Graham D. Parr

Pharmacokinetics and in vivo scintigraphic monitoring of a sustained release acetylsalicylic acid formulation

Abstract The in vivo dissolution and pharmacokinetics of a sustained release aspirin formulation labelled with ( 99m Tc]diethylenetriaminepentaacetic acid has been monitored in 5 subjects by the use of gamma scintigraphy and drug analysis undertaken of blood and urine samples. The data obtained enabled the position of the tablet in vivo to be related to the plasma and urinary salicylate levels. The study confirms the sustained release properties of the cellulose acetate phthalate formulation.

The acetotoluides as models for studying cyclodextrin inclusion complexes

Abstract The difference between the complexing abilities of α- and β-cyclodextrin (CD) with o , m -and p -acetotoluide (ACT) has been demonstrated by solubility and filtration cell studies and by thermal analysis. Interaction between α-CD and the ACTs is barely detectable, implying that the benzene ring of the ACTs was incapable of penetrating the α-CD cavity. The ACTs did form complexes with β-CD however, the p -ACT- β -CD complex being most stable. Even so, the complex was weak. Although the acetamido group appeared responsible for hindering the penetration of o - and m -ACT into the β-CD cavity, the methyl group of p -ACT would also appear to impede to some extent the penetration of the benzene ring into the CD molecule. Potential guest molecules having an unsubstituted benzene ring are predicted to form the most stable CD inclusion complexes.

Absorption of progabide from aqueous solutions in a modified recirculating rat intestinal perfusion system

Abstract The absorption rate of progabide from aqueous solutions was determined in a modified in situ recirculating rat intestinal loop. The absorption rate was found to be very rapid from the upper small intestine with a half-life of 8.1 min. The addition of Tween 80 drastically reduced the absorption rate of progabide. In comparison, the addition of β-cyclodextrin had only a slight negative effect.

The gastrointestinal transit investigation of a controlled release aminophylline formulation

Abstract The gastrointestinal transit and release of a radiolabelled marker from an orally administered controlled release preparation has been evaluated in vivo in a group of 6 subjects using the technique of gamma-scintigraphy. Excellent agreement between in vitro and in vivo release rates was obtained. Release of aminophylline was found to be constant throughout the gastrointestinal tract and was independent of changing pH and degree of gastrointestinal motility. Absorption of aminophylline is controlled by its rate of release from the tablet matrix.

A Reversed-Phase High-Performance Liquid Chromatography Assay Procedure for Progabide and Its Related Metabolic Derivatives

A reversed-phase high-performance liquid chromatography (HPLC) assay procedure for Progabide, its active acid metabolite (PGA), and its hydrolytic degradation product (SL79.182) has been developed. This highly specific technique has allowed the simultaneous determination of these drugs in aqueous samples, and when coupled with a single and easy extraction step, spiked plasma samples could also be analyzed. The method had a sensitivity of about 30, 45, and 100 ng/ml for Progabide, SL79.182, and PGA, respectively.

The stability and solubility of progabide and its related metabolic derivatives

The stability–pH profile of the γ-aminobutyric acid prodrug, Progabide, was found to be bell shaped, with maximum stability occurring at pH 6 to 7 with a t1/2 of 126 min. Of its metabolic derivatives, the deamidated product PGA degraded in a similar fashion to Progabide, whereas the hydrolytic degradation product SL79.182 was, as expected, a stable compound. Progabide behaved as a typical weak base, with its solubility increasing with a decrease in pH. SL79.182 behaved as a typical phenolic weak acid, with its solubility increasing with an increase in pH. Both compounds displayed low intrinsic solubilities of 14.5 × 10−5M for Progabide and 33.4 × 10−6M for SL79.182. An increase in temperature resulted in an increase in the solubility but a decrease in the stability of Progabide. The data obtained indicate that the gastric pH and gastric emptying rate will have a profound effect on the oral bioavailability of Progabide.

Polarographic detection of beta-cyclodextrin inclusion complexes

Abstract The effect of beta-cyclodextrin (β-CD) on the peak height and voltage of the polarographic reduction of several esters of hydroxybenzoic acid has been investigated. Complexation with β-CD decreased both the amount of current conducted upon reduction and the half-wave potential of that reduction for each of the esters of hydroxybenzoic acid. This fall in conducted current resulted from the decreased diffusion rate of the ester when complexed with β-CD as compared to the ester alone. The half-wave potentials of the reductions became more negative in the presence of β-CD. The change in potential was in the rank order ethyl > propyl > butyl. This was a result of the electron redistribution occurring in the presence of β-CD due to the formation of inclusion complexes, and reflected the tendency of these esters to complex with β-CD. These results suggest that polarography is suitable for studying the inclusion complexation phenomenon of β-CD with electroactive molecules in aqueous solution and may prove to be a powerful technique in further elucidating the nature of the inclusion complex.

Dissociation and partitioning of Progabide and its degradation product

Abstract The dissociation and partitioning behaviour of Progabide and one of its degradation products, SL79.182, were investigated. Progabide was found to be amphoteric with pKa values of 3.41 and 12.95. SL79.182 behaved as a typical weak acid with a pKa value of 8.94. The apparent partition coefficient-pH profile of Progabide for the water/n-octanol system was assessed by the filter-probe extractor method whereas that of SL79.182 was determined by the shake-flask method. Log (P) values of 2.97 for Progabide and 4.04 for SL79.182 were derived.

Modification of the aqueous solubility and stability of progabide

Abstract The intrinsic dissolution rate of progabide was determined using compressed non-disintegrating disks. The rate was very low especially at pH 5–7 (1.7 × 10 −3 mg · min −1 · cm −2 ). The effect of some surface active agents, cyclodextrins and other macromolecules in the solubility of progabide was examined. Tween 80, sodium deoxycholate, α-cyclodextrin, and β-cyclodextrin enhanced the solubility whereas polyvinylpyrrolidone-40 and urea slightly decreased it. Those agents that showed promise were further studied for their effect on the stability of the drug in aqueous solutions. With all the surfactants examined, the stability of progabide was improved above the critical micelle concentration. Further, β-cyclodextrin was found to enhance the stability in neutral media but not in acidic media.

Investigation of progabide absorption from the gastrointestinal tract of the rabbit

The oral bioavailability of progabide following its administration as suspensions of varying particle sizes was assessed in the rabbit. This was found to be low (<5%) with the drug exhibiting a large clearance (13.5 litre/h), large apparent volume of distribution (10.36 litre), and a very short elimination half-life (32 min) in this animal. The concomitant intravenous administration of ranitidine resulted in a drastic reduction of the oral bioavailability of progabide as a result of the inhibition of gastric acid secretion. It therefore appears that the solubility and stability of this drug play significant roles in controlling its oral bioavailability.