George Zografi

Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures

AbstractPurpose. To measure the molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures (Tg), using indomethacin, poly (vinyl pyrrolidone) (PVP) and sucrose as model compounds. Methods. Differential scanning calorimetry (DSC) was used to measure enthalpic relaxation of the amorphous samples after storage at temperatures 16-47 K below Tg for various time periods. The measured enthalpy changes were used to calculate molecular relaxation time parameters. Analogous changes in specimen dimensions were measured for PVP films using thermomechanical analysis. Results. For all the model materials it was necessary to cool to at least 50 K below the experimental Tg before the molecular motions detected by DSC could be considered to be negligible over the lifetime of a typical pharmaceutical product. In each case the temperature dependence of the molecular motions below Tg was less than that typically reported above Tg and was rapidly changing. Conclusions. In the temperature range studied the model amorphous solids were in a transition zone between regions of very high molecular mobility above Tg and very low molecular mobility much further below Tg. In general glassy pharmaceutical solids should be expected to experience significant molecular mobility at temperatures up to fifty degrees below their glass transition temperature.

The Relationship Between the Glass Transition Temperature and the Water Content of Amorphous Pharmaceutical Solids

The glass transition temperature of an amorphous pharmaceutical solid is a critical physical property which can dramatically influence its chemical stability, physical stability, and viscoelastic properties. Water frequently acts as a potent plasticizer for such materials, and since many amorphous solids spontaneously absorb water from their surroundings the relationship between the glass transition temperature and the water content of these materials is important. For a wide range of amorphous and partially amorphous pharmaceutical solids, it was found that there is a rapid initial reduction in the glass transition temperature from the dry state as water is absorbed, followed by a gradual leveling off of the response at higher water contents. This plasticization effect could generally be described using a simplified form of the Gordon–Taylor/ Kelley–Bueche relationships derived from polymer free volume theory. Most of the systems considered showed a nearly ideal volume additivity and negligible tendency to interact. This is consistent with the hypothesis that such mixtures behave as concentrated polymer solutions and indicates that water acts as a plasticizer in a way similar to that of other small molecules and not through any specific or stoichiometric interaction process(es).

The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state

It is well recognized that residual water associated with drugs in the solid state can have significant effects on a variety of physical and chemical properties, such as chemical degradation, dissolution rate, flow and compactibility. In this brief review, emphasis will be placed on the role of water in affecting drug entities that are believed to exist predominantly in the crystalline state, in the absence and presence of excipients and other drugs in the formulation.

Physical Properties of Solid Molecular Dispersions of Indomethacin with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl-acetate) in Relation to Indomethacin Crystallization

AbstractPurpose. To measure solid-state features of amorphous molecular dispersions of indomethacin and various molecular weight grades of poly(vinylpyrrolidone), PVP, and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA, in relation to isothermal crystallization of indomethacin at 30°C Methods. The glass transition temperatures (Tg) of molecular dispersions were measured using differential scanning calorimetry (DSC). FT-IR spectroscopy was used to investigate possible differences in interactions between indomethacin and polymer in the various dispersions. The enthalpy relaxation of 5% w/w and 30% w/w polymer dispersions was determined following various aging times. Quantitative isothermal crystallization studies were carried out with pure indomethacin and 5% w/w polymers in drug as physical mixtures and molecular dispersions. Results. All coprecipitated mixtures exhibited a single glass transition temperature. All polymers interacted with indomethacin in the solid state through hydrogen bonding and in the process eliminated the hydrogen bonding associated with the carboxylic acid dimers of indomethacin. Molecular mobility at 16.5°C below Tg was reduced relative to indomethacin alone, at the 5% w/w and 30% w/w polymer level. No crystallization of indomethacin at 30°C was observed in any of the 5% w/w polymer molecular dispersions over a period of 20 weeks. Indomethacin alone and in physical mixtures with various polymers completely crystallized to theγ form at this level within 2 weeks. Conclusions. The major basis for crystal inhibition of indomethacin at 30°C at the 5% w/w polymer level in molecular dispersions is not related to polymer molecular weight and to the glass transition temperature, and is more likely related to the ability to hydrogen bond with indomethacin and to inhibit the formation of carboxylic acid dimers that are required for nucleation and growth to the γ crystal form of indomethacin.

Assessment of disorder in crystalline solids

Abstract In the processing of pharmaceutical solids, disruption or activation of the crystalline structure often leads to varying degrees of disorder through the formation of defects and amorphous regions. Since percent disorder of processed samples must be assessed quantitatively using premixed standard samples of highly crystalline and amorphous solids, in the past, a number of questions about the validity of such an approach have been raised. Using sucrose as a model solid, a comprehensive assessment of such disorder has been carried out on predetermined mixtures of crystalline and amorphous samples, as well as on crystalline samples mechanically milled for various periods of time. Particular emphasis was placed on determining low levels of disorder in highly crystalline samples, since most techniques can detect no less than about 10% disorder. With predetermined mixtures, measurements of X-ray powder diffraction, density and heats of crystallization revealed good linearity with the percent disorder and acceptable detectability down to about 10%, as expected. However, using water vapor sorption measurements under very carefully controlled conditions proved effective in being able to detect disorder as low as 1%. A comparison of these four methods for estimating the percent disorder of milled samples of sucrose gave very consistent results, once the underlying factors that make these techniques sensitive to the concentration of amorphous structure present were recognized and taken into account.

Non-Isothermal and Isothermal Crystallization of Sucrose from the Amorphous State

The crystallization of a model compound, sucrose, from the amorphous solid state has been studied non-isothermally using differential scanning calorimetry to determine crystallization temperature, Tc, and isothermally at 30°C by subjecting samples to 32.4% relative humidity and gravimetrically monitoring water vapor uptake and subsequent loss with time due to crystallization. From the measurement of glass transition temperature, Tg, and melting temperature, Tm, for sucrose alone and in the presence of absorbed water it was possible to predict Tc and thus to directly relate the plasticizing effects of water to its tendency to promote crystallization. Colyo-philization of sucrose with lactose, trehalose, and raffinose, all having Tg values greater than that of sucrose, increased Tc significantly, even at levels as low as 1 – 10% w/w. In the isothermal studies the time required for crystallization to commence, due to the plasticizing effects of water, i.e., the induction time, assumed to be mostly affected by rates of nucleation, was greatly increased by the presence of the additives at these low levels, with raffinose producing a greater effect than lactose and trehalose. Similarly, these additives reduced the rate of water loss, i.e., the rate of crystal growth, but now no significant differences were noted between the three additives. The possible relationships of nucleation and crystal growth and the effects of additives on molecular mobility are discussed.

States of Water Associated with Solids

AbstractThis paper critically reviews the underlying factors which influence the physical chemical states of water when it is associated with solids, as well as the effects that this water can have on the properties of the solid. Situations considered include: adsorption to solid surfaces, absorption into amorphous solids, capillary condensation into micropores, deliquescence, and the formation of crystal hydrates.

Crystal nucleation and growth of indomethacin polymorphs from the amorphous state

Abstract The effect of temperature on the overall crystallization, and the crystal nucleation and growth rates of indomethacin polymorphs from the amorphous state were determined. Crystallization of amorphous indomethacin at temperatures close to or below its T g (42°C) favors the formation of the stable γ polymorphic form, while crystallization at higher temperatures favors the formation of the metastable α-crystal form. Both the nucleation and growth rates for γ-indomethacin have maxima that coincide just above the T g of amorphous indomethacin. The nucleation rate for α-indomethacin was found to have a maximum at 60°C, and the growth rate at 90°C. Assuming a temperature dependent crystal–amorphous interface free energy, good agreement was observed between the experimental nucleation data and the predictions of the classical theory of nucleation. The crystal–amorphous interface energy was higher for the γ than for the α-indomethacin. Analysis of the crystal growth rates for both crystal forms showed that the mechanism of growth is by two-dimensional nucleation, but quantitative agreement with the theory was not found. The interface energy for the α-crystal form, obtained from the growth data was in very good agreement with the value obtained from the nucleation data.

The quantitative analysis of crystallinity using FT-Raman spectroscopy.

AbstractPurpose. To establish if FT-Raman Spectroscopy can be used to quantitate the degree of crystallinity in a model compound. Methods. Mixtures containing different proportions of amorphous and crystalline indomethacin were prepared. Using the peak intensity ratio 1698 cm−1 (crystalline) to 1680 cm−1 (amorphous), a correlation curve was prepared. This correlation curve was validated by testing further samples of known composition. Partially crystalline indomethacin was prepared by milling crystalline indomethacin. Results. A linear correlation curve was obtained across the entire range of 0−100% crystallinity. Using this method, it was possible to detect down to either 1% amorphous or crystalline content. The largest errors were found to result from inhomogeneities in the mixing of the calibration and validation samples. The spectra of the mechanically processed samples were similar to the spectra of the calibration samples, and the degree of crystallinity could be estimated in these samples. Conclusions. FT-Raman Spectroscopy is a potentially useful method to complement existing techniques for the quantitative determination of crystallinity.

Assessing the performance of amorphous solid dispersions

The characterization and performance of stable amorphous solid dispersion systems were evaluated in 40 research papers reporting active pharmaceutical ingredient (API) dissolution and bioavailability from various systems containing polymers. The results from these studies were broadly placed into three categories: amorphous dispersions that improved bioavailability (∼82% of the cases), amorphous dispersions possessing lower bioavailability than the reference material (∼8% of the cases), and amorphous dispersions demonstrating similar bioavailabilities as the reference material (∼10% of the cases). A comparative analysis of these studies revealed several in vitro and in vivo variables that could have influenced the results. The in vitro factors compared primarily centered on dissolution testing and equipment, content and amount of dissolution media, sink or nonsink conditions, agitation rates, media pH, dissolution characteristics of the polymer, and dispersion particle size. The in vivo factors included reference materials used for bioavailability comparisons, animal species utilized, fasting versus fed conditions, and regional differences in gastrointestinal (GI) content and volume. On the basis of these considerations, a number of recommendations were made on issues ranging from the assessment of physical stability of API-polymer dispersions to in vivo GI physiological factors that require consideration in the performance evaluation of these systems.