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A Comprehensive Stability Study of Vardenafil Using Quality by Design Approach

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Abstract

A novel, dual gradient LC method for quantification of vardenafil (VR) and its degradant products was developed with a multivariate approach. In the QbD approach, primary parameters were screened from the Ishikawa diagram and studied via Plackett Barman’s design. Critical factors (mobile phase composition A, mobile phase composition B, temperature and flow rate) were optimized by central composite design (CCD). Optimized dual gradient method includes A: (water:ACN) (400:100, v/v) pH adjusted in the aqueous phase to 4.7 with acetic acid, B: (water: ACN) (200:300, v/v), 0.9 mL/min flow rate, 20 °C temperature and 36 min as run time. Found eight degradant peaks of VR in different stress conditions were evaluated by LC–PDA and are different from USP 2018 monograph. The study reveals that VR is prone to degrade in sunlight, thermal and hydrolysis, while stable in oxidation. The developed LC method found sensitive, specific, robust with linearity ranging 10–35 µg/mL and correlation coefficient (R2) 0.9997. The fully validated stability-indicating method is green, buffer-free, LC–MS compatible, precise, robust and accurate. The developed method can be successfully applied to monitor the stability of VR from its marketed formulation and can be extrapolated to measure the VR from biological samples.

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Abbreviations

CQA:

Critical quality attribute

DP:

Degradation product

DMSO:

Dimethyl sulfoxide

ED:

Erectile dysfunction

FTIR:

Fourier transforms infrared spectrometer

MFAT:

Multiple factors at a time

OFAT:

One factor at a time

QbD:

Quality by design

QTPP:

Quality target product profile

SIAM:

Stability indicating analytical method

VR:

Vardenafil

References

  1. Schmidt AH, Molnár I (2013) Using an innovative quality-by-design approach for development of a stability indicating UHPLC method for ebastine in the API and pharmaceutical formulations. J Pharm Biomed Anal 78:65–74. https://doi.org/10.1016/j.jpba.2013.01.032

    Article  CAS  PubMed  Google Scholar 

  2. Plackett RL, Burman JP (1946) The design of optimum multifactorial experiment, vol 33. Oxford University Press, Biometrika Trust Stable, pp 305–325

  3. Raihana WW (2012) Optimization of analytical methods using factorial designs. J Sep Sci 4:10–13

    Google Scholar 

  4. Karmarkar S, Garber R, Genchanok Y, George S, Yang X, Hammond R (2011) Quality by design (QbD) based development of a stability indicating HPLC method for drug and impurities. J Chromatogr Sci 49:439–446

    Article  CAS  Google Scholar 

  5. Maggio RM, Vignaduzzo SE, Kaufman TS (2013) Practical and regulatory considerations for stability-indicating methods for the assay of bulk drugs and drug formulations. Trends Anal Chem 49:57–70. https://doi.org/10.1016/j.trac.2013.05.008

    Article  CAS  Google Scholar 

  6. Hubert C, Lebrun P, Houari S, Ziemons E, Rozet E, Hubert P (2014) Improvement of a stability-indicating method by quality-by-design versus quality-by-testing: a case of a learning process. J Pharm Biomed Anal 88:401–409. https://doi.org/10.1016/j.jpba.2013.09.026

    Article  CAS  PubMed  Google Scholar 

  7. Gavin PF, Olsen BA (2008) A quality by design approach to impurity method development for atomoxetine hydrochloride (LY139603). J Pharm Biomed Anal 46:431–441. https://doi.org/10.1016/j.jpba.2007.10.037

    Article  CAS  PubMed  Google Scholar 

  8. The United States Pharmacopeia. National formulary, vol 1. United States Pharmacopeial Convention (2018) Collodion, Rockville, pp 4287–4289

  9. Paghadar B et al (2013) Q-absorbance ratio spectrophotometric method for the simultaneous estimation of vardenafil and dapoxetine hydrochloride in their combined dosage form. Int J Res Pharm Nano Sci 2(1):124–129

    CAS  Google Scholar 

  10. Patel PD et al (2014) Development and validation of analytical method for simultaneous estimation of vardenafil and dapoxetine HCl in bulk and in combined dosage form. Int J Pharm Res Sch 3(2):17–30

    Google Scholar 

  11. Chapla B et al (2012) Simultaneous estimation and validation of vardenafil and dapoxetine hydrochloride in pharmaceutical formulation by thin layer chromatographic densitometric method. Int Res J Pharm 3(5):480–483

    CAS  Google Scholar 

  12. Baker MM et al (2016) High-performance liquid chromatography with diode array detection method for the simultaneous determination of seven selected phosphodiesterase-5 inhibitors and serotonin reuptake inhibitors used as male sexual enhancers. J Sep Sci 39:1656–1665

    Article  CAS  Google Scholar 

  13. Kumar KK et al (2012) A validated rapid stability-indicating method for the determination of related substances in solifenacin succinate by ultra-fast liquid chromatography. Am J Anal Chem 3:59–66

    Article  CAS  Google Scholar 

  14. Young KH et al (2009) Liquid chromatography/tandem mass spectrometry method for the simultaneous determination of vardenafil and its major metabolite, N-desethylvardenafil, in human plasma: application to a pharmacokinetic study. J Chromatogr B 1–2:95–100 (Web)

    Google Scholar 

  15. Cheng CL, Kang GJ, Chou CH (2007) Development and validation of a high performance liquid chromatographic method using fluorescence detection for the determination of vardenafil in small volumes of rat plasma and bile. J Chromatogr A 1154(1–2):222–229

    Article  CAS  Google Scholar 

  16. Giuseppe C et al (2009) Development of a method for the determination of vardenafil in human plasma by high performance liquid chromatography with UV detection. Biomed Chromatogr 23(7):759–763 (Web)

    Article  Google Scholar 

  17. Cezariusz F, Ignatowicz D (2012) A process for the preparation of vardenafil hydrochloride trihydrate. WO2011079935A2

  18. Rao DV et al (2008) A stability indicating LC method for vardenafil HCl. Chromatographia 3(9):829–835

    Google Scholar 

  19. Krishnaiah C et al (2009) A validated stability indicating LC method for vardenafil hydrochloride trihydrate and its related impurities. Anal Chem Indian J 8(2):284–288

    CAS  Google Scholar 

  20. Kumar KK et al (2012) A Validated rapid stability indicating method for the determination of related substances in vardenafil hydrochloride by ultra performance liquid chromatography. Am J Anal Chem 3(1):59–66

    Article  CAS  Google Scholar 

  21. Yarbagi K et al (2017) Identification, method development and method validation for the process and degradation impurities of vardenafil HCl by RP-UPLC and UPLC-TOF. Int J Pharm Sci Res 8(1):107–119 (Web)

    CAS  Google Scholar 

  22. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. Pharmaceutical development Q8(R2). https://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

  23. Garg LK, Sait SS, Krishnamurthy T, Kumar RP (2015) Quality by design (QbD): a practical experimental design approach by blocking and varying certain factors of a stability indicating HPLC method for simultaneous determination of omeprazole and ketoprofen. J Liq Chromatogr Relat Technol 38:677–686. https://doi.org/10.1080/10826076.2014.951766

    Article  CAS  Google Scholar 

  24. Michael AM, Rezk MR, Lotfy HM, Shehata MA (2015) Comparative study of multivariate and univariate determination of zolmitriptan in the presence of its degradation products. Anal Chem Lett 3:73–84. https://doi.org/10.1080/22297928.2015.1039942

    Article  CAS  Google Scholar 

  25. Ren Z, Zhang X, Wang H, Jin X (2016) Using an innovative quality-by-design approach for the development of a stability-indicating UPLC/Q-TOF–ESI–MS/MS method for stressed degradation products of imatinib mesylate. RSC Adv 6:13050–13062. https://doi.org/10.1039/C5RA26456A

    Article  CAS  Google Scholar 

  26. Kurmi M, Kumar S, Singh B, Singh S (2014) Implementation of design of experiments for optimization of forced degradation conditions and development of a stability-indicating method for furosamide. J Pharm Biomed Anal 96:135–143. https://doi.org/10.1016/j.jpba.2014.03.035

    Article  CAS  PubMed  Google Scholar 

  27. Dharani S, Sogra F, Ali B, Afrooz H, Bhattacharya R, Khan M, Rahman Z (2018) Quality and in-use stability comparison of brand and generics of extended-release phenytoin sodium capsules. J Pharm Sci. https://doi.org/10.1016/j.xphs.2018.12.022

    Article  PubMed  Google Scholar 

  28. Prajapati P, Agrawal YK (2015) Development of a green method for separation and identification of the degradation impurity of isoniazid by SFC-MS/MS. Anal Methods 7:7776–7783. https://doi.org/10.1039/C5AY01852H

    Article  CAS  Google Scholar 

  29. Mohamed AM, Abdel Wadood HM, Mousa HS (2016) Dual design spaces for micro-extraction together with the core shell chromatographic determination of dorzolamide and timolol in rabbit plasma: an example of quality by design method development. New J Chem 40:8424–8437. https://doi.org/10.1039/C5NJ03719K

    Article  CAS  Google Scholar 

  30. Orlandini S, Pasquini B, Caprini C, Del Bubba M, Squarcialupi L, Colotta V, Furlanetto S (2016) A comprehensive strategy in the development of a cyclodextrin-modified microemulsion electrokinetic chromatographic method for the assay of diclofenac and its impurities: mixture process variable experiments and quality by design. J Chromatogr A 1466:189–198. https://doi.org/10.1016/j.chroma.2016.09.013

    Article  CAS  PubMed  Google Scholar 

  31. Plackett RL, Burman JP (2016) The design of optimum multifactorial experiments. Biometrika 33(4):305–325. https://doi.org/10.1093/biomet/33.4.305

    Article  Google Scholar 

  32. Bhandi MM, Borkar RM, Shankar G, Raut S, Nagesh N, Srinivas R (2016) Identification and characterization of stressed degradation products of rabeprazole using LC–ESI/MS/MS and 1H-NMR experiments: in vitro toxicity evaluation of major degradation products. RSC Adv 6:10719–10735. https://doi.org/10.1039/C5RA27965H

    Article  CAS  Google Scholar 

  33. Kalariya PD, Sharma M, Garg P, Thota JR, Ragampeta S, Talluri MV (2015) Characterization of stress degradation products of mirabegron using UPLC–QTOF–MS/MS and in silico toxicity predictions of its degradation products. RSC Adv 5:31024–31038. https://doi.org/10.1039/C5RA01711D

    Article  CAS  Google Scholar 

  34. Kalariya PD, Patel PN, Srinivas R, Talluri MV (2015) Quality by design based development of a selective stability-indicating UPLC method of dolutegravir and characterization of its degradation products by UPLC–QTOF–MS/MS. New J Chem 39:6303–6314. https://doi.org/10.1039/C5NJ00698H

    Article  CAS  Google Scholar 

  35. Kalariya PD, Patel PN, Sharma M, Garg P, Srinivas R, Talluri MV (2015) Characterization of stress degradation products of blonanserin by UPLC–QTOF–tandem mass spectrometry. RSC Adv 5:69273–69288. https://doi.org/10.1039/c5ra10641a

    Article  CAS  Google Scholar 

  36. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. Validation of analytical methods definations and terminology Q2(R1). https://ich.org/page/quality-guidelines. Accessed 21 Dec 2018

  37. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. Quality risk management Q9. https://ich.org/page/quality-guidelines

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Acknowledgements

The authors would like to thank the Institute of Pharmacy, Nirma University, India for providing necessary facilities and fellowship for this work.

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Authors and Affiliations

  1. Department of Pharmaceutical Analysis, Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Post: Chandlodia, Via: Gota, Ahmadabad, Gujarat, 382 481, India

    Mital N. Patel & Charmy S. Kothari

  2. Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS-Deemed to be University, Mumbai, 400056, India

    Mital N. Patel

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  1. Mital N. Patel
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Correspondence to Charmy S. Kothari.

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Patel, M.N., Kothari, C.S. A Comprehensive Stability Study of Vardenafil Using Quality by Design Approach. Chromatographia 84, 751–767 (2021). https://doi.org/10.1007/s10337-021-04059-2

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