallization processes are proposed. The first strategy is a path following control (PFC) approach which does not need access to kinetic models for crystal growth. The second approach consists of a considerably more complex nonlinear model predictive controller (NMPC) that requires the availability of multidimensional crystal growth rate models. The main focus lies in analyzing the effectiveness of these two controllers with respect to successfully operating the considered process, bearing in mind the differing requirements regarding the availability of kinetic models. To this end, both control strategies were coupled with a process simulation framework that features a detailed measurement model emulating the behavior of an existing monitoring device for the evolution of the particle size and shape distribution. It is demonstrated how both controllers can identify the attainable region for the average particle dimensions of a given seed population, and also reach an arbitrary target size and shape within the interior of this region. A performance benefit from operating the more complex NMPC was not observed, which renders the PFC approach suitable and sufficient for the considered application.ISSN:1528-7483ISSN:1528-750

Multi-Objective Path Planning for Single Crystal Size and Shape Modification

ISSN:1528-7483ISSN:1528-750