Hans Bundgaard

Sorption of drugs by plastic infusion bags

Abstract The sorption of warfarin sodium, various benzodiazepines and a number of other drugs from aqueous solutions by poly vinyl chloride infusion bags was investigated. The sorption kinetics for warfarin and diazepam could be accounted for by a diffusional model in which the loss of drug is determined primarily by the diffusivity of the compound in the plastic matrix. The rate and extent of sorption of warfarin showed a dependence on pH which could be interpreted in terms of ionization of the drug, i.e. only the unionized form was sorbed. A rank order relationship was shown between the initial rate of uptake by the plastic bag and the hexane-water partition coefficients of the compounds. It is suggested that the latter parameter may be useful for the prediction of interactions between a drug substance and polyvinyl chloride infusion bags. Sorption of the compounds by infusion bags made from polypropylene was insignificant except for the highly lipophilic medazepam and accordingly, such bags may be more safe to use than polyvinyl chloride bags in respect to drug sorption.

Pro-drugs as drug delivery systems XXIII. Improved dermal delivery of 5-fluorouracil through human skin via N-acyloxymethyl pro-drug derivatives

Abstract The percutaneous permeation characteristics of two N-1-acyloxymethyl derivatives of 5-fluorouracil were determined and compared with that of 5-fluorouracil using excised human skin mounted in open diffusion cells. The derivatives, particularly 1-butyryloxymethyl-5-fluorouracil, permeated more readily through the human skin than 5-fluorouracil and at the same time were delivered in the form of parent drug due to cutaneous metabolism as mediated by hydrolytic enzymes. The better permeabilities of the derivatives were ascribed to their higher lipophilicities as expressed in terms of the octanol-water partition coefficients. It appeared that N-acyloxymethyl derivatives of 5-fluorouracil may be promising pro-drug candidates with enhanced topical bioavailability compared to the parent drug. Leaching of hydrolytic enzymes from the skin preparations into the receptor phase was found to take place during the permeation study and its significance is discussed in relation to the question of extent of cutaneous and bulk phase metabolism.

Pro-drugs as drug delivery systems VIII. Bioreversible derivatization of hydantoins by N-hydroxymethylation

Abstract The kinetics and mechanism of decomposition of the N 3 -hydroxymethyl derivatives of various hydantoins (phenytoin, nitrofurantoin and 5,5-dimethylhydantoin) in aqueous solution at 37°C was studied to assess their potential utility as pro-drugs for the parent substances. The derivatives were found to undergo an apparent hydroxide ion-catalyzed decomposition in the pH range 3.3–6.1, the specific rate constants being 7.1 × 10 7 , 6.2 × 10 8 and 1.0 × 10 7 M −1 min −1 for the phenytoin, nitrofurantoin and dimethylhydantoin derivative, respectively. This difference m decomposition rates was correlated with the difference in the acidity of the parent hydantoins and the rate data for the hydantoins were shown to fit well with a rate—acidity relationship previously derived for a number of N-hydroxymethylated amides and imides. The N-hydroxymethyl hydantoins are very rapidly cleaved to formaldehyde and the parent compounds at pH 7.4 and 37°C (half-lives calculated to range from 0.1 to 6.9 s). The derivatives were shown to possess higher water solubilities than the parent compounds and it is suggested that N-hydroxymethylation may be a potentially useful means of obtaining pro-drug forms of hydantoins. In addition, it was demonstrated by determination of the hydrolysis kinetics of the acetate ester of 3-(hydroxymethyl)phenytoin that the N-hydroxymethylated hydantoins are amenable to further bioreversible derivatization.

Studies on the stability of corticosteroids VI. Kinetics of the rearrangement of betamethasone-17-valerate to the 21-valerate ester in aqueous solution

The kinetics of the degradation of betamethasone-17-valerate in aqueous solutions of pH 0.5–8 have been investigated at 60°C using a reversed-phase HPLC procedure for determining remaining steroid and the products of its degradation, betamethasone-21-valerate and betamethasone. The overall degradation was shown to proceed entirely through a rearrangement of the 17-valerate ester to the 21-valerate ester followed by hydrolysis of the latter to yield betamethasone. The acyl group migration from C17 to C21 was subject to both specific acid and base catalysis as well as to catalysis by water. The pH-rate profile for the rearrangement showed a minimum at pH 3.5.

Studies on the stability of corticosteroids V. The degradation pattern of hydrocortisone in aqueous solution

Abstract The degradation pattern of hydrocortisone in aqueous solution was investigated utilizing an HPLC procedure capable of separating and quantitating hydrocortisone and its major degradation products. The product distribution was characterized qualitatively and quantitatively as a function of pH in the range 0—11, nature of buffers and trace metal impurities. Two major decomposition pathways were observed, an oxidative degradation leading to the formation of 21 -dehydrohydrocortisone which subsequently degraded to a 17-carboxylic acid and a 17,20-dihydroxy-21-carboxylic acid derivative, and a non-oxidative reaction giving a 17-oxo, 17-deoxy-21-aldehyde and 17-deoxy-20-hydroxy-21-carboxylic acid derivative. The analytical consequences of the formation of steroid-glyoxals (21-aldehyde derivatives) in the evaluation of the stability-indicating properties of some spectrophotometric assays for corticosteroids are discussed as are possible means to prevent the conversion of corticosteroids to these products recently characterized as potentially immunogenic substances possibly involved in corticosteroid-mediated allergic reactions.

Kinetics of the acid-catalyzed hydrolysis of doxorubicin

The kinetics of hydrolysis of doxorubicin were studied in 0.01–0.5 M hydrochloric acid solutions (pH 0.4–2.1). The rate of hydrolysis exhibited a first-order dependency on the doxorubicin concentration and on the hydrogen ion concentration, the specific hydrogen ion catalytic rate constant being 1.02 M−1 · h−1 at 37°C. An activation energy of 92.0 kJ · mol−1 was determined. The acid-catalyzed hydrolysis was discussed in relation to liquid chromatographic procedures involving acidic mobile phases and with respect to gastric degradation of the drug. It was estimated that in the gastric pH range 1–2 and with a gastric emptying half-time of 50 min about 86–98% of an oral dose would leave the stomach in intact form.

Inclusion complexation of metronidazole benzoate with β-cyclodextrin and its depression of anhydrate-hydrate transition in aqueous suspensions

Abstract Metronidazole benzoate was found to form an inclusion complex with β-cyelodextrin (β-CyD) in aqueous solution and in the solid phase. A phase solubility diagram was obtained and an apparent 1:1 formation complex constant of 1.3 × 10 3 M −1 was determined. A microcrystalline inclusion complex was isolated and shown to have the stoichiometric composition of 1:1.5 (drug: β-CyD). By inclusion complexation of the metronidazole ester with β-CyD the phase transition of the clinically used anhydrous form of the compound to the monohydrate occurring in aqueous suspensions was inhibited as was the marked crystal growth resulting from the phase transition. Besides increasing the physical stability of metronidazole benzoate suspensions the complexation with β-CyD protected the drug against photochemical degradation and decreased the rate of hydrolysis.

Leaching of hydrolytic enzymes from human skin in cutaneous permeation studies as determined with metronidazole and 5-fluorouracil pro-drugs

Abstract The leaching of hydrolytic enzymes out of the dermal side of excised human skin into the receptor phase of a permeation cell was studied using the esters metronidazole benzoate and l-butyryloxymethyl-5-fluorouracil as test compounds. The enzyme activity in the receptor phase increased rapidly and was essentially complete after an exposure time of 20 h. The half-life for the hydrolysis of metronidazole benzoate in the phosphate buffer, pH 7.4, receptor phase exposed to the skin for 20 h was 3.1 h, whereas that in non-exposed receptor phase was 1000 h. It is emphasized that receptor phase metabolism due to leached enzymes may be of significance when assessing concurrent transport and metabolism of drugs or prodrugs in permeation studies using human skin. Metronidazole benzoate permeated more readily through the skin than metronidazole which was ascribed to its higher skin-vehicle partition coefficient. Only hydrolyzed metronidazole was detected in the receptor phase.

Spectrophotometric determination of the rates of hydrolysis of aldehyde-releasing pro-drugs in aqueous solution and plasma

Abstract A previously described spectrophotometric method for the determination of formaldehyde or other aliphatic aldehydes has been modified and demonstrated to be a highly useful and convenient means for assessing the rate of hydrolysis of various pro-drugs which upon reconversion to their parent drugs release an aldehyde. The pro-drugs tested include a number of acyloxyalkyl esters of carboxylic acids (pivampicillin, bacampicillin, pivmecillinam and esters of isoguvacine), N-acyloxymethyl esters of 5-fluorouracil and theophylline, N-Mannich bases and N-hydroxymethyl derivatives. Rate data are given for the hydrolysis of these pro-drugs in buffer solutions as well as in solutions containing human plasma and are compared with data obtained by various other methods.

Hydrolysis and epimerization kinetics of pilocarpine in basic aqueous solution as determined by HPLC

A high-performance liquid chromatographic method is described which allows the simultaneous determination of pilocarpine and the products of its degradation, isopilocarpine, pilocarpic acid and isopilocarpic acid. Using this method the degradation pattern of pilocarpine in basic aqueous solution was determined. The epimerization of pilocarpine to isopilocarpine was found to be a reversible reaction although the equilibrium is strong in favor of isopilocarpine. Isopilocarpine was readily detected during the overall degradation of pilocarpine and was found to possess the same stability as its diastereoisomer. The relative importance of epimerization to hydrolysis of pilocarpine increased with increased temperature, ranging from 12% at 18°C to 20% at 66°C.