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The main purpose of our studies is to demonstrate that commercially available mesoporous silica (MS) can be used to control the physical state of aripiprazole (ARP). The investigations performed utilizing differential scanning calorimetry and broadband dielectric spectroscopy reveal that silica can play different roles depending on its concentration in the system with amorphous ARP. At low MS content, it activates recrystallization of the active pharmaceutical ingredient and supports forming the III polymorphic form of ARP. At intermediate MS content (between ca. 27 and 65 wt %), MS works as a recrystallization inhibitor of ARP. At these concentrations, the formation of III polymorphic form is no longer favorable; therefore, it is possible to use this additive to obtain ARP in either IV or X polymorphic form. At the same time, employing MS in concentrations >65 wt % amorphous form of ARP with high physical stability can be obtained. Finally, regardless of the polymorphic form it crystallizes into, each composite is characterized by the same temperature dependence of relaxation times in the supercooled and glassy states.
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Aripiprazol , Varredura Diferencial de Calorimetria , Cristalização , Dióxido de Silício , Aripiprazol/química , Dióxido de Silício/química , Porosidade , Espectroscopia Dielétrica , Difração de Raios XRESUMO
Sizable glass formers feature numerous unique properties and potential applications, but many questions regarding their glass transition dynamics have not been resolved yet. Here, we have analyzed structural relaxation times measured as a function of temperature and pressure in combination with the equation of state obtained from pressure-volume-temperature measurements. Despite evidence from previous dielectric studies indicating a remarkable sensitivity of supercooled dynamics to compression, and contrary to intuition, our results demonstrated the proof for the almost equivalent importance of thermal energy and free volume fluctuations in controlling reorientation dynamics of sizable molecules. The found scaling exponent γ = 3.0 and Ev/Ep ratio of 0.6 were typical for glass-forming materials with relaxation dynamics determined by both effects with a minor advantage of thermal fluctuations involvement. It shows that the high values of key parameters characterizing the sensitivity of the glass transition dynamics to pressure changes, i.e., activation volume ΔV and dTg/dP, are not a valid premise for a remarkable contribution of volume to glass transition dynamics.
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The present study was designed to investigate the physical stability of three organic materials with similar chemical structures. The examined compounds revealed completely different crystallization tendencies in their supercooled liquid states and were classified into three distinct classes based on their tendency to crystallize. (S)-4-Benzyl-2-oxazolidinone easily crystallizes during cooling from the melt; (S)-4-Benzylthiazolidine-2-thione does not crystallize during cooling from the melt, but crystallizes easily during subsequent reheating above Tg; and (S)-4-Benzyloxazolidine-2-thione does not crystallize either during cooling from the melt or during reheating. Such different tendencies to crystallize are observed despite the very similar chemical structures of the compounds, which only differ in oxide or sulfur atoms in one of their rings. We also studied the isothermal crystallization kinetics of the materials that were shown to transform into a crystalline state. Molecular dynamics and thermal properties were thoroughly investigated using broadband dielectric spectroscopy, as well as conventional and temperature-modulated differential scanning calorimetry in the wide temperature range. It was found that all three glass formers have the same dynamic fragility (m = 93), calculated directly from dielectric structural relaxation times. This result verifies that dynamic fragility is not related to the tendency to crystallize. In addition, thermodynamic fragility predictions were also made using calorimetric data. It was found that the thermodynamic fragility evaluated based on the width of the glass transition, observed in the temperature dependence of heat capacity, correlates best with the tendency to crystallize.
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Tionas , Cristalização/métodos , Transição de Fase , Temperatura , Termodinâmica , Varredura Diferencial de CalorimetriaRESUMO
One of the challenging problems related to the liquid-glass transition phenomenon is establishing a link between the character of intermolecular interactions and the behavior of molecular dynamics. Introducing the density scaling concept, according to which dynamic quantities, e.g., viscosity or structural relaxation time (τ_{α}) measured at different thermodynamic conditions are expressed as a single universal curve if plotted against ρ^{γ}/T, led to significant progress in solving this problem since the scaling exponent γ defines the steepness of the repulsive part of the intermolecular potential. Herein, we found that relaxation dynamics of van der Waals and H-bonding glass formers, for which the Kirkwood factor (g_{K}) is an isomorph-invariant quantity, satisfy an alternative scaling, logτ_{α} vs T(Δϵ_{s}T)^{-γ}. As a result, the exponent γ is determined from the temperature and pressure evolutions of τ_{α} and dielectric relaxation strength Δϵ-both obtained in a single dielectric experiment, which makes the γ coefficient to be accessed in the future for an extensive database of glass-forming liquids.
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In this paper, we have examined a series of phenyl-substituted primary monohydroxy alcohols (phenyl alcohols, PhAs), from ethanol to hexanol by means of dielectric and Fourier transform infrared (FTIR) spectroscopies supported by the mechanical investigations. The combination of both dielectric and mechanical data allows calculation of the energy barrier, Ea, for dissociation by the Rubinstein approach developed to describe the dynamical properties of self-assembling macromolecules. It was observed that the determined activation energy remains constant, |Ea,RM| â¼ 12.9-14.2 kJ mol-1, regardless of the molecular weight of the examined material. Surprisingly, the obtained values agree very well with Ea of the dissociation process determined from the FTIR data analysed within the van't Hoff relationship, where Ea,vH â¼ 9.13-13.64 kJ mol-1. Thus, the observed agreement between Ea determined by both applied approaches clearly implies that in the case of the examined series of PhAs, the dielectric Debye-like process is governed by the association-dissociation phenomenon as proposed by the transient chain model.
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In this Letter, we analyze the dipole-dipole correlations obtained from the molecular dynamics simulations for strongly and weakly polar model liquids. As a result, we find that the cross-correlations' contribution to the system's total dipole moment correlation function, which is directly measured in the dielectric spectroscopy experiment, is negligible for weakly polar liquids. In contrast, the cross-correlations' term dominates over the self-correlations' term for the examined strongly polar liquid. Consequently, our studies strongly support the interpretation of the dielectric spectra nature of glass-forming liquids recently proposed by Pabst et al.
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In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature (Tg), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [ Carbohydr. Res. 2011, 346, 1061-1064] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.
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Bosentana/química , Varredura Diferencial de Calorimetria , Espectroscopia Dielétrica , Liberação Controlada de Fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Vitrificação , Difração de Raios XRESUMO
We study the molecular origin of a prepeak (PP) observed at low q values in the structure factors of three oligomers in a bulk (poly(mercaptopropyl)methylsiloxane, PMMS, poly(methylmercaptopropyl)-grafted-hexylmethacrylate, PMMS-g-HMA, and poly(methylphenyl)siloxane, PMPS) in order to understand the lowering of the PP intensity detected for oligomers confined in cylindrical pores with low diameter. For this purpose, we use a combination of X-ray diffraction measurements and coarse-grained bead-spring molecular dynamics simulations. Our molecular modelling demonstrated that the planarity of the pendant groups triggers the self-association of oligomers into nanoaggregates. However, the formation of oligomeric nanodomains is not sufficient for building-up the PP. The latter requires spatial disturbance in the arrangement of the side groups of oligomers within clusters. Importantly, our numerical analysis revealed that the increasing degree of the confinement of oligomers limits their aggregation and consequently lowers the amplitude of the PP observed in the experimental data.
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We present here the results of high-pressure broadband dielectric spectroscopy (BDS) measurements for a mixture of liquid-crystalline drug itraconazole (ITZ) and glycerol (GLY) at a critical concentration of 5% w/w in which the nematic order is eliminated. In the investigated system, smectic-A to isotropic phase transition leaves a clear fingerprint on the dielectric response, allowing for a phase diagram creation using BDS data. By following the α-relaxation dynamics under different thermodynamic conditions, we provide insights into the effect of pressure on temperature and the phenomenology of smectic-A to the isotropic phase transition. Additional measurements of specific volume as a function of pressure and temperature provide us with a deeper insight into material properties that could be analyzed comprehensively via the equation of state. We proved the validity of the density scaling concept, showing that the mixture's complexity does not exclude thermodynamic scaling of dynamic properties related to the α-process in the smectic-A phase. The low value of scaling exponent γ = 2.00 ± 0.02 and a high ratio of the activation energy at constant volume, EV, to the activation enthalpy at constant pressure, HP, indicate that temperature is a dominant variable controlling α-relaxation dynamics in the ordered smectic-A phase of the ITZ-GLY mixture.
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Itraconazol , Cristais Líquidos , Glicerol , Itraconazol/química , Cristais Líquidos/química , Simulação de Dinâmica Molecular , Transição de FaseRESUMO
In this paper, we show that a simple anisotropic model of supercooled liquid properly reflects some density scaling properties observed for experimental data, contrary to many previous results obtained from isotropic models. We employ a well-known Gay-Berne model earlier parametrized to achieve a supercooling and glass transition at zero pressure to find the point of glass transition and explore volumetric and dynamic properties in the supercooled liquid state at elevated pressure. We focus on dynamic scaling properties of the anisotropic model of supercooled liquid to gain a better insight into the grounds for the density scaling idea that bears hallmarks of universality, as follows from plenty of experimental data collected near the glass transition for different dynamic quantities. As a result, the most appropriate values of the scaling exponent γ are established as invariants for a given anisotropy aspect ratio to successfully scale both the translational and rotational relaxation times considered as single variable functions of densityγ/temperature. These scaling exponent values are determined based on the density scaling criterion and differ from those obtained in other ways, such as the virial-potential energy correlation and the equation of state derived from the effective short-range intermolecular potential, which is qualitatively in accordance with the results yielded from experimental data analyses. Our findings strongly suggest that there is a deep need to employ anisotropic models in the study of glass transition and supercooled liquids instead of the isotropic ones very commonly exploited in molecular dynamics simulations of supercooled liquids over the last decades.
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Simulação de Dinâmica Molecular , Vitrificação , Anisotropia , TemperaturaRESUMO
In this paper, we thoroughly investigated the physical stability of the anti-inflammatory drug etoricoxib, which has been reported earlier to be resistant to recrystallization in its glassy and supercooled states at ambient pressure. Our unique application of the standard refractometry technique showed that the supercooled liquid of the drug was able to recrystallize during isothermal experiments in atmospheric conditions. This enabled us to determine the crystallization onset timescale and nucleation energy barrier of etoricoxib for the first time. As the physical instability of etoricoxib requires working out an efficient method for improving the drug's resistance to recrystallization to maintain its amorphous form utility in potential pharmaceutical applications, we focused on finding a solution to this problem, and successfully achieved this purpose by preparing binary mixtures of etoricoxib with octaacetylmaltose. Our detailed thermal, refractometry, and molecular dynamics studies of the binary compositions near the glass transition revealed a peculiar behavior of the glass transition temperatures when changing the acetylated disaccharide concentration in the mixtures. Consequently, the anti-plasticization effect on the enhancement of physical stability could be excluded, and a key role for specific interactions in the improved resistance to recrystallization was expected. Invoking our previous results obtained for etoricoxib, the chemically similar drug celecoxib, and octaacetylmaltose, we formulated a hypothesis about the molecular mechanisms that may cause an impediment to crystal nuclei formation in the amorphous mixtures of etoricoxib with octaacetylmaltose. The most plausible scenario may rely on the formation of hydrogen-bonded heterodimers of the drug and excipient molecules, and the related drop in the population of the etoricoxib homodimers, which disables the nucleation. Nevertheless, this hypothesis requires further investigation. Additionally, we tested some widely discussed correlations between molecular mobility and crystallization properties, which turned out to be only partially satisfied for the examined mixtures. Our findings constitute not only a warning against manufacturing the amorphous form of pure etoricoxib, but also evidence for a promising outcome for the pharmaceutical application of the amorphous compositions with octaacetylmaltose.
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Simulação de Dinâmica Molecular , Vitrificação , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Etoricoxib , Excipientes/químicaRESUMO
In this work, we employed broad-band dielectric spectroscopy to determine the solubility limits of nimesulide in the Kollidon VA64 matrix at ambient and elevated pressure conditions. Our studies confirmed that the solubility of the drug in the polymer matrix decreases with increasing pressure, and molecular dynamics controls the process of recrystallization of the excess of amorphous nimesulide from the supersaturated drug-polymer solution. More precisely, recrystallization initiated at a certain structural relaxation time of the sample stops when a molecular mobility different from the initial one is reached, regardless of the temperature and pressure conditions. Finally, based on the presented results, one can conclude that by transposing vertically the results obtained at elevated pressures, one can obtain the solubility limit values corresponding to low temperatures. This approach was validated by the comparison of the experimentally determined points with the theoretically obtained values based on the Flory-Huggins theory.
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Química Farmacêutica/métodos , Espectroscopia Dielétrica/métodos , Composição de Medicamentos/métodos , Polímeros/química , Pressão , Sulfonamidas/química , Temperatura , Varredura Diferencial de Calorimetria/métodos , Cristalização , Estabilidade de Medicamentos , Pirrolidinas/química , Solubilidade , Soluções , Compostos de Vinila/químicaRESUMO
In this study, the phase diagram of the ternary system of ezetimibe-simvastatin-fenofibrate was established. It has been proven that the ternary composition recommended for the treatment of mixed hyperlipidemia forms a eutectic system. Since eutectic mixtures are characterized by greater solubility and dissolution rate, the obtained result can explain the marvelous medical effectiveness of combined therapy. Considering that another well-known method for improving the aqueous solubility is amorphization, the ternary system with eutectic concentration was converted into an amorphous form. Thermal properties, molecular dynamics, and physical stability of the obtained amorphous system were thoroughly investigated through various experimental techniques compared to both: neat amorphous active pharmaceutical ingredients (considered separately) and other representative concentrations of ternary mixture. The obtained results open up a new way of selecting the therapeutic concentrations for combined therapies, a path that considers one additional variable: eutecticity.
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Anticolesterolemiantes/química , Ezetimiba/química , Fenofibrato/química , Sinvastatina/química , Anticolesterolemiantes/uso terapêutico , Química Farmacêutica , Combinação de Medicamentos , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Ezetimiba/uso terapêutico , Fenofibrato/uso terapêutico , Humanos , Hiperlipidemias/tratamento farmacológico , Sinvastatina/uso terapêuticoRESUMO
The impact of the chain length or dispersity of polymers in controlling the crystallization of amorphous active pharmaceutical ingredients (APIs) has been discussed for a long time. However, because of the weak control of these parameters in the majority of macromolecules used in pharmaceutical formulations, the abovementioned topic is poorly understood. Herein, four acetylated oligosaccharides, maltose (acMAL), raffinose (acRAF), stachyose (acSTA), and α-cyclodextrin (ac-α-CD) of growing chain lengths and different topologies (linear vs cyclic), mimicking the growing backbone of the polymer, were selected to probe the influence of these structural factors on the crystallization of naproxen (NAP)-an API that does not vitrify regardless of the cooling rate applied in our experiment. It was found that in equimolar systems composed of NAP and linear acetylated oligosaccharides, the progress and activation barrier for crystallization are dependent on the molecular weight of the excipient despite the fact that results of Fourier transform infrared studies indicated that there is no difference in the interaction pattern between measured samples. On the other hand, complementary dielectric, calorimetric, and X-ray diffraction data clearly demonstrated that NAP mixed with ac-α-CD (cyclic saccharide) does not tend to crystallize even in the system with a much higher content of APIs. To explain this interesting finding, we have carried out further density functional theory computations, which revealed that incorporation of NAP into the cavity of ac-α-CD is hardly possible because this state is of much higher energy (up to 80 kJ/mol) with respect to the one where the API is located outside of the saccharide torus. Hence, although at the moment, it is very difficult to explain the much stronger impact of the cyclic saccharide on the suppression of crystallization and enhanced stability of NAP with respect to the linear carbohydrates, our studies clearly showed that the chain length and the topology of the excipient play a significant role in controlling the crystallization of this API.
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Naproxeno/química , Oligossacarídeos/química , Varredura Diferencial de Calorimetria/métodos , Carboidratos/química , Cristalização/métodos , Composição de Medicamentos/métodos , Excipientes/química , Simulação de Dinâmica Molecular , Peso Molecular , Transição de Fase/efeitos dos fármacos , Solubilidade/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodosRESUMO
Molecular dynamics of ionic liquids in an electric field can be decomposed into contributions from translational motions of ions, rotational motions of permanent dipoles and - in the case of ions equipped with long alkyl-chains - motions of ionic aggregates. The discrimination of these contributions in the dielectric spectrum is quite involved, resulting in numerous controversies in the literature. Here, we use dielectric spectroscopy at ambient and elevated pressures of up to 550 MPa to monitor the changes of the observed processes in five supercooled ionic liquids with octyl-chains independent of pressure and temperature. In most of the ionic liquids under investigation two dynamical processes are observed, one of them is identified as the ion hopping process, which we describe by the MIGRATION model. It turns out that this process is closely connected to the glass transition step as measured by differential scanning calorimetry. Concerning the second process, we rule out motions of aggregated ions to be its origin by comparison of our results with X-ray scattering literature data at elevated pressure. Instead, we tentatively ascribe it to dipolar reorientations and show that the dielectric strength of this slow process decreases as a function of increasing relaxation time, i.e. for decreasing temperatures and increasing pressures. We compare this behavior with literature data of other ion conducting systems and discuss its microscopic origin.
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Herein, we examined the effect of finite size and wettability on the structural dynamics and the molecular arrangement of the propylene carbonate derivative, (S)-(-)-4-methoxymethyl-1,3-dioxolan-2-one (assigned as s-methoxy-PC), incorporated into alumina and silica porous templates of pore diameters d = 4 nm-10 nm using Raman and broadband dielectric spectroscopy, differential scanning calorimetry, and x-ray diffraction. It was demonstrated that only subtle changes in the molecular organization and short-range order of confined s-methoxy-PC molecules were detected. Yet, a significant deviation of the structural dynamics and depression of the glass transition temperatures, Tg, was found for all confined samples with respect to the bulk material. Interestingly, these changes correlate with neither the finite size effects nor the interfacial energy but seem to vary with wettability, generally. Nevertheless, for s-methoxy-PC infiltrated into native (more hydrophilic) and modified (more hydrophobic) silica templates of the same nanochannel size (d = 4 nm), a change in the dynamics and Tg was negligible despite a significant variation in wettability. These results indicated that although wettability might be a suitable variable to predict alteration of the structural dynamics and depression of the glass transition temperature, other factors, i.e., surface roughness and the density packing, might also have a strong contribution to the observed confinement effects.
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Herein we show that the nanostructured interface obtained via modulation of the pore size has a strong impact on the segmental and chain dynamics of two poly(propylene glycol) (PPG) derivatives with various molecular weights (Mn = 4000 g/mol and Mn = 2000 g/mol). In fact, a significant acceleration of the dynamics was observed for PPG infiltrated into ordinary alumina templates (Dp = 36 nm), while bulklike behavior was found for samples incorporated into membranes of modulated diameter (19 nm < Dp < 28 nm). We demostrated that the modulation-induced roughness reduces surface interactions of polymer chains near the interface with respect to the ones adsorbed to the ordinary nanochannels. Interestingly, this effect is noted despite the enhanced wettability of PPG in the latter system. Consequently, as a result of weaker H-bonding surface interactions, the conformation of segments seems to locally mimic the bulk arrangement, leading to bulklike dynamics, highlighting the crucial impact of the interface on the overall behavior of confined materials.
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The flexibility of dose and dosage forms makes 3D printing a very interesting tool for personalized medicine, with fused deposition modeling being the most promising and intensively developed method. In our research, we analyzed how various types of disintegrants and drug loading in poly(vinyl alcohol)-based filaments affect their mechanical properties and printability. We also assessed the effect of drug dosage and tablet spatial structure on the dissolution profiles. Given that the development of a method that allows the production of dosage forms with different properties from a single drug-loaded filament is desirable, we developed a method of printing ketoprofen tablets with different dose and dissolution profiles from a single feedstock filament. We optimized the filament preparation by hot-melt extrusion and characterized them. Then, we printed single, bi-, and tri-layer tablets varying with dose, infill density, internal structure, and composition. We analyzed the reproducibility of a spatial structure, phase, and degree of molecular order of ketoprofen in the tablets, and the dissolution profiles. We have printed tablets with immediate- and sustained-release characteristics using one drug-loaded filament, which demonstrates that a single filament can serve as a versatile source for the manufacturing of tablets exhibiting various release characteristics.
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Química Farmacêutica/métodos , Cetoprofeno/química , Cetoprofeno/síntese química , Impressão Tridimensional , Comprimidos , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Composição de Medicamentos/métodos , Desenho de Fármacos , Liberação Controlada de Fármacos , Elasticidade , Excipientes/química , Álcool de Polivinil , Medicina de Precisão , Reprodutibilidade dos Testes , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Difração de Raios X , Microtomografia por Raio-XRESUMO
In this work, we proposed the method to maintain the desired level of drug's solubility within the polymer matrix by adjusting conditions to uphold the same molecular dynamics of the system (e.g., temperature for set elevated pressure or vice versa). Namely, we observed, that recrystallization of the drug from the supersaturated drug-polymer system, initiated for the same structural relaxation time of the sample (τα-1) ceases when certain, different than the initial, molecular mobility of the systems is reached (τα-2)-regardless of a given combination of temperature and pressure conditions. Based on the presented results, one can conclude that the molecular dynamics seem to control the process of recrystallization of the excess amount of solute from the supersaturated solution (e.g., small molecules dissolved within the polymer). Therefore, it appears that the elevated pressure compensates the effect of solubility enhancement caused by the elevated temperature. Such information not only is of fundamental relevance in science but also, from a much broader perspective, could be potentially very useful considering extrusion-based manufacturing methods.
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Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Polímeros/química , Cristalização , Estudos de Viabilidade , Pressão , Solubilidade , TemperaturaRESUMO
In this paper, broadband dielectric spectroscopy (BDS) has been applied to study the molecular dynamics and crystallization kinetics of the antihyperlipidemic active pharmaceutical ingredient (API), gemfibrozil (GEM), as well as its deuterated (dGEM) and methylated (metGEM) derivatives, characterized by different types and strengths of intermolecular interactions. Moreover, calorimetric and infrared measurements have been carried out to characterize the thermal properties of examined samples and to probe a change in the H-bonding pattern in GEM, respectively. We found that the dielectric spectra of all examined compounds, collected below the glass transition temperature (Tg), reveal the presence of two secondary relaxations (ß, γ). According to the coupling model (CM) predictions, it was assumed that the slower process (ß) is of JG type, whereas the faster one (γ) has an intramolecular origin. Interestingly, the extensive crystallization kinetics measurements performed after applying two paths, i.e., the standard procedure (cooling and subsequently heating up to the appropriate temperature, Tc), as well as annealing at two temperatures in the vicinity of Tg and further heating up to Tc, showed that the annealing increases the crystallization rate in the case of native API, while the thermal history of the sample has no significant impact on the pace of this process in the two derivatives of GEM. Analysis of the dielectric strength (Δε) of the α-process during annealing, together with the results of Fourier transform infrared spectroscopy (FTIR) measurements, suggested that the reorganization within dimeric structures formed between the GEM molecules is responsible for the observed behavior. Importantly, our results differ from those obtained by Tominaka et al. (Tominaka, S.; Kawakami, K.; Fukushima, M.; Miyazaki, A.Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-Tg Temperature Mol. Pharm. 2017 14 264 273 10.1021/acs.molpharmaceut.6b00866.), who demonstrated that the sub-Tg annealing of ritonavir (RTV), which is able to form extensive supramolecular hydrogen bonds, protects this active substance against crystallization. Therefore, based on these contradictory reports, one can hypothesize that materials forming H-bonded structures, characterized by varying architecture, may behave differently after annealing in the vicinity of the glass transition temperature.