RESUMO
For over a century, it was thought that the crystalline polymorph II of benzophenone does not possess a stable domain in the pressure-temperature phase diagram. With a combination of new experimental results and literature data, this case of crystalline dimorphism has finally been solved and it is shown that form II possesses a stable domain at high pressure and high temperature, even though its density is lower than that of form I, the stable form under ordinary pressure and temperature conditions. The phase diagram of benzophenone is a clear demonstration of the fact that to understand the phase behaviour of a chemical substance both the exchange of heat (due to the change in intermolecular interactions) and work (due to the change of volume at a given pressure) need to be taken into account.
RESUMO
The dimorphism of the corticosteroid anti-inflammatory drug prednisolone has been investigated by the construction of a topological pressure-temperature phase diagram, using crystallographic and calorimetric data. The system is enantiotropic, because the temperature of the I-II equilibrium under atmospheric conditions (400-463 K) is lower than that of the two melting equilibria (518.7 K for form II and 526.3 K for form I). The slope of the I-II equilibrium in the pressure-temperature phase diagram is negative and relatively steep; therefore, form II, which is the stable form at room temperature, will not easily encounter conditions where form I will become stable even under industrial processing conditions. On the other hand, extreme small amounts of form I have been observed to spontaneously transform into form II in a time interval of about six years at room temperature and it can be concluded that although form I is very persistent under ambient conditions, it does slowly convert into form II. Moreover, the system does not obey the density rule.
Assuntos
Prednisolona , Caracteres Sexuais , Calorimetria , Varredura Diferencial de Calorimetria , Cristalização , Temperatura , TermodinâmicaRESUMO
The pressure-temperature phase diagram of the dimorphism of the contraceptive drug gestodene is constructed using the temperature and enthalpy of fusion of form I (469.5K, 107Jg-1), and those of the endothermic transition from form II to form I (311K, 8.52Jg-1). At ordinary pressure, the sign of the enthalpy of this transition indicates that these polymorphs are enantiotropically related and that form II, whose melting temperature is calculated to be about 452K, is the stable form at room temperature. Considering the inequality in the specific volumes of the two polymorphs, it is shown that the two forms remain enantiotropically related on increasing pressure, because the I-II equilibrium and the melting equilibria I-L and II-L diverge as a consequence of the negative slope dP/dT of the solid-solid equilibrium. In addition, it is demonstrated that the heats of dissolution, inferred from solubility measurements, lead to virtually the same value of the heat of transition from II to I as for the differential scanning calorimetry measurements.
Assuntos
Anticoncepcionais Orais Hormonais/química , Norpregnenos/química , Algoritmos , Varredura Diferencial de Calorimetria , Liberação Controlada de Fármacos , Pressão , Progestinas/química , Sensibilidade e Especificidade , Solubilidade , Estereoisomerismo , Temperatura , TermodinâmicaRESUMO
Information about the solid-state properties of etifoxine has been lacking, even if the active pharmaceutical ingredient has been used for its anxiolytic properties for decennia. The crystal structure of the racemic compound possesses a monoclinic space group P21/n with cell parameters aâ¯=â¯8.489(2) Å, bâ¯=â¯17.674(2) Å, câ¯=â¯20.883(3) Å, ßâ¯=â¯98.860(10)° and a unit-cell volume of 3095.8(9) Å3 at 293â¯K. The unit cell contains 8 molecules, while 2 independent molecules with different conformations are present in the asymmetric unit. The density of the crystal is 1.291â¯g/cm3 and its melting point was found at 362.6⯱â¯0.3â¯K with a melting enthalpy of 85.6⯱â¯3.0â¯Jâ¯g-1. Its thermal expansion in the liquid and the solid state and the change in volume on melting and between the vitreous state and the crystalline solid have been studied. The results confirm the tendency of small organic molecules to increase about 11% in volume on melting, while the volume difference between the glass and the crystal at the glass transition temperature is about half this value at 6%. These values can be used in the construction of phase diagrams in the case that the experimental data for a given system is incomplete.
Assuntos
Ansiolíticos/química , Química Farmacêutica , Oxazinas/química , Cristalização , Transição de Fase , Pressão , Estereoisomerismo , Temperatura , Termodinâmica , Temperatura de TransiçãoRESUMO
The crystal structure of tetrazepam, a benzodiazepine derivative formerly used for its muscle relaxant properties, has been solved and found to be monoclinic, space group P21/c, with lattice parameters a=12.7386(7)Å, b=11.3774(7)Å, c=10.3084(7)Å, ß=103.175(5) and Vunit-cell=1454.69(16) Å3 at room temperature (293K) with Z=4 molecules in the unit-cell. A network of weak hydrogen bonds involving aliphatic hydrogen atoms plays an important role in the formation of this structure.
Assuntos
Benzodiazepinas/química , Ligação de Hidrogênio , Relaxantes Musculares Centrais/química , Cristalização , Cristalografia por Raios X , Hidrogênio/química , Modelos Moleculares , Temperatura , Difração de Raios XRESUMO
The pressure-temperature phase diagram of the dimorphism of racemic m-nisoldipine is constructed using temperatures and enthalpies of fusion of forms A and B. At ordinary pressure, the transition from form B to form A is found to occur around 192K, which indicates that these polymorphs are enantiotropically related and that form A is stable at room temperature. Nevertheless, the phase relationship turns to be monotropic when pressures become greater than about 100MPa, which indicates that form B becomes the sole stable phase.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Nisoldipino/química , Cristalização , Estabilidade de Medicamentos , Pressão , Estereoisomerismo , Temperatura , TermodinâmicaRESUMO
Understanding the phase behavior of active pharmaceutical ingredients is important for formulations of dosage forms and regulatory reasons. Nimesulide is an anti-inflammatory drug that is known to exhibit dimorphism; however up to now its stability behavior was not clear, as few thermodynamic data were available. Therefore, calorimetric melting data have been obtained, which were found to be TI-L=422.4±1.0K, ΔIâLH=117.5±5.2Jg-1,TII-L=419.8±1.0K and ΔIIâLH=108.6±3.3Jg-1. In addition, vapor-pressure data, high-pressure melting data, and specific volumes have been obtained. It is demonstrated that form II is intrinsically monotropic in relation to form I and the latter would thus be the best polymorph to use for drug formulations. This result has been obtained by experimental means, involving high-pressure measurements. Furthermore, it has been shown that with very limited experimental and statistical data, the same conclusion can be obtained, demonstrating that in first instance topological pressure-temperature phase diagrams can be obtained without necessarily measuring any high-pressure data. It provides a quick method to verify the phase behavior of the known phases of an active pharmaceutical ingredient under different pressure and temperature conditions.
Assuntos
Sulfonamidas/química , Temperatura , Cristalização , Estabilidade de Medicamentos , TermodinâmicaRESUMO
Cimetidine is a histamine H2-receptor antagonist used against peptic ulcers. It is known to exhibit crystalline polymorphism. Forms A and D melt within 0.35 degrees from each other and the enthalpies of fusion are similar as well. The present paper demonstrates how to construct a pressure-temperature phase diagram with only calorimetric and volumetric data available. The phase diagram provides the stability domains and the phase equilibria for the phases A, D, the liquid and the vapor. Cimetidine is overall monotropic with form D the only stable solid phase.
Assuntos
Cimetidina/química , Calorimetria , Cristalização , Estabilidade de Medicamentos , Pressão , Temperatura , TermodinâmicaRESUMO
After a short review of the controversies surrounding the discovery of crystalline polymorphism in relation to our present day understanding, the methods of how to solve the stability hierarchy of different polymorphs will be briefly discussed. They involve either theoretical calculations, or, more commonly, experimental methods based on classical thermodynamics. The experimental approach is mainly carried out using heat-exchange data associated to the transition of one form into another. It will be demonstrated that work-related data associated to the phase transition should be taken into account and the role of X-ray crystallography therein will be discussed. X-ray crystallography has become increasingly precise and can nowadays provide specific volumes and their differences as a function of temperature, and also as a function of pressure, humidity, and time.
Assuntos
Cristalização , Cristalografia por Raios X/métodos , TermodinâmicaRESUMO
The topological pressure-temperature phase diagram for the dimorphism of spiperone, a potent neuroleptic drug, has been constructed using literature data and improved crystal structures obtained with new crystallographic data from single-crystal X-ray diffraction at various temperatures. It is inferred that form II, which is the more dense form and exhibits the lower melting temperature, becomes the more stable phase under pressure. Under ambient conditions, form I is more stable.
Assuntos
Antipsicóticos/química , Espiperona/química , Cristalização , Modelos Moleculares , Temperatura , Termodinâmica , Difração de Raios XRESUMO
A topological pressure-temperature phase diagram involving the phase relationships of ritonavir forms I and II has been constructed using experimental calorimetric and volumetric data available from the literature. The triple point I-II-liquid is located at a temperature of about 407 K and a pressure as extraordinarily small as 17.5 MPa (175 bar). Thus, the less soluble solid phase (form II) will become metastable on increasing pressure. At room temperature, form I becomes stable around 100 MPa indicating that form II may turn into form I at a relatively low pressure of 1000 bar, which may occur under processing conditions such as mixing or grinding. This case is a good example for which a proper thermodynamic evaluation trumps "rules of thumb" such as the density rule.
Assuntos
Fármacos Anti-HIV/química , Ritonavir/química , Varredura Diferencial de Calorimetria , Cristalização , Formas de Dosagem , Estabilidade de Medicamentos , Pressão , Temperatura , TermodinâmicaRESUMO
The crystal structure of L-ornithinium α-ketoglutarate (C5H13N2O2, C5H5O5) has been solved by direct methods using single crystal X-ray diffraction data. It crystallizes in the monoclinic system, space group P21, unit cell parameters a=15.4326(3), b=5.2015(1), c=16.2067(3) Å and ß=91.986(1)°, containing two independent pairs of molecular ions in the asymmetric unit. An extensive hydrogen-bond network and electrostatic charges due to proton transfer provide an important part of the cohesive energy of the crystal. The conformational versatility of L-ornithine and α-ketoglutaric acid is illustrated by the present results and crystal structures available from the Cambridge Structural Database.
Assuntos
Ácidos Cetoglutáricos/química , Ornitina/química , Cristalização , Cristalografia por Raios X , Ligação de Hidrogênio , Íons , Modelos Moleculares , Conformação Molecular , Prótons , Eletricidade Estática , Difração de Raios XRESUMO
The amorphous, molecular solid dispersion of cefuroxime axetil and copovidone with the mass ratio 71/29 is compared to its pure components in the amorphous state and to an amorphous mechanical mixture with the same mass ratio. Calorimetric studies demonstrate that all these materials are vitreous. By using X-ray diffraction profiles, a clear difference can be observed between the local order of the solid dispersion and that of the mechanical mixture. More generally, it is shown how the presence or absence of additivity in the diffraction data can be used to distinguish between different amorphous mixtures.
Assuntos
Antibacterianos/química , Cefuroxima/análogos & derivados , Excipientes Farmacêuticos/química , Povidona/química , Calorimetria , Varredura Diferencial de Calorimetria , Cefuroxima/química , Difração de Raios XRESUMO
A high pressure differential scanning calorimeter (HP-DSC) has been used to investigate the pressure dependence of the melting of the monoclinic (Form I) and orthorhombic (Form II) polymorphs of paracetamol (acetaminophen). DSC scans obtained at ambient pressure show that the stable monoclinic form melts at 442 K while the metastable orthorhombic form melts at 430 K. HP-DSC scans obtained for pressures up to about 450 MPa show that the melting temperatures of both Forms I and II increase with increasing pressure, but the latter more rapidly than the former. This results in a cross-over at about 250 MPa, where the two forms have approximately the same melting temperature, while at higher pressures Form II becomes the more stable phase. Although no solid-solid transitions have been observed, the coordinates of the I-II-liquid triple point have been found experimentally (p = 258.7 MPa and T = 489.6 K) for the first time, and confirm those predicted by Espeau et al. from a topological p-T diagram based on theoretical arguments and experimental data at ambient pressure.
Assuntos
Acetaminofen/química , Analgésicos não Narcóticos/química , Varredura Diferencial de Calorimetria , Tecnologia Farmacêutica/métodos , Cristalização , Estabilidade de Medicamentos , Modelos Químicos , Transição de Fase , Pressão , Temperatura de TransiçãoRESUMO
The aim of the present study was to develop an analytical method for measuring amounts of a dendro[60]fullerene (DF) which is a highly water-soluble [60]fullerene derivative. We tried to define a straightforward methodology using capillary zone electrophoresis, a method which, to our knowledge, has not yet been used to that purpose. Preliminary assays showed that DF has almost the same mobility than the electroosmotic flow (EOF) but in the opposite direction. Attempts were carried out to reduce the EOF and positive results were obtained by adding hydroxypropylcellulose to the background electrolyte. In order to define optimal operating conditions, a Taguchi experimental plan was used to study simultaneously the effects of the main parameters that are pH, ionic strength, methanol amount and hydroxypropylcellulose concentration. Two parameters are of the utmost importance as to their effect on the migration time and separation efficiecy: pH and ionic strength whose actions are opposite.
Assuntos
Carbono/química , Eletroforese Capilar/métodos , Fulerenos , Solubilidade , ÁguaRESUMO
The effect of C60 "micronized fullerene was tested by a manual and automatised (Analyzer Bioscreen C(R)) micromethod on the microbial growth of 22 collection strains: E. coli (5), P. aeruginosa (2), S. Typhimurium (6), S. aureus (2), L. monocytogenes (2), E. hirae (1), B. cereus (1), B. subtilis (1), B. pumilus (1) et C. albicans (1). No effect on microbial growth was observed with C60 "micronized fullerene (43.2 microg/ml) on all strains studied: no difference was found with doubling time, slope and growth rate constant. The results of cytotoxicity obtained with animal models or in vitro cultures as human monocyte, leukocyte or macrophage confirm the absence of effect of C60 fullerene at a concentration compatible with microbial or biological models. This study is included in research program headed "Therapeutics perspectives of fullerenes.
Assuntos
Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Carbono/farmacologia , Fulerenos , Microesferas , Fatores de TempoRESUMO
A high-performance liquid chromatographic (HPLC) assay method for C60 fullerene, in blood, liver and spleen using photodiode-array detection or mass spectrometric detection (LC-MS) and C70 fullerene, as the internal standard, is described. The recovery from mouse blood and tissues spiked with micronized C60 exceeds 90%. The method is linear from 0.05 to 200 mg of C60 per liter of blood and from 0.05 to 5.00% of C60 per tissue weight. The limit of detection of the method is 0.1 ng of C60 per injection. This method was applied to mouse blood and tissue samples after intraperitoneal administration of a micronized C60 suspension.