Direct Design of Pharmaceutical Antisolvent Crystallization through Concentration Control (original) (raw)

Supersaturation tracking for the development, optimization and control of crystallization processes

Chemical Engineering Research & Design, 2010

Supersaturation is the key driving force in crystallization operations, determining nucleation and growth kinetics, and heavily influencing physical mechanisms such as agglomeration. Therefore, knowledge of the bulk supersaturation during crystallization can greatly enhance process understanding and optimization.In this paper, a method which facilitates the calibration-free use of in situ ATR-FTIR for crystallization development and control is presented. This methodology uses solute-specific ATR-FTIR absorption peak heights to describe solute solubility and dissolved concentration and, in turn, supersaturation, for the optimization of cooling crystallizations of an active pharmaceutical ingredient (API) and benzoic acid. The approach presented facilitates rapid process understanding, design and optimization. Specifically, the potential to significantly reduce cycle time for both systems studies is demonstrated. In addition, the potential of the method to form the basis of a process ...

First-principles and direct design approaches for the control of pharmaceutical crystallization

Journal of Process Control, 2005

Crystallization is the main separation and purification process for the manufacturing of drug substances. Not only does crystallization affect the efficiency of downstream operations such as filtering, drying, and formulating, the efficacy of the drug can be dependent on the final crystal form. Advances in simulation and control algorithms and process sensor technologies have enabled the development of systematic first-principles and direct design approaches for the batch control of crystallization processes. These approaches address different challenges associated with pharmaceutical crystallization control. This paper provides an overview of recent technological advances in the in situ control of pharmaceutical crystallization processes. Implementation of the first-principles and direct design approaches are compared, and their relative merits are explained. Areas of future opportunities for application of advanced control strategies in pharmaceutical crystallization are presented.

Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control

Organic Process Research & Development, 2020

Crystallization, as a solid-liquid separation process, is employed to purify and isolate a great diversity of crystalline pharmaceutical products. In recent years, continuous crystallization has attracted increasing attention due to the product and process robustness as well as higher productivity. In this work, we review the use of novel continuous crystallizers or modified conventional continuous crystallizers for the preparation of polymorphs, chiral enantiomers, solvates/hydrates, cocrystals, and spherical crystals. In addition, theoretical framework and verification for the model-based control approaches have been demonstrated. The application of the PAT tools in classical feedback loop control strategies in continuous crystallization has also been focused on. Despite all this, the application of continuous crystallization still remains challenging due to the existence of the drawbacks, such as fouling and blockages. Therefore, a systematic discussion should be done before the wider application of continuous crystallization.

Recent Developments in the Crystallization Process: Toward the Pharmaceutical Industry

Engineering

Crystallization is one of the oldest separation and purification unit operations, and has recently contributed to significant improvements in producing higher-value products with specific properties and in building efficient manufacturing processes. In this paper, we review recent developments in crystal engineering and crystallization process design and control in the pharmaceutical industry. We systematically summarize recent methods for understanding and developing new types of crystals such as co-crystals, polymorphs, and solvates, and include several milestones such as the launch of the first co-crystal drug, Entresto (Novartis), and the continuous manufacture of Orkambi (Vertex). Conventional batch and continuous processes, which are becoming increasingly mature, are being coupled with various control strategies and the recently developed crystallizers are thus adapting to the needs of the pharmaceutical industry. The development of crystallization process design and control has led to the appearance of several new and innovative crystallizer geometries for continuous operation and improved performance. This paper also reviews major recent progress in the area of process analytical technology.

Phase Diagram Determination and Process Development for Continuous Antisolvent Crystallizations

Crystals

The development of an antisolvent crystallization process requires the construction of an accurate phase diagram for this ternary system of compound, solvent and antisolvent, preferably as a function of temperature. This study gives an efficient methodology to systematically determine such antisolvent phase diagrams, exemplified with four model compounds: Sodium bromate, DL-Asparagine Monohydrate, Mefenamic acid and Lovastatin. Using clear point temperature measurements, single solvent and mixed solvent-antisolvent solubilities are obtained, showing strongly non-linear solubility dependencies as well as more complex solubility behaviour as a function of antisolvent fraction. A semi-empirical model equation is used to describe the phase diagram of the antisolvent crystallization system as a function of both temperature and antisolvent fraction. The phase diagram model then allows for the identification of condition ranges for optimal productivity, yield, and suspension density in con...

Batch Crystallization of Active Pharmaceutical Ingredient: Kinetics and Equilibrium Modelling

Kemija u industriji, 2018

Development of a mathematical model for batch crystallization of fesoterodine fumarate, an active pharmaceutical ingredient, in 2-butanone is presented. The model is based on population, mass and energy balances, and takes into account nucleation, crystal growth and agglomeration. Equilibrium solubility was determined experimentally by ATR-FTIR spectroscopy. Kinetic parameters were determined by fitting of experimental and simulated concentration curves and particle size distributions for six crystallization experiments, performed under different operating conditions. The model was validated and the results show good agreement with experimental data.

The impact of direct nucleation control on crystal size distribution in pharmaceutical crystallization processes

2009

The control of crystal size distribution (CSD) in pharmaceutical crystallization is of primary importance, as downstream processes such as filtration or drying are greatly affected by the properties of the CSD. It is recognized that the variability in the final CSD is mainly caused by the significant uncertainties in the nucleation rates, and therefore, a good control of nucleation events is necessary to achieve the desired CSD. In this paper, a new direct nucleation control (DNC) approach is introduced that directly controls the apparent onset of nucleation defined as the formation of new particles with detectable size using in situ instruments. The approach uses information on nucleation and dissolution, provided by focused beam reflectance measurement (FBRM), in a feedback control strategy that adapts the process variables, so that the desired quality of product is achieved, for example large crystals with a narrow CSD. In addition, DNC provides in situ fines removal through the operating protocol, rather than having additional equipment and external recycle loops. DNC does not require concentration measurement and has the advantage of being a model-free approach, requiring no information on nucleation or growth kinetics in order to design an operating curve. The DNC approach automatically and adaptively detects the boundary of the operating zone; hence it is more robust to the presence of impurities or residual solvent than the supersaturation control approach. The approach has been applied for the crystallization of glycine and experimental results demonstrate the benefits of DNC of producing larger crystals with narrower CSD compared to classical operations.

Antisolvent crystallization: Model identification, experimental validation and dynamic simulation

Chemical Engineering Science, 2008

This paper is concerned with the development, simulation and experimental validation of a detailed antisolvent crystallization model. A population balance approach is adopted to describe the dynamic change of particle size in crystallization processes under the effect of antisolvent addition. Maximum likelihood method is used to identify the nucleation and growth kinetic models using data derived from controlled experiments. The model is then validated experimentally under a new solvent feedrate profile and showed to be in good agreement. The resulting model is directly exploited to understand antisolvent crystallization behavior under varying antisolvent feeding profiles. More significantly, the model is proposed for the subsequent step of model-based optimization to readily develop optimal antisolvent feeding recipes attractive for pharmaceutical and chemicals crystallization operations.

Mathematical Modeling, Design, and Optimization of a Multisegment Multiaddition Plug-Flow Crystallizer for Antisolvent Crystallizations

Organic Process Research & Development, 2015

In the pharmaceutical industries, the requirements of rapid process development and scalable design have made the tubular crystallizer a promising platform for continuous manufacturing and crystallization processes, capable of replacing conventional capital-and labor-intensive batch operations. This paper takes a process systems engineering (PSE) approach to the optimal design of a continuous anti-solvent addition crystallizer to deliver the most promising product qualities, such as the crystal size distribution. A multi-segment multi-addition plug-flow crystallizer (MSMA-PFC) is considered as an example of a continuous anti-solvent crystallization processes, in which the total number, location, and distribution of anti-solvent additions are to be optimized. First principles dynamic and steady-state mathematical models for the MSMA-PFC are presented, based on example kinetic models for nucleation and growth of paracetamol crystallizing in acetone, with water as the anti-solvent. The performances of different crystallizer configurations operated under optimal design conditions are then compared. The configuration in which anti-solvent could be added at a variety of different locations along the tube length and at optimal flow rates was able to outperform previous designs in the literature which considered equally-spaced anti-solvent additions. The use of dynamic models to detect problems during startup of an MSMA-PFC was also highlighted.