Resistant hypertension is a condition in which blood pressure remains above the ideal value (120/80mmHg), despite concurrent use of three antihypertensive agents of different classes taken at maximally tolerated doses. Amiloride, a potassium-sparing diuretic agent, when added to the treatment regimen of these drugs has been found suitable for the management of resistant hypertension, especially in diabetic patients and those resistant to a similar diuretic, spironolactone. Currently, it is available as an oral tablet, administered once daily. The oral bioavailability of amiloride is 50%, which gets reduced to 30% when administered with food. In addition, gastrointestinal side effects are also reported. Patient’s adherence to the multi-drug treatment regimen has been found to be low in patients with resistant hypertension and hence, administering amiloride in the oral forms may not solve the problem, in spite of its proven pharmacological efficacy in such situations. Thus, considering the low oral bioavailability, associated side-effects, and prospects of better patient compliance with a skin patch of amiloride, our long term goal is to design a long-acting skin patch for transdermal delivery of amiloride in patients with resistant hypertension. The current study aims to investigate the passive transdermal delivery of amiloride and evaluate the effects of chemical and physical enhancement techniques on its permeation through dermatomed porcine ear skin. High performance liquid chromatography (HPLC) method for amiloride was developed. Absence of skin interference in the assay was confirmed using blank skin extract. Solubility of amiloride was screened in different solvents, some of which included propylene glycol, phosphate buffer saline, oleic acid in propylene glycol, etc. In vitro permeation of amiloride across intact and microneedle-treated (500 µm long stainless needles applied for 2 min) porcine ear skin was evaluated using Franz Diffusion cells over 30 h. The optimized reverse-phase HPLC method involved isocratic elution on Kinetex® 5 µm, 100 Ao, 250 X 4.6 mm C18 column using 100% mobile phase (0.2 M phosphate buffer, pH 4.5) at a flow rate of 0.8 mL/min, column temperature of 40°C, and UV detection at 360 nm. Drug retention time was found to be around 4 min. Amiloride was found to be most soluble in propylene glycol (57.18 ± 2.41 mg/mL) with least solubility in phosphate buffer saline (0.311 ± 0.004 mg/mL). Microneedles were found to significantly enhance the permeation flux of amiloride by 16 folds as compared to the control intact skin (p

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The effects of changes in temperature, mobile phase composition, flow rate, and stationary phase upon the enantiomeric separation of several racemic mixtures are investigated. The changes in capacity factor (k'), selectivity (α), and efficiency (N) and enantiomeric resolution (R), are explored. Resolution is then shown to be controlled by the specific combination of chiral stationary phase (CSP), solute, mobile phase and temperature. The key to optimizing chiral resolution lies in understanding the retention mechanism(s) for a given CSP. The proposed retention mechanisms for the two CSP used in the optimization studies are evaluated using chromatographic/thermodynamic data. Inferences are made which support the well-characterized "Pirkle"-type R-dinitrobenzoylphenylglycine retention mechanism, which depends solely on attractive-repulsive interactions to establish two diasteriomeric complexes having unequal internal energy, and therefore eluting at different times from the chromatographic system. For comparison, a more complicated CSP composed of a tris cellulose(3,5- dimethylphenylcarbamate) coated to a silica gel support is also examined. For this CSP the proposed mechanisms, which include both attractive-repulsive interactions and inclusion complex types, are evaluated according to the chromatographic optimization data, and compared to similar data for the single-mechanism "Pirkle" CSP. In contrast to the above"macromolecular"-level inferences about retention mechanisms drawn from chromatographic data, a second study was initiated using a model CSP attached to a l000-Å gold surface, with Fourier-Transform Infrared Spectrometry in a Reflectance-Absorbance mode, to probe the specific molecular interactions which make possible the diasteriomeric complex. This <i>in situ</i> experiment, in contrast to previous <i>ex situ</i>, stationary phase work, is designed to show that hydrogen bonding is, as predicted, a principal force holding the complexes together, and that a measurable difference exists between the weaker R-trifluoroanthrylethanol (TFAE) and the stronger S-TFAE complexes due to their different stereo-geometry. A further experiment to characterize the difference in mechanisms between the "Pirkle" and cellulose CSPs involves relating their chromatographic retention behavior to their structure, known as Qualitative Structure Retention Relationships (QSRR). Some structure-specific physical-organic chemistry parameters are determined using an EPA-developed computer program and correlations are made between retention on a given CSP and some of the parameters. / Ph. D.