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Ionic liquid (IL) salt of active pharmaceutical ingredient (API) represents a promising formulation strategy to address low drug solubility and polymorphism prevalent in API solid crystals. The present work developed for the first time a buccal delivery system of API-IL via fast-dissolving API-IL-loaded gelatin films. Imidazolium-based ibuprofen salt was used as the model API-IL. The effects of API-IL loading and gelatin concentration on the film's (i) mechanical strength, (ii) inter-batch uniformity in the films' API payload, weight, and thickness, (iii) thermal stability, (iv) API dissolution and solubility enhancement were investigated. The plasticizer role of API-IL was evident, where minimum 30 wt% API-IL loading was needed to produce flexible yet mechanically-strong films. Lower API-IL loading produced brittle films due to insufficient plasticization facilitated by hydrogen bond interactions between API-IL and gelatin. Gelatin concentration influenced films' mechanical strength, weight/thickness, and API dissolution rate. Depending on the API-IL loading and gelatin concentration, films with API payload (7–30 mg/cm2), thickness (300–900 µm), and weight (20–110 mg/cm2) were produced at nearly 100% efficiency and high inter-batch uniformity. API-IL existed as amorphous liquid in the film exhibiting fast API dissolution (100% in 15 min) and high kinetic solubility (8 times thermodynamic solubility) in simulated saliva fluid. [Display omitted] • API-IL's plasticizing effect is owed to hydrogen bond interaction with gelatin. • Minimum threshold in API-IL loading exists to produce flexible yet robust films. • API-IL loading affects film's mechanical strength and thermal stability. • Gelatin concentration affects films' strength, dissolution, weight and thickness. • API-IL is amorphous in the film with fast dissolution and high kinetic solubility. [ABSTRACT FROM AUTHOR]

There is a lack of methods to predict the isothermal crystallization behavior of amorphous freeze-dried formulations stored below the glass transition temperature. This study applies isothermal microcalorimetry to predict long-term crystallization during product storage time. The relaxation curve of a fresh sample recorded within 12 h after lyophilization is correlated with the long-term crystallization time at the same temperature. Storage conditions of 25 °C and 40 °C are examined and five model formulations containing either sucrose or trehalose with different concentrations of an IgG1 antibody are investigated. The amorphous formulations were created by different freeze-drying processes only differing in their freezing step (random nucleation; additional annealing step of 1.5 h and 3 h, controlled nucleation; quench cooling). Samples that crystallized during the study time of 12 months showed a promising correlation between their relaxation time and crystallization behavior upon storage. Furthermore, the study shows that polysorbate 20 strongly accelerates crystallization of sucrose and that the freezing step itself has a strong impact on the relaxation phenomena that is not levelled out by primary and secondary drying. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the temperature-dependent relaxation dynamics in the glassy and supercooled liquid state of dipolar and ionic eutectic mixtures made of two anesthetic agents (lidocaine and prilocaine) and their hydrochloride salts, respectively. In addition to eutectic phases containing 1:1 and 4:1 mol/mol of LD/PRL and LD-HCl/PRL-HCl, respectively, the relaxation properties of non-eutectic compositions and parent compounds are also studied. We found that electrostatic long-range forces determine strongly the dielectric and mechanical response of eutectic material. As a result of Coulomb interactions between ion pairs, an additional β-relaxation mode was found in the dielectric spectra of glassy LD-HCl/PRL-HCl mixtures. On the other hand, the studies of relaxation dynamics of ionic and non-ionic mixtures at T > T g revealed a continuous decrease of both fragility m P and the length scale of dynamic heterogeneity N α B (T g), with simultaneous growth of T g , when the electrostatics forces appear. At the same time, we found the charge transport being decoupled from structural dynamics in all studied ionic binary mixtures that is due to the fast proton hopping. However, the efficiency of proton transport is dropping down with an increase of T g. Unlabelled Image [ABSTRACT FROM AUTHOR]

In this paper, the role of mesoporous silica (MS) particle size in the stabilization of amorphous simvastatin (SVT) is revealed. For inhibiting recrystallization of the supercooled drug, the two MS materials (Syloid® XDP 3050 and Syloid® 244 FP) were employed. The crystallization tendency of SVT alone and in mixture with the MS materials was investigated by Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS). Neither confinement of the SVT molecules inside the MS pores nor molecular interactions between functional groups of the SVT molecules and the surface of the stabilizing excipient could explain the observed stabilization effect. The stabilization effect might be correlated with diffusion length of the SVT molecules in the MS materials that depended on the particle size. Moreover, MS materials possessing different particle sizes could offer free spaces with different sizes, which might influence crystal growth of SVT. All of these factors must be considered when mesoporous materials are used for stabilizing pharmaceutical glasses.

Abstract Nowadays the study of physiochemical stability of amorphous pharmaceuticals is of great interest in the field of medicinal application due to its enhanced water solubility and bioavailability than its crystalline counterpart. Molecular relaxations play an important role in understanding the physical stability of amorphous drugs. Hence herein, we investigated the molecular dynamics of three pharmaceutically important drugs, namely clofoctol, droperidol and probucol by means of broadband dielectric spectroscopy (BDS) and differential scanning calorimetry (DSC). The dielectric spectra in the supercooled state were fitted by Havriliak-Negami (HN) function, while in the glassy state with Cole-Cole equation. The structural relaxation followed non-Arrhenius temperature dependence and followed time-honored Vogel-Fulcher-Tamman (VFT) equation and the secondary relaxation followed Arrhenius equation. The Coupling model (CM) prediction was used to find the origin of the secondary relaxations. Although the three drugs were found to be fragile, clofoctol and droperidol showed recrystallization tendency. It was amazing that the three samples showed a good correlation between the stretch exponent β KWW and the dielectric strength Δ ε (T g). In addition, the molecular simulation was used to verify the presence of non-JG (Johari-Goldstein) secondary relaxation due to side chain rotation. Highlights • Molecular dynamics of three pharmaceuticals were studied using BDS and DSC. • Clofoctol and droperidol showed recrytallization tendency. • Origin of secondary relaxation verified by CM predictions. • The three samples showed good correlation between β KWW and Δ ε (T g). [ABSTRACT FROM AUTHOR]

Background Many pipeline drugs have low solubility in their crystalline state and require compounding in special dosage forms to increase bioavailability for oral administration. The use of amorphous formulations increases solubility and uptake of active pharmaceutical ingredients. These forms are rapidly gaining commercial importance for both pre-clinical and clinical use. Methods Synthesis of amorphous drugs was performed using an acoustic levitation containerless processing method and spray drying. The structure of the products was investigated using in-situ high energy X-ray diffraction. Selected solvents for processing drugs were investigated using acoustic levitation. The stability of amorphous samples was measured using X-ray diffraction. Samples processed using both spray drying and containerless synthesis were compared. Results We review methods for making amorphous pharmaceuticals and present data on materials made by containerless processing and spray drying. It was shown that containerless processing using acoustic levitation can be used to make phase-pure forms of drugs that are known to be difficult to amorphize. The stability and structure of the materials was investigated in the context of developing and making clinically useful formulations. Conclusions Amorphous compounds are emerging as an important component of drug development and for the oral delivery of drugs with low solubility. Containerless techniques can be used to efficiently synthesize small quantities of pure amorphous forms that are potentially useful in pre-clinical trials and for use in the optimization of clinical products. General significance Developing new pharmaceutical products is an essential enterprise to improve patient outcomes. The development and application of amorphous pharmaceuticals to increase absorption is rapidly gaining importance and it provides opportunities for breakthrough research on new drugs. There is an urgent need to solve problems associated with making formulations that are both stable and that provide high bioavailability. This article is part of a Special Issue entitled “Science for Life” Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo. [ABSTRACT FROM AUTHOR]

The slow molecular mobility in the amorphous solid state of 3 active pharmaceutical drugs (cimetidine, nizatidine, and famotidine) has been studied using differential scanning calorimetry and the 2 dielectric-related techniques of dielectric relaxation spectroscopy and thermally stimulated depolarization currents. The glass-forming ability, the glass stability, and the tendency for crystallization from the equilibrium melt were investigated by differential scanning calorimetry, which also provided the characterization of the main relaxation of the 3 glass formers. The chemical instability of famotidine at the melting temperature and above it prevented the preparation of the amorphous for dielectric studies. In contrast, for cimetidine and nizatidine, the dielectric study yielded the main kinetic features of the α relaxation and of the secondary relaxations. According to the obtained results, nizatidine displays the higher fragility index of the 3 studied glass-forming drugs. The thermally stimulated depolarization current technique has proved useful to identify the Johari–Goldstein relaxation and to measure τ βJG in the amorphous solid state, that is, in a frequency range which is not easily accessible by dielectric relaxation spectroscopy. [ABSTRACT FROM AUTHOR]

Amorphous molecular materials (molecular glasses) are useful for drug delivery, bio-preservation and organic electronics. A central issue in developing amorphous materials is the stability against crystallization and other transformations that can compromise material performance. We review recent progress in understanding the stability of molecular glasses, particularly the role for surface mobility. Surface diffusion in molecular glasses can be vastly faster than bulk diffusion. This high surface mobility enables fast crystal growth on the free surface. In this process, surface crystals grow upward and laterally, with the lateral growth rate being roughly proportional to surface diffusivity. Surface mobility also influences bulk crystal growth as the process can create fracture and free surfaces. During vapor deposition, surface mobility allows efficient equilibration of newly deposited molecules, producing low-energy, high-density glasses that are equivalent to liquid-cooled glasses aged for thousands of years. Free surfaces can accelerate chemical degradation of proteins. Measures for inhibiting surface-facilitated transformations include minimizing free surfaces, applying surface coatings, and preventing fracture. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The slow molecular mobility of the active pharmaceutical drug fenofibrate is studied by differential scanning calorimetry (DSC) and thermally stimulated depolarization currents (TSDC). The general kinetic features of the secondary relaxations and of the main relaxation, in particular their distribution of relaxation times, were determined by TSDC. Different experimental procedures were used to determine the fragility index by DSC and the obtained results were discussed. The TSDC fragility is in very good agreement with the value obtained by dielectric relaxation spectroscopy (DRS), and all the DSC, TSDC and DRS values indicate that fenofibrate is a very fragile liquid. Given that this means a strong aging sensitivity, we profited from this property to evaluate the influence of physical aging on the fragility values determined by TSDC. From the results of experiments designed to achieve this goal we can conclude that this influence can be considered as negligible. [ABSTRACT FROM AUTHOR]

The slow molecular mobility in the active pharmaceutical ingredient probucol was studied by Thermally stimulated depolarisation currents (TSDC) in the temperature region between −130 and 50 °C. The distribution of relaxation times was characterized for the secondary relaxations and for the glass transition relaxation. Based on aging results we were able to draw distinctions between the fast secondary relaxation on the one hand, and the slow-β or Johari–Goldstein relaxation on the other. The steepness index of probucol was calculated from the temperature dependent relaxation time of the glass transition and using methods based on the influence of the scanning rate on the glass transition signal (in DSC and TSDC). The obtained values show some scattering but they are in the frontier between the fragile and strong behaviors. [ABSTRACT FROM AUTHOR]

The thermal behaviour of crystalline and amorphous carvedilol (CAR) phases was studied by advanced thermal analysis using Quantum Design Physical Property Measurement System and Differential Scanning Calorimetry. Theoretical functions describing crystalline carvedilol heat capacity at low temperatures and the Debye-Einstein function for high temperatures were obtained. Based on the experimental heat capacity values, solid and liquid baselines were established, and the state functions (H , S , G) for solid and liquid states were calculated. A comprehensive characterization of melting and glass transition processes was obtained. CAR is easily amorphizable by cooling the liquid. The residual entropy, which quantifies the extent of frozen-in disorder in the amorphous solid, for glassy CAR was estimated as 51 J·mol–1·K–1. The Kauzmann temperature (T K) was estimated based on enthalpy and entropy. Molecular motions in the amorphous phase were also studied. The activation energy for structural relaxation (E a = 539 kJ·mol–1) and fragility parameter (m = 91) were obtained from the non-isothermal physical ageing. The isothermal physical ageing kinetics of amorphous CAR was studied by applying Kohlrausch-Williams-Watts (KWW) model. The mean molecular relaxation time constant (τ KWW = 117 min) and relaxation constant (β KWW = 0.33) were obtained. CAR was classified as a fragile glass-former. Furthermore, τ KWW constant for samples aged at 303.15 K is very low, thus, the physical ageing will occur during the short- and long-term storage of amorphous CAR, potentially changing its physicochemical properties during the ageing process. However, the results of molecular mobility studies (high molecular motions) show that the relationship between molecular motions in a glassy solid and its tendency to crystallization does not seem to follow an expected pattern, i.e., no crystallization occurred by thermal treatment of glassy, supercooled liquid and liquid phases of CAR as one would expect. Modern calorimetry and quantitative thermal analysis provided the fundamental kinetic and thermodynamic information about the crystalline and amorphous states of CAR. [Display omitted] • Functions describing crystalline carvedilol heat capacity at low T and the Debye-Einstein function for high T were obtained. • Equilibrium solid and liquid heat capacities baselines were established. • Thermal analysis provided the kinetic and thermodynamic information about crystalline, and unaged and aged amorphous states of CAR. [ABSTRACT FROM AUTHOR]

Abstract: Developing amorphous pharmaceuticals can be desirable due to advantageous biopharmaceutical properties. Low glass transition temperature (T g) amorphous drugs can be protected from crystallisation by mixing with high T g excipients, such as polymers, or with salt forms. However, both polymers and salts can enhance the water uptake. The aim of this study was to formulate physico-chemically stable amorphous materials, by co-processing different proportions of sulfathiazole and its sodium salt to produce an optimum ratio, characterised by the best physical stability and lowest hygroscopicity. Both sulfathiazole and salt amorphised upon spray drying. At room temperature, sulfathiazole crystallised within 1h at <5% relative humidity while the salt deliquesced when exposed to ambient humidity conditions. In the case of composite systems, FTIR spectroscopy, thermal and surface analysis suggested interactions with an acid:salt stoichiometry of 1:2. Increasing proportions of salt raised the T g, enhancing the storage stability, however this was opposed by an enhanced hygroscopicity. The water uptake mechanism within the different amorphous systems, analysed by fitting the water sorption isotherms with the Young and Nelson equation, was dependent on the ratio employed, with the salt and the acid facilitating absorption and adsorption, respectively. Tuning the properties of amorphous salt/acid composites by optimising the ratio appears potentially promising to improve the physical stability of amorphous formulations. [Copyright &y& Elsevier]

Highlights: [•] Acoustic levitation was used to make phase-pure glassy forms of pharmaceutical compounds. [•] Neutrons, X-rays and NMR were used to characterize the glasses. [•] The glass comprised of slightly distorted molecules packed in a random network. [•] Potential for new drug synthesis routes is discussed. [Copyright &y& Elsevier]

Purpose: To investigate the effect of cryogrinding on chemical stability of the diuretic agent furosemide and its mixtures with selected excipients. Methods: Furosemide was ground at liquid nitrogen temperature for 30, 60, 120 and 180 min. Mixtures of furosemide-PVP and furosemide-inulin (1:1) were milled under cryogenic conditions. Materials were analyzed by XRD, UPLC, MS and NMR. Results: Upon increasing the milling time, a significant build-up of an unidentified impurity 1, probably the main degradation product, was noticed. Cogrinding of furosemide with PVP and inulin worsened chemical stabilization of the pharmaceutical. The main degradation product formed upon cryomilling was subsequently identified as 4-chloro-5-sulfamoylanthranilic acid (CSA). Based on some theoretical considerations involving specific milling conditions, the milling intensity and an expected specific milling dose have been calculated. Results indicate that cryogenic grinding is capable to initiate mechanically induced decomposition of furosemide. Conclusions: Cryogenic grinding can activate and accelerate not only structural changes (solid state amorphization) but also chemical decomposition of pharmaceuticals. A cryogenic milling device should be considered as a chemical reactor, where under favourable conditions chemical reactions could be mechanically initiated. [ABSTRACT FROM AUTHOR]

Abstract: Spontaneous relaxation of an amorphous solid changes its properties with time, as does its slow crystallization, both resulting from slow molecular diffusion that decreases its free energy. When the solid is a pharmaceutical, this occurrence decreases its solubility and hence bioavailability, thus decreasing its effectiveness during storage. Its stability against crystallization or “shelf-life” is currently modeled by calculating the relaxation time, τ glass, by using the specific heat C p and the enthalpy of melting data in the viscosity-configurational entropy relation. We consider merits of such calculations, and find that use of, (i) the excess C p and its hyperbolic dependence on temperature, (ii) the enthalpy of melting, and (iii) the fictive temperature, is inconsistent with the glass relaxation phenomenology, and their use leads to overestimate of τ glass, and thus to a longer than real shelf-life of an amorphous pharmaceutical. We also argue that τ glass is not the same as the characteristic time of spontaneous structural relaxation of a glass, and would not determine the nucleation or crystal growth rate in it. [Copyright &y& Elsevier]

A previous method for measuring solubilities of crystalline drugs in polymers has been improved to enable longer equilibration and used to survey the solubilities of indomethacin (IMC) and nifedipine (NIF) in two homo-polymers [polyvinyl pyrrolidone (PVP) and polyvinyl acetate (PVAc)] and their co-polymer (PVP/VA). These data are important for understanding the stability of amorphous drug–polymer dispersions, a strategy actively explored for delivering poorly soluble drugs. Measuring solubilities in polymers is difficult because their high viscosities impede the attainment of solubility equilibrium. In this method, a drug–polymer mixture prepared by cryo-milling is annealed at different temperatures and analyzed by differential scanning calorimetry to determine whether undissolved crystals remain and thus the upper and lower bounds of the equilibrium solution temperature. The new annealing method yielded results consistent with those obtained with the previous scanning method at relatively high temperatures, but revised slightly the previous results at lower temperatures. It also lowered the temperature of measurement closer to the glass transition temperature. For D-mannitol and IMC dissolving in PVP, the polymer's molecular weight has little effect on the weight-based solubility. For IMC and NIF, the dissolving powers of the polymers follow the order PVP > PVP/VA > PVAc. In each polymer studied, NIF is less soluble than IMC. The activities of IMC and NIF dissolved in various polymers are reasonably well fitted to the Flory–Huggins model, yielding the relevant drug–polymer interaction parameters. The new annealing method yields more accurate data than the previous scanning method when solubility equilibrium is slow to achieve. In practice, these two methods can be combined for efficiency. The measured solubilities are not readily anticipated, which underscores the importance of accurate experimental data for developing predictive models. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4023–4031, 2010 [ABSTRACT FROM AUTHOR]

Abstract: The molecular relaxation in liquid and glassy states of Telmisartan (TEL) has been studied by Broadband Dielectric Spectroscopy (BDS) covering wide temperature and frequency range. Multiple relaxation processes were observed. Besides the primary α-relaxation, two secondary relaxations β and γ (labelled in order of decreasing time scale) have been reported. Well-separated β-process observed above and below glass transition temperature T g , has activation energy E β =81.8kJ/mol and was identified as intermolecular Johari–Goldstein (JG) process. The γ-relaxation visible in dielectric loss spectra at very low temperatures is most likely non-JG relaxation. The temperature dependence of the relaxation times of α-process, measured over 11 orders of magnitude, cannot be described by a single Vogel–Fulcher–Tamman–Hesse (VFTH) equation. At temperature T B =475.8K the change in relaxation dynamics occurred, consequently a new set of VFTH parameters was required. From low temperature VFTH fits the glass transition temperature T g was estimated as T g = 400.3K and fragility index m =87 was calculated. Of particular interest was the time scale of molecular motion below the glass transition temperature. Our observation clearly indicates that the α-relaxation times at room temperature most probably would exceed 3 years and amorphous TEL should maintain physically and chemically stable over prolonged storage time. [Copyright &y& Elsevier]

Stability of the amorphous state has been linked to molecular mobility of the matrix; however different techniques may capture different mobility substates. Our previous work suggested that two calorimetric techniques, Isothermal Microcalorimetry (TAM) and MDSC, measured different aspects of mobility with TAM measuring, in part, some faster modes of relaxation in addition to the modes mobilized at Tg. The aim of this work is to compare the relaxation times obtained using Thermally Stimulated Depolarization Current Spectroscopy (TSDC) with calorimetric mobility measured below Tg and to determine if all measures of relaxation times below Tg are consistent with relaxation times obtained above Tg using Dielectric Spectroscopy (DRS). Model compounds were indomethacin, ketoconazole, nifedipine, flopropione, felodipine. For all compounds, relaxation times obtained using Thermal Windowing-TSDC technique below Tg correlated well with relaxation times (τ) obtained above Tg by DRS. At any given temperature below Tg, relaxation times measured depended upon the technique used and were in the following order TSDC < TAM < MDSC (τ). TSDC captures some faster relaxations not measured by calorimetric techniques, and therefore, different techniques give different measures of relaxation times below Tg. This information is important in understanding the relationships between mobility in the glassy solid and pharmaceutical stability. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4498–4515, 2008 [ABSTRACT FROM AUTHOR]

The aim of the present study is to determine if the correlation between molecular mobility and crystallization growth rates exists over a broad temperature range from temperatures below the glass transition (Tg) to temperatures above the glass transition. Phenobarbital and solid dispersions of phenobarbital with PVP and L-proline were studied in this research. Relaxation times below and above the Tg were measured. Crystallization was followed in a hot-stage microscope and crystal growth rates were measured by observing radial growth of a single crystal. Arrhenius type temperature dependences were found both in relaxation times and crystal growth rates over studied temperature ranges, in all cases studied except in the case of pure phenobarbital, where a change of slope was observed for the crystal growth rate for the temperature range below Tg. For all cases, molecular mobility was correlated with crystal growth rate, for the temperature range studied, with a coupling coefficient of 0.38 for phenobarbital, and 0.23 and 0.28 for solid dispersions with PVP and proline respectively. By establishing the coupling between molecular mobility and crystal growth rate, predictive models can be created to estimate the stability of amorphous materials both, for pure form as well as for solid dispersions. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3830–3841, 2008 [ABSTRACT FROM AUTHOR]

Given a good correlation between onsets of crystallization and mobility above Tg, one might be able to predict crystallization onsets at a temperature of interest far below Tg from this correlation and measurement of mobility at a temperature below Tg. Such predictions require that: (a) correlation between crystallization onset and mobility is the same above and below Tg, and (b) techniques used to measure mobility above and below Tg measure the same kind of mobility [(b) demonstrated previously using dielectric and calorimetric techniques]. The objective of present work is to determine whether crystallization onset times couple with relaxation times determined above Tg, and if so to verify predictions made below Tg (from data above Tg) with experimental data. Model compounds were indomethacin, ketoconazole, flopropione, nifedipine, and felodipine. Onsets of crystallization measured above Tg were coupled with dielectric mobility for indomethacin, felodipine, and flopropione. Prediction of crystallization onset times for temperatures below Tg matched well with experimental data for indomethacin (25°C, 35°C: Predicted 473, 95 h; Experimental: 624 ± 158, 139 ± 49 h) and flopropione (35°C, 40°C; Predicted 115, 58 h; Experimental: 96 ± 30, 59 ± 10 h). The data suggests that coupling between crystallization onsets and molecular mobility at temperatures above Tg may be exploited to develop stability testing protocol for crystallization from amorphous state. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:455–472, 2008 [ABSTRACT FROM AUTHOR]

Amorphous molecule-macromolecule mixtures are ubiquitous in polymer technology and are one of the most studied routes for the development of amorphous drug formulations. For these applications it is crucial to understand how the preparation method affects the properties of the mixtures. Here, we employ differential scanning calorimetry and broadband dielectric spectroscopy to investigate dispersions of a small-molecule drug (the Nordazepam anxiolytic) in biodegradable polylactide, both in the form of solvent-cast films and electrospun microfibres. We show that the dispersion of the same small-molecule compound can have opposite (plasticizing or antiplasticizing) effects on the segmental mobility of a biopolymer depending on preparation method, temperature, and polymer enantiomerism. We compare two different chiral forms of the polymer, namely, the enantiomeric pure, semicrystalline L-polymer (PLLA), and a random, fully amorphous copolymer containing both L and D monomers (PDLLA), both of which have lower glass transition temperature (Tg) than the drug. While the drug has a weak antiplasticizing effect on the films, consistent with its higher Tg, we find that it actually acts as a plasticizer for the PLLA microfibres, reducing their Tg by as much as 14 K at 30%-weight drug loading, namely, to a value that is lower than the Tg of fully amorphous films. The structural relaxation time of the samples similarly depends on chemical composition and morphology. Most mixtures displayed a single structural relaxation, as expected for homogeneous samples. In the PLLA microfibres, the presence of crystalline domains increases the structural relaxation time of the amorphous fraction, while the presence of the drug lowers the structural relaxation time of the (partially stretched) chains in the microfibres, increasing chain mobility well above that of the fully amorphous polymer matrix. Even fully amorphous homogeneous mixtures exhibit two distinct Johari–Goldstein relaxation processes, one for each chemical component. Our findings have important implications for the interpretation of the Johari–Goldstein process as well as for the physical stability and mechanical properties of microfibres with small-molecule additives. [ABSTRACT FROM AUTHOR]

Four model compounds, nifedipine, indomethacin, felodipine, and ketoconazole, all with nearly identical glass transition temperatures, were chosen to study the effects of thermodynamics and molecular mobility on their crystallization propensities. The time and temperature dependence of the crystallization induction time of each compound was determined by differential scanning calorimetry (DSC) and enabled the generation of their time-temperature-transformation (TTT) diagrams. The relaxation times (τ α ) were measured by dielectric spectroscopy, and the Gibbs free energy (Δ G ) and entropy (Δ S ) difference between the crystalline and amorphous states were obtained by DSC. The temperature dependence of the crystallization induction time (τ 0 ( T )) is a function of the thermodynamic activation barrier and the frequency of "attempted jumps" (1/τ α ( T )) to overcome the barrier. Even though the four model compounds exhibited very similar molecular mobility (relaxation time) over a wide range of temperatures, their crystallization propensities were very different. The observed difference in crystallization propensity was explained in terms of the difference in the thermodynamic barrier, and it is correlated to the empirical relation ( T Δ S 3 )/Δ G 2 .

In this paper, the role of mesoporous silica (MS) particle size in the stabilization of amorphous simvastatin (SVT) is revealed. For inhibiting recrystallization of the supercooled drug, the two MS materials (Syloid® XDP 3050 and Syloid® 244 FP) were employed. The crystallization tendency of SVT alone and in mixture with the MS materials was investigated by Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS). Neither confinement of the SVT molecules inside the MS pores nor molecular interactions between functional groups of the SVT molecules and the surface of the stabilizing excipient could explain the observed stabilization effect. The stabilization effect might be correlated with diffusion length of the SVT molecules in the MS materials that depended on the particle size. Moreover, MS materials possessing different particle sizes could offer free spaces with different sizes, which might influence crystal growth of SVT. All of these factors must be considered when mesoporous materials are used for stabilizing pharmaceutical glasses. [ABSTRACT FROM AUTHOR]

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.

Crystallization of active pharmaceutical ingredients (APIs) from the supercooled liquid state is an important issue in determining the stability of amorphous pharmaceutical dispersions. In the present study, the isothermal crystallization from the supercooled liquid state of the pharmaceutical compound nifedipine was investigated by both rheological and differential scanning calorimetry (DSC) measurements, and the crystallization kinetics was fitted to the Johnson-Mehl-Avrami (JMA) equation. Both the crystallization induction time and completion time from the two methods were used to construct the time-temperature-transformation (TTT) diagram for nifedipine. A model based on a modification of classical homogeneous nucleation and crystal growth theory was employed to fit the induction and completion time curves. Both DSC and rheological methods give similar results for the crystallization kinetics of the nifedipine. From the crystallization kinetics modeling, the solid-liquid interfacial surface tension σ SL of nifedipine was estimated and the value was found to be consistent with prior results obtained from melting point depression measurements as a function of crystal size. Evidence is shown that for temperatures below 110 °C, at the early stage of nucleation, NIF first nucleates into the metastable β'-form and later converts into the stable α-form during the isothermal crystallization. We are also able to report the heat of fusion of the γ'-NIF based on the calorimetric experiments.

Cold crystallization of amorphous pharmaceuticals is an important aspect in the search to stabilize amorphous or glassy compounds used as amorphous pharmaceutical ingredients (APIs). In the present work, we report results for the isothermal crystallization of the compound GDC-0276 based on differential scanning calorimetric and rheometric measurements. The kinetics of isothermal crystallization from the induction time to the completion of crystallization can be described by the classic Johnson-Mehl-Avrami (JMA) equation. The time-temperature-transformation (TTT) diagrams were constructed for two time points-that of induction and that of completion of crystallization. The results show that the rheological measurement for GDC-0276 has a better overall sensitivity in detection of the early stage nucleation and, consequently, detects the onset of crystallization sooner than does the differential scanning calorimetry. Rheological measurements were also used to obtain the temperature dependence of the viscosity of GDC-0276 and the relevant parameters were used in a modified form of the JMA model to describe the temperature dependence of the crystal induction and completion times, that is, the TTT diagram for the material. In the modification, we assumed that the kinetics followed the viscosity to the 0.75 power as suggested by the recent work of Huang et al. (Huang, C., et al., J. Chem. Phys. 2018, 149, 054503). The relationship and the possible impact on crystallization kinetics of the break-down of the Stokes-Einstein relation in glass-forming liquids are discussed. From the crystallization kinetics modeling, the solid-liquid interfacial surface tension σ SL was obtained for GDC-0276 and was compared with that obtained from the melting point depression measurements of the material confined in nanoporous glasses. The differences between the values from the two methods are discussed.

Amorphization of drug formulations containing active pharmaceutical ingredients (APIs) and excipients has been proven to be an effective strategy to improve their poor aqueous solubility. The excipients can also impact the physical stability of the prepared amorphous forms. Generally, researchers are more apt to select excipients that have high values of glass transition temperature ( T g ) because of the antiplasticization effect of the additives on APIs. In this article, we studied the glass transition dynamics as well as crystallization behavior in binary blends composed of griseofulvin (GSF) and two low- T g additives, octaacetylmaltose (acMAL) and polyvinyl acetate (PVAc), with a particular focus on the plasticization effect. Effectively suppressed crystallization of GSF is observed in both systems when higher excipient contents are used. Our finding aims to encourage the use of specifically developed protocols in which suitable plasticizers are used as excipients for stabilizing the amorphous state of a drug.

We propose a simple approach to investigate the structural relaxation time and glass transition of amorphous drugs. Amorphous materials are modeled as a set of equal sized hard spheres. The structural relaxation time over many decades in hard-sphere fluids is theoretically calculated using the elastically collective nonlinear Langevin equation theory associated with Kramer's theory. Then, new thermal mapping from a real material to an effective hard-sphere fluid provides temperature-dependent relaxation time, which can be compared to experiments. Numerical results quantitatively agree with previous experiments for pharmaceutical binary mixtures having different weight ratios. We carry out experiments to test our calculations for an ezetimibe-simvastatin-Kollidon VA64 mixture. Our approach would provide a simple but comprehensive description of glassy dynamics in amorphous composites.

In this article, we investigated aripiprazole + Kollidon VA64 (ARP/KVA) and aripiprazole + Soluplus (ARP/SOP) amorphous solid dispersions. Thermal properties of all prepared systems have been examined by means of differential scanning calorimetry (DSC). Compositions revealing the recrystallization tendency were subsequently investigated by means of broadband dielectric spectroscopy (BDS). On the basis of dielectric data, the physically stable drug-polymer concentrations have been found. Finally, these systems have been investigated by rheology, which enables us to determine the minimal temperature required for dissolving the drug in the polymeric matrix, as well as the temperature dependence of the sample viscosity. Our investigations have shown that the amorphous form of the investigated antipsychotic drug might be effectively stabilized by both employed polymers. However, due to the better stabilization effect and the more favorable rheological properties, KVA proved to be a better polymeric excipient for extrusion of amorphous aripiprazole.

Currently, a research hotspot in amorphous active pharmaceutical ingredients (APIs) is to understand the key factors that dominate recrystallization and to develop effective methods for stabilizing amorphous forms. Consequently, we investigated the influence of the global molecular mobility and structural properties on the crystallization tendency of three 1,4-dihydropyridine derivatives (nifedipine, nisoldipine, and nimodipine) in their supercooled states using differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) techniques. The BDS is also employed to monitor the isothermal crystallization kinetics of supercooled nifedipine and nimodipine at T = 333 K under ambient pressure. As a result, we found that nimodipine exhibits much slower crystallization in comparison to nifedipine. However, nimodipine crystallizes much faster when as little as 10 MPa of pressure is exerted on sample. Such compression-induced crystallization of nimodipine as well as the inherent instability of nifedipine can be solved effectively by preparing coamorphous nifedipine/nimodipine combinations. Interestingly, the high physical stability of nifedipine/nimodipine mixtures is achieved despite the fact that the nimodipine acts as a plasticizer.

In this article we thoroughly investigated the physical stability of the amorphous form of a chloramphenicol drug. The tendency toward recrystallization of this drug has been examined (i) at nonisothermal conditions by means of a DSC technique; (ii) at isothermal conditions and temperature close to T room by means of dielectric spectroscopy; (iii) at isothermal conditions and elevated temperatures of T = 323 K and 338 K by dielectric spectroscopy; and (iv) at conditions imitating the manufacturing procedure (i.e., elevated temperature and compression procedure). Our investigations have shown that amorphous chloramphenicol, stored at both standard storage and elevated temperature conditions, does not reveal a tendency toward recrystallization. However, compression significantly changes this behavior and destabilizes the examined compound. We found that due to chemical equilibration of the sample, the elongation of the storage time before compression might improve the physical stability of the examined pharmaceutical exposed to compression 34-times.

Structural dynamics in the glassy state of two protic ionic liquids, carvedilol phosphate and procaine hydrochloride, were characterized from analysis of changes in the conductivity relaxation times during physical aging. The obtained relaxation times, having a magnitude exceeding feasible experimental time scales and thus not directly measurable, are consistent with published data from a method that relies on the presence of a secondary relaxation. We also observe a narrowing of the relaxation dispersion, specific to higher frequencies, that is a consequence of the heterogeneous dynamics of deeply supercooled materials.