The cross-linking reaction refers to a reaction in which two or more molecules (generally linear molecules) are bonded to each other to form a relatively stable molecule (body-shaped molecule) of a network structure. The cross-linking phenomenon of gelatin capsules indicates that the gel capsules change with time, and a film is formed on both inner and outer sides of the capsule shell. This transparent film is a water-insoluble protein which causes the disintegration, and dissolution (or release) of the content of capsule in the enzyme-free artificial gastric juice be significantly reduced or not completely collapsed.
This cross-linking reaction mainly occurs in two aspects. One is that the gelatin itself undergoes a cross-linking reaction: lysine and side chain amino group of arginine → oxidation → aldehyde group + amino group → amine acetal reaction → cross-linking. The second is the cross-linking reaction between the drug and the aldehyde-containing substance (drug, auxiliary material): lysine, arginine amino residue + aldehyde group → amine acetal reaction → cross-linking.
Factors affecting the cross-linking of capsules:
- Capsule shell prescription factor
Choice of gelatin: The degree of cross-linking is related to the content of amino acid residues in gelatin.
The water content of the capsule: 1. Accelerated oxidation of gelatin; 2. Increased formation of imine intermediates.
Plasticizers: glycerin, sorbitol, etc. will increase the auto-oxidation of gelatin.
Sunscreens and colorants: Inducing the production of low molecular aldehydes.
Drugs and additives containing aldehyde groups, preservatives, fatty substances, polyoxyethylene compounds, etc., may affect the crosslinking of the capsules.
- Storage conditions (temperature, humidity, light)
Studies have shown that high temperatures lead to a significant increase in the degree of crosslinking. In the presence of moisture, heat and air, lysine in gelatin can be reacted in multiple steps with aldehydes.
Ways to weaken cross-linking:
- 1. Reduce the amount of plasticizers, sunscreens and pigments in the capsule shell.
- 2. Add antioxidants (such as glycine, sodium metabisulfite, etc.)
- 3. If the contents are aldehyde-containing drugs, they are subjected to inclusion treatment.
- 4. Reduce the amount of additives that are easily oxidized.
- 5. When storing the capsule, choose the place with low temperature and low humidity and keep it away from light.