Coamorphous Systems of Valsartan: Thermal Analysis Contribution to Evaluate Intermolecular Interactions Effects on the Structural Relaxation.

Coamorphous formation in binary systems of valsartan (Val) with 4,4'-bipyridine (Bipy) and trimethoprim (Tri) was investigated for mixtures with a mole fraction of 0.16~0.86 of valsartan and evaluated in terms of the glass transition temperature. The glass transition of the systems had a behavior outside the values predicted by the Gordon-Taylor equation, showing that Val-Bipy (hydrogen bonding between the components) had a lower deviation and Val-Tri (ionic bonding between the components) had a higher deviation. Mixtures of compositions 2:1 Val-Bipy and 1:1 Val-Tri were selected for further investigation and verified to be stable, as no crystallization was observed during subsequent heating and cooling programs. For these systems, the effective activation energy during glass transition was evaluated. Compared to pure valsartan, the system with the lower glass transition temperature (Val-Bipy) presented the highest effective activation energy, and the system with the higher glass transition temperature (Val-Tri) presented a lower effective activation energy. The results presented a good correlation between the data obtained from two different techniques to determine the fragility and effective activation energy: non-isothermal kinetic analysis by DSC and TSDC.

Structural Elucidation of Poloxamer 237 and Poloxamer 237/Praziquantel Solid Dispersions: Impact of Poly(Vinylpyrrolidone) over Drug Recrystallization and Dissolution.

Praziquantel (PZQ) is the recommended, effective, and safe treatment against all forms of schistosomiasis. Solid dispersions (SDs) in water-soluble polymers have been reported to increase solubility and bioavailability of poorly water-soluble drugs like PZQ, generally due to the amorphous form stabilization. In this work, poloxamer (PLX) 237 and poly(vinylpyrrolidone) (PVP) K30 were evaluated as potential carriers to revert PZQ crystallization. Binary and ternary SDs were prepared by the solvent evaporation method. PZQ solubility increased similarly with PLX either as binary physical mixtures or SDs. Such unpredicted data correlated well with crystalline PZQ and PLX as detected by solid-state NMR (ssNMR) and differential scanning calorimetry in those samples. Ternary PVP/PLX/PZQ SDs showed both ssNMR broad and narrow superimposed signals, thus revealing the presence of amorphous and crystalline PZQ, respectively, and exhibited the highest PZQ dissolution efficiency (up to 82% at 180 min). SDs with PVP provided a promising way to enhance solubility and dissolution rate of PZQ since PLX alone did not prevent recrystallization of amorphous PZQ. Based on ssNMR data, novel evidences on PLX structure and molecular dynamics were also obtained. As shown for the first time using ssNMR, propylene glycol and ethylene glycol constitute the PLX amorphous and crystalline components, respectively.

The segmental and chain relaxation modes in high-cis-polyisoprene as studied by thermally stimulated currents.

The technique of Thermally Stimulated Currents is used to study the slow molecular mobility in a series of poly (1,4-cis-isoprene) samples with different molecular weights, Mw, and low polydispersity. The technique revealed a high resolution power, particularly useful in the study of the lower molecular weight samples where the chain and the segmental relaxations strongly overlap. The dynamic crossover that is reported for the normal mode by varying the molecular weight is clearly revealed by the thermally stimulated depolarization currents results through the temperature location, TMn, of the normal mode peak, the values of the relaxation time at TMn, τ(TMn), and the value of the fragility index of the normal mode, mn. The kinetic features of the glass transition relaxation of polyisoprene have also been determined.

A stable amorphous statin: solid-state NMR and dielectric studies on dynamic heterogeneity of simvastatin.

Statins have been widely used as cholesterol-lowering agents. However, low aqueous solubility of crystalline statins and, consequently, reduced biovailability require seeking for alternative forms and formulations to ensure an accurate therapeutic window. The objective of the present study was to evaluate the stability of amorphous simvastatin by probing molecular dynamics using two nondestructive techniques: solid-state NMR and dielectric relaxation spectroscopy. Glassy simvastatin was obtained by the melt quench technique. (13)C cross-polarization/magic-angle-spinning (CP/MAS) NMR spectra and (1)H MAS NMR spectra were obtained from 293 K up to 333 K (Tg ≈ 302 K). The (13)C spin-lattice relaxation times in the rotating frame, T1ρ, were measured as a function of temperature, and the correlation time and activation energy data obtained for local motions in different frequency scales revealed strong dynamic heterogeneity, which appears to be essential for the stability of the amorphous form of simvastatin. In addition, the (1)H MAS measurements presented evidence for mobility of the hydrogen atoms in hydroxyl groups which was assigned to noncooperative secondary relaxations. The complex dielectric permittivity of simvastatin was monitored in isochronal mode at five frequencies (from 0.1 to 1000 kHz), by carrying out a heating/cooling cycle allowing to obtain simvastatin in the supercooled and glassy states. The results showed that no dipolar moment was lost due to immobilization, thus confirming that no crystallization had taken place. Complementarily, the present study focused on the thermal stability of simvastatin using thermogravimetric analysis while the thermal events were followed up by differential scanning calorimetry and dielectric relaxation spectroscopy. Overall, the results confirm that the simvastatin in the glass form reveals a potential use in the solid phase formulation on the pharmaceutical industry.

Enthalpy of formation of anisole: implications for the controversy on the O-H bond dissociation enthalpy in phenol.

Significant discrepancies in the literature data for the enthalpy of formation of gaseous anisole, ΔfHmo(PhOCH3, g), have fueled an ongoing controversy regarding the most reliable enthalpy of formation of the phenoxy radical and of the gas phase O-H bond dissociation enthalpy, DHo(PhO-H), in phenol. In the present work ΔfHmo(PhOCH3, g) was reassessed using a combination of calorimetric determinations and high-level (W2-F12) ab initio calculations. Static-bomb combustion calorimetry led to the standard molar enthalpy of formation of liquid anisole at 298.15 K, ΔfHmo(PhOCH3, l) = −(117.1 ± 1.4) kJ·mol(-1). The corresponding enthalpy of vaporization was obtained as, ΔvapHmo(PhOCH3) = 46.41 ± 0.26 kJ·mol(-1), by Calvet-drop microcalorimetry. These results give ΔfHmo(PhOCH3, g) = −(70.7 ± 1.4) kJ·mol(-1), in excellent agreement with ΔfHmo(PhOCH3, g) = −(70.8 ± 3.2) kJ·mol(-1), obtained from the W2-F12 calculations. The ΔfHmo(PhOCH3, g) here recommended leads to ΔfHmo(PhO•, g) = 55.5 ± 2.4 kJ·mol(-)1 and DH°(PhO-H) = 368.1 ± 2.6 kJ·mol(-1).

Development of a dry powder insufflation device with application in in vitro cell-based assays in the context of respiratory delivery.

Research on pharmaceutical dry powders has been increasing worldwide, along with increased therapeutic strategies for an application through the pulmonary or the nasal routes. In vitro methodologies and tests that mimic the respiratory environment and the process of inhalation itself are, thus, essential. The literature frequently reports cell-based in vitro assays that involve testing the dry powders in suspension. This experimental setting is not adequate, as both the lung and the nasal cavity are devoid of abundant liquid. However, devices that permit powder insufflation over cells in culture are either scarce or technically complex and expensive, which is not feasible in early stages of research. In this context, this work proposes the development of a device that allows the delivery of dry powders onto cell surfaces, thus simulating inhalation more appropriately. Subsequently, a quartz crystal microbalance (QCM) was used to establish a technique enabling the determination of dry powder deposition profiles. Additionally, the determination of the viability of respiratory cells (A549) after the insufflation of a dry powder using the developed device was performed. In all, a prototype for dry powder insufflation was designed and developed, using 3D printing methods for its production. It allowed the homogenous dispersion of the insufflated powders over a petri dish and a QCM crystal, and a more detailed study on how dry powders disperse over the supports. The device, already protected by a patent, still requires further improvement, especially regarding the method for powder weighing and the efficiency of the insufflation process, which is being addressed. The impact of insufflation of air and of locust bean gum (LBG)-based microparticles revealed absence of cytotoxic effect, as cell viability roughly above 70 % was always determined.

Energetics and structure of simvastatin.

The study of structure-energetics relationships for active pharmaceutical ingredients has received considerable attention in recent years, due to its importance for the effective production and safe use of drugs. In this work the widely prescribed cholesterol-lowering drug simvastatin was investigated by combining experimental (combustion calorimetry and differential scanning calorimetry, DSC) and computational chemistry (quantum chemistry and molecular dynamics calculations) results. The studies addressed the crystalline form stable at ambient temperature (form I) and the liquid and gaseous phases. Heat capacity determinations by DSC showed no evidence of polymorphism between 293 K and the fusion temperature. It was also found that the most stable molecular conformation in the gas phase given by the quantum chemistry calculations (B3LYP-D3/cc-pVTZ) is analogous to that observed in the crystal phase. The molecular dynamics simulations correctly captured the main structural properties of the crystalline phase known from published single crystal X-ray diffraction results (unit cell dimensions and volume). They also suggested that, while preferential conformations are exhibited by the molecule in the solid at 298.15 K, these preferences are essentially blurred upon melting. Finally, the experiments and calculations led to enthalpies of formation of simvastatin at 298.15 K, in the crystalline (form I) ΔfH(m)(o) (cr I) = -1238.4 ± 5.6 kJ · mol(-1), liquid ΔfH(m)(o) (l) = -1226.4 ± 5.7 kJ · mol(-1), and gaseous ΔfH(m)(o) (g) = -1063.0 ± 7.1 kJ · mol(-1) states.

Understanding Fenofibrate Release from Bare and Modified Mesoporous Silica Nanoparticles.

To investigate the impact of the surface functionalization of mesoporous silica nanoparticle (MSN) carriers in the physical state, molecular mobility and the release of Fenofibrate (FNB) MSNs with ordered cylindrical pores were prepared. The surface of the MSNs was modified with either (3-aminopropyl) triethoxysilane (APTES) or trimethoxy(phenyl)silane (TMPS), and the density of the grafted functional groups was quantified via 1H-NMR. The incorporation in the ~3 nm pores of the MSNs promoted FNB amorphization, as evidenced via FTIR, DSC and dielectric analysis, showing no tendency to undergo recrystallization in opposition to the neat drug. Moreover, the onset of the glass transition was slightly shifted to lower temperatures when the drug was loaded in unmodified MSNs, and MSNs modified with APTES composite, while it increased in the case of TMPS-modified MSNs. Dielectric studies have confirmed these changes and allowed researchers to disclose the broad glass transition in multiple relaxations associated with different FNB populations. Moreover, DRS showed relaxation processes in dehydrated composites associated with surface-anchored FNB molecules whose mobility showed a correlation with the observed drug release profiles.

TSDC and DSC Investigation on the Molecular Mobility in the Amorphous Solid State and in the Glass Transformation Region of Two Benzodiazepine Derivatives: Diazepam and Nordazepam.

In this work we study the molecular mobility in the amorphous solid state and in the glass transformation region of two compounds, diazepam and nordazepam; these are two benzodiazepines, a family of psychotropic drugs with sedative, anxiolytic and muscle-relaxing properties. The experimental techniques used are thermostimulated currents (TSC) and differential scanning calorimetry (DSC). TSC is a time-dependent technique recognized for its high resolving power; the use of this technique in the depolarization and polarization modes (TSDC and TSPC respectively), provides results that confirm and complement results of dielectric relaxation spectroscopy (DRS) published recently. On the other hand, the variation with the heating rate of the temperature position of the DSC glass transition signal also allowed the estimation of the activation energy at Tg and of the dynamic fragility of the two glass formers.

Thermal behavior and molecular mobility studies in the supercooled liquid and glassy states of carvedilol and loratadine.

The thermal behavior of carvedilol and loratadine was studied by differential scanning calorimetry (DSC). The glass-forming ability, as well as the the tendency for crystallization from the glass (glass stability) and from the metastable and equilibrium melt were also investigated by DSC. In addition this technique was also used to characterize the glass transition of carvedilol and loratadine by determining the activation energy of the structural relaxation, the dynamic fragility, and the heat capacity jump associated with the glass transformation. Different aspects of the molecular mobility in carvedilol and loratadine were analyzed by Thermally Stimulated Depolarization Currents (TSDC), while in carvedilol the Dielectric Relaxation Spectroscopy (DRS) technique was also used. Carvedilol stands out for its high values of specific heat jump and dynamic fragility, which has been attributed to the particular mobility of this glass-former in the glass transformation region, a consequence of specific characteristics of its molecular structure. These molecular features are also at the origin of a relaxation above Tg that has been detected and characterized by TSDC; the DRS investigation allowed to better understand the molecular dynamics in carvedilol in the amorphous solid, in the metastable liquid state and in the glass transformation region. Finally, the secondary relaxations in loratadine were studied by TSDC, while those in carvedilol were studied by the two dielectric techniques and the results were compared and discussed.

Thermal Behavior and Slow Relaxation Dynamics in Amorphous Efavirenz: A Study by DSC, XRPD, TSDC, and DRS.

The analysis of the thermal behavior of efavirenz showed a high glass-forming ability and good glass stability of this glass-forming liquid at room temperature. No polymorphic forms were formed either by cold crystallization or by recrystallization from solvent acetone. The determination of the dynamic fragility by the differential scanning calorimetry, thermally stimulated depolarization currents (TSDC), and dielectric relaxation spectroscopy (DRS) techniques is unanimous in suggesting efavirenz as a moderately fragile liquid. With DRS, secondary relaxations were detected, however, with weak intensities that did not allow the respective kinetic analysis; in contrast, TSDC allows clearly resolving the components of the secondary ß-relaxation below Tg, with activation energies distributed between about 75 and 90 kJ mol-1 and Arrhenius prefactors of the order of 10-13 s. In this regard, the TSDC technique proved to be more effective compared to DRS in characterizing the secondary relaxation. The glass forming ability and glass stability found for efavirenz have been discussed in terms of various thermodynamic and kinetic parameters such as the reduced glass transition temperature, Tgred, the dynamic fragility, m, the stretching exponent, ßKWW, the melting entropy, ΔSfus, and the molecular stiffness. The exceptionally low value of efavirenz fusion entropy was highlighted as a key feature of the thermal behavior of this glass-forming liquid.

Experimental and molecular dynamics simulation study of the sublimation energetics of cyclopentadienyltricarbonylmanganese (Cymantrene).

The standard molar enthalpy of sublimation of monoclinic cyclopentadienyltricarbonylmanganese, Mn(eta (5)-C 5H 5)(CO) 3, at 298.15 K, was determined as Delta sub H m (o)[Mn(eta (5)-C 5H 5)(CO) 3] = 75.97 +/- 0.37 kJ x mol (-1) from Knudsen effusion and Calvet-drop microcalorimetry measurements, thus considerably improving the very large inaccuracy (>10 kJ x mol (-1)) of the published data. The obtained value was used to assess the extension of the OPLS-based all-atom force field we previously developed for iron metallocenes to manganese organometallic compounds. The modified force field was able to reproduce the volumetric properties (density and unit-cell volume) of crystalline Mn(eta (5)-C 5H 5)(CO) 3 with a deviation of 0.6% and the experimentally determined enthalpy of sublimation with an accuracy of 1 kJ x mol (-1). The interaction (epsilon) and atomic-diameter (sigma) parameters of the Lennard-Jones (12-6) potential function used to calculate dispersion contributions within the framework of the force field were found to be transferable from iron to manganese.

Experimental and molecular dynamics simulation study of the sublimation and vaporization energetics of iron metalocenes. crystal structures of Fe(eta5-C5H4CH3)2 and Fe[(eta5-(C5H5)(eta5-C5H4CHO)].

The standard molar enthalpies of sublimation of ferrocene, 1,1'-dimethylferrocene, decamethylferrocene, ferrocenecarboxaldehyde and alpha-methylferrocenemethanol, and the enthalpy of vaporization of N,N-dimethyl(aminomethyl)ferrocene, at 298.15 K, were determined by Calvet-drop microcalorimetry and/or the Knudsen effusion method. The obtained values were used to assess and refine our previously developed force field for metallocenes. The modified force field was able to reproduce the deltasubHdegreesm and deltavapHdegreesm values of the test-set with an accuracy better than 5 kJ.mol-1, except for decamethylferrocene, in which case the deviation between the calculated and experimental deltasubHdegreesm values was 16.1 kJ.mol-1. The origin of the larger error found in the prediction of the sublimation energetics of decamethylferrocene, and which was also observed in the estimation of structural properties (e.g., density and unit cell dimensions), is discussed. Finally, the crystal structures of Fe(eta5-C5H4CH3)2 and Fe[(eta5-(C5H5)(eta5-C5H4CHO)] at 293 and 150 K, respectively, are reported.

Relaxation behaviour of D(-)-salicin as studied by Thermally Stimulated Depolarisation Currents (TSDC) and Differential Scanning Calorimetry (DSC).

Thermally Stimulated Depolarisation Currents (TSDC) measurements on D(-)-salicin have been carried out in the temperature region from -165 degrees C up to 150 degrees C. The slow molecular mobility was characterised in the crystal and in the glassy state. The value of the steepness index or fragility (T(g)-normalized temperature dependence of the relaxation time) was obtained by Differential Scanning Calorimetry (DSC) from the analysis of the scanning rate dependency of T(g). The existence of an unknown polymorph of salicin is also reported.

Synthesis and Characterization of Isosorbide-Based Polyurethanes Exhibiting Low Cytotoxicity Towards HaCaT Human Skin Cells.

The synthesis of four samples of new polyurethanes was evaluated by changing the ratio of the diol monomers used, poly(propylene glycol) (PPG) and D-isosorbide, in the presence of aliphatic isocyanates such as the isophorone diisocyanate (IPDI) and 4,4'-methylenebis(cyclohexyl isocyanate) (HMDI). The thermal properties of the four polymers obtained were determined by DSC, exhibiting Tg values in the range 55⁻70 °C, and their molecular structure characterized by FTIR, ¹H, and 13C NMR spectroscopies. The diffusion coefficients of these polymers in solution were measured by the Pulse Gradient Spin Echo (PGSE) NMR method, enabling the calculation of the corresponding hydrodynamic radii in diluted solution (1.62⁻2.65 nm). The molecular weights were determined by GPC/SEC and compared with the values determined by a quantitative 13C NMR analysis. Finally, the biocompatibility of the polyurethanes was assessed using the HaCaT keratinocyte cell line by the MTT reduction assay method showing values superior to 70% cell viability.

Slow molecular mobility in the crystalline and amorphous solid states of pentitols: a study by thermally stimulated depolarisation currents and by differential scanning calorimetry.

The molecular mobility of the pentitol isomers (xylitol, adonitol, D-arabitol and L-arabitol) was studied by thermally stimulated depolarisation currents (TSDC) in the crystalline and in the amorphous solid states. Differential scanning calorimetry (DSC) was used to characterise the phase transformations, to detect polymorphism and to analyse the dynamics of the structural relaxation in the glassy state (from the heating rate dependence of the onset temperature of the glass transition signal). The mobility in crystalline xylitol and adonitol displays features that are different compared with crystalline arabitols. No difference of the dynamic behaviour seems to emerge from our results on the primary and secondary relaxations in the amorphous isomeric pentitols. The values of the steepness index or fragility obtained in this work by TSDC and DSC are compared with the values reported in the literature obtained from other experimental techniques, and with values predicted by empirical formulae.

Dipolar Reorientations in Amorphous Nimesulide: A TSDC and DSC Study.

BACKGROUND: The preparation of APIs in the amorphous solid form can be a means of circumventing problems arising from poor solubility and low dissolution rate of the crystalline drugs. However, molecular mobility can be responsible for the glass instability, so that the kinetic characterization of the different relaxations that subsist in the amorphous solid is useful to allow define the conditions for greater stability of the glassy pharmaceutical. Our purpose is to use the experimental techniques of differential scanning calorimetry (DSC) and thermally stimulated depolarization currents (TSDC) to study the thermal behavior of the pharmaceutical drug nimesulide and its slow molecular mobility in the amorphous solid state. METHODS: DSC provides us a general view of the thermal behaviour of nimesulide and allows a general kinetic characterization of its glass transition relaxation. TSDC allows isolating the individual modes of motion present in nimesulide (in the temperature range between -150ºC and +15ºC). From the experimental output of the TSDC experiments, the kinetic parameters associated with the different mobility modes of motion were obtained, which allowed a detailed characterisation of the distribution of relaxation times of the complex relaxations. RESULTS: No molecular mobility was detected below ∼ -30ºC. A sub-Tg relaxation, or secondary process, was found by TSDC in the temperature region between ∼ -15ºC and ∼ +7ºC; this is a local mobility that is affected by physical aging, and was attributed to a slow ß-relaxation (Johari-Goldstein). The analysis by DSC and TSDC of the α-relaxation showed that nimesulide is a moderately fragile glass former. The dynamic fragility obtained by DSC was mDSC = 52 while that obtained by TSDC was mTSDC = 70. CONCLUSIONS: From the DSC study of the thermal behaviour we concluded that nimesulide has a moderate glass forming ability and a week glass stability. The fact that the cold crystallization occurs only some few tens of degrees above the glass transition temperature, and shows a slow kinetics, allowed the study of the mobility by TSDC. TSDC thus proved to be an adequate technique to study the molecular mobility in the amorphous nimesulide. However, the study by spectroscopic dielectric relaxation is probably impossible under these conditions.

MechanoAPI-ILs: Pharmaceutical Ionic Liquids Obtained through Mechanochemical Synthesis.

An alternative, efficient, and green synthetic strategy for the preparation of pharmaceutical ionic liquids using mechanochemistry (MechanoAPI-ILs) is reported. Six new API-ILs based on gabapentin and l-glutamic acid were successfully synthesized and characterized, demonstrating that mechanochemistry is a very promising synthetic strategy. Results compare both the new and the classical approach and clearly show the advantages of the new method. This new technique is faster, solvent free, reproducible, selective, and leads to higher yields.

Dielectric study of the slow motional processes in the polymorphic States of anhydrous caffeine.

Molecular mobility in crystalline anhydrous caffeine was studied by the dielectric technique of thermally stimulated depolarization currents (TSDC). Two relaxational processes were found, one appearing at approximately -10 degrees C that is ascribed to a reorientational glass transition, and a higher temperature one that probably arises from local molecular motions that are precursors of diffusion and sublimation. The experimental results suggest that both crystalline phases II and I of caffeine, that have distinct crystal structures, are solid rotator phases. Furthermore, this dynamic reorientational disorder shows a reorientational glass transition at the same temperature in phase II and in metastable phase I.

The slow relaxation dynamics in active pharmaceutical ingredients studied by DSC and TSDC: Voriconazole, miconazole and itraconazole.

The slow molecular mobility of three active pharmaceutical drugs (voriconazole, miconazole and itraconazole) has been studied by differential scanning calorimetry (DSC) and thermally stimulated depolarization currents (TSDC). This study yielded the main kinetic features of the secondary relaxations and of the main (glass transition) relaxation, in particular their distribution of relaxation times. The dynamic fragility of the three glass formers was determined from DSC data (using two different procedures) and from TSDC data. According to our results voriconazole behaves as a relatively strong liquid, while miconazole is moderately fragile and itraconazole is a very fragile liquid. There are no studies in this area published in the literature relating to voriconazole. Also not available in the literature is a slow mobility study by dielectric relaxation spectroscopy in the amorphous miconazole. Apart from that, the results obtained are in reasonable agreement with published works using different experimental techniques.