Anhydrous Form Research Articles

Solid forms and β-cyclodextrin complexation of turinabol.

4-Chloro-17β-hydroxy-17α-methylandrosta-1,4-dien-3-one (C20H27ClO2), known as turinabol, is a synthetic anabolic-androgenic agent which belongs to the steroid class. Recrystallization from various solvents was performed and the following new solid forms of turinabol were obtained: the hemihydrate (C20H27ClO2·0.5H2O), the anhydrous form (C20H27ClO2), the multicomponent acetic acid hydrate (2C20H27ClO2·C2H4O2·H2O) and the 2,2,2-trifluoroethanol hemisolvate (C20H27ClO2·0.5C2H3F3O). The absolute structures were determined by single-crystal X-ray diffraction. The starting hemihydrate form contains one turinabol molecule in the asymmetric unit, while the others contain two molecules in the asymmetric unit. Structural features were investigated in terms of the conformational analysis of the steroid skeleton rings and intermolecular interactions. The magnitudes, the nature of the crystal structure energies and the intermolecular interactions were also evaluated. Complexation with β-cyclodextrin was performed and the obtained complex was investigated using powder X-ray diffraction, Fourier-transform infrared (FT-IR) spectroscopy and differential thermal analysis/thermogravimetric analysis (DTA/TGA).

Chemical preparation, crystallographic characterization, vibrational study and thermal behavior of a new cyclotriphosphate CaNH4P3O9 · H2O

Chemical preparation, crystallographic characterization, IR studies and thermal behavior are presented for the new cyclotriphosphate CaNH4P3O9 · H2O and its anhydrous form CaNH4P3O9. CaNH4P3O9 · H2O was prepared by the method of ion exchange resin. CaNH4P3O9 · H2O crystallizes hexagonal, space group is P63 or P63/m or P6322 with the following unit-cell dimensions: a = b = 14.75(2) Å, c = 9.934(3) Å and Z = 8. The total dehydration of CaNH4P3O9 · H2O, between 70 °C and 180 °C, leads to its anhydrous form CaNH4P3O9. CaNH4P3O9 crystallizes in the monoclinic space group P21/n, Z = 4, with the following unit-cell dimensions: a = 7.446 Å, b = 12.46 Å, c = 10.050 Å, β = 90.11° and Z = 4. CaNH4P3O9 · H2O is stable until its melting point at 1050 °C. The thermal behavior of CaNH4P3O9 · H2O was investigated and interpreted by comparison with IR absorption spectrometry and X-ray diffraction experiments.

X-ray diffraction and vibrational data for a series of triphosphates type MIINa3P3O10.12H2O (MII = Cu, Ni and Mg) and their anhydrous forms MIINa3P3O10

Chemical preparation methods, X-ray diffraction and vibrational data are reported for six triphosphates type MIINa3P3O10.12H2O (MII = Cu, Ni and Mg) and their anhydrous forms MIINa3P3O10. These condensed phosphates are respectively, CuNa3P3O10.12H2O, MgNa3P3O10.12H2O, NiNa3P3O10.12H2O, CuNa3P3O10, NiNa3P3O10 and MgNa3P3O10. The hydrate triphosphates were prepared by the method of ion-exchange resin, where as their anhydrous forms were prepared by total thermal dehydration of MIINa3P3O10.12H2O (MII = Cu, Ni and Mg).CuNa3P3O10.12H2O, MgNa3P3O10.12H2O and NiNa3P3O10.12H2O are isotypic, and crystallize in the monoclinic system, space group is P21/n, Z = 4, the unit-cell parameters are: CuNa3P3O10.12H2O, a = 15.052(8) Å, b = 9.234(3) Å,c = 14.767(8) Å and β = 90.03(5)°. MgNa3P3O10.12H2O: a = 15.049(1) (1) Å, b = 9.245(4) Å, c = 14 0.722(3) (2) Å and β = 90.00(5)°.NiNa3P3O10.12H2O: a = 15.010(1) Å, b = 9.208(4) Å, c = 14.710(2) Å and β = 90.00(5)°.The anhydrous forms CuNa3P3O10, MgNa3P3O10 and NiNa3P3O10 crystallize in the monoclinic system, space group is P21/n, Z = 4, the unit-cell parameters are: CuNa3P3O10, a = 12.464(0) Å, b = 8.437(7) Å, c = 12.083(1) Å and β = 109.77(8) °; MgNa3P3O10: a = 11.931(4) (1) Å, b = 12.912(2) Å, c = 10.057(0) Å and β = 113.83(2)° and NiNa3P3O10: a = 12.686(8)Å, b = 9.271(2) (4) Å, c = 11.440(3) Å and β = 102,95(5)°.

Probing the Structure, Cytocompatibility, and Antimicrobial Efficacy of Silver-, Strontium-, and Zinc-Doped Monetite.

Calcium phosphate phases are among the most widely accepted compounds for biomaterial applications, of which the resorbable phases have gained particular attention in recent years. Brushite and its anhydrous form monetite are among the most interesting resorbable calcium phosphate phases that can be applied as cements and for in situ fabrication of three-dimensional (3D) implants. Of these two dicalcium phosphate compounds, monetite is more stable and undergoes slower degradation than brushite. The purpose of the current study is to synthesize and dope monetite with the antimicrobial elements silver and zinc and the osteoinductive element strontium and investigate the possible structural variations as well as their biocompatibility and antimicrobial effectiveness. For this, powder X-ray diffraction (PXRD), energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and cryo-transmission electron microscopy (cryo-TEM) were used to thoroughly study the synthesized structures. Moreover, the ASTM E-2149-01 protocol and a cell proliferation assay were used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) and the cytocompatibility of the different phases with the Soas-2 cell line, respectively. The results confirm the successful synthesis and doping procedures, such that zinc was the most incorporated element into the monetite phase and strontium was the least incorporated element. The microbiological studies revealed that silver is a very effective antimicrobial agent at low concentrations but unsuitable at high concentrations because its cytotoxicity would prevail. On the other hand, doping the compounds with zinc led to a reasonable antimicrobial activity without compromising the biocompatibility to obviously high concentrations. The study also highlights that strontium, widely known for its osteoinductivity, bears an antimicrobial effect at high concentrations. The generated doped compounds could be beneficial for prospective studies as bone cements or for scaffold biomaterial applications.

Vapoluminescence hysteresis in a platinum(II) salt-based humidity sensor: Mapping the vapochromic response to water vapor

In an effort to address the scarcity of chemical sensors that can record precise, reproducible, and sensitive changes in humidity, this work reports a reversible system based on a coordinatively unsaturated, square-planar platinum(II) salt, [Pt(tpy)Cl]ClO4 (tpy = 2,2′6′,2″-terpyridine). The sensing methodology relies on humidity induced vapochromic/vapoluminescent behavior of the salt; the anhydrous form is yellow in color and demonstrates orange-yellow luminescence indicating weak intermolecular Pt•••Pt interactions. Exposure to water vapor changes the salt color to dark red and the luminescence to red; this is triggered by incorporation of water molecules in the crystal lattice. This reorganizes the crystal packing, and extends Pt•••Pt interactions, as verified by crystal structure. The conversion between the fully hydrated and the fully dehydrated end products are spectroscopically reversible, demonstrating recyclability across cycles. However, the vapoluminescence response trajectory of the dehydrated form to water vapor sorption does not exactly reverse trace the desorption profile of the hydrated form but shows a hysteresis effect, demonstrating the vapochromic journey to be equally important as the destination. This methodology serves as the basis of humidity sensing for both powder as well as crystalline samples. The proposed sensor demonstrates a large linear operational range of humidity sensing (10–80% for crystals) and a limit of detection of 3.3%. The crystals also demonstrate an ability to sense water vapor in the presence of interfering organic vapors. The work presents a new simple, economic and scalable method for humidity sensing.

Salification Controls the In-Vitro Release of Theophylline

Sustained released formulation is the most used strategy to control the efficacy and the adverse reactions of an API (active pharmaceutical ingredient) with a narrow therapeutic index. In this work, we used a different way to tailor the solubility and diffusion of a drug. Salification of Theophylline with Squaric Acid was carried out to better control the absorption of Theophylline after administration. Salification proved to be a winning strategy decreasing the dissolution of the APIs up to 54% with respect to Theophylline. Most importantly, this was accomplished in the first 10 min of the dissolution process, which are the most important for the API administration. Two polymorphs were identified and fully characterized. Theophylline squarate was discovered as trihydrate (SC-XRD) and as a metastable anhydrous form. Indeed, during the Variable Temperature-XRPD experiment, the trihydrate form turned back into the two starting components after losing the three molecules of water. On the other hand, the synthesis of the trihydrate form was observed when a simple mixing of the two starting components were exposed to a high humidity relative percentage (90% RH).

Precise Dosing of Pramipexole for Low-Dosed Filament Production by Hot Melt Extrusion Applying Various Feeding Methods.

The aim of this research was the production of low-dosed filaments via hot-melt extrusion (HME) with the model drug pramipexole for the treatment of Parkinson’s disease. The active pharmaceutical ingredient (API) and one of the polymers polyvinyl alcohol (PVA) or basic butylated methacrylate copolymer (bPMMA) were fed by various dosing techniques with the aim of achieving the smallest deviation (RSD) from the target concentration of 0.1% (w/w) pramipexole. It was found that deviation from target pramipexole concentration occurred due to degradation products in bPMMA formulations. Additionally, material temperature above 120 °C led to the formation of the anhydrous form of pramipexole within the extruded filaments and need to be considered in the calculation of the recovered API. This study clearly shows that even if equilibrium state of the extrusion parameters was reached, equilibrium condition for drug content was reached relatively late in the process. In addition, the RSD calculated by the Stange–Poole equation was proposed by us to predict the final content uniformity considering the sample size of the analyzed filament. The calculated RSD, depending on sample size and drug load, can serve as upper and lower limits of variation from target concentration and can be used to evaluate the deviations of drug content in equilibrium conditions of the HME process. The lowest deviations from target concentration in equilibrium condition for drug content were obtained in filaments extruded from previously prepared granule mixtures (RSD = 6.00%, acceptance value = 12.2). These promising results can be transferred to other API–excipient combinations to produce low-dosed filaments, which can be used for, e.g., fused filament 3D printing. The introduced calculation of the RSD by Stange–Poole equation can be used for precise determination of the homogeneity of an extruded batch.

Conformational Selectivity and Evolution Affected by the Desolvation Process

The inconsistency between solution chemistry and the crystal structure indicates the potential conformational evolution and rearrangement during the nucleation process. However, the mechanism of how the conformation is selected to form the corresponding polymorph is still not clear due to the complicated crystallization environment. In this work, conformation and polymorph selectivity of three anhydrous forms of gabapentin were investigated. Quantum chemical computation was used to analyze gabapentin conformations in the solution state and explore their transformation pathway. Besides, visual molecular dynamics was adopted to calculate the structural difference of the conformers in solution and crystal states, which was closely related to conformational selectivity. Moreover, the effects of solvent types and the supersaturation on solute–solvent interactions were investigated by Fourier transform infrared spectra and molecular dynamics simulations. Combined with the outcome of rapid cooling experiments, it was found that the solute–solvent interaction may affect the difficulty of desolvation so as to affect the conformational selectivity before nucleation. A special evaporation experiment was designed to obtain the unstable polymorph of gabapentin. Finally, the possible mechanism of selective polymorph crystallization was proposed and analyzed.

Two anhydrous forms and one monohydrate of a cocrystal of axitinib and glutaric acid: characterization, property evaluation and phase transition study

Two anhydrous forms and one monohydrate of a cocrystal of axitinib and glutaric acid were obtained, and investigation of their phase transition relationship as well as characterization and property evaluation was carried out.

Monetite as a potential ideal bone substitute: A short review on fabrication and properties

The use of autologous bone for grafting, although remains as gold standard, still presents high complication rate. Calcium phosphates have been developed to fulfil the requirements as an ideal bone substitute. Among calcium phosphates, hydroxyapatite (HA), beta-tricalcium phosphate (β-TCP), and brushite are considered popular. Albeit being the most popular, those are not without drawbacks. The main issues with hydroxyapatite, β -TCP, and brushite is their solubility and resorption behaviour. On the other hand, monetite, the anhydrous form of brushite, were proven to have better solubility and resorption rate. Past studies have confirmed its osteoconductive and osseo-integrative ability, proving it as a material of importance in bone grafting field. Seeing its potentials, monetite is starting to gain more popularity to be an ideal candidate for bone grafting. This paper intends to present a review of monetite as a bone substitute material. Here, we narrate a review of the fabrication and properties of monetite that have been conducted from previous studies. We also discuss the application of monetite as graft in dental and orthopaedic field. Hopefully readers may find this review helpful to find key information about the emerging importance of monetite and utilize this work as a conduct for further research.

Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile.

A new cocrystal of Norfloxacin, a poorly soluble fluoroquinolone antibiotic, has been synthetized by a solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. The new cocrystal exists in both anhydrous and monohydrate forms with the same (1:1) Norfloxacin/resorcinol stoichiometry. The solubility of Norfloxacin and the hydrated cocrystal were determined by the shake-flask method. While Norfloxacin has a solubility of 0.32 ± 0.02 mg/mL, the cocrystal has a solubility of 2.64 ± 0.39 mg/mL, approximately 10-fold higher. The dissolution rate was tested at four biorelevant pH levels of the gastrointestinal tract: 2.0, 4.0, 5.5, and 7.4. In a first set of comparative tests, the dissolution rate of Norfloxacin and the cocrystal was determined separately at each pH value. Both solid forms showed the highest dissolution rate at pH 2.0, where Norfloxacin is totally protonated. Then, the dissolution rate decreases as pH increases. In a second set of experiments, the dissolution of the cocrystal was evaluated by a unique dissolution test, in which the pH dynamically changed from 2.0 to 7.4, stepping 30 min at each of the four biorelevant pH values. Results were quite different in this case, since dissolution at pH 2 affects the behavior of Norfloxacin at the rest of the pH values.

Understanding Crystal Structures to Guide Form Selection of Active Pharmaceutical Ingredients: A Case Study of AZD9567

AZD9567 is a novel oral selective glucocorticoid receptor modulator drug candidate in AstraZeneca’s pipeline. Three distinctive solid forms of AZD9567 were identified during early development where Form A was found to be a hydrate, and both Forms B and C are anhydrous. In this study, we present the significance of applying crystal structure assessments along with typical solid-state experimental characterizations in early stage drug development to guide solid form selection. The Form A hydrate, which is usually regarded as the preferred form in liquid formulation, is found not stable, narrowing the form selection toward Forms B and C. Anhydrous Form C has disorder depending on the temperature and is more stable than anhydrous Form B, and this is supported by a higher melting point and experimental density as well as a series of density functional theory calculations. This eventually results in the recommendation of selecting anhydrous AZD9567 Form C as the solid form to move forward for further development.

Chemical preparation, crystal structure and vibrational study of MnNa3P3O10.12H2O and X-ray characterization of the new anhydrous triphosphate MnNa3P3O10

ABSTRACT The MnNa3P3O10.12H2O was prepared by the ion exchange resin process. Its structure was studied by X-ray diffraction and determined in the monoclinic, space group P121/c1 with the unit-cell parameters a = 14.6650 (5) Å, b = 9.1916 (3) Å, c = 15.0239 (5) Å, α = γ = 90 °, β = 90.2210 (10) °, Z = 4 and V = 2025.13 (12) Å3. The thermal dehydration of this compound was performed, leading to an anhydrous new form MnNa3P3O10, which was characterized by X-ray diffraction. The obtained MnNa3P3O10 is monoclinic of space group: P21/n with the unit-cell parameters: a = 15.3774 (1) Å, b = 7.6988 (5) Å, c = 14.2832 (3) Å, β = 92.9115 (5) °. The characteristic IR wavenumbers of the P3O10 5− ions observed in the vibrational spectra were calculated by using isotopic substitutions, which confirms the existence of these groups in the studied compound. A comparison between the IR and Raman wavenumbers of MnNa3P3O10.12H2O, MnNa3P3O10 and Na5P3O10.12H2O was performed. A kinetic study was also made for MnNa3P3O10·12H2O.

Solid-State Study of the Structure, Dynamics, and Thermal Processes of Safinamide Mesylate─A New Generation Drug for the Treatment of Neurodegenerative Diseases.

Safinamide mesylate (SM), the pure active pharmaceutical ingredient (API) recently used in Parkinson disease treatment, recrystallized employing water–ethanol mixture of solvents (vol/vol 1:9) gives a different crystallographic form compared to SM in Xadago tablets. Pure SM crystallizes as a hemihydrate in the monoclinic system with the P21 space group. Its crystal and molecular structure were determined by means of cryo X-ray crystallography at 100 K. SM in the Xadago tablet exists in anhydrous form in the orthorhombic crystallographic system with the P212121 space group. The water migration and thermal processes in the crystal lattice were monitored by solid-state NMR spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. SM in Xadago in the high-humidity environment undergoes phase transformation to the P21 form which can be easily reversed just by heating up to 80 °C. For the commercial form of the API, there is also a reversible thermal transformation observed between Z′ = 1 ↔ Z′ = 3 crystallographic forms in the 0–20 °C temperature range. Analysis of molecular motion in the crystal lattice proves that the observed conformational polymorphism is forced by intramolecular dynamics. All above-mentioned processes were analyzed and described employing the NMR crystallography approach with the support of advanced theoretical calculations.

Citric Acid in Endodontics: A Review

Naturally occurring in citrus fruits, citric acid is categorized as a weak organic acid, which may exist both as a monohydrate or in an anhydrous form. In biochemistry, this organic acid acts as an intermediate in an essential metabolic process in all aerobic organisms called the Krebs cycle. The literature on citric acid in the context of endodontics up to June 2020 was reviewed using PubMed and MEDLINE. This review aimed to address the antibacterial efficacy of citric acid on endodontic microbiota, its effectiveness on the smear layer, the effects of its toxicity on fracture resistance of dentin, as well as the effectiveness of this acid on the removal of intra-canal medicaments. This report also addressed citric acid-containing endodontic irrigants.

Alkali Metal Dithiocarbamato Carboxylates (DTCCs) – Synthesis, Properties, and Crystal Structures

AbstractA series of alkali metal salts of dithiocarbamate‐substituted carboxylate (DTCC) anions were prepared by reaction of the parent amino acids with carbon disulfide and an alkali metal hydroxide. The target compounds, which were isolated in anhydrous form or as hydrates, were extensively characterized by elemental analyses, IR and NMR spectroscopy, thermal analyses, cyclic voltammetry, and single‐crystal X‐ray diffraction. The isolated compounds are more or less hygroscopic and display a varying dehydratization and decomposition behavior upon heating. The assumed degradation of the DTCC scaffold was found to depend on the substitution pattern as well as on the alkali metal counterion, and covers a range between 200 and 340 °C. In aqueous solution, the DTCC anions show irreversible electrochemical oxidations, where the corresponding redox potentials are governed by the substitution pattern of the nitrogen atom. Single‐crystal structural analyses of sodium and potassium derivatives revealed that these compounds exist as two‐ or three‐dimensional coordination polymers in the solid state, with the alkali‐metal ions adopting typical irregular coordination environments with coordination numbers of six or higher.

Pseudopolymorphism Driven by Stoichiometry and Hydrated/Anhydrous Reagents: The Riveting Case of Methyl Gallate·l-Proline

Among GRAS molecules, α-amino acids have been extensively used to produce molecular salts and cocrystals of APIs thanks to their nontoxicity, ready availability, cheapness, and their zwitterionic nature. Here we report on the use of both anhydrous and hydrated l-proline (Pro and Pro·H2O, respectively) with methyl gallate (MG) to selectively obtain by mechanochemical methods anhydrous and hydrated cocrystals: MG·Pro2 and MG2·Pro2·H2O, respectively. The two new forms were characterized by means of single-crystal and powder X-ray diffraction (SCXRD and PXRD), solid-state nuclear magnetic resonance (SSNMR), DSC, and TGA. Interestingly, the choice of the starting material together with the stoichiometry drives the formation of the cocrystal toward either the anhydrous or the hydrate form: the anhydrous form could be obtained only on starting from anhydrous Pro, whereas the hydrate could be obtained with Pro·H2O or with Pro by matching the correct stoichiometry. An energy framework analysis allowed us to rationalize this peculiar water uptake behavior in terms of both the relative interaction strengths of proline–proline, proline–water, and proline–methyl gallate pairs and packing features.

Physico-chemical properties of two anhydrous azathioprine forms and their interaction with typical pharmaceutical excipients: highlighting new findings in drug formulation development

The physico-chemical properties of two anhydrous AZA forms and their interaction with typical pharmaceutical excipients were assessed by applying various methods (such as PXRD, HPLC, TG/DSC, IR, Raman, PL or UV-Vis) in order to highlight new directions for drug formulation. The stability assessment of AZA anhydrous forms I and II was performed in order to determine the risk of degradation of the active ingredient by accidental exposure to nonstandard conditions in the industrial environment, under different storage, transport or processing conditions. The benefits of form II include increased resistance to chemical degradation over a wide range of pH, but further control of storage and processing conditions is necessary to avoid polymorphic transformation into form I. The solubility assessment on the AZA solid forms in different environments that simulate the conditions of the gastrointestinal tract has the advantage of a significantly increased solubility of form II compared with the commercial form I due to the modification of the crystalline structure. In the case of capsules compared to AZA form I or II as powder, an improvement in their solubility was observed, promoted by the presence of one or more excipients in the formulation mixture.

Mechanochemical Synthesis and Physicochemical Characterization of Previously Unreported Praziquantel Solvates with 2-Pyrrolidone and Acetic Acid.

Two new solvates of the widely used anthelminthic Praziquantel (PZQ) were obtained through mechanochemical screening with different liquid additives. Specifically, 2-pyrrolidone and acetic acid gave solvates with 1:1 stoichiometry (PZQ-AA and PZQ-2P, respectively). A wide-ranging characterization of the new solid forms was carried out by means of powder X-ray diffraction, differential scanning calorimetry, FT-IR, solid-state NMR and biopharmaceutical analyses (solubility and intrinsic dissolution studies). Besides, the crystal structures of the two new solvates were solved from their Synchrotron-PXRD pattern: the solvates are isostructural, with equivalent triclinic packing. In both structures acetic acid and 2-pyrrolidone showed a strong interaction with the PZQ molecule via hydrogen bond. Even though previous studies have shown that PZQ is conformationally flexible, the same syn conformation as the PZQ Form A of the C=O groups of the piperazinone-cyclohexylcarbonyl segment is involved in these two new solid forms. In terms of biopharmaceutical properties, PZQ-AA and PZQ-2P exhibited water solubility and intrinsic dissolution rate much greater than those of anhydrous Form A.

A Study on the Crystal Transformation Relationships of Valacyclovir Hydrochloride Polymorphs: Sesquihydrate, Form I, and Form II

AbstractValacyclovir hydrochloride is a kind of antiviral drug and has several crystal forms including sesquihydrate (SH), anhydrous Form I, and Form II. Here, the dehydration process of SH by heat drying is investigated by powder X‐ray diffraction, differential scanning calorimetry, thermogravimetry analysis, vapor sorption analysis, and ReactRaman spectroscopy, and the dehydration and absorption of crystal water are revealed. The transformations of SH to Form I, Form II to Form I, and SH to Form II in aqueous ethanol suspension are monitored by ReactRaman spectroscopy, and the mechanisms of two different transition processes are defined through the analysis of ReactRaman spectra. The crystal transformation relationship of the mentioned forms is established.