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eye on and polyvinyl acetate phthalate (PVAP). The common term in the nomenclature of these high-molecular- weight polymers is the word "phtha- late" because these enteric polymers have been modified by esterification with orthophthalic acid groups. The enteric polymers are large molecules, with typical molecular weights in the range of 60,000 to 130,000 daltons. Unlike phthalate enteric poly- mers, esters of orthophthalic acid with low-molecular-weight alcohols, such as dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP), have been developed and used com- mercially as plasticizers. DBP and DEHP are small molecules with mol- ecular weights of only 278 and 390, respectively. The enteric polymers are very dif- ferent from DBP and DEHP based on properties such as chemical structure and molecular weight and have com- pletely different functions. Recent data suggest that many of these phtha late plasticizers may pose sig- nificant hazards to human health and the environment. Despite substantial differences in the chemical properties between the phthalate plasticizers and enteric polymers containing or - tho phthalic acid, recent safety con- cerns for the phthalate plasticizers have prompted some scientists to question whether the polymers that are used as excipients for enteric coatings of pharmaceuticals pose similar safety concerns. Accordingly, we set out herewith to clarify the applications of the enteric polymer excipients, explain why the safety concerns relating to phthalate plasti- cizers do not apply to these enteric polymers, and summarize the data that support the continued safe use of these materials. Nomenclature The term "phthalate" has been defined by the EPA (2012 EPA Action Plan) and other regulatory agencies to identify diesters of orthophthalic acid, also called simply phthalic acid, an aromatic dicar- boxylic acid in which the two car- boxylic acid groups are located on adjacent carbons (positions 1 and 2) in the benzene ring. Both DBP and DEHP are examples of such phtha- lates, and these phthalates are chemi- cally and toxicologically distinct from diesters of iso- or tere-phthalic acids, which are not considered "phthalates" as defined by the EPA. There are important distinctions regarding iso- and tere-phthalic acid derivatives with the orthophthalates. The colloquial use of "phthalates" in several publications has created unsubstantiated and erroneous safety concerns. The specific toxicological concern with DEHP and DBP arises from their metabolic conversion to their corresponding monoesters (Thomas et al., 1982; Curto and Tho - Tablets & Capsules April 2014 39 David Kossor Eastmann Chemical Chris DeMerlis Colorcon Sakae Obara SE Tylose USA (Shin-Etsu Chemical) April Hernandez FMC Chris Moreton FinnBrit Consulting excipients In this edition of the column, members of the Working Group on Phthalate Excip- ients, part of the International Pharma- ceutical Excipients Council of the Amer- icas (IPEC-Americas) dispel some of the misunderstandings about excipients that contain the word "phthalate" in their name. Phthalates have been defined by the EPA and FDA as diesters of low- molecular-weight alcohols and orthophthalic acid. By contrast, phthalate enteric polymers are mono-esters of orthophthalic acid, and the alcohol is present in the form of a polymer backbone. These differ- ences in structure translate to differ- ences in chemical properties and bio- logical activities. Phthalate enteric polymers are used to form enteric coatings. These coatings are applied to tablets or cap- sules to delay release: The coatings remain intact in the stomach but dis- sociate and release the contents of the drug product in the small intes- tine. Their prime purpose is to delay the release of the active pharmaceuti- cal ingredient (API), which may be inactivated in the stomach or cause irritation of the gastric mucosa. Commonly used enteric polymers include cellulose acetate phthalate (CAP), CAP aqueous dispersion, hypromellose phthalate (HPMCP), i-EOE_38-45_Masters 4/3/14 2:58 PM Page 39

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