White Paper: Determination Of Extractable And Leachable Formaldehyde In Hydroxypropyl Methylcellulose Capsules By Derivatization And Gas Chromatography

BY Analytical Bio-Chemistry Laboratories (ABC Labs)

Hydroxypropyl methyl cellulose (HPMC) are becoming increasinglypopular as capsule materials for drug delivery and dietarysupplements. HPMC is synthetic (not animal based)and is chemically less active than traditional gelatin. HPMC isinert to formaldehyde, while gelatin cross-links in the presenceof formaldehyde. Cross linking of gelatin causes incompletecapsule shell dissolution and, thereby problems with drugrelease.

HPMC is produced by the reaction of methyl chloride and alkalicellulose. The resulting methylcellulose is then further reactedwith propylene oxide to give hydroxypropyl methyl cellulose.During the manufacturing process propylene oxide can reactwith hydroxide to form formaldehyde and acetaldehyde. Also,methyl esters can be oxidized to produce formaldehyde.Therefore, leachable formaldehyde from HPMC is a majorconcern to pharmaceutical industry. Formaldehyde leachingout of the capsule material could react with any activepharmaceutical ingredient (API) with an amine group anddegrade it to its imine (N-methyl derivative). Insulin is knownto be modified by reaction with formaldehyde.Formaldehyde-induced modifications change the accessibilityand reactivity of the peptides forming small proteins. Anestimation of the amount of formaldehyde leaching out ofHPMC capsules and possibly reacting with the API is animportant toxicological concern in all pharmaceuticalapplications.

Formaldehyde is a known carcinogen. Both EPA and OSHAhave set permissible exposure limits for formaldehyde. TheProduct Quality Research Institute (PQRI) recommends a safetyconcern threshold (SCT) for carcinogens. SCT is the level oftoxicity over which leachables must be identified and quantitated.

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