Nicholas G. Lordi

Evaluation of release from selected thermosoftening vehicles

Abstract— Release of D&C Yellow No. 10 and anhydrous theophylline have been determined from a thermosoftening, hydrophilic matrix, Gelucire 50/13, incorporating a water‐soluble additive, polyethylene glycol 4000. As additive level increased, release also increased. The effect of mixtures of Gelucire 50/13 (G50/13) and Gelucire 50/02 (G50/02) on release was also investigated as a function of temperature and pH. As the level of G50/02 increased, release decreased and became predominantly diffusional. As temperature was increased, release changed from diffusion to a mixed model of both diffusion and erosion. At basic pH, release from these composite systems became more erosional in character, possibly reflecting partial hydrolysis of the ester‐linked matrices. Diffusion coefficients and apparent diffusion coefficients were calculated in G50/02 and G50/13 matrices, respectively, and were in agreement with published data.

Thermal Analysis Studies of Glass Dispersion Systems

AbstractGlass dispersion systems were examined using differential scanning calorimetry. The addition of a crystalline additive to a glassy vehicle resulted in a reduction of the vehicles glass transition temperature. Mixtures of glassy materials were immiscible, partially miscible, or completely miscible. The results can be explained using the concept of miscibility among liquids. By combining two miscible glasses in the proper ratio, it was possible to obtain greater physical stability than with either of its glassy components. This was demonstrated with a 1:1 mixture of citric acid and acetaminophen which showed no changes in its thermogram after seven weeks of storage at 23°C. The glass transition of this mixture is about 18° C.

Evaluation of methodology for assessing release characteristics of thermosoftening vehicles

Abstract— Methodology has been devised for the testing and evaluation of the mechanistic release of drug or markers from thermosoftening materials, as represented by the Gelucire class of excipients, which could be predictive. Release of a drug (anhydrous theophylline) and a marker (D&C yellow No. 10) was determined using a calibrated stationary disc/rotating fluid system. Of the fourteen commercially available Gelucire excipients, six were investigated in detail (G46/07, G48/09, G50/02, G50/13, G53/10, G62/05) and found to have biphasic release profiles. Lipid soluble materials demonstrated predominantly diffusion‐controlled release, while water‐dispersible materials absorbed water and showed signs of swelling which led to erosion as an additional component of the release characteristics.

Mechanism of Hardness of Aged Compacts

AbstractThe hardness changes in aged compacts of the chloride, bromide and iodide salts of sodium, potassium and ammonium, stored at various relative humidities, were studied. The effect of moisture on hardness followed a parabolic curve. Hardness increased with increasing moisture content, reached a maximum value in the region of deliquescence and then decreased drastically as the salt deliquesced. The incorporation of moisture in the starting material resulted in compacts with a pronounced decrease in strength. However, no further significant hardness changes were observed on aging. Addition of lubricants drastically reduced tablet hardness, and significantly reduced the hardening on aging.

Use of sorption isotherms to study the effect of moisture on the hardness of aged compacts

AbstractHardness changes in aged compacts of the salts of sodium, potassium and ammonium were studied at various humidities. The anionic and cationic effects on tablet hardening were determined from sorption isotherms of the salts. The sorption isotherms were obtained by inverse gas chromatography. The isosteric heats of adsorption were calculated from isotherms measured at temperatures from 40–60°C. The heat of sorption was highest for the chloride salt, intermediate for the bromide salt, and the least for the iodide salt. Potassium chloride attained the highest hardness increase while the iodide salt experienced the least hardness increase. The cationic effect was also rationalized from the heat of sorption data.

Comparative Dissolution Performance of Internationally Available Piroxicam Products

Piroxicam is a widely used nonsteroidal antiinflammatory drug available worldwide under various trade names by several manufacturers. Only one brand of piroxicam (Feldene) is currently marketed in the U.S., and the United States Pharmacopeial Convention established an official dissolution requirement for piroxicam in 1985. The purpose of this study was to evaluate and compare the dissolution performance of several internationally available piroxicam products using the United States Pharmacopeia (USP) dissolution test for piroxicam capsules. Of 25 brands of piroxicam capsules evaluated, 72 percent of the brands failed to meet the USP requirement, several by a wide margin. Although there is no specific USP dissolution test for tablets, the test for capsules was applied to five different brands of piroxicam tablets, and 80 percent of the tablet brands tested failed to meet the USP requirement. Although comparative bioavailability studies would be required to establish any definitive relationship between dissolution test performance and bioavailability, the failure of most of these products to meet the USP requirement for dissolution indicates formulation differences that could result in altered bioavailability. The substantial differences in dissolution performance observed among the piroxicam oral dosage forms tested have implications concerning the equivalency and standards of multisource products available on the international market, and should be taken into account by health care providers worldwide.

Analytical interpretation of powder compaction during the loading phase

Abstract A new powder compaction equation which describes compaction data during the loading phase has been proposed. The equation takes the form PV = K [1−exp(− bP )]+ V d P where V is the specific volume at applied pressure P , V d is the dynamic limiting specific volume of the material, 1/ b is defined as the initial yield pressure ( P o ) and K is a measure of the total work of compaction. At pressures > P d , the dynamic yield pressure of the material, a linear relation is observed between the PV and P . Pressure–volume data for high density polyethylene, polyethylene glycol 8000, starch 1500 and sodium chloride is presented to illustrate the applicability of the proposed powder compaction equation. V d values were ca. 5% higher than values calculated from measured true densities. P d values varied from 14.6 (polyethylene) to 93.4 (starch 1500) MPa. Starch 1500 showed the largest K value (16.3 MPa cc/g) as compared to polyethylene (7.25 MPa cc/g).

Influence of Dose Range on Degree of Nonlinearity Detected in Dose-Proportionality Studies for Drugs with Saturable Elimination: Single-Dose and Steady-State Studies

Deviation from proportionality occurs when the ratio of area under the curve (AUC) values is not equal to the ratio of administered doses. The degree of nonlinearity (fNL) can be quantitated as the ratio of AUCs divided by the ratio of doses. We explore positive deviation from proportionality (fNL > 1) using the classical Michaelis–Menten model of nonlinear elimination after a single dose (n = 1) or at steady state (ss). The degree of nonlinearity is related to the ratio of the highest dose to the lowest dose (Rd = DH/DL): fNLn=1 = (2 + Rd · ε)/(2 + ε), fNLss= (Rd · Ω −1) /(Rd · Ω −Rd), where ε is the ratio of the initial concentration after the lowest dose to the Km (ε = DL/Km · V) and Ω is the ratio of the Vmax to the average rate of input for the highest dose (Ω = Vmaxτ/F · DH). From these relationships, we find that (1) for single-dose studies, Km is the important Michaelis–Menten parameter, while Vmax is important at steady state; (2) the degree of nonlinearity cannot exceed the ratio of doses in single-dose studies, and when doses in extreme excess of Km· V are chosen, the degree of nonlinearity is equal to the dose range; and (3) at steady state, the degree of nonlinearity can exceed the ratio of doses and approaches infinity as the average input rate approaches Vmax. Literature data (phenytoin and ethanol) support these findings. We conclude that the degree of nonlinearity is not a useful measure of nonlinearity in and of itself and propose percentage saturation as being more informative.

Axial to Radial Pressure Transmission of Tablet Excipients using a Novel Instrumented Die

A die instrumented with four piezoelectric force transducers was developed for use on the Rutgers Integrated Compaction Research System. It was calibrated and characterized using high density polyethylene as the calibrating material. Results showed that the radial response measured by the four die wall transducers was dependent upon the thickness of the compact being compressed and its location within the die. These two factors were incorporated into the calibration constant which converted the die wall response from voltage units into pressure units. Sample compaction profiles showing axial to radial pressure transmission of selected materials of interest in tableting were generated using this die.

Effect of Physical and Chemical Properties on Drug Release From Selected Thermosoftening Vehicles

Abstract— The release profile of several drugs, (chlorpheniramine maleate, salicylic acid, hydrochlorothiazide, p‐hydroxy benzoic acid, sulphafurazole, anhydrous theophylline) and the marker (D&C yellow No. 10) was detailed to determine the effect of physical and chemical properties on release from selected thermosoftening matrices (Gelucire 50/02 and 50/13). At a concentration of drug or marker of 2·5% w/w, hydrochlorothiazide showed the slowest release from G50/02, due to its low aqueous solubility, while theophylline showed the highest release owing to its low mol. wt and moderate aqueous solubility. Release reflected two of the selection criteria, aqueous solubility and mol. wt, set forth for the drug/markers used in the study. The hydrophobic matrix, G50/02, offered no enhancement in drug release and functioned in a manner commensurate with other hydrophobic matrices. No hydrogen bonding was noted between any of the drugs or markers and the matrix. As drug or marker concentration increased from 2·5 to 15% w/w, potential hydrogen bonding was noted between p‐hydroxy benzoic acid and the matrix. Theophylline no longer had the highest release being replaced by chlorpheniramine maleate and D&C yellow No. 10. With Gelucire excipient G50/13, chlorpheniramine maleate showed the highest release; it dissolved within the matrix at experimental temperature and lowered the matrix melting point. The matrix swelled upon exposure to the dissolution medium and it was from this swollen layer that release occurred. Sulphafurazole, hydrochlorothiazide, salicylic acid and p‐hydroxy benzoic acid exerted a similar effect to chlorpheniramine maleate on the matrix. No hydrogen bonding was observed between the drugs and matrix. As drug or marker concentration was further increased, chlorpheniramine maleate and D&C yellow No. 10 demonstrated the highest release; all other drugs formed a cluster. Apparent diffusion coefficients for G50/02 and G50/13 matrices were in agreement with published data confirming the predictive ability of the experimental design and postulated mechanistic models of release from hydrophilic and lipophilic matrices.