Development Of Crystallization Process Research Articles

Derisking Crystallization Process Development and Scale-Up Using a Complementary, “Quick and Dirty” Digital Design

Derisking Crystallization Process Development and Scale-Up Using a Complementary, “Quick and Dirty” Digital Design

Automated Continuous Crystallization Platform with Real-Time Particle Size Analysis via Laser Diffraction.

The fourth industrial revolution is gaining momentum in the pharmaceutical industry. However, particulate processes and suspension handling remain big challenges for automation and the implementation of real-time particle size analysis. Moreover, the development of antisolvent crystallization processes is often limited by the associated time-intensive experimental screenings. This work demonstrates a fully automated modular crystallization platform that overcomes these bottlenecks. The system combines automated crystallization, sample preparation, and immediate crystal size analysis via online laser diffraction (LD) and provides a technology for rapidly screening crystallization process parameters and crystallizer design spaces with minimal experimental effort. During the LD measurements, to avoid multiple scattering events, crystal suspension samples are diluted automatically. Multiple software tools, i.e., LabVIEW, Python, and PharmaMV, and logic algorithms are integrated in the platform to facilitate automated control of all the sensors and equipment, enabling fully automated operation. A customized graphical user interface is provided to operate the crystallization platform automatically and to visualize the measured crystal size and the crystal size distribution of the suspension. Antisolvent crystallization of ibuprofen, with ethanol as solvent and water with Soluplus (an additive) as antisolvent, is used as a case study. The platform is demonstrated for antisolvent crystallization of small ibuprofen crystals in a confined impinging jet crystallizer, performing automated preplanned user-defined experiments with online LD analysis.

Loop-Configuration for Plug Flow Crystallization Process Development

Loop-Configuration for Plug Flow Crystallization Process Development

Emerging microfluidic platforms for crystallization process development

The microfluidic platform offers an exclusive environment compatible with different analytical tools to investigate crystallization processes. Moreover, microfluidic devices allow precise and convenient control of crystallization conditions at nano or meso scales, making them suitable for pharmaceutical and energy applications. These miniaturized screening devices can be effective during drug discovery stages for screening active ingredients available on micro/milligram scales. In this review, we discuss the advancements and applications of microfluidics platforms in the development of crystallization processes, including measurement of crystal growth and nucleation rates, screening of co-crystals, polymorphs and morphology, synthesis of nanocrystals, and determination of metastable zones and solubility. In addition, the latest microfluidics setups for high-throughput screening and lab-on-chip enhancements with sensors and automation are presented in this review. Lastly, an outlook on how microfluidic platforms can be adapted to improve workflow in crystallization process development is presented.

Febuxostat–p-Toluenesulfonic Acid Multi-Component Crystal: Characterization, Crystal Growth and Elucidation of the Salt/Co-Crystal Nature

The multi-component solid form of febuxostat (FEB) with p-toluenesulfonic acid was synthesized by solvent-drop grinding and cooling-evaporative crystallization and characterized by powder X-ray diffraction (XRPD), thermogravimetry (TGA), differential scanning calorimetry (DSC), and infrared spectroscopy (FT-IR). The multi-component form was stable after exposure at elevated temperature and relative humidity and powder dissolution measurements revealed five-fold aqueous solubility improvement relative to FEB. Additionally, the decrease in pH after dissolution suggests a potential for enhancing the drug absorption in the lower stomach. In the context of the regulatory requirements, the salt/co-crystal nature of the form was elucidated by a combination of crystallization process development and crystal growth, followed by SC-XRD and FT-IR. Despite the very weak basicity of the drug, crystal structure determination combined with spectroscopy analysis revealed salt formation by the transfer of the acidic proton from p-toluenesulfonic acid to FEB. Our study emphasizes the importance of the crystal structure knowledge in understanding the type of interactions present in multi-component crystals as well as complying with the specific regulatory requirements.

Nucleation kinetics-based solvent selection for the liquid antisolvent crystallization of a lipophilic intermediate

The fundamental understanding of solubility and nucleation kinetics are two primary pillars for liquid antisolvent crystallization (LASC) process development. In our present work, the solubility of intermediate A in four different solvents and binary mixtures with water, in the temperature range from 273 K to 323 K, was determined using a liquid chromatographic method to acquire the fundamental thermodynamic information for the LASC process. Intermediate A was monitored both in the solid phase and in the liquid phase by in line Raman spectroscopy. The importance of selection of the optimum scale and mixing conditions (volume and fluid dynamics dependency) for conducting metastable zone width (MSZW) measurements for the nucleation kinetics study, due to stochastic nature of nucleation, has been demonstrated to translate the findings to larger industrial scales. The 3.5 mL volume in reactor with a 3 blade downflow overhead impeller in the Crystalline™ (Technobis) was found to be an optimal platform for the data generation for the extraction of nucleation kinetics. The minimum detection threshold value (fN) reported in the literature was experimentally derived for the intermediate A-solvent systems used, covering the effect of supersaturation, reaction volume and agitation rate. The combined polythermal and antisolvent addition approach was applied to determine MSZWs and, subsequently, the kinetic parameters were estimated based on both linearized integral and 3D nucleation models. It was demonstrated how the derived parameters complemented with accurate solubility data are required to guide solvent selection for bottom-up generation of nanosuspensions. The findings were validated by conducting batch and continuous LASC of intermediate A. Particle size distributions derived from electron scanning microscopy obtained at similar driving forces confirmed the solvents selection order based on their nucleation tendency of dissolved intermediate A. These results serve as an example for applying a nucleation kinetics-based fundamental approach for solvent selection in the development of LASC process for generation of long-acting injectable suspensions.

Co-crystal Phase Diagram Determination by the Solution Addition Method

Multicomponent crystals such as co-crystals, salts, and solid solutions can be used to modify physical properties of active pharmaceutical ingredients. Phase diagrams of such multicomponent crystals are essential for crystallization process development, especially in the case where multiple solid phases may coexist. However, additional components and solid phases make phase diagrams more complex and their determination more time consuming. We propose to accelerate this process by identifying the eutectic points and constructing the rest of the phase diagram using thermodynamic models, informed by further measurements, if necessary. In this work, a novel solution addition method is proposed for determining the eutectic points in a co-crystal system. This method implements gradual compositional changes to traverse various regions of the phase diagram. Phase boundaries are determined by monitoring changes in the liquid phase (UV–vis) and solid phase (Raman), and eutectic points are obtained from intersection of phase boundaries. The results from solution addition are compared to those of an equilibration method, which combines gravimetry, XRPD, and NMR to identify the eutectic solution composition starting from a composition in the three-phase region of a co-crystal phase diagram. Both methods were able to locate all eutectic points, allowing construction of the ternary phase diagrams of benzoic acid and isonicotinamide in ethanol.

Development and Optimization of Antisolvent Cooling Coupled Crystallization Process for Coenzyme Q10

AbstractThe solubility of coenzyme Q10 in binary mixed solvents (tetrahydrofuran (THF) + ethanol) is determined at the temperature range from 278.15 to 313.15 K by static high‐performance liquid chromatography. The super‐solubility of coenzyme Q10 at fC = 0.4(C is ethanol), fC = 0.6, fC = 0.8 is measured by dynamic laser method, thus the metastable zone of coenzyme Q10 in binary mixed solvent (THF + ethanol) is obtained. The measurement results show that the solubility of coenzyme Q10 and the width of the metastable zone increase with the increasing of temperature and increasing of THF content in the mixed solvent. Coenzyme Q10 antisolvent cooling coupled crystallization process is developed based on thermodynamic data, and the crystallization conditions are investigated experimentally. The diameter span of crystal size distribution decreases from 5.542 to 1.981 and the median particle size (Dv50) increases from 41.8 to 81.3 μm, which means that the crystal products of coenzyme Q10 are improved by adjusting the crystallization process parameters.

Direct Image Feature Extraction and Multivariate Analysis for Crystallization Process Characterization

Small-scale crystallization experiments (1–8 mL) are widely used during early-stage crystallization process development to obtain initial information on solubility, metastable zone width, as well as attainable nucleation and/or growth kinetics in a material-efficient manner. Digital imaging is used to monitor these experiments either providing qualitative information or for object detection coupled with size and shape characterization. In this study, a novel approach for the routine characterization of image data from such crystallization experiments is presented employing methodologies for direct image feature extraction. A total of 80 image features were extracted based on simple image statistics, histogram parametrization, and a series of targeted image transformations to assess local grayscale characteristics. These features were utilized for applications of clear/cloud point detection and crystal suspension density prediction. Compared to commonly used transmission-based methods (mean absolute error 8.99 mg/mL), the image-based detection method is significantly more accurate for clear and cloud point detection with a mean absolute error of 0.42 mg/mL against a manually assessed ground truth. Extracted image features were further used as part of a partial least-squares regression (PLSR) model to successfully predict crystal suspension densities up to 40 mg/mL (R2 > 0.81, Q2 > 0.83). These quantitative measurements reliably provide crucial information on composition and kinetics for early parameter estimation and process modeling. The image analysis methodologies have a great potential to be translated to other imaging techniques for process monitoring of key physical parameters to accelerate the development and control of particle/crystallization processes.

Enhancement of protein crystallization with the application of Taylor vortex and Poly(ionic liquid)s

With the increase demands for biopharmaceuticals, the development of efficient protein crystallization processes for manufacturing highly pure crystalline products has become critical for downstream biomanufacturing. This work focused on the combined effects of the uniform shear rate in a solution created by using the Taylor vortex and the macromolecular architecture of a solution developed using poly(ionic liquid)s during protein crystallization. The results were as follows: (1) the accelerated primary nucleation rate with a uniform shear force that was generated by the Taylor vortex; (2) the stability of the protein product prepared using the poly(ionic liquid)s was high in the crystallization solution; and (3) improved control of supersaturation of the polymer was achieved with the salting-out effect. The average crystal size in the control group was considerably lower than 1 μm with low quality (9.00 Å) and yield (56%) of crystals, but the average size of lysozyme crystals obtained using the Taylor vortex and poly(ionic liquid)s increased up to 5 μm with high quality (1.86 Å) of crystals and yield (86%). A higher diffraction resolution indicated a better ordered crystalline structure, demonstrating that the Taylor vortex and poly(ionic liquid)s are useful for improving the crystal quality.

Crystal Growth, Dissolution, and Agglomeration Kinetics of Sodium Chlorate

The analysis, development, and implementation of novel complex industrial crystallization processes requires kinetic knowledge of not only crystal growth and nucleation but also breakage, dissolution, and agglomeration processes. In this work, the crystal growth, dissolution, and agglomeration kinetics of sodium chlorate (NaClO3) in aqueous solutions are estimated via seeded batch experiments with in-line particle size distribution measurements. Contrary to previous works, the growth/dissolution kinetics are expressed in terms of the fundamental driving force of crystallization calculated from the activity of supersaturated solutions. The activity-based driving force is roughly 2-fold higher than the commonly used representation, which assumes ideal solutions. By fitting experimental desupersaturation data to mechanistic and empirical growth models, we show that the growth of sodium chlorate is surface integration controlled and is best described by a two-dimensional birth and spread surface nucleation mechanism. The dissolution of sodium chlorate crystals is diffusion controlled and is ∼4 times faster than the growth at an equal initial driving force. Particle agglomeration is substantial in the early stages of crystallization experiments, likely due to a strong increase in the particle number due to initial breeding secondary nucleation upon seeding. The agglomeration rate constant increases with supersaturation and decreases at higher energy dissipation rate (by increased agitation) due to a strong decrease in the efficiency of interparticle collisions. Seeding with material of different sizes does not influence the agglomeration rate constant, although substantial amount of small particles was present in all seeding materials.

Independent Validation of an In Silico Tool for a Pilot-Scale Pharmaceutical Crystallization Process Development

There are many published models for predicting crystal size distribution (CSD) in the literature. However, none of them have been independently and comprehensively tested, which is important for industrial acceptance and confidence of these models. Therefore, in this study, using solubility and kinetic data from the literature, an in silico tool for predicting the crystallization process performance of a model compound system (paracetamol in ethanol) was developed and challenged by independent experiments at the 50 L pilot scale. The solute concentration was tracked, and the final CSD was quantified using three measurement techniques including a novel image analysis tool. The reported parameter uncertainties were also addressed using Monte Carlo simulations. The results showed that, when the models were used within their validity range (e.g., suspended solids), they were able to describe the observed process trends/dynamics (CSD and solute concentration) under varying experimental conditions (cooling time and seed mass) with R2 ranging from 0.72 and 0.90. Overall, the results indicate that, using Monte Carlo simulations to account for known parametric uncertainties, the models can support model-based approaches for crystallization process development from scale-down to scale-up studies as well as control evaluation.

Iron removal stations’ sludges postprocessing for its resource potential identification

Introduction. The sludge of the washing waters of the underground water iron removal station is a large-tonnage technogenic waste that is dangerous for the environment. The homogeneous chemical composition and finely dispersed structure of the sludge make it possible to consider it as a valuable raw material for the production of various products in the conditions of a forward movement towards a circular economy. Obtaining nanosized metal powders from the sludge of iron removal stations has a number of advantages over traditional physical, chemical and mechanical methods. To optimize the process of obtaining highly dispersed metal powders from the sludge of iron removal stations, it is necessary to study the influence of the main technological parameters on the size, shape and chemical composition of the final material.
 Materials and methods. Thermal treatment of the sludge of the iron removal station in the carbon monoxide medium was carried out in the temperature range of 400–600 °C. Ultrasonic dispersion was used to get an idea of the true particle size. The granulometric composition of the sludge was studied by electron microscopy and laser beam scattering.
 Results. The results of experimental studies of the granulometric composition of the treated sludge of iron removal stations are presented. The particles obtained at a temperature of 450 °C had the most pronounced spherical shape, low open porosity, and a low degree of adhesion to neighboring particles. These properties are key for micro- and nanopowder-based products. An increase in the temperature of sludge processing led to the adhesion of particles and their fusion into large aggregates with a brittle structure as a result of the development of crystallization processes.
 Conclusions. The proposed methods of physicochemical treatment in an environment of carbon monoxide and ultrasonic action of the sludge of an iron removal station, which is currently a technogenic waste, makes it possible to obtain a highly dispersed metal powder. This material has the necessary properties for use in modern high-tech industries.

Crystallization Process Development for the Final Step of the Biocatalytic Synthesis of Islatravir: Comprehensive Crystal Engineering for a Low-Dose Drug

Islatravir (MK-8591), a highly potent nucleoside reverse transcriptase translocation inhibitor, is being developed to stem the spread of global HIV infections. Following a nine-enzyme in vitro synt...

Perspectives on the Current State, Challenges, and Opportunities in Pharmaceutical Crystallization Process Development

Crystallization is the primary process used to purify synthetic drug substances and intermediates as well as to control bulk properties, including particle size, surface area, and flowability. Acco...

Comprehensive sensitivity analysis and process risk assessment of large scale pharmaceutical crystallization processes

This work presents an in silico tool that supports crystallization process development and optimization studies by means of mechanistic modeling, uncertainty identification, comprehensive sensitivity analysis and a quantified process risk assessment. Kinetic model parameters and operation design parameters are considered as a source of uncertainty and variation. Monte Carlo simulations are performed to propagate input uncertainty/variation to model output in terms of process yield, mean crystal diameter and size distribution. To quantify the individual effects and importance of these parameters, global sensitivity analysis e.g. Morris Screening and variance-based decomposition, is performed. The process risk is defined as failure to reach target product specifications and its consequences for the given design space is quantified. This promising study shows, that global uncertainty and sensitivity analysis coupled with the quantification of process risk assessment is a powerful tool and should be of interest to those participating in effective and efficient crystallization process development.

Polymorphic Control and Scale-up Strategy for Crystallization from a Ternary Antisolvent System by Supersaturation Control

Antisolvent crystallization of indomethacin (IMC) was investigated in this work by using an acetone–methanol (66.5–33.5 wt %) mixture as solvent and water as antisolvent. Selecting the binary mixture as the solvent led to an increased yield of the batch process, as the solubility of IMC is higher in the mixed solvents. Adding methanol to the solvent system mitigated the nucleation of the acetone solvate, which is dominating in the acetone–water system. Process analytical technologies were implemented to ensure that the desired polymorph was present throughout the process. Supersaturation control (SSC) was applied as a closed-loop feedback control strategy, to achieve a rapid direct design of the crystallization process using the principles of quality by control. The antisolvent flow-rate profiles, obtained by the SSC, were implemented in open loop and used for scaling up the process by 1 order of magnitude. The results show how feedback control of crystallization from a ternary solvent mixture increases productivity and simultaneously ensures suppression of nucleation to obtain the desired particle size distribution and polymorph. The direct design approach can be applied in the design and development of crystallization processes to yield the chosen solid phase of IMC when scaling from small to large scale.

A Thermodynamic Approach for the Prediction of Oiling Out Boundaries from Solubility Data

Many pharmaceutical molecules, fine chemicals, and proteins exhibit liquid–liquid phase separation (LLPS, also known as oiling out) during solution crystallization. LLPS is of significant concern in crystallization process development, as oiling out can compromise the effectiveness of a crystallization and can lead to operational problems. A comprehensive methodology that allows a process scientist/engineer to characterize the various phase boundaries relevant to oiling out is currently lacking. In this work, we present a modeling framework useful in predicting the binodal, spinodal, and gelation boundaries starting from the solubility data of a solute that is prone to oiling out. We collate the necessary theoretical concepts from the literature and describe a unified approach to model the phase equilibria of solute–solvent systems from first principles. The modeling effort is validated using experimental data reported in the literature for various solute–solvent systems. The predictive methods presented in this work can be easily implemented and help a process engineer establish the design space for a crystallization process that is affected by liquid–liquid phase separation.

Quantitative Link between Secondary Nucleation and Mixing Hydrodynamics in Batch Cooling Crystallization: A New Approach in Process Development

Precise control of a crystallization process requires a clear understanding of nucleation kinetics. Interpreting secondary nucleation threshold (SNT) of a given crystallization process under optimized hydrodynamic conditions can highlight the impact of critical process variables on product particle size distribution (PSD). In this work, a new approach is proposed in industrial crystallization process development in which a quantitative link was developed between batch cooling crystallization and fluid turbulent shear stress (TSS). The experiments involve solution crystallization of paracetamol in isopropanol. A novel method was adopted in which a large single seed crystal of paracetamol was held stationary in an agitating reactor. Using particle imaging velocimetry, a constant TSS was obtained across different scales which resulted in a constant SNT because of crystal nuclei breeding. This led to better control over the crystallization process which eventually resulted in a consistent PSD, independent of ...

Cambrex will double solid-form screening

The small-molecule-drug services firm Cambrex will double the size of its solid-form screening and crystallization process development facility in Edinburgh, Scotland. To be completed by year-end, the project will allow Cambrex to add up to 40 more scientists to its 50 employees at the site. Cambrex acquired the facility with its purchase of Avista Pharma Solutions earlier this year.