Incompatibility of indometacin and benzalkonium in eye drops due to ion-pair formation.

Eye drop formulations containing indometacin and benzalkonium salt often show an opalescence as a result of ion-pair formation. The insoluble ion pair was isolated and characterized by infrared and ultraviolet spectroscopy and thin layer chromatography. This ion pair is also responsible for the bad assay results of benzalkonium using the ion-pair extraction method with bromothymol blue as counterion. The distribution constant (KD = 1O4) of indometacin and the extraction constant (Kex = 3 X 1O4) of the ion pair indometacin-benzalkonium in a water-chloroform system at various pH values were determined. A discussion on the preservation of indometacin eye drop formulations with benzalkonium salt in view of this chemical incompatibility is presented.

Generalized theory for two-phase ion-pair and complexometric titrations. I. Two-phase titrations without side reactions.

A systematic theoretical treatment of the two-phase titration based on ion-pair and metal-complex formation is presented. Equations for the titration curve, accuracy, equivalence point and choice of the indicator are derived. Much attention is paid to the parameters determining the 'titratability' viz. extraction constant, distribution constant, phase volume ratio and the concentration of the analyte. Special attention is given to the role of intermediate ion-pair and metal-complex formation in the aqueous phase. The ion-pair formation in aqueous solution is examined closer by means of the relationship between the association constant in water, the degree of dissociation of the ion pair (alpha) and the concentration of the counter ion. The merits of this theoretical treatment are illustrated with literature examples.

Generalized theory for two-phase ion-pair and complexometric titrations. II. Two-phase titrations with side reactions.

For the two-phase titration based on ion-pair and metal-complex formation full attention is given to side reactions in both phases. Their significance for the applicability of this type of titration is evaluated. Side reactions in the aqueous phase diminish and in the organic phase promote the 'titratability'. Equations for the calculation of the side reaction coefficients, the titration curve and the selection of the optimal pH and minimal side reaction interference (in the aqueous phase) are presented. Finally a full description is given of the two-phase titration including all parameters determining the 'titratability'. The merits of the developed theory are illustrated by literature examples.

Hydrolysis and determination of meprobamate.

Most pharmacopoeial methods for meprobamate are based on acid hydrolysis, followed by determination of the ammonia formed. In order to find optimum conditions the hydrolysis was studied with the aid of TLC. Various types and concentrations of acid were tested. Refluxing with 25% (wt/vol) HCl for two hours proved to be sufficient to achieve complete hydrolysis (99.4 +/- 1%). This method is less time-consuming than that of the European Pharmacopoeia and the hydrolysate does not turn brown as is the case with high concentrations of H2SO4.

Determination of phenol in the presence of resorcinol applying substitution with excess bromine water; structure of the bromination products.

Bromination with a large excess of bromine results in the formation of a tetrabromo product for phenol and a pentabromo derivative for resorcinol. It is possible to determine the active bromine in the tetrabromo product after its isolation by filtration. This can also be done in the presence of resorcinol as its pentabromo derivative does not precipitate. The method gives good results (96-97% +/- 1%) for quantities of 8 mg and higher of phenol in the presence of a maximum of 25 mg resorcinol. From the 1H- and 13C-NMR spectra of the bromination products it could be concluded that they have a quinoidal structure.