Pharmaceutical Crystallization Research Articles

CO2 Promoting Polymorphic Transformation of Clarithromycin: Polymorph Characterization, Pathway Design, and Mechanism Study

Carbon dioxide (CO2) has a wide range of uses such as food additives and raw materials for synthetic chemicals, while its application in the solid-state transformation of pharmaceutical crystals is rare. In this work, we report a case of using 1 atm CO2 as an accelerator to promote the polymorphic transformation of clarithromycin (CLA). Initially, crystal structures of Form 0′ and three solvates were successfully determined by single crystal X-ray diffraction (SCXRD) analysis for the first time and found to be isomorphous. Powder X-ray diffraction (PXRD) and thermal analysis indicated that the solvate desolvates and transforms into the structurally similar non-solvated Form 0′ at room temperature to ~50 °C. Form 0′ and Form II are monotropically related polymorphs with Form II being the most stable. Subsequently, the effect of CO2 on the transformation of CLA solvates to Form II was studied. The results show that CO2 can significantly facilitate the transformation of Form 0′ to Form II, despite no significant effect on the desolvation process. Finally, the molecular mechanism of CO2 promoting the polymorphic transformation was revealed by the combination of the measurement of adsorption capacity, theoretical calculations as well as crystal structure analysis. Based on the above results, a new pathway of preparing CLA Form II was designed: transform CLA solvates into Form 0′ in 1 atm air at 50 °C followed by the transformation of Form 0′ to Form II in 1 atm CO2 at 50 °C. This work provides a new idea for promoting the phase transformation of pharmaceutical crystals as well as a new scenario for the utilization of CO2.

Heterogeneous crystallization of Chlorzoxazone for modulating the physicochemical properties of crystals

The polymer on modulating the crystal's habit is an evolving research in pharmaceutical crystallization. This study demonstrates the crystal habit modification of chlorzoxazone (CHZ) by heterogeneous crystallization (HC) in the binary solvent acetonitrile-ethanol (A-E (1:1)) in the presence of polyvinylpyrrolidine (PVP) at concentrations of 0.50, 0.75, and 1.00 wt%. The A-E (1:1) and PVP in HC experiments influenced to change the shape of crystals from needle to plate shape and reduced the crystal size producing a lower aspect ratio (in the range of 1.5–2.3). In the presence of PVP, the CHZ size distribution is 65–78 μm which tends to enhance the powder flow-ability of CHZ crystals and as the PVP concentration increases, the nucleation rate decreases. The solubility of size-reduced CHZ crystals at different pH is found to be improved by 1.2–1.4 times. Hence, HC is deemed effective in modifying the physicochemical attributes of CHZ.

Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane‐Based Technologies

AbstractContinuous crystallization of pharmaceuticals has been in the center of attention during the past two decades, with a more focus on the large‐scale production of active pharmaceutical ingredients. The increasing demand for pharmaceuticals requires high‐throughput production of drug crystals with different solubilities, stabilities, shapes, habits, polymorphs, and size distributions. With numerous advantages including low cost, ease of scale‐up, and superior control over polymorph and size distribution of drug crystals, antisolvent crystallization is one of the most promising crystallization methods recently attempted. However, it fails to deliver the required characteristic where the crystal systems tend to grow and for the preparation of metastable polymorphs. This review focuses on the most recent efforts to tackle these drawbacks by coupling antisolvent crystallization with cooling, supercritical‐assisted, microfluidics‐assisted, and membrane‐assisted crystallization. This systematic review aims to provide a concise summary of each coupled antisolvent technique and their positive and negative aspects. This review can be used as a guideline for pharmacist, biologists, and chemists, who are interested in the crystal engineering of pharmaceuticals to pave the way for further developments in this field.

Scrolling in Supramolecular Gels: A Designer's Guide.

Gelation by small molecules is a topic of enormous importance in catalysis, nanomaterials, drug delivery, and pharmaceutical crystallization. The mechanism by which gelators self-organize into a fibrous gel network is poorly understood. Herein, we describe the crystal structures and gelation properties of a library of bis(urea) compounds and show, via molecular dynamics simulations, how gelator aggregation progresses from a continuous pattern of supramolecular motifs to a homogeneous fiber network. Our model suggests that lamellae with asymmetric surfaces scroll into uniform unbranched fibrils, while sheets with symmetric surfaces undergo stacking to form crystals. The self-assembly of asymmetric lamellae is associated with specific molecular features, such as the presence of narrow and flexible end groups with high packing densities, and likely represents a general mechanism for the formation of small-molecule gels.

Medium-chain dicarboxylic acids: chemistry, pharmacological properties, and applications in modern pharmaceutical and cosmetics industries.

Succinic (SUA), glutaric (GLA), pimelic (PA), suberic (SUBA), adipic (ADA), azelaic (AZA), and sebacic acids (SA) make up the majority of medium-chain dicarboxylic acids (MCDAs) with chain lengths of C4-C10, and are widely utilised in the chemical, food, textile, pesticide, pharmaceutical, and liquid crystal sectors. The MCDAs' two carboxyl groups provide them with an incredibly broad variety of applications. The focus of significant scientific research now is on the increasingly varied pharmacological effects of MCDAs. However, only a few studies have compared the biological characteristics of MCDAs in the contemporary pharmaceutical and cosmetic sectors and thoroughly examined the most recent research and marketing initiatives for MCDAs. This review's objective is to offer a thorough analysis of academic works on MCDAs, to assess the usefulness of these substances' chemical-pharmacological properties for use in the contemporary pharmaceutical and cosmetic industries, and to investigate the direction of their possible applications in these two disciplines. In addition, this review investigates how these compounds are metabolised in the human body.

Population balance model enabled digital design and uncertainty analysis framework for continuous crystallization of pharmaceuticals using an automated platform with full recycle and minimal material use

A systematic digital design framework for the development of a digital twin of a continuous crystallization process was presented using the model compound, diphenhydramine hydrochloride (DPH). The key features of the framework include operating space investigations, kinetic parameter estimation using population balance modeling, and systematic batch-to-continuous crystallization translation of the estimated parameters. An approach that compares experimental uncertainties with model-prediction uncertainties was used to justify the robustness of the parameter estimation procedure. For continuous crystallization development, a continuous configuration with full recycle and dissolution was developed, which enabled rapid process design with minimal material use. The results demonstrated successful model development for both batch and mixed-suspension-mixed-product-removal (MSMPR) crystallization configurations. This experimentally validated model, along with quantified uncertainty space of the kinetic parameters, serves as a digital twin of the process, which was later used to optimize the multistage MSMPR process to produce larger crystals with narrower distributions.

Cocrystal: A Review on the Design and Preparation of Pharmaceutical Cocrystals

The majority of the active pharmaceutical components have issues with poor solubility, bioavailability, chemical stability, and moisture absorption. Pharmaceutical crystals are a reliable way to change the aforementioned physicochemical properties of drugs without changing their pharmacological behaviour. However, the success of these approaches depends on the physical and chemical properties of the molecules being developed. The development of drug products with superior physicochemical characteristics, such as melting point, tablet ability, solubility, stability, bioavailability, and permeability, while preserving the pharmacological properties of the active pharmaceutical ingredient is greatly facilitated by co-crystallization of drug substances. All the components of a cocrystal, which is a stoichiometric homogeneous multicomponent system connected by non-covalent interactions, are solid under ambient conditions.

Review of the Application of PAT in the Pharmaceutical Continuous Crystallization Process.

As an important pharmaceutical process, crystallization greatly impacts the final product. In recent years, the continuous crystallization process has attracted more attention from researchers, with the promotion of continuous manufacturing (CM) by the Food and Drug Administration (FDA). The continuous crystallization process has the advantages of high economic benefit, stable and uniform quality, a short production cycle, and personalization. To carry out continuous crystallization, some related process analytical technology (PAT) tools have become the focus of breakthroughs. Infrared (IR) spectroscopy, Raman spectroscopy, and focused beam reflection measurement (FBRM) tools have gradually become research hotspots due to their fast, non-destructive, and real-time monitoring characteristics. This review compared the advantages and disadvantages of the three technologies. Their applications in the upstream mixed continuous crystallization process, the middle reaches of crystal nucleation and growth, and the process of the downstream refining were discussed to provide corresponding guidance for the practice and further development of these three technologies in the continuous crystallization process and promote the development of CM in the pharmaceutical industry.

Preparation, characterization, and stability enhancement of metoprolol pharmaceutical multicomponent crystals

Crystal engineering is a crucial technology in improving the physicochemical properties of active pharmaceutical ingredients (APIs). To address the drawback of the instability and low melting point of metoprolol (MET), multi-component compounds of metoprolol were designed and synthesized to enhance their stability. Six stable multi-component crystals with dihydrocaffeic acid (DA), p-hydroxybenzoic acid (p-HA), 4-chlorobenzoic acid (4-CA), 3,5-dinitrobenzoic acid (3,5-DA), cinnamic acid (CA) and oxalic acid (OA) were obtained for the first time. Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) and thermogravimetric analysis (TG) techniques were used to characterize the novel multicomponent crystals. In addition, the stability of the solid drug forms was evaluated. The results indicate that the stability of all six multicomponent crystals was significantly higher than that of the raw materials.

Case Studies in the Application of a Workflow-Based Crystallization Design for Optimized Impurity Rejection in Pharmaceutical Development

Crystallization is an important unit operation in pharmaceutical drug substance manufacturing for the isolation of organic products. Impurity control is a recurring critical quality attribute in most commercial pharmaceutical crystallization processes. A systematic workflow that can reveal the incorporation mechanism of various impurities during crystallization and guide us to understand impurity rejection is useful for crystallization process design. Such a workflow was recently published by Urwin et al. Herein, we present three case studies implementing this workflow, covering surface deposition, conglomerate formation, and agglomeration as principal routes for impurity incorporation during crystallization of a drug substance’s active pharmaceutical ingredient and its intermediates. We demonstrate the experimental steps to identify various impurity incorporation mechanisms and discuss the strategy for impurity rejection in each case. We built upon the previous approach to demonstrate a material sparing approach through our case studies. We highlight the value of stepwise dissolution and show the importance of doing it early in the impurity incorporation identification stage. At this stage, we introduce a missing incorporation mechanism in prior work, namely, conglomerate systems. We show how to identify and resolve this mode of incorporation mechanism through stepwise dissolution and solubility-limited rejection maps.

Solubility Prediction of Lornoxicam in Different Pure Solvents Using Semi-Empirical Correlations and Thermodynamic Models

The solubility data of Active Pharmaceutical Ingredients in organic solvents is an essential for pharmaceutical crystallization and drug formulation. In this work, two semi-empirical correlations- the Yaws model and λ-h model- and two thermodynamic models – Wilson Model and the Non-random two-liquid model- are used to estimate the solubility of lornoxicam in ethanol and water. The model parameters and correlations coefficients are calculated by optimizing the average relative deviation. The values of these parameters will be helpful to estimate the solubility of lornoxicam at different temperatures where the experimental solubility data is not available. The predicted solubility data of lornoxicam can be further utilized in the pharmaceutical crystallization and drug formulation.

Supramolecular Organization in Salts of Riluzole with Dihydroxybenzoic Acids—The Key Role of the Mutual Arrangement of OH Groups

Intermolecular interactions, in particular hydrogen bonds, play a key role in crystal engineering. The ability to form hydrogen bonds of various types and strengths causes competition between supramolecular synthons in pharmaceutical multicomponent crystals. In this work, we investigate the influence of positional isomerism on the packing arrangements and the network of hydrogen bonds in multicomponent crystals of the drug riluzole with hydroxyl derivatives of salicylic acid. The supramolecular organization of the riluzole salt containing 2,6-dihydroxybenzoic acid differs from that of the solid forms with 2,4- and 2,5-dihydroxybenzoic acids. Because the second OH group is not at position 6 in the latter crystals, intermolecular charge-assisted hydrogen bonds are formed. According to periodic DFT calculations, the enthalpy of these H-bonds exceeds 30 kJ·mol-1. The positional isomerism appears to have little effect on the enthalpy of the primary supramolecular synthon (65-70 kJ·mol-1), but it does result in the formation of a two-dimensional network of hydrogen bonds and an increase in the overall lattice energy. According to the results of the present study, 2,6-dihydroxybenzoic acid can be treated as a promising counterion for the design of pharmaceutical multicomponent crystals.

Mechanochemical Synthesis of Dendrimers as Nanocarriers: A Review

The process of mechanically activating chemical bonds usually involves applying external force. Since mechanical chemistry can be performed without solvents or with minimal amounts of solvent (catalytic quantities), it has become an imperative synthetic tool in multiple fields (e.g., physics, chemistry, and materials science) and is an attractive greener method for preparing diverse molecules. Catalysis, organic synthesis, solid-state medicinal preparation, metal complex synthesis, and many other chemistry fields have benefited from sustainable methods. The purpose of this paper is to shed light on the benefits of using mechanochemical methods to produce a pharmaceutical crystal that is composed of dendrimer nanocrystals. Consequently, we describe and examine the importance of mechanical procedures in forming dendrimers and pharmaceutical crystals in this review.

Highly Thermally Resistant Bisamide Gelators as Pharmaceutical Crystallization Media.

Three simple bisamide derivatives (G1, G2 and G3) with different structural modifications were synthesized with easy synthetic procedures in order to test their gel behaviour. The outcomes showed that hydrogen bonding was essential in gel formation; for this reason, only G1 provided satisfactory gels. The presence of methoxy groups in G2 and the alkyl chains in G3 hindered the hydrogen bonding between N-H and C=O that occurred G1. In addition, G1 provided thermally and mechanical stable gels, as confirmed with Tsol and rheology experiments. The gels of G1 were also responsive under pH stimuli and were employed as a vehicle for drug crystallization, causing a change in polymorphism in the presence of flufenamic acid and therefore providing the most thermodynamically stable form III compared with metastable form IV obtained from solution crystallization.

Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements

Obtaining a particle size within the specifications for a pharmaceutical compound in an industrial crystallization can be a challenging task. The events affecting the final particle size of the product include nucleation, growth, breakage, and agglomeration, which are often convoluted. Secondary nucleation may significantly influence the particle size distribution. The strategies and techniques relevant to obtaining an in-spec particle size in crystallization are summarized and discussed from a perspective of process parameters. The effect of cooling profiles, seeding strategies, as well as mixing by agitation are reviewed, and an efficient and controlled crystallization process may be achieved using an optimized combination of these conditions. Multiple characterization methods for particle size and distribution are compared, and the discrepancies associated with the measurements are addressed.

A REVIEW ON ADVANCES IN PHARMACEUTICAL CO-CRYSTAL PREPARATION ROUTES, INTELLECTUAL PROPERTY PERSPECTIVE AND REGULATORY ASPECTS

As in recent years, due to the pervasiveness of poorly soluble APIs that demonstrates poor and erratic bioavailability, pharmaceutical cocrystal’s applicability to tailor the physicochemical properties has gained attention. Pharmaceutical cocrystal has been an exciting field of interest to researchers as this encouraged several regulatory bodies to create regulatory standards, which led to the approval of these crystals for marketing in various nations. With the upsurge in the growth of pharmaceutical cocrystals, the major concern is over the intellectual property perspective and regulatory status of cocrystals. With the new guidelines from the United States Food and Drug Administration (USFDA) and European Medicines Agency (EMA), the manufacturing and characterization of cocrystal have become less complicated. In this article, various preparation routes are mentioned along with this intellectual property perspective and regulatory perspective, including regulatory guidelines, which give an idea of whether cocrystals meet the criteria for patent eligibility and how they would change the current state of the pharmaceutical industry. Here, we also reviewed some recently approved patients on pharmaceutical crystals, which provided benefits over poor physicochemical property of drug substances and also enhanced the therapeutic effectiveness of that drugs.

Towards the Development of Novel Diclofenac Multicomponent Pharmaceutical Solids

Multicomponent pharmaceutical materials offer new opportunities to address drug physicochemical issues and to obtain improved drug formulation, especially on oral administration drugs. This work reports three new multicomponent pharmaceutical crystals of the non-steroidal anti-inflammatory drug diclofenac and the nucleobases adenine, cytosine, and isocytosine. They have been synthesized by mechanochemical methods and been characterized in-depth in solid-state by powder and single crystal X-ray diffraction, as well as other techniques such as thermal analyses and infrared spectroscopy. Stability and solubility tests were also performed on these materials. This work aimed to evaluate the physicochemical properties of these solid forms, which revealed thermal stability improvement. Dissociation of the new phases was observed in water, though. This fact is consistent with the reported observed layered structures and BFDH morphology calculations.

Simple Methods to Predict Particle Size for Growth-Only Systems Undergoing One or More Temperature Cycles

Three simple methods are presented for predicting particle size distribution (PSD) percentiles when subjecting a pharmaceutical crystallization wet-milled slurry to a single temperature cycle for two of Biogen’s drug substances. The methods are (I) a mathematical manipulation of the wet-milled PSD based on particle death during dissolution; (II) a linear empirical model fit of product PSD percentiles as a function of the wet-milled PSD percentiles and the amount of material dissolved; and (III) a nonlinear model fit to the change in PSD as a function of the amount of material dissolved and the particle surface area/volume ratio. The three methods were verified on production scale batches. Method II’s approach was also used for particle size control during manufacture by implementing a temperature solved from the model using the batch’s wet-milled particle size percentiles and a final target size. Method III was found to be the most accurate at prediction because it models particle surface area to volume ratio influencing crystal dissolution and growth rates. Method II was found to be not as accurate as method III; however, it was easily implementable during process control at the production scale. Method I provided the quickest estimate of final particle size using only the initial PSD and a solubility expression. Method III was recommended for best particle size prediction.

Remarkable similarity of molecular packing in crystals of racemic and enantiopure 2-phenylpropionamide: Z' = 4 structures, molecular disorder, and the formation of a partial solid solution.

Substituted acetamides (many of which are chiral) are known to be pharmacologically active. 2-Phenylpropionamide (2PPA) is one of the simplest chiral α-substituted acetamides and thus is of interest as a model compound in the growth and design of pharmaceutical crystals. In this study, the crystal structures of racemic and enantiopure forms of 2PPA were determined for the first time using single crystal X-ray diffraction at 100 K. The relationship between the signs of optical rotation and the absolute configurations is (+)-(S)-2PPA and (-)-(R)-2PPA. Four symmetrically independent molecules with different conformations are observed in crystals of both racemic and enantiopure forms. Remarkably, all forms adopt very similar supramolecular structures, H-bonded corrugated layers, that can be described using a graph set. The outer surfaces of these layers are built of nonpolar phenyl groups, and their inner structures are composed of H-bonded amide groups. The presence of these layers determines the thin plate shape of 2PPA crystals. Spectroscopically, the racemic and enantiopure forms substantially differ only in the low-frequency Raman region. X-ray diffraction data suggest that the racemic form of 2PPA is a partial solid solution made possible by statistical occupancy of molecular positions by (R)- and (S)-enantiomers.

Continuous synthesis of dolutegravir sodium crystals using liquid-gas heterogeneous microreactor

In this work, a liquid-gas heterogeneous microreactor was developed for investigating continuous crystallization of dolutegravir sodium (DTG), as well as revealing reaction kinetics and mixing mechanism with 3-min data acquisition. The reaction kinetics models were established by visually recording the concentration variation of reactants over time in the microchannel via adding pH-sensitive fluorescent dye. The mixing intensification mechanism of liquid-gas flow was quantified through the fluorescent signal to indicate mixing process, demonstrating an outstanding mixing performance with a mixing time less than 0.1 s. Compared with batch crystallization, continuous synthesis of dolutegravir sodium using liquid-gas heterogenous microreactor optimizes crystal distribution size, and successfully modifies the crystal morphology in needle-like habit instead of rod-like habit. The microreactor continuous crystallization can run for 5 h without crystal blockage and achieve D90 of DTG less than 30 µm. This work provides a feasible approach for continuously synthesizing dolutegravir sodium, and can optimize the existing pharmaceutical crystallization.