International pharmacopoeia monographs for zinc acetate and zinc gluconate active pharmaceutical ingredients used in the treatment of paediatric diarrhoea

Abstract

Acute diarrhoea is one of the largest health challenges globally, causing millions of child deaths every year. A continued effort is made by the WHO, in collaboration with other institutions, to successfully combat diarrhoea. A new formulation for ORS (with a reduced osmolarity), in combination with zinc supplementation, was proposed to reduce the severity and duration of diarrhoea (WHO, 2006:1). Appropriate zinc supplementation for the treatment of diarrhoea includes: zinc sulfate, zinc acetate dihydrate and zinc gluconate. With no monographs available in The Ph. Int. for zinc acetate dihydrate and zinc gluconate APIs, the development thereof has become a priority to the WHO. During this study, suitable methods according to The Ph. Int. for the quality control testing of zinc acetate dihydrate and zinc gluconate APIs were investigated and proposed. The following monograph requirements were proposed for zinc acetate dihydrate API: * Identification of zinc by means of a precipitation reaction of zinc hydroxide and zinc sulfide, * Identification of acetate by means of a precipitation reaction of ferric acetate, * Clarity and colour of a 0.05 g/ml solution, * pH value of a 0.05 g/ml solution, * Assay by means of a complexometric titration with disodium EDTA, * Impurities / Limit tests: o reducing substances by means of a reduction reaction with potassium permanganate, o chlorides by means of a precipitation reaction with silver nitrate, o sulfates by means of a precipitation reaction of barium sulfate, o arsenic by means of reaction between arsine and bromide, o aluminium, cadmium, copper, iron and lead by means of atomic absorption spectrometry. The following monograph requirements were proposed for zinc gluconate API: * Identification of zinc by means of a precipitation reaction of zinc ferrocyanide, * Identification of gluconate by means of a thin layer chromatographic separation method, * Clarity and colour of a 0.01 g/ml solution, * pH value of a 0.01 g/ml solution, * Water by means of the Karl Fischer method, * Assay by means of a complexometric titration with disodium EDTA, * Impurities / Limit tests: o reducing sugars by means of a reduction reaction with cupri–tartaric test solution, o chlorides by means of a precipitation reaction with silver nitrate, o sulfates by means of a precipitation reaction of barium sulfate, o heavy metals by means of a precipitation reaction of sulfides in acidic solutions, o cadmium by means of atomic absorption spectrometry, and o microbial testing if required by The Ph. Int. The proposed methods were then validated or verified according to international standards. Once the methods were proven to be fit for purpose, they were assembled into the respective monographs for inclusion in The Ph. Int. The newly developed monographs were then evaluated by determining the compliance of commercially available zinc acetate dihydrate and zinc gluconate to the proposed specifications. The study contributes to the WHO, pharmaceutical industry and medicines regulatory authorities by making these two monographs globally available, thus providing a quality gauge to ensure the availability of zinc acetate dihydrate and zinc gluconate APIs of pharmaceutical acceptable quality.