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Biomedical subjects

G Zografi

Publications and source records attributed to G Zografi.

At least 37 records · Page 2Linked to original sources
PubMed1998

Phase behavior of binary and ternary amorphous mixtures containing indomethacin, citric acid, and PVP.

PURPOSE: To better understand the nature of drug-excipient interactions we have studied the phase behavior of amorphous binary and ternary mixtures of citric acid, indomethacin and PVP, as model systems. METHODS: We have prepared amorphous mixtures by co-melting or coprecipitation from solvents, and have measured glass transition temperatures with differential scanning calorimetry. RESULTS: Citric acid and indomethacin in the amorphous state are miscible up to 0.25 weight fraction of citric acid, equivalent to about 2 moles of citric acid and 3 moles of indomethacin. Phase separation, as reflected by two Tg values, occurs without crystallization leading to a saturated citric acid-indomethacin amorphous phase and one essentially containing only citric acid. PVP-citric acid and PVP-indomethacin form non-ideal miscible systems at all compositions. A ternary system containing 0.3 weight fraction of PVP produces a completely miscible system at all citric acid-indomethacin compositions. The use of 0.2 weight fraction of PVP, however, only produces miscibility up to a weight fraction of 0.4 citric acid relative to indomethacin. The two phases above this point appear to contain citric acid in PVP and citric acid in indomethacin, respectively. CONCLUSIONS: Two components of an amorphous solid mixture containing citric acid and indomethacin with limited solid state miscibility can be solubilized as an amorphous solid phase by the addition of moderate levels of PVP.

Citric Acid↗
PubMed1998

Enthalpy relaxation in binary amorphous mixtures containing sucrose.

PURPOSE: To compare the enthalpy relaxation of amorphous sucrose and co-lyophilized sucrose-additive mixtures near the calorimetric glass transition temperature, so as to measure the effects of additives on the molecular mobility of sucrose. METHODS: Amorphous sucrose and sucrose-additive mixtures, containing poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl-acetate) (PVPNA) dextran or trehalose, were prepared by lyophilization. Differential scanning calorimetry (DSC) was used to determine the area of the enthalpy recovery endotherm following aging times of up to 750 hours for the various systems. This technique was also used to compare the enthalpy relaxation of a physical mixture of amorphous sucrose and PVP. RESULTS: Relative to sucrose alone, the enthalpy relaxation of co-lyophilized sucrose-additive mixtures was reduced when aged for the same length of time at a comparable degree of undercooling in the order: dextran approximately PVP > PVPNA > trehalose. Calculated estimates of the total enthalpy change required for sucrose and the mixtures to relax to an equilibrium supercooled liquid state (deltaHinfinity) were essentially the same and were in agreement with enthalpy changes measured at longer aging times (750 hours). CONCLUSIONS: The observed decrease in the enthalpy relaxation of the mixtures relative to sucrose alone indicates that the mobility of sucrose is reduced by the presence of additives having a Tg that is greater than that of sucrose. Comparison with a physically mixed amorphous system revealed no such effects on sucrose. The formation of a molecular dispersion of sucrose with a second component, present at a level as low as 10%, thus reduces the mobility of sucrose below Tg, most likely due to the coupling of the molecular motions of sucrose to those of the additive through molecular interactions.

Biocompatible Materials↗
PubMed1997

Characteristics and significance of the amorphous state in pharmaceutical systems.

The amorphous state is critical in determining the solid-state physical and chemical properties of many pharmaceutical dosage forms. This review describes the characteristics of the amorphous state and some of the most common methods that can be used to measure them. Examples of pharmaceutical situations where the presence of the amorphous state plays an important role are presented. The application of our current knowledge to pharmaceutical formulation problems is illustrated, and some strategies for working with amorphous character in pharmaceutical systems are provided.

Chemistry, Pharmaceutical↗
PubMed1997

Effects of sorbed water on the crystallization of indomethacin from the amorphous state.

The water sorption isotherm and the crystallization rates for amorphous indomethacin were determined at 30 degrees C as a function of relative humidity (RH), along with the effects of water content on the glass transition temperature (T(g)). Below 43% RH, only the stable gamma crystal form appears, whereas at higher RH, only the metastable alpha crystal form appears. The tendency for the alpha crystals to form at higher RH is consistent with the Ostwald step rule. The crystallization rate of the alpha form continuously increased with increasing RH due to increasing molecular mobility. The crystallization mechanism of the gamma form changed from surface-initiated to bulk-initiated crystallization at 21% RH, and although crystallization rates of the gamma form increased with increasing RH in both cases, they were higher when crystallization was surface-initiated. The complex crystallization behavior of the gamma form is explained by the higher water content and molecular mobility of the surface relative to the bulk and the general effect of water on alpha or gamma crystal form selection as described by the Ostwald step rule.

Absorption↗
PubMed1997

Properties of citric acid at the glass transition.

To better understand the properties of citric acid when used in solid dosage forms as an acid-base buffer, we initiated a study of its properties in the amorphous state. Such a state often arises during processes such as lyophilization and wet granulation. In view of inconsistencies in the literature concerning the glass transition temperature, Tg, of citric acid in the dry and hydrated states, we measured the Tg of samples formed by a melt-quench cool sequence in a DSC. We also used DSC to measure Tg', the glass transition temperature of the maximally freeze-concentrated solution. It was shown that dry citric acid has a Tg of 11 degrees C, while that containing 8.6% water (equimolar) has a value of -25 degrees C. The Tg' of a frozen solution of citric acid is -53 degrees C. Measuring Tg for the dry and hydrated samples at various scanning rates allowed measurement of the activation energy for enthalpy relaxation at Tg and enabled estimation of the degree of fragility (or the strength parameter) for both samples. It was shown that citric acid is a fairly fragile liquid expected to exhibit non-Arrhenius dynamic behavior and that the presence of residual water at a level of 8.6% causes a decrease in fragility.

Calorimetry, Differential Scanning↗
PubMed1997

Molecular mobility of supercooled amorphous indomethacin, determined by dynamic mechanical analysis.

PURPOSE: To determine the viscosity and the frequency-dependent shear modulus of supercooled indomethacin as a function of temperature near and above its glass transition temperature and from these data to obtain a quantitative measure of its molecular mobility in the amorphous state. METHODS: Viscoelastic measurements were carried with a controlled strain rheometer in the frequency domain, at 9 temperatures from 44 degrees to 90 degrees C. RESULTS: The viscosity of supercooled indomethacin shows a strong non-Arrhenius temperature dependence over the temperature range studied, indicative of a fragile amorphous material. Application of the viscosity data to the VTF equation indicates a viscosity of 4.5 x 10(10) Pa.s at the calorimetric Tg of 41 degrees C. and a T0 of -17 degrees C. From the complex shear modulus and the Cole-Davidson equation the shear relaxation behaviour is found to be non-exponential, and the shear relaxation time at Tg is found to be approximately 100 sec. CONCLUSIONS: Supercooled indomethacin near and above its Tg exhibits significant molecular mobility, with relaxation times similar to the timescales covered in the handling and storage of pharmaceutical products.

Cold Temperature↗
PubMed1997

Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions.

PURPOSE: To study the molecular structure of indomethacin-PVP amorphous solid dispersions and identify any specific interactions between the components using vibrational spectroscopy. METHODS: Solid dispersions of PVP and indomethacin were prepared using a solvent evaporation technique and IR and FT-Raman spectra were obtained. RESULTS: A comparison of the carbonyl stretching region of gamma indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of alpha indomethacin is not as dimers. Addition of PVP to amorphous indomethacin increased the intensity of the infrared band assigned to non-hydrogen bonded carbonyl. Concomitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a solution of indomethacin in methylpyrrolidone at the same weight percent. CONCLUSIONS: Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystallisation kinetics by preventing the self association of indomethacin molecules. The similarity of results for solid dispersions and solutions emphasises the "solution" nature of this binary amorphous state.

Crystallization↗
PubMed1995

Hydration and dehydration of crystalline and amorphous forms of raffinose.

The trisaccharide raffinose was prepared in its crystal pentahydrate, anhydrous methanolate, and amorphous forms and evaluated with regard to dehydration and hydration properties at various temperatures and relative humidities. The pentahydrate, when stored at relative humidities (RHs) of < 60% but > 10%, showed no loss of water after 3 months of storage at 30 degrees C. When stored below 10% RH, only one water molecule could be removed over a period of 3 months, whereas within 24 h at 30 degrees C in a vacuum oven, two water molecules were removed with no change in crystal structure. Increasing the temperature to 60 degrees C progressively removed the remaining three molecules, causing the crystal, however, to collapse into an amorphous form identical to one prepared by lyophilization. Rehydration at 30 degrees C, which was sufficient to reduce the glass transition temperature to < 30 degrees C, rapidly restored the pentahydrate crystal structure. Rehydration of the methanolate also restored the pentahydrate structure. The significant amount of water accommodated by raffinose in both the crystalline and amorphous forms would appear to make it a potentially useful water scavenger in certain types of dosage forms.

Chemistry, Pharmaceutical↗
PubMed1995

Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates.

Differential scanning calorimetry and powder X-ray diffraction studies have been carried out with amorphous coprecipitates of indomethacin and poly(vinylpyrrolidone), PVP, to measure the glass transition temperature, Tg, as a function of mixture composition and the nonisothermal and isothermal crystallization of the indomethacin. Values of Tg as a function of mixture composition followed the ideal Gordon-Taylor equation up to about 50% w/w PVP. Inhibition of crystallization occurred at levels as low as 5% PVP and very significant inhibition was observed at and above 20% PVP. Inhibition of crystallization of indomethacin in the absence of PVP required a storage temperature 40-50 degrees C below Tg, whereas comparable inhibition with PVP was observed at storage temperatures 5 degrees C above Tg. This suggests that the inhibition of indomethacin crystallization by PVP may involve mechanisms other than just the general antiplasticizing effect (raising Tg) by PVP.

Calorimetry, Differential Scanning↗
PubMed1995

Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures.

PURPOSE: 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.

Calorimetry↗
PubMed1994

Crystallization of indomethacin from the amorphous state below and above its glass transition temperature.

The solid state crystallization of amorphous polymers, sugars, and inorganic glasses is often thought to be restricted to the region above the glass transition temperature, Tg, because insufficient molecular mobility (high viscosity) exists below Tg for nucleation and crystal growth. Here we report on the isothermal and nonisothermal crystallization of dry amorphous indomethacin in the temperature range of 20 degrees C above and below its Tg. These studies were carried out with two amorphous samples having different degrees of metastability relative to the crystalline state. It was shown that in both samples significant crystallization to the most stable polymorphic form occurred over several days when stored below Tg, and in some cases this process was preceded by the relaxation of one amorphous form to the other. At storage temperatures near to and above Tg the rates of crystallization increased as expected but a second less thermodynamically stable polymorph also appeared with the more stable crystal form. This behavior was explained by the possible relationship between the degree of metastability relative to the crystalline state of each amorphous form and the interfacial energy existing at the respective nucleation sites, in accord with the Ostwald step rule.

Calorimetry, Differential Scanning↗
PubMed1994

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).

Chemistry, Pharmaceutical↗
PubMed1994

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 degrees 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. Colyophilization 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.

Absorption↗
PubMed1993

The surface properties of lung 36 kDa Ca(2+)-dependent phospholipid-binding protein.

The intrinsic surface activity of a 36 kDa rabbit lung calcium-dependent phospholipid-binding protein (PLBP), a member of the annexin family of such proteins, at the air/water interface has been determined from measurements of surface tension of aqueous solutions, and surface concentration of 14C-labeled PLBP adsorbed from aqueous solution in the absence and presence of Ca2+. It was also possible to spread insoluble monolayers of PLBP to determine surface pressure vs. surface concentration isotherms, as well as surface elasticity and surface viscosity as a function of frequency from electrocapillary wave diffraction measurements. PLBP has been shown to exhibit significant intrinsic surface activity at the air/water interface, comparable to a variety of other hydrophobic proteins known to be quite surface active. In all cases, surface properties were enhanced by the presence of Ca2+, particularly the degree of surface viscoelasticity at close-packing in the monolayer. This is believed to reflect changes in protein conformation at the surface.

Animals↗