Gelatin is widely used material in many pharmaceutical formulations due to its many positive mechanical and technological properties. Use of gelatin is problematic because of its reactivity, which leads to formation of strong covalent bonds between amino groups on the polymer chain and results in a cross-linked polymer with altered characteristics. Molecule of cross-linked gelatin has changed structure, is less hydrofillic and has higher molecular mass. Dosage forms, which contain gelatin in the outer layer, for example hard an soft gelatin capsules and gelatin coated tablets, are especially proned to change of quality due to altered characteristics of cross-linked gelatin.
In this master’s degree we were researching and evaluating effect of formaldehyde on the characteristics of hard gelatin capsules. In the first part of research work hard gelatin capsules were exposed to formaldehyde atmosphere at elevated temperature for different time periods. As a result we got different extent of cross-linked gelatin capsules. In order to exclude possible effects of elevated temperature and presence of the solvent on the results we have performed control experiments. In the second part of research work hard gelatin capsules were filled with excipients, which during degradation process produce formaldehyde in situ. We used excipients hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG). Content of formaldehyde in excipients was experimentally determined by HPLC method. On stressed hard gelatin capsules we performed gravimetric determination of insoluble residue, dissolution tests and recorded their FT-IR spectra.
We have followed kinetics of crosslinking reaction by gravimetric determination of insoluble residue from which we found the rate of reaction is determined by concentration of formaldehyde. We observed an increase in mass of insoluble residue when capsules were exposed to formaldehyde for longer time periods of time. By analyzing FT-IR spectra we could not distinguish between specters of cross-linked and uncross-linked capsules. After chemometric treatment of the specters with PCA software, we observed that with longer exposure of the capsules to formaldehyde one of the principal components was diminishing. During dissolution testing formaldehyde stressed capsules showed changed dissolution profiles. Capsules, which were exposed to formaldehyde atmosphere for longer time periods, showed slower drug release and had higher coefficient of variation. In comparison to unstressed capsules, capsules filled with HPMC and PEG had higher mass of insoluble residue and slowed down drug release at dissolution testing. Practice showed that the best method for detection of cross-linking in hard gelatin capsules is dissolution test.
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