Anhydrous Form Research Articles

Crystal structure and Hirshfeld surface analysis of the anhydrous form of the nucleoside analogue entecavir.

The nucleoside analogue entecavir {systematic name: 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one}, C12H15N5O3, is an antihepatitis B virus drug that has been approved in the US, EU and several countries worldwide. We report here the single-crystal structure of the anhydrous form and compare it with that of the previously reported monohydrate form [Jiang & Liu (2009). Acta Cryst. E65, o2232]. Hirshfeld surface analysis has been employed to understand and visualize the subtle packing differences between the two crystalline forms. The results show that, compared to the previously reported hydrated form, the anhydrous crystal has significantly different intermolecular interactions and packing patterns.

Physico-chemical study of norfloxacin and metronidazole binary mixtures

The physico-chemical characterization of norfloxacin commercial sample (NF), norfloxacin anhydrous form A (NFanhA), norfloxacin pentahydrate (NF·5H2O) and metronidazole (MZ) has been carried out. It was determined that the commercial sample is a mixture of 74% anhydrous NF form A and 26% hemipentahydrate NF. From XRPD analysis, it was observed that after the water loss, NF·5H2O undergoes a solid–solid transition and is converting to NFanhA. Solid–liquid equilibrium for NFanhA–MZ and NF·5H2O–MZ binary systems has been investigated using differential scanning calorimetry, and simple eutectic point was observed, in good approximation, at 419 K for all the mixtures studied. The experimental solid–liquid phase diagram was compared with predictions obtained from available eutectic equilibrium models. The results indicate non-ideality for the mixture. The mixing enthalpy was determined at the eutectic composition and the negative value obtained, ΔMH = − 13.28 kJ mol−1, indicates that molecules of the two components form clusters in the eutectic melt.

A novel process for dehydration of antibiotics fermentation residues

Wet antibiotics fermentation residues (AFRs) are rich in water and organic matters. AFRs can cause environmental pollution via secondary fermentation, which also makes them inconvenient to be stored, transported and disposed. A novel dehydration process of wet AFRs was developed by applying inorganic salts as dehydration agent (DA), in which colloidal water in wet AFRs was transferred into the hydrate of DA and formed solid AFRs–DA mixture at room temperature. When Na2SO4 was used as the optimal DA, differential thermal gravity (DTG) analysis demonstrated that the temperature of complete dewatering of AFRs–DA mixture decreased from 162.7 to 98.5°C compared with wet AFRs, and the dewatering energy consumption decreased by 26.58%. The suitable mass ratio of Na2SO4 and AFRs was in the range of 1.2–2.0. During the process of incineration at 750°C, the organic matters in the AFRs–DA mixture were completely converted into small molecules, for example, H2O and CO2, and the harmless disposal of AFRs was realized. Meanwhile, DA changed from hydrate to anhydrous form, from which DA can be recycled. The dewatering reaction time decreased by 61.8% with the recycled Na2SO4 at least five recycles. This study provides a promising energy saving approach for wet AFRs disposal. © 2018 American Institute of Chemical Engineers Environ Prog, 37: 1901–1907, 2018

Anhydrates and hemihydrate of tasimelteon: Synthesis, structure, and pharmacokinetic study

Two new crystal forms of tasimelteon TSM-I and TSM-II were reported here. Crystallization of crude in methanol or mixture solvent results in anhydrate crystal form (TSM-I) and hemihydrate crystal form (TSM-II) respectively. To the best of our knowledge, it is the first report about crystalline form of tasimelteon. The two crystal forms were exhaustively characterized by Scanning Electron Microscopy, Fourier Transform Infrared Spectroscopy, Raman Spectra, Differential Scanning Calorimetry, Thermogravimetric Analysis, Solid State NMR Spectroscopy and Powder X-ray diffraction and Single Crystal X-ray Diffraction. Furthermore, the pharmacokinetic behavior of TSM-I and TSM-II in rats were measured. We found that though TSM-II is considerably more soluble than TSM-I under water (pH = 7.0) and pH 1.2 buffer conditions, the bioavailability of TSM-Ivia oral administration was better compared to that of TSM-II.

Electrospun Poly(Amino Acid) Based Nano GEL Fiber Matrices and Their Biocompatibility and Biodegradability

Interest in the development of biocompatible and biodegradable polymer matrices has increased with their usability in wide range. Artificial polymer based fibrous scaffolds resemble to the native extracellular matrix. Electrospinning technique enables the possibility to prepare a wide variety of matrices built of fibers in the nano or micrometer diameter range. These matrices can be tailored for tissue engineering, however the use of water soluble polymers is inappropriate because of their fast dissolution in biological fluids. By utilizing reactive electrospinning, chemically cross-linked gel fibers can be created which without enzymatic or chemical degradation will not dissolve in physiological conditions. Poly(amino acid)-based polymers that have desirable chemical, mechanical and biological properties have recently emerged as promising new class of biomaterials. The aim of our research was to make poly(amino acid) based scaffolds available for tissue engineering. In the present work have utilized the anhydrous form of poly(aspartic acid), the poly(succinimide) as base polymer. To prevent the polymer fibers from early dissolution poly(succinimide) molecules were grafted by thiol side chains. During the electro-spinning process at cross-linking reaction took place between these side chains. For the characterisation AFM, SEM, IR was used. Investigation of swelling behaviour due to the change of pH was carried out on the macroscopic matrix of nanofibers. It was followed by in vivo experiments on 6-6 albino rats for 72 h and 1 week period. We found that the fiber matrix hydrolise in 72 hours and turns into poly(aspartic acid) based hydrogel matrix and degrades in 1 week. Histology showed no inflammation and irritation. These preliminary experiments proved biocompatibility and biodegradability of our material. Financial support: OTKA K 115259, NKFIH FK 124147, Supported BY the ÚNKP-17-3-III-SE-18 New National Excellence Program of the Ministry of Human Capacities.

Dextrose monohydrate as a non-animal sourced alternative diluent in high shear wet granulation tablet formulations

The feasibility of dextrose monohydrate as a non-animal sourced diluent in high shear wet granulation (HSWG) tablet formulations was determined. Impacts of granulation solution amount and addition time, wet massing time, impeller speed, powder and solution binder, and dry milling speed and screen opening size on granule size, friability and density, and tablet solid fraction (SF) and tensile strength (TS) were evaluated. The stability of theophylline tablets TS, disintegration time (DT) and in vitro dissolution were also studied. Following post-granulation drying at 60 °C, dextrose monohydrate lost 9% water and converted into the anhydrate form. Higher granulation solution amounts and faster addition, faster impeller speeds, and solution binder produced larger, denser and stronger (less friable) granules. All granules were compressed into tablets with acceptable TS. Contrary to what is normally observed, denser and larger granules (at ≥21% water level) produced tablets with a higher TS. The TS of the weakest tablets increased the most after storage at both 25 °C/60% RH and 40 °C/75% RH. Tablet DT was higher for stronger granules and after storage. Tablet dissolution profiles for 21% or less water were comparable and did not change on stability. However, the dissolution profile for tablets prepared with 24% water was slower initially and continued to decrease on stability. The results indicate a granulation water amount of not more than 21% is required to achieve acceptable tablet properties. This study clearly demonstrated the utility of dextrose monohydrate as a non-animal sourced diluent in a HSWG tablet formulation.

The Effect of Compaction Force on the Transition to Hydrate of Anhydrous Aripiprazole.

Aripiprazole (APZ) is used to treat schizophrenia and is administered as a tablet containing the anhydrous form of APZ. In this study, the effect of compaction force on the crystal form transition was investigated. The crystalline state was observed by X-ray diffraction (XRD). APZ Anhydrous Form II was compacted into tablets. The XRD intensity of anhydrous APZ became lower with higher compressive force. The degree of crystallinity decreased with the compaction force. The powder and the compacted tablets of anhydrous APZ were stored for one week under 60°C and 75% relative humidity. The powder showed no crystal form transition after storage. For the tablets, however, XRD peaks of APZ hydrate were observed after storage. The tablets compacted with higher force showed the higher XRD diffraction intensity of hydrate form. We concluded that the crystallinity reduction of APZ Anhydrous Form II by compaction caused and accelerated the transition to hydrate under high temperature and humidity conditions. In order to manufacture crystallographically stable tablets containing anhydrous APZ, it is important to prevent this crystallinity reduction during compaction.

4-Methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic Acid. Peculiarities of Preparation, Structure, and Biological Properties.

In order to determine the regularities of the structure–analgesic activity relationship, the peculiarities of obtaining, the spatial structure, and biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and some of its derivatives have been studied. Using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction analysis, it has been proven that varying the reaction conditions using alkaline hydrolysis of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate makes it possible to successfully synthesize a monohydrate of the target acid, its sodium salt, or 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine. The derivatographic study of the thermal stability of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid monohydrate has been carried out; based on this study, the optimal conditions completely eliminating the possibility of unwanted decomposition have been proposed for obtaining its anhydrous form. It has been shown that 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine is easily formed during the decarboxylation of not only 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid, but also its sodium salt, which is capable of losing СО2 both in rather soft conditions of boiling in an aqueous solution, and in more rigid conditions of dry heating. The NMR spectra of the compounds synthesized are given; their spatial structure is discussed. To study the biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and its sodium salt, the experimental model of inflammation caused by subplantar introduction of the carrageenan solution in one of the hind limbs of white rats was used. The anti-inflammatory activity and analgesic effect were assessed by the degree of edema reduction and the ability to affect the pain response compared to the animals of control groups. According to the results of the tests performed, it has been found that after intraperitoneal injection, the substances synthesized demonstrate a moderate anti-inflammatory action and simultaneously increase the pain threshold of the experimental animals very effectively, exceeding Lornoxicam and Diclofenac in a similar dose by their analgesic activity.

Changing π-Interactions and Conformational Adjustments of N-(Isonicotinylhydrazide)-1,8-naphthalimide by Hydration and Complexation Affect Photophysical Properties

Noncovalent self-assemblies of different forms of a 1,8-naphthalimide derivative N-(isonicotinylhydrazide)-1,8-naphthalimide adopt different conformational adjustments due to the interplay of weak interactions. In such assemblies stacking interactions significantly contribute to direct the orientations of tether, which also influenced packing patterns. Effects of weak noncovalent interactions are reflected in the physicochemical properties of solvate and metal complexes of this naphthalimide derivative. Dual fluorescence emissions were observed from hydrate and silver complex of N-(isonicotinylhydrazide)-1,8-naphthalimide, which was not observed in anhydrous form of the compound. These results are compared with fluorescence emission study performed with solution of N-(isonicotinylhydrazide)-1,8-naphthalimide. Aggregation induced fluorescence emission of a solution in DMSO was caused by adding water. This emission in solution occurred at a much different emission wavelength than the emission observed from ...

Impact of Solid-State Form on the Disproportionation of Miconazole Mesylate.

Approximately 50% of solid oral dosage forms utilize salt forms of the active pharmaceutical ingredient (API). A major challenge with the salt form is its tendency to disproportionate to produce the un-ionized API form, decreasing the solubility and negatively impacting product stability. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties of the salt on the disproportionation reaction is unknown. Herein, various solid forms of a model salt, miconazole mesylate (MM), were evaluated for their tendency to undergo disproportionation when mixed with basic excipients, namely tribasic sodium phosphate dodecahydrate (TSPd) and croscarmellose sodium (CCS), and exposed to moderate relative humidity storage conditions. It was observed that the rate and extent of salt disproportionation were significantly different for the various solid forms of MM. As expected, the amorphous salt was highly susceptible to disproportionation, while the dihydrate salt form was resistant to conversion under the conditions tested. In addition, binary excipient blends of amorphous and anhydrous forms exhibited a reduced extent of disproportionation at a higher relative humidity storage condition. This was due to the competitive kinetics between disproportionation to the free base and conversion to the dihydrate salt form. The results of this study provide important insights into the impact of solid-state form on susceptibility to disproportionation that can be utilized for rationally designing robust pharmaceutical formulations.

A rapidly-reversible absorptive and emissive vapochromic Pt(II) pincer-based chemical sensor

Selective, robust and cost-effective chemical sensors for detecting small volatile-organic compounds (VOCs) have widespread applications in industry, healthcare and environmental monitoring. Here we design a Pt(II) pincer-type material with selective absorptive and emissive responses to methanol and water. The yellow anhydrous form converts reversibly on a subsecond timescale to a red hydrate in the presence of parts-per-thousand levels of atmospheric water vapour. Exposure to methanol induces a similarly-rapid and reversible colour change to a blue methanol solvate. Stable smart coatings on glass demonstrate robust switching over 104 cycles, and flexible microporous polymer membranes incorporating microcrystals of the complex show identical vapochromic behaviour. The rapid vapochromic response can be rationalised from the crystal structure, and in combination with quantum-chemical modelling, we provide a complete microscopic picture of the switching mechanism. We discuss how this multiscale design approach can be used to obtain new compounds with tailored VOC selectivity and spectral responses.

Preparation of Microcrystals of Piroxicam Monohydrate by Antisolvent Precipitation via Microfabricated Metallic Membranes with Ordered Pore Arrays.

Microcrystals of piroxicam (PRX) monohydrate with a narrow size distribution were prepared from acetone/PRX solutions by antisolvent crystallization via metallic membranes with ordered pore arrays. Crystallization was achieved by controlled addition of the feed solution through the membrane pores into a well-stirred antisolvent. A complete transformation of an anhydrous form I into a monohydrate form of PRX was confirmed by Raman spectroscopy and differential scanning calorimetry. The size of the crystals was 7–34 μm and was controlled by the PRX concentration in the feed solution (15–25 g L–1), antisolvent/solvent volume ratio (5–30), and type of antisolvent (Milli-Q water or 0.1–0.5 wt % aqueous solutions of hydroxypropyl methyl cellulose (HPMC), poly(vinyl alcohol) or Pluronic P-123). The smallest crystals were obtained by injecting 25 g L–1 PRX solution through a stainless-steel membrane with a pore size of 10 μm into a 0.06 wt % HPMC solution stirred at 1500 rpm using an antisolvent/solvent ratio of 20. HPMC provided better steric stabilization of microcrystals against agglomeration than poly(vinyl alcohol) and Pluronic P-123, due to hydrogen bonding interactions with PRX and water. A continuous production of large PRX monohydrate microcrystals with a volume-weighted mean diameter above 75 μm was achieved in a continuous stirred membrane crystallizer. Rapid pouring of Milli-Q water into the feed solution resulted in a mixture of highly polydispersed prism-shaped and needle-shaped crystals.

Acetylhydroxamic acid

There is one independent molecule in the asymmetric unit of the title compound (alternatively namedN-hydroxyacetamide), C2H5NO2. It crystallizes in the noncentrosymmetric space groupP43. The structure is an anhydrous form of acetylhydroxamic acid with typical geometry that corresponds well with the hydrated structure described by Bracher & Small [Acta Cryst.(1970), B26, 1705–1709]. In the crystal, N—H...O and O—H...O hydrogen bonds connect the molecules into chains in thec-axis direction.

Synthesis, Characterization, and Crystal Chemistry of Tasimelteon, a Melatonin Agonist, in Its Anhydrous and Hemihydrate Forms

Two crystalline forms of tasimelteon, a drug approved by the U.S. Food and Drug Administration for the treatment of non-24-h sleep-wake disorder, have been studied by single crystal and powder diffraction analyses, thermogravimetric analysis, differential scanning calorimetry, spectroscopic, and optical methods. The synthetic method forming tasimelteon is described in detail, with its full analytical, spectroscopic, and enantiopurity characterization. Solid tasimelteon hemihydrate, C15H19NO2·0.5H2O, is tetragonal with a = b = 7.3573(2) Å, c = 52.062(2) Å, V = 2818.1(2) Å3; Z = 8. Its crystal structure has been solved and refined in the P43212 space group, showing the occurrence of polymeric (H-bonded) slabs, thanks to the presence of water molecule (OW) tetrahedrally linked to 4 distinct tasimelteon molecules in a N2(OW)O2 fashion. The anhydrous form of tasimelteon, C15H19NO2, crystallizes in the monoclinic P21 space group, with a = 11.130(4), b = 4.907(2), c = 12.230(6) Å, β = 91.03(3)°, V = 667.8(5) Å3; Z = 2. Thanks to the availability of good-quality specimens, the structure of the latter phase was solved by conventional single-crystal diffraction analysis, showing short intermolecular C=O…H–N interactions between (translationally related) tasimelteon molecules, forming, in the crystal, well-defined chains running along the b axis. The morphology of the 2 crystal forms has been analyzed by the means of optical microscopy and particle size distribution analysis. Worthy of note, the newly determined crystal structures enable the successful usage of full-pattern matching X-ray-based quantitative analyses of batches of industrial interest, in search for contamination or phase stability issues.

Full spectroscopic characterization of two crystal pseudopolymorphic forms of the antiandrogen cortexolone 17α-propionate for topic application

Cortexolone-17α-propionate (CP) is a topically active antiandrogen useful in the treatment of skin disorders. In the solid state, three anhydrous forms of this drug (CPI, CPII and CPIII) occur, together with one hydrated crystal (CPW). The single crystal structure of the monohydrated phase, CPW, compared with that of the anhydrous form CPIII, shows a markedly different solid state behavior. These latter pseudopolymorphic forms have also been fully characterized by spectroscopic methods.

Characterization of crystalline linear (1 → 3)-α-d-glucan synthesized in vitro

We investigated the crystal structure and molecular arrangement of the linear (1→3)-α-d-glucan synthesized by glucosyltransferase GtfJ cloned from Streptococcus salivarius using sucrose as a substrate. The synthetic products had two morphologies: wavy fibril-like crystals as major and thin lamellae as minor products. Their structures were analyzed using electron microdiffraction, synchrotron X-ray powder diffraction, and solid-state 13C NMR spectroscopy. The fibrils and lamellae had the same allomorphic form but different molecular arrangements. The wet crystals were in a hydrated form, which converted into an anhydrous form with a significant decrease in crystallinity on drying. The hydrated and anhydrous forms had an extended-chain conformation with 2/1 helix, and the hydrated form was estimated to contain one water molecule per glucose residue. The long glucan chains were folded in the fibril crystals, while the short, extended chains were arranged perpendicular to the base plane of the lamellae.

The Influence of Mannitol Hemihydrate on the Secondary Drying Dynamics of a Protein Formulation: A Case Study

The objective of this research was to study the atypical secondary drying dynamics observed during the freeze-drying of a formulation consisting of mannitol, disaccharide, and sodium chloride, where “bursts” of water vapor release were observed during secondary drying as detected by comparative pressure measurement. “Thief” samples were removed at the end of primary drying and during secondary drying as the shelf temperature was increased in a stepwise fashion. These samples were examined by X-ray powder diffraction and thermal analysis. From the X-ray powder diffraction data, we determined that mannitol crystallized predominantly as its hemihydrate. The physical state of mannitol changed from the hemihydrate form to anhydrous forms during secondary drying. Investigation of the effect of excipients on mannitol crystallization demonstrated that sodium chloride (at 225 mM, 1.3% w/v) had the greatest influence on hemihydrate crystallization, followed by trehalose and sucrose. However, only negligible hemihydrate formation was observed when mannitol was freeze-dried either by itself or in the presence of 150 mM sodium chloride and no hemihydrate in the presence of 75 mM sodium chloride. In general, a combination of a disaccharide and sodium chloride promoted the hemihydrate formation to a greater extent than the individual components. Comparative pressure measurement was demonstrated to be an effective tool to monitor mannitol hemihydrate dehydration during secondary drying.

Thermal hazard investigation of a pharmaceutical intermediate

During the process development of a pharmaceutical advanced intermediate, new chemistry using an aqueous workup resulted in the discovery of a new hydrated crystal form of this intermediate. This hydrated crystal form showed thermal instability at a relatively low temperature compared to the original anhydrous form. Thermal stability and associated process safety hazards were investigated in order to ensure process safety and transportation safety of this intermediate. © 2017 American Institute of Chemical Engineers Process Saf Prog 37: 263–267, 2018

Molecular beam epitaxy growth of SmFeAs(O,F) films with Tc = 55 K using the new fluorine source FeF3

REFeAs(O,F) (RE: rare-earth element) has the highest-Tc (∼58 K) among the iron-based superconductors, but a thin-film growth of REFeAs(O,F) is difficult. This is because it is not only a complex compound consisting of five elements but also requires doping of highly reactive fluorine to achieve superconductivity. We have reported in our previous article that fluorine can be supplied to a film by subliming solid-state fluorides such as FeF2 or SmF3. In this article, we report on the growth of SmFeAs(O,F) using FeF3 as an alternative fluorine source. FeF3 is solid at ambient temperatures and decomposes at temperatures as low as 100–200 °C, and releases fluorine-containing gas during the thermal decomposition. With this alternative fluorine source, we have grown SmFeAs(O,F) films with Tc as high as 55 K. This achievement demonstrates that FeF3 has potential as a fluorine source that can be employed ubiquitously for a thin-film growth of any fluorine containing compounds. One problem specific to FeF3 is that the compound is highly hydroscopic and contains a substantial amount of water even in its anhydrous form. In this article, we describe how to overcome this specific problem.

Structure and hydrogen bonding in 5-(dimethylphenylammonium)-valeric acid bromide hydrate

The molecular structure and properties of 5-(dimethylphenylammonium)-valeric acid bromide hydrate have been characterized by X-ray diffraction, B3LYP/6–311++G(d,p) calculations, FTIR and Raman spectra. The molecules are linked through the water molecules into centrosymmetric dimers arranged into a layered strongly anisotropic structure. It has been found that the bromide anion interacts with water molecule. The FTIR spectrum shows a broad absorption in the 3300–2200cm−1 region attributed to the νCOOH⋯OH2 and νBr−⋯H2O. A comparison was made between the conformation of valeric acid unit in hydrate and anhydrous forms in the isolated molecules and in the crystal. The experimental and theoretical infrared spectra are discussed. The potential energy distributions (PED) have been used to assign the bands in vibrational spectrum.