Development of a stability– indicating HPLC method

Journal of Pharmaceutical and Biomedical Analysis 149 (2018) 133–142

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Development of a stability– indicating HPLC method for simultaneous determination of ten related substances in vonoprazan fumarate drug substance Zhiqiang Luo a,1 , Aoxue Liu a,1 , Yang Liu a,∗ , Guopeng Wang b,∗∗ , Xinjing Chen a , Hao Wang a , Mengwei Li a , Haili Zhang c , Yanhua Qiu d , Huaqiang Zhai a,∗ a

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China Zhongcai Health (Beijing) Biological Technology Development Co., Ltd., Beijing 101500, China c Chifeng Wanze Pharmaceutical Co., Ltd., Chifeng 024000, China d ChemFuture PharmaTech (Jiangsu) Ltd., Jiangsu 214135, China b

a r t i c l e

i n f o

Article history: Received 19 July 2017 Received in revised form 28 September 2017 Accepted 1 November 2017 Keywords: Vonoprazan fumarate Impurities HPLC Method development Validation Forced degradation study

a b s t r a c t Vonoprazan fumarate is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. In the present study, a simple, fast, and economic reversed-phase liquid chromatography (LC) method was developed for the analysis of ten related substances (raw materials, by-products and degradants) in vonoprazan fumarate. The optimized separation was performed on a Phenomenex Kinetex EVO C18 (250 mm × 4.6 mm, 5.0 ␮m) column. The mobile phase consisted of (A) 0.03 M sodium phosphate buffer (pH adjusted to 6.5) – methanol – acetonitrile (72:25:3, v/v/v) and (B) 0.03 M sodium phosphate buffer (pH adjusted to 6.5) – acetonitrile (30:70, v/v). Detection of the analytes was conducted at 230 nm using a UV detector. The stability-indicating ability of this method was demonstrated by carrying out forced degradation studies. Vonoprazan underwent significant degradation when subjected to alkaline and oxidative stress conditions, while the drug proved to be stable to acidic, thermal and photolytic degradation. The degradants did not interfere with the detection of vonoprazan fumarate and its impurities. The performance of this method was validated in accordance to the regulatory guidelines recommended by the International Conference on Harmonisation (ICH) and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The method proposed in this paper could be applied for process development as well as quality assurance of vonoprazan in bulk drug, since no monograph is available in official compendia. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Vonoprazan fumarate, 1-(5-(2-fluorophenyl)-1-(pyridin-3ylsulfonyl)-1H–pyrrol −3-yl)-N-methylmethanamine fumarate, is an orally bioavailable potassium-competitive acid blocker (P-CAB) [1,2]. The drug works by competitively inhibiting the binding of potassium ion to H+ , K+ -ATPase (proton pump) in the final step

∗ Corresponding authors at: School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6, Zhonghuan South Road, Wangjing, Chaoyang District, Beijing 100102, China. ∗∗ Corresponding author at: Zhongcai Health (Beijing) Biological Technology Development Co., Ltd., Building 2, No. 8, Xingsheng South Road, Miyun District, Beijing 101500, China. E-mail addresses: [email protected] (Y. Liu), [email protected] (G. Wang), [email protected] (H. Zhai). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.jpba.2017.11.011 0731-7085/© 2017 Elsevier B.V. All rights reserved.

of gastric acid secretion in gastric parietal cells. It was discovered by Takeda Pharmaceuticals and approved in Japan in 2014 for the treatment of gastroesophageal reflux disease, peptic ulcer, and other acid-related diseases. Compared with other current marketed proton pump inhibitors (PPIs), vonoprazan fumarate exerts more potent, sustained suppression of gastric acid secretion with a more favourable safety profile [3]. Currently, high-performance liquid chromatography (HPLC) has been considered the most appropriate technique for impurity analysis which is very important for drug approval and can exhibit a significant effect on process development [4–6]. A survey of the literature showed that limited methods based on liquid chromatography have been reported for the analysis of vonoprazan. Qiao et al. [2] have published a method, using liquid chromatography-tandem mass spectrometry (LC–MS), for the quantification of vonoprazan pyroglutamate in rat plasma and tissues. Yoneyama et al. [1] have

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developed a LC–MS method for the simultaneous quantification of vonoprazan and its 4 metabolites in human plasma. However, these trace analysis LC–MS methods were not suitable for routine impurity analysis of bulk materials of vonoprazan, because they were expensive, complex, and potential lack of robustness [7,8]. To the best of our knowledge, there was only one paper reporting a HPLCUV method for the quantification of process-related impurities in vonoprazan fumarate [9]. This method was time-consuming (a total run time of 67 min) for practice and gave insufficient information about degradation products. Further, vonoprazan is not yet official in any of the pharmacopoeia for compendial applications. Under these circumstances, there is a great need to develop a simple, sensitive and effective HPLC method which can detect and separate all the possible degradants and process impurities in bulk drug materials to assure the safety and quality of vonoprazan fumarate. Hence, the aim of the current research was to develop a stabilityindicating analytical method based on HPLC-UV for the separation and determination of ten potential related impurities (namely Imp1, 2, 3, 4, 5, 6, 7, 8, 9, and 10) in vonoprazan fumarate (Table 1). This newly developed method was validated and proved to meet the requirements delineated by ICH guidelines. The method proposed here is a suitable mean for routine testing as well as stability analysis of vonoprazan fumarate. 2. Materials and methods 2.1. Materials and reagents Samples of vonoprazan fumarate, raw materials and impurities were kindly provided by Chifeng Wanze Pharmaceutical Co., Ltd. (Chifeng, China) and ChemFuture PharmaTech (Jiangsu) Ltd (Wuxi, China). HPLC grade acetonitrile, methanol and formic acid were purchased from Fisher Scientific (Beijing, China). Deionizeddistilled water was obtained from Watson’s Food & Beverage (Guangzhou, China). All other reagents used throughout this work were of analytical grade and commercially available. 2.2. Instrumentation A Shimadzu LC-16 series HPLC system consisting of a binary pump with an on-line degasser, an autosampler, a column thermostat, and an ultraviolet absorbance detector (Shimadzu, Kyoto, Japan) was used for method development and validation. The chromatograms were recorded and analyzed through SHIMADZU LabSolutions Essentia Version 5.62. 2.3. Chromatographic conditions The analysis of all compounds was carried out at 35 ◦ C using a Phenomenex Kinetex EVO C18 (250 mm × 4.6 mm, 5 ␮m) column (Phenomenex, Guangzhou, China). The mobile phase-A was composed of 0.03 M sodium phosphate buffer (pH adjusted to 6.5), methanol and acetonitrile in the ratio of 72:25:3, and the mobile phase-B was a mixture solvent of 0.03 M sodium phosphate buffer (pH adjusted to 6.5) and acetonitrile in the ratio of 30:70. The developed gradient program was 0.01 min–0% B, 10.0 min–26% B, 24.0 min–100% B, 26.0 min–100% B, 30.0 min–0% B and 35.0 min–0% B. The mobile phase was filtered through a 0.22 ␮m membrane filter and delivered at a constant flow rate of 1 mL min−1 . The injection volume was 10 ␮L and the analytes were detected by UV at 230 nm. 2.4. Preparation of standard solutions An acetonitrile and water mixture (10:90, v/v) was used as the diluent in the sample preparation. A stock solution of vonoprazan was prepared at a concentration of 5 mg mL−1 by dissolving

appropriate amount of reference standard in the diluent. Mixed and individual stock solutions of the related substances were also prepared in the diluent to a final concentration of 100 ␮g mL−1 . The combination solution used to investigate the system suitability was freshly prepared by spiking the vonoprazan fumarate sample (0.5 mg mL−1 ) with ten impurities at 0.1% of the sample concentration (system suitability solution). All solutions were filtered through 0.22 ␮m membrane filters before use. 3. Results and discussion 3.1. Possible mechanisms for the formation of impurities After a comprehensive investigation on manufacturing process of vonoprazan fumarate [9], the potential impurities originating in each stage were tracked (Fig. 1). Among them, the routes for the formation of Imp–3, 4, 5, 10 and vonoprazan fumarate had been described in detail by Liu et al. [9].The possible formation mechanisms of other impurities were described as follows. The unreacted SMA(Imp-8) and intermediate-2 (Imp-9) were quite possible to exist in the final vonoprazan fumarate samples. In addition, Imp-9 was speculated as a oxidative degradation product of vonoprazan, which was confirmed in degradation test (Route 8). In route 3, intermediate-1 may react with CH3 NH2 to form Imp-1. Besides, Imp-1 was speculated as a base degradation product of vonoprazan, which was also confirmed in forced degradation studies (Route 7). In these two ways, Imp-1 was formed. In route 4, intermediate-1 may react with HCl to form Imp-7. In route 5, intermediate-2 may be hydrogenated by NaHB4 , affording Imp-6. Finally, recrystallization of vonoprazan furmarate by dissolving it into organic solvent at high temperatures afforded Imp-2 (Route 9). 3.2. Optimization of chromatographic conditions The main criteria for developing a successful HPLC method for the quantitative analysis of vonoprazan fumarate and its impurities were as follows: the analytical method should be stability-indicating, robust and straightforward enough for routine analyses in quality control laboratories [5,10]. The first step of method development for the quantification of process-related impurities in vonoprazan fumarate drug substance is the appropriate selection of the wavelength to obtain good sensitivity with minimum noise. It was studied by measuring the ultraviolet absorption spectrum of all analytes. Vonoprazan and its impurities showed significant UV absorbance at wavelength of 230 nm (Fig. S1). Hence, the detector wavelength was kept at 230 nm throughout the analysis. The column selectivity for the separation of all the related substances was critical because of similar chemical structure and polarities. Preliminary experiments were performed using three different columns including Waters XBridge Shield RP18 (250 × 4.6 mm, 5 ␮m), Phenomenex Kinetex EVO C18 (250 mm × 4.6 mm, 5 ␮m) and Waters XBridge C18 (250 mm × 4.6 mm, 5 ␮m) column. It was noticed that the studied compounds were well retained and separated with comparatively sharp peaks on Phenomenex Kinetex EVO C18 (250 mm × 4.6 mm, 5.0 ␮m) column (Fig. S2). So, further optimization was carried out on this column. Several mobile phases with different compositions and polarities were examined for their efficiency in resolution e.g.: water – acetonitrile, water – methanol, sodium phosphate buffer – acetonitrile, sodium phosphate buffer – methanol. The mobile phase of sodium phosphate buffer– methanol – acetonitrile was finally selected for subsequent investigations as it yielded the best separation between the test compounds. Then trials were undertaken using different ratios of sodium phosphate buffer, methanol and

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Table 1 Chemical structures of vonoprazan fumarate and its associated impurities. Name

Structure

Chemical name

Source

Vonoprazan fumarate

1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)1H–pyrrol-3-yl)-N-methylmethanamine fumarate

Target compound

Imp-1

1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-Nmethylmethanamine

Byproduct/Degradation product

Imp-2

N-((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl)methyl)-N-methylaspartic acid

Byproduct

Imp-3

N-methyl-1-(5-phenyl-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl)methanamine

Byproduct

Imp-4

1-(5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl)-N-methylmethanamine

Isomer

Imp-5

1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl)-N,N-dimethylmethanamine

Byproduct

Imp-6

(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl)methanol

Byproduct

Imp-7

2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3carbaldehyde

Byproduct

Imp-8

5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

Starting material

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Table 1 (Continued) Name

Structure

Chemical name

Source

Imp-9

5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde

Intermediate/Degradation product

Imp-10

5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbonitrile

Byproduct

acetonitrile to obtain a significant improvement in resolution. Satisfactory separation was achieved using a sodium phosphate buffer– methanol – acetonitrile (72:25:3, v/v/v) mixture as mobile phaseA and a sodium phosphate buffer–acetonitrile (30:70, v/v) mixture as mobile phase-B. Giving consideration to the separations, analysis time and column back-pressure, the mobile phase flow rate and the temperature of the column oven were fixed at 1.0 mL min−1 and 35 ◦ C, respectively. The pH level of mobile phase may affect the chromatographic behaviors of the investigated compounds [11] . Vonoprazan has a high pKa of 9.37 [12] and it is unstable in base condition. So acidic pH (2.5, 4.5, 5.5 and 6.5) was selected for the initial experiment. It was found that varying the pH of the buffer has great effects on the retention time of Imp-5 and thus the resolution (Fig. S3). When the buffer pH was adjusted to 6.5, the best separation of all analytes was obtained. The effect of the buffer salt concentration on separation was also investigated by changing its concentration from 0.01 M to 0.03 M. It was found that the tailing factors of vonoprazan was highly sensitive to the concentration of sodium phosphate, and proper peak shapes for vonoprazan and its ten impurities were obtained with a sodium phosphate concentration of 0.03 M. In this optimized method, a representative chromatogram of the separation of the target compounds was presented in Fig. 2. System suitability parameters were described in Table 2.

ence compounds to the forced degradation samples. Moreover, the purity of each peak was checked using diode array detection, and the results indicated that there was no merging of any known peak with any unknown peak in all stressed samples. These forced degradation samples were also assayed against vonoprazan qualified reference compounds. The mass balance was assessed by comparing the decrease in vonoprazan with the increase in all detectable degradation products [16] and found to range from 90% to 110%. The entire evidence confirmed that this newly developed analytical method was highly specific and selective for intended use. 3.4. Method validation 3.4.1. Precision The precision of the assay was studied taking into account its repeatability and intermediate precision aspects [17]. Repeatability was determined by injecting six individual preparations of system suitability solutions in the same equipment on the same day. The relative standard deviation (% RSD) values for the response area of all analyte peaks were calculated and found to be less than 1.5% (Table 3). The intermediate precision was also checked by different analysts in different laboratories on different days using different pieces of equipment [18]. The% RSD values of the contents of the detected impurities was calculated and found to be in the range 0.4–1.3%. Thus, the conclusion could be drawn that this method was sufficiently precise.

3.3. Specificity Specificity can be defined as absence of any interference at retention times of peaks of interest, and was demonstrated by analysis of the sample spiked with all potential impurities [13]. Stress studies were conducted to confirm the stability-indicating power of this analytical method [14,15]. Vonoprazan was subjected to the following ICH-recommended forced degradation conditions: acid (1 mol L−1 HCl, 100 ◦ C, for 5 h), base (1 mol L−1 NaOH, at room temperature, for 20 min), oxidation (3% H2 O2 , at 100 ◦ C, for 3 h), thermal (100 ◦ C, for 7 h), and photolytic (5000 lux, for 48 h). The HPLC chromatograms recorded after degradation were shown in Fig. 3(A)–(E). It was found during the course of stress studies that under thermal, acidic and photolytic conditions, no evidence of degradation of vonoprazan was noted. However, the drug was susceptible to degradation in alkaline and oxidative media and the detected degradation products were satisfactory separated from each other and from the vonoprazan peak. The stress induced degradation products observed at RRT 0.64 (Imp-1) and RRT 1.71 (Imp-9) were preliminarily identified by co-injecting the refer-

3.4.2. Limit of detection (LOD) and limit of quantification (LOQ) The limit of detection (LOD) and limit of quantification (LOQ) for all ten impurities were determined at respective signal to noise ratio (S/N) of 3:1 and 10:1, by injecting a series of diluted solutions with known concentrations [19]. The obtained LODs of ten analytes were in the range of 0.02–0.05 ␮g mL−1 and the LOQs were in the range of 0.05–0.17 ␮g mL−1 (Table 3). The results indicated that this method was sufficiently sensitive to carry out the quantification of impurities in vonoprazan fumarate drug substance at low level. 3.4.3. Linearity The linearity of detector response to different concentrations was checked for vonoprazan and its related substances using six different concentration levels ranging from the LOQ to 300% of the specification level (0.1% of impurities with respect to 0.5 mg mL−1 vonoprazan). The slope, intercept and regression coefficient values were determined by least squares linear regression analysis. The correlation coefficients obtained were in the range

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Fig. 1. Ten routes of producing impurities of vonoprazan fumarate and their relationship.

of 0.9992–0.9999 (Table 3), indicating satisfactory linearity of the method. 3.4.4. Accuracy The accuracy of the analytical method was determined by measuring recovery through spiking known amounts of the impurity in vonoprazan fumarate bulk drug sample. It was carried out in triplicate at three different concentration levels ranging from 50% to

150% of the specification level. The observed% recoveries (Table 4) of the test compounds (83.5–118.3%) were well within the specified limit of 80–120%, confirming the accuracy of the determination. 3.4.5. Robustness The robustness was established by evaluating the influence of minor but significant changes in certain analytical parameters affecting selectivity or affecting quantitative results [20].

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Fig. 2. Blend chromatogram of vonoprazan and its related impurities in final chromatographic conditions. Table 2 System suitability parameters. Compound

RT(% RSD)a

Peak area(% RSD)a

USP tailingb

Theoretical plates( × 104 )b

Resolutionb

Imp-1 Imp-2 Vonoprazan Imp-3 Imp-4 Imp-5 Imp-6 Imp-7 Imp-8 Imp-9 Imp-10

0.02 0.14 0.03 0.03 0.03 0.02 0.04 0.04 0.04 0.04 0.03

0.44 0.14 0.03 0.66 0.32 0.25 0.22 0.12 0.21 0.11 0.13

1.86 ± 0.03 1.11 ± 0.01 2.05 ± 0.01 1.32 ± 0.02 1.32 ± 0.02 1.21 ± 0.01 1.15 ± 0.01 1.15 ± 0.01 0.97 ± 0.01 0.92 ± 0.01 1.18 ± 0.01

1.39 ± 0.02 2.81 ± 0.03 2.26 ± 0.01 6.09 ± 0.06 7.46 ± 0.04 10.17 ± 0.06 17.73 ± 0.07 18.80 ± 0.03 19.46 ± 0.06 17.40 ± 0.04 24.92 ± 0.08

– 9.33 ± 0.02 6.53 ± 0.05 3.79 ± 0.01 6.45 ± 0.02 10.95 ± 0.06 8.03 ± 0.04 8.76 ± 0.01 2.79 ± 0.01 2.67 ± 0.01 9.56 ± 0.02

a b

Six injections. Mean ± SD (n = 6 preparations).

Table 3 Regression and precision data Parameter −1

LOD (␮g mL ) LOQ (␮g mL−1 ) Regression equation (y) Slope (b) Intercept (a) Correlation coefficient Precision (%RSD) Intermediate precision (%RSD)

Imp-1

Imp-2

Imp-3

Imp-4

Imp-5

Imp-6

Imp-7

Imp-8

Imp-9

Imp-10

0.05 0.17

0.03 0.10

0.03 0.10

0.05 0.17

0.02 0.07

0.02 0.07

0.02 0.05

0.02 0.05

0.02 0.07

0.02 0.05

12451 −368.9 0.9998 0.2 0.5

13980 23.4 0.9999 0.3 0.7

20890 −292.2 0.9996 1.3 1.3

23178 −174.5 0.9992 0.2 0.5

24315 132.5 0.9993 0.1 0.6

21192 65.7 0.9997 0.4 0.4

32474 1072.1 0.9996 0.2 0.4

16019 1496.9 0.9995 0.4 0.7

48906 −1319.9 0.9997 0.2 0.8

29042 1090.3 0.9992 0.2 0.8

Table 4 Evaluation of accuracy. Amount spikeda (%)

50% 100% 150% a b

%Recoveryb Imp-1

Imp-2

Imp-3

Imp-4

Imp-5

Imp-6

Imp-7

Imp-8

Imp-9

Imp-10

102.5 ± 0.29 103.2 ± 0.93 107.6 ± 2.56

97.0 ± 4.31 97.0 ± 3.05 103.6 ± 1.32

83.5 ± 0.74 92.9 ± 2.32 97.6 ± 0.77

116.1 ± 0.16 105.5 ± 3.88 99.5 ± 1.09

115.7 ± 2.70 113.5 ± 0.95 115.9 ± 0.63

100.5 ± 3.06 102.1 ± 1.46 103.4 ± 0.54

117.3 ± 1.15 117.4 ± 1.23 118.3 ± 1.57

97.7 ± 1.75 93.5 ± 1.30 91.3 ± 1.19

105.3 ± 1.93 102.2 ± 1.68 105.3 ± 0.79

96.0 ± 2.43 89.3 ± 6.79 83.6 ± 0.39

Amount of 10 impurities spiked with respect to 0.1% specification level individually to 0.5 mg mL−1 of vonoprazan. Mean ± SD (n = 6 preparations).

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Fig. 3. (A) Chromatogram of vonoprazan fumarate under acid stress condition; (B) Chromatogram of vonoprazan fumarate under base stress condition; (C) Chromatogram of vonoprazan fumarate under oxidative stress condition; (D) Chromatogram of vonoprazan fumarate under thermal stress condition; (E) Chromatogram of vonoprazan fumarate under photolytic stress condition.

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Fig. 3. (Continued).

These intended variations included the column temperature, ± 5 ◦ C, the pH value of the buffer solution, ± 0.5 pH units, the flow rate, ± 0.2 mL min−1 , and using different columns (same type, different batches). In all the deliberate varied chromatographic con-

ditions, system suitability studies were carried out by analyzing the system suitability solution in triplicate. The results showed that system suitability parameters of all the impurities and principal

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Fig. 3. (Continued).

peaks were not significantly differing, indicating that the method is robust enough to maintain reliable results. 3.4.6. Solution stability Solution stability of the ten impurities was checked by analyzing system suitability solutions at appropriate time intervals at room temperature for 15 h, and calculating the%RSD values of peak areas and retention times of ten analytes. The results indicated that peak areas and retention times of all analyte peaks did not change significantly during this period. So it was concluded that the samples were chemically stable for at least 15 h at room temperature, which was sufficient for the whole analytical process. 4. Conclusion A simple and rapid HPLC method with UV detection was rationally developed for the separation and quantification of possible impurities in vonoprazan fumarate bulk drug sample. This method was then fully validated following the regulatory guidelines and found to be specific, linear, precise, accurate and robust. Hence, the developed HPLC method can be easily applied for the quality control of the bulk manufacturing of vonoprazan fumarate drug substance. Acknowledgment The authors are thankful to the management of Chifeng Wanze Pharmaceutical Co., Ltd. (Chifeng, China) and ChemFuture PharmaTech (Jiangsu) Ltd. (Wuxi, China) for supporting this work.

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