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Marija Čarapić Medicines and Medical Devices Agency of Serbia, Vojvode Stepe 458, 11000, Belgrade, Serbia

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Bojan Marković Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, PO Box 146,11000 Belgrade, Serbia

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Milena Pavlovic Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, PO Box 146,11000 Belgrade, Serbia

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Danica Agbaba Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, PO Box 146,11000 Belgrade, Serbia

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Katarina Nikolic Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, PO Box 146,11000 Belgrade, Serbia

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https://orcid.org/0000-0002-3656-9245
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Abstract

Ziprasidone is the second generation antipsychotic drug with unique multipotent G-protein-coupled (GPCR) receptor binding profile. Since ziprasidone is a highly lipophilic and unstable compound, development of efficient method for a concurrent assay of ziprasidone and its main impurities was a very challenging task.

The UHPLC-MS/MS method that we developed for simultaneous determination of ziprasidone and its main impurities (BITP, Chloroethyl-chloroindolinone, Zip-oxide, Zip-dimer, and Zip-BIT) was compared with some other related HPLC-UV methods of our own and other authorship. An increase of the mobile phase pH value from 2.5 to 4.7 units in the examined analytical methods influenced elution order of the investigated compounds. It was found out that the UHPLC-MS/MS method is more selective and sensitive than the earlier developed HPLC-UV method. Similar to our earlier HPLC-UV method, the UHPLC-MS/MS method is linear with a correlation coefficient (r) above 0.99 for all the analysed compounds, but with a negligibly lower precision and accuracy. Finally, with shorter analysis time, smaller column size and reduction of solvent consumption, UHPLC-MS/MS is assumed as a greener method than HPLC-UV for the ziprasidone purity assay.

After transfer of the UHPLC-MS/MS method to the UHPLC-DAD system, suitability of the UHPLC-DAD method for routine control of ziprasidone and its main impurities is examined and confirmed based on the retained good selectivity, resolution and short analysis time.

Abstract

Ziprasidone is the second generation antipsychotic drug with unique multipotent G-protein-coupled (GPCR) receptor binding profile. Since ziprasidone is a highly lipophilic and unstable compound, development of efficient method for a concurrent assay of ziprasidone and its main impurities was a very challenging task.

The UHPLC-MS/MS method that we developed for simultaneous determination of ziprasidone and its main impurities (BITP, Chloroethyl-chloroindolinone, Zip-oxide, Zip-dimer, and Zip-BIT) was compared with some other related HPLC-UV methods of our own and other authorship. An increase of the mobile phase pH value from 2.5 to 4.7 units in the examined analytical methods influenced elution order of the investigated compounds. It was found out that the UHPLC-MS/MS method is more selective and sensitive than the earlier developed HPLC-UV method. Similar to our earlier HPLC-UV method, the UHPLC-MS/MS method is linear with a correlation coefficient (r) above 0.99 for all the analysed compounds, but with a negligibly lower precision and accuracy. Finally, with shorter analysis time, smaller column size and reduction of solvent consumption, UHPLC-MS/MS is assumed as a greener method than HPLC-UV for the ziprasidone purity assay.

After transfer of the UHPLC-MS/MS method to the UHPLC-DAD system, suitability of the UHPLC-DAD method for routine control of ziprasidone and its main impurities is examined and confirmed based on the retained good selectivity, resolution and short analysis time.

Introduction

Ziprasidone (Fig. 1.), which is the benzisothiazolpiperazinyl (BITP) derivative, is an atypical (second-generation) antipsychotic drug, which has a unique G protein coupled receptor (GPCR) binding profile [1]. Ziprasidone has very high affinity to the 5HT2A and 5HT2C receptors and to the 5HT1B, 5HT1D, 5HT7, α1B, D2, D3 sites, and a moderate affinity to the 5HT1A, 5HT2B, 5HT5, 5HT6, α1A, α2A, α2B, α2C, D1, D4 and H1 receptors. Its indication is for treatment of positive, negative and affective symptoms of schizophrenia, with a relatively low incidence of extrapyramidal side effects [2]. Furthermore, ziprasidone inhibits neuronal uptake of serotonin and norepinephrine in the way comparable to some antidepressants [3]. Recent investigation demonstrates that ziprasidone exerts a neuroprotective action and it could be effective in prevention of mitochondrial dysfunction and oxidative stress in schizophrenia [4]. Until now, multipotent mechanism of the ziprasidone action and the complex therapeutic effects have not been clearly elucidated [5].

Fig. 1.
Fig. 1.

Chemical structures of ziprasidone and its main impurities

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01060

Since ziprasidone is one of the most lipophilic antipsychotics with high incidence of photodegradation and tautomerisation, development of efficient analytical method for simultaneous determination of ziprasidone and its main impurities is a very challenging task. Several methods have been developed for therapeutic monitoring of ziprasidone and for pharmacokinetic studies in biological (both human and animal) samples such, as voltammetry [6], high performance liquid chromatography (HPLC) with the ultraviolet (UV) [7–9] and fluorescence detection [10], and HPLC with monitoring of radioactivity for investigation of the primary oxidative metabolites [11]. Determination of ziprasidone by means of HPLC with the single and tandem MS detection was performed mainly in biological samples, either alone, or in combination with the other CNS drugs [12–20]. Quantitative determination of ziprasidone in raw materials and pharmaceuticals was performed by spectrophotometry [21], high performance thin layer chromatography (HPTLC) [22], thin-layer chromatography (TLC) [23], capillary electrophoresis (CE) [24], HPLC with UV detection [25–27] and ultra high performance liquid chromatography (UHPLC) with UV detection [28].

Although ziprasidone has been on the market for over twenty years now, still a limited number of studies is reported on investigation and quantification of the ziprasidone purity profile in raw materials and pharmaceuticals. There also is an increasing need in pharmaceutical analysis for development of fast and ultra-fast methods with good separation efficiency, in order to contribute to the quality control of ziprasidone, for which the impurity profile is a critical attribute, as impurities can affect drug quality, efficacy and safety. Two UHPLC methods with the UV detection are available for determination of some ziprasidone impurities [29, 30], but none of them covers a whole set of the investigated compounds (BITP (3-(1-piperazinyl)-1,2-benzisothiazole), Chloroethyl-chloroindolinone (6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one) and BITP, Zip-oxide (5-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2,3-dione), Zip-dimer (5,5′-bis[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6,6′-dichloro-1,1′,3,3′-tetrahydro-3-hydroxy-[3,3′-bi-2H-indole]-2,2′-dione), Zip-BIT (3-(1,2-benzisothiazol-3-yl)-5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one), respectively). Our set of ziprasidone related compounds consists of impurities which are on the transparent list of monographs in European Pharmacopoeia [31] such, as impurity A (BITP), B (Zip-Oxide), D (Zip-dimer) and E (Zip-BIT), and one more impurity, Chloroethyl-chloroindolinone (Fig. 1). Moreover, the open-chain ziprasidone (Ph. Eur. Impurity C) is not included in our data set.

Ziprasidone is synthesized by coupling of the synthesis precursors BITP with Chloroethyl-chloroindolinone. Due to the presence of the benzisothiazole (BIT) moiety, both ziprasidone and impurity BITP are photosensitive in solution. The mechanism of photoisomerization was investigated by means of the LC/MS/MS and GC/MS methods [32]. Major photodegradation products of ziprasidone are also formed as a result of the indole ring degradation and keto-enol tautomerisation, which was examined with use of the UHPLC-DAD/ESI-Q-TOF systems [33]. Depending on the reaction pathway applied to synthesis of ziprasidone, purification procedure and storage conditions, the by-product and the degradation products can arise such, as Zip-oxide, Zip-dimer and Zip-BIT. Reactivity of the alpha position of the 2-indolinone moiety of ziprasidone basically is a consequence of its instability. Thus, the three aforementioned ziprasidone degradants structurally differ at this position. Ziprasidone significantly degrades in the alkaline media and moderately degrades at elevated temperatures. Earlier, determination of ziprasidone and its degradation products and/or impurities was performed with use of the HPLC-UV method [34], the TLC and HPLC-UV methods [35], but without a possibility to elucidate chemical structure of the degradation products and purity characteristics for the main ziprasidone-related compounds.

With use of the official HPLC method for analysis of ziprasidone and its related substances, separation of all official impurities is impossible, because of a significant difference in polarity. Three official chromatographic systems exist, one used for the assay of ziprasidone and two others (A and B) for the assay of the early-eluting (BITP, Zip-oxide, ziprasidone-open ring) and the late-eluting (Zip-dimer, Zip-BIT) impurities, with a minimum total run time of 88 min [31]. Very recently, the single HPLC method became official in the United States Pharmacopoeia for testing of the related compounds A (BITP), B (Zip-oxide), C (Zip-dimer), D (Zip-BIT), and F, and for testing of the process impurity Chloroindolinone in raw materials and capsules of ziprasidone hydrochloride, but still with a long run time of 75 min [36]. In our earlier investigation, the single liquid chromatographic (HPLC-UV) system was developed and validated for simultaneous determination of ziprasidone and its five main impurities [37]. We modelled HPLC separation of 10 structurally related ziprasidone compounds (i.e., metabolites, impurities, and degradants) with aid of the Quantitative Structure Retention Relationship (QSRR) approach [38]. Finally, based on the developed UHPLC-MS/MS method and the NMR studies, we managed to successfully separate and determine ziprasidone and its five main impurities, and to identify a novel ziprasidone degradant [39].

To our best knowledge, no other HPLC-UV methods, nor a highly sensitive UHPLC-MS/MS method has been reported for simultaneous quantification of ziprasidone and its five main impurities. These facts prompted us to validate the UHPLC-MS/MS method [39] and to compare its performances with that of our earlier developed HPLC-UV method [37] for separation and determination of the investigated set of compounds. We managed to prove that the UHPLC-MS/MS analytical procedure is convenient for the assay and purity control of ziprasidone in raw materials and pharmaceuticals. Finally, the validated UHPLC-MS/MS method was successfully transferred to the UHPLC–DAD system for convenient and fast separation of ziprasidone and its five main impurities.

Materials and methods

Chemicals and reagents

Ziprasidone mesilate trihydrate, (5-[2[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one metanesulfonate trihydrate); BITP (3-(1-piperazinyl)-1,2-benzisothiazole and 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one); Zip-oxide (5-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2,3-dione); Zip-dimer (5,5′-bis[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6,6′-dichloro-1,1′,3,3′-tetrahydro-3-hydroxy-[3,3′-bi-2H-indole]-2,2′-dione); Chloroethyl-chloroindolinone (6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one) and Zip-BIT (3-(1,2-benzisothiazol-3-yl)-5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one) were kindly supplied by Pfizer, Connecticut, USA. Zeldox® (Ziprasidone Hydrochloride) capsules (40 mg) and Zeldox® (Ziprasidone Mesilate) powder for preparation of the injection solutions (20 mg mL−1) were obtained from Pfizer, Illertissen, Germany and Pocesur-Cisse, France, respectively. All the reagents used in the experiment were of analytical grade. Water was of the HPLC grade (purified by the Simplicity 185 system, Millipore, Billerica, MA). Formic acid (for LC-MS; J.T. Baker, Deventer, Netherlands), hydrochloric acid (Merck, Darmstadt, Germany), methanol (Chromasolv® for HPLC, ≥99.9%), ammonium formate (Chromasolv® for HPLC, ≥99.0%), and acetonitrile (LC-MS Chromasolv® ≥99.9%, Fluka Analytical, Sigma Aldrich Chemie GmbH, Steinheim, Germany), were used for preparation of the mobile phase and solutions.

Chromatographic conditions

Chromatographic analyses were performed with use of the Thermo ACCELA UHPLC system (Thermo Scientific, Waltham, MA, USA) equipped with triple quad Mass Spectrometer Thermo TSQ Quantum Access Max (Thermo Scientific, Waltham, MA, USA) with a heated electro-spray ionization (HESI) interface. Samples were placed in the thermostatted autosampler at 4 °C. The 10 µL samples were injected onto an Acquity UPLC BEH 50 mm × 2.1 mm, 1.7 μm (Waters) column and eluted at the temperature of 30 °C at the flow rate of 0.3 mL min−1. The MS analysis was performed in the positive ionization mode, except for Chloroethyl-chloroindolinone which was analysed in the negative ionization mode. For each compound, optimization of the spectrometer working parameters was done by injection of an appropriate concentration of solution (ziprasidone, 1 mg mL−1; impurities BITP, Zip-dimer, Zip-BIT, 2 μg mL−1; Zip-oxide, 3 μg mL−1; Chloroethyl-chloroindolinone, 0.5 mg mL−1), using the integrated syringe pump (flow rate 10 μL min−1). The optimized MS conditions were the following ones: spray voltage, 4000 V; temperature in the capillary adjusted to 300 °C; vaporizer temperature, 400 °C; sheet gas pressure adjusted to 60 arbitrary units; auxiliary valve flow of 55 units; collision cell pressure, 1.5 mTorr argon. The MS detector was working at the unit resolution in the selective reaction monitoring mode (SRM). The Q1 mass analyzer was tuned to monitor one precursor ion (m/z signal of the molecular ion [M + H] +, or [M – H] ), and the Q3 analyzer was tuned to monitor one known fragment ion which was selected as m/z signal of maximum intensity in the MS spectrum. Selected transitions from molecular ions to product ions were at m/z 412.9→193.9 for ziprasidone, m/z 219.6→177.0 for BITP, m/z 427.9→177.0 for Zip-oxide, m/z 227.8→192.0 for Chloroethyl-chloroindolinone, m/z 840.9→413.0 for ZIP-dimer, and 545.9→326.8 for Zip-BIT. The dwell time for each SRM channel was set at 100 ms. The tube lens (TL) potentials of ziprasidone, BITP, Zip-oxide, Chloroethyl-chloroindolinone, ZIP-dimer and Zip-BIT were 162, 162, 162, 68, 128 and 162 V, respectively, and the collision energies (Ecoll) were 28, 20, 29, 16, 19 and 31 V, respectively. The values of individual Ecoll and the TL potentials of ionic optics for the tested compounds were adjusted on the basis of selected ion transitions in order to achieve the best possible sensitivity of the detector. Mass spectrometer resolution value was defined as equal to 0.7 Da. System control and data acquisition were performed with the Xcalibur software (Thermo Fisher, San Jose, CA, USA).

Gradient elution was performed with use of the mobile phase A (10 mM ammonium-formate aqueous solution adjusted with formic acid to pH = 4.7) and mobile phase B (acetonitrile). The gradient mode was t (min)/B%: 0 min/40%, 1 min/40%, 4 min/60%, 5.6 min/60%, 5.8 min/40%, 7 min/40%. Nylon filter (0.22 µm) was used for the mobile phase filtration.

The UHPLC–DAD analyses were carried out with use of the Thermo Scientific Dionex UltiMate 3000 (Thermo Scientific Germany) system consisting of quaternary pump (620 bars), UV detector (DAD, 100 Hz), Acquity UPLC BEH 50 mm × 2.1 mm, 1.7 μm (Waters) column, thermostatted autosampler and degasser. The same chromatographic conditions were used with the small modification of the gradient mode: t (min)/B%: 0 min/22%, 0.5 min/22%, 1 min/30%, 3 min/30%, 5.5min/70%, 7 min/70%, 7.2 min/22%, 8min/22%. In order to evaluate suitability of the UHPLC-DAD system, the retention factor (k), peak asymmetry (As), selectivity (α), resolution (Rs), and number of theoretical plates were calculated with use of the Chromeleon 7 Chromatography Data System (Thermo Fisher Scientific) Software Version 7.1.1.1127.

Preparation of solutions

Standard solutions

Standard Stock solutions were prepared by dissolving the working standard substances in the solvent (methanol/water/concentrated hydrochloric acid, 20/5/0.01 (v/v/v)), in order to obtain concentration of 500 ppm for ziprasidone and its impurities. Solution of Zip-dimer was stored for one day at 4 °C, and those of ziprasidone and the other impurities for 7 days, according to an earlier established stability. Due to photosensitivity of ziprasidone, all solutions were protected from light by storage in the amber glass bottles.

Solution for optimization contains ziprasidone and its impurities at following concentrations: ziprasidone, 150 ppm; impurities BITP, ZIP-dimer, Chloroethyl-chloroindolinone, and Zip-BIT, 0.3 ppm; Zip-oxide, 0.45 ppm. This solution was obtained by diluting standard stock solutions with the solvent to obtain proper concentrations. The placebo solution (containing substances of the Ph. Eur. quality such, as lactose monohydrate, pregelatinized maize starch, and magnesium stearate in the solvent) was used to test selectivity.

Sample solutions

Capsule solution

The content of each out of twenty capsules was measured and mixed. The amount of the mixed content of twenty capsules equivalent to 10 mg pure ziprasidone was transferred to the 20 mL amber glass volumetric flask. The 10-mL volume of the solvent was added and after 15 min of shaking and sonication the mixture, it was made up to the volume with the solvent. After centrifugation (for 10 min at 4000 rpm), clear supernatant was further diluted with the solvent in order to obtain working concentration for ziprasidone (solution S, 150 ppm), which was used for the impurities assay.

Powder for the injection solution

After dissolving the content of one vial which contained 20 mg pure ziprasidone with the solvent, it was transferred to the 20-mL amber glass volumetric flask and made up to the volume with the solvent. Further dilution was performed in order to obtain ziprasidone (solution S, 150 ppm). The assumed procedure was the same one as that used for processing of the capsules.

Further dilution of solutions S with the solvent was performed in order to obtain working concentration of ziprasidone equal to 1.5 ppm for the assay of ziprasidone.

Method validation

All standard solutions for validation were prepared by diluting stock solution with the solvent to an appropriate concentration.

Selectivity

Selectivity testing of the method was performed by injection of four solutions under the optimal chromatographic conditions: the placebo capsule solution, solution for optimization, and both sample solutions. Selectivity was tested by examination of the TIC (Total Ion Chromatogram) and SRM (Selected Reaction Monitoring) chromatograms of the placebo solution, solution for optimization, capsule solution, and powder for the injection solution.

Linearity

For determination of calibration curves, a series of seven solutions of ziprasidone were prepared by diluting stock solution in the concentration range from 1.05 to 1.95 ppm. Calibration solutions for impurities of ziprasidone were obtained by diluting respective stock solutions with the solvent to obtain for each impurity concentration within the range from LOQ to 0.9 ppm. Each point of the calibration graph corresponded to the mean value which was obtained from the three independent measurements.

Sensitivity

Limit of quantification (LOQ) and limit of detection (LOD) were determined by injecting a series of dilutions in the declining concentration order (from 0.05 to 0.00007 ppm).

Precision

Repeatability of the method was determined using six samples of known concentration (1.5 ppm for ziprasidone; 0.3 ppm for impurities BITP, Zip-dimer, Chloroethyl-chloroindolinone, Zip-BIT, and 0.45 ppm for impurity Zip-oxide). Six solutions of the mixture of the analytes at 100% test concentration in the placebo capsule solution were prepared and injected in the triplicate.

Accuracy

Accuracy of the method was tested by spiking solution of the placebo capsule at the three different concentration levels, 80, 100 and 120% for ziprasidone and 50, 100 and 200% for its impurities. For the recovery studies, three samples at each concentration level were injected on to the chromatographic system.

Results and discussion

Method development

Ziprasidone is a highly hydrophobic drug with basic properties attributed to the presence of the piperazine moiety. Impurity Chloroethyl-chloroindolinone is the only one which lacks basic properties, due to the lack of the piperazine moiety, while impurities BITP, Zip-dimer, Zip-BIT and Zip-oxide are basic compounds. Reactivity of Chloroethyl-chloroindolinone as a synthetic precursor depends on the presence of the benzyl halide functionality, which could also be responsible for mutagenicity [40, 41]. The degradation impurities are ZIP-dimer, Zip-BIT and Zip-oxide, with the greatest structural similarity occurring between Ziprasidone and Zip-oxide. Position α of Ziprasidone (next to the lactam carbonyl) is susceptible to nucleophiles, allowing easy formation of the oxidative degradant (e.g., Zip-oxide) (Fig. 1). Due to activation of the carbonyl group in Zip-oxide by the neighbouring lactam, it can participate in aldol condensation with ziprasidone and form the impurity, Zip-dimer [42]. This condensation reaction can be facilitated by interaction with cyclodextrine used as a solubilizer in the injectable ziprasidone formulations [43]. Zip-BIT is a highly lipophilic photodegradant formed in the solid‐state ziprasidone at ambient temperature as a product of the side reaction of benzisothiazole at the alpha position of the 2-indolinone moiety of ziprasidone.

In the course of development of the sensitive and selective UHPLC-MS/MS method, we have investigated a combined effect on the behaviour of ziprasidone and its impurities of the columns, the elution mode, the pH value, and composition of the volatile organic mobile phase modifiers and additives [39]. A satisfactory peak symmetry and separation, and appropriate signal intensity were achieved using the 10 mM ammonium-formate buffer with formic acid adjusted to pH 4.7. Compared with the HPLC/UV method developed earlier which employed buffer pH 2.5 [37], the pH 4.7 influenced retention characteristics in a different manner. Namely at pH 4.7, the elution order was distinct, with impurity BITP eluting prior to Ziprasidone and Chloroethyl-chlorindolinone eluting prior to Zip-dimer (Fig. 2 a). This order could be explained with different quantities of dominant forms of Zip-oxide and Zip–dimer protonated on the tertiary piperazinyl nitrogen at pH 2.5 [38] and at pH 4.7. An increase of the pH value did not significantly affect the elution sequence of the most lipophilic impurity, i.e., Zip-BIT, as it elutes as the last one in both systems.

Fig. 2.
Fig. 2.

TIC and SRM chromatograms: a) TIC and SRM chromatogram of ziprasidone and its impurities, channels: a) 1 (tR-1.58 min), Chloroethyl-chloroindolinone; 2 (tR-0.72min), BITP; 3 (tR-1.12min), Ziprasidone; 4 (tR-1.43min), Zip-oxide; 5 (tR-4.58min), Zip-BIT; 6 (tR-3.68min), ZIP-dimer; b) TIC and SRM chromatogram of placebo solution, channels: 1 TIC; 2 (tR-1.58 min), Chloroethyl-chloroindolinone; 3 (tR-0.72min), BITP; 4 (tR-1.12min), Ziprasidone; 5 (tR-1.43min), Zip-oxide; 6 (tR-4.58min), Zip-BIT; 7 (tR-3.68min), ZIP-dimer

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01060

Optimization of the UHPLC-MS/MS working conditions was done with use of the chemometric approach [39]. Finally, the best obtained chromatographic conditions were the following ones: stationary phase, Acquity UPLC BEH 50 mm × 2.1 mm, 1.7μm (Waters); column temperature, 30 °C; flow rate, 300 μL min−1; injection volume, 10 µL; mobile phase composed of A (10 mM ammonium-formate aqueous solution with formic acid adjusted to pH 4.7) and B (acetonitrile), the time gradient mode t (min)/B%: 0 min/40%, 1 min/40%, 4 min/60%, 5.6 min/60%, 5.8 min/40%, 7 min/40%. Good separation was achieved within the short analysis time of 7 min only (Fig. 2a).

Fully optimized separation of the structurally similar impurities was a favourable precondition for an efficient transfer of the UHPLC–MS/MS method to the newly developed UHPLC–DAD system. With slight yet deliberate modification of the gradient mode (t (min)/B%: 0 min/22%, 0.5 min/22%, 1 min/30%, 3 min/30%, 5.5min/70%, 7 min/70%, 7.2 min/22%, 8min/22%), we successfully transferred our method to the new UHPLC-DAD system with the DAD detector and with the better data acquisition rate (100 Hz). Under similar chromatographic conditions, good chromatographic performance was achieved with resolution of Rs > 1.5 and the short analysis time of 8 min. The obtained UHPLC-DAD chromatogram is shown in Fig. 3.

Fig. 3.
Fig. 3.

The UHPLC-DAD chromatogram of of ziprasidone and its impurities

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01060

Chromatographic parameters and retention times of ziprasidone and its impurities are given in Table 1. The UHPLC-DAD system shows better selectivity and resolution, and the reduced run time for the investigated set of compounds than the earlier developed HPLC/UV system [37] (Table 1). According to the results obtained, this rapid UHPLC-DAD method can in the future be used for the routine and fast quality control of ziprasidone drug.

Table 1.

Chromatographic parameters for the UHPLC-DAD and HPLC-UV analysis of the ziprasidone compounds

tR, min Retention factor(k) Peak asymmetry(As) Resolution (Rs) Selectivity factor(α)
Compound UHPLC-DAD *HPLC-UV UHPLC-DAD *HPLC-UV UHPLC-DAD *HPLC-UV UHPLC-DAD *HPLC-UV UHPLC-DAD *HPLC-UV
BITP 0.6 3.7 1.4 1.1 1.21 0.81 / / / /
Ziprasidone 3 7.9 7 3.5 / / 17.3 5.13 1.09
Zip-oxide 3.3 7.3 7.8 3.2 1.45 1.28 1.77 1.55 1.12 2.22
Chloroethyl-chlorindolinone 3.8 12.6 9.1 6.2 1.07 1.08 2.6 1.17 1.25
Zip-dimer 6.3 10.3 15.8 4.8 1.46 0.81 14.79 1.73 1.33
Zip-BIT 6.6 16.1 16.7 8.2 1.27 0.85 2.5 1.05 1.29

*earlier HPLC-UV method [37].

There are certain advantages of the newly developed methods. Knowing the need for an enhanced greenness profile of analytical methods [44], the proposed method with the reduced run time factor equal to ca. 3 (from 21 to 7 min with UHPLC-MS/MS, or to 8 min with UHPLC-DAD), the reduced flow rate factor equal to 5 (from 1.5 mL to 300 μL min−1), the reduced column length factor equal to 5 (e.g., from 250 to 50 mm), and with general reduction of column size, the new method can be considered as greener (i.e., as more environmental friendly) than the previously published methods [37]. Furthermore, the great advantage of UHPLC method over official ones is significantly shorter analysis time for the investigation of similar impurity profile comparing to minimum total run time of 88 min for three Ph. Eur. procedures [31] and to total run time of 75 min for USP procedure [36]. Moreover, the UHPLC-MS/MS method was validated for its selectivity, linearity, precision, accuracy and sensitivity.

Comparative analysis of performances of UHPLC-MS/MS and HPLC-UV methods

Validation of the optimized UHPLC–MS/MS method took into consideration a number of parameters outlined in the ICH guidelines Q1A (R2) [45]. To assess selectivity of the UHPLC-MS/MS method, we compared the TIC and SRM chromatograms (i.e., the placebo solution, the capsule sample solution and powder for preparation of the injection solution). Solution for optimization contains ziprasidone in the amount of 100% and its impurities in the amount of 0.2%, i.e., 0.3% (Zip-oxide) relative to the test concentration of ziprasidone in the sample solution. The chromatograms are shown in Figs 2 and 4 and no interference of the neighbouring bands is observed. Purity and assay of ziprasidone were not affected by the presence of its impurities and degradation products, which confirms good selectivity of the developed method. No interference was found with placebo. UHPLC-MS/MS system showed better selectivity comparing to the HPLC-UV method due to significant structural similarity of investigated compounds.

Fig. 4.
Fig. 4.

TIC and SRM chromatograms: a) TIC and SRM chromatogram of Capsule solution; b) TIC and SRM chromatogram of the powder for injection solution; channels: 1 TIC; 2 (tR-1.58 min), Chloroethyl-chloroindolinone; 3 (tR-0.72min), BITP; 4 (tR-1.12min), Ziprasidone; 5 (tR-1.43min), Zip-oxide; 6 (tR-4.58min), Zip-BIT; 7 (tR-3.68min), ZIP-dimer

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01060

Solutions of ziprasidone for linearity test were prepared from stock solution at seven concentration levels, in the range from 1.05 to 1.95 ppm. Calibration solutions for impurities were obtained by diluting the impurity stock solutions with the solvent to the required seven concentration levels within the respective range from LOQ to 0.9 ppm (Table 2). Statistical analysis of the obtained data was performed by linear regression, using the least squares method. The obtained regression equations were the following ones: BITP (y = 2.32E+04 + 1.24E+06x), Ziprasidone (y = 5.51E+07 + 1.27E+08x), Zip-oxide (y = 1.18E+04 + 1.37E+06x), Chloroethyl-chloroindolinone (y = -1.13E+03 + 2.54E+04x), Zip-dimer (y = -1.23E+04 + 7.17E+05x), Zip-BIT (y = 9.06E+05 + 7.20E+07x). Calibration curves were drawn by plotting the analysed average areas for triple injections (x) and the concentrations (y). For all five impurities, the obtained correlation coefficients were higher than 0.995 and for ziprasidone, the correlation coefficient was equal to 0.991 (Table 2), showing an excellent linear response with all investigated compounds.

Table 2.

Statistical data for linearity and LOD/LOQ values for UHPLC-MS/MS and HPLC-UV analysis of the ziprasidone compounds

Compound Concentration range (ppm) Correlation coefficient (r) LOQ (ppm) LOD (ppm)
UHPLC-MS/MS* HPLC-UV** UHPLC-MS/MS* HPLC-UV** UHPLC-MS/MS* HPLC-UV** UHPLC-MS/MS* HPLC-UV**
BITP LOQ-0.9 LOQ-6.0 0.9983 0.9999 0.002 0.06 0.0007 0.02
Ziprasidone 1.05–1.95 70–130 0.9911 0.9991 / / / /
Zip-oxide LOQ-0.9 LOQ-6.0 0.9986 0.9997 0.002 0.06 0.0007 0.02
Chloroethyl-chlorindolinone LOQ-0.9 LOQ-6.0 0.995 0.9999 0.05 0.07 0.01 0.02
Zip-dimer LOQ-0.9 LOQ-6.0 0.9987 0.9997 0.02 0.08 0.007 0.02
Zip-BIT LOQ-0.9 LOQ-6.0 0.9959 0.9993 0.00007 0.04 0.00003 0.01

* UHPLC-MS/MS method [39].

** earlier HPLC –UV method [37].

Correlation coefficients for all the investigated compounds were higher than 0.99, the same as with the earlier developed HPLC-UV method [37], which shows that for both methods concentration is well correlated with the linear range (Table 2). Nevertheless the correlation coefficient for each of the investigated compound were slightly lower for UHPLC than for HPLC system, the significance of the intercept on the y-axis for the UHPLC system was checked by Student's t-test (Table 3). With the help of Student's t-test, it was shown that with the proposed UHPLC-MS/MS method, the intercept on the y axis is not statistically significantly higher than zero, because the calculated t-values for each of the calibration curves (t a ) were lower than the t-values from the t-distribution table (t tab ) (Table 3). Furthermore, for the UHPLC-MS/MS method the range is narrower than that for the earlier developed HPLC-UV method (70–130 ppm for ziprasidone and LOQ-6 ppm for the impurities) [37].

Table 3.

Calibration data for estimation of significance of the intercept of the UHPLC-MS/MS analysis of the ziprasidone compounds

Compound S a S b ta
BITP 1.67E+04 4.21E+04 1.39
Ziprasidone 1.84E+07 1.24E+07 2.99
Zip-oxide 1.50E+04 4.04E+04 0.79
Chloroethyl-chloroindolinone 3.92E+02 1.02E+03 2.89
Zip-dimer 5.60E+03 1.37E+04 2.19
Zip-BIT 1.07E+06 2.67E+06 0.85

S a – standard deviation of intercept, S b - standard deviation of slope.

t a calculated (t tab = 3,71, P = 0,01, φ = 6).

The LOQ values were determined by injecting a series of dilutions with known concentrations from the stock solutions. The LOQ value for impurities was defined in agreement with the EURACHEM method, where LOQ is calculated, when the RSD value is equal to 10% [46]. The LOD values were calculate by means of equation LOD = (3/10) × LOQ and confirmed experimentally. The LOQ values for impurities BITP, Zip-oxide, Chloroethyl-chloroindolinone, Zip-dimer and Zip-BIT were found as equal, respectively, to 0.002, 0.002, 0.05, 0.02, and 0.00007 ppm, which are equivalent to the impurity levels of 0.001, 0.001, 0.03, 0.01 and 0.00005% calculated against the content of ziprasidone. The LOD values for impurities BITP, Zip-oxide, Chloroethyl-chloroindolinone, Zip-dimer and Zip-BIT were equal, respectively, to 0.0007, 0.0007, 0.014, 0.007, and 0.00003 ppm, which are equivalent to the impurity levels of 0.0005, 0.0005, 0.009, 0.005 and 0.00002%, calculated against the content of ziprasidone. The LOQ and LOD data valid for the UHPLC-MS/MS method exhibit much higher sensitivity (Table 2) in regard to HPLC-UV. For this reason, the proposed UHPLC-MS/MS method can be applied to trace analysis of the ziprasidone impurities, as there are certain impurities known as unusually potent, genotoxic or producing unexpected pharmacological effects and for which specific thresholds have to be applied [47].

In order to assess accuracy of the method for each investigated compound, the placebo solution was spiked with known amounts of ziprasidone and impurities Accuracy was evaluated in triplicate at three different concentration levels (0.15, 0.3 and 0.6 ppm/50%, 100% and 200%, respectively) for each impurity except for Zip-oxide (0.22 ppm, 0.45 and 0.9 ppm/50%, 100% and 200%, respectively). The investigated concentration levels for ziprasidone were 1.2 ppm, 1.5 and 1.8 ppm/80%, 100% and 120%, respectively. Recovery obtained for ziprasidone ranged from 100.56 to 101.41%. The recovery range of impurities was, as follows: BITP, 97.32%–108.34%; Zip-oxide, 91.86–99.46%; Chloroethyl-chloroindolinone, 97.49%–101.62%; Zip-dimer, 96.57%–101.97%; and Zip-BIT, 102.14%–109.71%. The RSD values for all impurities were within the range of 0.72–4.5%, and for ziprasidone within the range of 1.30–3.79%, respectively. Accuracy of the method was confirmed in the examined range. The recovery range and RSD for all the impurities observed in the earlier developed HPLC-UV method [37] were 92.15–104.96% and 0.29–3.77%, respectively, thus indicating that accuracy of both methods is quite satisfactory, especially for trace analysis with use of the UHPLC-MS/MS method (Table 4).

Table 4.

Recovery data for the UHPLC-MS/MS and HPLC-UV analysis of the ziprasidone compounds

Compound Concentration levels (ppm) Average recovery (%) Average RSD (%)
UHPLC-MS/MS* HPLC-UV** UHPLC-MS/MS* HPLC-UV** UHPLC-MS/MS* HPLC-UV**
BITP 0.15-0.30-0.60 1.6-2.0-2.4 102.78 100.74 3.3 2.67
Ziprasidone 1.2-1.5-1.8 80-100-120 100.92 100.64 2.26 0.82
Zip-oxide 0.22-0.45-0.9 2.4-3.0-3.6 95.63 96.64 2.43 0.95
Chloroethyl-chlorindolinone 0.15-0.30-0.60 1.6-2.0-2.4 99.02 98.63 2.74 0.94
Zip-dimer 0.15-0.30-0.60 1.6-2.0-2.4 99.12 100.45 3.88 1.69
Zip-BIT 0.15-0.30-0.60 1.6-2.0-2.4 106.77 98.66 2.35 1.53

* UHPLC-MS/MS method [39].

** earlier HPLC-UV method [37].

Repeatability of the method was checked by replicate injections (n = 6) of six individual sample solutions at 100% of the test concentration (1.5 ppm for ziprasidone, 0.45 ppm for impurity Zip-oxide, and 0.3 ppm for other impurities). Precision reflects the analysis deviation and it is expressed in form of the SD and RSD values. The SD values for the respective test concentrations were, as follows: ziprasidone, 1.479 ppm ± 0.015; BITP, 0.282 ppm ± 0.008; Zip-oxide, 0.419 ppm ± 0.011; Chloroethyl-chloroindolinone, 0.279 ppm ± 0.007; Zip-dimer, 0.296 ppm ± 0.008, and Zip-BIT, 0.277 ppm ± 0.007 (Table 5). It was shown that the RSD value for ziprasidone equals to 0.997% and the RSD value for the impurities BITP, Zip-oxide, Chloroethyl-chloroindolinone, Zip-dimer and Zip-BIT equals to 2.84, 2.56, 2.51, 2.73 and 2.36%, respectively. These RSD values confirm that the repeatability data are within the acceptance criteria (RSD for ziprasidone ≤ 2%, RSD for impurities ≤ 5%) and they also confirm high precision of the method. The RSD values for the earlier developed HPLC-UV method [37] and for the wide concentration range, were lower (0.22% for ziprasidone and contained within the range of 0.23%–0.93% for impurities) than the RSD values for the UHPLC-MS/MS method (Table 5). These results suggest that the earlier developed HPLC-UV method shows better precision at higher concentrations of ziprasidone and its impurities, which seems reasonable.

Table 5.

Precision data for the UHPLC-MS/MS and HPLC-UV analysis of the ziprasidone compounds

Compounds Concentration level (ppm) Found ± SD RSD (%)
UHPLC-MS/MS* HPLC-UV** UHPLC-MS/MS* HPLC-UV** UHPLC-MS/MS* HPLC-UV**
BITP 0.3 2 0.282±0.008 1.98±0.01 2.841 0.23
Ziprasidone 1.5 100 1.479±0.015 99.5±0.23 0.997 0.22
Zip-oxide 0.45 3 0.419±0.011 3.04±0.02 2.558 0.52
Chloroethyl-chlorindolinone 0.3 2 0.279±0.007 1.98±0.01 2.509 0.68
Zip-dimer 0.3 2 0.296±0.008 1.96±0.01 2.732 0.94
Zip-BIT 0.3 2 0.277±0.007 2.04±0.02 2.365 0.93

* UHPLC-MS/MS method [39].

** earlier HPLC-UV method [37].

Upon evaluation, the UHPLC-MS/MS method was further used to screen the ziprasidone containing commercial dosage forms. Compared with label declarations, recoveries of ziprasidone from the pharmaceutics were high and the levels of all impurities were below the LOD values (Figs 4a and b). The only impurity was Zip-dimer detected in the capsules (Fig. 4a).

Conclusions

Rapid UHPLC-MS/MS method for simultaneous determination of ziprasidone and its five main impurities (BITP, Chloroethyl-chloroindolinone, Zip-oxide, Zip-dimer and Zip-BIT) was compared with our earlier established HPLC-UV method. The UHPLC-MS/MS method characterizes with higher sensitivity, shorter analysis time, smaller column size and reduction of solvent consumption, and for this reason with an enhanced green profile. Based on comparative analysis, the UHPLC-MS/MS method is more selective and sensitive than the HPLC-UV method and it demonstrates high accuracy at low concentrations of analytes. Thus, the developed UHPLC-MS/MS method can be applied to simultaneous identification and quantification of ziprasidone and its main impurities in raw materials and pharmaceuticals. Successful transfer of the UHPLC-MS/MS method to the UHPLC-DAD system results in the UHPLC-DAD method suitable for routine use as a part of strategy aiming at simplification of the quality control procedures.

Conflict of interest

The fourth author, Danica Agbaba is a member of the Editorial Board of the journal. Therefore, the submission was handled by a different member of the editorial board, and she did not take part in the review process in any capacity.

Acknowledgments

This research was funded by the Ministry of Education, Science and Technological Development, Republic of Serbia through Grant Agreement with University of Belgrade-Faculty of Pharmacy No: 451-03-68/2022-14/200161 and COST Action CA18133 - European Research Network on Signal Transduction (ERNEST).

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Senior editors

Editor(s)-in-Chief: Kowalska, Teresa

Editor(s)-in-Chief: Sajewicz, Mieczyslaw

Editors(s)

  • Danica Agbaba (University of Belgrade, Belgrade, Serbia)
  • Ivana Stanimirova-Daszykowska (University of Silesia, Katowice, Poland)
  • Monika Waksmundzka-Hajnos (Medical University of Lublin, Lublin, Poland)

Editorial Board

  • R. Bhushan (The Indian Institute of Technology, Roorkee, India)
  • J. Bojarski (Jagiellonian University, Kraków, Poland)
  • B. Chankvetadze (State University of Tbilisi, Tbilisi, Georgia)
  • M. Daszykowski (University of Silesia, Katowice, Poland)
  • T.H. Dzido (Medical University of Lublin, Lublin, Poland)
  • A. Felinger (University of Pécs, Pécs, Hungary)
  • K. Glowniak (Medical University of Lublin, Lublin, Poland)
  • B. Glód (Siedlce University of Natural Sciences and Humanities, Siedlce, Poland)
  • A. Gumieniczek (Medical University of Lublin, Lublin, Poland)
  • U. Hubicka (Jagiellonian University, Kraków, Poland)
  • K. Kaczmarski (Rzeszow University of Technology, Rzeszów, Poland)
  • H. Kalász (Semmelweis University, Budapest, Hungary)
  • K. Karljiković Rajić (University of Belgrade, Belgrade, Serbia)
  • I. Klebovich (Semmelweis University, Budapest, Hungary)
  • A. Koch (Private Pharmacy, Hamburg, Germany)
  • Ł. Komsta (Medical University of Lublin, Lublin, Poland)
  • P. Kus (Univerity of Silesia, Katowice, Poland)
  • D. Mangelings (Free University of Brussels, Brussels, Belgium)
  • E. Mincsovics (Corvinus University of Budapest, Budapest, Hungary)
  • G. Morlock (Giessen University, Giessen, Germany)
  • A. Petruczynik (Medical University of Lublin, Lublin, Poland)
  • R. Skibiński (Medical University of Lublin, Lublin, Poland)
  • B. Spangenberg (Offenburg University of Applied Sciences, Germany)
  • T. Tuzimski (Medical University of Lublin, Lublin, Poland)
  • Y. Vander Heyden (Free University of Brussels, Brussels, Belgium)
  • A. Voelkel (Poznań University of Technology, Poznań, Poland)
  • B. Walczak (University of Silesia, Katowice, Poland)
  • W. Wasiak (Adam Mickiewicz University, Poznań, Poland)
  • I.G. Zenkevich (St. Petersburg State University, St. Petersburg, Russian Federation)

 

KOWALSKA, TERESA
E-mail: kowalska@us.edu.pl

SAJEWICZ, MIECZYSLAW
E-mail:msajewic@us.edu.pl

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2021  
Web of Science  
Total Cites
WoS
652
Journal Impact Factor 2,011
Rank by Impact Factor Chemistry, Analytical 66/87
Impact Factor
without
Journal Self Cites
1,789
5 Year
Impact Factor
1,350
Journal Citation Indicator 0,40
Rank by Journal Citation Indicator Chemistry, Analytical 72/99
Scimago  
Scimago
H-index
29
Scimago
Journal Rank
0,27
Scimago Quartile Score Chemistry (miscellaneous) (Q3)
Scopus  
Scopus
Cite Score
2,8
Scopus
CIte Score Rank
General Chemistry 210/409 (Q3)
Scopus
SNIP
0,586

2020
 
Total Cites
650
WoS
Journal
Impact Factor
1,639
Rank by
Chemistry, Analytical 71/83 (Q4)
Impact Factor
 
Impact Factor
1,412
without
Journal Self Cites
5 Year
1,301
Impact Factor
Journal
0,34
Citation Indicator
 
Rank by Journal
Chemistry, Analytical 75/93 (Q4)
Citation Indicator
 
Citable
45
Items
Total
43
Articles
Total
2
Reviews
Scimago
28
H-index
Scimago
0,316
Journal Rank
Scimago
Chemistry (miscellaneous) Q3
Quartile Score
 
Scopus
393/181=2,2
Scite Score
 
Scopus
General Chemistry 215/398 (Q3)
Scite Score Rank
 
Scopus
0,560
SNIP
 
Days from
58
submission
 
to acceptance
 
Days from
68
acceptance
 
to publication
 
Acceptance
51%
Rate

2019  
Total Cites
WoS
495
Impact Factor 1,418
Impact Factor
without
Journal Self Cites
1,374
5 Year
Impact Factor
0,936
Immediacy
Index
0,460
Citable
Items
50
Total
Articles
50
Total
Reviews
0
Cited
Half-Life
6,2
Citing
Half-Life
8,3
Eigenfactor
Score
0,00048
Article Influence
Score
0,164
% Articles
in
Citable Items
100,00
Normalized
Eigenfactor
0,05895
Average
IF
Percentile
20,349
Scimago
H-index
26
Scimago
Journal Rank
0,255
Scopus
Scite Score
226/167=1,4
Scopus
Scite Score Rank
Chemistry (miscellaneous) 240/398 (Q3)
Scopus
SNIP
0,494
Acceptance
Rate
41%

 

Acta Chromatographica
Publication Model Online only
Gold Open Access
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Article Processing Charge 400 EUR/article
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Acta Chromatographica
Language English
Size A4
Year of
Foundation
1992
Volumes
per Year
1
Issues
per Year
4
Founder Institute of Chemistry, University of Silesia
Founder's
Address
PL-40-007 Katowice, Poland, Bankowa 12
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2083-5736 (Online)

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