The successful development of the drug begins with a thorough understanding of chemical reactions, in our work we focused on knowledge of breakup mechanisms and modelling of the reaction rates and activation energies of the decay of active substances (ZU), which are used to treat cold diseases and are ingested in the form of a beverage. Prior to the planning of the experimental work, we carried out a review of the stability test guidelines and the prescribed instructions for the use of currently available medicines on the market for the treatment of cold diseases, which are in the form of powder, granules or effervesced tablets for the preparation of beverages. As part of my master's thesis, we studied the stability of reconstituted solutions of the following products: medicine A (ZU acetylcysteine), B (ZU paracetamol and phenylephrine), C (ZU paracetamol and ascorbic acid) and medicine D (ZU acetylsalicylic acid). Reconstituted solutions were prepared by following the instructions for use, exposed to different temperatures. Solutions were monitored on different responses depending on time and temperature. We observed changes in appearance, pH, ZU content and degradation content. Our main goal was to determine the stability of prepared beverages for the treatment of cold and to determine how long after the beverage preparation, the solution still complies to the strictest quality guidelines. In the first hypothesis we assumed, that the most critical and thus decisive parameter in terms of stability of prepared solutions will be the increase in degradation products. Another hypothesis assumed that a higher temperature of the beverage leads to a worse stability.
The experiments were designed as worst-case scenarios for stability evaluation, thus setting the shortest shelf life for reconstituted solutions. The stability conditions were created by maintaining a constant temperature for sample solutions during the stability evaluation and monitoring responses at different time points. We observed that when exposed to prepared reconstituted solutions/suspensions at higher temperatures depending on the time, all the preparations tested result in a decrease in the content of the active substances and the occurrence of a higher number and higher level of degradation products. By varying temperature conditions, especially with longer exposure time, we obtained different levels of degradation products and ZU content, thus gaining a comprehensive set of data for the need of modelling of the course of chemical reactions. Based on the experimental data obtained, we have built reaction models using the Berkeley Madonna program to confirm our hypothesis that the compliance of prepared beverages with the criteria depends mainly on the increase in degradation products and that the higher temperature of the beverage leads to a shorter period of use of the reconstituted beverage. However, the ZU content has also been shown to be a critical parameter for determining stability after reconstitution. Particularly for medicine D, where the increase of salicylic acid as well as the drop in acetylsalicylic acid content are the most stability-in-point parameters determining the shelf-life of the reconstituted preparation. Based on the ICH Q3B criteria, we predicted the shelf life of the reconstituted solution if it is prepared at room temperature. Of the products tested, the reconstituted solution is the longest stable in the case of medicine A, where the shelf-life of 11,7 hours after the beverage is prepared defines the increase of unknown impurities. The following is medicine C (5 hours), whereas the increase in the PAR-3-hydroxy impurity content is a parameter defining stability. This is followed by medicine B, where we predict stability up to 4,3 hours after the preparation of the beverage based on the increase of PAR-3-hydroxy impurity. Finally, medicine D, which is projected to be stable 150 minutes after the beverage preparation, as the content of the rapidly emerging degradation product salicylic acid and decrease of acetylsalicylic acid content both define the shelf life.
The conclusions we reached prove that it is also possible to explain more complex degradation mechanisms. The main key in understanding the subject is an in-depth understanding of the degradation mechanisms, an appropriate design for the implementation of the experimental tested and the knowledge of modelling equations of the speed of degradation reactions. Our findings could be further deepened by continuing research, such as how stability is affected by exposure to different pH values if the solution is not prepared in water, but in another drink (e.g. orange juice).
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