Discovery of the hemifumarate and (alpha-L-alanyloxy)methyl ether as prodrugs of an antirheumatic oxindole: prodrugs for the enolic OH group.

Ether, ester, and carbonate derivatives of the antirheumatic oxindole 1 were prepared and screened as potential prodrugs of 1. This effort led to the discovery of the (alpha-L-alanyloxy)-methyl ether and hemifumarate derivatives of 1 which deliver the drug efficiently into the circulation of test animals, are stable in the solid state, and possess good stability in solution at low pH as required to ensure gastric stability. Success in achieving acceptable bioavailabilities of 1 across species (rats, dogs, and monkeys) followed the inclusion of ionizable functionality within the promoiety to compensate for masking the polar enolic OH group of the free drug. However, the introduction of ionizable functionality was often associated with decreased stability, as demonstrated by the hemisuccinate, hemiadipate, hemisuberate, and alpha-amino ester derivatives of 1 which could not be isolated. A clear exception was the hemifumarate derivative of 1 which was not only isolable but actually more stable at neutral pH than the nonionizable ester analogues. The solution and solid state stability of the hemifumarate, together with its activity as a prodrug of 1, suggests that hemifumarate be considered as an alternative to hemisuccinate as a prodrug derivative for alcohols, particularly in situations where solution state stability is an issue.

Water vapor sorption by peptides, proteins and their formulations.

The interactions of pharmaceutical peptides, proteins and their formulations with environmental water vapor are reviewed. Particular attention is paid to the importance of the physical structure and chemical diversity of peptides and proteins, and comparisons are made with the mechanisms of water vapor sorption by synthetic macromolecular systems. The influences of formulation processes and additives are also considered and suggestions made for future areas of research.

Mixing behavior of colyophilized binary systems.

The purpose of this study was to investigate the factors which govern the mixing of amorphous sucrose with trehalose, poly(vinylpyrrolidone) (PVP), dextran, and poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA). These materials were chosen as model systems to represent multicomponent freeze-dried pharmaceutical preparations. Mixtures were prepared by colyophilization of the components from aqueous solutions. The glass transition temperatures (Tg) of these mixtures were measured using differential scanning calorimetry (DSC) and were compared to predictions based on simple mixing rules. FT-Raman spectroscopy was used to probe selected mixtures for evidence of molecular interactions between components. Colyophilized mixtures were confirmed to be amorphous by X-ray powder diffraction. The Tg values of the various mixtures generally were lower than values predicted from free volume and thermodynamic models, indicating that mixing is not ideal. The FT-Raman spectra of colyophilized sucrose-PVP and sucrose-PVP/VA mixtures provided evidence for interaction between the components through hydrogen bonding. Hydrogen bonds formed between components in colyophilized sucrose-additive mixtures are formed at the expense of hydrogen bonds within sucrose and in some cases within the additive. A thermodynamic analysis of these mixtures indicates that mixing is endothermic, which is consistent with a net loss in the degree of hydrogen bonding on mixing. There is also a positive excess entropy of mixing which accompanies the net loss in hydrogen bonds. Despite this gain in excess entropy, the excess free energy of mixing is positive, consistent with the observed deviations in Tg from values predicted using models which assume ideal mixing.

Interpretation of relaxation time constants for amorphous pharmaceutical systems.

The molecular mobility of amorphous pharmaceutical materials is known to be a key factor in determining their stability, reactivity, and physicochemical properties. Usually such molecular mobility is quantified using relaxation time constants. Typically relaxation processes in amorphous systems are non-exponential and relaxation time constants are usually obtained from experimental data using a curve fitting procedure involving the empirical Kohlrausch-Williams-Watts (KWW) equation. In this article we explore the possible relationship between the KWW curve fitting parameters (tau(KWW), beta(KWW)) and common statistical measures of the average and the distribution (e.g., median, standard deviation) of the relaxation time values. This analysis is performed for several common statistical distributions (e.g., normal, lognormal, and Lorentzian), and the results are compared and analyzed in the context of pharmaceutical product stability predictions. The KWW function is able to describe relaxation processes stemming from several different statistical distribution functions. Under some circumstances the "average" relaxation time constant of the KWW equation (tau(KWW)) is significantly different from common statistical measures of the central value of a distribution (e.g., median). Simply knowing the relaxation time constants from the fit of the KWW equation is not sufficient to completely characterize and quantify the molecular mobility of amorphous pharmaceutical materials. An appreciation of the distribution of relaxation times and the resulting effects upon the KWW constants should be considered to be essential when working with amorphous pharmaceutical materials, especially when attempting to use relaxation time constants for predicting their physical or chemical stability.

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.

The effects of absorbed water on the properties of amorphous mixtures containing sucrose.

PURPOSE: To measure the water vapor absorption behavior of sucrose-poly(vinyl pyrrolidone) (PVP) and sucrose-poly(vinyl pyrrolidone co-vinyl acetate) (PVP/VA) mixtures, prepared as amorphous solid solutions and as physical mixtures, and the effect of absorbed water on the amorphous properties, i.e., crystallization and glass transition temperature, Tg, of these systems. METHODS: Mixtures of sucrose and polymer were prepared by co-lyophilization of aqueous sucrose-polymer solutions and by physically mixing amorphous sucrose and polymer. Absorption isotherms for the individual components and their mixtures were determined gravimetrically at 30 degrees C as a function of relative humidity. Following the absorption experiments, mixtures were analyzed for evidence of crystallization using X-ray powder diffraction. For co-lyophilized mixtures showing no evidence of crystalline sucrose, Tg was determined as a function of water content using differential scanning calorimetry. RESULTS: The absorption of water vapor was the same for co-lyophilized and physically mixed samples under the same conditions and equal to the weighted sums of the individual isotherms where no sucrose crystallization was observed. The crystallization of sucrose in the mixtures was reduced relative to sucrose alone only when sucrose was molecularly dispersed (co-lyophilized) with the polymers. In particular, when co-lyophilized with sucrose at a concentration of 50%, PVP was able to maintain sucrose in the amorphous state for up to three months, even when the Tg was reduced well below the storage temperature by the absorbed water. CONCLUSIONS: The water vapor absorption isotherms for co-lyophilized and physically mixed amorphous sucrose-PVP and sucrose-PVPNA mixtures at 30 degrees C are similar despite interactions between sugar and polymer which are formed when the components are molecularly dispersed with one another. In the presence of absorbed water the crystallization of sucrose was reduced only by the formation of a solid-solution, with PVP having a much more pronounced effect than PVP/VA. The effectiveness of PVP in preventing sucrose crystallization when significant levels of absorbed water are present was attributed to the molecular interactions between sucrose, PVP and water.

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.

A pragmatic test of a simple calorimetric method for determining the fragility of some amorphous pharmaceutical materials.

PURPOSE: To evaluate a simple calorimetric method for estimating the fragility of amorphous pharmaceutical materials from the width of the glass transition region. METHODS: The glass transition temperature regions of eleven amorphous pharmaceutical materials were characterized at six different heating and cooling rates by differential scanning calorimetry (DSC). RESULTS: Activation energies for structural relaxation (which are directly related to glass fragility) were estimated from the scan rate dependence of the glass transition temperature, and correlations between the glass transition widths and the activation energies were examined. The expected correlations were observed, and the exact nature of the relationship varied according to the type of material under consideration. CONCLUSIONS: The proposed method of determining the fragility of amorphous materials from the results of simple DSC experiments has some utility, although "calibration" of the method for each type of materials is necessary. Further work is required to establish the nature of the relationships for a broad range of amorphous pharmaceutical materials.