Effect of Empty Hard Gelatin Capsule Shell Cross-Linking on Dissolution

Capsules are widely used in the pharmaceutical industry due to their simple preparation process and easy swallowing. However, when aldehydes are present or exposed to high temperature, high humidity and other conditions, gelatin capsules will undergo cross-linking, making the capsules insoluble in water, resulting in reduced in vitro dissolution results. Wecaps will share with you the effects of cross-linking of empty and hard gelatin capsule shells on dissolution and countermeasures.

The Principle and Reason of Gelatin Cross-Linking

Gelatin can be obtained from animal bones and skins and contains 4.1% lysine and 8.5% arginine. The reactivity of gelatin molecules comes from the amino acids it contains, and lysine is the key factor in its cross-linking reaction. The water exchange between the capsule shell and the contents may make the capsule shell brittle, and the chemical reaction between the contents and the capsule shell and the capsule shell and the external environment may cause the cross-linking of the capsule shell.

The strongest and most common type of crosslinking is the formation of a covalent bond between the amine group on the lysine branch of the gel and the similar amine group on another molecule. The reaction is usually catalyzed by a small amount of reactive aldehydes, such as formaldehyde and glutaric acid. Aldehydes, glyoxal and degraded sugars are common catalysts. This reaction is irreversible.

If the capsule shell is to be dissolved, it will involve the destruction of other bonds. For example, enzymatic hydrolysis will destroy the peptide bonds in the protein. It has been proposed that adding succinic acid groups to the side chains of lysine can reduce or even prevent the cross-linking reaction of gelatin. Another way to reduce this type of cross-linking reaction is the complexation reaction between the two free carboxyl groups and trivalent metal ions in the two gel molecules.

Common Causes of Cross-Linking inEmpty Hard Gelatin Capsule Shells

1.During storage, APIs, auxiliary materials, packaging materials, and degradation products contain aldehydes;

2.Store in high humidity conditions;

3.Some substances that promote the cross-linking reaction appear;

4.The stabilizer (cyclohexamethylenetetramine) in corn starch degrades to form ammonia and formaldehyde;

5.Man-made fiber bottle containing aldehyde functional group (furfural);

6.Polyethylene glycol that can automatically oxidize to form aldehydes;

7.Ultraviolet light, especially under high temperature and humidity conditions;

8. Thermal energy catalyzes the formation of aldehydes.

Phenomenon Caused by Cross-Linking

Cross-linking will form a film on both sides of the capsule shell. This transparent film is a water-insoluble protein, which will cause the contents of the capsule to dissolve slowly or even insoluble. One of the phenomena of cross-linking of the capsule shell is during dissolution. A film or gel-like mass can be observed.

Once the capsule shell is cross-linked, the cross-linking will not be terminated even if the substance causing the cross-linking is removed. The capsule with the liquid content will rupture at the seam, leading to the early release of the content. Since the degree of crosslinking is different between different capsule shells and even at different positions on the same capsule, this will lead to an increase in the difference in dissolution.

Non-gelatin capsules will not produce capsule shell cross-linking, so modified corn starch, potato starch, pea starch, and modified cellulose such as hypromellose can also be used to make medicinal capsule shells, but these capsule shells are more The dissolution time of the gelatin capsule shell is slightly longer.

Cross-Linking of Gelatin Capsules and Dissolution of Preparations

According to the degree of cross-linking of the capsule shell, the cross-linking of the capsule shell is divided into moderate cross-linking and deep cross-linking. The study found that the capsule shells with moderate crosslinking and deep crosslinking and the capsule shells without crosslinking were filled with the same content and compared the release in vivo and in vitro. It is found that the dissolution of moderately cross-linked capsule shells in water and simulated gastric juice cannot meet the requirements, but the dissolution in artificial gastric juice with enzymes can meet the requirements; the dissolution of deeply cross-linked capsule shells in water and simulated gastric juice cannot meet the requirements. The dissolution in the artificial gastric juice is also not up to the requirement. In vivo studies have found that the moderately crosslinked capsules are bioequivalent to the uncrosslinked capsules, while the deeply crosslinked capsules and the uncrosslinked capsules are not bioequivalent. Therefore, when the dissolution of gelatin capsules in water or other media does not meet the requirements due to cross-linking, enzymes can be added to the media for in vitro dissolution comparison.

USP stipulates that for gelatin capsules or gelatin-coated tablets, when the dissolution rate does not meet the requirements, it is necessary to retest after adding enzymes in the dissolution medium. For the specific preparation method of each dissolution medium, see each monograph. When the dissolution medium is water or the pH value of the dissolution medium is less than 6.8, pure pepsin can be added, with no more than 750,000 active units per 1000ml; when the pH value of the dissolution medium is greater than 6.8 , Trypsin can be added, no more than 1750 active units per 1000ml. However, studies have shown that pepsin has good activity below pH 4.0, and there is almost no activity when the pH value is greater than 5.5. Therefore, papain and bromelain can be selected when the pH is 4.0-6.8. Papain is a protease isolated from the latex of papaya leaves and green fruits. It is almost completely soluble in water. The optimal pH of papain is 4.0~7.0. Bromelain is a general term for proteolytic enzymes found in bromeliaceae. Bromelain, which is extracted from pineapple, is widely used commercially. It is easily soluble in water and has an optimum pH range of about 4.5 to 7.5.

When the capsule contains a surfactant, the surfactant may react with the capsule shell to hinder the disintegration and dissolution of the capsule, and may also inactivate the enzyme added to the dissolution medium. In this case, pretreatment, that is, the stepwise addition of enzymes and surfactants can be adopted. First dissolve the cross-linked capsule shell with a dissolution medium containing some enzymes (generally no more than 15 minutes), and then add a dissolution medium containing a surfactant to improve the dissolution of the drug.

During the dissolution process of gelatin-containing dosage forms, it is necessary to evaluate and determine whether there is cross-linking of gelatin. When enzymes are added to the dissolution medium, in addition to the general parameters for verification (filters, sinkers, degassing, specificity, linearity, accuracy, precision, etc.), the selection of enzymes and the identification of activities should also be evaluated. Do you need pretreatment and pretreatment methods (selection of enzymes, volume of pretreatment dissolution media, pretreatment time, etc.), etc.