The presence of an ionized carboxyl group in the widely used non-steroidal anti-inflammatory (NSAID) drug diclofenac potassium results in a high mobility of diclofenac and in its low sorption under conditions of slow sand filtration or subsoil passage. No diclofenac degradation was detected in pure water or sludge during one month. Tertiary treatments of wastewater indicated that the effective removal of diclofenac was by reverse osmosis, but the removal by activated carbon was less satisfactory. This study presents an efficient method for the removal of diclofenac from water by micelle-clay composites that are positively charged, have a large surface area and include large hydrophobic domains. Adsorption of diclofenac in dispersion by charcoal and a composite micelle (otadecyltrimethylammonium [ODTMA] and clay [montmorillonite]) was investigated. Analysis by the Langmuir isotherm revealed that charcoal had a somewhat larger number of adsorption sites than the composite, but the latter had a significantly larger binding affinity for diclofenac. Filtration experiments on a solution containing 300 ppm diclofenac demonstrated poor removal by activated carbon, in contrast to very efficient removal by micelle-clay filters. In the latter case the weight of removed diclofenac exceeded half that of ODTMA in the filter. Filtration of diclofenac solutions at concentrations of 8 and 80 ppb yielded almost complete removal at flow rates of 30 and 60 mL min(-1). One kilogram of ODTMA in the micelle-clay filter has been estimated to remove more than 99% of diclofenac from a solution of 100 ppb during passage of more than 100 m3.
Density functional theory calculation results demonstrated that the efficiency of the acid-catalyzed hydrolysis of Kirby's acid amides 1-15 is strongly dependent on the substitution on the C-C double bond and the nature of the amide N-alkyl group. Further, the results established that while in the gas phase the hydrolysis rate-limiting step is the tetrahedral intermediate formation in polar solvents such as water, the rate-limiting step could be either the formation or the collapse of the tetrahedral intermediate depending on the substitution on the C-C double bond and on the amide nitrogen substituent. Based on a linear correlation between the calculated and experimental effective molarities, the study on the systems reported herein could provide a good basis for designing prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log effective molarities values, the predicted t 1/2 (a time needed for 50% of the reactant to be hydrolyzed to products) for acyclovir prodrugs, ProD 1-4, was 29.2 h, 6097 days, 4.6 min, and 8.34 h, respectively. Hence, the rate by which acyclovir prodrug releases acyclovir can be determined according to the structural features of the linker (Kirby's acid amide moiety).Key words: acyclovir prodrugs, bioavailability of acyclovir, density functional theory calculations, intramolecular amide hydrolysis, maleamic acid amides Acyclovir is a synthetic acyclic purine nucleoside analog that is the first agent to be licensed for the prevention and treatment for viral infections such as herpes simplex (HSV), varicella zoster (chicken pox), and herpes zoster (shingles) (1). Acyclovir is poorly water soluble and has an oral bioavailability of 10-20%; hence, intravenous administration is necessary if high dosing is required. When orally administered, peak plasma concentration occurs after 1-2 h. Acyclovir has a high distribution rate with only 30% is protein-bound in plasma. The elimination half-life of acyclovir is about 3 h. It is renally excreted by both glomerular filtration and tubular secretion (2).Acyclovir is marketed as tablets of 200, 400, and 800 mg, suspension for oral administration, intravenous injection, and ophthalmic and skin topical creams. Per os acyclovir is mostly used as 200 mg tablets, five times daily. In addition, 6 month to a year administration of acyclovir is required in immunocompetent patient with relapsing herpes simplex infection (2).The currently available oral administration therapy is associated with a number of drawbacks such as highly variable absorption and low bioavailability (10-20%). The main problem with the therapeutic effectiveness of acyclovir is its absorption that is highly variable and dose dependent, thus reducing the bioavailability to 10-20%. In commercially available dosages forms of acyclovir, the amount of drug absorbed is very low because of short residence time of the dosage forms at the absorption site...
The future of prodrug technology is exciting yet extremely challenging. Advances must be made in understanding the chemistry of many organic reactions that can be effectively utilized to enable the development of even more types of prodrugs. Despite the increase in the number of marketed prodrugs, we have only started to appreciate the potential of the prodrug approach in modern drug development, and the coming years will witness many novel prodrug innovations.
Based on DFT, MP2, and the density functional from Truhlar group (hybrid GGA: MPW1k) calculations for an acid-catalyzed hydrolysis of nine Kirby's N-alkylmaleamic acids and two atenolol prodrugs were designed. The calculations demonstrated that the amide bond cleavage is due to intramolecular nucleophilic catalysis by the adjacent carboxylic acid group and the rate-limiting step is determined based on the nature of the amine leaving group. In addition, a linear correlation of the calculated and experimental rate values has drawn credible basis for designing atenolol prodrugs that are bitterless, are stable in neutral aqueous solutions, and have the potential to release the parent drug in a sustained release manner. For example, based on the calculated B3LYP/6-31 G (d,p) rates, the predicted t 1/2 (a time needed for 50% of the prodrug to be converted into drug) values for atenolol prodrugs ProD 1-ProD 2 at pH 2 were 65.3 hours (6.3 hours as calculated by GGA: MPW1K) and 11.8 minutes, respectively. In vitro kinetic study of atenolol prodrug ProD 1 demonstrated that the t 1/2 was largely affected by the pH of the medium. The determined t 1/2 values in 1N HCl, buffer pH 2, and buffer pH 5 were 2.53, 3.82, and 133 hours, respectively.
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