Monotropic Polymorphs Research Articles

Polymorphic phase transitions in triglycerides and their mixtures studied by SAXS/WAXS techniques: In bulk and in emulsions

Triacylglycerols (TAGs) exhibit a monotropic polymorphism, forming three main polymorphic forms upon crystallization: α, β’ and β. The distinct physicochemical properties of these polymorphs, such as melting temperature, subcell lattice structure, mass density, etc., significantly impact the appearance, texture, and long-term stability of a wide range products in the food and cosmetics industries. Additionally, TAGs are also of special interest in the field of controlled drug delivery and sustained release in pharmaceuticals, being a key material in the preparation of solid lipid nanoparticles. The present article outlines our current understanding of TAG phase behavior in both bulk and emulsified systems. While our primary focus are investigations involving monoacid TAGs and their mixtures, we also include illustrative examples with natural TAG oils, highlighting the knowledge transfer from simple to intricate systems. Special attention is given to recent discoveries via X-ray scattering techniques. The main factors influencing TAG polymorphism are discussed, revealing that a higher occurrence of structural defects in the TAG structure always accelerates the rate of the α → β polymorphic transformation. Diverse approaches can be employed based on the specific system: incorporating foreign molecules or solid particles into bulk TAGs, reducing drop size in dispersed systems, or using surfactants that remain fluid during TAG particle crystallization, ensuring the necessary molecular mobility for the polymorphic transformation. Furthermore, we showcase the role of TAG polymorphism on a recently discovered phenomenon: the creation of nanoparticles as small as 20 nm from initial coarse emulsions without any mechanical energy input. This analysis underscores how the broader understanding of the TAG polymorphism can be effectively applied to comprehend and control previously unexplored processes of notable practical importance.

Structural Origin of Anisotropic Thermal Expansion of Molecular Crystals and Implication for the Density Rule Probed with Four ROY Polymorphs

The objective of this work was to investigate the molecular origin of the differences in the thermal expansivity of four ROY polymorphs (Y, R, OP, and ON) using variable temperature single crystal X-ray diffractometry (VT-SCXRD). Thermal expansivity was found to be directly influenced by the crystal packing and the number and type of directional interactions, such as hydrogen bonds, involved in packing. Polymorphs with layered molecular packing, i.e., ON, OP, and R, show higher volume expansivity, where the axial component of the expansion is the largest in the directions perpendicular to the hydrogen-bonded layers and the smallest along the layers. Polymorph Y shows the least volume expansivity, which corresponds to the presence of a denser hydrogen-bonded network structure in the crystal, and absence of apparent molecular layers. The largest overall expansivity is observed for polymorph ON that lacks intermolecular hydrogen bonds and exhibits a layered packing pattern along two axes. The differences in the thermal expansivity of the ROY polymorphs lead to violations of the density rule in polymorph stability prediction due to crossover in crystal density with change in temperature, which means the rank order of crystal density of polymorphs is temperature-dependent. Thus, at absolute zero, the most thermodynamically stable polymorph Y is predicted to not have the highest density, which violates the density rule. Likewise, for all enantiotropic polymorphs undergoing the density crossover phenomenon, the density rule is valid only within the temperature range bracketed by the temperatures of density crossover (Td) and thermodynamic transition (Tt). For all monotropic polymorphs, the density rule is valid only above Td.

Solid solution polymorphs afford two highly soluble co-drug forms of tolbutamide and chlorpropamide.

The search for solid solutions of class-two insulin secretagogues, tolbutamide and chlorpropamide, reveals a rare case of monotropic polymorphism for the mixed crystals. At any stoichiometry, two crystal forms are isolated that are kinetically stable at room temperature from a few months to over a year. Dissolution tests certify the solubility advantage of the solid solutions over the pure drugs as well as their physical mixture, suggesting a potential application as a highly soluble co-drug formulation.

Thermodynamics of polymorphism in a bulk metallic glass: Heat capacity measurements by fast differential scanning calorimetry

The Au-based bulk metallic glass-forming alloy Au70Cu5.5Ag7.5Si17 is the first atomic system in which monotropic polymorphism has been experimentally found. In this study, strategies for measuring thermodynamic quantities such as heat capacity, transformation enthalpy and entropy, and Gibbs free energy for stable and metastable phases are evaluated based on this system. The transformation enthalpies between phases are determined via differential scanning calorimetry (DSC); the corresponding heat capacities are measured via stochastic temperature-modulated DSC (TOPEM); and the equilibrium melting temperatures of metastable phases, only detectable at high rates, are determined via fast DSC (FDSC). Whereas the slow heating rate of conventional DSC limits the characterization of metastable phases, the combination of both DSC and FDSC allows for their detailed heat-capacity determination. Furthermore, various approximation functions that have previously been used to determine the temperature dependence of the thermodynamic driving force for nucleation and crystallization are compared with the experimental data.

Monotropic polymorphism in a glass-forming metallic alloy

This study investigates the crystallization and phase transition behavior of the amorphous metallic alloy Au70Cu5.5Ag7.5Si17. This alloy has been recently shown to exhibit a transition of a metastable to a more stable crystalline state, occurring via metastable melting under strong non-equilibrium conditions. Such behavior had so far not been observed in other metallic alloys. In this investigation fast differential scanning calorimetry (FDSC) is used to explore crystallization and the solid–liquid–solid transition upon linear heating and during isothermal annealing, as a function of the conditions under which the metastable phase is formed. It is shown that the occurrence of the solid–liquid–solid transformation in FDSC depends on the initial conditions; this is explained by a history-dependent nucleation of the stable crystalline phase. The microstructure was investigated by scanning and transmission electron microscopy and x-ray diffraction. Chemical mapping was performed by energy dispersive x-ray spectrometry. The relationship between the microstructure and the phase transitions observed in FSDC is discussed with respect to the possible kinetic paths of the solid–liquid–solid transition, which is a typical phenomenon in monotropic polymorphism.

Modeling the Competition between Polymorphic Phases: Highlights on the Effect of Ostwald Ripening

This work aims to evaluate the effect of Ostwald ripening on the crystallization of polymorphic phases by means of the kinetic equation model, which was adapted to describe the competition between the nucleation, the growth, and the Ostwald ripening of the different phases. The kinetic equation model is a very convenient way to simultaneously implement these three mechanisms and quantify their respective roles on the formation and the dissolution of the clusters. The polymorphic system studied is l-glutamic acid (LGlu), which exhibits two monotropic polymorphs: α LGlu and β LGlu. The model assumptions consider the main differences between both polymorphs (shape, solubility, interfacial energy, and growth rate) as well as the supersaturation decrease. The simulation results at various temperatures show that the crystallization process of small nuclei (<40 nm) can be greatly affected by the Ostwald ripening mechanism. In particular, Ostwald ripening can induce the total dissolution of the stable phase clust...

Phase transitions in secnidazole: Thermal stability and polymorphism studied by X-ray powder diffraction, thermal analysis and vibrational spectroscopy

Secnidazole is an old drug efficient as an antimicrobial agent used against some anaerobic bacteria and parasites, such as giardia, ameba and trichomonas that are causing some neglected diseases. This drug is commercialized as a hemihydrate, being stable at room temperature, but showing relevant phase transitions on heating. The understanding of the dehydration process on solvates provides valuable information for quality control and development of solid formulations. In order to study the thermal behavior of secnidazole, Raman spectroscopy, X-ray powder diffraction, hot-stage microscopy and thermal analysis were employed to verify the structural modifications involved with this drug. Raman spectroscopy was a key technique to monitor the dehydration process in situ, providing the spectral fingerprints for identifying the anhydrous form. In addition, the reported results suggest the existence of two anhydrous monotropic polymorphs.

New Advances in the One-Dimensional Coordination Polymer Copper(II) Alkanoates Series: Monotropic Polymorphism and Mesomorphism

The polymorphism in the copper(II) alkanoates, recently discovered for one member, has been thoroughly studied for the whole series, from 3 to 16 C atoms. Three polymorphic phases have been found, all of them sharing the same molecular unit, the paddle-wheel, which grows forming a 1D coordination polymer or catena. The three polymorphs are defined by a different packing of these catenae and a specific arrangement of the alkyl chains. Ten new crystal structures of those compounds have been solved by high resolution powder diffraction and presented in this paper. The polymorphism in this series has been found to be monotropic and is responsible for the complex thermal behavior observed. The most characteristic feature, the endothermic–exothermic effect, has been explained for the first time in these compounds by a combination of data from differential scanning calorimetry (in normal and modulated modes), powder X-ray diffraction and Fourier transform infrared spectroscopy. These techniques, together with small-angle X-ray scattering and optical microscopy, were used to analyze the hexagonal columnar discotic liquid crystal phase of copper(II) alkanoates. Thus, new information has been found in the packing and stacking of the discs formed by the paddle-wheel units, also maintained in the mesophase.

Crystallization from the Amorphous State: Nucleation–Growth Decoupling, Polymorphism Interplay, and the Role of Interfaces

The physical stability of the amorphous state is governed by crystallization, which results from the complex interplay of nucleation and growth processes. These processes can be further complicated by the preferred initial nucleation of less-stable phases, and interpretation requires the evaluation of the relative roles of structure, dynamics, and thermodynamics on the kinetics of the recrystallization. As a contribution to this issue, we reanalyze data sets concerning recrystallization of two pharmaceutical compounds: L-arabitol and RS ibuprofen. These compounds share the property of being good glass formers and present monotropic polymorphism. In the present analysis, we are mainly focusing on the localization of nucleation and growth zones and the role of a transient crystallization of the metastable phase. On the basis of the elementary theories, the results offer the opportunity to discuss the impact of interfacial energies, molecular mobility, crystal disorder, liquid short-range order, and crack formation in the glass.

Multimelting Behavior and Glass Transition of Monotropic Polymorphs of 3,5-Diphenyl-4-hydroxyphenyl-substituted Galvinol

Abstract A galvinol derivative bearing the 3,5-diphenyl-4-hydroxyphenyl substituent exists in three polymorphic forms, i.e., I (melting point, 208 °C), II (203 °C), and III (138 °C), which are interrelated as monotropic polymorphs. Of these forms, III exhibits multiple melting behavior. The relative thermodynamic stability of the three forms was determined and is represented in a semischematic energy/temperature diagram. All three forms, once melted and cooled, solidify to form glass with a glass-transition temperature of 109 °C.

Monotropic Polymorphism in Ester-Based Phase Change Materials from Fatty Acids and 1,4-Butanediol

This article reports on the synthesis, thermal behavior, and morphology of phase change materials based on diesters from 1,4-butanediol with palmitic (BD16), stearic (BD18), or behenic (BD22) acid. The crystalline contents and melting enthalpies of all substances exceed 90% and 180 J/g, respectively. The molecules display monotropic polymorphism. The metastable β′ form is built from outstretched molecules, whereas the denser, stable β form is composed of molecules with a kinked conformation. BD18 and BD22 crystallize into the β′ form during cooling. Only BD18 transforms into the β form during subsequent heating via a solid–solid transition. The resistance of BD22 to convert into the β form is believed to originate from the lack of mobility associated with longer aliphatic chains. In contrast, the polymorphic conversion is thought to be very efficient and to take place during cooling for the shorter BD16 molecules. The hypothesis is put forward that the original BD16 β′ nuclei are rapidly overgrown by the ...

Stability and physical structure tests of piperidyl and morpholinyl derivatives of diphenyl-diketo-pyrrolopyrroles (DPP)

Crystalline structure, thermo-oxidative and thermal stability of symmetrical and asymmetrical piperidyl and morpholinyl derivatives of both N-substituted and non-N-substituted butyl diphenyl-diketo-pyrrolopyrrole (DPP) pigments were studied using differential scanning calorimetry (DSC) and thermogravimetry (TG). Except for the asymmetrical morpholine DPP derivative, all the samples showed melting peaks which were relatively close to their degradation temperatures (from 260 to 430 °C). Using DSC, monotropic polymorphism was revealed in the symmetrical piperidyl-N-butyl-derivative which confirmed earlier observation about tendency of symmetrical N-alkyl DPP derivates to form several crystalline structures. TG carried out under nitrogen atmosphere served for distinguishing of evaporation/sublimation and degradation temperatures. Temperatures of evaporation/sublimation were typically 10–30 °C lower in comparison with temperatures of thermal degradation. The highest thermal (450 °C) and thermo-oxidative stability (around 360 °C) showed the DPP derivatives containing morpholine moieties with no alkyl substitution on NH-group of DPP core. The presence of the latter was found to be the most destabilizing factor. Piperidyl group showed more stabilizing effect due to its polar character and its influence on π–π intermolecular interactions of neighbouring phenyl groups. The highest stabilizing effect of morpholine moiety on DPP structure was explained based on the presence of polar oxygen atom in that group. The preparations of 3,6-di-(4-morpholinophenyl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione and 3-(phenyl)-6-(4-morpholinophenyl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione are reported.

Polymorphism in metoclopramide hydrochloride and metoclopramide.

Metoclopramide hydrochloride (MCPHCl.H2O) and metoclopramide base (MCP) have been studied by DSC, thermomicroscopy, X-ray diffraction and infrared spectroscopy. MCPHCl.H2O does not readily lose water of crystallization either from the solid state or from the melt, but depending on the conditions, dehydration can give rise to two anhydrous polymorphs, MCPHCl/Form I (mp 187 degrees C) and MCPHCL/Form II (mp 155 degrees C). Form I crystallizes from the melt of Form II and not by a reversible solid-solid transition. The anhydrous hydrochloride therefore shows monotropic polymorphism where Form I is the stable polymorph and Form II, a metastable polymorph. Thermal analysis of MCP shows that the base exists as two enantiotropic polymorphs. The transition of the form stable at room temperature (MCP/Form I) to the form stable at high temperatures (MCP/Form II mp 147 degrees C) occurs extremely rapidly at 125 degrees C but the reverse process requires one month at room temperature (approximately equal to 22 degrees C). It is therefore possible to compare the X-ray diffraction powder patterns and infrared spectra of MCP Forms I and II.

Crystallization Process Development of an Active Pharmaceutical Ingredient and Particle Engineering via the Use of Ultrasonics and Temperature Cycling

Process development of a Bristol-Myers Squibb drug substance candidate involved the development of crystallization and particle engineering protocols to address polymorphism, oiling out, and particle size control issues. Two monotropic polymorphs were evaluated, and one was determined to be thermodynamically more stable. The oiling problem was solved by adjusting the polarity of the solvent system and conducting controlled nucleation at low supersaturation. Two protocols were developed to produce the desired form consistently in high quality and yield with a short processing time. Slow crystallization was required to ensure product quality since the final crystallization served as an important purification step, but slower crystallization led to larger crystals. To avoid dry milling, ultrasound was used for particle size reduction in the crystal slurry post-crystallization. Temperature cycling followed for particle size uniformity. The scale-up involved use of an ultrasonic tube through which the crystal ...

Order‐Disorder Enantiotropy, Monotropy, and Isostructurality in a Tetroxoprim‐Sulfametrole 1:1 Molecular Complex: Crystallographic and Thermal Studies

Two enantiotropic polymorphs of a tetroxoprim (TXP)‐sulfametrole (SMTR) 1:1 molecular complex monohydrate and two isostructural TXP‐SMTR 1:1 molecular complex solvates with methanol and ethanol were grown and studied by X‐ray diffraction and thermal methods (thermogravimetric analysis and differential scanning calorimetry). Interconversion of the polymorphic hydrates is essentially an order/disorder transition involving a substituent on the TXP molecule. These hydrated phases may be described as “nearly isostructural” with the methanol and ethanol solvates. Thermal data for decomposition of the solvates were rationalized on the basis of the location and topologies of solvent crystallographic sites. Solid‐state properties of two monotropic polymorphs of the unsolvated TXP‐SMTR 1:1 molecular complex were also investigated and the theoretical and experimental phase diagrams of the individual components were assessed. The existence of polymorphic and pseudopolymorphic forms is determined by conformational flexibility of the TXP‐SMTR bimolecular complex components, a tendency for molecular disorder in TXP, the ability of the drug complex to form intricate, highly stabilized hydrogen‐bonded frameworks, and the competition between nonspecific van der Waals and specific hydrogen bond interactions. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2164–2176, 2003

Low temperature polymorphism in 3-amino-1-propanol

3-Amino-1-propanol ( 3AP) was investigated by differential scanning calorimetry, and low temperature powder X-ray diffraction and Raman spectroscopy. Within the range of temperatures studied (−150–25 °C), 3AP was found to be able to crystallize in two monotropic polymorphs. Fast cooling rates produce an amorphous state that, on heating, crystallizes into the metastable polymorph. At higher temperatures, this metastable crystalline phase converts into the stable crystal. Using intermediate cooling rates, 3AP crystallizes as the metastable polymorph, the solid⇛solid transition leading to conversion of this form into the stable polymorph occurring during the subsequent heating. Slower cooling rates enable formation of the stable crystal on cooling. The two crystalline polymorphs were structurally characterized by powder X-ray diffraction and Raman spectroscopy. It was concluded that different conformations are assumed by the individual molecules of 3AP in the two crystalline varieties, with the molecules assuming the all- trans configuration in the metastable crystalline state and having the heavy atom backbone trans but the NH 2 and OH groups gauche in the stable crystal.

Dielectric studies of two liquid crystalline benzoates with coupled and decoupled CN groups

The results of dielectric studies performed in a broad frequency range for two compounds, 4-cyanophenyl 4-n-heptylbenzoate (7BBCN) and 4-(4-cyanobutyloxy)phenyl 4- n-heptylbenzoate (7BB4CN), are compared. They have the same molecular core whereas the strongly polar CN group is attached to the benzene ring in 7BBCN or is separated from it by the butyloxy chain in 7BB4CN. 7BBCN has a nematic phase, whereas 7BB4CN exhibits a monotropic nematic and smectic A2 polymorphism. Large differences in the dielectric properties of the two substances were found. The analysis of the results led to the conclusion that the antiparallel dipole-dipole associations are considerably stronger in the substance with a decoupled CN group.

Solid State Characterization of Dehydroepiandrosterone

Three polymorphs (forms I–III), a monohydrate (form S2), and three new solvates [4:1 hydrate (form S1), monohydrate (form S3), and methanol half‐solvate (form S4)] were isolated and characterized by X‐ray powder diffractometry (XRPD), IR spectroscopy, differential scanning calorimetry (DSC), hot stage microscopy, solution calorimetry, and their dissolution rates. A new polymorph, designated as form V, melting at 146.5–148°C, was observed by hot stage microscopy. Our results indicate that only forms I and S4 exhibit reproducible DSC thermograms. Five of the isolated modifications undergo phase transformation on heating, and their DSC thermograms are not reproducible. Interpretation of DSC thermograms was facilitated by use of hot stage microscopy. The identification of each modification is based on XRPD patterns (except forms S3 and S4, for which the XRPD patterns are indistinguishable) and IR spectra. In the IR spectra, a significant difference was observed in the OH stretching region for all seven modifications. In a purity determination study, 5% of a contaminant modification in binary mixtures of several modifications could be detected by use of XRPD. To obtain a better understanding of the thermodynamic properties of these modifications, a series of increasing heating rates and different pan types were used in DSC. According to Burger's rule, forms I–III are monotropic polymorphs with decreasing stability in the order form I > form II > form III. The melting onsets and heats of fusion for forms I–III are 149.1 °C, 25.5 kJ/mol; 140.8 °C, 24.6 kJ/mol; and 137.8 °C, 24.0 kJ/mol, respectively. For form III the heat of fusion was calculated from heat of solution and DSC data. In the case of form S1 the melting point, 127.2°C, was obtained by DSC using a hermetically sealed pan. The relative stabilities of the six modifications stored under high humidity conditions were predicted to be, on the basis of the heat of solution and thermal analysis data, form S2 > form S3 > form S1 > form I > form II > form III. However, the results of the dissolution rate determination were inconsistent with the heat of solution data. The stable form I shows a higher initial dissolution rate than the metastable form II and unstable form III. All modifications were converted into the stable monohydrate, form S2, during the dissolution study, suggesting that the moisture level in solid formulations should be carefully controlled.

The effect of polymorphism and metastability on the characterization and isolation of two pharmaceutical compounds

L-706,000, a class III antiarrhythmic compound, has been found to exist in several different crystalline structures including two anhydrous polymorphs, two dihydrated enantiotropic polymorphs, a monohydrate, and several organic solvent solvates. The isolation of the desired crystal modification, dihydrate type A, can be accomplished under thermodynamic or kinetic control depending on the conditions. Under kinetic control, the isolation depends on a suspended transformation of a metastable state, L-700,462, a thrombotic agent, has been found to exist in three crystalline structures: a monohydrate and two anhydrous monotropic polymorphs. Both anhydrous polymorphs, when hydrated, yielded the single monohydrate. Drying of the monohydrate, depending on the conditions and sample, will give either anhydrous form. The varying results obtained upon drying are, once again, indicative of the presence of metastable states and suspended transformations in connection with the solid state of L-700,462.

Structural characteristics of chlorine-substituted diazadienes in the solid state from35NQR data

The quadrupole resonance spectra and the quadrupole spin-lattice relaxation times of the35Cl nuclei are correlated with the molecular structures of the two chlorine-containing diazadienes CCl3CCl=NCCl=NC6H5 and CCl3CCl=NCCl=NCCl2CCl3. The monotropic polymorphism found in the case of the second crystal is discussed.