Antisolvent Crystallization Process Research Articles

Comprehensive exploration of riboflavin solid forms and preparation mechanism of stable forms

Riboflavin is a water-soluble vitamin regarded as an essential nutrient participating in biological oxidation in vivo. The strong hygroscopicity and crystalline phase impurity of riboflavin in the solid state are obstacles to its industrial production and storage. Riboflavin is polymorphic and is usually produced and marketed in crystalline form. However, the phase transformation among riboflavin polymorphs and preparation mechanism of stable crystal form have not been clarified, hindering the production optimization and storage management of products. In this work, the relationship of phase transformation among the riboflavin polymorphs was elucidated, and their thermal stability as well as hygroscopicity were evaluated. Anhydrate I is the most stable form with the best thermal stability and lowest hygroscopicity could not be prepared in antisolvent crystallization process, where monohydrate is the most frequent form. Consequently, a solution-mediated phase transformation (SMPT) process was proposed to prepare anhydrate I from monohydrate. In-situ Raman, UV–VIS spectrum and Powder X-ray Diffraction were utilized to monitoring the SMPT process. It was found that the nucleation and growth of anhydrate I was the rate-determining step. Elevated temperatures, reduced solid loads and addition of seeds can accelerate the conversion procedure. This work provides guiding significance for the product development and quality control of Riboflavin.

CFD-population balance modelling for a flat sheet membrane-assisted antisolvent crystallization

A comprehensive model has been developed to couple CFD with the population balance equation (PBE) for a flat sheet membrane-assisted antisolvent crystallization (FS-MAAC) process. The model accurately depicts the fluid dynamics, mass transfer, heat transfer and crystal size distribution (CSD) in the FS-MAAC crystallizer. The crystallization system considered was to produce α-form crystals of glycine. The model investigates the effects of different parameters, such as the velocities of the crystallizing and antisolvent solutions, antisolvent composition, temperature, and gravity. A good agreement was observed between the simulation results and experimental data for the α-form crystals of glycine. The simulation results show a steady-state antisolvent concentration profile in the liquid layer and varied only in the z-direction. Regardless of the variations in the velocity of either the antisolvent solution or the crystallizing solution, the CSD remained narrow, with mean crystal sizes ranging from 27 to 40 μm. Furthermore, increasing mass transfer through the antisolvent transmembrane flux leads to a narrower CSD. Slower antisolvent permeation rates at higher temperatures also promote crystal growth. Also, a narrow CSD is maintained regardless of the initial circulation position of the antisolvent solution. In conclusion, membrane antisolvent crystallization provides a reliable and consistent solution for obtaining crystals with desired CSD under optimal operating conditions.

Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations.

A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process was optimized and afterward compared to an earlier developed microchannel reactor-based continuous liquid antisolvent crystallization (MCR-CLASC) setup, using itraconazole (ITZ) as the model drug. After operating parameter optimization and downstream processing (i.e., concentrating the suspensions), stable microsuspensions were generated with a final solid loading of 300 mg ITZ/g suspension. The optimized post-precipitation feed suspension consisted of 40 mg ITZ/g suspension with a drug-to-excipient ratio of 53:1. Compared to the MCR-CLASC setup, where the post-precipitation feed suspensions contained 10 mg ITZ/g suspension and had a drug-to-excipient ratio of 2:1, a higher drug concentration and lower excipient use were successfully achieved to produce LAI microsuspensions using the SCT-CLASC setup. To ensure stability during drug crystallization and storage, the suspensions' quality was monitored for particle size distribution (PSD), solid-state form, and particle morphology. The PSD of the ITZ crystals in suspension was maintained within the target range of 1-10 µm, while the crystals displayed an elongated plate-shaped morphology and the solid state was confirmed to be form I, which is the most thermodynamically stable form of ITZ. In conclusion, this work lays the foundation for the SCT-CLASC process as an energy-efficient, robust, and reproducible bottom-up approach for the manufacture of LAI microsuspensions using ITZ at an industrial scale.

Spherical Crystallization Based on Liquid-Liquid Phase Separation in a Reverse Antisolvent Crystallization Process

Vanillin crystals undergo needle-like morphology that results in poor flowability, crystal breakage, and low packing density. The spherical crystallization technology can produce particles with improved flowability and stability. A reverse antisolvent crystallization based on liquid-liquid phase separation is proposed in this work to produce vanillin spherical agglomerates. Hansen Solubility Parameters are applied to explain the liquid-liquid phase separation (LLPS) phenomenon. The Pixact Crystallization Monitoring system is applied to in-situ monitor the whole process. A six-step spherical crystallization mechanism is revealed based on the recorded photos, including the generation of oil droplets, nucleation inside oil droplets, the coalescence and split of oil droplets, crystal growth and agglomeration, breakage of oil droplets, and attrition of agglomerates. Different working conditions are tested to explore the best operation parameters and a frequency-conversion stirring strategy is proposed to improve the production of spherical crystals.

Antisolvent Crystallization of Papain

Protein crystallization plays a crucial role in the food and pharmaceutical industries, enhancing product quality and efficiency by improving purity and controlled particle characteristics. This study focused on the crystallization of the versatile protein papain, extracted from papaya. Antisolvent crystallization was performed. This method is cost-effective and is a simple and energy-efficient approach. Beyond protein crystal production, the antisolvent crystallization process serves as a method for encapsulating active pharmaceutical ingredients (APIs). The study investigated organic solvents like ethanol, acetone, and acetonitrile as potential antisolvents. Additionally, the impact of variables such as the solvent-to-antisolvent (S:AS) volume ratio and papain concentration on particle size, particle size distribution, zeta potential, crystallization yield, and residual activity of papain crystals were examined. Ethanol emerged as the optimal antisolvent, reducing the solubility of papain and preserving papain’s crystalline structure with minimal activity loss. Optimal conditions were identified at a 1:4 S:AS volume ratio and a papain concentration of 30 mg/mL, resulting in nanosized spherical crystals with a high yield and preserved activity. This research underscored the crucial role of thoughtful parameter selection in antisolvent crystallization to achieve specific particle characteristics while maintaining the functionality of the crystallized substance.

Estimation of secondary nucleation kinetics of benzoic acid in batch crystallizer

The nucleation and growth kinetics of benzoic acid were determined in a population balance model, describing the seeded batch antisolvent crystallization process. The process analytical technologies (PATs) were utilized to record the evolution of chord length distributions (CLDs) in solid phase together with the concentration decay in liquid phase, which provided essential experimental information for parameter estimation. The model was solved using standard method of moments based on the moments calculated from CLDs and solute concentration. A developed model, incorporating the nucleation and crystal growth as functions of both supersaturation and solvent composition, has been constructed by fitting the zeroth moment of particles and concentration trends. The determined kinetic parameters were consequently validated against a new experiment with a different flow rate, indicating that the developed model predicted crystallization process reasonably well. This work illustrates the strategy in construct a population balance model for further simulation, model-based optimization and control studies of benzoic acid in antisolvent crystallization.

Improvement of drug processability in a connected continuous crystallizer system using formulation additive

Continuous crystallization in the presence of polymer additives is a promising method to omit some drug formulation steps by improving the technological and also pharmacological properties of crystalline active ingredients. Accordingly, this study focuses on developing an additive-assisted continuous crystallization process using polyvinylpyrrolidone in a connected ultrasonicated plug flow crystallizer and an overflow mixed suspension mixed product removal (MSMPR) crystallizer system. We aimed to improve the flowability characteristics of small, columnar primary plug flow crystallizer-produced acetylsalicylic acid crystals as a model drug by promoting their agglomeration in MSMPR crystallizer with polyvinylpyrrolidone. The impact of the cooling antisolvent crystallization process parameters (temperature, polymer amount, total flow rate) on product quality and quantity was investigated. Finally, a spatially segmented antisolvent dosing method was also evaluated. The developed technology enabled the manufacture of purified, constant quality products in a short startup period, even with an 85% yield. We found that a higher polymer amount (7.5–14%) could facilitate agglomeration resulting in “good” flowability without altering the favorable dissolution characteristics of the primary particles.

Experimental Design for the Efficient Determination of the Crystallization Kinetics of a Polymorphic System in Combined Cooling and Antisolvent Crystallization

In this work, the polymorphic transformation of a dimorphic model compound, ortho-aminobenzoic acid (OABA), is investigated using experimental characterization in combination with population balance modeling. A novel experimental design is proposed to estimate the crystallization kinetic parameters of the polymorphic system in a combined cooling and antisolvent crystallization (CCAC) process with a minimum number of experiments, which can reduce the resources and time required to obtain kinetic information, which is of great importance in the drug substance development stage. The modeling studies revealed that the growth rates of the two polymorphs depend on the solvent composition. At a particular temperature and supersaturation, the form I growth rate increased as the solvent content proportion increased, whereas the form II growth rate decreased as the solvent content increased. The identified kinetic parameters of the nucleation and growth rate expressions of the two polymorphs were validated for different solvent compositions and temperatures. The validated model was then used to perform in silico design of experiments to develop a design space that can be used to identify operating conditions to achieve the desired crystal size and polymorphic form.

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.

Controlling the Polymorphism of Indomethacin with Poloxamer 407 in a Gas Antisolvent Crystallization Process.

The polymorphic control of active pharmaceutical ingredients (APIs) is a major challenge in the manufacture of medicines. Crystallization methods that use supercritical carbon dioxide as an antisolvent can create unique solid forms of APIs, with a particular tendency to generate metastable polymorphic forms. In this work, the effects of processing conditions within a gas antisolvent (GAS) crystallization method, such as pressure, stirring rate, and temperature, as well as the type of solvent used and the presence of an additive, on the polymorphism of indomethacin were studied. Consistent formation of the X-ray powder diffraction-pure α polymorphic form of indomethacin by GAS was only achieved when a polymer, poloxamer 407, was used as an additive. Using the GAS method in combination with poloxamer 407 as a molecular additive enabled full control over the polymorphic form of indomethacin, regardless of the processing conditions employed, such as pressure, temperature, stirring rate, and type of solvent. A detailed molecular modeling study provided insight into the role of poloxamer 407 in the polymorphic outcome of indomethacin and concluded that it favored the formation of the α polymorph.

Process intensification of atorvastatin calcium crystallization for target polymorph development via continuous combined cooling and antisolvent crystallization using an oscillatory baffled crystallizer

In this paper, continuous crystallization of Atorvastatin calcium (ASC) using a continuous oscillatory baffled crystallizer (COBC) has been investigated. Like most API manufacturing, ASC is manufactured batchwise and the pure API is recovered via batch combined cooling and antisolvent crystallization (CCAC) process, which has the challenges of low productivity, wide crystal size distribution (CSD) and sometimes polymorphic form contamination. To overcome the limitations of the batch crystallization, continuous crystallization of ASC was studied in a NiTech (United Kingdom) DN15 COBC, manufactured by Alconbury Weston Ltd. (AWL, United Kingdom), with the aim to improve productivity and CSD of the desired polymorph. The COBC has the advantage of high heat transfer rates and improved mixing that significantly reduces the crystallization time. It also has the advantage of spatial temperature distribution and multiple addition ports to control supersaturation and hence the crystallization process. This work uses an array of process analytical technology (PAT) tools to assess key process parameters that affect the polymorphic outcome and CSD. Two parameters were found to have significant impact on the polymorph, they are ratio of solvent to antisolvent at the point of mixing of the two streams and presence of seeds. The splitting of antisolvent into two addition ports in the COBC was found to give the desired form. The CCAC of ASC in COBC was found to be -30-fold more productive than the batch CCAC process. The cycle time for generating 100 g of desired polymorphic form of ASC also significantly reduced from 22 h in batch process to 12 min in the COBC. The crystals obtained using a CCAC process in a COBC had a narrower CSD compared to that from a batch crystallization process.

Shifting a nucleation dominant antisolvent crystallization process for rare earth scandium‐ammoniumfluoride towards crystal growth

Shifting a nucleation dominant antisolvent crystallization process for rare earth scandium‐ammoniumfluoride towards crystal growth

Phase Diagram Determination and Process Development for Continuous Antisolvent Crystallizations

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 continuous antisolvent crystallization processes.

Solvent effects on the original molecular recovery from the solvated solute monomers of cyclic nitramine explosives

This work aims to understand the relationship between crystallization phenomena and solvation effects. Three cyclic nitramine explosives, including hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), octahydro-1,3,5,7-tetranitro-1,3,5,7- tetrazocine (HMX) and 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (HNIW, CL-20), are selected to study the solvent effects on the original molecular recovery from the solvated solute monomers in the crystallization process using the quantum mechanical approach. Simulated results indicates that the low energy barrier can be overcome by the positive energy increase during the antisolvent crystallization process, leading to recovering original α-RDX molecules from their solvated monomers through the one-step transition state mechanism. Whereas for the molecules of HMX and HNIW, due to significant solvation effects on the molecular energy, it is suggested that the final presence of these original molecules in the crystalline order of the metastable crystals has to rely on the amorphous nucleus in the two-step nucleation mechanism.

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.

Finding Conditions to Process Hydrate Crystals and Amorphous Solids of Disodium Guanosine 5′‐Monophosphate by an Antisolvent Crystallization Process

AbstractA screening of amorphous, heptahydrate, and tetrahydrate forms of disodium guanosine 5′‐monophosphate is investigated using an antisolvent crystallization process with the aim to selectively produce each solid form. The concentrations of the solution and solid forms are monitored by in situ Raman spectroscopy using a calibration tool. Particle sizes and particle counts are measured with elapsed time by a focal beam reflection measurement. Concentrations of amorphous and hydrates phases are determined using in‐line measurement techniques. The variables studied are temperature, initial concentration, addition rate, and solvent fraction. The results demonstrate that transformation from amorphous to hydrate forms consists of four stages, which are the nucleation of the amorphous form, predissolution of amorphous form, the nucleation of hydrate crystal and dissolution of amorphous solid, and the growth of hydrate crystal. The rate‐controlling step, in this case, is the dissolution of amorphous form. Transformation between heptahydrate to tetrahydrate crystals is a nucleation‐growth‐controlled step. It is possible to obtain selectively the solid forms of disodium guanosine 5′‐monophosphate by referring to the supersaturation and solubility data.

Optimal start-up strategies of a combined cooling and antisolvent multistage continuous crystallization process

A model-based optimization methodology was developed to systematically address all possible optimal start-up scenarios of a multistage combined cooling and antisolvent continuous MSMPR (mixed-suspension, mixed-product removal) crystallizer. The crystallization of aspirin (acetylsalicylic acid, ASA) in ethanol (solvent) and water (antisolvent) was used as a case study. A steady state optimization was firstly conducted to optimize the crystallizer design and operating conditions and set-up the reference trajectories. The discretised profiles of the jacket temperatures, antisolvent flowrates and seeding policies, which includes the seed flowrates, loading and mean size, were used as decision vectors for the dynamic optimization problem. Scenarios with single and combined decision vectors were addressed and analysed in start-up situations involving prefilled or empty vessels. The impact of simplified optimization and operating procedures or refined discretization schemes were also addressed. It was shown that several options may provide comparable performance and the start-up time can be improved by nearly 80% in the case of combined decision vectors involving all possible decision vectors.

Preparation of Aspirin Nanosuspension by Antisolvent Precipitation Method

Preparation of Aspirin Nanosuspension by Antisolvent Precipitation Method

Tailoring the crystal size distribution of an active pharmaceutical ingredient by continuous antisolvent crystallization in a planar oscillatory flow crystallizer

An active pharmaceutical ingredient is currently produced in a traditional batch antisolvent crystallization process. Although well-established, this process lacks flexibility to control the crystal size distribution (CSD). Therefore, a new process was developed to enable the control of the CSD according to different specifications. This new process was implemented in continuous in a planar oscillatory flow crystallizer (planar-OFC). In this work, the main goal was to enable the production of small crystals to meet very specific formulation requirements and, simultaneously, promote the aggregation of these small particles to optimize the filtration operation. First, the operating conditions were optimized for continuous operation. Then, the planar-OFC was divided into two spatially independent sections, the nucleation zone (where nucleation is dominant) and the crystal growth zone (where crystal growth is dominant), so as to control the CSD as a function of the residence time in each zone. In particular, the formation of aggregates could be promoted by increasing the residence time in the nucleation zone. Ultimately, the planar-OFC was able to produce smaller particles with significantly narrower CSDs than the traditional batch process. This is particularly important when small particle sizes are required, thus reducing manufacturing time and operating costs.

Preparation of CNTs Coated with Polydopamine–Ni Complexes and Their Catalytic Effects on the Decomposition of CL-20

To improve the condensed-phase reaction rate of ε-CL-20, polydopamine (PDA)–nickel complex-coated multiwalled carbon nanotubes (CNTs) have been prepared and used as combustion catalysts. The PDA–Ni complex has been prepared and in situ coprecipitated with ε-CL-20 by an antisolvent crystallization process in its dimethyl sulfoxide (DMSO) solution. It has been shown that crystalline CL-20 composites included with PDA–Ni complexes are polygon-shaped with a smooth surface and an average diameter of 10–15 μm, whereas it is 140 μm for raw ε-CL-20 crystals. The catalytic reactivity of the complex on thermolysis of CL-20 has been investigated using the differential scanning calorimetry (DSC) and thermogravimetry (TG)-coupled Fourier transform infrared (FT-IR) spectroscopy technique. It has been found that CNT@PDA–Ni complexes have catalytic effects on the decomposition of ε-CL-20 by decreasing/shifting of the exothermic peak from Tp = 240.1 to 238.7 °C. The FT-IR spectra of CL-20 decomposition products under the effect of the catalyst predominantly show peaks at 1274, 1644 and 1596, 1912, 2265, and 1956–1800 cm–1, indicating the presence of fragments with N2O, NO2, NO, HNCO, and NO/CO, respectively. The change in the ε-CL-20 decomposition mechanism should be attributed to the catalytic action of CNT, decreasing the formation of NO2. Also, under the effect of the carbon-based catalyst, the HNCO formation was detected at another temperature in comparison with raw CL-20, with peak absorption at 224.1 vs 232.3 °C and the evolution was completed at 250.8 vs 246.2 °C, respectively.