Technoeconomic Evaluation of Multiple Mixed Suspension-Mixed Product Removal (MSMPR) Crystallizer Configurations for Continuous Cyclosporine Crystallization

Continuous crystallization using Mixed Suspension-Mixed Product Removal (MSMPR) crystallizers has been demonstrated as a feasible method for implementing continuous separations in pharmaceutical manufacturing processes. This work conducts a steady-state process modeling and simulation study of the continuous cooling crystallization of cyclosporine, comparing processes with and without solids recycle for their technoeconomic viability. The model describes population balance equations, crystallization kinetics, and process mass balances to compare attainable crystallization and plantwide yields of different process configurations. Total cost components using an established economic analysis methodology are compared for varying numbers of crystallizers, operating temperatures, total crystallizer cascade residence times and API feed concentrations. Economic analyses and the calculation of normalized cost components with respect to total crystallizer volumes identify the process without recycle as the most economically viable option, achieving the lowest total costs and low <i>E</i>-factors for pharmaceutical processes. The sensitivity of total costs to the selected total residence times for economic analyses highlights the need for rigorous comparison methodologies. This work identifies the need for technoeconomic optimization studies of continuous crystallization processes to establish the optimal design of manufacturing campaigns prior to further development

PLANTWIDE CONTROL OF ACETYLENE HYDROGENATION PROCESS

As an application of Plantwide control, where few papers have been published about the integrated process design and control of complete plants, the acetylene hydrogenation process has been considered as the goal of this research. Firstly, all plant units were controlled separately using PID controllers, then, complete plant control was based on the 15 steps of Luyben’s plantwide control strategy. An acceptable overall plant control behavior was achieved in terms of settling times and overshoot. An improvement was also, noticed on the plantwide control application when cascaded controllers are used for the developed control system. The improvement was clearly on the temperature control

Modeling, optimization, and sensitivity analysis of a continuous multi-segment crystallizer for production of active pharmaceutical ingredients

We have investigated the simulation-based, steady-state optimization of a new type of crystallizer for the production of pharmaceuticals. The multi-segment, multi-addition plug-flow crystallizer (MSMA-PFC) offers better control over supersaturation in one dimension compared to a batch or stirred-tank crystallizer. Through use of a population balance framework, we have written the governing model equations of population balance and mass balance on the crystallizer segments. The solution of these equations was accomplished through either the method of moments or the finite volume method. The goal was to optimize the performance of the crystallizer with respect to certain quantities, such as maximizing the mean crystal size, minimizing the coefficient of variation, or minimizing the sum of the squared errors when attempting to hit a target distribution. Such optimizations are all highly nonconvex, necessitating the use of the genetic algorithm. Our results for the optimization of a process for crystallizing flufenamic acid showed improvement in crystal size over prior literature results. Through the use of a novel simultaneous design and control (SDC) methodology, we have further optimized the flowrates and crystallizer geometry in tandem.^ We have further investigated the robustness of this process and observe significant sensitivity to error in antisolvent flowrate, as well as the kinetic parameters of crystallization. We have lastly performed a parametric study on the use of the MSMA-PFC for in-situ dissolution of fine crystals back into solution. Fine crystals are a known processing difficulty in drug manufacture, thus motivating the development of a process that can eliminate them efficiently. Prior results for cooling crystallization indicated this to be possible. However, our results show little to no dissolution is used after optimizing the crystallizer, indicating the negative impact of adding pure solvent to the process (reduced concentration via dilution, and decreased residence time) outweighs the positive benefits of dissolving fines. The prior results for cooling crystallization did not possess this coupling between flowrate, residence time, and concentration, thus making fines dissolution significantly more beneficial for that process. We conclude that the success observed in hitting the target distribution has more to do with using multiple segments and having finer control over supersaturation than with the ability to go below solubility. Our results showed that excessive nucleation still overwhelms the MSMA-PFC for in-situ fines dissolution when nucleation is too high

Integration of process design and control: A review

There is a large variety of methods in literature for process design and control, which can be classified into two main categories. The methods in the first category have a sequential approach in which, the control system is designed, only after the details of process design are decided. However, when process design is fixed, there is little room left for improving the control performance. Recognizing the interactions between process design and control, the methods in the second category integrate some control aspects into process design. With the aim of providing an exploration map and identifying the potential areas of further contributions, this paper presents a thematic review of the methods for integration of process design and control. The evolution paths of these methods are described and the advantages and disadvantages of each method are explained. The paper concludes with suggestions for future research activities

Kinetics based characterization of struvite dissolution

As phosphorus removal and recovery has become the new standard of wastewater treatment new technologies have quickly been implemented to meet the task. The Ostara Pearl is a crystallizer technology well known in the field of struvite precipitation for plants equipped with enhanced biological phosphorus removal (EBPR). By feeding anaerobically digested EBPR sludge to the Pearl and dosing Mg, struvite precipitation is induced for high rates of P removal. However, one downfall of crystallizers is the generation of poorly characterized fine particulate matter during normal operation, which leave the reactor and disrupt EBPR efficacy. The main objective of this work was to characterize the dissolution of field grown struvite from an Ostara Pearl reactor. Dissolution rate constants between 0.94 and 2.61 mm/min were found for field grown struvite using the shrinking object model – a surface area dependent empirical kinetics-based dissolution model. Enhanced solubility of some field recovered struvite relative to reference struvite was also observed in short-term experiments leading to a need a deeper characterization of those samples. Long-term dissolution experiments, used to characterize the dissolution of any co-precipitants, found little Ca, Fe, and K content in field grown struvite. XRD and FTIR were used to identify any physical and chemical differences in field grown struvite samples which exhibited increased solubility compared to a reference struvite sample. Dittmarite (MgNH4PO4*H2O) and another unknown crystalline solid were found to potentially lead to enhanced solubility. The importance of characterizing plant specific struvite was noted when instances of enhanced solubility were seen in samples which exhibit distinct FTIR bands when comparing surface to internal spectra

Computational modelling of separation processes for green continuous pharmaceutical manufacturing

The pharmaceutical industry has traditionally implemented batch manufacturing for the production of a wide range of products due to its mature technological development and ability for recall of products where necessary. However, several demonstrations of Continuous Pharmaceutical Manufacturing (CPM) in the past two decades have drawn significant attention from academia, industry and regulatory bodies due to its potential for smaller equipment, enhanced efficiencies, access to difficult or hazardous process conditions with greater ease and safety and reduced costs and waste. While continuous processing is not new in other manufacturing sectors, its application to pharmaceutical production has only drawn significant attention in recent years due to the numerous demonstrations of continuous flow syntheses of complex molecules and functional groups inherent of Active Pharmaceutical Ingredients (APIs), which is the foundation of any end-to-end CPM plant. The literature to date has predominantly focussed on design and optimisation of flow synthesis routes; however, the development of efficient continuous separation processes is a major bottleneck to CPM and are often challenging and materially intensive unit operations. The design of effective continuous separation processes for societally important APIs amenable to continuous production is essential for CPM success. Mathematical modelling is a viable and useful tool in the elucidation of promising designs prior to pilot plant studies that can allow rapid screening of multiple candidate configurations and can circumvent expensive and laborious experimental campaigns. Moreover, they allow optimisation of process design configurations to maximise their operational and economic benefits. This PhD thesis aims to elucidate cost-optimal upstream CPM plant and continuous separation process designs for a range of APIs. Steady-state process models for upstream CPM plants for different APIs are constructed, using published data for reaction rate law elucidation and kinetic parameter estimation, activity coefficient and group contribution models for non-ideal multicomponent mixture phase equilibria prediction and pharmaceutical process costing methodologies. The constructed models are then used for process simulation, design and optimisation of CPM plants, using Nonlinear Programming (NLP) for individual case-based process optimisation and Mixed Integer Nonlinear Programming (MINLP) for CPM process synthesis to optimality. The systematic frameworks and methods used in this work can be expanded to other APIs amenable to CPM with similar processes. This work highlights the immense value in systematic and rigorous model-based simulation and optimisation campaigns for CPM process development

Plantwide Control and Simulation of Sulfur-Iodine Thermochemical Cycle Process for Hydrogen Production

A PWC structure has developed for an industrial scale SITC plant. Based on the performance evaluation, it has been shown that the SITC plant developed via the proposed modified SOC structure can produce satisfactory performance – smooth and reliable operation. The SITC plant is capable of achieving a thermal efficiency of 69%, which is the highest attainable value so far. It is worth noting that the proposed SITC design is viable on the grounds of economic and controllability