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At least 109 records · Page 6Linked to original sources
PubMed1994

Automated analytical systems for drug development studies. I--A system for the determination of drug stability.

An automated system consisting of a pH-stat, microdialysis sampling and a liquid chromatograph was assembled to measure the rate of rapid chemical reactions. 2',3',5'-Triacetyl-6-azauridine was used as a model compound to validate the performance of the automated system. Buffer catalysis was minimized by using a non-catalytic concentration of borate buffer along with a pH-stat to maintain the pH during the kinetic run. The microdialysis sampling technique permitted sample quenching and buffering of the solutions to a pH compatible with the LC column materials. The combination of microdialysis sampling and rapid LC analysis allowed reactions with a half-life of approximately 1 min to be sampled every 30 s. The rates of hydrolysis of the drug, measured at different conditions of temperature (37-70 degrees C) and pH (9.0-10.5) using the automated system, compared well with the previously determined values.

Autoanalysis↗
PubMed2005

Protein drug stability: a formulation challenge.

The increasing use of recombinantly expressed therapeutic proteins in the pharmaceutical industry has highlighted issues such as their stability during long-term storage and means of efficacious delivery that avoid adverse immunogenic side effects. Controlled chemical modifications, such as substitutions, acylation and PEGylation, have fulfilled some but not all of their promises, while hydrogels and lipid-based formulations could well be developed into generic delivery systems. Strategies to curb the aggregation and misfolding of proteins during storage are likely to benefit from the recent surge of interest in protein fibrillation. This might in turn lead to generally accepted guidelines and tests to avoid unforeseen adverse effects in drug delivery.

Animals↗
PubMed2005

Precision from drug stability studies. Investigation of reliable repeatability and intermediate precision of HPLC assay procedures.

A multi-company investigation is presented to obtain and compare precision results for LC assay procedures. Forty-four drug substances and drug products of various types subjected to 156 stability studies, with 2915 assay values in total, were included. This provides an excellent source of real long-term precision estimates, as the same analytical procedure was applied during the whole stability study, extending from 12 to 60 months. Intermediate precision was calculated either using the residual standard deviation of the regression line or applying an analysis of variances, depending on whether there was a significant degradation of the analyte or not. The results show impressively the large intervals where the individually calculated parameters scatter. Distribution ranges and averages for repeatability, intermediate precision, and the ratio between the two precision levels are mainly dependent on the type of drug product. Repeatabilities were found up to 0.8% for solutions, 1.6% for drug substances, 1.9% for tablets, 2.3% for creams, and 3.4% for a bath. For intermediate precision, which includes additional variability factors due to the reference standard, operator, equipment, reagents, etc., a similar dependency was obtained with a slightly changed order: up to 1.1% for drug substances, 2.2% for solutions, 2.3% for tablets, 3.1% for creams, and 3.2% for a bath. The ratio between the precision levels is up to 2.5 and similar for all investigated drug product types, apart from solutions with up to 5.3. These differences for the types of drug product may be explained by the influence of the sample and/or the sample preparation: the more complex, the higher the variability contribution. For the investigated examples, the impact of the analyte and of the concentration (dosage) seems to be of less importance. Therefore, a classification of drug product types for orientation on acceptable precision (ranges) for LC assay seems to be possible.

Algorithms↗
PubMed2003

Variable-ionic strength kinetic experiments in drug stability studies.

The dependence of the pseudo-first-order rate constant on the ionic strength for the alkaline hydrolysis of indomethacin has been obtained, for the first time, in a single kinetic experiment carried out by varying with time the salt concentration inside the reaction vessel. The kinetic profile obtained was processed using as a mathematical model the variable-parameter kinetic equation containing the Bronsted-Bjerrum equation as the dependence function. The results are in good agreement with those obtained by the traditional method but the experimental time is reduced to about one-tenth.

Drug Stability↗
PubMed2003

Fast drug stability determination by LC variable-parameter kinetic experiments.

Variable-parameter kinetic experiments were carried out using HPLC as analytical instrument. The hydrolysis of aspirin was followed both at variable-temperature and at variable-pH conditions. The peak areas relative to salicylic acid were processed by direct fit to a mathematical model and/or by differential method obtaining, by single experiments, the values of the apparent rate constant in the whole range of temperature and pH studied. The results, although the discontinuity of this kind of analysis, are in agreement with those obtained by constant-parameter kinetics but saving experimental time.

Aspirin↗
PubMedDate not supplied

Susceptibility testing interpretive criteria and drug stability for cefdinir, cefetamet, and cefpodoxime against Neisseria gonorrhoeae.

Cefdinir, cefetamet, and cefpodoxime, three orally administered cephalosporins, were tested against 100 strains of Neisseria gonorrhoeae having various antimicrobial susceptibility patterns. Triplicate testing of each organism strain was performed for all agar dilution and disk diffusion tests. Cefdinir was the most active compound (MIC90) micrograms/ml) especially against gonococci with chromosomal-mediated resistance to penicillin. The recommended susceptible interpretive criteria were as follows: for the 5-micrograms cefdinir disk, > or = 31 mm (MIC correlate, < or = 0.25 microgram/ml); for the 10-micrograms cefetament disk, > or = 29 mm (MIC correlate, < or = 0.5 microgram/ml; for the 30-micrograms cefetamet disk, > or = 31 mm (MIC correlate, < or = 0.5 microgram/ml); and for the 10-micrograms cefpodoxime disk, > or = 29 mm (MIC correlate, < or = 0.5 microgram/ml). No organisms resistant to these new cephalosporins were detected. Cefdinir, cefetamet, and defpodoxime were stable in GC agar medium for at least 21 days when stored at 2 degrees-5 degrees C.

Cefdinir↗
PubMed1992

Interpretive criteria for susceptibility testing of CI-960 (PD127391, AM-1091), fleroxacin, lomefloxacin, and temafloxacin against Neisseria gonorrhoeae, including drug stability in GC agar medium.

CI-960, fleroxacin, lomefloxacin, and temafloxacin were tested against over 100 strains of Neisseria gonorrhoeae. Each organism was tested in triplicate by using agar dilution and disk diffusion methods recommended by the National Committee for Clinical Laboratory Standards. CI-960 was the most potent compound, with a MIC against 90% of the strains tested of 0.008 microgram/ml, and the least active was fleroxacin (MIC against 90% of strains, 0.12 microgram/ml). Only the susceptible interpretive category was recommended for the CI-960 tests as follows: 5-micrograms disk, greater than or equal to 39 mm (MIC correlate, less than or equal to 0.12 microgram/ml). Three interpretive categories were proposed for the other fluoroquinolones as follows: fleroxacin, 5-micrograms disk susceptible at greater than or equal to 33 mm (MIC correlate, less than or equal to 0.25 microgram/ml), intermediate at 28 to 32 mm (MIC correlate, 0.5 microgram/ml), and resistant at less than or equal to 27 mm (MIC correlate, greater than 0.5 microgram/ml); lomefloxacin, 10-micrograms disk susceptible at greater than or equal to 35 mm (MIC correlate, less than or equal to 0.12 microgram/ml), intermediate at 28 to 34 mm (MIC correlates, 0.25 to 0.5 microgram/ml), and resistant at less than or equal to 27 mm (MIC correlate, greater than 0.5 microgram/ml); and temafloxacin, 5-micrograms disk susceptible at greater than or equal to 36 mm (MIC correlate, less than or equal to 0.06 microgram/ml), intermediate at 28 to 35 mm (MIC correlates 0.12 to 0.25 microgram/ml), and resistant at less than or equal to 27 mm (greater than 0.25 microgram/ml). Interpretive agreement between disk diffusion results and the MICs was 100% for each agent, with the exception of lomefloxacin, which had a 0.9% minor error. All drugs were stable in GC agar medium for at least 21 days when stored at 2 to 5 degrees C.

Agar↗
PubMed1982

Drug stability in liposomal suspensions: hydrolysis of indomethacin, cyclocytidine, and p-nitrophenyl acetate.

First-order rate constants (kL) for hydrolysis of p-nitrophenyl acetate, cationic cyclocytidine, and anionic indomethacin in the presence of buffered liposomal suspensions of positive, negative, and neutral charge were compared to those determined in the corresponding buffers (kB) using the ratio, Rk = kL/kB. Association between the reactants and the liposomes was evaluated by comparing assays for concentration in the filtrates (CF) with the total concentration in the liposomal suspension (CT) using RC = CF/CT. Liposomes did not influence cyclocytidine hydrolysis rates and no association was observed (Rk congruent to RC congruent to 1). In contrast, indomethacin showed approximately 80% reduction in hydrolysis rate and approximately 80% liposome association value (Rk congruent to 0.2 congruent to RC). In neutral and negatively charged liposomal suspensions, p-nitrophenyl acetate displayed approximately 30% decrease in kB (Rk congruent to 0.7) together with approximately 90% liposomal association (RC congruent to 0.1). However, hydrolysis was greatly accelerated in positively charged liposomal suspensions. Loss was described by a biexponential equation where alpha is the fast and beta is the slow pre-exponential coefficient and alpha/beta/kB = 39:6:1. The observed relationships between hydrolysis rates and reactant-liposome associations are reconciled in terms of the hydrophilicity of the reactants and the potential influence of the liposomes on the expected transition states for the hydrolysis reactions.

Ancitabine↗
PubMed2004

Structure-activity relationships in platinum-acridinylthiourea conjugates: effect of the thiourea nonleaving group on drug stability, nucleobase affinity, and in vitro cytotoxicity.

The synthesis, cytotoxicity, and nucleoside binding of some platinum-acridinylthiourea conjugates derived from the prototypical compound [PtCl(en)(ACRAMTU)](NO3)2 ("PT-ACRAMTU"; en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, protonated form) are reported. To establish structure-activity relationships within this class of compounds, systematic changes were made to the thiourea nonleaving group, which links the intercalator to platinum. Three new derivatives of ACRAMTU, one di-, one tri-, and one tetraalkylated, were generated, where the degree of alkylation indicates the number of alkyl groups attached to the SCN2 framework. Subsequent reaction of the tri- and tetraalkylated derivatives with activated [PtCl2(en)] yielded the corresponding platinum conjugates. The dialkylated thiourea gave an unstable complex, which was not included in the studies. The crystal structure of PT-ACRAMTU x MeOH has been determined. In the solid state, one axial position of the square-planar platinum coordination sphere is partially shielded by the bulky thiourea group, providing a strong rationale for the kinetic inertness of the compound. The cytotoxicity of the prototype, the two new conjugates, and cisplatin was assessed in ovarian (A2780, A2780/CP), lung (NCI-H460), and colon (RKO) cancer cell lines using clonogenic survival assays. The derivatives containing trialkylated thiourea groups showed activity similar or superior to cisplatin, with IC50 values in the low micromolar concentration range. The complex modified with the tetraalkylated (bulkiest) thiourea was significantly less active, possibly due to the greatly decreased rate of binding to nucleobase nitrogen (1H NMR spectroscopy), but was most efficient at overcoming cross resistance to cisplatin in A2780/CP. Possible consequences of the reported structural modifications for the mechanism of action of these agents are discussed.

Antineoplastic Agents↗
PubMed1977

Determination of porosity and pore-size distribution of aspirin tablets relevant to drug stability.

Total porosity and pore-size distribution of aspirin tablets prepared from aspirin, starch USP, and precipitated colloidal silicon dioxide were determined using mercury porosimetry. The model represented a hydrolyzable drug substance in combination with simple excipients. The role of starch and silicon dioxide on the microstructure of the tablets was investigated, as was the chemical stability of various systems. In general, the porosity of tablets containing a constant quantity of starch increased linearly with silicon dioxide concentration. Examination of the pore-size distribution, however, revealed that a low concentrations silicon dioxide functioned primarily to reduce the size and volume of coarse pores representing the spaces between the agglomerates of starch and aspirin particles. This effect was optimum at 3%. A further increase in silicon dioxide concentration produced tablets with relatively larger pore sizes. Studies of changes in the porosity characteristics of tablets as influenced by water vapor over time showed distinct differences in this complex parameter. A unique trend in the change of the pore-size distribution was noted with tablets containing 3% silicon dioxide. These observations are discussed relative to the stability of aspirin tablets in which this concentration of silicon dioxide produced a maximum stabilizing effect.

Aspirin↗