Stable Polymorph Research Articles

Theoretical Prediction and Experimental Evaluation of Topological Landscape and Thermodynamic Stability of a Fluorinated Zeolitic Imidazolate Framework

The prediction of topological preferences and polymorph stability remains a challenge for the design of metal–organic frameworks exhibiting a rich topological landscape, such as zeolitic imidazolat...

Multiscale Experimental Study and Modeling of l-Glutamic acid Crystallization: Emphasis on a Kinetic Explanation of the Ostwald Rule of Stages

This work presents an experimental and a numerical study to highlight a kinetic explanation to of the Ostwald rule of stages (ORS). To demonstrate this explanation, L-glutamic acid (LGlu) (a monotropic system with two polymorphs) were crystallized in three different scales: Liter scale in a 2L stirred crystallizer, milliliter scale in a 4ml stagnant cell and microliter scale in microfluidic channels. Cooling crystallization experiments were performed in water at different temperature and supersaturation conditions. The LGlu polymorphic system was found to follow the ORS at low temperature (between 5°C and 30°C). However, in similar operating conditions, the stable polymorph crystallized preferentially or exclusively in the stagnant cell and in microfluidics. To explain the ORS in the stirred crystallizer at low temperature, a model based on the kinetic equation was used. By taking into account the Gibbs Thomson effect (Solubility variation with size), the simulations in the nanoscopic scale showed the dissolution of the slow-growing stable phase nuclei in favor of the fast-growing metastable phase nuclei. Consequently, the numerical results showed that the Gibbs Thomson effect is a key factor in polymorph competition and that considering this effect, in certain kinetic and equilibrium conditions, could allow explaining and simulating the ORS.

Solid Forms of Ciprofloxacin Salicylate: Polymorphism, Formation Pathways, and Thermodynamic Stability

The crystallization of ciprofloxacin—an antibacterial fluoroquinolone compound—with salicylic acid resulted in the isolation of five distinct solid forms of the drug, namely, an anhydrous salt, two...

Supramolecular Polymorphism in One-Dimensional Self-Assembly by Kinetic Pathway Control.

Controlling polymorphism in molecular solids is of great interest since the properties and performances of molecular materials depend on the molecules' mutual packing arrangements. Herein, we describe a perylene bisimide (PBI) organogelator molecule PBI-4 that self-assembles into three different one-dimensional supramolecular polymorphs (Agg 1-3) in the same solvent and at the same concentration at room temperature. The three supramolecular polymorphs were characterized by UV/vis, CD, fluorescence and IR spectroscopy, atomic force microscopy (AFM), and theoretical calculations, revealing that their packing arrangements are governed by distinct π-π-stacking modes and unique hydrogen-bonding patterns. Nudged elastic band (NEB) calculations for the nucleation processes toward Agg 2 and Agg 3 indicate that nucleation starts from a central kinetically trapped state Agg 1 and involves the reorganization of Agg 1 dimers. Time-, concentration-, and temperature-dependent UV/vis experiments provided insights into the thermodynamic stability of the supramolecular polymorphs of PBI-4 and the kinetics for their interconversion. On the basis of this information the production of a certain polymorph could be accomplished either physically by ultrasonication or chemically by seeding. This work contributes to the understanding of polymorphism at the lowest level of hierarchy that is the generation of self-assembled 1D aggregate structures.

Control of the formation and luminescent properties of polymorphic erbium silicates on silicon

We report on the control of the formation and the luminescent properties of polymorphic forms of erbium (Er) silicates by the modification of annealing temperatures, annealing atmospheres and chemical compositions. Four Er silicate polymorphs, X1-Er2SiO5, y-Er­2Si2O7, α-Er2Si2O7 and β-Er2Si2O7, are fabricated in Er-doped SiO2 films. Higher annealing temperatures turn the Er silicates into more stable polymorphs, but the annealing in O2 and the deviation of chemical compositions from the stoichiometry of Er silicates will restrain this process. The luminescent properties of these polymorphs are quite different due to their strong correlation with the crystallographic structures. Photoluminescence spectra with the main peaks at 1530 nm, 1536 nm, 1529 nm, and 1539 nm are obtained for X1-Er2SiO5, y-Er­2Si2O7, α-Er2Si2O7 and β-Er2Si2O7, respectively, and the highest photoluminescence efficiency is associated to Er ions in y-Er2Si2O7.

Thermodynamic stability and pressure dependence of FePO4 polymorphs

Olivine LiFePO4 is a promising cathode material for lithium ion batteries. Its delithiated form FePO4 has attracted interest as potential cathode for rechargeable lithium ion batteries due to high charge/discharge capacity and low cost. This paper report pressure dependence DFT + U calculations and stability of FePO4 polymorphs. The heats of formation predict that berlinite polymorph is thermodynamically stable up to 4 GPa, while HP phase reaches a transition above 4 GPa at 0 K. The energy band gap is relatively wide, suggesting that FePO4 polymorphs are low in electronic conductivity. However, conductivity is expected to improve at high pressure (4 to 7.5 GPa). All independent elastic constants are positive corresponding to stability of FePO4 polymorphs, except for berlinite. Its phonon dispersion curves display negative vibrations along high symmetry direction (condition of instability) at 0 GPa. However, at pressure above 7 GPa, the berlinite becomes stable due to absence of soft modes.

Control of Pharmaceutical Cocrystal Polymorphism on Various Scales by Mechanochemistry: Transfer from the Laboratory Batch to the Large-Scale Extrusion Processing

We demonstrate a controllable mechanochem. synthesis of cocrystal polymorphs of ascorbic acid (vitamin C) and nicotinamide (vitamin B3) on different scales and without using bulk solvents. Next to the previously described polymorph of the 1:1 cocrystal, which is one of the first cocrystals approved for human consumption, we report here a new, thermodynamically more stable polymorph detected during in situ synchrotron powder X-​ray diffraction monitoring of milling reactions. The new polymorph is currently available exclusively by mechanochem. synthesis, and its crystal structure was detd. from synchrotron powder X-​ray diffraction data. Lab. in situ monitoring by Raman spectroscopy provided direct insight into the cocrystals formation and was further used to optimize the manufg. procedure. Subgram synthesis using a lab. mixer mill was transferred to the 10 g scale on a planetary ball mill and continuous manufg. using a twin-​screw extruder. Both cocrystal polymorphs perform excellently in tableting, thus alleviating the notoriously poor compactible properties of vitamin C, while the mechanochem. cocrystn. does not harm its antioxidant properties.

Flexible and Transferable ab Initio Force Field for Zeolitic Imidazolate Frameworks: ZIF-FF.

We have developed a transferable ab initio intramolecular force field for zeolitic imidazolate frameworks (ZIFs), "ZIF-FF", that is capable of quantitatively describing the structural properties and relative stabilities of ZIFs. In contrast to nearly all prior force fields, ZIF-FF properly describes the relative stability of ZIF polymorphs, a crucial element in ZIF nucleation and crystal growth. Beginning with a general Amber force field (GAFF), Zn-related force field parameters were optimized against dispersion-corrected DFT-calculated properties using a genetic algorithm. We validated the resulting force field by examining bond and angle distributions, phonon density of states, mechanical properties, diffusion properties and via modeling a ZIF amorphization process. Furthermore, we find that ZIF-FF is transferable, successfully describing relative stability of various ZIF surface structures, as well as the densities of ZIFs with diverse functionalized linkers.

Polymorph Selection by Continuous Crystallization in the Presence of Wet Milling

The polymorph selection in a continuous crystallization process combined with wet milling is investigated. To this end, a dimensionless population balance equation model accounting for secondary nucleation, crystal growth, and breakage is formulated and solved numerically. We show that a surprisingly small number of dimensionless parameter groups (combinations of kinetic parameters and operating conditions) is decisive in controlling the polymorphic outcome. Specifically, we show how the operating region where the stable polymorph is obtained can be enlarged by tuning the milling intensity, feed concentration, and residence time. We further rationalize the dependence of the mean size of the particles obtained, the fraction of solute recovered, and the productivity of such a process on the dimensionless variables. We showcase this for the model system l-glutamic acid crystallized from water and show that our analysis is in agreement with previously reported experimental studies. Summarizing, the analysis a...

Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026

Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed.

Kinetics of the γ-δ phase transition in energetic nitramine-octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine.

The solid, secondary explosive nitramine-octahydro-1,3,5,7-tetranitro-1,3,5,7 or HMX has four different stable polymorphs which have different molecular conformations, crystalline structures, and densities, making structural phase transitions between these nontrivial. Previous studies of the kinetics of the β-δ HMX structural transition found this to happen by a nucleation and growth mechanism, where growth was governed by the heat of fusion, or melting, even though the phase transition temperature is more than 100 K below the melting point. A theory known as virtual melting could easily justify this since the large volume difference in the two phases creates a strain at their interface that can lower the melting point to the phase transition temperature through a relaxation of the elastic energy. To learn more about structural phase transitions in organic crystalline solids and virtual melting, here we use time-resolved X-ray diffraction to study another structural phase transition in HMX, γ-δ. Again, second order kinetics are observed which fit to the same nucleation and growth model associated with growth by melting even though the volume change in this transition is too small to lower the melting point by interfacial strain. To account for this, we present a more general model illustrating that melting over a very thin layer at the interface between the two phases reduces the total interfacial energy and is therefore thermodynamically favorable and can drive the structural phase transition in the absence of large volume changes. Our work supports the idea that virtual melting may be a more generally applicable mechanism for structural phase transitions in organic crystalline solids.

Characterization and Kinetic Studies of the Thermal Degradation of Mebendazole Polymorphs A and C

Mebendazole is an anthelmintic drug of low solubility, which exhibits three polymorphic forms (A, B, and C) with different thermodynamic stability (A > C > B). Form C is the most appropriate for pharmaceutical development due to its adequate bioavailability and lower toxicity. This form is stable between room temperature ± 180 °C. The aim of this work was to characterize and study the thermal degradation kinetics of Mebendazole polymorphs A and C by isothermal and non-isothermal (Ozawa method) thermogravimetric methods. Thermogravimetry (TG), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR), and elementary analysis (EA) were used to identify Mebendazole polymorphs A and C. Isothermal and non-isothermal thermogravimetric methods were used to study the thermal degradation kinetics of Mebendazole polymorphs. The results showed that form C converts to the polymorphic form A after heating at 200 °C, exhibiting both exothermic and endothermic events before the first mass loss. Subsequent to this transformation, CO2 was released and the formation of a solid product occurred, which was characterized by EA and FTIR. These results suggested the presence of a Mebendazole impurity. The degradation kinetics studies of polymorphs A and C obtained by both methods indicated activation energy (Ea) values greater for polymorph C. In fact, part of the energy provided to the polymorph C was used for the transformation to polymorph A, which explains its greater thermal stability. This indicates that polymorph C is very stable under ambient conditions, but at high temperatures (above 180 °C) the stability of polymorph A predominates.

Inverse Correlation between Lethality and Thermodynamic Stability of Contact Insecticide Polymorphs

Contact insecticides often involve the interaction of whole organisms and toxicant crystal surfaces. The crystalline phase of these compounds has not, however, been considered for the optimization of insecticide performance. Lindane (1R,2r,3S,4R,5r,6S-hexachlorocyclohexane) has been one of the most widely used insecticides, but other (inactive) stereoisomers accompanying its manufacture have led to massive chemical waste remediation problems. Crystalline polymorphs are also isomers in the broadest sense, yet only one crystal structure of lindane has been reported. Herein, we report the discovery and characterization of two new polymorphs, Forms II and III. The efficacy of Forms I, II, and III against Drosophila melanogaster revealed an inverse correlation between lethality and thermodynamic stability; the least stable kills fastest. This understanding provides a crystal engineering opportunity wherein formulations containing the most active contact insecticide polymorph can achieve infectious disease prop...

Polymorph Selection and Process Intensification in a Continuous Crystallization–Milling Process: A Case Study on l-Glutamic Acid Crystallized from Water

The continuous crystallization of l-glutamic acid from water in a single-stage mixed-suspension mixed-product-removal crystallizer coupled to a milling loop is studied. We show that the stable β polymorph can be obtained in the presence of milling under operating conditions that would lead to the metastable α polymorph without milling. The effect is first shown through a series of experiments carried out at different residence times and feed concentrations in the absence or presence of milling. The experimental observations are rationalized through the use of a population balance equation model. We conclude that the observed effects result from fines generation and the corresponding increase in crystal surface area. Using the model, we obtain a map of polymorphic outcomes and process productivity in dependence on the operating conditions. It is shown that the combined crystallization–milling process exhibits higher productivity and an enlarged region of operating conditions where the stable polymorph of l...

New Crystal Forms for Biologically Active Compounds. Part 1: Noncovalent Interactions in Adducts of Nevirapine with XB Donors

Stabilization of specific crystal polymorphs of an active pharmaceutical ingredient is crucial for preventing uncontrollable interconversion of various crystalline forms, which affects physicochemical properties as well as physiological activity. Co-crystallization with various excipients is an emerging productive way of achieving such stabilization in the solid state. In this work, we identified an opportunity for co-crystallization of antiviral drug nevirapine (NVP) with a classical XB donor, 1,2,4,5-tetrafluoro-3,6-diiodobenzene (1,4-FIB), as well as 1,3-diiodobenzene (1,3-DIB), which has been seldom employed as an XB donor to date. In the X-ray structures of NVP·1,4-FIB and NVP·1,3-DIB co-crystals, different hydrogen and halogen bonding modes were detected and further investigated via DFT calculations as well as topological analysis of the electron density distribution within the framework of the QTAIM method at the M06/DZP-DKH level of theory. Estimated energies of these supramolecular contacts vary from 0.6 to 5.7 kcal/mol.

Simple and Efficient Spherical Crystallization of Clopidogrel Bisulfate Form-I via Anti-Solvent Crystallization Method

Clopidogrel bisulfate (CLP) form-I crystals are irregular, rectangular-shaped crystals. Because of their poor compressibility, flowability and their strong surface tension, manufacturers apply spherical crystallization methods to produce CLP form-I spherical agglomerates with a uniform particle size distribution. Consequently, manufacturers primarily synthesize CLP form-I crystal salts utilizing very complex methods, which produces form-I spherical agglomerates by means of spherical crystallization. In this study, spherical crystals of CLP Form-I were directly prepared from CLP Form-II, the most stable polymorph at room temperature, by using ethanol as solvent and a mixture of isopropyl alcohol (IPA)/n-Hexane (Hex) as an anti-solvent. To provide systematic inputs for the development of spherical agglomerates of optimal morphology, size, particle size distribution (PSD), and polymorphic form, processing parameters such as anti-solvent type, a mixture of IPA/Hex, pure Hex, or pure acetone; stirring speeds of 500, 600, 700, or 800 rpm; and temperatures ranging from 25 to 40 °C were explored. The effects of these parameters on spherical crystallization and polymorphic form were studied in terms of supersaturation, a driving force for polymorphic transformation, and the crystallization solution. Notably, our method does not require a large volume of anti-solvent which is the main complication of conventional anti-solvent crystallization methods.

Detonation Velocity Measurement of a Hydrogen Peroxide Solvate of CL‐20

AbstractSynthesis and development of new energetic molecules is a resource‐intensive process, yielding materials with relatively unpredictable performance properties. Cocrystallization and crystalline solvate formation have been explored as possible routes towards developing new energetic materials that reduce the initial investment required for discovery and performance uncertainty because existing energetic molecules with known properties serve as the constituents. The formation of a hydrogen peroxide (HP) solvate of CL‐20 was previously reported and has a density comparable to that of ϵ‐CL‐20, the densest and most stable polymorph of CL‐20. CL‐20/HP produces a second crystalline form, which was unexpected given the high density of the original CL‐20/HP solvate. Both forms were predicted to have improved detonation performance relative to that of ϵ‐CL‐20. In this work, the detonation velocity of a solvate of CL‐20/HP is measured and compared to that of CL‐20. Using the measured enthalpy of formation, the solvate was predicted to detonate 80 m s−1 faster at a powder density of 1.4 g cm−3; however, experimentally, the solvate detonates 300 m s−1 faster than CL‐20. Thermochemical predictions are also used to show that the solvate detonates 100 m s−1 faster than ϵ‐CL‐20 at the theoretical maximum density, making it the first energetic cocrystal or solvate of ϵ‐CL‐20 predicted to detonate faster than CL‐20 at full density.

Selective Formation of Yttrium Manganese Oxides through Kinetically Competent Assisted Metathesis Reactions.

The synthesis of complex oxides requires high temperatures to overcome barriers imparted by solid-state diffusion; as such, reactions typically yield the most stable polymorph for a given composition. To synthesize new or metastable complex oxides, kinetically competent reactions with lower initial energy barriers must be devised to control the reaction pathway and resulting products. This contribution details the selective synthesis of different yttrium manganese oxides through assisted metathesis reactions between Mn2O3, YCl3, and A2CO3 under flowing oxygen; where A = Li, Na, K. With lithium carbonate, the orthorhombic perovskite o-YMnO3 (o-YMnO3+δ) forms over the temperature range of 550-850 °C. With sodium carbonate, the pyrochlore Y2Mn2O7 forms at 650 °C. No apparent selectivity is observed with K2CO3, and all alkalis yields hexagonal YMnO3 at T > 950 °C. The alkali species modify the reaction pathway and thus impart kinetic control in the formation of both phases.

Challenges in the use of atomistic simulations to predict solubilities of drug-like molecules.

Background:Solubility is a physical property of high importance to the pharmaceutical industry, the prediction of which for potential drugs has so far been a hard task.We attempted to predict the solubility of acetylsalicylic acid (ASA) by estimating the absolute chemical potentials of its most stable polymorph and of solutions with different concentrations of the drug molecule. Methods:Chemical potentials were estimated from all-atom molecular dynamics simulations. We used the Einstein molecule method (EMM) to predict the absolute chemical potential of the solid and solvation free energy calculations to predict the excess chemical potentials of the liquid-phase systems. Results:Reliable estimations of the chemical potentials for the solid and for a single ASA molecule using the EMM required an extremely large number of intermediate states for the free energy calculations, meaning that the calculations were extremely demanding computationally.Despite the computational cost, however, the computed value did not agree well with the experimental value, potentially due to limitations with the underlying energy model.Perhaps better values could be obtained with a better energy model; however, it seems likely computational cost may remain a limiting factor for use of this particular approach to solubility estimation. Conclusions:Solubility prediction of drug-like solids remains computationally challenging, and it appears that both the underlying energy model and the computational approach applied may need improvement before the approach is suitable for routine use.

Tuning crystallization and stability of the metastable polymorph of dl-methionine by a structurally similar additive

Polymorph formation, transformation and crystal morphology were simultaneously tuned through a tailor-made additive via theoretical simulations combined with experimental methods.