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Mechanisms for Dehydration of Three Sodium Naproxen Hydrates
No full textSodium naproxen, a member of the class of nonsteroidal anti-inflammatory drugs (NSAID), exists in an anhydrous form and the following four hydrated ones: one monohydrate, two dehydrates, and one tetrahydrate. In the present work, the authors observed the isothermal dehydration of some of these hydrates by thermogravimetry at several temperatures. The rate of water removal from the crystal was used to determine the mechanism of dehydration in the solid state, by fitting results with selected expressions corresponding to the most common solid-state processes. The water loss was then evaluated according to Eyring's equation, and both changes in activation enthalpy (Delta H*) and activation entropy (Delta S*) were estimated from rate constant values. Experiments made it possible to distinguish different dehydration mechanisms for these hydrate forms, and in particular, to discern the dehydration behavior of two different dihydrate forms, one obtained by crystallizing sodium naproxen from water (CSN) and the other obtained after exposure to 55% RH (DSN). These results add new evidence supporting the X-ray powder diffraction study carried out in this work, showing different patterns for these two forms. X-ray powder diffractometry evaluation of the phase transitions occurring during dehydration of these two dihydrate forms showed that they vary according to dehydration temperature
Effect of poly(vinylpyrrolidone) or sodium alginate on the stability of the amorphous form of nimesulide
No full textNimesulide is a non-steroidal anti-inflammatory drug with a potent analgesic activity, but because it is practically insoluble in water, its bioavailability is significantly limited. One of the possible approaches for increasing the solubility and dissolution rate of a drug is to convert it from the crystalline to the amorphous form. Unfortunately, amorphous forms are generally unstable and do not guarantee an appropriate shelf life for the drug product. An interesting possibility for countering this difficulty is to use amorphous polymers to disperse the crystalline drug into the amorphous matrix, thus forming stable amorphous drug dispersions. In the present study, the thermal behavior of nimesulide and its physical stability in the amorphous state were fully characterized, and then, the possibility of prolonging its stability in the amorphous state was evaluated by dispersing the drug into two different amorphous polymers: poly(vinylpyrrolidone) or sodium alginate. The drug-polymer dispersion was obtained by co-heating the mix in a differential scanning calorimetry apparatus. The physicochemical stability of the pure nimesulide and the binary systems was evaluated by the Kolhaush-William-Watts equation. Aging experiments were carried out at different temperatures, and for each one the mean relaxation time constant was calculated to predict the physical stability of the amorphous system. The physical interaction between the drug and the polymer upon heating was determined according to the Gordon-Taylor equation. Our results showed that amorphous nimesulide is fragile, with limited stability, and thus inappropriate for industrial application. The observation that poly(vinylpyrrolidone) strongly increased the mean relaxation time constant of amorphous nimesulide was ascribed to the capacity of the binary system to form hydrogen bonds that stabilize the system. On the contrary, the sodium alginate was unable to increase the stability of the amorphous system and the mean relaxation time constant was even inferior to that of pure nimesulide. The failure of the two compounds to interact can be explained by the sterical hindrance of the sodium alginate chains
Effect of particle size reduction and crystalline form on dissolution behaviour of nimesulide
No full textThe objective of this study was to develop and examine innovative and very simple and easily scalable techniques able to improve solubility and/or dissolution rate and thus oral bioavailability of nimesulide. Three different nimesulide batches were obtained by three different laboratory-scale methods: Method A (Batch A) used crystallization by solvent evaporation in a nanospray dryer, Method B (Batches G and GLN) involved cryo-milling, and Method C (Batch Neu) dispersed nimesulide in Neusilin® UFL2. All the nimesulide batches were fully characterized for chemical stability, thermal behaviour, physicochemical and micromeritics properties, and intrinsic dissolution and particle dissolution rates. Batch A not only showed a good reduction in particle size but also exhibited a reduced degree of crystallinity by both differential scanning calorimetry and X-ray powder diffractometry, which could explain the increase in intrinsic dissolution rate (IDR) and particle dissolution. Batch GLN showed an acceptable increase in IDR, probably caused by a slight decrease in the degree of crystallinity, and good improvement in dissolution rate due to a certain decrease in particle size. Batches G and native crystals exhibited very close IDRs, while G showed somewhat higher particle dissolution, probably attributed to the particle size reduction. The dispersion of nimesulide in Neusilin UFL2 in a 1:6 drug-polymer ratio made it possible to recover anamorphous powder, as proven by thermal analysis and X-ray powder diffractometry, characterized by pronounced particle size reduction to nanometric dimensions. Both amorphous character and nanometric dimensions could account for the fastest particle dissolution during the first 10 min of the experiment. The stability study conducted according to the International Conference on Harmonization (ICH) confirmed the good chemical and physicochemical stability of all the batches
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Formation, Physicochemical Characterization, and Thermodynamic Stability of the Amorphous State of Drugs and Excipients
No full textDrugs and excipients used for pharmaceutical applications generally exist in the solid (crystalline or amorphous) state, more rarely as liquid materials. In some cases, according to the physicochemical nature of the molecule, or as a consequence of specific technological processes, a compound may exist exclusively in the amorphous state. In other cases, as a consequence of specific treatments (freezing and spray drying, melting and co-melting, grinding and compression), the crystalline form may convert into a completely or partially amorphous form. An amorphous material shows physical and thermodynamic properties different from the corresponding crystalline form, with profound repercussions on its technological performance and biopharmaceutical properties. Several physicochemical techniques such as X-ray powder diffraction, thermal methods of analysis, spectroscopic techniques, gravimetric techniques, and inverse gas chromatography can be applied to characterize the amorphous form of a compound (drug or excipient), and to evaluate its thermodynamic stability. This review offers a survey of the technologies used to convert a crystalline solid into an amorphous form, and describes the most important techniques for characterizing the amorphous state of compounds of pharmaceutical interest
Preformulation study of nicergoline solid dispersions
No full textNicergoline, a semisynthetic ergot derivative, which, in its crystalline state, is insoluble in water, was dispersed in polyvinylpyrrolidone K30 (PVP K30) to improve drug particle dissolution. Preformulation studies were carried out initially by differential scanning calorimetry and X-ray powder diffraction in order to predict the conditions and the possibility to actually obtain solid dispersions by mixing the two components at different proportions. Solid dispersions were finally prepared by dissolving nicergoline and PVP K30 in chloroform that was next evaporated under reduced pressure. Under these conditions, an amorphous powder was recovered in every proportion of the two components. Nicergoline demonstrated to be physically and chemically stable for 1 year. The dissolution studies revealed a very high dissolution rate of nicergoline from solid dispersions only lower than the pure amorphous form. This is the consequence of the molecular dispersion of nicergoline in the polymer that enhances the rate of drug release from the polymer. © 2013 Akadémiai Kiadó, Budapest, Hungary
Influence of relative humidity on the interaction between different aryl propionic acid derivatives and poly(vinylpyrrolydone) K30: Evaluation of the effect on drug bioavailability
No full textThe present work assessed the physical interactions between several aryl propionic acid derivatives and polyvinyl(pyrrolidone) K30 (PVP), stored together at 298±0.5K at different relative humidities (RH 55, 75 and 86%). Results were compared to those obtained at low RH (22%), published in a previous paper. The water uptake percentage of binary mixtures were intermediate between that of pure PVP and pure drugs. By X-ray powder diffraction, for all the drugs, it was possible to note a marked decrease in crystallinity degree, in particular at highest RH%. The loss in crystallinity degree may be considered an evidence of the physicochemical interaction between the polymer and the drug, supporting the formation of a solid dispersion. By high-resolution 1H solid-state NMR spectrometry, it was possible to observe an increase of drug-polymer interaction with aging, with the only exception of ibuprofen. Molecular docking proved the establishment of Van der Waals and electrostatic interactions for all the mixtures, and for mixtures with fenbufen and naproxen, also hydrogen bonds. The application of Gordon-Taylor rule to the thermal analysis revealed that the requirement of volume additivity of this rule was not fulfilled for any mixture, and a negative deviation from theoretical behaviour was always observed. The hydration of drug-PVP mixtures had important repercussion on drug solubility and intrinsic dissolution rate (IDR). In general, an increase in water solubility and consequently an increase in IDR were observed, with few exceptions, at highest RH%. © 2010 Elsevier B.V
Influence of pH and method of crystallization on the solid physical form of indomethacin.
No full textThe purpose of this study was to investigate the effect of pH and method of crystallization on the solid physical form of indomethacin (IDM). IDM, a non steroidal anti-inflammatory drug poorly soluble in water, underwent two different crystallization methods: crystallization by solvent evaporation under reduced pressure at 50.0°C (method A), and crystallization by cooling of solution from 50.0 to 5.0°C (method B). In both cases, several aqueous ethanolic solutions of IDM of different pHs were prepared. pHs were adjusted by adding acidic solutions (HCl 2M) or alkali (NaOH or NH4OH 2M) to an aqueous ethanolic solution of IDM. Thus, several batches were recovered after crystallization. The chemical stability of IDM was verified through (1)H NMR and mass spectroscopy (FIA-ESI-MS), that revealed that IDM degraded in strong alkali media (pH ≥ 12). Crystals obtained under different crystallization conditions at pHs of 1.0, 4.5, 7.0, 8.0, 10.0 and chemically stable were thus characterized for crystal habit by scanning electron microscopy, for thermal behaviour by differential scanning calorimetry, and thermogravimetry, and for solid state by X-ray powder diffractometry. Under the Method A, IDM always crystallized into pure metastable alpha form when solutions were acidified or alkalized respectively with HCl and NH4OH. On the contrary, in presence of NaOH, IDM crystallized under a mixture of alpha and sodium trihydrate form, because the presence of the sodium counter ion orientates the crystallization towards the formation of the trihydrate salt. Under the method B, at pH of 1.0, IDM crystallized under the alpha form; at pH 4.5, IDM crystallized under the form alpha in presence of some nuclei of gamma form; at pH 7.0, 8.0, and 10.0 for NH4OH, IDM crystallized under the most stable polymorph gamma form, whereas in presence of NaOH, a mix of alpha, and salt forms was formed whatever the pH of the solution
Influence of crystal hydration on the mechanical properties of sodium naproxen
No full textThe aim of this work is to establish a correlation between water uptake by anhydrous sodium naproxen (ASN) at two different relative humidities and modifications in tableting and densification behaviour under hydration. Water uptake was evaluated at different relative humidities. Models for the hydration kinetics of ASN at 55% and 86%. corresponding to the formation of the dihydrated and tetrahydrated forms, respectively, were evaluated assuming Eyring's dependence on temperature. Tabletability, compressibility, compactibility, and densification behaviour were determined using an instrumented single punch tablet machine. Kinetic data are consistent with a model where water molecules enter the crystal preferentially along hydrophilic tunnels existing in the crystal structure and corresponding to the propionate side chain. Water inclusion perturbs the crystallographic structure, causing slight structural changes according to the amount and associated to an increase in entropy. The interposition of water molecules between sodium naproxen molecules weakens intermolecular bonds, and these sites can behave like sliding planes under compression. Such structural changes may explain the improved compression behaviour and modified densification propensity mechanism. Kinetic data describing the water hydration mechanism of ASN explain in an original way the improved tableting and densification properties under hydration. (C) 2008 Elsevier B.V. All rights reserved
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