Correlation between Molecular Mobility and Physical Stability in Pharmaceutical Glasses.

We investigated the influence of drug-polymer hydrogen bonding interactions on molecular mobility and the physical stability in solid dispersions of nifedipine with each of the polymers polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS), and poly(acrylic acid) (PAA). The drug-polymer interactions were monitored by FT-IR spectroscopy, the molecular mobility was characterized using broadband dielectric spectroscopy, and the crystallization kinetics was evaluated by powder X-ray diffractometry. The strength of drug-polymer hydrogen bonding, the structural relaxation time, and the crystallization kinetics were rank ordered as PVP > HPMCAS > PAA. At a fixed polymer concentration, the fraction of the drug bonded to the polymer was the highest with PVP. Addition of 20% w/w polymer resulted in ∼65-fold increase in the relaxation time in the PVP dispersion and only ∼5-fold increase in HPMCAS dispersion. In the PAA dispersions, there was no evidence of drug-polymer interactions and the polymer addition did not influence the relaxation time. Thus, the strongest drug-polymer hydrogen bonding interactions in PVP solid dispersions translated to the longest structural relaxation times and the highest resistance to drug crystallization.

Relation between the dispersion of α-relaxation and the time scale of β-relaxation at the glass transition

We used broadband dielectric spectroscopy in the frequency range from 10–2 Hz up to 107 Hz and we found dynamics of the primary α- and intermolecular Johari-Goldstein (JG) β-processes are strongly correlated in diglycidyl ether of bisphenol-A over a wide temperature from 193 to 283K and pressure P range from 0.1 to 600 MPa. Analysing the temperature and pressure behavior of the α - and (JG) β-processes, a clear correlation has been found between the structural relaxation time, the Johari-Goldstein relaxation time and the dispersion of the structural relaxation. These results support the idea that the Johari-Goldstein relaxation acts as a precursor of the structural relaxation and therefore of the glass transition phenomenon.

Dielectric spectroscopy was used to characterize the structural relaxation in pharmaceutical dispersions containing nifedipine (NIF) and either poly(vinyl) pyrrolidone (PVP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS). The shape of the dielectric response (permittivity versus log time) curve was observed to be independent of temperature. Thus, for the pure NIF as well as the dispersions, the validity of the time-temperature superposition principle was established. Furthermore, though the shape of the full dielectric response varied with polymer concentration, the regime related to the α- or structural relaxation was found to superimpose for the dispersions, though not with the response of the NIF itself. Hence, there is a limited time-temperature-concentration superposition for these systems as well. Therefore, in this polymer concentration range, calculation of long relaxation times in these glass-forming systems becomes possible. We found that strong drug-polymer hydrogen bonding interactions improved the physical stability (i.e., delayed crystallization) by reducing the molecular mobility. The strength of hydrogen bonding, structural relaxation time, and crystallization followed the order: NIF-PV P>NIF-HPMCAS>NIF. With an increase in polymer concentration, the relaxation times were longer indicating a decrease in molecular mobility. The temperature dependence of relaxation time, in other words fragility, was independent of polymer concentration. This is the first application of the superposition principle to characterize structural relaxation in glassy pharmaceutical dispersions.

Conventional (frequency domain) dielectric spectroscopy (FDDS) is very useful for studying molecular interactions in systems which are in equilibrium. However, it is not usually convenient, or in some cases feasible, to investigate transient processes by FDDS. A major advantage of time domain dielectric spectroscopy (TDDS) is that many types of transient phenomena can be studied. As a point in question, the use of TDDS for the investigation of the kinetic processes associated with the nucleation and growth of a second phase in an initial phase will be discussed. The use of the technique for the study of phase separation in polymer blends will also be discussed and preliminary results for a model system, phenol-water, will be presented.

The influence of different preparation methods on the physicochemical properties of amorphous solid forms have gained considerable attention, especially with recent publications on pharmaceutical polyamorphism. In the present study, we have investigated the possible occurrence of polyamorphism in the drug celecoxib (CEL) by investigating the thermal behavior, morphology, structure, molecular mobility and physical stability of amorphous CEL obtained by quench-cooling (QC), ball milling (BM) and spray drying (SD). Similar glass transition temperatures but different recrystallization behaviors were observed for CEL-QC, CEL-BM and CEL-SD using modulated differential scanning calorimetry analysis. A correlation between the different recrystallization behaviors of the three CEL amorphous forms and the respective distinct powder morphologies, was also found. Molecular dynamics simulations however, reveal that CEL presents similar molecular conformational distributions when subjected to QC and SD. Moreover, the obtained molecular conformational distributions of CEL are different from the ones found in its crystal structure and also from the ones found in the lowest-energy structure obtained by quantum mechanical calculations. The type and strength of CEL hydrogen bond interactions found in CEL-QC and CEL-SD systems are almost identical, though different from the ones presented in the crystal structure. Pair distribution function analyses and isothermal microcalorimetry show similar local structures and structural relaxation times, respectively, for CEL-QC, CEL-BM and CEL-SD. The present work shows that not only similar physicochemical properties (glass transition temperature, and structural relaxation time), but also similar molecular conformational distributions were observed for all prepared CEL amorphous systems. Hence, despite their different recrystallization behaviors, the three amorphous forms of CEL did not show any signs of polyamorphism.

Solid state chemistry of proteins: II. The correlation of storage stability of freeze‐dried human growth hormone (hGH) with structure and dynamics in the glassy solid

Knowledge of relaxation processes is fundamental in glass science and technology because relaxation is intrinsically related to vitrification, tempering as well as to annealing and several applications of glasses. However, there are conflicting reports—summarized here for different glasses—on whether the structural relaxation time of glass can be calculated using the Maxwell equation, which relates relaxation time with shear viscosity and shear modulus. Hence, this study aimed to verify whether these two relaxation times are comparable. The structural relaxation kinetics of a lead metasilicate glass were studied by measuring the refractive index variation over time at temperatures between 5 and 25 K below the fictive temperature, which was initially set 5 K below the glass‐transition temperature. Equilibrium shear viscosity was measured above and below the glass‐transition range, expanding the current knowledge by one order of magnitude. The Kohlrausch equation described very well the experimental structural relaxation kinetics throughout the investigated temperature range and the Kohlrausch exponent increased with temperature, in agreement with studies on other glasses. The experimental average structural relaxation times were much longer than the values computed from isostructural viscosity, as expected. Still, they were less than one order of magnitude higher than the average relaxation time computed through the Maxwell equation, which relies on equilibrium shear viscosity. Thus, these results demonstrate that the structural relaxation process is not controlled by isostructural viscosity and that equilibrium shear viscosity only provides a lower boundary for structural relaxation kinetics.

Self-diffusion coefficients of different classes of polar solvents are measured by the proton spin echo method in the temperature range of 288–318 K. In the same temperature range viscosities and dielectric relaxation times of the liquids under study are measured or taken from the literature and the activation energies of self-diffusion processes, viscous flow, and dielectric relaxation are calculated. The results obtained are compared with the literature data on structural relaxation times in the studied solvents and the conclusion is drawn about the role of the spatial hydrogen bond network in the mobility of molecules forming this network.

The glass transition temperature Tg for many foods has been determined by thermal analysis such as differential scanning calorimetry (DSC). The thermal analysis, however, does not provide information on molecular mobility. In this review, the analysis of the glass transition of foods by electrical methods and proton-NMR was explained and compared with that obtained by DSC. The dielectric relaxation, i.e., the peak of the dielectric loss, e″, was observed for some glassy foods and ascribed to the local motion of molecules. The relaxation time τ and the activation energy Eact seemed suitable parameters to describe the enhancement effect of water on the mobility of molecules in the glassy state. However, when the ionic conductivity dominated the electrical properties, the e″ peak was masked. For analyzing such a system, the electric modulus, M* was an effective tool. The value of the activation energy obtained through M* formalism in the glassy state was larger than that in the rubbery state, probably due to a change in the free volume size by glass transition. For NMR research, the mobility of glucose syrup in the glassy and rubbery states has been examined. Free induction decay (FID) was measured with low-resolution NMR and was best fitted by a Gaussian lineshape multiplied by sinc function plus an exponential function. The T2 of mobile protons reached the rigid-lattice limit at a temperature lower than the midpoint Tg obtained by DSC.

In this work, the dynamics of the primary - and the Johari-Goldstein (JG) - processes are studied with dielectric spectroscopy. We found the relaxations at glass transition temperature in polyphenylglycidylether and diglycidyl ether of bisphenol-A to be strongly correlated over a wide temperature T and pressure P range. Analysing the temperature and pressure behaviour of the - and (JG) -processes, a clear correlation has been found between the structural relaxation time, the Johari-Goldstein relaxation time and the dispersion of the structural relaxation.

On relaxation nature of glass transition in amorphous materials

Broadband dielectric spectroscopy and aging of glass formers

A supercooled binary mixture of soft disks in 2D, studied using molecular dynamics simulations, exhibits a breakdown of scaling between the self-diffusion constant and a structural relaxation time below a crossover temperature. Evidence is presented that this breakdown arises from two causes. First, the small displacements involved in structural relaxation correspond to the transition between ballistic and diffusive motion. Second, the different physical quantities averaged to obtain transport and relaxation time scales sample different parts of the increasingly heterogeneous distribution of local relaxation times and, hence, exhibit different temperature variation.

Polyvinylpyrrolidone (PVP) has proven to be a highly versatile material, as evidenced by its long history as multifunctional biomaterial with a wide range of high-performance applications (e.g., tissue engineering, drug delivery systems, and ophthalmologic applications). PVP was frequently used in medical and pharmaceutical field due to its several interesting properties (higher glass transition temperature, water solubility, biocompatibility, biodegradability, chemical stability, very good adhesive, and emulsifying agent). This chapter highlights the multifunctional roles of PVP in pharmaceutical formulations in solid state. In fact, PVP acted as a stabilizing agent for various amorphous drug molecules by minimizing their molecular mobility. Physical stabilization resulted from the reinforcement of intermolecular interactions in binary or ternary systems due to the synergetic effect of PVP. This made it possible to overcome several challenges for drug formulations (e.g., solubility and bioavailability weakness, physical instability under stress conditions, complexation efficiency of cyclodextrin molecules). In this chapter, the effect of PVP on the binary solid dispersion (indomethacin:kaolin) is discussed. We have shown that PVP enhanced physical stability of amorphous indomethacin under stress conditions (at RH: 75% and T = 40°C for three months), leading to the improvement of drug aqueous solubility by suppressing kaolin adsorption effect.