Concomitant Polymorphs Research Articles

Mechanism and kinetic modeling study on the crystallization of concomitant polymorphs

AbstractConcomitant polymorphs routinely observed in fine chemical industry could impact product purity and consistency; however, both molecular mechanism and process kinetics of concomitant crystallization remain elusive. Herein, we developed a population balance model to understand process kinetics of concomitantly dipolymorphic crystallization using DL‐methionine as a model compound. Kinetic parameters were estimated from induction time measurements and unseeded crystallization experiments. Experimental and simulation results demonstrate that the stable β form has a comparable nucleation rate with α form thanks to their close nucleation barrier leading to the concurrent nucleation. Several solution chemistry techniques were utilized to examine the speciation of solute molecules, together revealing the solutes' self‐association and the formation of micelle‐like aggregates driven by hydrophobic interactions, not hydrogen bonds. These aggregates show dynamic nature against conventional thoughts of classical nucleation kinetics. Finally, the molecular mechanism of concomitant crystallization was uncovered and the implications for polymorph selection and control were discussed.

Unraveling the concomitant polymorphism phenomenon in crystallization process: A case study on risperidone in ethyl acetate

Concomitant polymorphism is a widespread occurrence in industrial crystallization processes. A thorough understanding of this phenomenon is essential to prevent the emergence of undesirable polymorphs and ensure the production of high-quality products. In this study, the induction time method was employed to investigate the concomitant polymorphism phenomenon of risperidone in ethyl acetate. The impact of crystallization temperature and stirring rate on the concomitant polymorphism region was explored. Additionally, an analysis of the nucleation tendencies of risperidone form I and form II was conducted from both thermodynamic and kinetic perspectives. Based on the induction time theory, the nucleation parameters of form I and form II were calculated. Through an examination of the change in these nucleation parameters with supersaturation, a comprehensive explanation was provided for the reasons behind the occurrence of concomitant polymorphism and the nucleation behavior of form I and form II under varying degrees of supersaturation. Moreover, the concomitant polymorphism phenomenon during the slow-cooling crystallization process was investigated, and the relationship between operational conditions and the concomitant polymorphism region was discussed.

Concomitant polymorphs of 2-imino-2H-chromene-3-carboxylic acid amide: experimental and quantum chemical study.

2-Iminocoumarin-3-carboxamide (2-imino-2 H-chromene-3-carboxylic acid) is a perspective compound for use in the pharmaceutical industry. This compound crystallized from several solvents as two concomitant polymorphic forms. The monoclinic polymorph, crystallized initially, is formed due to strong N-H...O hydrogen bonds, weak C-H...O and C-H...N(π) hydrogen bonds, and stacking interactions of `head-to-head' type. The triclinic polymorphic form obtained due to slow evaporation of the same solution is formed due to only strong intermolecular interactions, N-H...O hydrogen bonds of two types, and stacking interactions of two types. Analysis of pairwise interaction energies showed that the monoclinic structure is columnar while the triclinic one is layered. Calculations in a periodic approximation of their lattice energies confirmed that the monoclinic polymorphic crystals are metastable as compared to the stable triclinic polymorph. Further quantum chemical modeling of possible structure deformations proved that both concomitant polymorphs can not be transformed into a new polymorphic form under external influence.

Use of quantum chemical methods to study concomitant polymorphs of a new benzimidazole-1,2,3-triazole hybrid compound

Two concomitant polymorphs formed due to different conformations of the molecule have been studied thoroughly using methods of quantum chemistry.

Two Structurally Different Polymers from a Single Monomer.

We designed and synthesized a malonamide-derived monomer, containing azide and alkyne units, for topochemical polymerization to yield nylon (n,3). This monomer on crystallization gave two concomitant polymorphs M1 and M2. Both the polymorphs show crystal packings that are suitable for topochemical azide-alkyne cycloaddition polymerization. On heating, polymorph M1 reacts regiospecifically to give 1,4-disubstituted-1,2,3-triazolyl-linked polymer, whereas polymorph M2 yields 1,5-disubstituted-1,2,3-triazolyl-linked polymer regiospecifically. In the case of polymorph M1, polymerization proceeds perpendicular to the hydrogen bonding direction, whereas in M2, the reaction occurs along the hydrogen bonding direction. This results in the two structurally different polymers having distinct topologies. These single-crystal-to-single-crystal polymerizations allowed us to study their structure at atomic resolution by single-crystal X-ray diffraction. This is the first report on the topochemical synthesis of two structurally isomeric polymers from a single monomer.

Polymorph and Morphology Formation of Cerium Carbonate from Reactive Crystallization

Semibatch reactive crystallization and hydrothermal reaction of cerium carbonate were investigated with cerium chloride and sodium carbonate as the reactants in order to determine the key factor and the foremost step that affect the polymorph and morphology. Pure Ce2(CO3)3·8H2O, pure CeCO3OH, and the concomitant polymorphism of the two were obtained at different temperatures and the concentrations of cerium chloride solution. The relative stability of Ce2(CO3)3·8H2O and CeCO3OH, the solubilities of the two forms in low concentration of sodium chloride solution and the dehydration and decomposition processes with heating were first discussed in this study. Rodlike forms, short rodlike forms, platelike aggregations or blocks, regular intercrescence, and regular spindle morphology of cerium carbonate crystals were obtained from semibatch and hydrothermal reactive crystallization, respectively. Raman spectroscopy and a focused beam reflection measuring (FBRM) instrument were applied in situ to monitor the reaction, nucleation, and growth processes. It was found that CeCO3OH is more stable than Ce2(CO3)3·8H2O. The thermodynamics driving force of supersaturation of cerium carbonate generated from the reaction between cerium chloride and sodium carbonate at different temperatures contributed mainly to the nucleation, which, in turn, controls the crystal phase formation and the morphology of cerium carbonate. Finally, the routes for cerium chloride and sodium carbonate to transform into cerium oxide were summarized.

The HPV-TP53-MALAT1 Axis: Unravelling interactions in cervical cancer development.

Cervical cancer, primarily driven by Human Papillomavirus (HPV) infection, stands as a substantial global health challenge. The TP53 gene's, Arg72Pro polymorphism has emerged as a noteworthy player in cervical cancer development, particularly among individuals harboring high-risk (HR) HPV types. Additionally, long non-coding RNAs (lncRNAs), exemplified by metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), exert critical roles in cancer biology. This study delves into unravelling the intricate connections linking HPV infection, TP53 Arg72Pro polymorphism, and MALAT1 expression in the context of cervical cancer. Within a cohort of cervical cancer patients, we discerned HPV infection statuses, executed genotyping for the TP53 Arg72Pro polymorphism, and quantified MALAT1 expression through quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Statistical analyses meticulously probed relationships intertwining HPV infection, TP53 polymorphism, and MALAT1 expression. Our investigation revealed a striking prevalence of the TP53 Arg72Pro polymorphism among HPV-positive subjects, accompanied by a robust and statistically significant correlation linking MALAT1 overexpression (p<0.01) and HR-HPV positivity (p<0.03). Importantly, a subset of MALAT1 overexpression cases unveiled a concomitant TP53 Pro72Pro polymorphism. In contrast, HPV-negative invasive cervical carcinoma samples exhibited no discernible shifts in MALAT1 expression. The contours of our findings sketch a compelling landscape wherein HR-HPV infection, TP53 polymorphism, and MALAT1 expression intertwine significantly in cervical cancer. The voyage ahead entails delving deeper into molecular underpinnings to decipher MALAT1's nuanced role and its dance with TP53 within HPV-associated cervical carcinogenesis. This expedition promises insights that may engender targeted therapeutic interventions and bespoke prognostic markers, tailored to the realm of HR-HPV-related cervical cancer.

Synergistic Control of Nonlinear Growth Kinetics and Nucleation Kinetics in the Concomitant Crystallization of Aripiprazole as Reflected by the Ostwald Ratio

Some polycrystalline drugs are subject to concomitant polymorphism during the manufacturing process, resulting in large batch-to-batch variation and reduced drug bioavailability. Most existing studies on concomitant polymorphism have focused only on differences in nucleation kinetics and lacked analysis of the role of growth processes in polymorph control. Herein, we conducted a systematic study on the concomitant crystallization of aripiprazole Form III and Form V under the influence of thermodynamic and kinetic factors employing thermal analysis with the Ostwald ratio as a medium. It shows that the nucleation and growth rates of both forms cross over with increasing supersaturation. The comparison between the polymorph composition computed by the Ostwald ratio and the experiments highlights the considerable influence of crystal growth on the formation of concomitant polymorphism. The effect of crystal growth at lower supersaturation is indeed minimal due to the large difference in nucleation rates, but as the supersaturation increases, the difference in nucleation rates becomes smaller and the growth rate ratio gradually becomes a key factor. The images plotted with initial concentration and crystallization temperature further demonstrate that the introduction of actual nonlinear growth kinetics can lead to improved computation accuracy of the Ostwald ratio. This work provides evidence for the application of the Ostwald ratio in the design of batch crystallization for a concomitant system.

Luminescent N-aryl-heteroacene derivatives

The incorporation of heteroatoms into polycyclic aromatic hydrocarbons can alter their optical and electronic properties. Here, we report the synthesis and characterization of a series of N,N′-diaryl diazadioxatetrahydropentacenes (4a–e) as well as related N-phenyl azatrioxatetrahydropentacene and triazatetrahydrotetracene derivatives (5, 6) to investigate their photophysical properties and solid-state organization. These compounds were prepared from readily available compounds via a concise approach involving copper-catalyzed aryl amination, followed by nucleophilic aromatic substitution. The compounds display bright luminescence in solution and in the solid state and strong solvatochromism. Single-crystal X-ray diffraction of N,N′-aryl diazadioxatetrahydropentacenes (4b–d) revealed that all the compounds possessed nearly planar polycyclic aromatic systems with the pendant aryl groups nearly orthogonal to the pentacyclic core. Nonetheless, different substituents on the pendant aryl groups resulted in differences in photophysical properties because of differences in molecular geometries and solid-state packing. Interestingly, the N,N′-aryl diazadioxatetrahydropentacene bearing 2,6-dimethylphenyl groups attached to the nitrogen atoms (4d) gave two different polymorphs from the same solvent system, constituting a relatively rare example of concomitant polymorphism for such a rigid structure.

Preference of High-Nitrogen-Content Compounds to Form Hydrates and the Tandem Contacts of Azide Groups

Under ambient conditions, the high-nitrogen-content compound, 6-azido-7-methyl[1,2,4]triazolo[4,3-b]pyridazine (C6H5N7), favorably crystallizes in the form of two concomitant monohydrate polymorphs: α-C6H5N7·H2O and β-C6H5N7·H2O; also anhydrate C6H7N7 is obtained from the acetone solution. High-pressure isochoric recrystallizations lead to new forms of these compounds. The α-hydrate can be reversibly isothermally compressed to 0.6 GPa at the least and the β-hydrate can be compressed to and from 1 GPa. However, the isochoric recrystallizations above 0.3 GPa favor the α-hydrate. This hydrate occurs as metastable phase, in accordance with the Ostwald rule of stages. Compound C7H7N7 could be recrystallized only from aqueous solution in the form of sesquihydrate C7H7N7·1.5H2O. The molecular packing in all hydrates is governed by hydrogen bonds OH···N and tandem contacts between azide groups.

The formation of highly stable form of isotactic polybutene-1 electrospun membrane via self-seeding

The non-isothermal crystallization behavior from the incomplete melting of isotactic polybutene-1 (iPB-1) electrospun (e-spun) membranes is investigated. The standard sample of e-spun iPB-1 contains the concomitant form II and I′, which are less stable than form I. So, we adopted a pathway of treating a nucleation stage of concomitant polymorphs. Cross-nucleation was observed when a stable polymorph nucleates and grows on a formerly existing polymorph. The present outcomes revealed that upon non-isothermal crystallization of a partially molten state, an appropriate Domain of self-seeding temperature (Ts) 115 °C to 125 °C directed towards forming highly stable iPB-1 form I. Such phenomena might be typified to the memory effect of their pristine crystalline structure and the inter-lamella confinement effect in that particular and constrained environment of the partially molten state. In addition, the influence of variable applied voltage on the self-nucleation mechanism was also considered comparatively. Based on their morphology, spectral, and thermal analysis, samples spun at 11 kV were relatively preeminent to proceed with the self-seeding route.

Role of Cl• • •Cl halogen bonds in tuning the crystals of Uranyl-Dicholorothiophene carboxylate based hybrid cluster materials through N-donor counter ions

• Eight new uranyl complexes containing 2,5-Dichlorothiophene-3-carboxylic acid with differently sized N-donor ligands were utilized to assemble under hydrothermal conditions. • The crystal structures of these uranyl complexes display the propensity of CTDC ligand and its capability of partaking in Cl•••Cl interactions and the Cl•••Cl interactions are confirmed through QTAIM analysis as well. • Photocatalytic behavior under UV light irradiation, shows remarkable advantages in the degradation of organic dyes. Hydrothermal synthesis has afforded eight uranyl bearing hybrid materials with various ancillary ligands such as 2,5-Dichlorothiophene-3-carboxylate (CTDC) as the main ligand and 4,4’-bipyridine (4BPY), 4,4′-Trimethylenedipyridine (4TBY), trans-1-(2-pyridyl)-2-(4-pyridyl)ethylene (TTPY), 1,10-Phenanthroline (PHEN), or 2,2′-Dipyridylamine (2DPY). These uranyl complexes; (UO 2 ) 0.5 (CTDC)(4BPY) 0.5 ( I ), UO 2 (CTDC) 2 (4BPY) 0.5 , ( II ); [(UO 2 ) 4 (μ 3 -O) 2 (μ 2 -OH) 2 (CTDC) 4 (4TBY) 2 ].(H 2 4TBY).2H 2 O ( III ); [(UO 2 ) 2 (μ3-O)(CTDC) 3 ].(HTTPY).H 2 O ( IV ); [(UO 2 )(CTDC) 2 (PHEN)] 2 ( V ); [(UO 2 )(μ 2 -OH)(CTDC)(PHEN)] ( VI ); [UO 2 (CTDC) 3 ] 2 (H2DPY) 2 ( VII ); [UO 2 (CTDC) 3 ] 2 (H4TBY) 2 ( VIII ) were characterized by single-crystal X-ray diffraction, powder X-ray diffraction, elemental analysis, FT-IR spectroscopy, thermogravimetric analysis and by their uranyl emission spectra. The complexes ( I ) and ( II ) are the first examples of uranyl complexes with aromatic carboxylates formed in the presence of a coordinated 4,4’-bipyridine ligand. Here, the complexes ( V ) and ( VI ) were concomitant polymorphs while ( II ) and ( VIII ) are polymorphs of ( I ) and ( III ) respectively and were obtained by varying the pH in synthetic procedures. Halogen bonding (Cl···Cl) interactions were found to play a strong role in expanding their dimensionality into 3D and defining their crystal packing patterns. To gain insights into the Cl···Cl interactions, a detailed QTAIM study is taken up. The photocatalytic properties of ( I - VIII ) for degradation of various organic dyes under Hg-lamp irradiation were performed. Interestingly, complexes ( I, II, V ) which are mononuclear uranyl clusters possess the highest efficiency in degradation of organic dyes than the tetranuclear uranyl clusters ( III, IV ). Thus, this work sheds light on the structural features of these uranyl complexes to extend our knowledge and understanding of uranyl chemistry.

Kinetic Retraction at the Onset of Concomitant Crystallization and Implication on Polymorphic Formation.

The four-quadrant regimes of attainable polymorph crystallization (FQR-APC) plot was recently developed through numerical simulations of crystallization kinetics of a dipolymorphic system. Retraction in the polymorphic composition of the most stable form in crystallized samples was unveiled a characteristic indication of concomitant polymorphism. Comparisons were made with a recently developed concept, the Ostwald ratio (OR), in light of characterization of polymorphic formation. It was shown that both schemes display a good agreement in describing polymorphic outcomes, despite their distinct theoretical origins.

Crystallization of dl-methionine polymorphs in the presence of structurally compatible additives

In general, amino acid additive is a key factor in controlling the crystallization of polymorphs. The effect of dl-leucine (dl-leu) on the growth mechanism of dl-methionine (dl-met) crystals was investigated under aqueous medium by varying the additive concentrations at ambient temperature. However, when the additive concentration was gradually increased, the disappearance of the prominent face of β-form (200) was observed with the emergence of (100) facets of α-form, which obviously indicates the change in the type of nucleation induced by the additive dl-leu. On the other hand, concomitant polymorphism (α and β-form) was identified at low (x = 0.001 mol/lit) additive concentration. Instead, for all other concentrations, α-form morphology was observed. Therefore, increasing the quantity of dl-leu (0.001 < x < 0.1 mol/lit) strongly influences the stability of the metastable state corresponding to α-form. Moreover, the lattice parameter values and the distinguished peaks ((600) and (113) planes) obtained from XRD analysis confirms the occurrence of α and β-form morphologies, respectively. Differential scanning calorimetry analysis indicates that the crystal undergoes a solid-state phase transformation from β form to α form. Hence, the overall premise is that addition of dl-leu to dl-met in aqueous medium is a promising technique to acquire pure α-form at ambient temperature.

Controlling the Formation of Two Concomitant Polymorphs in Hg(II) Coordination Polymers.

Controlling the formation of the desired product in the appropriate crystalline form is the fundamental breakthrough of crystal engineering. On that basis, the preferential formation between polymorphic forms, which are referred to as different assemblies achieved by changing the disposition or arrangement of the forming units within the crystalline structure, is one of the most challenging topics still to be understood. Herein, we have observed the formation of two concomitant polymorphs with general formula {[Hg(Pip)2(4,4′-bipy)]·DMF}n (P1A, P1B; Pip = piperonylic acid; 4,4′-bipy = 4,4′-bipyridine). Besides, [Hg(Pip)2(4,4′-bipy)]n (2) has been achieved during the attempts to isolate these polymorphs. The selective synthesis of P1A and P1B has been successfully achieved by changing the synthetic conditions. The formation of each polymorphic form has been ensured by unit cell measurements and decomposition temperature. The elucidation of their crystal structure revealed P1A and P1B as polymorphs, which originates from the Hg(II) cores and intermolecular associations, especially pinpointed by Hg···π and π···π interactions. Density functional theory (DFT) calculations suggest that P1B, which shows Hg(II) geometries that are further from ideality, is more stable than P1A by 13 kJ·mol–1 per [Hg(Pip)2(4,4′-bipy)]·DMF formula unit, and this larger stability of P1B arises mainly from metal···π and π···π interactions between chains. As a result, these structural modifications lead to significant variations of their solid-state photoluminescence.

Simultaneous control of polymorphism and morphology via gelatin induction for concomitant systems: case study of sulfathiazole

Gelatin is a promising additive for controlling concomitant polymorphism and inducing organic spherulites, and gelatin concentration is the dominant factor in the dual regulatory process.

Competitive Hydrogen Bonding and Unprecedented Polymorphism in Selected Chiral Phosphorylated Thioureas

New racemic and enantiopure N-phosphorylated thioureas bearing 1-phenylethyl or tetrahydronaphthalenyl fragments were synthesized. According to NMR data assisted by DFT calculations, the preferred conformation is stabilized by an intramolecular hydrogen bond. This form in solution is in equilibrium with dimeric N–H···S hydrogen-bonded associates, the population depending on the concentration. In the crystalline phase the low-energy conformation with an intramolecular H-bond is realized only in the racemic tetrahydronaphthalenyl derivative. In most crystals various types of intermolecular hydrogen bonding are observed, accompanied by the formation of infinite linear chains or helical structures. Due to the conformational lability of compounds and competitive intermolecular H-bonding, multiple polymorphic modifications are formed. Therefore, crystallization of enantiopure 1-phenylethyl derivatives from various solvents results in concomitant polymorphs at room temperature. One of them undergoes reversible two-step phase transitions from the high-symmetry I41 space group (Z′ = 1, no disorder) via the P41 space group (Z′ = 6) to the monoclinic P21 space group (Z′ = 16) accompanied by drastic concerted conformational changes. Notably, the optimization of the crystal packing is observed upon phase transitions with a gradual reduction of the void space in the unit cell from 4.5% to 0.8%. This is a rare case of several high-Z′ polymorphs for one compound, with chirality playing an important role.

Concomitant Polymorphism and Nucleation Control of DL‐Methionine Through Antisolvent Crystallization

AbstractThe concomitant polymorphism of the sulfur‐containing essential amino acid DL‐methionine was revealed, and α‐ and β‐polymorphic forms were separated from aqueous solution through antisolvent crystallization with ethanol as antisolvent. The addition of different volume fractions of ethanol into the mother solution reduces the solubility of DL‐methionine in double‐distilled water and in turn proportionately generates a range of supersaturation levels. This induces the nucleation of a stable β‐polymorph at low supersaturation levels, a mixture of α‐ and β‐ polymorphs at intermediate supersaturation levels, and a metastable α‐form at high supersaturation levels. Needle‐shaped α‐polymorphs and platy‐shaped β‐polymorphs were well distinguished through in‐situ optical microscopic analysis and their structural confirmation was done by X‐ray diffraction analysis.

A comprehensive approach toward concomitant triclabendazole polymorphism in pharmaceutical products

Triclabendazole (TCB) is a highly effective and low-cost anti-parasitic active pharmaceutical ingredient (API) used in the treatment of fascioliasis, a neglected tropical disease caused by Fasciola hepatica. It belongs to Class II/IV in the Biopharmaceutics Classification System, where API dissolution results in the limiting step for its absorption.TCB exhibits tautomeric and conformational polymorphism, where Form I contains different conformations of tautomer A, and Form II is a 1:1 conglomerate of tautomers A and B, each in a single conformation. Since both forms may precipitate concomitantly during the preparation of the API, the control of polymorphic quality is critical for this anti-parasitic agent.A comprehensive approach was developed to address the determination of the polymorphic quality of drug-products when pure solid forms are not available, such as the case of concomitant crystallization of TCB I and II.First, both solid forms of the drug were isolated and characterized (digital optical microscopy, differential scanning calorimetry, hot stage microscopy, mid-infrared, near-infrared and solid-state 13C nuclear magnetic resonance). Next, lab-scale crystallization of Forms I and II was optimized, following a smart approach (green solvent and robust procedures), in order to obtain standards for calibration.A strategy based on NIR spectroscopy coupled to PLS was developed and validated to assess the polymorphic composition of drug-products. The new method was successfully applied to formulated products.The intrinsic dissolution rate of the pure forms demonstrated that Form II dissolves up to 60% faster than Form I, reinforcing the need for polymorphic control to assure the lot-to-lot equivalence. Thus, NIR-PLS emerges as a unique tool able to control the risk of polymorphic changes and their impact on bioavailability in formulated products.

Usage of Quantum Chemical Methods to Understand the Formation of Concomitant Polymorphs of Acetyl 2-(N-(2-Fluorophenyl)imino)coumarin-3-carboxamide.

Crystallization of concomitant polymorphs is a very intriguing process that is difficult to be studied experimentally. A comprehensive study of two polymorphic modifications of acetyl 2-(N-(2-fluorophenyl)imino)coumarin-3-carboxamide using quantum chemical methods has revealed molecular and crystal structure dependence on crystallization conditions. Fast crystallization associated with a kinetically controlled process results in the formation of a columnar structure with a nonequilibrium molecular conformation and more isotropic topology of interaction energies between molecules. Slow crystallization may be considered as a thermodynamically controlled process and leads to the formation of a layered crystal structure with the conformation of the molecule corresponding to local minima and anisotropic topology of interaction energies. Fast crystallization results in the formation of a lot of weak intermolecular interactions, while slow crystallization leads to the formation of small amounts of stronger interactions.