Date of Award

2007

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Environmental Science

First Advisor

Dr. Alaa EI-Din Salem

Second Advisor

Dr. Ali AI Marzouqi

Third Advisor

Dr. John Graham

Abstract

Cyclodextrin chemistry involves non-covalent molecular interactions between the interacting species. The majority of these interactions are of the host-guest type. In the present work, UV-Vis spectrophotometry and 1H-NMR studies were used to study the interaction between amantadine hydrochloride, acyclovir and their derivatives with β­cyclodextrin. Additionally, quantification of amantadine hydrochloride and acyclovir by 1H-NMR spectroscopy were carried out.

This study is based on preparing amantadine hydrochloride and acyclovir derivatives. Anthraquinone-2-carboxylic acid and benzoyl chloride were used as derivatizing agents for amantadine hydrochloride and acyclovir, respectively. Derivatization procedure was based on nucleophilic displacement by an amino group (amantadine or acyclovir) to the acyl carbonyl in 2-anthraquinone carbonyl chloride or benzoyl chloride. As a result, an amide bond was formed between each drug (amantadine hydrochloride or acyclovir) and 2-anthraquinone carbonyl chloride or benzoyl chloride, respectively.

Complexation in solution with β-cyclodextrin was evaluated using UV-Vis spectroscopy for 2-Anthraquinonyl amantadine (AqA) and 2-N-benzoyl acyclovir (NBACV). The effect of β-cyclodextrin concentration as well as the effect of pH was studied. The association constants (Ka) for the formation of the inclusion complexes were determined using the linear Benesi-Hildebrand plots. Values of Ka >108 were obtained indicating high affinity for forming the inclusion complexes between, β-cyclodextrin and both 2-Anthraquinonyl amantadine and 2-N-benzoyl acyclovir.

Amantadine hydrochloride, 2-Anthraquinonyl amantadine, acyclovir and 2-N-benzoyl acyclovir were used as guest molecules to investigate the inclusion complexation behavior using 1H-NMR spectroscopy. Integrations of the H-3', 5’, 7’ proton at δ 2.07 ppm for amantadine, 2-Anthraquinonyl amantadine as well as H-8' at δ 57.82 ppm for acyclovir and 2-N-benzoyl acyclovir were used to calculate the stoichiometries and formation constants for β-cyclodextrin inclusion complexes.

The results showed that amantadine hydrochloride and acyclovir exhibit 1: 1 stoichiometry with β-cyclodextrin, while 2-Anthraquinonyl amantadine and 2-N-benzoyl acyclovir exhibit 1:2 stoichiometry. The Ka values of 3.1 x 101 mol L1 and 4.3 x 101 mol-1 L1 for amantadine β-cyclodextrin and acyclovir- β-cyclodextrin 1: 1 inclusion complexes were obtained. 2-Anthraquinonyl amantadine β-cyclodextrin and 2-N-benzoyl acyclovir-β-cyclodextrin 1:2 inclusion complexes gave Ka values of 3.2 x 104 mol-2 L2 and 5.9 x 102 mol-2 L2 at room temperature.

NMR spectroscopy has been used for quantitative determination of pharmaceutical compounds in different matrices. This is due to its simplicity and straightforward evaluation and interpretation. Other advantages of NMR are its nondestructive nature and selectivity, together with the fact that it gives structural information about other contaminants that may be present. Furthermore, it is fast, easily performed and almost no sample preparation or sophisticated reagents are needed. NMR as a quantitative spectroscopic tool enabled the determination of the amount of amantadine hydrochloride and acyclovir antiviral drugs in pharmaceutical and human plasma samples. This method was based on using malonic acid as an internal standard. 1H-NMR signals at 52.07 ppm for amantadine hydrochloride and δ 7.82 ppm for acyclovir, respectively, were used for calculating the concentrations of both drugs in pharmaceutical and plasma samples. The malonic acid signal at δ 53.24 ppm was used as the reference signal. Average percent recoveries in the ranges of 97.70-100.40 % and 96.51-103.68% were obtained in pharmaceutical and plasma samples, respectively.

Applying the statistical Student t-test revealed insignificant difference between the real and measured contents at the 95 % confidence level. The F-test revealed insignificant differences in precision between the developed NMR method and HPLC method for analyzing amantadine hydrochloride and acyclovir.

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