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R E Notari

Publications and source records attributed to R E Notari.

At least 19 recordsLinked to original sources
PubMed1999

A nomogram to evaluate intrinsic absorption rate constants of potential oral prolonged-release candidates.

The purpose of this study was to devise a simple method to determine whether or not a drug's absorption rate constant favored the selection of that drug for an oral prolonged-release drug delivery system (DDS). Computer simulations were used to observe the drug time-course in the DDS, the gastrointestinal tract, and the cumulative amount absorbed following administration of an 8-, 12-, and 24-hr zero-order DDS. For each DDS, the drug's intrinsic absorption rate constant, ka, was systematically varied from 0.1 to 10 hr-1. Results demonstrated that the DDS controlled the absorption rate whenever drug release was rate-limiting. However, the release rate did not determine the length of time that a DDS controlled the absorption rate. Instead, the duration of DDS-controlled absorption increased as the ka value increased. When ka > or = 2 hr-1, the DDS controlled more than 80% of the 8-, 12-, and 24-hr dosing intervals. Conversely, when ka < or = 0.12 hr-1, the DDS failed to control absorption. In conclusion, this investigation developed a technique to ascertain the rate-limiting step when a zero-order DDS releases a drug that undergoes first-order absorption. This technique was employed to construct a nomogram that allows its users to estimate the duration of control by an 8-, 12-, or 24-hr DDS based on the ka value for the drug.

Adsorption↗
PubMed1998

A kinetic oxymoron: concentration-dependent first-order rate constants for hydrolysis of ceftazidime.

The influence of pH, temperature, and buffers on the hydrolysis of 10(-4) M ceftazidime was previously reported. The pH-rate profiles showed that maximum stability occurred in the pH-independent region from 4.5 to 6.5. In the present study, hydrolysis rates of 0.031, 0.14, 0.25, and 0.35 M ceftazidime were measured at 30 and 65 degrees C, pH 5.5-6.2. The data were consistent with beta-lactam hydrolysis and the rapid release of pyridine. The sum of the time-dependent concentrations of ceftazidime and pyridine provided mass balance. Simultaneous nonlinear regression for ceftazidime loss and pyridine formation provided similar rate constants (k) to those determined from first-order plots of ceftazidime loss. Although the loss of ceftazidime was first-order for each initial concentration, the k values increased as the initial concentrations increased. Plots of k versus initial concentration were linear with intercepts similar to the k values for 10(-4) M solutions, thus implying that ceftazidime catalyzed its own degradation. At the pH of these studies ceftazidime exists as a base. The ceftazidime catalytic constant, calculated from the slope of the plot, was similar to that found for the general-base catalyst, HPO4(2-). Therefore, it is feasible that ceftazidime also behaved as a intermolecular general-base catalyst. However, first-order plots exhibited excellent linearity even though the catalyst (ceftazidime) was consumed. This would require that the catalytic moieties on ceftazidime remained relatively constant throughout its hydrolysis. This hypothesis was shown to be consistent with literature reports which indicate that the general-base catalytic groups can remain relatively constant during cephalosporin hydrolysis.

Biotransformation↗
PubMed1998

Influence of pH, temperature and buffers on cefepime degradation kinetics and stability predictions in aqueous solutions.

First-order rate constants (k) were determined for cefepime degradation at 45, 55, 65, and 75 degrees C, pH 0.5 to 8.6, using an HPLC assay. Each pH-rate profile exhibited an inflection between pH 1 and 2. The pH-rate expression was k(pH) = kH1 f1(aH+) + kH2 f2(aH+) + ks + kOH(aOH-), where kH1 and kH2 are the catalytic constants (M(-1) h(-1)) for hydrogen ion activity (aH+), kOH is the catalytic constant for hydroxyl ion activity (aOH-), and ks is the first-order rate constant (h(-1)) for spontaneous degradation. The protonated (f1) and unprotonated (f2) fractions were calculated from the dissociation constant, Ka = (8.32x10(-6))e(5295)/RT where T was absolute temperature (T). Accelerated loss due to formate, acetate, phosphate, and borate buffer catalysis was quantitatively described with the catalytic constant, kGA (M(-1) h(-1)) for the acidic component, [GA], and kGB (M(-1) h(-1) for the basic component, [GB], of each buffer. The temperature dependency for each rate constant was defined with experimentally determined values for A and E and the Arrhenius expression, kT = Ae-E/RT, where kT represented kH1, kH2 , kS, kOH, kGA, or kGB. Degradation rate constants were calculated for all experimental pH, temperature, and buffer conditions by combining the contributions from pH and buffer effects to yield, k = k(pH) + kGA[GA] + kGB[GB]. The calculated k values had <10% error for 103 of the 106 experimentally determined values. Maximum stability was observed in the pH-independent region, 4 to 6. Degradation rate constants were predicted and experimentally verified for cefepime solutions stored at 30 degrees C, pH 4.6 and 5.6. These solutions maintained 90% of their initial concentration (T90) for approximately 2 days.

Arginine↗
PubMed1996

A nomogram to predict the best biological half-life values for candidates for oral prolonged-release formulations.

It is sometimes possible to maintain plasma concentrations between desired maximum and minimum limits by repetitively administering a drug in an oral prolonged-release formulation when this goal cannot be achieved with a rapid-release formulation. However, this approach does not work with all drugs. The biological half-life value of the drug can be one cause for failure of this approach. Although it is recognized that a half-life may be too long or too short, neither the criteria for determining these values nor the consequences of failing to meet them have been established. The best half-life values for prolonged-release candidates were found by simulating once-a-day and twice-a-day administration of formulations and examining the capacity of these formulations to maintain steady-state plasma concentrations between various selected limits. These observations were used to establish criteria to judge the acceptability of half-lives. Half-life values were considered too long if drugs were self-sustaining and simulations of their rapid-release formulations were also successful. Half-life values were considered too short if minor variability in prolonged-release rates resulted in plasma concentrations above and/or below the selected limits. The actual half-life values that were considered too long or too short depended on the dosing interval and the selected maximum and minimum plasma concentrations. A nomogram was constructed to assess the acceptability of the biological half-life of a candidate for once-a-day or twice-a-day prolonged-release formulations. The nomogram employs the user-selected limits for the desired plasma concentrations to predict whether the half-life of a candidate is (1) too long, (2) too short, or (3) acceptable (i.e., between 1 and 2).

Administration, Oral↗
PubMed1995

Methodology for using oral dose pharmacokinetic data to select drugs for prolonged release formulations and validation of the method using simulated data.

A computer aided method for selecting drugs as potential candidates for oral prolonged release formulations has been previously published. In order to decide whether trial formulations were warranted, prolonged release dosing was simulated to find all release rates and doses producing successful regimens in every subject for whom clinical pharmacokinetic data were available. Intravenous dose data were required because the models and their parameter values could not be assessed with oral doses. The new method uses model independent equations derived from rapidly absorbed oral doses to simulate the administration of prolonged release formulations. Using these equations, repetitive oral dosing regimens were reiteratively simulated to search for all successful release rates and doses in every available subject. Results were validated by comparison to those obtained with the published method using theophylline and hypothetical drugs, which included examples of flip-flop and vanishing exponentials. When the oral reference dose data were reliable, results were similar even when the model independent parameter values did not agree with those used to generate the oral reference dose data. Differences were observed only when the random errors in the oral reference dose data were large. If more than one model independent equation provided equivalent fits to the oral reference dose data, the final results were similar independent of which equation was employed.

Administration, Oral↗
PubMed1995

Influence of pH, temperature, and buffers on the kinetics of ceftazidime degradation in aqueous solutions.

First-order rate constants (k) were determined for the hydrolysis of ceftazidime in the pH range of 0.5 to 8.5 at 45, 55, and 65 degrees C by a stability-indicating HPLC assay. In the absence of buffer effects, the pH-rate expression was k = kH1f1(aH+) + kH2f2(aH+) + kH3f3(aH+) + kSf3 + kOHf3(aOH-), where KH and KOH are the catalytic rate constants for the activity of hydrogen (aH+) and hydroxyl (aOH-) ions, respectively, and kS is the rate constant for spontaneous hydrolysis. The fractions of ceftazidime in various stages of dissociation (f1, f2, and f3) were calculated from kinetically determined apparent Ka values of 2.03 x 10(-2) and 4.85 x 10(-5). Catalytic constants (kcat) were calculated for formate, acetate, phosphate, and borate buffers, which accelerated hydrolysis. Each of the rate constants (kH1, kH2, kH3, kS, kOH, and kcat) were described as a function of temperature with calculated A and E values in the Arrhenius equation, kT = Ae-E/RT. Ceftazidime hydrolysis rate constants (k) were calculated as a function of pH, temperature, and buffer by combining the pH-rate expression with the buffer contributions calculated from kcat values and the temperature dependencies. These equations and their parameter values successfully calculated 95 of 104 experimentally determined rate constants with errors of < 10%. Maximum stability was observed in the relatively pH-independent region from 4.5 to 6.5. Hydrolysis rate constants at 30 degrees C were predicted and experimentally verified for four ceftazidime solutions, three of which (pH 4.4 acetate buffer and pH 5.5 and 6.5 phosphate buffers) maintained 90% of their initial concentration for approximately 1.5 days.

Buffers↗
PubMed1994

Cefuroxime hydrolysis kinetics and stability predictions in aqueous solution.

Cefuroxime hydrolysis rate constants (k) were determined to predict the degradation rate of cefuroxime in aqueous solution as a function of pH, temperature, and buffer. At constant temperature, the pH-rate expression was: k = kH(aH+) + kS1f1 + kS2f2 + kOH(aOH-), where f1 is the fraction of cefuroxime in the undissociated form and f2 is the anionic fraction, kH and kOH are the catalytic rate constants for hydrogen activity (aH+) and hydroxyl ion activity (aOH-), and kS1 and kS2 are first-order rate constants for spontaneous hydrolysis. Formate, acetate, phosphate, and borate buffers did not catalyze degradation. Temperature dependencies for kH, kS1, kS2, and kOH were described with values for A (pre-exponential term) and E (energy of activation) calculated from k = Ae-E/RT (where R is 1.987 cal/mol-deg and T is absolute temperature). Combining the pH and temperature equations allowed predictions for cefuroxime hydrolysis rates in aqueous solutions at any pH and temperature. Results were validated by predicting the observed rate constants for every experimental condition and also for a reconstituted commercial product stored at 30 degrees C. Maximum stability was observed in the pH-independent region from pH 4 to 7, where the time during which cefuroxime concentration exceeded 90% of its initial concentration at 25 degrees C was 1.2 days. Rate constants employed in predictions were based on stability-indicating HPLC assays. For selected conditions, additional rate constants were calculated from changes in cefuroxime UV absorbance.(ABSTRACT TRUNCATED AT 250 WORDS)

Buffers↗
PubMed1993

An efficient method for computer-aided dosage form design.

It is desirable to have slow-release dosage form to be taken once daily, or at most twice daily, as compared to three or four times in a single day. However, the existing computer-aided dosage form design method requires a large amount of computer time when applied to nonlinear disposition drugs. This large commitment of computer time makes it inconvenient to study the feasibility for prolonged-release products containing such drugs. Instead of evaluating all possible combinations of the amount of dose and release rates that produce acceptable steady-state plasma concentrations, only the contour of the dose-release rate domain needs to be determined. An image boundary tracking method has been used to determine such contours. When combined with several modifications of the numerical solution process, the acceptable dose and release rate constants can be determined efficiently. When this modified boundary tracking method was applied to phenytoin, which exhibits nonlinear disposition, the required computer time was reduced to about 5% of the previous method, making the dosage form feasibility assessment practical.

Computer Simulation↗
PubMed1991

Computer-aided dosage form design. III. Feasibility assessment for an oral prolonged-release phenytoin product.

Previous publications described computer-aided methodology for assessing the feasibility of designing prolonged release oral dosage forms containing linear-disposition drugs. Those methods determined all useful release rates and examined those rates to decide whether product development was warranted. The present study developed software to obtain similar information for phenytoin, which exhibits Michaelis-Menten disposition. The values for Vmax, Km, and Vd in 27 patients were employed to assess the ability of prolonged absorption to maintain steady-state plasma concentrations between 10 and 20 mg/liter following oral administration at 8-, 12-, and 24-hr intervals. Phenytoin steady-state plasma concentrations in this range were controlled by elimination and were not extended by prolonged absorption. Furthermore, single i.v. bolus doses resulting in an initial plasma level of 20 mg/liter provided concentrations above 10 mg/liter for approximately 1 to 3 days. When an oral multiple-dose regimen was found to maintain steady-state concentrations between 10 and 20 mg/liter, that dose and interval produced concentrations within that range regardless of the absorption rate. While absorption rate was not important, each patient's dose ranges were extremely narrow, emphasizing that dose size was the dominant factor in the control of phenytoin levels.

Absorption↗
PubMed1989

Substituent effects on degradation rates and pathways of cytosine nucleosides.

A previous report on the influence of a 6-methyl substituent on cytosine nucleoside degradation proposed that N-glycosyl hydrolysis predominated over the deamination pathway which was characteristic of the unsubstituted parent compounds. The UV absorption data which led to this hypothesis were not conclusive. Evidence for N-glycosyl hydrolysis was indirect and the product concentration was not quantitated. In the present study, specific HPLC methods were employed to assay four cytosine nucleosides and their corresponding bases, thus allowing comparison of the N-glycosyl hydrolysis rate to the overall rate of loss for each nucleoside. These data indicated that the 6-methyl nucleosides underwent partial or complete hydrolysis to yield their corresponding sugars and 6-methylcytosine, which then deaminated to 6-methyluracil. An increase in the reactivity and a change in the reaction products of the 6-methyl nucleosides were attributed to an alteration in conformation. In addition, the 6-methyl arabinosyl nucleoside reacted much faster than the 6-methyl ribosyl nucleoside, presumably due to 2'-OH participation. Degradation of 5-methyl deoxycytidine was also re-examined since its degradation was previously attributed solely to N-glycosyl hydrolysis. In the present study, simultaneous deamination and hydrolysis were measured, although N-glycosyl hydrolysis was found to predominate.

Biotransformation↗
PubMed1988

Potential improvement in shelf life using the prodrug approach. II. A systematic examination of kinetic requirements.

The utilization time (UT) for a solution of a prodrug that is rapidly and completely converted to drug in the blood may be longer than the time for 10% loss of the initial concentration. The UT for an intravenous prodrug solution is the period during which the total prodrug and drug concentration exceeds 90% of the initial concentration. The influence of the rate of prodrug degradation (knc), its conversion (kc) to drug, and the subsequent drug degradation (kh) on the UT of a stored solution was examined by simulating the prodrug and drug concentration-time courses. The ratio of the shelf life of a prodrug solution to that of the parent drug (UTratio) was calculated using a wide range of values for the three rate constants. Three-dimensional plots relating the UTratio to the kc, knc, and kh values provide a basis for making a priori assessments of kinetic requirements for designing a prodrug to increase storage time. A parenteral prodrug intended to increase storage time may have a larger overall rate of loss than the parent drug, but it must have a smaller degradation rate (knc less than kh) to be successful. The UT for an oral prodrug solution depends upon the bioavailability of the prodrug relative to the drug in addition to the values for knc, kc, and kh. Two ampicillin prodrugs were used as models to calculate actual UTratio versus pH profiles. Intravenous solutions showed modest gains in the UTratio in the acid region, whereas oral solutions reached a UTratio as high as 22 by combining favorable rate constants with increased bioavailability.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1988

Potential improvement in the shelf life of parenterals using the prodrug approach: bacampicillin and talampicillin hydrolysis kinetics and utilization time.

The utilization time for a parenteral prodrug solution with a bioavailable fraction of unity was defined as the time during which the total of the prodrug concentration and the drug concentration equals or exceeds 90% of the initial prodrug concentration. This utilization time was calculated as a function of pH, buffer, and temperature using the experimentally determined rate expressions for bacampicillin and talampicillin. The results were compared to the shelf life of ampicillin solutions under identical storage conditions. First-order rate constants were determined for conversion of the prodrugs to ampicillin (kc), for beta-lactam degradation of the prodrugs (knc), for the overall loss of prodrugs (ksum), and for beta-lactam degradation of ampicillin (kh) in aqueous solutions at 25.0 to 60.0 degrees C, mu = 0.5, in the pH range 0.90 to 8.4. Loss of bacampicillin proceeded primarily by degradation at pH levels below 4 but was due predominantly to conversion at pH levels above 5. Loss of talampicillin was due primarily to conversion throughout the entire pH range. While the prodrug utilization times were approximately twice the shelf life of ampicillin in acidic solutions, ampicillin was significantly better in neutral solutions. The results illustrate the potential for increased prodrug storage periods when utilization time is defined on the basis of the bioactivity rather than on the prodrug concentration alone.

Ampicillin↗
PubMed1988

Predicting caffeine plasma concentrations resulting from consumption of food or beverages: a simple method and its origin.

Multiple dosage regimens for therapeutic agents are commonly comprised of a constant dosing interval and a constant dose size. This is not true for the ingestion of a pharmacologically active agent that is a component in a dietary source. Caffeine is contained in foods and beverages that are regular components of the diet for many people. Because daily intake is unsystematic, a computer program was written to simulate caffeine plasma concentration-time courses following ingestion of variable amounts on irregular schedules. Literature values for caffeine pharmacokinetics, for the caffeine content in various foods and beverages, and for consumer habits were employed to simulate various caffeine plasma concentration-time courses. By searching for predictable traits in a wide variety of plasma concentration-time courses representing normal adults, a simple noncomputer method was developed to allow individuals to estimate caffeine plasma concentrations based on personal intake habits. Changes in the time courses due to smoking, oral contraceptive use, and liver disease, all of which alter caffeine pharmacokinetics, were also examined.

Adult↗
PubMed1987

Kinetics and mechanism of captopril oxidation in aqueous solution under controlled oxygen partial pressure.

The stability of captopril in aqueous solution at 32 degrees C was studied in the pH range 6.6 to 8.0 under controlled oxygen partial pressure (90-760 mm Hg) with and without the addition of cupric ion. The oxidation product, captopril disulfide, was found to be the sole degradation product. A change in reaction rate from first order to zero order occurs as the captopril concentration decreases. The concentration at which this transition takes place is a function of the pH, oxygen partial pressure, and cupric ion concentration. The apparent first-order rate constants show a first-order dependency on both the oxygen partial pressure and the cupric ion concentration. However, the apparent zero-order rate constants show a first-order dependency on oxygen partial pressure and a second-order dependency on cupric ion concentration. As the pH increases from 6.6 to 8.0, the first-order process becomes more predominant. A mechanism which consists of cupric ion- and molecular oxygen-catalyzed oxidation is proposed to explain those observations.

Captopril↗
PubMed1987

Computer-aided dosage form design. I. Methods for defining a long-acting first-order delivery system of maximum formulating flexibility.

The method provides an a priori assessment of the maximum allowable flexibility in the rate of release from a prolonged-release formulation. The clinical pharmacokinetic parameters describing the drug candidate are employed to calculate the ranges of rate constants and doses required for the formulation to provide a selected therapeutic duration. For a given patient, there may be an infinite number of combinations of release rate constants and dose sizes which will maintain steady-state plasma drug concentrations within a desired range when the formulation is administered at the selected dosing interval. Computer simulations of steady-state plasma concentrations are employed to establish the ranges for all of the acceptable rate constants and doses for each member of a group. The entire group is then examined to define the range of release rate constants and doses which would provide a useful formulation for every member in the group. Literature values for theophylline clinical pharmacokinetics in children and adults have been employed to illustrate the application of this method. The method is unique in that it provides an entire range of release rates on which to gauge the feasibility for success.

Administration, Oral↗
PubMed1987

Computer-aided dosage form design. II. Methods for defining a zero-order sustained-release delivery system of maximum formulating flexibility.

Classical methods employing pharmacokinetic data to calculate zero-order release rates for sustained release products require that a constant-rate drug delivery system must have a duration which is exactly equal to the desired dosage interval. This traditional approach fails to establish the minimum acceptable duration and also fails to provide any flexibility in the formulation goal. While it does calculate one pair of duration and dose values, there are infinite pairs of values capable of maintaining the desired plasma concentrations using the selected dosing interval. In the current method, computer simulations are used to establish the boundary conditions within which any pair of duration and dose values will maintain the desired levels when administered on the chosen dosing interval. By comparing the boundary conditions for every subject in a group, a single set of conditions which would work for the entire group can be selected. These final limits represent the broadest specifications for zero-order drug delivery system design for that particular drug combined with the plasma concentration goals and the desired dosing interval. The method is illustrated using theophylline pharmacokinetics.

Adult↗
PubMed1985

Decreased stability in liposomal suspensions: accelerated loss of p-nitrophenyl acetate.

The goal of this investigation was to determine the reason for the previously reported increase in the rate of hydrolysis of p-nitrophenyl acetate to p-nitrophenol in the presence of positively charged liposomes. When this charge was due to incorporation of stearylamine, the rate of loss increased 5- to 10-fold relative to the control buffers. This rate enhancement was accompanied by formation of N-stearylacetamide, an event which was not previously considered. Similar results were obtained with either L-alpha- or dimyristoyl phosphatidylcholine. When the positive charge on the liposomes was conferred by the cetrimonium ion, however, the acceleration was replaced by a reduction in rate together with the absence of amide formation. Separation of the continuous phases from the liposomes provided media which were kinetically equivalent to the control buffers, indicating that rate enhancement and reduction were both due to the liposomal phases. Increasing the pH produced an increase in ester clearance values due to the stearylamine-containing liposomal phase, which is consistent with the formation of free amine, providing increased aminolysis. Although amide formation was also observed in stearylamine suspensions, the rate of p-nitrophenyl acetate loss was much greater in liposomal suspensions. Accelerated loss in the presence of positively charged liposomes is due to the formation of N-stearylacetamide by reaction with stearylamine and not to the positive charge, a hypothesis disproved by use of cetrimonium ion containing liposomes.

Amines↗