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K J Himmelstein

Publications and source records attributed to K J Himmelstein.

13 recordsLinked to original sources
PubMed1992

Dissolution of ionizable drugs into unbuffered solution: a comprehensive model for mass transport and reaction in the rotating disk geometry.

A model has been developed to describe the mass transport and reaction of ionizable compounds where mass transfer is caused by convection and diffusion from a rotating disk. Dissolution rates of benzoic acid, 2-naphthoic acid, and indomethacin in aqueous solutions of high ionic strength (I = 0.5 with potassium chloride) at 25 degrees C were investigated. The model includes the effects of diffusion, convection, and simultaneous acid/base reaction at all points in the region adjacent to the dissolving solid. The solution of the transport equations is obtained numerically with an iterative algorithm which uses (a) closure of all material balances and (b) equilibria at the solid/liquid surface as constraints. The model solution yields both the flux of the dissolving acid and the concentration profile of each component. Reduced values of all reaction rate constants are used in the region adjacent to the dissolving surface to allow convergence of the computation. Although nonequilibrium concentration values are calculated, it is shown that the theoretical dissolution rate determined as the solution of the model is insensitive to the magnitude of the rate constants as their maximum useable values are approached. Comparisons of the model results with experimentally determined fluxes show close agreement and confirm that the transport mechanisms in the model formulation are consistent with the measured values. Further, the inclusion of convection allows accurate calculations without utilization of an arbitrary boundary layer thickness. Accurate dissolution rates can be determined using this technique under a wide range of conditions, except at low pH.

Acids↗
PubMed1992

Precorneal sampling techniques for ophthalmic gels.

Drug-cornea contact time is a critical issue in ocular drug delivery. Existing methods for its experimental determination are developed mainly for eye drops and ointments, and have not been reported for ophthalmic gels. The present study evaluated two tear film sampling techniques (capillary tubes and Schirmer strips) and one recovery technique (cotton swab) for their suitability for the determination of precorneal drug concentration as a function of time for ophthalmic gels. The study was conducted using the rabbit eye model, and the gel studied was a commercial polyacrylate-based gel containing pilocarpine HCl. The three techniques explored yield similar results with respect to drug-cornea contact time, about one hour for the gel studied. The strip method suffers from a gel-carry-over problem at the early time points; therefore it is not recommended for tear sampling until most of the gel is cleared from the cul-de-sac. Successful tear sampling was accomplished using capillary tubes. Drug concentration in the tear film as a function of time determined using this technique reveals not only the duration of contact between the drug and the cornea, but also demonstrates a nonuniform drug distribution in the tear film at the early time points (10 and 30 minutes). Finally the cotton swab technique is gentle, easy, and nondestructive. It recovers total drug remaining in the cul-de-sac but does not yield information for the tear film.

Animals↗
PubMed1991

Experimental determinations of diffusion coefficients in dilute aqueous solution using the method of hydrodynamic stability.

Diffusion coefficients were experimentally determined in dilute aqueous solution at 25 +/- 0.1 degrees C, ionic strength 0.5 M, using Taylor's method of hydrodynamic stability. The methodology described is accurate enough to show significant differences in diffusion coefficients between the various ionic forms of the same species as a function of degree of ionization. In Taylor's method, diffusion coefficients were measured by allowing two solutions of differing solute concentration to contact in a capillary tube, forming a stable, measurable concentration gradient. The solute diffusion coefficient is a function of the gradient, the solution viscosity, the solution density, and some capillary dimensions. Viscosity was maintained constant across experiments and values of sufficient accuracy were available in the literature. Solution densities were measured with a tuning fork densimeter. Compounds studied were o-aminobenzoic acid, benzoate anion, the four forms of phosphate and citrate, and the zwitterionic forms of glycine, diglycine, and triglycine. Based on the results for the four forms of phosphate and citrate, experimental diffusivity values vary with the ionic state of the diffusant, presumably because of the altered state of hydration as charge varies. For the glycine series, the diffusivity showed an unexpected dependency on molecular weight (size).

Aminobenzoates↗
PubMed1985

Dissolution of carboxylic acids. III: The effect of polyionizable buffers.

The dissolution behavior of three carboxylic acids of variable aqueous solubility but with approximately equal pKa values into aqueous buffered solutions has been studied as a function of pH and of buffer properties. The dissolution from constant-surface-area compressed disks of benzoic acid, 2-naphthoic acid, and indomethacin into solutions of constant ionic strength (mu = 0.5 with potassium chloride) and constant pH (maintained by pH stat) at 25 degrees C using a rotating disk apparatus was evaluated. Models for dissolution of these weak acids into diprotic and triprotic buffering media are developed to predict the flux of the acid as a function of bulk solution pH and the physical and chemical properties of the buffer and acid. The models assume that mass transfer can be represented by a single second order diffusive term and that instantaneous equilibrium between all reactive species exists. Values of flux and pH at the solid-liquid interface are calculated and the fluxes compared to experimentally determined values. Reasonable correlation was found between values predicted by the models and experimental flux values. Major influences on model accuracy are the Ka and physical properties of the buffer.

Benzoates↗
PubMed1978

Preliminary pharmacokinetic model of pilocarpine uptake and distribution in the eye.

A pharmacokinetic model that permits prediction of aqueous humor pilocarpine levels following topical application to rabbit eyes was developed. The model is able to account for changes in both instilled solution volume and drug concentration. The model, although simplified, relies mainly on experimentally verifiable and independently measured parameters. Its utility lies in its ability to account quantitatively for the large drainage loss of instilled drug solutions and its predictive ability regardless of the instilled volume or concentration. The framework established by this model will allow further sophistication as more experimental data become available and should be adaptable to other ophthalmic drugs.

Animals↗
PubMed1978

Prediction of adriamycin disposition in cancer patients using a physiologic, pharmacokinetic model.

A ten-compartment flow-limited pharmacokinetic model scaled from rabbit tissue distribution data was used to predict plasma adriamycin concentrations in 23 patients and adriamycin tissue uptake in nine surgery patients following iv bolus doses of 10--60 mg/m2. The predicted concentrations were compared to experimentally determined adriamycin using a specific thin-layer chromatographic fluorescence scanning procedure. The predicted plasma time course for 11 of 16 patients with relatively normal liver and kidney function agreed closely with the observed plasma time course. Deviations in the other five patients were ascribed to possible changes in the profile of metabolite formation and/or fluctuations in biliary clearance. All four patients with elevated serum bilirubin demonstrated significantly higher and more prolonged plasma levels than predicted. The results of two patients with impaired kidney function and one patient with both hepatic and renal involvement were inconclusive. The comparison between predicted and observed tissue concentrations in biopsy samples was varied; however, all were within an order of magnitude. It is concluded that the model depicts adriamycin uptake and distribution reasonably well; however, more needs to be known concerning individual variation in metabolic and biliary excretion rates for this to become more patient-specific. Also, a tumor compartment appears to be an important addition in modifying the model to allow for clinical utility.

Animals↗
PubMed1977

Mathematical model for cyclocytidine pharmacokinetics.

The pharmacokinetics of the drug cyclocytidine in humans were modeled by using a physiological and anatomical approach. Each pertinent tissue is represented by a single compartment, and these compartments are linked together by the circulatory system. Each compartment is then represented by an ordinary differential equation that represents the rate of change in drug concentration as function of convecting transport, metabolism, and urinary clearance. The models for cyclocytidine and cytarabine are linked together by a hydrolysis term in each equation set. The resulting equation sets are then solved numerically to predict the concentration of both drug species in situ. The models use physiological blood flows, tissue volumes, and clearance parameters. The results of the model show that cyclocytidine can act as a reservoir for cytarabine in vivo over the time studied. This effect is confined to relatively long times and relatively low plasma concentrations.

Ancitabine↗
PubMedDate not supplied

Pharmacokinetics of non-protein-bound platinum species following administration of cis-dichlorodiammineplatinum(II).

The pharmacokinetics of non-protein-bound platinum species derived from cis-dichlorodiammineplatinum(II) (cis-platinum) was studied under a variety of dosing conditions. Following rapid infusions (15-minute) of cis-platinum at 100 mg/m2, the unbound drug declined in a biphasic mode with a mean terminal half-life of 48 minutes. The mean beta-phase half-life after a 6-hour infusion of the same dose of cis-platinum was 26 minutes. Urinary excretion of filterable platinum was substantially greater after a 6-hour infusion than after a 15-minute injection. Concomitant administration of mannitol appeared to result in higher peak plasma concentrations and decreased urinary excretion of unbound platinum species but did not alter the terminal half-life. Renal impairment was associated with extremely high plasma levels of filterable platinum but did not affect other pharmacokinetic parameters. Preliminary data on the distribution of cis-platinum to ascitic fluid are also presented.

Ascitic Fluid↗