Use of Enzymes in the Dissolution Testing of Gelatin Capsules and Gelatin-Coated Tablets-Revisions to Dissolution <711> and Disintegration and Dissolution of Dietary Supplements <2040>

Abstract

A revision to the general chapters Dissolution <711> and Disintegration and Dissolution of Dietary Supplements <2040> is being proposed to address the shortcomings of the current chapters regarding the use of enzymes in the dissolution test of gelatin capsules or gelatin-coated tablets. The recommendations are to use the enzymes pepsin (medium with pH equal to or below 4.0), papain or bromelain (medium with pH above 4.0 and below 6.8), and pancreatin (medium with pH equal to or above 6.8) if the dosage form does not comply to the appropriate Acceptance Table or, in the case of dietary supplements, appropriate Tolerances requirements due to the presence of cross-linking in the gelatin. Also, the revision clarifies how the enzyme activity should be determined, the amount of enzymes to be added to the medium, and a pre-treatment procedure to be used when the dissolution medium contains surfactant or any other ingredient known or suspect to inactivate the enzyme being used. This Stimuli article provides the rationale for these revisions and presents data to support the recommendations being made. Readers are encouraged to send any comments, questions, suggestions or data to the corresponding author. Also, see the section Other Related Revisions at the end of this article for information on other related general chapters and monographs.

Dissolution of Gelatin Capsules: Evidence and Confirmation of Cross-Linking

“…Pictures can be taken at specific time points to see the disintegration of the dosage form, dispersion of particulates, and gelatin cross-linking effects. Figure 2 (a) and (b) shows pellicles from cross-linked gelatin capsules in USP apparatus 1 and 2 (3,44). The capsules are hydrated and swollen but not ruptured.…”

“…Since these two enzymes are not found in the human body, their application is not intended to mimic any in vivo behavior. Both enzymes can effectively digest the cross-linked gelatin in dissolution media in the pH range from 4 to 7 (3,(43)(44).…”

“…Instrumental techniques such as various spectroscopies have been applied to evaluate gelatin cross-linking (3,29). These spectroscopic techniques include NMR, UV, fluorescence spectrophotometry (FS), near infrared (NIR), and Fourier transform-infrared (FT-IR).…”

“…Under alkaline conditions (i.e., pH 7.2 and 13.0), when a 6% solution of gelatin in water is treated with 2000 ppm or 100 ppm 13 C-enriched formaldehyde, the unprotonated ɛ-amino functional group in lysine and the guanidine functional group in arginine reacted with the formaldehyde resulting in cross-linking. 3 C-NMR spectra were obtained by using a Varian VXR-300 spectrometer, which showed peaks representing methylols of arginine and lysine as well as a methylene cross-link between arginine and lysine (see Figure 7). However, the lysine-arginine cross-linking was not detected when gelatin was exposed to formaldehyde at pH 2.0 under identical conditions.…”

“…The USP General Chapters Dissolution <711> (1) and Disintegration and Dissolution of Dietary Supplements <2040> (2) allow the addition of enzymes to the dissolution medium when the dosage forms do not conform to the dissolution acceptance criteria due to gelatin cross-linking. Recent revisions in these two USP chapters (which became official on May 1, 2016) further addressed current challenges regarding enzyme use in the dissolution medium and provided new recommendations to overcome the challenges associated with the use of enzymes (3). The recommendations covered three aspects.…”