Metastable Form Research Articles

Solid-State Characterization and Interconversion of Recrystallized Amodiaquine Dihydrochloride in Aliphatic Monohydric Alcohols.

Amodiaquine dihydrochloride monohydrate (AQ-DM) was obtained by recrystallizing amodiaquine dihydrochloride dihydrate (AQ-DD) in methanol, ethanol, and n-propanol. Solid-state characterization of AQ-DD and AQ-DM was performed using X-ray powder diffractometry, Fourier transform infrared spectroscopy, thermogravimetry, and differential scanning calorimetry. All recrystallized samples were identified as AQ-DM. Crystal habits of AQ-DD and AQ-DM were shown to be needle-like and rhombohedral crystals, respectively. When AQ-DD and AQ-DM were exposed to various relative humidity in dynamic vapor sorption apparatus, no solid-state interconversion was observed. However, AQ-DM showed higher solubility than AQ-DD when exposed to bulk water during solubility study, while excess AQ-DM was directly transformed back to a more stable AQ-DD structure. Heating AQ-DM sample to temperatures ≥190°C induced initial change to metastable amorphous form (AQ-DA) which was rapidly recrystallized to AQ-DD upon ≥80%RH moisture exposure. AQ-DD was able to be recrystallized in alcohols (C1-C3) as AQ-DM solid-state structure. In summary, AQ-DM was shown to have different solubility, moisture and temperature stability, and interconversion pathways when compared to AQ-DD. Thus, when AQ-DM was selected for any pharmaceutical applications, these critical transformation and property differences should be observed and closely monitored.

Selective recrystallization of metastable polymorph of melt acetaminophen by using tempering operation

In organic melt crystallization, the control of polymorphism is important because of the bioavailability enhancement. In this present study, the methods for stable production of Acetaminophen (ACM) metastable polymorph are investigated in the tempering operation. The purpose is to obtain the operating guidelines for tempering operation for selective manufacturing technique of the polymorphic form. As the results, metastable form II was obtained with sufficient reproducibility under the condition of recrystallization during reheating stage. The operating conditions for crystallization of ACM metastable polymorph were determined by defining four requirements. The operating guidelines for production method of ACM metastable polymorph were proposed.

Crystallization of Probucol in Nanoparticles Revealed by AFM Analysis in Aqueous Solution.

The crystallization behavior of a pharmaceutical drug in nanoparticles was directly evaluated by atomic force microscopy (AFM) force curve measurements in aqueous solution. A ternary spray-dried sample (SPD) was prepared by spray drying the organic solvent containing probucol (PBC), hypromellose (HPMC), and sodium dodecyl sulfate (SDS). The amorphization of PBC in the ternary SPD was confirmed by powder X-ray diffraction (PXRD) and solid-state 13C NMR measurements. A nanosuspension containing quite small particles of 25 nm in size was successfully prepared immediately after dispersion of the ternary SPD into water. Furthermore, solution-state 1H NMR measurements revealed that a portion of HPMC coexisted with PBC as a mixed state in the freshly prepared nanosuspension particles. After storing the nanosuspension at 25 °C, a gradual increase in the size of the nanoparticles was observed, and the particle size changed to 93.9 nm after 7 days. AFM enabled the direct observation of the morphology and agglomeration behavior of the nanoparticles in water. Moreover, AFM force-distance curves were changed from (I) to (IV), depending on the storage period, as follows: (I) complete indentation within an applied force of 1 nN, (II) complete indentation with an applied force of 1-5 nN, (III) partial indentation with an applied force of 5 nN, and (IV) nearly no indentation with an applied force of 5 nN. This stiffness increase of the nanoparticles was attributed to gradual changes in the molecular state of PBC from the amorphous to the crystal state. Solid-state 13C NMR measurements of the freeze-dried samples demonstrated the presence of metastable PBC Form II crystals in the stored nanosuspension, strongly supporting the AFM results.

New Textures of Chocolate Are Formed by Polymorphic Crystallization and Template Effects: Velvet Chocolate

We report new types of chocolate textures with a soft mouth-feel (velvet effect) formed by controlling the crystallization and polymorphic transformation of cocoa butter (CB) with thermal treatment and template effects. A quick spray of molten chocolate liquor on chilled substrates (normally formed chocolate or metal) caused the crystallization of metastable forms of CB, which transformed to a stable form during subsequent heating processes. Cryo-scanning electron microscopy and confocal interferometric scanning microscopy were employed to observe the surface structures of the velvet chocolate. We characterized the domain sizes of the βV form for the CB crystals in velvet chocolate, which were much smaller and exhibited a lower melting temperature and softer mouth-feel than those in normally tempered chocolate. Polymorphic crystallization and transformation of CB were monitored in situ by X-ray diffraction by changing the temperatures of the substrates. It was obvious that the velvet effect was induced solely by decreasing the temperature of the substrates below 16 °C, because crystallization of the metastable γI form and subsequent transformation to βV of CB are prerequisites for forming velvet chocolate. The chocolate substrate was much more effective than the metal substrate in forming the velvet chocolate because of the template effect.

Solubility measurement and prediction of clopidogrel hydrogen sulfate polymorphs in isopropanol and ethyl acetate

The solubility of an active pharmaceutical ingredient (API) in various solvents is extremely important for its manufacturing and development as a drug. In this work, the solubility of two polymorphs of clopidogrel hydrogen sulfate (CHS) in the solvents of isopropanol (IPA) and ethyl acetate (EA) has been experimentally measured and theoretically predicted. The nonrandom two-liquid (NRTL) and universal quasichemical (UNIQUAC) models have been employed for the solubility prediction. The results show that, the solubility of both polymorphs generally increases with the temperature and the content of isopropanol in the mixed solvent, and meanwhile polymorph I has a higher solubility than polymorph II which demonstrates that polymorph I is a metastable form. Through taking into account that the binary interaction parameters aij (i≠j) are temperature-dependent, both NRTL and UNIQUAC can well predict the solubility of the polymorphs of clopidogrel hydrogen sulfate in organic solvents with the average relative deviation of 0.0545 and 0.0417, respectively. Finally the free energy difference between two polymorphs, ΔG, indicating their transformation tendency, has been calculated as a function of temperature, and in this way the transition temperature between two polymorphs is obtained as T=384.4K.

Thermal analysis of novel biphenylamide derivatives

The physicochemical properties of a small library of 4-methyl-biphenylamide derivatives have been investigated by means of differential scanning calorimetry, thermogravimetric analysis and hot-stage microscopy. The obtained results show that positional isomerism has a significant influence on the thermal behaviour of the 4-methyl-biphenylamide derivatives; however, no clear relationship between functional group isomerism and thermal properties could be established. Ortho-substituted derivatives revealed two polymorphic forms, whilst the para-substituted derivatives exhibit three polymorphic forms. The ortho-substituted biphenylamides were more likely to generate metastable forms when cooled from the melt. Furthermore, the self-heating properties were revealed by the para-substituted 4-methyl-biphenylamide derivatives, in which the highly energetic crystallization processes raised the sample temperature by as much as 4 °C during cooling. Such a high-energy exothermic crystallization process suggests crystallization to be highly favourable, from a thermodynamic standpoint. Hence, the para-substituted derivatives are unlikely to generate amorphous forms. Pharmaceutical application of these compounds will depend on the solubility of their crystalline forms, but their manufacture may possess some challenges due to the number of monotropic polymorphic forms that may coexist.

Crystallization kinetics and molecular mobility of an amorphous active pharmaceutical ingredient: A case study with Biclotymol

The present case study focuses on the crystallization kinetics and molecular mobility of an amorphous mouth and throat drug namely Biclotymol, through differential scanning calorimetry (DSC), temperature resolved X-ray powder diffraction (TR-XRPD) and hot stage microscopy (HSM). Kinetics of crystallization above the glass transition through isothermal and non-isothermal cold crystallization were considered. Avrami model was used for isothermal crystallization process. Non-isothermal cold crystallization was investigated through Augis and Bennett model. Differences between crystallization processes have been ascribed to a site-saturated nucleation mechanism of the metastable form, confirmed by optical microscopy images. Regarding molecular mobility, a feature of molecular dynamics in glass-forming liquids as thermodynamic fragility index m was determined through calorimetric measurements. It turned out to be around m=100, describing Biclotymol as a fragile glass-former for Angell’s classification. Relatively long-term stability of amorphous Biclotymol above Tg was analyzed indirectly by calorimetric monitoring to evaluate thermodynamic parameters and crystallization behavior of glassy Biclotymol. Within eight months of storage above Tg (T=Tg+2°C), amorphous Biclotymol does not show a strong inclination to crystallize and forms a relatively stable glass. This case study, involving a multidisciplinary approach, points out the importance of continuing looking for stability predictors.

Solid-State and Solution Characterization of Myricetin.

Myricetin (MYR) is a natural compound that has been investigated as a chemopreventative agent. MYR has been shown to suppresses ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) protein expression and reduce the incidence of UVB-induced skin tumors in mice. Despite MYR's promise as a therapeutic agent, minimal information is available to guide the progression of formulations designed for future drug development. Here, data is presented describing the solid-state and solution characterization of MYR. Investigation into the solid-state properties of MYR identified four different crystal forms, two hydrates (MYR I and MYR II) and two metastable forms (MYR IA and MYR IIA). From solubility studies, it was evident that all forms are very insoluble (<5 μg/ml) in pure water. MYR I was found to be the most stable form at 23, 35, and 56°C. Stability determination indicated that MYR undergoes rapid apparent first-order degradation under basic pH conditions, and that degradation was influenced by buffer species. Apparent first-order degradation was also seen when MYR was introduced to an oxidizing solution. Improved stability was achieved after introducing 0.1% antioxidants to the solution. MYR was found to have good stability following exposure to ultraviolet radiation (UVR), which is a consideration for topical applications. Finally, a partitioning study indicated that MYR possess a log P of 2.94 which, along with its solid-state properties, contributes to its poor aqueous solubility. Both the solid-state properties and solution stability of MYR are important to consider when developing future formulations.

Aqueous Synthesis and Visible‐Light Photochromism of Metastable h‐WO3 Hierarchical Nanostructures

AbstractA facile aqueous approach to the synthesis of metastable hexagonal tungsten oxide (h‐WO3) hierarchical nanostructures at low temperature was investigated. The spherelike h‐WO3 architectures are constructed from 1D nanorods. Polyvinyl pyrrolidone (PVP) in the reaction system facilitates the quick formation of h‐WO3 nuclei of the metastable phase through electrostatic interactions between protonated PVP and tungstate anions, which is in accord with the rule of kinetics favoring the formation of the metastable form. PVP also acts as a soft template for the assembly of WO3 crystallites. Oriented growth of WO3 crystallites along the [001] direction resulted in the nanorod‐assembled h‐WO3 architectures. The h‐WO3‐rich samples all exhibited good recycled visible‐light photochromic performance.

Monitoring the Dissolution Mechanisms of Amorphous Bicalutamide Solid Dispersions via Real-Time Raman Mapping.

Real-time in situ Raman mapping has been employed to monitor, during dissolution, the crystallization transitions of amorphous bicalutamide formulated as a molecular dispersion in a copovidone VA64 matrix. The dissolution performance was also investigated using the rotating disc dissolution rate methodology, which allows simultaneous determination of the dissolution rate of both active ingredient and polymer. The dissolution behavior of two bicalutamide:copovidone VA64 dispersion formulations, containing 5% (w/w) and 50% (w/w) bicalutamide, respectively, was investigated, with the aim of exploring the effect of increasing the bicalutamide loading on the dissolution performance. Spatially time-resolved Raman maps generated using multivariate curve resolution indicated the simultaneous transformation of amorphous bicalutamide present in the 50% drug-loaded extrudate into metastable polymorphic form II and low-energy polymorphic form I. Fitting a kinetic model and spatially correlating the data extracted from the Raman maps also allowed us to understand the re-crystallization mechanisms by which the low-energy form I appears. Form I was shown to crystallize mainly directly from the amorphous solid dispersion, with crystallization from the metastable form II being a minor contribution.

Red-shifted red/green-type cyanobacteriochrome AM1_1870g3 from the chlorophyll d-bearing cyanobacterium Acaryochloris marina

Cyanobacteriochromes (CBCRs) are diverse photoreceptors that are found only from cyanobacteria and cover wide range of light qualities. CBCRs are divided into two types regarding the chromophore species they contain: phycocyanobilin (PCB) and phycoviolobilin. Red/green-type CBCRs are widely distributed subfamily among the PCB-binding CBCRs and photoconvert between a red-absorbing thermostable form and a green-absorbing metastable form. Our recent study discovered that a red/green-type CBCR, AM1_1557g2, from a cyanobacterium Acaryochloris marina covalently binds not only PCB but also biliverdin (BV). BV-binding AM1_1557g2 photoconverts between a far-red absorbing form and an orange-absorbing form. We report, herein, that another red/green-type CBCR, AM1_1870g3, from the cyanobacterium A. marina also bound both PCB and BV. PCB- and BV-binding ones showed red/green and far-red/orange reversible photoconversions, respectively. Unexpectedly, absorbing wavelengths are 10–20 nm red-shifted compared with those of AM1_1557g2. These red-shifted characteristics may be useful for optogenetic light switches that work in various organisms.

New metastable form of glibenclamide prepared by redispersion from ternary solid dispersions containing polyvinylpyrrolidone-K30 and sodium lauryl sulfate

Modification of polymorphic forms of poorly water-soluble drugs is one way to achieve the desirable properties. In this study, glibenclamide (GBM) particles with different polymorphic forms, including a new metastable form, were obtained from redispersion of ternary solid dispersion systems. The ternary solid dispersion systems, consisting of GBM, polyvinylpyrrolidone-K30 (PVP-K30) and sodium lauryl sulfate (SLS), were prepared by solvent evaporation method and subsequently redispersed in deionized water. The precipitated drug particles were then collected at a given time period. The drug particles with different polymorphic forms could be achieved depending on the polymer/surfactant ratio. Amorphous drug nanoparticles could be obtained by using a high polymer/surfactant ratio, whereas two different crystalline forms were obtained from the systems containing low polymer/surfactant ratios. Interestingly, a new metastable form IV of GBM with improved dissolution behavior could be obtained from the system of GBM:PVP-K30:SLS with the weight ratio of 2:2:4. This new polymorphic form IV of GBM was confirmed by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffractometry (PXRD) and solid state 13C nuclear magnetic resonance (NMR) spectroscopy. The molecular arrangement of the new polymorphic form IV of GBM was proposed. The GBM particles with polymorphic form IV also showed an improved dissolution behavior. In addition, it was found that the formation of the new polymorphic form IV of GBM by this process was reproducible.

Changes in the solid state of anhydrous and hydrated forms of sodium naproxen under different grinding and environmental conditions: Evidence of the formation of new hydrated forms

The aim of the present work was to investigate the solid state change of the anhydrous and hydrate solid forms of sodium naproxen under different grinding and environmental conditions. Grinding was carried out manually in a mortar under the following conditions: at room temperature under air atmosphere (Method A), in the presence of liquid nitrogen under air atmosphere (Method B), at room temperature under nitrogen atmosphere (Method C), and in the presence of liquid nitrogen under nitrogen atmosphere (Method D). Among the hydrates, the following forms were used: a dihydrate form (DSN) obtained by exposing the anhydrous form at 55% RH; a dihydrate form (CSN) obtained by crystallizing sodium naproxen from water; the tetrahydrate form (TSN) obtained by exposing the anhydrous form at 75% RH. The metastable monohydrate form (MSN), previously described in the literature, was not used because of its high physical instability.The chemical stability during grinding was firstly assessed and proven by HPLC. Modification of the particle size and shape, and changes in the solid state under different grinding methods were evaluated by scanning electron microscopy, and X-ray powder diffractometry and thermogravimetry, respectively. The study demonstrated the strong influence of starting form, grinding and environmental conditions on particle size, shape and solid state of recovered sodium naproxen forms. In particular, it was demonstrated that in the absence of liquid nitrogen (Methods A and C), either at air or at nitrogen atmosphere, the monohydrate form (MSN) was obtained from any hydrates, meaning that these grinding conditions favored the dehydration of superior hydrates. The grinding process carried out in the presence of liquid nitrogen (Method B) led to further hydration of the starting materials: new hydrate forms were identified as one pentahydrate form and one hexahydrate form. The hydration was caused by the condensation of the atmospheric water on sodium naproxen particles by liquid nitrogen and by the grinding forces that created a close contact between water and drug. The simultaneous disruption of the crystals, occurring during grinding, and their close contact with water molecules promoted the conversion in higher hydrates. Under the Method D, it was possible to highlight a certain tendency to hydration probably due to a rearrangement of water already present into the hydrates, but results were substantially different from Method B. Thus, summarizing, the different SN forms behave differently under different grinding and environmental conditions.

Thermodynamically metastable thiocyanato coordination polymer that shows slow relaxations of the magnetization.

Reaction of cobalt thiocyanate with 4-acetylpyridine leads to the formation of [Co(NCS)2(4-acetylpyridine)2]n (3/I). In its crystal structure the Co cations are connected by pairs of μ-1,3-bridging thiocyanato ligands into dimers that are further connected into layers by single anionic ligands. DTA-TG measurements of Co(NCS)2(4-acetyl-pyridine)4 (1) led to the formation of 3/I. In contrast, when the hydrate Co(NCS)2(4-acetyl-pyridine)2(H2O)2 (2) is decomposed, a mixture of 3/I and a thermodynamically metastable form 3/II is obtained. Further investigations reveal that thermal annealing of 2 leads to the formation of 3/II, that contains only traces of the stable form 3/I. DSC and temperature dependent X-ray powder diffraction (XRPD) measurements prove that 3/II transforms into 3/I on heating. The crystal structure of 3/II was determined ab initio from XRPD data. In its crystal structure the Co cations are linked by pairs of bridging thiocyanato anions into a 1D coordination polymer, and thus, 3/II is an isomer of 3/I. Magnetic measurements disclose that the stable form 3/I only shows paramagnetism without any magnetic anomaly down to 2 K. In contrast, the metastable form 3/II shows ferromagnetic behavior. The phase transition into ordered state at Tc = 3.8 K was confirmed by specific heat measurements. Alternating current susceptibility measurements show frequency dependent maxima in χ' and χ″, which is indicative for a slow relaxation of the magnetization.

Crystal structure of two paracetamol polymorphs at 20 K: A search for the “structure-property” relationship

At a temperature of 20 K the crystal structures of two paracetamol polymorphs (monoclinic, form I, SPG P21/n and orthorhombic, form II, SPG Pbca) are solved by single crystal X-ray diffraction and a comparative analysis of the geometric characteristics of intra- and intermolecular interactions is performed. Polymorphous transformations were not observed until cooling to this temperature. It is shown that in form II hydrogen bonds remain longer than those in form I up to a temperature of 20 K, and the density of metastable form II remains higher than that of stable form I. At the same time, in form II, thermal parameters of nitrogen and oxygen atoms remain higher than those in form I. The features observed in the behavior of the heat capacity of both forms at temperatures below 100 K are not directly related to a change in the geometry of hydrogen bonds. The methyl group orientation determined from the electron density maps does not alter as compared to higher temperatures in both modifications. Thus, changes in the Raman spectra observed in the orthorhombic paracetamol form below 100 K are explained by the features of its dynamics rather than a change in the overall average orientation of the methyl group determined by X-ray diffraction.

Microstructural evolution of diamond films from CH4/H2/N2 plasma and their enhanced electrical properties

The influence of N2 concentration in CH4/H2/N2 plasma on microstructural evolution and electrical properties of diamond films is systematically investigated. While the diamond films grown in CH4/H2 plasma contain large diamond grains, for the diamond films grown using CH4/H2/(4%)N2 plasma, the microstructure drastically changed, resulting in ultra-nanosized diamond grains with Fd3m structure and a0 = 0.356 nm, along with the formation of n-diamond (n-D), a metastable form of diamond with space group Fm3m and a0 = 0.356 nm, and i-carbon (i-C) clusters, the bcc structured carbon with a0 = 0.432 nm. In addition, these films contain wide grain boundaries containing amorphous carbon (a-C). The electron field emission (EFE) studies show the best EFE behavior for 4% N2 films among the CH4/H2/N2 grown diamond films. They possess the lowest turn-on field value of 14.3 V/μm and the highest EFE current density value of 0.37 mA/cm2 at an applied field of 25.4 V/μm. The optical emission spectroscopy studies confirm that CN species are the major criterion to judge the changes in the microstructure of the films. It seems that the grain boundaries can provide electron conduction networks to transport efficiently the electrons to emission sites for field emission, as long as they have sufficient thickness. Whether the matrix nano-sized grains are 3C-diamond, n-D or i-C is immaterial.

Crystallization of selective polymorph using relationship between supersaturation and solubility

For polymorph screening, the plot of ΔCmet/Cc against C*/Cc in nucleation kinetics was investigated. The polymorph screening for forms I and II and amorphous form of clopidogrel hydrogen sulfate was carried out according to the nucleation kinetics expressed by this plot. The stability order of polymorphs for famotidin was also predicted successfully by this model. This model was used in the expectation of supersaturation level for polymorphic formation. Two types of polymorphic crystallization: transformation from metastable form to stable form and nucleation and growth of polymorphic form without transformation can be explained. Amorphous form was also expected by this model. Even though polymorphs depend on lots of crystallization parameters such as solvent, temperature, concentration, cooling rate, and so forth, plot of ΔCmet/Cc and the C*/Cc in various nucleation kinetics gives a guide line for screening of polymorph. © 2015 American Institute of Chemical Engineers AIChE J, 61: 1372–1379, 2015

Structural and thermal properties of ternary narrow-gap oxide semiconductor; wurtzite-derived β-CuGaO2.

The crystal structure of the wurtzite-derived β-CuGaO2 was refined by Rietveld analysis of high-resolution powder diffraction data obtained from synchrotron X-ray radiation. Its structural characteristics are discussed in comparison with the other I-III-VI2 and II-VI oxide semiconductors. The cation and oxygen tetrahedral distortions of the β-CuGaO2 from an ideal wurtzite structure are small. The direct band-gap nature of the β-CuGaO2, unlike β-Ag(Ga,Al)O2, was explained by small cation and oxygen tetrahedral distortions. In terms of the thermal stability, the β-CuGaO2 irreversibly transforms into delafossite α-CuGaO2 at >460 °C in an Ar atmosphere. The transformation enthalpy was approximately -32 kJ mol(-1), from differential scanning calorimetry. This value is close to the transformation enthalpy of CoO from the metastable zincblende form to the stable rock-salt form. The monovalent copper in β-CuGaO2 was oxidized to divalent copper in an oxygen atmosphere and transformed into a mixture of CuGa2O4 spinel and CuO at temperatures >350 °C. These thermal properties indicate that β-CuGaO2 is stable at ≤300 °C in both reducing and oxidizing atmospheres while in its metastable form. Consequently, this material could be of use in optoelectronic devices that do not exceed 300 °C.

Oxygen defects in phosphorene.

Surface reactions with oxygen are a fundamental cause of the degradation of phosphorene. Using first-principles calculations, we show that for each oxygen atom adsorbed onto phosphorene there is an energy release of about 2eV. Although the most stable oxygen adsorbed forms are electrically inactive and lead only to minor distortions of the lattice, there are low energy metastable forms which introduce deep donor and/or acceptor levels in the gap. We also propose a mechanism for phosphorene oxidation involving reactive dangling oxygen atoms and we suggest that dangling oxygen atoms increase the hydrophilicity of phosphorene.

Ab Initio Prediction of the Diversity of Second Harmonic Generation from Pharmaceutically Relevant Materials

A model for predicting the anticipated second harmonic generation (SHG) activity of crystalline active pharmaceutical ingredients (APIs) was developed based on combining time-dependent Hartree–Fock calculations of the molecular building block with analytical theory for the predicted intensity from the lattice. Predicted trends agreed well overall with experimental measurements for 18 representative APIs. Inspection of the SHG images suggests that outliers from the predicted trends likely arose from the presence of trace SHG-active metastable crystal forms not considered in the predictions. The success of this relatively simple computational approach suggests a route for reliably predicting the anticipated SHG activities of API target molecules, which in turn can serve to indicate their potential compatibility with analysis by SHG.