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1.
Eur J Pharm Sci ; 148: 105334, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32259678

RESUMO

To decide whether an active pharmaceutical ingredient can be used in its amorphous form in drug formulations, often the glass transition is studied in relation to the melting point of the pharmaceutical. If the glass transition temperature is high enough and found relatively close to the melting point, the pharmaceutical is considered to be a good glass former. However, it is obviously important that the observed melting point and glass transition involve exactly the same system, otherwise the two temperatures cannot be compared. Although this may seem trivial, in the case of hydrates, where water may leave the system on heating, the composition of the system may not be evident. Atorvastatin calcium is a case in point, where confusing terminology, absence of a proper anhydrate form, and loss of water on heating lead to several doubtful conclusions in the literature. However, considering that no anhydrate crystal has ever been observed and that the glass transition of the anhydrous system is found at 144 °C, it can be concluded that if the system is kept isolated from water, the chances that atorvastatin calcium crystallises at room temperature is negligible. The paper discusses the various thermal effects of atorvastatin calcium on heating and proposes a tentative binary phase diagram with water.

2.
Chemistry ; 25(61): 13837, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31691398

RESUMO

Invited for the cover of this issue is the group of Gérard Coquerel at Université de Rouen Normandie. The image depicts a pyramid-like tetrahedron of the quaternary phase diagram showing where symmetry breaking can take place. Read the full text of the article at 10.1002/chem.201903338.

3.
Chemistry ; 25(71): 16405-16413, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31566820

RESUMO

A new entry of chiral anti-hyperlipoproteinemia drug is reported, showing an excellent preferential enrichment (PE) phenomenon which is not caused by a polymorphic transition during crystallization, but is proposed to occur by a novel mechanism involving partially irregular stacking of R and S homochiral two-dimensional (2D) sheets with a large dipole moment, followed by selective redissolution of one homochiral 2D sheet into the mother liquor during crystallization. The cocrystal composed of (RS)-2-{4-[(4-chlorophenoxy)methyl]phenoxy}propionic acid (CPPPA) and achiral isonicotinamide exhibited a substantial enrichment in the mother liquor up to 93 % ee by simply repeating recrystallization under nonequilibrium conditions using high supersaturation. Furthermore, the deposited crystals with low ee values obtained at the end of PE experiment were second harmonic generation (SHG)-positive, indicating the formation of homochiral domains in the deposited crystals, which reflects the proposed mechanism of PE.

4.
Mol Pharm ; 16(11): 4670-4676, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31545612

RESUMO

The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution (ß = 2.3) remains clear for almost 1 h at 20 mL scale, revealing a slow nucleation rate. Seeding the supersaturated solution with the pure enantiomer triggered its crystallization both isothermal and polythermic modes of PC were successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC toward slowly crystallizing racemic compounds.

5.
Chemistry ; 25(61): 13890-13898, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31393026

RESUMO

A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2 O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second-order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate-forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes.

6.
Phys Chem Chem Phys ; 21(2): 702-717, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30543221

RESUMO

The present work focusses on the molecular mobility characterization of amorphous N-acetyl-α-methylbenzylamine (Nac-MBA) by Broadband Dielectric Relaxation Spectroscopy (DRS) coupled with Fast Scanning Calorimetry (FSC) and Molecular Dynamics (MD) simulations covering over 12 decades in the frequency range. This study reveals another example of a secondary amide that shows a very intense Debye-like contribution (almost 90% of the global dielectric intensity) in addition to the structural α-relaxation and secondary Johari-Goldstein ß-relaxation. The D- and α-relaxations are separated by about one decade (in frequency) and their relaxation times follow a near parallel temperature evolution (Vogel-Fulcher-Tammann-Hesse). The micro-structure of Nac-MBA has been investigated from MD simulations. It is shown that the intense Debye-like process emanates from the formation of linear intermolecular H-bonding aggregates (precursors of the crystalline structure) generating super-dipole moments.

7.
Chemistry ; 24(65): 17293-17302, 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30378204

RESUMO

A unique superparamagnetic-like behavior and a large "positive magneto-LC effect" were observed in the solid phases and the hexagonal columnar (Colh ) liquid crystalline (LC) phase, respectively, of novel achiral non-π-delocalized nitroxide diradical compounds (R,S)-1, which showed polymorphism in the solid phases (solids I and II). The SQUID magnetization measurement revealed that (1) (R,S)-1 containing a small amount of racemic diastereomers (R*,R*)-1 possessed an unusual and large temperature-independent magnetic susceptibility (χTIM >0) component in the original nanocrystalline solid I that was responsible for the observed superparamagnetic-like behavior under low magnetic fields and did not arise from the contamination by extrinsic magnetic metal or metal ion impurities, besides ordinary temperature-dependent paramagnetic susceptibility (χpara >0) and temperature-independent diamagnetic susceptibility (χdia <0) components, (2) a large increase in molar magnetic susceptibility (χM ) (positive magneto-LC effect) that occurred at the solid I-to-liquid crystal transition upon heating was preserved as an additional χTIM increase in the resulting polymorphic nanocrystalline solid II by cooling, and (3) such unique magnetic phenomena were induced by thermal processing for (R,S)-1 or by adding a small amount of (R*,R*)-1 to (R,S)-1 as the impurity.

8.
Int J Pharm ; 540(1-2): 11-21, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29407191

RESUMO

The investigation of the glassy state of 5-ethyl-5-methylhydantoin (i.e. 12H, a chiral Active Pharmaceutical Ingredient) was attempted by Differential Scanning Calorimetry (DSC) and Fast Scanning Calorimetry (FSC). This compound exhibits a high crystallization propensity for every enantiomeric composition. Nevertheless, glassy states of pure enantiomer or mixtures between enantiomers were successfully reached by FSC at cooling rates of: 1000 °C/s and 300 °C/s respectively, even though limitations on the sampling reproducibility were evidenced due to FSC sample size. The Glass Forming Ability (GFA) was proven to increase with the counter-enantiomer content. From the glassy state, pure enantiomer displayed a more pronounced crystallogenic character (with a crystallization occurring 36 °C below Tg during ageing) than that of the mixture between enantiomers. Ageing of amorphous 12H promotes a strong nucleation behavior in both samples but enantiopure 12H crystallizes upon ageing while scalemic 12H evolves towards the metastable equilibrium. Finally, potential new phase equilibria (previously not reported) in the enantiomeric phase diagram could have been highlighted by FSC by recrystallization from the amorphous state.


Assuntos
Hidantoínas/química , Temperatura de Transição , Varredura Diferencial de Calorimetria , Cristalização , Composição de Medicamentos , Estereoisomerismo , Tecnologia Farmacêutica/métodos
9.
Mol Pharm ; 15(3): 1112-1125, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29328661

RESUMO

The effect of low molecular weight excipients on drug-excipient interactions, molecular mobility, and propensity to recrystallization of an amorphous active pharmaceutical ingredient is investigated. Two structurally related excipients (α-pentaacetylglucose and ß-pentaacetylglucose), five different drug:excipient ratios (1:5, 1:2, 1:1, 2:1, and 5:1, w/w), and three different solid state characterization tools (differential scanning calorimetry, X-ray powder diffraction, and dielectric relaxation spectroscopy) were selected for the present research. Our investigation has shown that the excipient concentration and its molecular structure reveal quasi-identical molecular dynamic behavior of solid dispersions above and below the glass transition temperature. Across to complementary quantum mechanical simulations, we point out a clear indication of a strong interaction between biclotymol and the acetylated saccharides. Moreover, the thermodynamic study on these amorphous solid dispersions highlighted a stabilizing effect of α-pentaacetylglucose regardless of its quantity while an excessive concentration of ß-pentaacetylglucose revealed a poor crystallization inhibition. Finally, through long-term stability studies, we also showed the limiting excipient concentration needed to stabilize our amorphous API. Herewith, the developed procedure in this paper appears to be a promising tool for solid-state characterization of complex pharmaceutical formulations.


Assuntos
Química Farmacêutica , Excipientes/química , Simulação de Dinâmica Molecular , Fenóis/química , Cristalização , Estabilidade de Medicamentos , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica , Difração de Raios X
10.
Int J Pharm ; 536(1): 426-433, 2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-29225097

RESUMO

Cinchonidine and Theophylline vitrification abilities have been investigated by differential and fast scanning calorimetry. These active pharmaceutical compounds are known in the literature to have a very high tendency to crystallize which has been confirmed by classical differential scanning calorimetry. Due to the growing interest in amorphous pharmaceutical compounds, their possible vitrifications have been investigated by fast scanning calorimetry. This work shows the high potential of this advanced thermal analysis technique to investigate the vitrification of active pharmaceutical compounds by melt-quenching protocol. For the first time, glass transitions of Cinchonidine and Theophylline were measured. From Cinchonidine, it has been shown that complete glassy state can be obtained by cooling from the melt at 2000K/s. Crystallization has also been suppressed by cooling down from the melt at 2K/s. However, such rate does not avoid the formation of nuclei. Theophylline crystallization process has been suppressed by a melt-quenching protocol carried out with a cooling rate of 4000K/s. However, the phenomenon of nuclei formation upon cooling seems unavoidable at this cooling rate. For both active pharmaceutical compounds, physical aging has been observed to play a role on the nuclei formation below the glass transition leading to modify the subsequent crystallization.


Assuntos
Preparações Farmacêuticas/química , Varredura Diferencial de Calorimetria/métodos , Cristalização/métodos , Vidro/química , Transição de Fase , Temperatura , Teofilina/química , Vitrificação
11.
J Phys Chem B ; 121(32): 7729-7740, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28726403

RESUMO

A dielectric relaxation spectroscopy (DRS) study was performed to investigate the molecular mobility of amorphous chiral diprophylline (DPL). For this purpose, both racemic DPL and a single enantiomer of DPL were considered. After fast cooling from the melt at very low temperature (-140 °C), progressive heating below and above the glass transition (Tg ≈ 37 °C) induces two secondary relaxations (γ- and δ-) and primary relaxations (α-) for both enantiomeric compositions. After chemical purification of our samples by means of cooling recrystallization, no γ-process could be detected by DRS. Hence, it was highlighted that the molecular mobility in the glassy state is influenced by the presence of theophylline (TPH), the main impurity in DPL samples. We also proved that the dynamic behavior of a single enantiomer and the racemic mixture of the same purified compound are quasi-identical. This study demonstrates that the relative stability and the molecular mobility of chiral amorphous drugs are strongly sensitive to chemical purity.


Assuntos
Preparações Farmacêuticas/química , Cristalização , Espectroscopia Dielétrica , Transição de Fase , Estereoisomerismo , Temperatura , Teofilina/química
12.
J Phys Chem B ; 121(19): 5142-5150, 2017 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-28430440

RESUMO

We study the physicochemical transformations of crystalline quinidine upon high-energy milling. The investigations have been achieved by classical, high performance, and fast scanning calorimetry combined with broadband dielectric spectroscopy and X-ray powder diffraction. As evolution of crystalline quinidine with time of milling revealed a prominent sub-Tg cold-crystallization phenomenon, independent and complementary analytical techniques were implemented. Fast scanning calorimetry was performed for the first time on a milled pharmaceutical compound to postpone the crystallization event to higher temperatures. These fast thermal analyses allowed one to spotlight a genuine glass transition event. In addition, an aging experiment on the milled powder revealed a clear structural relaxation testifying to the presence of a glassy fraction in the milled sample. Last, dielectric analysis of milled quinidine disclosed the presence of localized and delocalized molecular mobility characteristics of glasses. Results for samples obtained by two distinct amorphization routes, vitrification and high-energy milling, indicate that amorphous fraction in milled quinidine behaves the same way as melt-quenched quinidine. These above-mentioned techniques proved their relevancy and efficiency to characterize milled quinidine, and fast scanning calorimetry in particular appears a promising screening tool for disordered systems.


Assuntos
Quinidina/química , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cristalização , Espectroscopia Dielétrica , Difração de Pó , Temperatura
13.
J Chromatogr A ; 1485: 101-119, 2017 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-28108081

RESUMO

This study aims at modelling and predicting solute retention in capillary Gas Chromatography (GC) and Flow Modulation comprehensive GC (FM-GCxGC). A new thermodynamic model, taking into account the effects of temperature and pressure, is proposed to describe the variation of the equilibrium partition constant of a solute during its elution. This retention model was challenged with the classical one, and both were applied to: (i) stationary phase film thickness indirect estimation; (ii) retention time (RT) prediction of a set of 11 model polycyclic aromatic hydrocarbons (PAHs) on the SLB-IL60 and DB-35MS columns, in temperature-programmed mode. Film thickness determination led to values about 2 times lower than those indicated by column nominal dimensions, whatever the employed model. Prediction of retention times in GC led to 0.84 and 0.26% mean errors using the classical and the extended models, respectively. Prediction in GCxGC gave 5.5 and 0.44% mean errors in 1st dimension RTs, and 7.3 and 2.2% mean errors in 2nd dimension RTs, using the classical and the extended models, respectively.


Assuntos
Cromatografia Gasosa/métodos , Hidrocarbonetos Policíclicos Aromáticos/análise , Pressão , Temperatura , Termodinâmica
14.
Int J Pharm ; 515(1-2): 702-707, 2016 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-27818243

RESUMO

Brivaracetam, or (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide, is an active pharmaceutical ingredient designed for the treatment of epilepsy. During the development of the IV administration mode, a liquid-liquid miscibility gap has been observed with pure water, isotonic and hypertonic solutions (vehicle at 0.9% w/w and 5%w/w NaCl respectively). The study reveals that the NaCl concentration has a direct impact on the extent of the demixing domain; from a sub-micronic demixing in pure water towards a macroscopic miscibility gap in hypertonic aqueous solutions. The thorough exploration of these heterogeneous equilibria led to define experimental parameters for safe IV injections without risk of liquid - liquid miscibility gap at 37°C.


Assuntos
Pirrolidinonas/química , Cloreto de Sódio/química , Água/química , Administração Intravesical , Pirrolidinonas/administração & dosagem , Soluções/química
15.
Chemistry ; 22(45): 16103-16112, 2016 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-27667660

RESUMO

The crystallisation behaviour of (RS)-diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised.

16.
Curr Pharm Des ; 22(32): 4929-4941, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27510486

RESUMO

A mixture of two enantiomers can crystallize according to three types of heterogeneous equilibria: a racemic compound (a 1:1 stoichiometric compound), a conglomerate (a physical mixture of particles with opposite chirality) or, more rarely, as a solid solution (a crystalline architecture exhibiting a lack of chiral discrimination with respect to the two enantiomers). Due to the scarce occurrence of solid solutions, only a few examples of such behavior are known, and even fewer systems have been investigated by means of single crystal X-ray diffraction. Yet, preliminary work performed in the 1970s by several research teams revealed that structural investigations of solid solutions could provide valuable insights into chiral discrimination mechanisms at the crystal lattice scale. In the present paper, our aim is to review published cases of enantiomeric solid solutions for which both melting phase diagrams and crystal structures are available in order to analyze the lack of chiral discrimination associated to these phases. Our methodology consists in considering both the molecular and crystallographic aspects of stereoselectivity with the final aim of identifying structural criteria responsible for the occurrence of solid solutions. The experimental conditions allowing access to solid solutions will also be considered in light of these structural criteria.


Assuntos
Preparações Farmacêuticas/química , Cristalização , Estrutura Molecular , Soluções , Estereoisomerismo
17.
J Phys Chem B ; 120(30): 7579-92, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27391029

RESUMO

In this article, we conduct a comprehensive molecular relaxation study of amorphous Quinidine above and below the glass-transition temperature (Tg) through broadband dielectric relaxation spectroscopy (BDS) experiments and theoretical density functional theory (DFT) calculations, as one major issue with the amorphous state of pharmaceuticals is life expectancy. These techniques enabled us to determine what kind of molecular motions are responsible, or not, for the devitrification of Quinidine. Parameters describing the complex molecular dynamics of amorphous Quinidine, such as Tg, the width of the α relaxation (ßKWW), the temperature dependence of α-relaxation times (τα), the fragility index (m), and the apparent activation energy of secondary γ relaxation (Ea-γ), were characterized. Above Tg (> 60 °C), a medium degree of nonexponentiality (ßKWW = 0.5) was evidenced. An intermediate value of the fragility index (m = 86) enabled us to consider Quinidine as a glass former of medium fragility. Below Tg (< 60 °C), one well-defined secondary γ relaxation, with an apparent activation energy of Ea-γ = 53.8 kJ/mol, was reported. From theoretical DFT calculations, we identified the most reactive part of Quinidine moieties through exploration of the potential energy surface. We evidenced that the clearly visible γ process has an intramolecular origin coming from the rotation of the CH(OH)C9H14N end group. An excess wing observed in amorphous Quinidine was found to be an unresolved Johari-Goldstein relaxation. These studies were supplemented by sub-Tg experimental evaluations of the life expectancy of amorphous Quinidine by X-ray powder diffraction and differential scanning calorimetry. We show that the difference between Tg and the onset temperature for crystallization, Tc, which is 30 K, is sufficiently large to avoid recrystallization of amorphous Quinidine during 16 months of storage under ambient conditions.

18.
Chemistry ; 22(33): 11660-6, 2016 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-27406004

RESUMO

The kinetic/thermodynamic origin of preferential enrichment (PE), which is a spontaneous enantiomeric resolution phenomenon applicable to racemic crystals, is described. The mechanism of PE, which was unveiled with respect to the first-generation of chiral organic compounds showing PE, has been interpreted in terms of a nonlinear complexity phenomenon including two unique processes: a solvent-assisted solid-to-solid polymorphic transition and subsequent selective redissolution of the excess one enantiomer from the transformed disordered crystals into the mother liquor. The present works confirm that PE takes place because of the unique nonlinear solubility properties of the two enantiomers after the occurrence of a polymorphic transition under PE crystallization conditions at high supersaturation. Furthermore, a ternary phase diagram that is consistent with the mechanism of PE is proposed.

19.
J Pharm Sci ; 105(1): 64-70, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26852840

RESUMO

Two polymorphs of the 1:1 fumarate salt of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester, developed for the treatment of cognitive symptoms of schizophrenia and Alzheimer disease, have been characterized. The 2 crystal structures have been solved, and their phase relationships have been established. The space group of form I is P21/c with a unit-cell volume of 1811.6 (5) Å(3) with Z = 4. The crystals of form I were 2-component nonmerohedral twins. The space group of form II is P21/n with a unit-cell volume of 1818.6 (3) Å(3) with Z = 4. Relative stabilities have been inferred from experimental and topological P-T diagrams exhibiting an overall enantiotropic relationship between forms I and II although the solid-solid transition has never been observed. The slope of the I-II equilibrium in the P-T diagram is negative, form II is the stable phase below the solid-solid transition temperature of 371 K, and form I exhibits a stable melting equilibrium. The I-II transition temperature has been obtained from the intersection of the sublimation curves of the 2 solid forms.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Agonistas Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cristalização , Agonismo Parcial de Drogas , Fumaratos/química , Modelos Químicos , Agonistas Nicotínicos/farmacologia , Transição de Fase , Termogravimetria
20.
Int J Pharm ; 499(1-2): 67-73, 2016 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-26707413

RESUMO

This study investigates for the first time the thermodynamic changes of Biclotymol upon high-energy milling at various levels of temperature above and below its glass transition temperature (Tg). Investigations have been carried out by temperature modulated differential scanning calorimetry (TM-DSC) and X-ray powder diffraction (XRPD). Results indicate that Biclotymol undergoes a solid-state amorphization upon milling at Tg-45 °C. It is shown that recrystallization of amorphous milled Biclotymol occurs below the glass transition temperature of Biclotymol (Tg=20 °C). This displays molecular mobility differences between milled Biclotymol and quenched liquid. A systematic study at several milling temperatures is performed and the implication of Tg in the solid-state transformations generally observed upon milling is discussed. Influence of analysis temperature with respect to interpretation of results was investigated. Finally, it is shown that co-milling Biclotymol with only 20 wt% of amorphous PVP allows a stable amorphous dispersion during at least 5 months of storage.


Assuntos
Química Farmacêutica/métodos , Fenóis/química , Termodinâmica , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Fenóis/administração & dosagem , Temperatura , Temperatura de Transição , Difração de Raios X
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