Metastable Form Research Articles

Influence of Coformer Stoichiometric Ratio on Pharmaceutical Cocrystal Dissolution: Three Cocrystals of Carbamazepine/4-Aminobenzoic Acid.

Cocrystallization is a technique to optimize solid forms that shows great potential to improve the solubility of active pharmaceutical ingredients (APIs). In some systems, an API can form cocrystals in multiple stoichiometries with the same coformer. However, it remains unclear how coformer stoichiometry influences solubility. This paper investigates the pharmaceutical:coformer pair carbamazepine (CBZ)/p-aminobenzoic acid (PABA); both CBZ/PABA 1:1 and 2:1 cocrystals are known, and a novel 4:1 CBZ/PABA cocrystal is reported here. The 4:1 cocrystal is structurally characterized, and phase stability data suggest that it is a thermodynamically unstable form. Dissolution experiments show that there is no correlation between the cocrystal stoichiometry and dissolution rate in this system. On the other hand, with the relatively weak intermolecular interactions, metastable forms can be beneficial to dissolution rate, which suggests that more effort should be devoted to cocrystal production with kinetic growth methods.

Dispersion of carbon nanotubes in aluminum improves radiation resistance

We can mass-produce metal/carbon nanotube (CNT) composites that show improved radiation tolerance. The 0.5wt% Al+CNT composite showed improved tensile strength without reduction of tensile ductility before radiation, and reduced void/pore generation and radiation embrittlement at high displacements per atom (DPA). Under helium ion irradiation up to 72DPA, the 1D carbon nanostructures survive, while sp2 bonded graphene transforms to sp3 tetrahedral amorphous carbon. Self-ion (Al) irradiation converts CNTs to a metastable form of Al4C3, but still as slender 1D nanorods with prolific internal interfaces that catalyze recombination of radiation defects, reducing radiation hardening and porosity generation. The 1D fillers may also form percolating paths of “nano-chimneys” that outgas the accumulated helium and other fission gases, providing an essential solution to the gas accumulation problem.

Formation Monocrystalline Carbon Micro-and Nanostructures Under Femtosecond Laser Irradiation of graphite in Liquid Nitrogen

The combination of high energy and ultra short duration of femtosecond laser pulses allow to reach in the area of impact the local conditions which can change the phase composition of irradiated material. Traditional methods of structural phase transformation of the graphite at high pressures do not provide the abrupt simultaneous cancellation of the applied pressure and temperature. As a result, some of the synthesized nanostructures and metastable forms of carbon are destroyed. The suggested method allows to eliminate this disadvantage. Femtosecond laser radiation provides ultrafast heating of the target material, and the use of liquid nitrogen dramatically accelerates the process of it cooling. The formation of new carbon micro- and nanostructures has been registered at experimental approbation of the proposed method. The check of elemental composition of the created crystals showed that they are formed solely of carbon. The experimental results show the possibility of creation of new (less studied) carbon forms with a variety of properties.

Controlled production of the elusive metastable form II of acetaminophen (paracetamol): a fully scalable templating approach in a cooling environment.

A scalable, transferable, cooling crystallisation route to the elusive, metastable, form II of the API acetaminophen (paracetamol) has been developed using a multicomponent "templating" approach, delivering 100% polymorphic phase pure form II at scales up to 120 g. Favourable solubility and stability properties are found for the form II samples.

Stabilisation of metastable polymorphs: the case of paracetamol form III.

The design of a melt synthesis of the first air-stable formulation of the metastable form III of paracetamol is derived from thermo-spectroscopic and thermo-diffraction experiments. Melt crystallisation in the presence of β-1,4-saccharides produces form III selectively and the excipients appear to act as stabilising 'active' templates of the metastable polymorph.

Polymorphism of vanillin revisited: the discovery and selective crystallization of a rare crystal structure

While polymer induced heterogeneous nucleation (PIHn) has been shown to be a powerful tool for crystallization control and polymorph screening the factors influencing PIHn, such as solvent selection, supersaturation and method of crystallization are not well understood. Herein, we report on the use of PIHn to selectively crystallize a new and rare crystal structure of vanillin. Nearly 65 years ago, Walter McCrone postulated vanillin to be trimorphic. However, only one crystal form, Form I, had been structurally characterized to this point. Form II crystallizes in the space group Pna21 with four molecules in the asymmetric unit. Achiral molecules exhibiting such crystal structures account for less than 0.008% of all organic entries in the Cambridge Structural Database. Polymorphic control by PIHn was observed to be highly dependent on the method of crystallization. In the presence of poly(acrylic acid) and poly(methyl methacrylate) micro-particles the thermodynamically stable Form I was crystallized from isopropanol by quench cooling, while metastable Form II was obtained by slow evaporation. To our knowledge this is the first deliberate study to highlight the influence of crystallization method on PIHn.

Polymorphic Crystallization and Structural Aspects of Agomelatine Metastable Form X Prepared by Combined Antisolvent/Cooling Process

Polymorphism is of great interest to the pharmaceutical industry because polymorphs have different physicochemical properties such as dissolution rate. In the present work, the influence of process conditions on the polymorphic antisolvent crystallization and transformations during cooling crystallization of agomelatine metastable form X from water/methanol solution has been investigated with a view of designing a robust process that includes not only crystallization but also filtration, filter cake washing, and drying. The competitive stability method was used in order to identify regions of the parametric space (water/methanol ratio, process temperature, and initial concentration) in which the crystallization of form X can be feasible. The formation of agomelatine form X was confirmed by subsequent kinetic experiments. The influence of process parameters such as the intensity of agitation, the antisolvent addition rate, and the precipitation temperature on the yield and particle size of the crystalline ...

Cyclodextrin based ternary system of modafinil: Effect of trimethyl chitosan and polyvinylpyrrolidone as complexing agents

Modafinil is an approved drug for the treatment of narcolepsy and have a strong market presence in many countries. The drug is widely consumed for off-label uses and currently listed as a restricted drug. Modafinil has very low water solubility. To enhance the aqueous solubility of modafinil by the formation of a ternary complex with Hydroxypropyl-β-cyclodextrin and two hydrophilic polymers was the main objective of the present study. Pyrrolidone (PVP K30) and a water soluble chitosan derivative, trimethyl chitosan (TMC) were studied by solution state and solid state characterization methods for their discriminatory efficiency in solubility enhancement of modafinil. Phase solubility study depicted the highest complexation efficiency (2.22) of cyclodextrin derivative in the presence of TMC compared to the same in the presence of PVP K30 (0.08) and in the absence of any polymer (0.92). FT-IR analysis of binary and ternary complex expressed comparable contribution of both polymers in formation of inclusion complex. The thermal behaviour of binary and ternary complex, involving individual polymers disclosed the influence of TMC on polymorphism of the drug. DSC study revealed efficiency of TMC to prevent conversion of metastable polymorphic form to stable polymorphic form. Ternary complex, involving TMC enhanced water solubility of the drug 1.5 times more compared to the binary complex of the drug whereas PVP K30 reduced the Solubility.

Exotic stable cesium polynitrides at high pressure.

New polynitrides containing metastable forms of nitrogen are actively investigated as potential high-energy-density materials. Using a structure search method based on the CALYPSO methodology, we investigated the stable stoichiometries and structures of cesium polynitrides at high pressures. Along with the CsN3, we identified five new stoichiometric compounds (Cs3N, Cs2N, CsN, CsN2, and CsN5) with interesting structures that may be experimentally synthesizable at modest pressures (i.e., less than 50 GPa). Nitrogen species in the predicted structures have various structural forms ranging from single atom (N) to highly endothermic molecules (N2, N3, N4, N5, N6) and chains (N∞). Polymeric chains of nitrogen were found in the high-pressure C2/c phase of CsN2. This structure contains a substantially high content of single N-N bonds that exceeds the previously known nitrogen chains in pure forms, and also exhibit metastability at ambient conditions. We also identified a very interesting CsN crystal that contains novel N44− anion. To our best knowledge, this is the first time a charged N4 species being reported. Results of the present study suggest that it is possible to obtain energetic polynitrogens in main-group nitrides under high pressure.

Amorphous Sulfadoxine: A Physical Stability and Crystallization Kinetics Study.

Poor aqueous solubility of drugs and the improvement thereof has always been a challenge for the pharmaceutical industry. With this, one of the focuses of the pharmaceutical research scientist involves investigating possible metastable forms of a given drug to be incorporated into solid dosage forms. The rationale being, the improved solubility offered by the metastable solid-state forms of drugs. Solubility remains a major challenge for formulation scientists, especially with antimicrobial agents where the emergence of resistance is directly dependent on the concentration and duration of the parasite exposed to the drug. Sulfadoxine-pyrimethamine combination therapies are still the recommended treatments for uncomplicated Plasmodium falciparum malaria. The aim of this study was to prepare an amorphous form of sulfadoxine and to investigate the stability and recrystallization behavior thereof. The amorphous form was prepared by the well-known quench cooling of the melt. The physico-chemical properties and stability of amorphous sulfadoxine were studied using hot-stage microscopy (HSM), scanning electron microscopy (SEM), x-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), as well as microcalorimetry. The recrystallization kinetics were studied isothermally by applying the Johnson-Mehl-Avrami model and non-isothermally by applying the Kissinger model. The physical stabilization of the amorphous form was investigated using physical mixtures of amorphous sulfadoxine with polyvinylpyrrolidone-25 (PVP-25). It was proved that sulfadoxine is a good glass former with relative high physical stability; however, water acts as a strong plasticizer for amorphous sulfadoxine, detrimentally affecting the stability during exposure to high moisture conditions.

Effect of organic solvent vapors on the crystallization rate of amorphous indomethacin

Many pharmaceutical bulk powders are known to have various solid states, such as polymorphic forms, solvates, and amorphous forms. The amorphous form is known to be recrystallized by absorbing various solvent vapors depending on the chemical properties. It is possible to perform a search for polymorphs of drugs by utilizing this property. In this study, the solvent properties of solvent vapor by using amorphous indomethacin (A-IMC) as a model drug were measured using X-ray diffraction (XRD) in terms of the effect on crystallization. A-IMC was exposed for 2h at 30°C in a sealed container with normal alcohols with different carbon number (ethanol, 1-propanol, 1-butanol, 1-pentanol, and 1-octanol), and changed to the stable crystalline form (γ-IMC) and the metastable form (α-IMC). Exposure to alcohol vapor with a long alkyl chain provided a high yield of the γ-form and a long induction period. It was considered that the rapid generation of crystal nuclei was performed by increasing the polarity of alcohol.

The NaNO3–KNO3 phase diagram

Many papers have been published in relation to the NaNO3–KNO3 phase diagram determination in the last 160 years. These papers fall in two categories: (1) the solid–liquid equilibrium is assumed to be of the eutectic type, and (2) the solid–liquid equilibrium is considered as a loop with a minimum. The discordance between the two views is related to the slow transition kinetics that complicate the assessment of thermal ‘fluctuations’, and also to the appearance of a metastable form of potassium nitrate. The main result of this paper is the experimental phase diagram constructed with new experimental data so that we can assure that the second option is correct. This phase diagram is defined by a eutectoid invariant, an asymmetric immiscibility gap and a continuous solid solution with a minimum of melting point. Additionally, the ABθ model simulates correctly the experimental piece of evidence.

Thermal Analysis by Structural Characterization as a Method for Assessing Heterogeneity in Complex Solid Pharmaceutical Dosage Forms.

Characterizing inter- and intrasample heterogeneity of solid and semisolid pharmaceutical products is important both for rational design of dosage forms and subsequent quality control during manufacture; however, most pharmaceutical products are multicomponent formulations that are challenging in this regard. Thermal analysis, in particular differential scanning calorimetry, is commonly used to obtain structural information, such as degree of crystallinity, or identify the presence of a particular polymorph, but the results are an average over the whole sample; it cannot directly provide information about the spatial distribution of phases. This study demonstrates the use of a new thermo-optical technique, thermal analysis by structural characterization (TASC), that can provide spatially resolved information on thermal transitions by applying a novel algorithm to images acquired by hot stage microscopy. We determined that TASC can be a low cost, relatively rapid method of characterizing heterogeneity and other aspects of structure. In the examples studied, it was found that high heating rates enabled screening times of 3-5 min per sample. In addition, this study demonstrated the higher sensitivity of TASC for detecting the metastable form of polyethylene glycol (PEG) compared to conventional differential scanning calorimetry (DSC). This preliminary work suggests that TASC will be a worthwhile additional tool for characterizing a broad range of materials.

A Giant Reconstruction of α-quartz (0001) Interpreted as Three Domains of Nano Dauphine Twins.

Silica (SiO2) is one of the most common materials on Earth. The crystalline form α-quartz is the stable silica polymorph at ambient conditions although metastable forms exist. α-quartz is a piezoelectric material, it can be produced artificially and is widely used for example in electronics and the biosciences. Despite the many application areas, the atomic surface structures of silica polymorphs are neither well understood nor well characterized. Here we present measurements of α-quartz (0001). Helium Atom Scattering combined with Atomic Force Microscopy reveals a giant reconstruction consisting of 5.55 ± 0.07 nm wide ribbons, oriented 10.4° ± 0.8° relative to the bulk unit cell. The ribbons, with the aid of atomistic modelling, can be explained as a self-organised pattern of nano Dauphine twins (nano electrical twins).

The Influence of Manganese Amount in Oxyhydroxide of Aluminium – Precursor of MnO<sub>x</sub>-Al<sub>2</sub>O<sub>3</sub> Catalysts on Catalytic Activity in Reaction of Oxidation of C<sub>1</sub>-C<sub>3</sub> of Hydrocarbons

The authors have synthesized nanofibrous aluminum oxyhydroxide (AlOOH), modified with different amounts of manganese ions (II), which is the precursor for methane deep oxidation catalysts. It was shown that the catalytic activity of the manganese-based system obtained depends on manganese amount and thermal activation conditions. It is approved that as the catalyst for deep oxidation of hydrocarbons the system with manganese content of 10.5 wt. % is the most perspective despite the fact that the oxidation rate of methane is lower in it than in the catalyst with Mn content of 5.7 wt. %. As opposed to the catalyst with Mn content of 5.7 wt. %., where the aluminium oxide is in metastable form (s-Al2O3), the catalyst with manganese content of 10.5 wt. % contains in its structure a thermodynamically and thermally stable α-Al2O3 phase.

When is 6 less than 5? Penta- to hexa-graphene transition

Penta-graphene is a recently proposed graphene allotrope consisting of repeating pentagons. Here, we characterize the small-strain mechanical properties of finite penta-graphene using full atomistic molecular dynamics (MD). Using tensile tests, the uniaxial yield strength (12.7 N/m) and stiffness (approximately 378.3 N/m) are characterized. Extreme strain is observed at ultimate failure (> 50%), with an associated elastic toughness on the order of 5.4 J/m2. In addition, the bond structure of penta-graphene enables a structural transition from a repeating penta- to hexa-form, e.g., the common hexagonal-based sp2-bonding structure of graphene. We show that penta-graphene can be transitioned to a hexagonal energy-reducing graphene form, via applied strain or temperature. The pentagon-based structure begins to degenerate to a graphene-like hexagonal structure at a critical strain of 5.1%, as the system transitions to a lower energy structure. Beyond this critical strain, the system behaves plastically, and does not revert to initial conditions upon stress removal. The hexagonal form (6-ring) represents a lower energy state than the pentagonal form (5-ring). We further observe conformational changes occur due to thermal energy, leading to a transition at T > 600 K. Post-transition, the system behavior reflects that of graphene with lattice defects. This represents a new paradigm of nanomaterials, whereby one material (graphene) can emerge from another metastable form (penta-graphene).

Effect of surfactants or a water soluble polymer on the crystal transition of clarithromycin during a wet granulation process

To generate products containing a stable form of clarithromycin (CAM) (form II) regardless of the initial crystal form of CAM or type of granulation solvent, the effects of five surfactants, or a water-soluble polymer (macrogol 400) were determined on the crystal transition of CAM. The metastable form (form I) was kneaded with water, after adding surfactants, or a water-soluble polymer. Form II was also kneaded with ethanol, after adding the same additives. The resulting samples were analyzed by powder X-ray diffraction. Form I was completely converted to form II by a wet granulation using water with additives bearing polyoxyethylene chains such as polysorbate 80 (PS80), polyoxyl 40 stearate or macrogol 400. The granulation of the form II using ethanol with these additives did not result in a crystal transition to form I. Furthermore, CAM tablets were manufactured using granules with PS80, and these crystal forms and dissolution behaviors were investigated. As a result, the wet granulation of CAM with PS80 gave CAM tablets containing only form II and PS80 did not have any adverse effects on tablet characteristics. Therefore, these data suggests that the crystal form of CAM can be controlled to be form II using a wet granulation process with additives bearing polyoxyethylene chains regardless of the initial crystal form of CAM or type of granulation solvent.

A new metastable form of glycolide obtained via large scale high pressure experiments

A new metastable form of glycolide obtained via large scale high pressure experiments

Dynamics of changes in the colored form of spiroantrooxazine incorporated into polytetrafluoroethylene F-42 in a supercritical carbon dioxide medium

It is shown that the incorporation of spiroantrooxazine (SAO), which has pronounced photochromic properties, into polytetrafluoroethylene F-42 in supercritical carbon dioxide medium leads to the formation of metastable colored photochromic states of different structure. In the subsequent relaxation of the polymer-SAO system, these states give rise to the most thermodynamically stable isomeric form of SAO for the given system. The kinetics of these reactions is analyzed in supercritical CO2 medium and after placing the test sample in air upon the formation of the unstable colored form of the photochromic molecule in the polymeric matrix. It is noted that in these cases, comparison of the rate constants of relaxation transitions allows us to numerically assess how the matrix plasticization by carbon dioxide affects the formation of photochromic colored states and the relaxation reorganization of the photochromic metastable forms.

Suppressed Release of Clarithromycin from Tablets by Crystalline Phase Transition of Metastable Polymorph Form I

The pharmaceutical properties of clarithromycin (CAM) tablets containing the metastable form I of crystalline CAM were investigated. Although the dissolution rate of form I was higher than that of stable form II, the release of CAM from form I tablet was delayed. Disintegration test and liquid penetration test showed that the disintegration of the tablet delayed because of the slow penetration of an external solution into form I tablet. Investigation by scanning electron microscopy revealed that the surface of form I tablet was covered with fine needle-shaped crystals following an exposure to the external solution. These crystals were identified as form IV crystals by powder X-ray diffraction. The phenomenon that CAM releases from tablet was inhibited by fine crystals spontaneously formed on the tablet surface could be applied to the design of sustained-release formulation systems with high CAM contents by minimizing the amount of functional excipients.