Metastable Form Research Articles

Pervaporation-assisted crystallization of active pharmaceutical ingredients (APIs)

Crystallization of active pharmaceutical ingredients is essential in pharmaceutical production. Pervaporation, a thermally-driven membrane process, has not been explored in API crystallization. Here we demonstrated PV-assisted crystallization (PVaC) for simultaneous recovery of API ortho-aminobenzoic acid (o-ABA) and pure solvent. The PERVAP 4060 made of organophilic polymer was found suitable given the reasonable flux of ethanol of 3.69 ​kg/m2/h at 45 ​°C with saturated solution and 99.9% o-ABA rejection. A parametric study showed that the membrane permeance increased with feed flow rate and temperature, but decreased with supersaturation. In the sequential PVaC, the stable form I of o-ABA was obtained with 25 ​°C PV; while with 45 ​°C PV, only metastable form II crystallized. In the simultaneous PVaC, at 0 time lag pure form II was produced; by increasing time lag, form I increased significantly. The results indicated potential routes to control polymorph formation via PVaC, providing a promising alternative for API production.

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.

On the polymorphism of La2SiMoO8: New metastable high temperature forms and NTE (negative thermal expansion) phase transitions

Following a previous study on scheelite LT-La2SiMoO8, a new high temperature polymorph was discovered after metastabilization down to room temperature (HT). An attempt at structural determination by neutron diffraction led to large atomic displacement parameters of the Mo cation and/or of some of its oxygen neighbors, suggesting structural instability. It was confirmed by thermal analysis and X-ray thermodiffraction, showing the existence of a phase transition at 440 ​°C between two very close polymorphs, probably mixed in the HT sample. The structural derivation of the two HT forms from the baryte-type BaSO4 structure was identified, with alternating [LaMoO4]+ and [LaSiO4]- layers. The differentiation between these two forms most likely comes from a slightly different arrangement of their respective [LaMoO4] layers. The anisotropic thermal expansion is accompanied by a volume contraction of −0.56% between the two HT forms, and a much larger one (−5.3%) at higher temperatures when the LT form stabilizes.

Characterization of an atmospheric pressure plasma jet producing the auroral transition O(1S) to O(1D)

We present a detailed characterization of an atmospheric pressure plasma jet that produces the metastable oxygen states O(1S) and OD) with emission of the ‘auroral’ green line. The device used 99.999 pure argon as a working gas for the plasma generation. Optical emission spectroscopy was used to understand the active species present in the plasma jet and to infer the mechanism of O(1S) creation and destruction. The continuum spectrum was used in conjunction with a method based on machine learning for determining the arbitrary electron probability distribution function. Discharge and plasma properties were estimated from Lissajous plots and using calculations with the BOLSIG+ software. The metastable oxygen forms for all operating parameters of the plasma jet system in a linear electrode configuration. The camera images provided information of the overall plasma jet behavior as parameters were altered. While the metastable oxygen was produced for every iteration, the plasma jet behavior changed considerably when the powered and grounded electrodes are switched. Small admixtures of oxygen and nitrogen were introduced in the plasma jet to understand the kinetic processes of metastable oxygen destruction and the 557.7 nm auroral line. This behavior has implications for plasma reactive chemistry in fundamental areas such as auroral physics as well as technological applications of plasmas.

Surfactant Provided Control of Crystallization Polymorphic Outcome and Stabilization of Metastable Polymorphs of 2,6-Dimethoxyphenylboronic Acid

2,6-Dimethoxyphenylboronic acid was used as a model substance to investigate the additive crystallization approach for polymorph control in phenylboronic acids. It was crystallized under different conditions by performing evaporation and cooling crystallization from different solvents. Most of the crystallizations from pure solvents produced the thermodynamically stable Form I, but in evaporation crystallization from alcohols, Form II or even a new polymorph, Form III, could be obtained. Structurally related substances, polymers, and surfactants with diverse intermolecular interaction possibilities were tested as additives. Surfactants were found to facilitate the crystallization of the metastable forms and therefore were investigated more extensively. The surfactants Span 20 and n–octyl-β-D-glucopyranoside provided crystallization of the metastable forms in the evaporation crystallization and notably stabilized Form II. The lattice energy, energy frameworks, Hirshfeld surface analysis, full interaction maps, and morphology prediction were used to identify the structural differences between Forms I and II and rationalize the ability of the additives to provide formation of Form II in the crystallization and to stabilize it.

Screening, packing systematics, Hansen solubility parameters and desolvation of resmetirom (MGL-3196) solvates

Resmetirom (MGL-3196) can form masses of solvates with a variety of solvents. In this study, a series of solvates, including those reported in patents and newly discovered solvates, were prepared by experimental screening. Hansen solubility parameters (HSPs) were used to investigate the formation rules of MGL-3196 solvates, and the results showed that the formation of MGL-3196 solvates was most related to the parameterΔδt. When the Δδt value between MGL-3196 and solvent was less than 14.23 MP0.5 a, MGL-3196 tended to form solvate with an accuracy of 84.09%. The precise crystal structures of six solvates and one solvent-free form (form A) were acquired by single crystal X-ray diffraction (SCXRD). After analyzing the structures of obtained solvates in-depth from the aspects of conformation, dimeric synthon, molecular packing, porosity and isostructuralism, the six solvates were classified into alcohol solvates (group 2), ester solvates (group 3) and other types of solvates (group 1). Generally, these three groups of solvates had completely different crystal structures. The solvates in group 1 and group 3 were channelized and isostructural in which solvents could be substituted without great influence on the structure, while in the alcohol solvates (group 2) solvents were fixed by strong hydrogen bonds to be a part of the crystal structure. Moreover, when solvates were desolvated, two metastable solvent-free forms (i.e., B and C) were crystallized and then transformed to form A through a structural rearrangement. The possible mechanisms for the phase transformation during different desolvation processes were finally proposed. All results shall provide an understanding and inspiration on the screening and production of polymorphic and pseudopolymorphic forms of MGL-3196 for the pharmaceutical industry.

Co‐Substituted BiFeO3: Electronic, Ferroelectric, and Thermodynamic Properties from First Principles

AbstractBismuth ferrite, BiFeO3, is a multiferroic solid that is attracting increasing attention as a potential photocatalytic material, because the ferroelectric polarization enhances the separation of photogenerated carriers. With the motivation of finding routes to engineer the band gap and the band alignment, while conserving or enhancing the ferroelectric properties, the thermodynamic, electronic, and ferroelectric properties of BiCoxFe1−xO3 solid solutions (x = 0, 0.0625, 0.125) using density functional theory are investigated. It is shown that the band gap can be reduced from 2.9 to 2.1 eV by cobalt substitution, while simultaneously increasing the spontaneous polarization, which is associated with a notably larger Born effective charge of Co compared to Fe cations. The interaction between Co impurities is discussed, which is strongly attractive and can drive the aggregation of Co, as evidenced by Monte Carlo simulations. Phase separation into a Co‐rich phase is therefore predicted to be thermodynamically preferred, and the homogenous solid solution can only exist in metastable form, protected by slow cation diffusion kinetics. Finally, the band alignment of pure and Co‐substituted BiFeO3 with relevant redox potentials, in the context of its applicability in photocatalysis, is discussed.

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.

Controlled crystallization of metastable polymorphic pharmaceutical: Comparative study of batchwise and continuous tubular crystallizers

The deliberate and reproducible crystallization of metastable polymorphs of active pharmaceutical ingredients (APIs) from solution remains difficult and is still far from trivial. The main challenge is to prevent cross nucleation of the stable form. The traditional cooling experiments in a batch crystallizer cannot repeatably produce aripiprazole (APZ) metastable Form III within selected initial concentrations and cooling rates. The computational fluid dynamics simulations confirmed that fluctuations in temperature and solution concentration in the batch crystallizer would induce the nucleation of stable crystal forms and accelerate solvent-mediated phase transformation. This work presents, for the first time, ultrasonic- and slug-assisted tubular crystallizers for the continuous and controllable preparation of pure metastable crystal Form III of APZ. The ultrasound-assisted air segmented plug flow tubular crystallizer provides an efficient configuration to produce high purity metastable polymorphism pharmaceuticals, which also offers a facile approach for the continuous manufacturing of drug substances.

Designer Gelators for the Crystallization of a Salt Active Pharmaceutical Ingredient-Mexiletine Hydrochloride.

We report an approach to obtain drug-mimetic supramolecular gelators, which are capable of stabilizing metastable polymorphs of the pharmaceutical salt mexiletine hydrochloride, a highly polymorphic antiarrhythmic drug. Solution-phase screening led to the discovery of two new solvated solid forms of mexiletine, a type C 1,2,4-trichlorobenzene tetarto-solvate and a type D nitrobenzene solvate. Various metastable forms were crystallized within the gels under conditions which would not have been possible in solution. Despite typically crystallizing concomitantly with form 1, a pure sample of form 3 was crystallized within a gel of ethyl methyl ketone. Various type A channel solvates were crystallized from gels of toluene and ethyl acetate, in which the contents of the channels varied from those of solution-phase forms. Most strikingly, the high-temperature-stable form 2 was crystallized from a gel in 1,2-dibromoethane: the only known route to access this form at room temperature. These results exemplify the powerful stabilizing effect of drug-mimetic supramolecular gels, which can be exploited in pharmaceutical polymorph screens to access highly metastable or difficult-to-nucleate solid forms.

Application of functionalized magnetic silica nanoparticles for selective induction of three coumarin metastable polymorphs

The precise control of active pharmaceutical ingredient (API) crystal nucleation and polymorphism is a key consideration in pharmaceutical manufacturing. In this study, tunable nanoparticles were developed to regulate the nucleation process of coumarin. Magnetic silica nanoparticles with four different functional groups (–NH 2 , –COOH, –SH, –NCO) were prepared and coated on the substrate for inducing the crystallization of coumarin. Confined melt crystallization and microspacing sublimation crystallization methods were used to investigate the regulation mechanism. The results indicated that three metastable forms of coumarin can be obtained as pure components based on the combined influence of crystallization methods and functionalized nanoparticles. Form II could be selectively obtained by microspacing sublimation crystallization on Fe 3 O 4 @SiO 2 –SH substrates, and Form IV could be obtained by confined melt crystallization on Fe 3 O 4 @SiO 2 –NCO substrates. Form III could be obtained by further heating Form IV crystals to 52 °C on Fe 3 O 4 @SiO 2 –NCO substrates. Moreover, the polarized light microscopy results also indicated that the introduction of nanoparticles could also increase the stability of the metastable crystalline forms of coumarin. Finally, the diffusion and surface dynamics during nanoparticle induced crystallization were comparatively investigated and the corresponding polymorphic selectivity mechanism was proposed.

Dissolution and Growth Kinetics and the Rate-Controlling Step in Transformation of Amorphous to Crystalline Phase Using Antisolvent Crystallization

The kinetics of the formation of amorphous disodium guanosine 5′-monophosphate and its transformation to the heptahydrate phase were studied under various operating conditions using in situ Raman and focused beam reflectance measurement (FBRM). Supersaturation, solvent composition, feed concentration, addition rate, and viscosity were shown to affect the rate-determining steps of the transformation. The rate-controlling mechanisms in the overall kinetics have been confirmed. The observation of the slurry viscosity of the suspension of the amorphous phase shows the option to observe the phase transformation. The transformation process was affected by the dissolution, growth, and supersaturation in which the rate-controlling step was divided into two sections, such as the initial and later sections of the transformation. The overall rate constants were determined by combining the constants of the dissolution rate and the growth rates of each section. In situ Raman spectroscopy examination of the concentration of solution and solids can determine the rate-limiting processes during the transformation. The zero-order, first-order, and surface reaction equations as kinetic equations are highlighted and compared for the dissolution of the amorphous solids and the growth of the heptahydrate crystals. The dissolution of the amorphous (metastable form) and the growth of the heptahydrate (stable form) were found to be best fitted to the zero-order kinetic model. In particular, the variation of particle size distribution over time can give the rate-determining steps. These results suggest that the data measured by Raman spectroscopy and FBRM can be successfully coupled into a dissolution and growth model to further grasp and interpret the phase transformation. A dissolution rate-controlling step was dominated by a pattern in which both supersaturation and amorphous dissolution decreased simultaneously, and the growth rate-controlling step was shown in a pattern in which either supersaturation or amorphous dissolution was constant. Furthermore, the growth of heptahydrate crystals at a viscosity of the suspension with the amorphous solids below 70 cp and the dissolution of the amorphous solids above it can be used as the key determinant. Using the method developed and the kinetic constants obtained in this work, it is possible to create an appropriate control strategy to produce the desired form in the final product.

Quantitative Monitoring of Cocrystal Polymorphisms in Model Tablets Using Transmission Low-Frequency Raman Spectroscopy

Cocrystallization is a technique for improving the physical properties of active pharmaceutical ingredients. However, cocrystals can transform into more stable polymorphs as well as dissociate to original materials. Therefore, an analytical technique is required to determine the polymorphic transformation quickly and accurately in tablets. The purpose of this study is to develop a method to monitor cocrystal polymorphs in model tablets using transmission low-frequency Raman spectroscopy. The tablets, consisting of only metastable polymorphs of caffeine-glutaric acid cocrystals, were stored under various relative humidity levels. The composition of the cocrystal polymorphs were calculated from a calibration curve relating the actual composition to the predicted values calculated by partial least squares regression processing of low-frequency Raman spectra. The metastable form gradually converted to a stable form, and polymorphic phase transformation occurred with increasing relative humidity. Ninety-six percent of the metastable form converted into a stable form stored at 25 °C after 3 h at 95% RH. In conclusion, transmission low-frequency Raman spectroscopy can be used to quantitatively monitor cocrystal polymorphs. This technique is one of the candidate techniques to quantifiably evaluate the physico-chemical stability of cocrystal polymorphs in tablets.

Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation.

Long-acting injectables are a unique drug formulation strategy, providing a slow and sustained release of active pharmaceutical ingredients (APIs). In this study, a novel approach that combines liquid antisolvent precipitation with seeding to obtain a stable form of the API indomethacin while achieving the desired particle size distribution is described. It was proven that when a metastable form of indomethacin was initially nucleated, the rate of its transformation to the stable form was influenced by the presence of excipients and seeds (17.10 ± 0.20 μm), decreasing from 48 to 4 h. The final particle size (D50) of the indomethacin suspension produced without seeding was 7.33 ± 0.38 μm, and with seeding, it was 5.61 ± 0.14 μm. Additionally, it was shown that the particle size distribution of the seeds and the time point of seed addition were critical to obtain the desired solid-state form and that excipients played a crucial role during nucleation and polymorphic transformation. This alternative, energy-efficient bottom-up method for the production of drug suspensions with a reduced risk of contamination from milling equipment and fewer processing steps may prove to be comparable in terms of stability and particle size distribution to current industrially accepted top-down approaches.

SARS-CoV-2 prefusion spike protein stabilized by six rather than two prolines is more potent for inducing antibodies that neutralize viral variants of concern

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main target for neutralizing antibodies (NAbs). The S protein trimer is anchored in the virion membrane in its prefusion (preS) but metastable form. The preS protein has been stabilized by introducing two or six proline substitutions, to generate stabilized, soluble 2P or HexaPro (6P) preS proteins. Currently, it is not known which form is the most immunogenic. Here, we generated recombinant vesicular stomatitis virus (rVSV) expressing preS-2P, preS-HexaPro, and native full-length S, and compared their immunogenicity in mice and hamsters. The rVSV-preS-HexaPro produced and secreted significantly more preS protein compared to rVSV-preS-2P. Importantly, rVSV-preS-HexaPro triggered significantly more preS-specific serum IgG antibody than rVSV-preS-2P in both mice and hamsters. Antibodies induced by preS-HexaPro neutralized the B.1.1.7, B.1.351, P.1, B.1.427, and B.1.617.2 variants approximately two to four times better than those induced by preS-2P. Furthermore, preS-HexaPro induced a more robust Th1-biased cellular immune response than preS-2P. A single dose (104 pfu) immunization with rVSV-preS-HexaPro and rVSV-preS-2P provided complete protection against challenge with mouse-adapted SARS-CoV-2 and B.1.617.2 variant, whereas rVSV-S only conferred partial protection. When the immunization dose was lowered to 103 pfu, rVSV-preS-HexaPro induced two- to sixfold higher antibody responses than rVSV-preS-2P in hamsters. In addition, rVSV-preS-HexaPro conferred 70% protection against lung infection whereas only 30% protection was observed in the rVSV-preS-2P. Collectively, our data demonstrate that both preS-2P and preS-HexaPro are highly efficacious but preS-HexaPro is more immunogenic and protective, highlighting the advantages of using preS-HexaPro in the next generation of SARS-CoV-2 vaccines.

On a molecular origin of properties of water

Using the Reference-Average-Mayer perturbation theory, effective temperature-dependent site-site potentials are constructed from a realistic water model to provide a missing direct link between complex force fields (intermolecular interaction models) and artificial simple theoretical models used to explain properties of supercooled water. It is shown, using the TIP4P interaction model, that the effective site-site interactions change qualitatively their character with changes of thermodynamic conditions and assume, at low temperatures, the form of a double well which gives rise to the existence of two metastable forms of supercooled water. Since the theory possesses capacity to provide the site-site correlation functions even in an analytic form it may form a basis for developing a molecular-based equation of state of water.

Controlling the Polymorphic Outcome of 2,6-Dimethoxybenzoic Acid Crystallization Using Additives

In this study, 2,6-dimethoxybenzoic acid (2,6MeOBA) was used as a model substance to investigate the use of additives to control the polymorphic outcome of crystallization. 2,6MeOBA exists as three polymorphs. Two of the 2,6MeOBA polymorphs, I and III, obtained in most of the crystallization experiments, were characterized by thermal analysis, and their relative thermodynamic stability was determined. Forms I and III are enantiotropically related, where form III is the high-temperature form. Pure form II was very difficult to obtain. Crystallization of 2,6MeOBA was explored under different conditions by performing evaporation and cooling crystallization from different solvents. Surfactants, polymers, and different molecular compounds with diverse possibilities for the formation of intermolecular interactions were tested as additives. The additives facilitating the crystallization of the metastable forms were additionally studied under different crystallization conditions. The effect of additives polyethylene glycol (PEG) and hydroxypropyl cellulose (HPC) on the thermodynamic stability and solvent-mediated phase transition (SMPT) kinetics was evaluated. HPC and PEG showed the potential to favor the formation of form III in crystallization from water.

The polymorph and crystal habit control of dl-methionine assisted by ultrasound

In this work, ultrasound was applied to the batch crystallization of dl-methionine, dedicated to developing the strategy to achieve pure metastable form, regular crystal habit, and high yields of dl-methionine. Experimental analyses for batch crystallization were performed to investigate the effects of ultrasound field, supersaturation, and temperature on dl-methionine crystal form. It was found that ultrasound was more conducive to the formation of dl-methionine metastable crystals by promoting nucleation. Moreover, the artificial neural network was used to predict crystal form according to the input of experimental samples. Based on the goal of crystal habit optimization, experiments were designed to find the key factors to control product quality, and the experimental results correspond to the prediction results. It was found that ultrasound could result in high bulk density of the product due to the optimization of crystal habit and crystal size distribution, and the mechanism of ultrasound on crystal habit and yield was investigated. This study provided a deeper insight into the mechanisms of ultrasound on nucleation and crystal growth, which could also be used as an effective strategy to improve the physicochemical properties of a product by applying ultrasound to achieve simultaneous multi-objective optimization.

Continuous crystallisation of organic salt polymorphs

Organic salt crystallisation is of great importance to the pharmaceutical industry as many pharmaceutical products are marketed as salts with salt formation being an essential step in drug development. The model compound used in this work is the polymorphic organic salt ethylenediammonium 3,5-dinitrobenzoate (EDNB) which is the 2:1 salt of 3,5-dinitrobenzoic acid with ethylenediamine. Crystallisation of the two EDNB polymorphs, the stable monoclinic form and the metastable triclinic form, was performed in both semi-batch and continuous processes using continuous mixing approaches. It was demonstrated that continuous mixing approaches, using various types of continuous mixers (co-axial, Ehrfeld, X-mixer) can be used to crystallise the EDNB salt with consistent yield and particle size distribution while achieving control over polymorphic form. The experiments were designed with use of a solution speciation model which provided process understanding and insight to guide development of salt crystallisation processes.

Metastable Crystallization by Drop Impact

It has been reported that cavitation bubbles (air–liquid interface) by femtosecond laser and ultrasonic irradiations are effective for metastable phase crystallization in polymorph control. It has also been noted that cavitation bubbles are generated by mechanical shock when dropping a vial. Here we describe the crystallization of acetaminophen by drop impact. In the condition where spontaneous nucleation did not occur, the drop impact produced the metastable form (form II) and trihydrate. This supports the potency of the air–liquid interface in metastable phase formation. Furthermore, crystallization by drop impact is a completely new phenomenon, and new developments are expected in the future.