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

BY Analytical Bio-Chemistry Laboratories (ABC Labs)

Hydroxypropyl methyl cellulose (HPMC) are becoming increasingly popular as capsule materials for drug delivery and dietary supplements. HPMC is synthetic (not animal based) and is chemically less active than traditional gelatin. HPMC is inert to formaldehyde, while gelatin cross-links in the presence of formaldehyde. Cross linking of gelatin causes incomplete capsule shell dissolution and, thereby problems with drug release.

HPMC is produced by the reaction of methyl chloride and alkali cellulose. The resulting methylcellulose is then further reacted with propylene oxide to give hydroxypropyl methyl cellulose. During the manufacturing process propylene oxide can react with hydroxide to form formaldehyde and acetaldehyde. Also, methyl esters can be oxidized to produce formaldehyde. Therefore, leachable formaldehyde from HPMC is a major concern to pharmaceutical industry. Formaldehyde leaching out of the capsule material could react with any active pharmaceutical ingredient (API) with an amine group and degrade it to its imine (N-methyl derivative). Insulin is known to be modified by reaction with formaldehyde. Formaldehyde-induced modifications change the accessibility and reactivity of the peptides forming small proteins. An estimation of the amount of formaldehyde leaching out of HPMC capsules and possibly reacting with the API is an important toxicological concern in all pharmaceutical applications.

Formaldehyde is a known carcinogen. Both EPA and OSHA have set permissible exposure limits for formaldehyde. The Product Quality Research Institute (PQRI) recommends a safety concern threshold (SCT) for carcinogens. SCT is the level of toxicity over which leachables must be identified and quantitated.