Crystallization Of Active Pharmaceutical Ingredients Research Articles

Predicting the API partitioning between lipid-based drug delivery systems and water

Partitioning tests in water are early-stage standard experiments during the development of pharmaceutical formulations, e.g. of lipid-based drug delivery system (LBDDS). The partitioning behavior of the active pharmaceutical ingredient (API) between the fatty phase and the aqueous phase is a key property, which is supposed to be determined by those tests. In this work, we investigated the API partitioning between LBDDS and water by in-silico predictions applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and validated these predictions experimentally. The API partitioning was investigated for LBDDS comprising up to four components (cinnarizine or ibuprofen with tricaprylin, caprylic acid, and ethanol). The influence of LBDDS/water mixing ratios from 1/1 up to 1/200 (w/w) as well as the influence of excipients on the API partitioning was studied. Moreover, possible API crystallization upon mixing the LBDDS with water was predicted.This work showed that PC-SAFT is a strong tool for predicting the API partitioning behavior during in-vitro tests. Thus, it allows rapidly assessing whether or not a specific LBDDS might be a promising candidate for further in-vitro tests and identifying the API load up to which API crystallization can be avoided.

Combining crystalline and polymeric excipients in API solid dispersions – Opportunity or risk?

Amorphous solid dispersions (ASDs) are often metastable against crystallization of the active pharmaceutical ingredient (API) and thus might undergo unwanted changes during storage. The crystallization tendency of ASDs is influenced by the API crystallization driving force (CDF) and the mobility of the molecules in the ASD. Low molecular weight-excipients are known to stabilize amorphous APIs in so-called co-amorphous formulations. Due to their success in stabilizing co-amorphous APIs, low-molecular weight excipients might also enhance the stability of polymeric ASDs. In this work, we investigated the potential of combined low-molecular weight excipient/polymer formulations with in-silico tools and validated the predictions with long-term stability tests of the most promising excipient/polymer combinations. The considered critical quality attributes for the ASDs were the occurrence of amorphous phase separation, API CDF, and molecular mobility in the ASD.As an example, carbamazepine/polyvinylpyrrolidone ASDs were investigated combined with the excipients fructose, lactose, sucrose, trehalose, saccharin, tryptophan, and urea. Although all excipients had a negative impact on the ASD stability, saccharin still turned out to be the most promising one. Long-term stability studies with ASDs containing either saccharin or tryptophan verified -in agreement to the predictions- that API crystallization occurred faster than in the reference ASDs without additional excipient.This work showed that the addition of crystalline excipients to polymeric ASDs might not only offer opportunities but might also bear risks for the long-term stability of the ASD, even though the crystalline excipient stabilizes the polymer-free API. Consequently, excipients should be evaluated based on the thermodynamic phase behavior of the individual mixture of API/polymer/excipient, rather than based on pure-component properties of the excipient only. In-silico predictions proposed in this work remarkably decrease the number of screening tests for identifying suitable formulation excipients.

Effect of Choice of Solvent on Crystallization Pathway of Paracetamol: An Experimental and Theoretical Case Study

The choice of solvents influences crystalline solid formed during the crystallization of active pharmaceutical ingredients (API). The underlying effects are not always well understood because of the complexity of the systems. Theoretical models are often insufficient to describe this phenomenon. In this study, the crystallization behavior of the model drug paracetamol in different solvents was studied based on experimental and molecular dynamics data. The crystallization process was followed in situ using time-resolved Raman spectroscopy. Molecular dynamics with simulated annealing algorithm was used for an atomistic understanding of the underlying processes. The experimental and theoretical data indicate that paracetamol molecules adopt a particular geometry in a given solvent predefining the crystallization of certain polymorphs.

Crystal-size distribution-based dynamic process modelling, optimization, and scaling for seeded batch cooling crystallization of Active Pharmaceutical Ingredients (API)

Crystallization of active pharmaceutical ingredients (API) is one of the most important and complex multiphase engineering operations in pharmaceutical manufacturing industry. The desired physicochemical properties of solid crystalline product, such as crystal size distribution (CSD), are achieved by optimizing appropriate analyzed process operating conditions. In this application-derived study, an efficient straightforward mathematical modelling approach for the d value targeted CSD (characterized by 10th, 50th, and 90th centiles d10, d50, and d90) optimization of the API fesoterodine fumarate (FF) batches in different solvent mixtures on reactor dimension scales from 0.1 to 15 L is presented. The model is based on energy, mass, and population balance equations, the thermodynamic system equilibrium between solute/solution, and the kinetics of nucleation, crystal growth, and crystal agglomeration. In the first set of two experiments, the ability of the model to predict final CSD under chosen operating conditions was validated applying particular previously estimated kinetic parameters. An excellent statistical agreement between predicted and experimental CSD results was observed. Furthermore, the utility of the model to determine suitable operating conditions for the formation of FF crystals with d value defined CSD is presented. Two additional experiments were designed where stirring, cooling rate, and the amount of seed were optimally regressed. Good agreement between targeted and experimental CSD was shown and depending on the chosen vessel unit, mixing & cooling rates had the strongest relative impact on CSD. Algorithm may be beneficially utilized early during API industrial technological development, intensification, and scale-up, or transferred to continuous flow.

The Role of Ionic Liquids in the Pharmaceutical Field: An Overview of Relevant Applications.

Solubility, bioavailability, permeation, polymorphism, and stability concerns associated to solid-state pharmaceuticals demand for effective solutions. To overcome some of these drawbacks, ionic liquids (ILs) have been investigated as solvents, reagents, and anti-solvents in the synthesis and crystallization of active pharmaceutical ingredients (APIs), as solvents, co-solvents and emulsifiers in drug formulations, as pharmaceuticals (API-ILs) aiming liquid therapeutics, and in the development and/or improvement of drug-delivery-based systems. The present review focuses on the use of ILs in the pharmaceutical field, covering their multiple applications from pharmaceutical synthesis to drug delivery. The most relevant research conducted up to date is presented and discussed, together with a critical analysis of the most significant IL-based strategies in order to improve the performance of therapeutics and drug delivery systems.

Disparities of Single-Particle Growth Rates in Buried Versus Exposed Ritonavir Crystals within Amorphous Solid Dispersions.

Seeded growth rates of ritonavir in copovidone at 75% relative humidity (RH) and 50 °C were evaluated by single-particle tracking second harmonic generation (SHG) microscopy and found to be ∼3-fold slower for crystallites at the surface compared to the bulk. The shelf lives of final dosage forms containing amorphous solid dispersions (ASDs) are often dictated by the rates of active pharmaceutical ingredient crystallization. Upon exposure to elevated RH, the higher anticipated water content near the surfaces of ASDs has the potential to substantially impact nucleation and growth kinetics relative to the bulk. However, quantitative assessment of these differences in growth rates is complicated by challenges associated with discrimination of the two contributions (supersaturation and molecular mobility) in ensemble-averaged measurements. In the present study, "sandwich" materials were prepared, in which sparse populations of ritonavir single-crystalline seeds were pressed between two similar ASD films to assess bulk crystallization rates. These sandwich materials were compared and contrasted with analogously prepared "open-faced" samples, without the capping film, to assess the surface crystallization rates. Single-particle analysis by SHG microscopy time-series during in situ crystallization produced average growth rates of 3.8 μm/h for bulk columnar crystals with a particle-to-particle standard deviation of 0.9 μm/h. In addition, columnar crystal growth rates for surface particles were measured to be 1.3 μm/h and radiating crystal growth rates for surface particles were measured to be 1.0 μm/h, both with a particle-to-particle deviation of 0.4 μm/h. The observed appearance of radiating crystals upon surface seeding is attributed to reduced ritonavir solubility upon water adsorption at the interface, leading to higher defect densities in crystal growth. Despite substantial differences in crystal habit, correction of the surface growth rates by a factor of 4 from geometric effects resulted in relatively minor but statistically significant differences in the growth kinetics for the two local environments. These results are consistent, with viscosity being a relatively weak function of water absorption coupled with primarily diffusion-limited growth kinetics.

An investigation on the behavior and morphology of sulphanilamide crystallization in different nucleation conditions

BackgroundCrystallization is used as a purification process in majority of the industries such as pharmaceuticals, food products, chemicals, catalysts, and cosmetics. Crystallization of active pharmaceutical ingredients is carried out to increase the dissolution rate and attain sufficient bioavailability in pharmaceutical industries. It can also enhance the flow properties and drug dosage control of the active pharmaceutical ingredients.Single crystals give us a lucid understanding of the intrinsic properties of a material. A material made up of many crystals will have grain boundaries which do not allow us to measure properties such as thermal and electrical resistance effectively. Single crystals will not have defects or impurities in them. Thus, help us in making comparisons with other materials and contribute to a better understanding of particular behaviors. Therefore, it is important to investigate the growth of single crystals.Sulphanilamide is a sulpha class drug used as an intermediate and starting material for the production of various drugs. It is an antibacterial agent and is often used in pharmaceutics and cosmetics. In this study, we wanted to obtain sulphanilamide crystals by two different crystallization methods and compare the results gathered. Sulphanilamide usually crystallizes in the form of needles, thus is ideal for the purpose of this study. In this work, crystallization of sulphanilamide was carried out by cooling method and solvent evaporation method. In Cooling method as temperature was brought down the crystals separated out. On the other hand, in solvent evaporation method, the solvent evaporated leaving behind the crystals. The process parameters that varied included stirring rate of the solution at a constant temperature, concentration of the solute in a constant volume of solvent, solvent systems chosen-acetone, methanol and ethanol, and time allowed for crystallization.ResultsCrystals were obtained under the varying conditions. Characterization of the crystals formed was carried out using X-ray diffraction method, scanning electron microscopy, and differential scanning calorimetry. The size and morphology of the crystals formed was observed and the results were compared. It was found that the crystals obtained from using methanol as solvent, with high concentration of solute, gave the most uniform and large-sized cubic crystals under solvent evaporation method. The surface of the crystal was also seen to be smooth with well-defined edges as shown in the SEM images. Stirring reduced the size of crystals formed, and longer time of crystal formation resulted in larger crystals. Solvent evaporation method gave more uniform crystals compared to cooling method.ConclusionThis study gives us an understanding of how each parameter affects crystal growth. Thus, optimum conditions for crystal growth can be determined.

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization.

Crystallization is an important and difficult to control unit operation in the pharmaceutical industry. Crystallization can control molecular (i.e., polymorphism) and particulate (i.e., particle size and crystal habit) properties of active pharmaceutical ingredient (API). Moreover, these molecular and particulate properties govern the manufacturability, stability, and biopharmaceutical performance of the API and drug product. Nucleation is a key step and primary heterogeneous nucleation is a common mode of nucleation during crystallization. Hence, it is important to understand the parameters affecting primary heterogeneous nucleation, to achieve desirable properties in crystalline APIs. Primary heterogeneous crystallization has usually been linked to the surface characteristics like topography and functionality of the heteronucleant. The review outlines recent findings in the primary heterogeneous crystallization with specific emphasis on its pharmaceutical applications including regulatory considerations. Molecular-level mechanisms governing heteronucleation and subsequent outcome in terms of molecular as well as particulate-level properties of API have also been discussed. Moreover, general guidance for the selection of heteronucleant has also been included. Heterogeneous crystallization is a promising tool for efficient crystallization of API having properties for optimal pharmaceutical performance.

Advantages of Utilizing Population Balance Modeling of Crystallization Processes for Particle Size Distribution Prediction of an Active Pharmaceutical Ingredient

Active pharmaceutical ingredient (API) particle size distribution is important for both downstream processing operations and in vivo performance. Crystallization process parameters and reactor configuration are important in controlling API particle size distribution (PSD). Given the large number of parameters and the scale-dependence of many parameters, it can be difficult to design a scalable crystallization process that delivers a target PSD. Population balance modeling is a useful tool for understanding crystallization kinetics, which are primarily scale-independent, predicting PSD, and studying the impact of process parameters on PSD. Although population balance modeling (PBM) does have certain limitations, such as scale dependency of secondary nucleation, and is currently limited in commercial software packages to one particle dimension, which has difficulty in predicting PSD for high aspect ratio morphologies, there is still much to be gained from applying PBM in API crystallization processes.

Mixed-Suspension, Mixed-Product Removal Studies of Ciprofloxacin from Pure and Crude Active Pharmaceutical Ingredients: The Role of Impurities on Solubility and Kinetics

Despite the known effects of foreign species on crystallization and the frequently large number of impurities present in multistep pharmaceutical syntheses, the early characterization of continuous crystallization operations may be limited by the availability of representative crude material. As part of the development of an end-to-end process for ciprofloxacin HCl monohydrate, this work evaluates the impact of upstream impurities on mixed-suspension, mixed-product removal (MSMPR) crystallization kinetics. The kinetic parameters for nucleation and crystal growth in MSMPR crystallization have been estimated for the commercial, purified active pharmaceutical ingredient (API), as well as crude API containing approximately 60 unknown impurities. Results show that, while the upstream impurities did not have a significant impact on the nucleation rate, both the temperature-dependent growth rate coefficient and the growth activation energy decreased in crude API crystallization. This behavior implies that the ef...

Model-Based Optimization of Cooling Crystallization of Active Pharmaceutical Ingredients Undergoing Thermal Degradation

Many active pharmaceutical ingredients (APIs) undergo degradation at high temperature. Optimum cooling profiles from first principle models usually do not consider this degradation mechanism. Gener...

Crystallization of fesoterodine fumarate active pharmaceutical ingredient: Modelling of thermodynamic equilibrium, nucleation, growth, agglomeration and dissolution kinetics and temperature cycling

The crystallization of active pharmaceutical ingredients (API) is an important, but complex unit operation in drug manufacturing industry, due to the diverse chemical nature of medicinal formulation compounds, several physicochemical phenomena that take place during particle formation process, and multi-phase governing resistances. This research paper presents a combined experimental–modelling approach to understanding fesoterodine fumarate crystallization and dissolution in 2-butanone. A rigorous in-house mechanistic model algorithm that includes calibration, thermodynamic equilibrium description, energy, mass and population balance equations, heat transfer limitations, and ordering, agglomeration and detachment step kinetics was developed. On the basis of experimentally-determined saturated solubility, a specified initial number of designed dissolution and cooling crystallization experiments was performed, monitored by attenuated total reflection Fourier-transform infrared (ATR–FTIR) spectroscopy, focused beam reflectance measurement (FBRM) technique and microscopy. The estimated kinetic parameters of transport, nucleation, crystal lattice growth, agglomeration and dissolution were evaluated by fitting the measured/simulated concentration curves with crystallite size distributions. Correlation was validated with additional trial results, observing a rather good agreement. The behaviour of the component during validations’ temperature cycling was thoroughly examined by simulations to achieve a solid final insight into mechanisms, which may aid further production development, optimization, as well as scale-up.

Development and Implementation of a Quality Control Strategy for an Atropisomer Impurity Grounded in a Risk-Based Probabilistic Design Space

In the development process of an active pharmaceutical ingredient (API), determination of the design space used for control of critical quality attributes (CQAs) is a key component of the quality by design (QbD) framework outlined by the regulatory agencies. Herein, we propose the use of probabilistic (Bayesian) methods to drive the development of the design space and control strategy for a process. Using probabilistic methods to quantify the risk of failure for different processing options allows for informed process design and control strategy decisions, enabling robust processes. We present a case study of a complex API reaction and crystallization: first, probabilistic models are built using lab and plant data. Next, these models are used to compare different processing options in the context of reliability pertaining to a critical quality attribute (CQA). A process decision is outlined based on the reliability estimates from the models, and last, a control strategy is proposed for the CQA for a defin...

Microfluidic droplet liquid reactors for active pharmaceutical ingredient crystallization by diffusion controlled solvent extraction.

A novel method for crystallization utilizing solvent/antisolvent extraction in microfluidic droplet liquid reactors has been developed for rapid and low-cost screening of crystal polymorphism (i.e. molecular crystallographic arrangement or internal structure) and habit (i.e. crystallographic shape or external structure). The method involves a ternary solvent system consisting of a dispersed phase of two miscible fluids, one in which the active pharmaceutical ingredient (API) is soluble (solvent) and one in which the API is insoluble (antisolvent). The solvent/antisolvent dispersed phase is immiscible with a third continuous phase. Crystallization of an API, GSK1, was controlled within droplets by altering the rate of solvent extraction from droplets into the continuous phase, thereby decreasing API solubility. Crystal size, habit, and population per droplet were directly impacted by the solvent's rate of extraction. Single crystals were grown in individual droplets by slow extraction of solvent into the surrounding continuous phase, which occurs when crystal growth gradually reduces API concentration such that it is maintained within the metastable zone throughout extraction. Rapid extraction of solvent from droplets results in API concentration significantly exceeding its metastable limit, producing a greater number of crystal nuclei compared to slow extraction conditions. When holding constant solubilized API mass per droplet, crystal sizes were larger for slow extraction rates (l = 96.3, w = 16.6 μm) compared to fast extraction rates (l = 48.8, w = 9.5 μm) as a result of crystal growth occurring on fewer crystal nuclei per droplet. Crystal habit can be controlled by adjusting the solvent extraction rate and consequently the saturation, where minimal saturation resulted in a rhombohedral habit and comparatively higher saturation resulted in an acicular habit with a higher aspect ratio. Antisolvents were tested using two hydrophobic APIs demonstrating the method's capability for rapidly identifying favorable crystal morphologies for downstream manufacturability using miniscule amounts of API.

Unraveling the Link between Solvent-Mediated Proton Transfer and the Salt Formation of Saccharin and Sulfamethazine

Molecular tautomerism has been reported to play an important role in the crystallization of active pharmaceutical ingredients, particularly in the formation of pharmaceutical cocrystals and salts. In this work, by combining molecular modeling, crystallization experiments, and spectroscopic techniques, we investigate possible molecular mechanisms by which solvent can mediate proton transfer in a tautomerization process. We found that the salt formation of sulfamethazine-saccharin takes place in the presence of protic solvent (ethanol, water), but is prohibited in aprotic solvent such as toluene. Our density functional theory calculations reveal that protic (polar) solvents such as ethanol and water facilitate proton transfer, serving as catalysts of the transformation of saccharin into its tautomerized (enol) form, being a prerequisite to the formation of the salt. In line with these predictions, our FTIR results confirm that the proton transfer and the resulting transformation from the keto to enol form o...

Process Analytical Technology for Crystallization of Active Pharmaceutical Ingredients.

Pharmaceutical industry is witnessing increased pressure to introduce innovative and efficient processes for manufacturing Active Pharmaceutical Ingredients (APIs) in order to be competitive as well as to meet the stringent product quality requirements set by regulatory authorities. Crystallization with its ability to engineer the final product to the desired qualities such as purity, polymorphic form, particle size and shape is one of the most important steps involved in the manufacturing of APIs. Therefore, development of crystallization processes with better understanding of process parameters and their impact on quality of APIs and subsequently the drug products assume great significance for the pharmaceutical industry. This review paper focuses on the application of PAT tools, an integral part of Quality by Design (QbD) approach, for better understanding, control, and design of crystallization processes in the manufacturing of APIs. Firstly, various steps involved in the drug development process are introduced briefly with emphasis on crystallization as one of the most important steps in manufacturing of drug products. Secondly, Critical Quality Attributes (CQAs) of drug products, their dependence on material attributes of APIs and role of crystallization in manipulating material attributes of APIs has been discussed. Finally, application of PAT tools such as advanced process analyzers for continuous monitoring, chemometric methods for multivariate data analysis, and control strategy for APIs crystallization processes has been reviewed along with some examples. Application of PAT in crystallization of APIs facilitates development of robust processes that works within the design space to produce the drug products of consistent quality. Furthermore, it opens up the opportunities for continuous improvement of the process by generating knowledge base of existing processes.

Evaluation of solvents’ effect on solubility, intermolecular interaction energies and habit of ascorbic acid crystals

Solubility of active pharmaceutical ingredient (API) in solvents is very important for drug development and manufacturing. Solubility data may provide further information such as thermochemical properties and intermolecular interactions that may lead to a better understanding of the formation of API crystals. In this study, solubility of ascorbic acid was determined by gravimetric method in four different commonly used polar protic solvents: water, methanol, ethanol and 2-propanol. The solubility of ascorbic acid crystal was also predicted using Conductor-like Screening Model – Realistic Solvent (COSMO-RS) approach. In this computational analysis, the generated ΔG values are based on the solubilities that were experimentally obtained to simulate the intermolecular forces. The intermolecular interaction data from COSMO-RS provide an insight into the relationship between the intermolecular interactions and its crystal habit across four different polar protic solvents. The habit of the crystals was then determined using light microscopy and scanning electron microscopy techniques, while the polymorphic form of the crystals was identified by X-ray powder diffraction and single X-ray diffraction techniques. The solubility and characterization data showed that the solvents with high polarity increased the solubility of ascorbic acid. The data also showed that different solvent polarity influenced the crystal habit, but did not change the crystal structure to form a new polymorph.

Continuous crystallization of α-form L-glutamic acid in an MSMPR-Tubular crystallizer system

Continuous crystallization of active pharmaceutical ingredients is of prime significance. A continuous mixed suspension mixed product removal (MSMPR)-tubular crystallizer geometry is designed and optimized to produce the metastable α-form crystals of L-glutamic acid with uniform mean size of 130 µm. The MSMPR is used to produce well-tuned seed crystals that undergo further growth in a series of tubular crystallizers. The effects of the initial supersaturation, stirring speed, nucleation temperature and residence time were optimized in the MSMPR crystallizer to tune the supply of continuous seeds by using the principal component analysis and in-situ particle tracking measurement. The continuous seeds of the desired metastable polymorphic form with specific size ranging from 5.0 to 15.0 µm and number density ranging from 500 to 1500 counts, were transferred to a series of three coiled tubular crystallizers for further growth. In addition, the cooling strategy in the tubular crystallizers was utilized to further optimize the quality of the final crystal product. The crystal size distribution (CSD) in the MSMPR-tubular crystallizer system was compared with a single MSMPR with the same residence time and found to be superior. Finally, a potential scale up strategy of the MSMPR-tubular crystallizer system was proposed for further study.

Technoeconomic Optimization of Continuous Crystallization for Three Active Pharmaceutical Ingredients: Cyclosporine, Paracetamol, and Aliskiren

Mixed suspension, mixed product removal (MSMPR) crystallizers are widely implemented for the continuous crystallization of active pharmaceutical ingredients (APIs), allowing enhanced efficiency, flexibility, and product quality compared to currently dominant batch crystallizer designs. Establishing cost-effective continuous crystallization process configurations for societally and economically important APIs is essential to ensure the successful implementation of end-to-end continuous pharmaceutical manufacturing (CPM) campaigns. Process modeling and optimization allow rapid, systematic comparative technoeconomic evaluations. This paper pursues total cost minimization of different crystallizer configurations of three APIs—cyclosporine, paracetamol, and aliskiren hemifumarate—whose continuous MSMPR crystallization has been experimentally demonstrated. Nonlinear optimization for total cost minimization is implemented for one to three crystallizers for different plant API capacities with crystallizer tempera...

Supramolecular Metal–Phenolic Gels for the Crystallization of Active Pharmaceutical Ingredients

The use of supramolecular gel media for the crystallization of active pharmaceutical ingredients (APIs) is of interest for controlling crystal size, morphology, and polymorphism, as these features determine the performance of pharmaceutical formulations. In contrast to supramolecular systems prepared from synthetic gelators, herein, supramolecular metallogels based on a natural polyphenol (tannic acid) are used for the crystallization of APIs. The gel-grown API crystals exhibit considerable differences in size, morphology, and polymorphism when compared with those formed in solutions. These physical features can also be tailored by varying the gel composition and additives, suggesting an influence of the gel medium on the crystallization outcomes. Furthermore, these gel-API crystal composites can be used for sustained drug release, indicating their potential as drug delivery systems. The facile preparation of these supramolecular gels and the use of naturally abundant components in their synthesis provide a generic platform for studying gel-mediated crystallization of diverse APIs.