Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 218-232). Available also in a digital version from Dissertation Abstracts.

No description available.

Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.

No description available.

Thesis (DMed)--University of Stellenbosch, 2007. / Bibliography. Also available via the Internet.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 172-185).

Rigid analogues of the tricyclic antidepressant imipramine and the phenothiazine tranquilizer promazine were designed and their syntheses were attempted. Conformational rigidity was expected to reduce the side effects of these drugs by limiting their binding to multiple receptors. Ortho-directed metalation followed by acylation provided synthetic intermediates for the formation of the desired pentacyclic congeners. The known dilithiation of phenothiazine and iminodibenzyl and n-butyllithium, followed by acylation with dimethylformamide, gave carboxaldehydes at the 1 and 4 positions respectively. Ortho-lithiated nicotinamides were acylated by these aldehydes exclusively at the 4 position to provide the key intermediate alcohol amides. Difficulties in amide hydrolysis are discussed. Catalytic hydrogenation over palladium-on-carbon in refluxing acetic acid yielded carboxylic acids, apparently via the gamma-lactones formed in situ. The lactones could not be isolated easily due to instability to oxidation. Pentacyclic lactams were formed by dehydration, and borane was used to reduce the carbonyl function. Only the iminodibenzyl lactam was reduced, and problems encountered in subsequent pyridine ring reduction are discussed. Cis and trans ring fusion isomers were identified by ¹³C nmr. Attempted one-pot synthesis of this pentacycle and a regioisomer by double acylation of 4,5-dilithioiminodibenzyl with 2,3-pyridinedicarboxylic anhydride, and 3,4-pyridinedicarboxylic anhydride failed. Mechanistic considerations are discussed regarding regiochemistry and reactivity of the nitrogen and carbon anions involved. Ortho-lithiation of 3-bromopyridine to form 3-pyridyne in the presence of the preformed N-lithioiminodibenzyl-4-carboxaldehyde was unsuccessful in providing a pentacyclic benzonaphthyridinobenzazepine. The resulting 2- and 4-lithiated 3-bromopyridines were trapped by the aldehyde instead. Both hydroxymethylbromopyridines were identified by their proton coupling patterns in the pyridine ring. These compounds are discussed as potential precursors to pentacyclic benzazepinopyridobenzazepines. Several other attempts at forming benzonaphthyridinobenzazepines and naphthyridinophenothiazines were unsuccessful. Intermediates were obtained by carbon acylation of the dilithiated iminodibenzyl and phenothiazine with arecoline esters, arecaidine, and pyridine-3-carboxaldehyde. Dibenzylic alcohol reduction is discussed, as is its labile oxidation. None of the resulting pyridylmethyl heterocycles could be cyclized.

Thesis (M.S.)--Rochester Institute of Technology, 1988. / Includes Addendum: High-performance liquid chromatographic analysis of commonly used drugs: Six laboratory experiments for clinical chemistry students. Includes bibliographical references (leaves 48-52).

This dissertation describes formulation of a gastric retention device (GRD) and sustained release (SR) hydrochlorothiazide beads at Oregon State University. Formulation condition and amounts of excipients had significant influence on characteristic of the GRD. The GRD containing SR hydrochlorothiazide beads was employed to assess bioavailability/bioequivalency study in healthy subjects. An original GRD was retained in the stomach with food and completed the drug release. However, this original GRD failed to stay on an empty stomach, leading to lower bioavailability than an immediate release (IR) tablet due to insufficient rigidity. The original device was modified to be more rigid, and this more rigid device successfully stayed on an empty stomach and achieved completion of the drug release at a slow release rate, the bioavailability and the drug effect on diuresis increased compared to the drug in an IR tablet. Less amount of hydrochlorothiazide at a slow release rate achieved equivalent diuresis to higher amount of the drug at a rapid release rate, which indicated slow drug release resulted in higher efficiency of hydrochlorothiazide. In vivo/in vitro correlation of hydrochlorothiazide in a modified GRD and an IR tablet was established to predict in vivo profile with in vitro dissolution profile prior to a clinical study. Pharmacokinetic/pharmacodynamic of nicotine was reviewed in terms of a relationship between plasma nicotine concentrations and pharmacological changes including heart rate and craving. Considering craving and development of tolerance to nicotine effect on cardio-acceleration, a dosing regimen with a combination of rapid input and constant slow input was suggested to improve smoking cessation. A simulation study was carried out to verify the current regulatory policy on assessing bioequivalency of enantiomeric drugs. First-order dissolution and absorption process, and nonlinear stereo-specific pre-systemic and systemic metabolism was taken into account to establish a pharmacokinetic model for the simulation. Four different dissolution profiles, within- and between-subject variability, dose and sample size were considered to simulate 1000 cross-over bioequivalency trials under standard bioequivalency criteria. Probability of false positives was determined to evaluate the current policy. The simulation study validated the importance of individual enantiomer pharmacokinetic for assessing bioequivalency study of the chiral drugs. / Graduation date: 2003