Estudi de compatibilitat i estabilitat química de mescles intravenoses per analgèsia multimodal en mostres Viaflo® mitjançant UHPLC-DAD


Marcé Briansó, Mireia


Multimodal analgesia is characterized by combining different types of drugs that present different mechanisms of action and, thanks to their combination, it is possible to reduce postoperative pain in patients.
The main objective of this project is to study the physical and chemical stability of the postoperative multimodal analgesia mixtures used by the Hospital Clínic de Barcelona. The Hospital Pharmacy Service is interested in optimizing its preparation to be able to create product stocks in periods of less workload. Specifically, the Hospital has studied the physical stability of analgesia mixtures through a change in color, turbidity, pH and the formation of possible precipitates. While the Chemical Institute of Sarrià (IQS) has studied chemical stability using liquid chromatography (UHPLC-DAD) and establishing as a stability criterion a variation of no greater than 90 - 110% of the initial concentration of drugs.
The drugs that are used to make the combinations of the mixtures and that, therefore, are the object of study in this work are the following: Ketamine, Methadone, Tramadol, Ketorolac and Dexketoprofen. These mixtures are prepared in physiological saline. The stability of analgesia mixtures is studied in different periods of time and storage temperature: room temperature (22 - 25 ° C: 0 hours, 24 hours and 48 hours) and temperature with refrigeration in a refrigerator (2 - 8 ° C: 0 days, 7 days, 15 days and 30 days). This study works with two reverse phase columns (HSS and BEH ligand C18) with two mobile phases of different pH (acid and slightly basic) in order to: (i) confirm the results obtained with both; (ii) ensure that if an impurity is overlapped by a drug in one chromatographic method, it can be determined with the second. Regarding the chromatographic method, a gradient is performed with acetonitrile and Milli-Q water. An acidic aqueous phase is also used for the HSS column (HCOONH4 / HCOOH) and a slightly basic aqueous phase for the BEH column (HCOONH4 / NH3).To achieve the objective, first, a design is developed to perform the quantitative analysis of the samples quickly, agile and efficient. Then, from a study of stability of the standards, it is determined that the standards remain stable for up to 15 days from their preparation and that the best storage site is the injection tray of the equipment (10 ± 5 oC). It is also concluded that the excipients present in the commercial solutions of the drugs used by the Hospital do not represent an interference due to the stability study.
In addition, a chemical stability study design is carried out with the corresponding schedule and parameters to verify that the analytical method is reliable and robust.
Lastly, the four multimodal analgesia mixtures used by the Hospital (Viaflo® 1, Viaflo® 2, Viaflo® 3 and Viaflo® 4) are chemically stable when stored at room temperature for up to 48 hours and refrigerated (refrigerator) for up to 48 hours. 30 days, since they meet the acceptance criteria established 90 - 110%. In addition, the samples did not show impurities greater than 0.12% with respect to the Tramadol peak. During the chemical stability study, new impurities are detected in the analgesia samples. The highest impurity is not higher than: 0.04% with respect to Tramadol, 0.05% with respect to Dexketoprofen, 0.98% with respect to Ketamine and 2.25% with respect to Methadone.
Finally, the active principle with more impurities (Dexketoprofen) is individually scanned using UHPLC-MS / Q-TOF and an impurity is detected at minute 7.68 that could be compatible with impurity D of the European Pharmacopoeia.



Báguena Polo, Judith
Broto Puig, Francesc


IQS SE - Master’s Degree in Analytical Chemistry