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Gelatin obtained from collagen, a component of skin and bone, is the primary excipient ingredient of pharmaceutical capsules. The gelatin capsules are designed to progressively dissolve, leading to controlled release of the active pharmaceutical ingredient directly in the patient’s digestive tract. The dissolution rate of the gelatin can become altered during storage. Drugmakers therefore apply a standard accelerated ageing protocol followed by a dissolution test to sort their production batches according to dissolution ability. The industry knows that the dissolution ability of gelatin varies between production areas, but nobody has yet been able to explain where this variation comes from.

RESULTS

Here we led a study spanning three production sites—two in Europe and one in the USA—with two objectives: 1) to unravel the mechanisms underpinning variability in gelatin dissolution ability, 2) to identify potential ‘markers’ of gelatin dissolution in order to predict its properties during shelf-life ageing. Circular dichroism analysis on different batches of ‘fresh’ gelatin makes it possible to predict their post-ageing dissolution ability.
Artificially-aged gelatins that are not dissolution rate-compliant have a higher amorphous phase content than dissolution rate compliant gelatins. Among other major findings, note the changes in intermolecular structure, with the formation of dityrosine, a potential marker of shelf-life ageing. The chemical composition of gelatin can be used to map its source based on the extent of dityrosine formation in the fresh and age-accelerated gelatins or the physicalchemical arginine environment. The oxidative potential of the coextracted lipids and amine functions of the gelatin is thought to cause the molecular chains to cross-link. The decrease in dissolution ability has multifactorial causes—for instance, it only correlates with iron content for one of the three production sites.

FUTURE OUTLOOK
Our findings offer lines of action for reducing the variability in gelatin dissolution rates: control and reduce the level of oxidation, and control and reduce lipid content.