Multi-technique approach for qualitative and quantitative characterization of furazidin degradation kinetics under alkaline conditions.

Degradation of drug furazidin was studied under different conditions of environmental pH (11-13) and temperature (30-60°C). The novel approach of hybrid hard- and soft-multivariate curve resolution-alternating least squares (HS-MCR-ALS) method was applied to UV-vis spectral data to determine a valid kinetic model and kinetic parameters of the degradation process. The system was found to be comprised of three main species and best characterized by two consecutive first-order reactions. Furazidin degradation rate was found to be highly dependent on the applied environmental conditions, showing more prominent differences between both degradation steps towards higher pH and temperature. Complimentary qualitative analysis of the degradation process was carried out using HPLC-DAD-TOF-MS. Based on the obtained chromatographic and mass spectrometric results, as well as additional computational analysis of the species (theoretical UV-vis spectra calculations utilizing TD-DFT methodology), the operating degradation mechanism was proposed to include formation of a 5-hydroxyfuran derivative, followed by complete hydrolysis of furazidin hydantoin ring.

Solvates of Dasatinib: Diversity and Isostructurality.

A series of dasatinib crystalline forms were obtained, and a hierarchical cluster analysis of their powder X-ray diffraction patterns was performed. The resulting dendrogram implies 3 structural groups. The crystal structures of several solvates representing 2 of these groups were determined. The crystal structure analysis confirms the isostructurality of solvates within structural group I and suggests a correlation between solvent molecule size and trends in crystal structures within this group. In addition, the formation relationships in 2-solvent media between different dasatinib solvate groups were determined. The formation preference of solvates was found to follow the ranking group I > group III > group II.

The effect of excipients on the stability and phase transition rate of xylazine hydrochloride and zopiclone.

The compatibility of thermodynamically unstable polymorph of two active pharmaceutical compounds (xylazine hydrochloride form X and zopiclone form C) with different excipients was investigated. The effects of the excipient and its amount in the sample on the thermal properties and possible chemical interactions were studied. The most commonly used excipients in the pharmaceutical industry - calcium carbonate, lactose hydrate, cellulose, magnesium stearate hydrate and calcium stearate hydrate were selected for this study. The dependence of the phase transition rate from an unstable to a more stable polymorph on the excipients and their amounts in the initial sample was analysed at 80°C, and the corresponding phase transition rate constants were calculated.

Protonation effects on the UV/Vis absorption spectra of imatinib: a theoretical and experimental study.

An experimental and theoretical investigation of protonation effects on the UV/Vis absorption spectra of imatinib showed systematic changes of absorption depending on the pH, and a new absorption band appeared below pH 2. These changes in the UV/Vis absorption spectra were interpreted using quantum chemical calculations. The geometry of various imatinib cations in the gas phase and in ethanol solution was optimized with the DFT/B3LYP method. The resultant geometries were compared to the experimentally determined crystal structures of imatinib salts. The semi-empirical ZINDO-CI method was employed to calculate the absorption lines and electronic transitions. Our study suggests that the formation of the extra near-UV absorption band resulted from an increase of imatinib trication concentration in the solution, while the rapid increase of the first absorption maximum could be attributed to both the formation of imatinib trication and tetracation.

Effect of experimental and sample factors on dehydration kinetics of mildronate dihydrate: mechanism of dehydration and determination of kinetic parameters.

The dehydration kinetics of mildronate dihydrate [3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propionate dihydrate] was analyzed in isothermal and nonisothermal modes. The particle size, sample preparation and storage, sample weight, nitrogen flow rate, relative humidity, and sample history were varied in order to evaluate the effect of these factors and to more accurately interpret the data obtained from such analysis. It was determined that comparable kinetic parameters can be obtained in both isothermal and nonisothermal mode. However, dehydration activation energy values obtained in nonisothermal mode showed variation with conversion degree because of different rate-limiting step energy at higher temperature. Moreover, carrying out experiments in this mode required consideration of additional experimental complications. Our study of the different sample and experimental factor effect revealed information about changes of the dehydration rate-limiting step energy, variable contribution from different rate limiting steps, as well as clarified the dehydration mechanism. Procedures for convenient and fast determination of dehydration kinetic parameters were offered.

Investigation of the phase transitions occurring during and after the dehydration of xylazine hydrochloride monohydrate.

This paper reports an investigation of a complex solid state phase transition where two inter-converting polymorphs (X and A) of the pharmaceutical molecule xylazine hydrochloride formed and transformed during and after the dehydration of its monohydrate (H). The crystal structures of all three forms were compared. During the investigation of this solid state phase transition it was determined that the dehydration of H produced either a pure X form, or a mixture of the X and A forms. The phase composition depended on the sample preparation procedure and the experimental conditions. It was found that grinding of the hydrate enhanced the formation of polymorph X as a product of dehydration, whereas higher humidity, temperature, or mechanical compression enhanced the formation of polymorph A. The transition mechanism of this complex process was analysed and explained by taking into account the crystal structures of these three forms.

Structure determination of three polymorphs of xylazine from laboratory powder diffraction data.

The crystal structures of three xylazine hydrochloride [N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiaz-2-amine hydrochloride] polymorphs A, Z and X have been solved from powder diffraction data and refined using Rietveld refinement. Data were obtained with Cu Kα radiation. All polymorphs were found to have structures with Z' = 1 and Z = 4. All the structures determined contained strong hydrogen bonds between the amino groups and chloride anions. The crystal structures of forms A and X featured π-π stacking interactions.

Application of LA-ICP-MS as a rapid tool for analysis of elemental impurities in active pharmaceutical ingredients.

The control of inorganic contaminants in active pharmaceutical ingredients has a significant role in the quality control of drug products. The concentration limits for metal residues in drug products have been defined by various regulatory guidelines. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a powerful and fast analytical technique for multi-elemental analysis. A disadvantage in using LA-ICP-MS method is the lack of matrix reference materials for validation and calibration purposes. This article focuses on the handling strategy of laboratory-made matrix calibration standards for the quantification of elemental impurities in an active pharmaceutical ingredient by LA-ICP-MS.

Organic solvent desorption from two tegafur polymorphs.

Desorption behavior of 8 different solvents from α and ß tegafur (5-fluoro-1-(tetrahydro-2-furyl)uracil) has been studied in this work. Solvent desorption from samples stored at 95% and 50% relative solvent vapor pressure was studied in isothermal conditions at 30 °C. The results of this study demonstrated that: solvent desorption rate did not differ significantly for both phases; solvent desorption in all cases occurred faster from samples with the largest particle size; and solvent desorption in most cases occurred in two steps. Structure differences and their surface properties were not of great importance on the solvent desorption rates because the main factor affecting desorption rate was sample particle size and sample morphology. Inspection of the structure packing showed that solvent desorption rate and amount of solvent adsorbed were mainly affected by surface molecule arrangement and ability to form short contacts between solvent molecule electron donor groups and freely accessible tegafur tetrahydrofuran group hydrogens, as well as between solvents molecule proton donor groups and fluorouracil ring carbonyl and fluoro groups. Solvent desorption rates of acetone, acetonitrile, ethyl acetate and tetrahydrofuran multilayers from α and ß tegafur were approximately 30 times higher than those of solvent monolayers. Scanning electron micrographs showed that sample storage in solvent vapor atmosphere promotes small tegafur particles recrystallization to larger particles.

Two polymorphs of afobazole from powder diffraction data.

Afobazole {systematic name: 2-[2-(morpholin-4-yl)ethylsulfanyl]-1H-benzimidazole} is a new anxiolytic drug and Actins, Auzins & Petkune [(2012). Eur. Patent EP10163962] described four polymorphic modifications. In the present study, the crystal structures of two monoclinic polymorphs, 5-ethoxy-2-[2-(morpholin-4-ium-4-yl)ethylsulfanyl]-1H-benzimidazol-3-ium dichloride, C15H23N3O2S(2+)·2Cl(-), (II) and (IV), have been established from laboratory powder diffraction data. The crystal packing and conformation of the dications in (II) and (IV) are different. In (II), there are channels in the [001] direction, which offer atmospheric water molecules an easy way of penetrating into the crystal structure, thus explaining the higher hygroscopicity of (II) compared with (IV).

Organic solvent vapor effects on phase transition of α and ß tegafur upon grinding with solvent additives.

Solvent effects on α tegafur (5-fluoro-1-(tetrahydro-2-furyl)uracil) phase transition to ß tegafur during grinding with solvent additive, as well as phase transition in samples exposed to 95% relative solvent vapor pressure has been studied in this research. Samples containing 0.5% and 0.1% of ß tegafur in α and ß tegafur mixture, as well as samples of pure α tegafur were ground with different solvent additives, and conversion degrees depending on the solvent were determined using PXRD method. Samples with α and ß tegafur weight fraction of 1:1 were exposed to 95% relative solvent vapor pressure, and phase transition rates were determined. Solubility of α tegafur, solvent sorption and desorption behavior on α and ß tegafur have been examined. It was found that the conversion degree of α tegafur to ß tegafur mainly depends on solubility of α tegafur in the relevant solvent, and the conversion degree to ß tegafur is higher in such solvents, where solubility of α tegafur is higher. The samples ground in a ball mill with solvent additive had a trend of phase transition dynamics from α tegafur to ß tegafur similar to the samples exposed to 95% relative solvent vapor pressure.

Pimobendan B from powder diffraction data.

The title mol-ecule, C19H18N4O2 {systematic name: (RS)-6-[2-(4-meth-oxy-phen-yl)-1H-benzimidazol-5-yl]-5-methyl-4,5-di-hydro-pyridazin-3(2H)-one}, adopts an extended conformation. The dihedral angles between the central benzimidazole ring sytem and the pendant meth-oxy-phenyl and pyridazinone residues are 1.41 (18) and 9.7 (3)°, respectively. In the crystal, N-H⋯N hydrogen bonds link the imadazole groups into [001] chains, and pairs of N-H⋯O hydrogen bonds link the pyridazinone groups into dimers. Together, these generate a two-dimensional supra-molecular structure parallel to (010). The layers are linked by C-H⋯π inter-actions.

Optimization of sample preparation conditions for detecting trace amounts of ß-tegafur in α- and ß-tegafur mixture.

We report a semiquantitative method for determining trace amounts (<1%) of thermodynamically stable forms in polymorphic mixtures, focusing on sample preparation effects on solid phase transitions. Tegafur [5-fluoro-1-(oxolan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione] was used as a model material in this study. The amounts of the thermodynamically stable ß tegafur were increased to levels detectable by powder X-ray diffractometry by grinding the samples in a ball mill in the presence of water. The limit of detection for this method was as low as 0.0005% of ß tegafur in α and ß tegafur mixtures. The amount of ß tegafur after sample preparation was found to be proportional to the initial weight fraction of ß tegafur. The sum of Langmuir and Cauchy-Lorentz equations was used to describe the change in conversion degree due to the added water volume, where Langmuir equation described water sorption during the sample preparation and Cauchy-Lorentz equation described the grinding efficiency.

The effect of pH on polymorph formation of the pharmaceutically active compound tianeptine.

The anti-depressant pharmaceutical tianeptine has been investigated to determine the dynamics of polymorph formation under various pH conditions. By varying the pH two crystalline polymorphs were isolated. The molecular and crystal structures have been determined to identify the two polymorphs. One polymorph is an amino carboxylic acid and the other polymorph is a zwitterion. In the solid state the tianeptine moieties are bonded through hydrogen bonds. The zwitterion was found to be less stable and transformed to the acid form. During this investigation an amorphous form was identified.

Organic solvents vapor pressure and relative humidity effects on the phase transition rate of α and ß forms of tegafur.

The objective of this work was to investigate the relative humidity (RH) and solvent vapor pressure effects on the phase transition dynamics between tegafur polymorphic forms that do not form hydrates and solvates. The commercially available α and ß modifications of 5-fluoro-1-(tetrahydro-2-furyl)-uracil, known as the antitumor agent tegafur, were used as model materials for this study. While investigating the phase transitions of α and ß tegafur under various partial pressures of methanol, n-propanol, n-butanol, and water vapor, it was determined that the phase transition rate increased in the presence of solvent vapors, even though no solvates were formed. By increasing the relative air humidity from 20% to 80%, the phase transition rate constant of α and ß tegafur was increased about 60 times. After increasing the partial pressure of methanol, n-propanol, or n-butanol vapor, the phase transition rate constant did not change, but the extent of phase transformation was increased. In the homologous row of n-alcohols, the phase transition rate constant decreased with increasing carbon chain length. The dependence of phase transformation extent versus the RH corresponded to the polymolecular adsorption isotherm with a possible capillary condensation effect.

7-[(3-Chloro-6-methyl-6,11-dihydro-dibenzo[c,f][1,2]thia-zepin-11-yl)amino]-hepta-noic acid S,S-dioxide hydro-chloride.

In the title compound, C(21)H(26)ClN(2)O(4)S(.)Cl, also known as tianeptine hydro-chloride, the seven-membered ring adopts a boat conformation. The dihedral angle between the mean planes of the benzene rings is 44.44 (7)°. There is an intra-molecular hydrogen bond formed via S= O⋯H-N. In the crystal, mol-ecules are connected via pairs of N-H.·O, N-H⋯Cl and O-H⋯Cl hydrogen bonds, forming inversion dimers, which are consolidated by C-H⋯O inter-actions. The dimers are linked by C-H⋯O and C-H⋯Cl inter-actions, forming a two-dimensional network lying parallel to (011).

Determination of trace amounts of ß tegafur in commercial α tegafur by powder X-ray diffractometric analysis.

OBJECTIVES: The main objective of this work was to develop a suitable analytical technique for determining trace amounts of the thermodynamically stable solid form in bulk samples of metastable form, to a sensitivity of 0.005%-1.0%. Tegafur (5-fluoro-1-(tetrahydro-2-furyl)-uracil) α and ß crystalline forms were used as a model for this problem. METHODS: The trace content of the thermodynamically stable ß polymorphic form in tegafur samples was increased by promoting phase transition from the bulk of thermodynamically metastable α form to ß form, and achieving sufficient ß form content for a quantitative powder X-ray diffractometry (PXRD) analysis. The phase transition was stimulated by adding water to the samples and then grinding in controlled conditions (temperature, time, grinding speed). A calibration line was constructed using the least squares method. KEY FINDINGS: By using a solvent that does not form hydrates with the analysed polymorphs, it was possible to promote the phase transformation from metastable form to the thermodynamically stable form. After sample preparation, the thermodynamically stable solid form content in the analysed mixture had increased proportionally to the initial weight fraction (0.005%-1.0%) of the stable form seed crystals in the samples, and the coefficient of proportionality was 43.0±0.9, with a standard deviation S(n) =1.5%. CONCLUSIONS: A simple, sensitive, semi-quantitative analytical method was developed for the low-level determination of the thermodynamically stable polymorphic form in mixtures of thermodynamically stable and metastable polymorphs.

Flecainide acetate acetic acid solvates.

Flecainide acetate forms acetic acid solvates with 0.5 and 2 acetic acid molecules. Powder X-ray diffraction, differential thermal analysis/thermogravimetric, infrared, and potentiometric titration were used to determine the composition of solvates. Flecainide acetate hemisolvate with acetic acid decomposes to form a new crystalline form of flecainide acetate. This form is less stable than the already known polymorphic form at all temperatures, and it is formed due to kinetic reasons. Both flecainide acetate nonsolvated and flecainide acetate hemisolvate forms crystallize in monoclinic crystals, but flecainide triacetate forms triclinic crystals. Solvate formation was not observed when flecainide base was treated with formic acid, propanoic acid, and butanoic acid. Only nonsolvated flecainide salts were obtained in these experiments.

Modelling phase transition kinetics of chenodeoxycholic acid with the Runge-Kutta method.

The phase transition kinetics of two chenodeoxycholic acid polymorphic modifications-form I (stable at high temperature), form III (stable at low temperature) and the amorphous phase has been examined under various conditions of temperature and relative humidity. Form III conversion to form I was examined at high temperature conditions and was found to be non-spontaneous, requiring seed crystals for initiation. The formation kinetic model of form I was created incorporating the three-dimensional seed crystal growth, the phase transition rate proportion to the surface area of form I crystals, and the influence of the amorphous phase surface area changes with an empirical stage pointer q that contained the incomplete transition of the amorphous phase to form I with a residue omega(A)(infinity). The extent of transition and the phase transition rate constant depended on form I seed crystal amount in the raw mixture, and on the sample preparation. To describe phase transition kinetic curves, we employed the Runge-Kutta differential equation numeric solving method. By combining the Runge-Kutta method with the multi-point optimization method, the average quadratic deviation of the experimental results from one calculated series was under 2%.

The relative stability of xylazine hydrochloride polymorphous forms.

All four known xylazine hydrochloride polymorphous forms were obtained and their relative stabilities were compared directly at three different temperatures. At higher temperatures, it is possible to determine the relative stability of all forms directly by measuring the changes in the composition of the mixtures of two polymorphous forms using powder x-ray diffraction methods. At lower temperatures, a solvent was added to the mixture and the changes in composition were determined. Polymorph transition temperatures were determined directly. To predict the transition temperature which was not found using the direct method, the polymorph melting data and determined transition temperatures were used. A phase stability diagram was constructed from the acquired data. The stability of all anhydrous polymorphous forms was compared in the presence of water vapor pressure that was higher than the equilibrium pressure.