Biomedical subjects

S A Varia

Publications and source records attributed to S A Varia.

9 recordsLinked to original sources

PubMed2000

Study of phase behavior of poly(ethylene glycol)-polysorbate 80 and poly(ethylene glycol)-polysorbate 80-water mixtures.

Mixtures of poly(ethylene glycols) (PEGs) with polysorbate 80 are often used to dissolve poorly water-soluble drugs in dosage forms, where polysorbate 80 helps either in enhancing dispersion or in inhibiting precipitation of drugs once the solution is mixed with water. Binary phase diagrams of polysorbate 80 with several low molecular weight PEGs and a ternary phase diagram of polysorbate 80 with PEG 400 and water are presented. Two phases were observed in the binary mixtures when the concentration of PEG 200, PEG 300, PEG 400, or PEG 600 was >55%(w/w). The miscibility of the binary mixtures increases with an increase in temperature; the upper consolute temperatures of PEG 200-polysorbate 80, PEG 300-polysorbate 80, PEG 400-polysorbate 80, and PEG 600-polysorbate 80 mixtures were 100, 85, 75, and 40 degrees C, respectively. The upper consolute temperature of PEG 1000-polysorbate 80 could not be determined because the melting temperature of the mixtures is approximately 40 degrees C and the consolute temperature appeared to be less than this temperature. The decrease in upper consolute temperature with an increase in PEG molecular weight indicated a greater miscibility of the two components. In the ternary system, phase separation of polysorbate 80 was observed when the concentration of PEG 400 was >50-60 % (w/w), possibly because of the high exclusion volume of PEG 400.

Dosage Forms↗

PubMed1999

Selection of solid dosage form composition through drug-excipient compatibility testing.

A drug-excipient compatibility screening model was developed by which potential stability problems due to interactions of drug substances with excipients in solid dosage forms can be predicted. The model involved storing drug-excipient blends with 20% added water in closed glass vials at 50 degrees C and analyzing them after 1 and 3 weeks for chemical and physical stability. The total weight of drug-excipient blend in a vial was usually kept at about 200 mg. The amount of drug substance in a blend was determined on the basis of the expected drug-to-excipient ratio in the final formulation. Potential roles of several key factors, such as the chemical nature of the excipient, drug-to-excipient ratio, moisture, microenvironmental pH of the drug-excipient mixture, temperature, and light, on dosage form stability could be identified by using the model. Certain physical changes, such as polymorphic conversion or change from crystalline to amorphous form, that could occur in drug-excipient mixtures were also studied. Selection of dosage form composition by using this model at the outset of a drug development program would lead to reduction of "surprise" problems during long-term stability testing of drug products.

Calcium Channel Blockers↗

PubMed1991

Optimization of cosolvent concentration and excipient composition in a topical corticosteroid solution.

Physicochemical factors involved in the development of a topical solution of a novel corticosteroid, tipredane (1), are described. A cosolvent system consisting of polyethylene glycol 400 (PEG 400), propylene glycol, and water was used to dissolve the concentration (0.1% w/w) of 1 required for the formulation. The solvent mixture was also nonirritating to the skin. Buffering agent, antioxidant, and metal-chelating agent were required to stabilize the drug. Solubilities of hydrophilic and lipophilic excipients were ensured by careful adjustment of their concentrations, as well as that of PEG 400. Two formulations, one containing potassium citrate and the other tromethamine as the buffering agents, were identified. Upon storage, sodium metabisulfite, an antioxidant used in the formulation, oxidized to form K2SO4 in the formulation containing potassium citrate. Potassium citrate decreased the solubility and resulted in the precipitation of K2SO4 by exerting a common ion effect. Lowering of the concentrations of potassium citrate, sodium metabisulfite, and PEG 400 ensured the solubility of K2SO4 formed. There was no such precipitation of K2SO4 in the formulation buffered with tromethamine, thus indicating that tromethamine is a good buffering agent in cosolvent systems.

Administration, Topical↗

PubMed1984

Phenytoin prodrugs III: water-soluble prodrugs for oral and/or parenteral use.

Various bioreversible derivatives of phenytoin, a poorly water soluble and erratically absorbed drug after both oral and parenteral dosing, were synthesized. Initial evaluation of these expected prodrugs, i.e., their aqueous solubility, cleavage in the presence of various animal tissues, and anticonvulsant activity in mice, confirmed that a number of the derivatives did indeed behave as prodrugs. The more promising prodrugs were the disodium phosphate ester and various amino groups containing acyl esters of 3-(hydroxymethyl)-5,5-diphenylhydantoin.

Administration, Oral↗

PubMed1984

Phenytoin prodrugs IV: Hydrolysis of various 3-(hydroxymethyl)phenytoin esters.

The aqueous chemical stability of various bioreversible derivatives or prodrugs of phenytoin, a poorly water-soluble and erratically absorbed drug after both oral and intramuscular parenteral dosing, were evaluated. This study, together with assessments of other physiochemical properties including cleavage in the presence of various animal tissues and anticonvulsant activity in mice, helped identify a number of promising candidate prodrugs. Various amino groups containing acyl esters of 3-(hydroxymethyl)phenytoin [3-(hydroxymethyl)-5,5-diphenylhydantoin] were identified as potential orally and perhaps parenterally useful prodrugs, while the disodium phosphate ester of 3-(hydroxymethyl)phenytoin appears to be ideally suited as a parenteral form of phenytoin.

Chemical Phenomena↗

PubMed1984

Phenytoin prodrugs V: In vivo evaluation of some water-soluble phenytoin prodrugs in dogs.

Phenytoin bioavailability was evaluated in beagle dogs after oral and intravenous administrations of sodium phenytoin and two amino acyl esters and a disodium phosphate ester of 3-(hydroxymethyl)phenytoin (three prodrugs of phenytoin). Phenytoin displayed nonlinear pharmacokinetics in the dogs, complicating the determination of the absolute bioavailability of phenytoin from sodium phenytoin and the prodrugs. All three prodrugs essentially released phenytoin after intravenous administration in a quantitative manner, and all gave plasma levels of phenytoin after oral administration greater than those found after administration of sodium phenytoin. Based on the behavior in dogs and the earlier determination of the physicochemical properties of the prodrugs, it was concluded that one of the amino acyl esters, 3-(hydroxymethyl)-5,5-diphenylhydantoin N,N-dimethylglycine ester methanesulfonate, would be the most useful prodrug for oral administration, while 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester would be the most useful for parenteral administration.

Administration, Oral↗

PubMed1984

Phenytoin prodrugs VI: In vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats.

Tissue damage caused by subcutaneous and intramuscular administration of three phenytoin prodrugs to rats was assessed. Since two of the prodrugs caused significant irritation, only 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester might be useful as a nonirritant phenytoin prodrug suitable for parenteral administration. To confirm the release of phenytoin from this prodrug, phenytoin availability after intramuscular and intravenous administrations of the phosphate prodrug was evaluated in rats and compared with sodium phenytoin. The prodrug quantitatively released phenytoin after intravenous administration, and phenytoin levels from intramuscular administration of the prodrug were far superior to those generated from similarly administered sodium phenytoin. Based on this and earlier studies, it was concluded that this prodrug should be further assessed as a parenteral form of phenytoin.

Animals↗

PubMed1979

Radiochemical plasma salicylamide assay using ring-labeled tritiated salicylamide.

A rat plasma salicylamide assay was developed using ring-labeled tritiated salicylamide, synthesized by reacting salicylamide with tritium oxide in the presence of heptafluorobutyric acid. The reaction yielded 3H-salicylamide of specific activity up to 8.41 mCi/mmole, 60% yield. Plasma containing 3H-salicylamide and its metabolites was extracted with a toluene-based scintillation fluid, which was subsequently counted. Specificity for free salicylamide was demonstrated by radio chemical and standard fluorescence plasma salicylamide level-time curves. Specificity resulted from nonextraction of the salicylamide sulfate and glucuronide metabolites. Sulfatase and beta-glucuronidase treatment allowed the analysis of plasma sulfate and glucuronide conjugates as free salicylamide. This procedure should be effective for the analysis of salicylamide and its metabolites in the presence of similar phenolic compounds.

Animals↗

PubMedDate not supplied

Moisture sorption behavior of selected bulking agents used in lyophilized products.

To develop a rational approach for the formulation of lyophilized products, six bulking agents commonly used in freeze-dried formulations were lyophilized under identical conditions, and their moisture sorption behavior, before and after lyophilization, were determined as a function of relative humidity at 25 degrees C. The bulking agents evaluated were mannitol, anhydrous lactose, sucrose, D(+)-trehalose, dextran 40 and povidone (PVP K24). The materials were also characterized for their crystal and thermal properties by powder X-ray diffraction, DSC and TG after exposure to various relative humidity conditions. Mannitol was crystalline and non-hygroscopic both before and after lyophilization with total moisture contents of 0.1 to 0.3% w/w between 10 and 60% RH. Anhydrous lactose, sucrose and trehalose were crystalline prior to lyophilization with moisture contents of 0.86, 0.15 and 9.2%, respectively, and the crystalline materials were relatively non-hygroscopic. Upon lyophilization, they converted to the amorphous form and had moisture contents of 1.6, 2.5 and 1.2%, respectively. The amorphous materials sorbed moisture rapidly upon exposure to increasing relative humidity conditions. The amorphous lactose converted to its crystalline hydrate form at 55% RH after sorption of an additional 10% moisture. This conversion to the crystalline hydrate form was accompanied by desorption of practically all the moisture sorbed by the amorphous form. Similarly, lyophilized sucrose converted to its crystalline form after the sorption of additional 4.5% moisture at 50% RH, and the lyophilized trehalose sorbed additional 10% moisture prior to its conversion to a crystalline hydrate form at 50% RH. Dextran and povidone were amorphous and hygroscopic both before and after lyophilization and they sorbed as much as 10-20% moisture at 50% RH. It is well established that different drugs, especially proteins, need different levels of moisture for optimal stability. The results of the present study show that moisture contents of lyophilized cakes may be varied and optimized by the selection of suitable excipients.

Calorimetry, Differential Scanning↗