Biomedical subjects

Douglas R Flanagan

Publications and source records attributed to Douglas R Flanagan.

9 recordsLinked to original sources

PubMed2006

Solid-state kinetic models: basics and mathematical fundamentals.

Many solid-state kinetic models have been developed in the past century. Some models were based on mechanistic grounds while others lacked theoretical justification and some were theoretically incorrect. Models currently used in solid-state kinetic studies are classified according to their mechanistic basis as nucleation, geometrical contraction, diffusion, and reaction order. This work summarizes commonly employed models and presents their mathematical development.

Chemistry, Physical↗

PubMed2006

Salt effects on an ion-molecule reaction--hydroxide-catalyzed hydrolysis of benzocaine.

PURPOSE: This work investigates the effect of various salts on the rate of a reaction involving a neutral species (benzocaine alkaline hydrolysis). METHODS: Benzocaine hydrolysis kinetics in NaOH solutions in the presence of different salts were studied at 25 degrees C. Benzocaine solubility in salt solutions was also determined. Solubility data were used to estimate salt effects on benzocaine activity coefficients, and pH was used to estimate salt effects on hydroxide activity coefficients. RESULTS: Salts either increased or decreased benzocaine solubility. For example, solubility increased with 1.0 M tetraethylammonium chloride (TEAC) approximately 3-fold, whereas solubility decreased approximately 35% with 0.33 M Na2SO4. Salt effects on hydrolysis rates were more complex and depended on the relative magnitudes of the salt effects on the activity coefficients of benzocaine, hydroxide ion, and the transition state. As a result, some salts increased the hydrolysis rate constant, whereas others decreased it. For example, the pseudo-first-order rate constant decreased approximately 45% (to 0.0584 h(-1)) with 1 M TEAC, whereas it increased approximately 8% (to 0.116 h(-1)) with 0.33 M Na2SO4. CONCLUSIONS: Different salt effects on degradation kinetics can be demonstrated for a neutral compound reacting with an ion. These salt effects depend on varying effects on activity coefficients of reacting and intermediate species.

Anesthetics, Local↗

PubMed2006

Basics and applications of solid-state kinetics: a pharmaceutical perspective.

Most solid-state kinetic principles were derived from those for homogenous phases in the past century. Rate laws describing solid-state degradation are more complex than those in homogenous phases. Solid-state kinetic reactions can be mechanistically classified as nucleation, geometrical contraction, diffusion, and reaction order models. Experimentally, solid-state kinetics is studied either isothermally or nonisothermally. Many mathematical methods have been developed to interpret experimental data for both heating protocols. These methods generally fall into one of two categories: model-fitting and model-free. Controversies have arisen with regard to interpreting solid-state kinetic results, which include variable activation energy, calculation methods, and kinetic compensation effects. Solid-state kinetic studies have appeared in the pharmaceutical literature over many years; some of the more recent ones are discussed in this review.

Chemistry, Pharmaceutical↗

PubMed2005

New drug salt formation in biodegradable microspheres.

PURPOSE: To investigate the effects of inorganic salts in the external phase of an oil-in-water (O/W) emulsion method during microsphere preparation. METHODS: An O/W emulsion method was used to prepare poly(D,L-lactic acid) microspheres containing quinidine sulfate. Different inorganic salts were used in the external phase during microsphere preparation. Microsphere drug loading was determined by UV and the drug salt anions inside the microspheres were determined by ion chromatography. RESULTS: New drug salts were formed during encapsulation in the microspheres when salts with non-common anions to the drug salt were used. Drug loading increased when NaClO4 or NaSCN were used. The fraction of drug as the new salt in microspheres increased non-linearly with the salt concentration in the external phase, however, the fraction of drug as the new encapsulated salt was linearly related to drug loading. Drug loading decreased and new salt fraction increased with increasing organic solvent volume or with decreasing cosolvent polarity. CONCLUSIONS: Introducing salts containing non-common anions to the drug salt employed in the external phase of O/W emulsion microsphere method leads to new salt formation. The extent of new drug salt formation is affected by salt levels added, cosolvent type and polymer concentration.

Anions↗

PubMed2005

Complementary use of model-free and modelistic methods in the analysis of solid-state kinetics.

There are many methods for analyzing solid-state kinetic data. They are generally grouped into two categories, model-fitting and isoconversional (model-free) methods. Historically, model-fitting methods were widely used because of their ability to directly determine the kinetic triplet (i.e., frequency factor [A], activation energy [E(a)], and model). However, these methods suffer from several problems among which is their inability to uniquely determine the reaction model. This has led to the decline of these methods in favor of isoconversional methods that evaluate kinetics without modelistic assumptions. This work proposes an approach that combines the power of isoconversional methods with model-fitting methods. It is based on using isoconversional methods instead of traditional statistical fitting methods to select the reaction model. Once a reaction model has been selected, the activation energy and frequency factor can be determined for that model. This approach was investigated for simulated and real experimental data for desolvation reactions of sulfameter solvates.

Kinetics↗

PubMed2005

Anticholinesterase and pharmacokinetic profile of phenserine in healthy elderly human subjects.

OBJECTIVE: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of the acetyl-selective anticholinesterase, phenserine tartrate, in healthy elderly subjects. METHODS: 32 healthy elderly volunteers received single oral doses of phenserine tartrate (5-20 mg). Physical and vital signs were monitored over the ensuing 24 hours. Analyses were performed on plasma samples to determine PK, and PD were assessed using an erythrocyte acetylcholinesterase (AChE) inhibition assay. RESULTS: No serious adverse events (AEs) occurred; the most common were headache and vomiting. The MTD of phenserine tartrate was 10 mg. The Cmax and AUC(0-24) of phenserine increased with dose, but neither were dose-proportional. Subjects receiving 10 mg of phenserine tartrate had a Cmax of 1.95 ng/mL at 1.5 hours, and the mean peak inhibition (Imax) of AChE was 26% (range: 18-34%) at 1.75 hours (tImax) following dosing. The half-life of AChE inhibition (tI1/2) was 11 hours. Evaluation of PK/PD relationships suggested a linear correlation between plasma phenserine concentration and AChE inhibition in the blood. CONCLUSIONS: Phenserine tartrate was safe and well tolerated when administered as a single oral dose of either 5 mg or 10 mg. An increase in the severity and frequency of AEs occurred at the 20 mg dose level.

Acetylcholinesterase↗

PubMed2002

General solution for diffusion-controlled dissolution of spherical particles. 2. Evaluation of experimental data.

Our general particle dissolution model unified three traditional particle dissolution models and predicted that dissolution rates depend on surface curvature. Spherical benzocaine particles were prepared with a hot-melt dispersion method and physicochemically characterized. Their dissolution behavior was studied to evaluate the general dissolution model. A flow-through dissolution test system was used which employed an HPLC pump, an HPLC UV detector, a cylindrical-shaped dissolution cell, and a data collection system. Single benzocaine particle dissolution profiles were determined at ambient temperature (22-23 degrees C) in water at a constant flow rate. Dissolution rate normalized by surface area was found to be particle radius-dependent and fitted well by the general particle dissolution model with a diffusion layer thickness of 110 microm and benzocaine diffusion coefficient of 1.4 x 10(-5) cm(2)/s. Analysis of literature particle dissolution data also supported this general model. Our general model accounts for literature reports of apparent diffusion layer thicknesses being smaller for small particles compared with large particles. This study supports the applicability of the general particle dissolution model for a flow-through dissolution test system.

Anesthetics, Local↗

PubMed2002

Salt effects on caffeine solubility, distribution, and self-association.

In this investigation, salt effects on monomeric solubility and distribution are separated from self-association for caffeine. For self-associating compounds, the Setschenow equation is inadequate because it does not separate salt effects into their different contributions. Solubilities of caffeine, theophylline, and theobromine were determined in water and salt solutions at 25 degrees C. Caffeine, theophylline, and theobromine solubilities decreased with added Na(2)SO(4) or NaCl (i.e., salting-out) and increased with added NaClO(4) or NaSCN (i.e., salting-in). Caffeine distribution coefficients (D(W/O)) also decreased with added Na(2)SO(4) or NaCl and increased with added NaClO(4) or NaSCN. To separate salt-caffeine effects from salt effects on caffeine self-interaction, salting parameters (k(s)) were calculated from D(W/O) at infinite dilution instead of solubilities with the Setschenow equation. Caffeine k(s) values were smaller than the Setschenow constants (K) indicating that, for caffeine, K is not simply a salting-in/out parameter. Distribution data were used to characterize caffeine self-association using either a dimerization model (k(d), dimerization constant) or an isodesmic model (k(iso), stepwise association constant). Caffeine self-association constants (k(d) or k(iso)) decreased with NaClO(4) or NaSCN and increased with Na(2)SO(4) or NaCl.

Bromates↗

PubMedDate not supplied

Swelling and permeability characteristics of zein membranes.

Zein is a hydrophobic corn protein, rich in leucine, proline and alanine, that has has previously been investigated as a potential excipient in pharmaceutical manufacturing. We have investigated the diffusion through or from zein-containing systems and proposed aqueous channels formed by hydration and swelling as the dominant diffusional pathway. In this study, the swelling properties of zein membranes under various conditions and effect of swelling on membrane permeability were investigated. Conditions such as ionic strength and the effect of charged or neutral permeants altered the swelling behavior of zein. Although some permeants (which are highly bound to zein) interact through electrostatic interaction, van der Waals, hydrophobic, and hydrogen bonding interactions, they did not alter membrane swelling behavior significantly. Zein membranes were also cast from different solvent systems but membrane swelling was not affected by casting solvent and the aqueous channels produced in water are independent of membrane preparation. There was no significant permeation difference between different sides of the zein membrane (air or petri dish side). Thus, it appears that zein's permeability largely depends on swelling behavior that is affected by the aqueous ionic content in which it is immersed.

Chemistry, Pharmaceutical↗