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1.
Sci Rep ; 13(1): 11914, 2023 Jul 24.
Article in English | MEDLINE | ID: mdl-37488270

ABSTRACT

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.

2.
Int J Pharm ; 624: 122047, 2022 Aug 25.
Article in English | MEDLINE | ID: mdl-35902055

ABSTRACT

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.


Subject(s)
Prednisolone , Sex Characteristics , Calorimetry , Calorimetry, Differential Scanning , Crystallization , Temperature , Thermodynamics
3.
Ann Pharm Fr ; 78(4): 303-309, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32444029

ABSTRACT

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.


Subject(s)
Contraceptives, Oral, Hormonal/chemistry , Norpregnenes/chemistry , Algorithms , Calorimetry, Differential Scanning , Drug Liberation , Pressure , Progestins/chemistry , Sensitivity and Specificity , Solubility , Stereoisomerism , Temperature , Thermodynamics
4.
Int J Pharm ; 572: 118812, 2019 Dec 15.
Article in English | MEDLINE | ID: mdl-31715343

ABSTRACT

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 a = 8.489(2) Å, b = 17.674(2) Å, c = 20.883(3) Å, ß = 98.860(10)° and a unit-cell volume of 3095.8(9) Å3 at 293 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 1.291 g/cm3 and its melting point was found at 362.6 ±â€¯0.3 K with a melting enthalpy of 85.6 ±â€¯3.0 J 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.


Subject(s)
Anti-Anxiety Agents/chemistry , Chemistry, Pharmaceutical , Oxazines/chemistry , Crystallization , Phase Transition , Pressure , Stereoisomerism , Temperature , Thermodynamics , Transition Temperature
5.
Ann Pharm Fr ; 77(2): 121-125, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30678803

ABSTRACT

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.


Subject(s)
Benzodiazepines/chemistry , Hydrogen Bonding , Muscle Relaxants, Central/chemistry , Crystallization , Crystallography, X-Ray , Hydrogen/chemistry , Models, Molecular , Temperature , X-Ray Diffraction
6.
Ann Pharm Fr ; 76(5): 341-347, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29798781

ABSTRACT

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.


Subject(s)
Calcium Channel Blockers/chemistry , Nisoldipine/chemistry , Crystallization , Drug Stability , Pressure , Stereoisomerism , Temperature , Thermodynamics
7.
Int J Pharm ; 525(1): 54-59, 2017 Jun 15.
Article in English | MEDLINE | ID: mdl-28411142

ABSTRACT

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, ΔI→LH=117.5±5.2Jg-1,TII-L=419.8±1.0K and ΔII→LH=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.


Subject(s)
Sulfonamides/chemistry , Temperature , Crystallization , Drug Stability , Thermodynamics
8.
Ann Pharm Fr ; 75(2): 89-94, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28160941

ABSTRACT

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.


Subject(s)
Cimetidine/chemistry , Calorimetry , Crystallization , Drug Stability , Pressure , Temperature , Thermodynamics
10.
Ann Pharm Fr ; 74(1): 12-20, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26601884

ABSTRACT

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.


Subject(s)
Crystallization , Crystallography, X-Ray/methods , Thermodynamics
11.
Ann Pharm Fr ; 74(2): 129-36, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26601885

ABSTRACT

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.


Subject(s)
Antipsychotic Agents/chemistry , Spiperone/chemistry , Crystallization , Models, Molecular , Temperature , Thermodynamics , X-Ray Diffraction
12.
Ann Pharm Fr ; 73(1): 22-30, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25496722

ABSTRACT

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.


Subject(s)
Anti-HIV Agents/chemistry , Ritonavir/chemistry , Calorimetry, Differential Scanning , Crystallization , Dosage Forms , Drug Stability , Pressure , Temperature , Thermodynamics
13.
Ann Pharm Fr ; 72(4): 238-43, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24997885

ABSTRACT

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.


Subject(s)
Ketoglutaric Acids/chemistry , Ornithine/chemistry , Crystallization , Crystallography, X-Ray , Hydrogen Bonding , Ions , Models, Molecular , Molecular Conformation , Protons , Static Electricity , X-Ray Diffraction
14.
Ann Pharm Fr ; 72(2): 95-100, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24630310

ABSTRACT

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.


Subject(s)
Anti-Bacterial Agents/chemistry , Cefuroxime/analogs & derivatives , Pharmaceutic Aids/chemistry , Povidone/chemistry , Calorimetry , Calorimetry, Differential Scanning , Cefuroxime/chemistry , X-Ray Diffraction
15.
J Pharm Sci ; 96(10): 2784-94, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17542017

ABSTRACT

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.


Subject(s)
Acetaminophen/chemistry , Analgesics, Non-Narcotic/chemistry , Calorimetry, Differential Scanning , Technology, Pharmaceutical/methods , Crystallization , Drug Stability , Models, Chemical , Phase Transition , Pressure , Transition Temperature
17.
Electrophoresis ; 22(20): 4341-6, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11824600

ABSTRACT

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.


Subject(s)
Carbon/chemistry , Electrophoresis, Capillary/methods , Fullerenes , Solubility , Water
18.
Ann Pharm Fr ; 58(3): 170-5, 2000 May.
Article in French | MEDLINE | ID: mdl-10844277

ABSTRACT

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.


Subject(s)
Bacteria/drug effects , Bacteria/growth & development , Carbon/pharmacology , Fullerenes , Microspheres , Time Factors
20.
J Chromatogr B Biomed Sci Appl ; 696(1): 153-9, 1997 Aug 15.
Article in English | MEDLINE | ID: mdl-9300920

ABSTRACT

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.


Subject(s)
Antiviral Agents/analysis , Carbon/analysis , Chromatography, High Pressure Liquid/methods , Drug Residues/analysis , Fullerenes , Liver/chemistry , Spleen/chemistry , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , Carbon/administration & dosage , Carbon/blood , Carbon/pharmacokinetics , Circadian Rhythm , Injections, Intraperitoneal , Linear Models , Male , Mice , Reproducibility of Results , Sensitivity and Specificity , Specific Pathogen-Free Organisms , Spectrophotometry, Ultraviolet
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