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

Abstract

Cross-linking is a common problem in the dissolution of gelatin capsules. Cross-linking is characterized by a bridge across the peptide backbone of the gelatin molecule which creates water insoluble membranes or pellicles during dissolution testing. The chemical covalent bonding between gelatin chains is typically triggered by catalytic amounts of aldehyde and/or from exposure to high temperature and humidity. Cross-linking gelatin capsules results in a slower release of the drug or no release at all in common dissolution media. If the gelatin capsule dissolution fails acceptance criteria due to evidence of cross-linking, the US Pharmacopeia allows the use of enzymes in the dissolution medium and requires twotier dissolution testing. Studies have shown that drugs from cross-linked capsules are available in vivo to the patient, justifying the use of enzymes in the in vitro dissolution test. The literature contains several examples supporting evidence of cross-linking. However, confirming the degree of cross-linking continues to be a practical challenge due to a lack of quantitative procedures for measuring the extent of cross-linking and variability in options for formulations, excipients, level and types of stresses, and the experience level of the analysts. This article reviews the methodologies to confirm the evidence of cross-linking such as visual observation, capsule shell switch test, and spectroscopic determination of cross-linking, with an aim to facilitate the discussion and establishment of an acceptable standard approach.

Self-emulsifying drug delivery systems and the application in drugs and cosmetics

“…i) Tương tác hóa học giữa các thành phần dịch nhân với vỏ nang Vỏ nang mềm thường chứa chủ yếu là gelatin nên có thể xảy ra hiện tượng liên kết chéo (crosslinking) dưới tác động của các thành phần trong dịch nhân khiến vỏ nang trở nên khó rã hơn theo thời gian, ngăn cản sự giải phóng dịch nang và ảnh hưởng đến độ hòa tan của viên [45][46][47][48]. Các nguyên nhân phổ biến gây ra hiện tượng liên kết chéo: aldehyd có trong các thành phần hoạt chất, tá dược, vật liệu đóng gói hoặc chất chuyển hóa được hình thành tại chỗ trong quá trình bảo quản; độ ẩm cao, nhiệt độ có thể xúc tác cho sự hình thành aldehyd; ánh sáng, đặc biệt là trong điều kiện nhiệt độ cao và độ ẩm, dịch thuốc đóng nang có chứa polyethylen glycol có thể tự động oxy hóa để tạo thành aldehyd [49];…”

Challenges of Dissolution Methods Development for Soft Gelatin Capsules

“…There are several reports of decreased dissolution rates of the SGCs attributed to the cross-linking of gelatin ( Figure 10). Cross-linking of hard and SGCs is well-described in the literature [43,128,142], and it must be addressed during the development of SGCs because it can affect the release properties of the finished drug product. Several methods can be used to assess the cross-linking of these formulations, and one of them is by the observation of pellicles where the gelatin shell swells, becomes rubbery, and is insoluble in water.…”

Novel biopharmaceutical development investigations towards drug and formulation performance optimization

“…Cross-linking can cause slower drug release from the gelatin capsule or even no release altogether. Several examples of crosslinking are reported in the literature (125,(204)(205)(206).…”