Cilostazol is a commonly used active pharmaceutical ingredient (API) to treat and reduce the symptoms of intermittent claudication in peripheral vascular disease. Recently, it was found to be a potential medicine in the effective treatment of COVID-19. In addition to the positive effects of this API, genotoxic sodium azide is used in the synthesis of cilostazol that can appear in the API. In this work, a method was developed for the determination of sodium azide (as azide anion) in cilostazol API at 7.5 ppm limit level by using ion chromatography (IC) and liquid–liquid extraction (LLE) sample preparation. The liquid–liquid extraction allows the application of high sample concentrations. Because of the low limit concentration (7.5 ppm), 500 mg sample was dissolved in 5 mL solvent. By using LLE for sample preparation, the huge amount of cilostazol was omitted and column overload was avoided. The developed method was validated in accordance with the relevant guidelines. Specificity, accuracy, precision, limit of detection and limit of quantification parameters were evaluated. The calculated limit of detection was 0.52 ppm (S/N:3) and the limit of quantification was 1.73 ppm (S/N:10) for sodium azide. The recovery of the sodium azide was 102.4% and the prepared solutions were stable in the sample holder for 24 h.

Product safety is important for medicines. For drugs on the market, it must be demonstrated that the levels of toxic contaminants are below the permitted limits. These impurities are used as reagents or are generated during synthesis. N-bromosuccinimide is used as a brominating agent in the synthesis of some active pharmaceutical ingredients. The determination of N-bromosuccinimide is difficult due to its high reactivity. In this work, a high-performance ion chromatographic method was developed for the determination of N-bromosuccinimide. The ion chromatographic measurement can be performed in two ways, one involves the assay of the resulting bromide ion and the other is via the assay of the 3-carbamoyl propanoic acid ion produced from the succinimide. Both acid ions were analyzed on an anion exchange column by gradient elution with potassium hydroxide eluent and detection was performed by a suppressed conductivity detector. During the method development, the results showed that the measurement of bromide ion was more selective than the measurement of 3-carbamoyl propanoic acid ion. Two different types of active pharmaceutical ingredients (API), i.e., prasugrel and favipiravir, were chosen to test the developed method and sample preparation. For both APIs, sample preparation was performed in a vial and consists of liquid–liquid extraction with an alkaline reagent. Finally, the anion exchange ion chromatography method was validated at the limit value level, and harmonized with the guidelines. For prasugrel, the quantification limits and the accuracy at the limit level are 7.2 ppm and 96.4%, while for favipiravir these are 7.5 ppm and 114.7%, respectively.

Összefoglalás. Gyógyszermolekulák kémiai szintézissel történő előállítása során előfordulhat, hogy a szintézisút toxikus vegyületeket tartalmaz, vagy szintézis során képződik toxikus melléktermék. Ezeket az anyagokat alacsony koncentrációszinten kell kizárni a gyártott végtermékben, hogy az adott hatóanyag törzskönyvezése sikeres legyen. Így a genotoxikus (megváltoztatja a DNS által tárolt genetikai információt), rákkeltő szennyezők analitikai kontrollja folyamatos kihívás elé állítja az analitikusokat. Erre a vizsgálatra a legelterjedtebb módszer a nagyhatékonyságú folyadékkromatográfia. Ennek egyik speciális változata, a nagyhatékonyságú ionkromatográfia alkalmas a kis méretű ionos vagy ionizálható molekulák, pl. szervetlen anionok és kationok, szerves savak, aminok, valamint hidrolizálható vegyületek vizsgálatára. A kéziratban bemutatásra kerül a nagyhatékonyságú ionkromatográfiás technika, valamint annak gyógyszeranalitikai alkalmazása. Summary. In the production of drug molecules, the synthesis pathway may contain toxic compounds, or a toxic by-product may be formed during synthesis. These substances must be excluded at low concentration levels in the final manufactured product in order for the registration of the active substance to be successful. The drug analytics task to quantify these contaminations. This part of the pharmaceutical industry involves a wide spectrum of analytical techniques, which together complement each other to give a complete picture of the product being manufactured. Measurement techniques range from titration to large instrumentation (mass spectrometry, nuclear magnetic resonance spectrometry). Chromatography is one of the most widely used techniques. Lots of pollutant which must have quantified, have polar properties and its may present a risk for patients. The analytical control of genotoxic (altering the genetic information stored in DNA), carcinogenic contaminants is a constant challenge for analysts. Organic acids, amines, acid chlorides which are easily ionizable, hydrolysable are difficult to analyze at low concentration limits by the means of gas chromatography or high performance liquid chromatography. For the analysis of such contaminants, the high performance ion exchange chromatography method is a possible solution. In drug analytics, the ion chromatography techniques (ion exchange, ion exclusion, ion pair, ligand exchange) are not as widely used as the other liquid chromatography methods. In addition to inorganic anions and cations, ion chromatography is a suitable chromatographic method for the analysis of organic acids, amines, and hydrolysable compounds. In case of amines, this technique has better peak symmetry and theoretical plate height than gas chromatography. However, additional acidic API may cause the disappearance of these peaks. With this instrument, not only impurities can be tested, but also the counter ions of basic drug substances can be easily measured to verify the molecular composition of the active pharmaceutical ingredient. The manuscript describes the applications of ion exchange chromatography through some examples from pharmaceutical industry. In some cases, the methods have been validated according to international guidelines to demonstrate the applicability of high-performance ion exchange chromatography for the analysis of ionizable organic/inorganic compounds in pharmaceutical production.