Mario A. Gonzalez

Effect of phenobarbital on theophylline disposition

The effect of chronic phenobarbital administration on the pharmacokinetics of theophylline was studied in 6 healthy, nonsmoking adults. Subject compliance was verified by the determination of plasma phenobarbital levels. Following four weeks of phenobarbital administration, all six subjects showed a resultant increase in serum clearance varying from 11% to 60% with a mean increase of 34% (from 3.01 to 4.04 L/hr/1.73 M2). Theophylline appears to be metabolized more rapidly during chronic phenobarbital administration. This effect, therefore, must be taken into account when administering barbiturates to asthmatic patients for whom theophylline therapy is prescribed.

Physiologic considerations in drug absorption from the gastrointestinal tract

The dynamic interaction between variables within the gastrointestinal tract and the physiochemical properties of a drug in a delivery system determine the rate and extent of absorption of that drug. Among the major physiologic variables are pH, gastric emptying time, and intestinal transit time. Some physicochemical properties of interest include solubility, particle size, and chemical form of the drug. Attributes of the formulation such as controlled-release mechanism, pH sensitivity, and size, shape, and density of the product can also affect absorption. Food has also been reported to influence the absorption from some but not all controlled-release products. As a more thorough understanding of the many factors involved in drug absorption is developed, the formulation of more sophisticated oral drug delivery systems will be possible.

Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration’s Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro–in vivo correlation considerations for transdermal systems.

Best Practices for the Development, Scale-up, and Post-approval Change Control of IR and MR Dosage Forms in the Current Quality-by-Design Paradigm

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro–in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

PHARMACOKINETICS AND THE VARIABILITY OF PERCUTANEOUS ABSORPTION

AbstractTransdermal delivery systems have gained wide acceptance over the past decade. These systems allow more control over the surface area and, therefore, the doses delivered to a patient compared to conventional ointments and creams; however, as with ointments, the skin and not the delivery system controls the absorption rate for most drugs. The in vivo percutaneous absorption of nitroglycerin, a highly potent cardiovascular drug with good absorption characteristics, has been investigated over the course of 5 years in more than 300 subjects. Various types of delivery systems, utilizing gel and adhesive matrices and “membrane control” were included in these investigations. Each subject received at least two different formulations on 2 different days. The delivery systems were left in place for 24 hr, after which they were removed and subsequently analyzed for residual nitroglycerin content. The apparent dose for each subject was determined. This parameter is defined as the difference between the initia...

Bioavailability and pharmacokinetics of a new sustained-release potassium chloride tablet.

The bioavailability of a new sustained-release potassium chloride (KC1) tablet, designed for once-a-day dosing, was compared to a KC1 elixir using urinary excretion data. The study utilized 25 male volunteers dosed in a crossover design in a dietary/activity-controlled environment. The regimens consisted of a total of 80 mEq of potassium in three equally divided doses of elixir every 6 hr and a single 80-mEq dose using four 20-mEq sustained-release (SR) tablets. The mean time to maximum rate of potassium urinary excretion was 2.2 hr for the first elixir dose and 5.5 hr after the SR tablet (P < 0.01), thereby supporting the prolonged-release properties of this formulation. After correction for baseline urinary potassium excretion, the mean total 24-hr urinary potassium excretion was 42.18 mEq for the elixir and 40.41 mEq for the SR tablet. The results indicate that the absorption pattern from the SR tablet is equal to three doses of KC1 elixir dosed 6 hr apart.

High-Performance Liquid Chromatographic (HPLC) Assay Using Fluorescence Detection for the Simultaneous Determination of Gallopamil and Norgallopamil in Human Plasma

Gallopamil is a calcium-channel antagonist with reported activity in experimental animals three to five times higher than that of verapamil. An automated high-performance liquid chromatographic (HPLC) method with fluorescence detection is described for the simultaneous determination of gallopamil and its metabolite norgallopamil in plasma. Gallopamil was well resolved from norgallopamil and other metabolites, allowing simultaneous quantitation of both drugs. The detection limit for both gallopamil and norgallopamil was 0.9 ng/ml. This method has been successfully used for the determination of gallopamil and norgallopamil following the administration of 25-, 37.5-, and 50-mg oral doses of drug.

Determination of Thermodynamic Solubility of Active Pharmaceutical Ingredients for Veterinary Species: A New USP General Chapter

This Stimuli article discusses the approach for the development of a new general chapter on solubility determination for veterinary drug products. Possible procedures are discussed, with emphasis on the shake-flask method. Recommendations are included on the test conditions for products to treat dogs and cattle. The Expert Panel welcomes comments from the public and stakeholders. dx.doi.org/10.14227/DT240117P36

GAS CHROMATOGRAPHIC DETERMINATION OF GALLOPAMIL AND NORGALLOPAMIL IN HUMAN PLASMA

A highly sensitive gas chromatographic assay is described for the simultaneous determination of gallopamil, a calcium channel blocking agent, and its major metabolite, norgallopamil. A multi-step extraction procedure is employed followed by on-column capillary gas chromatographic analysis using nitrogen-selective detection. Acetylation of norgallopamil is performed to enable accurate quantification of the metabolite. Linearity was achieved over the range 1-50 ng/ml for both analytes. Assay specificity, precision and accuracy were investigated.

The Determination of the Entrapment Efficiency for a Molecular Dispersion System

AbstractThe entrapment of d-propoxyphene in ethyl cellulose pseudolatex systems was studied. Heat of fusion measurements were used to determine the extent of molecular scale entrapment. When δHf = 0, the drug was assumed to he entrapped on a molecular level while δHfvalues greater than zero indicated the presence of crystal structure. Zeta potential measurements were also used to indicate the point of maximum entrapment efficiency. A good correlation was obtained between zeta potential and heat of fusion measurements.