الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 192 |  |  |
| | | from | 192 | | |
Abstract
Summary and conclusions
The present thesis includes a photostability study of oxicam derivative non steroidal antiinflammatory drug (NSAID) lornoxicam (LRX) and tenoxicam (TNX) in dilute aqueous solutions at different pH media. The photodegradation of the mentioned drugs were also studied in the existence of eleven additives (sodium benzoate, p- aminobenzoic acid, tartaric acid, boric acid, citric acid, titanium dioxide, methyl paraben, propyl paraben, caffeine, ascorbic acid and βcyclodextrin). The thesis comprises three chapters:
Chapter I includes an introduction on the importance of photostability studies of drugs, major modes of the photodegradtion of drugs and methods of photostabilization. Also, it includes Introduction and literature survey on the selected photostabilizing agents and the drugs under investigation.
Chapter II includes the experimental work, which includes materials, preparation of various solutions, apparatus used and general procedures that were done for photostablity studies of the drugs in their bulk powder, their pharmaceutical formulation and human plasma as well.
Chapter III includes the results and discussion.
The results showed that:
1- The photodegradation rates of LRX and TNX in diluted aqueous solutions were higher at pH 7 and 10 than at pH 2.
2- The photodegradation rates of LRX and TNX in their dosage forms were approximately the same as that in their bulk powder.
3- LRX and TNX showed high photolability in human plasma and completely degraded.
4- The photodegradation rates of LRX and TNX solutions were described by first order kinetic under the applied experimental conditions.
5- photodegradation products of LRX and TNX in diluted aqueous solutions at pH 7 were characterised by liquid chromatography tandem mass spectrometry (LC MS/MS). The mass spectrum of LRX after irradiation exhibited mass ion peaks at m/z: 198.96, 196.94, 96.95, 78.94, 61.94, 59.98 and 45.94. The mass spectrum of TNX after irradiation exhibited mass ion peaks at m/z: 206.99, 165.03, 162, 146, 96.92, 88.98, 60.95, 59.94, 58.99 and 47.9, The photodegradation rates of LRX and TNX in the existence of eleven additives (p-aminobenzoic acid, tartaric acid, ascorbic acid, boric acid, citric acid, sodium benzoate, titanium dioxide, methyl paraben, propyl paraben, caffeine and β-cyclodextrin) separately were calculated. It was found that citric acid and PABA were the best photostabilizing agents as shown in figures 69 and 70 for LRX and TNX, respectively. Citric acid decreased the rates of photodegradation of LRX and TNX from 0.109 and 0.114 to 0.023 and 0.019, respectively. Ascorbic acid decreased the rates of photodegradation of LRX and TNX from 0.109 and 0.114 to 0.038 and 0.025, respectively. PABA decreased the rates of photodegradation of LRX and TNX from 0.109 and 0.114 to 0.043 and 0.038, respectively.
Fig. 69. Column chart showed the influence of dissimilar photostabilizers on the photodegradation rate of LRX in comparison with none photostabilizers
Fig. 70. Column chart showed the influence of dissimilar photostabilizers on the photodegradation rate of TNX in comparison with none photostabilizers
6- The photodegradation rates of LRX and TNX in diluted aqueous solutions in presence of different concentrations of citric acid were calculated. It was found that 1.5% citric acid was the best concentration. 1.5% citric acid decreased the rates of photodegradation of LRX and TNX from 0.109 and 0.114 to 0.018 and 0.016, respectively.
7- The photodegradation rates of LRX and TNX in dosage forms in presence of 1.5% citric acid were calculated. It was found that 1.5% citric acid decreased the rate of photodegradation of LRX and TNX in dosage forms from 0.106 and 0.123 to 0.019 and 0.015, respectively.
8- Also 1.5% citric acid enhanced the photostability of LRX and TNX in human plasma.
9- The obtained data were validated in accordance with the International Conference on Harmonization (ICH) guideline. The calibration graphs were linear over the concentration ranges of (7.3×10-7–2.9×10-5) mol L-1 for LRX and (5×10-6–2×10-4) mol L-1 for TNX in presence of 1.5% citric acid. The LOD for LRX and TNX was 1.13×10-7 and 9.3×10-7 mol L-1 respectively. The LOQ for LRX and TNX was 3.43×10-7 and 2.8×10-6 mol L-1, respectively. The obtained experimental data indicated that the presence of 1.5% citric acid didn’t affect linearity, precision, LOD and LOQ of the used methods for LRX or TNX determination.
Chapter IV includes introduction about cyclodextrin and its types and definition of computational chemistry, the applied theories how to prepare LRX and TNX inclusion complex by means of βcyclodextrin and discussion the results
The results showed that:
10- LRX and TNX, create a constant 1:1 inclusion complex by means of βcyclodextrin (βCD) in aqueous solution. The experimentally determined association constants (K) of LRX- βCD and TNX- βCD refer to stable complexes. The favorite orientation of guest molecules into the host was simulated via ONIOM quantum chemical computations, which identified the structure and showed that both drugs were partly encapsulated within the βCD cavity. The calculated inclusion binding energy (BE, kcal mol-1) reveals the obvious thermal stability of LRX-βCD (-24.19 kcal/mol) over the TNX-βCD (-13.45 kcal/mol) capsulate. Furthermore, the photostabilities of the encapsulated drugs were tested. Drug encapsulation did not result in any additional photostability. Furthermore, encapsulation of the drugs in the β-CD resulted in noticeable changes in the electronic characteristics of the drugs, as reflected in their reactivity indices. The encapsulation results in a slight enhancement of the chemical potential and the electrophilicity of the drug, while the hardness and nucleophilicity values slightly fall. The fact that βCD formed inclusion complexes with water-insoluble LRX and TNX indicates its utility to enable the drug delivery vehicle for oral administration.