ABSTRACT
General principles and applications of microcalorimetry are reviewed. Microcalorimetry is useful in the study of physical, chemical, and biological drug interactions. The sensitivity of the present instrumentation is approximately 0.1 microW. With this high sensitivity, additional applications have been developed, including the interactions of drugs with food, lymphoma cells, microorganisms, blood, excipients, and cyclodextrin. A recent application of microcalorimetry is the measurement of degradation rates of drugs.
Subject(s)
Calorimetry , Chemistry, Pharmaceutical/instrumentation , Animals , Drug Stability , Excipients , Food-Drug Interactions , HumansABSTRACT
A new technique has been developed to calculate rapidly the solid-state room-temperature degradation rate of drugs and drug candidates. The technique utilizes measurements of the initial rate of heat output at several elevated temperatures by isothermal calorimetry and the degradation rate of the compound determined at a single elevated temperature by chromatography. The activation energies and degradation rates at 25 degrees C calculated by conventional methods and by isothermal calorimetry are compared and discussed. The compounds studied were phenytoin, triamterene, digoxin, tetracycline, theophylline, diltiazem, and several proprietary ICI compounds.
Subject(s)
Drug Stability , Thermodynamics , Calorimetry/methods , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid , Kinetics , Temperature , Tetracycline/chemistryABSTRACT
Although micellar chromatography has been used for the determination of drugs in biological fluids since 1985, relatively few researchers have applied the technique to therapeutic monitoring. The reasons for this are rather unclear. It may be that most of the present extraction/reconstitution techniques are well established or that the method development procedure is unfamiliar. Significantly lower detection limits can be obtained with micellar mobile phases and column switching than with micellar mobile phases alone. Only two groups have used micellar mobile phases in conjunction with column switching for the determination of drugs in biological fluids. Since column switching with micellar mobile phases is a relatively new and untried technique, it will take some time before the full range of its applicability and limitations are known.
Subject(s)
Body Fluids/chemistry , Chromatography, Liquid/methods , Pharmaceutical Preparations/chemistry , Humans , Micelles , Spectrophotometry, UltravioletABSTRACT
The feasibility of directly assaying drugs in physiological fluids using on-line preconcentration and microbore high-performance liquid chromatography has been demonstrated. The untreated sample is injected onto a hydrophobic pre-column, using micellar sodium dodecyl sulfate (SDS) in the case of serum or phosphate buffer in the case of urine, as the load mobile phase. This traps the components of interest which are then backflushed onto a microbore analytical column using a stronger mobile phase. This procedure was then applied to diazepam in serum and phenobarbital in urine. Recovery was linear and quantitative over the range 30-3000 ng/ml for diazepam in serum and 2-200 micrograms/ml for phenobarbital in urine. The diazepam method was specific against caffeine and the three major metabolites of diazepam: oxazepam, temazepam, and nordiazepam. The effects of varying pre-column dimensions, pre-column loading time, and SDS concentration volume were evaluated.
Subject(s)
Pharmaceutical Preparations/analysis , 1-Propanol/analysis , Chromatography, High Pressure Liquid , Diazepam/blood , Humans , Indicators and Reagents , Micelles , Pharmaceutical Preparations/blood , Pharmaceutical Preparations/urine , Phenobarbital/urineABSTRACT
The feasibility of determining trace analytes in human serum using on-line preconcentration and microbore high-performance liquid chromatography has been demonstrated. The serum is subjected to ultracentrifugation and injected onto a hydrophobic pre-column using water as the mobile phase. This traps the components of interest which are then backflushed onto a microbore analytical column using a stronger mobile phase. The column-switching apparatus was evaluated using highly dilute aqueous paraben solutions and sample enrichment factors as high as 1500 were obtained. The procedure was then applied to diazepam in serum. Recovery was linear and quantitative over the range from at least 4 to 1000 ng/ml. The method was specific against caffeine and the three major metabolites of diazepam: oxazepam, temazepam, and nordiazepam. The effects of varying pre-column dimensions, pre-column loading time, and sample volume were evaluated.
