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64 January 2015 Tablets & Capsules Gelatin capsules are a popular dosage form because they are simple to use in formulating and manufac - turing drug products from powders, granules, pellets, liquids, semisolids, and suspensions, even at elevated tem - peratures. Capsules are also easy to swallow and effectively mask odors and the bitter taste of APIs [1]. They are also used to mask (blind) products being compared in clinical trials. Gelatin can cross-link in the pre - sence of certain compounds such as aldehydes, or when exposed to high humidity or temperature. Cross- linked gelatin is insoluble in aqueous solvents. Depending on the degree of cross-linking, it may not present a problem in vivo, but it will pose a problem during in vitro dissolution testing of gelatin capsules. The easiest way to confirm the presence of cross- linking in gelatin capsules is by visual observation: A thin, insol uble mem - brane or gelatinous mass can be seen during dissolution test ing. This insoluble membrane prevents the capsule from releasing its contents. Avoiding or minimizing cross-linking requires formulators to properly characterize and select excipients, the API, and packaging materials. All should be free of or contain very little aldehye, and none should produce aldehydes during storage. Follow the storage recommendations of the gelatin capsule manufacturer to re - duce the chance of the gelatin be - coming cross-linked. In the early 1990s, a group of experts was formed to study non - compliance of gelatin capsule pro - ducts during in vitro dissolution and to assess the potential for changes in bioavailability. The group—a joint effort of the FDA's Center for Drug Evaluation and Research, pharma - ceutical trade associations, gelatin capsule manufacturers, the US Pharm - a copeia (USP), and academia—de - veloped a protocol using differentially stressed hard and soft gelatin capsules to determine the correlation between in vitro and in vivo performance. The results indicated bio equiv - alence of moderately stressed and unstressed capsules, whereas over - stressed capsules failed to demon - strate bioequivalence. In vitro disso - lution testing was conducted to de termine the proper amounts of enzyme that would allow bioequi - valent capsules to pass both tiers of the dissolution test, while ensuring that bioinequivalent capsules would fail. From the results of these studies, USP established how much enzyme could be added to the dissolution medium in the case of test failure due to cross-linking. This two-tier dis - solution testing appeared in the first supplement of USP 24. It states that pepsin is added to acidic media; for media at or above pH 6.8, water and pancreatin is added in the amounts specified in the USP general chapter <711> "Dissolution" [2]. While pepsin shows good proteo - lytic activity up to pH 4, it has al most no protease activity above pH 5.5. Pancreatin shows good proteo lytic activity in the pH range of 6 to 8. As a consequence, there is a need to use appropriate proteases with dissolution media whose pH range from 4 to 6.8. Papain and bromelain were identified as potential candidates. Preliminary studies showed that papain in the amount of 500,000 units per liter, and bromelain in the amount of 30 gelatin-digesting units, or GDU, per liter are appropriate to digest moderately cross-linked gelatin capsules during dissolution testing. For dissolution media that contain surfactants or other com - pounds that could inactivate the en - zyme, the cross-linked gelatin cap - sules may require pre-treatment in the media [3]. A revision to the USP general chap - ter <711> "Dissolution" was published in Pharmacopeial Forum 40(6), and USP has proposed the use of these two new proteases and the pre-treatment step. The deadline for comments and suggestions regarding this revision is January 31, 2015. T&C References 1. Marques M.R.C., Cole E., Kruep D., Gray V., Murachanian D., Brown W.E., and Giancaspro G.I. Liquid-filled gelatin capsules. Pharm Forum 2009;35(4). 2. Marques M.R.C. Enzymes in the dissolution testing of gelatin capsules. AAPS PharmSciTech 2014;15(6): 1410-6. 3. Gray V.A., Cole E., Toma J.M.D.R., Guidorsi L., Guo J.H., Han J.H., et al. Use of enzymes in the dissolution testing of gelatin capsules and gelatin-coated tablets—revisions to "Dissolution" <711> and "Disin - tegration and Dissolution of Dietary Supplements" <2040>. Pharm Forum 2014;40(6). [Editor's note: To comment on the Back Page, visit www.tabletscapsules. com.] Margareth R. C. Mar- ques, Ph.D., is principal scientific liaison at the US Pharmacopeia, 12601 Twinbrook Park- way, Rockville, MD 20852. Tel. 301 816 8106. E-mail: mrm@usp.org. Website: www.usppf.com. b a c k p a g e Gelatin capsules and dissolution