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\begin{document}


\def\RunningAuthor{Sanju Nanda and Mohini Bajaj}
\firstPage{3738}
\articleType{Original Article}
\receivedDate{21.07.2019}
\acceptedDate{21.10.2019}
\revisedDate{15.10.2019}
\journalVolume{10}
\journalIssue{4}
\journalDoi{ijrps.v10i4.1763}
\copyrightYear{2019}
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\def\journalTitle{International Journal of Research in Pharmaceutical Sciences}

\title{Solution state stress degradation studies of antifilarial drug albendazole}
\author{Sanju~Nanda\textsuperscript{*}, 
            Mohini~Bajaj~\\[5pt]{Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana- 124001, India}}

\begin{abstract}
This study was conducted to explore the stress degradation studies of antifilarial drug albendazole (ALB) in the solution state. The stress conditions targeted were hydrolytic (acidic, neutral, and basic) as well as oxidative. The drug was degraded under different concentrations of stressor and the time of exposure. All the degraded samples were then subjected to reversed-phase high-performance liquid chromatography using photodiode array (HPLC-PDA) as a detector. The final concentration of stressor, as well as the duration of exposure for each condition, were optimized from the results. The method optimization was done on a C18 stationary phase with a varying mobile phase composition. The parameters of the mobile phase varied were organic modifier, buffer (type and concentration) and gradient as well as run time. The optimized method included acetonitrile as an organic modifier, 10 mM potassium dihydrogen orthophosphate (pH 3.0) as a buffer that was pumped in a gradient mode, and run time was fixed at 57.00 min. The samples were further characterized by subjecting to instrumental technique Liquid Chromatography High-Resolution Mass Spectrometry (LC-HRMS). The results highlighted the degradation products formed under the study conditions. Some of the degradation products were common to all hydrolytic conditions, but some were seen only under oxidative conditions. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Albendazole,\newline hydrolytic,\newline oxidative,\newline pH,\newline solution-state stability
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Sanju~Nanda~\\ Phone:\ +91-9416265876~\\  Email:\ sn\_mdu@rediffmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
        \textsc{DOI:}\ \href{https://doi.org/10.26452/\@journalDoi}{\textcolor{blue}{\underline{\smash{https://doi.org/10.26452/\@journalDoi}}}}\par%
        \vspace*{-11pt}\hrulefill\\{\fontsize{9.12}{10.12}\selectfont Production and Hosted by}\par{IJRPS |~\href{https://ijrps.com}{https://ijrps.com}}\par%
        \vspace*{-2pt}{\fontsize{9.12}{10.12}\selectfont\textcopyright\ \@copyrightYear\ $|$ All rights reserved.}\par%
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        \makeatother
        
    
\section{Introduction}
Albendazole (ALB) Figure~\ref{f-168a72914052}, a benzimidazole, is used in the treatment of broad-spectrum intestinal helminthic infections \unskip~\citep{621492:14611913,621492:14611915,621492:14611914}. The drug is most effective for the treatment of intestinal helminthic infections caused by nematode \textit{(Necator americanus, Ancylostoma duodenale, Ascaris lumbericoides, Trichuris trichiura, Trichinella spiralis, Loa loa, Onchocerca volvulus}) and cestode (Taenia saginata, Taenia solium) \unskip~\citep{621492:14611909} \textit{. }The drug is effective in mixed infections also. The main mechanism of action of albendazole is its inhibitory action on tubulin polymerization, which results in the loss of cytoplasmic microtubules. Albendazole is also the preferred drug for mass drug administration in school going children \unskip~\citep{621492:14611915}. 


\bgroup
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\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/2d7deef8-6649-48ba-bd41-35438ab2da0d-upicture1.png}{\includegraphics{images/2d7deef8-6649-48ba-bd41-35438ab2da0d-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Structures of the drug albendazole}}
\label{f-168a72914052}
\end{figure}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Sample preparation for the solution state studies of ALB} }
\label{tw-ed14c0fb3333}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.13629999999999999\linewidth-2\tabcolsep}p{\dimexpr.2512\linewidth-2\tabcolsep}p{\dimexpr.2125\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{Handling}} & \multicolumn{3}{p{\dimexpr(.6637\linewidth-2\tabcolsep)}}{\cAlignHack Hydrolytic 80 \ensuremath{^{0}}C} & {\multirow{2}{*}{Oxidative at RT}}\\
\rowcolor{kwdboxcolor} & \cAlignHack Acid & \cAlignHack Neutral & \cAlignHack Base & \\
\tblmidrule 
Diluent  &
  MeOH: 0.2 N HCl (50:50) &
  ACN: H\ensuremath{_{2}}O (50:50) &
  MeOH: 0.2 N NaOH (50:50) &
  30\%H\ensuremath{_{2}}O\ensuremath{_{2}}: MeOH (50:50)\\
Procedure &
  The drug was poured and sonicated &
  The drug was poured and sonicated  &
  The drug was poured and sonicated &
  The drug was poured and sonicated\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Optimized stress conditions for all the solution state studies on selected drug} }
\label{tw-66c0bbdd013c}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0827\linewidth-2\tabcolsep}p{\dimexpr.2316\linewidth-2\tabcolsep}p{\dimexpr.1657\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{}} & {\multirow{2}{*}{\cAlignHack Stressors}} & \multicolumn{3}{p{\dimexpr(.4857\linewidth-2\tabcolsep)}}{\cAlignHack Hydrolytic at 80 \ensuremath{^\circ}C} & {\multirow{2}{*}{\cAlignHack Oxidative at RT}}\\
\rowcolor{kwdboxcolor} &  & \cAlignHack Acid & \cAlignHack Neutral & \cAlignHack Base & \\
\tblmidrule 
\multicolumn{1}{p{\dimexpr(.0827\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{ALB}} &
  The concentration of the stressor &
  1N HCl &
  ACN: H\ensuremath{_{2}}O (50:50)  &
  0.1N NaOH &
  15\% H\ensuremath{_{2}}O\ensuremath{_{2}}\\
 &
  Duration of exposure &
  72 h &
  72 h &
  6 h &
  2 h\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Optimized gradient HPLC method} }
\label{tw-e41c40d036d1}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.25\linewidth-2\tabcolsep}p{\dimexpr.2258\linewidth-2\tabcolsep}p{\dimexpr.25340000000000003\linewidth-2\tabcolsep}p{\dimexpr.2708\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Time (min) & ACN (\%) & KH\ensuremath{_{2}}PO\ensuremath{_{4\ }}(\%) & Elution\\
\tblmidrule 
0 &
  5 &
  95  &
  Equilibration\\
0.01-5.00  &
  5 &
  95  &
  Isocratic\\
5.00 - 35.00 &
  5 $\rightarrow $80 &
  95$\rightarrow $20  &
  Linear gradient\\
35.01 - 42.00  &
  80$\rightarrow $80 &
  20$\rightarrow $20  &
  Isocratic\\
42.01- 49.00  &
  80$\rightarrow $5 &
  20 $\rightarrow $95  &
  Linear gradient\\
49.01- 57.00  &
  5  &
  95  &
  Isocratic\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Parameters of the developed ESI positive MS/TOF} }
\label{tw-0368827293e4}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.4931\linewidth-2\tabcolsep}p{\dimexpr.5069\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Capillary voltage  & 3kV\\
\tblmidrule 
Reference Scan Frequency(sec) &
  10.0 \\
Reference DRE Setting  &
  7.610\\
Cone voltage &
  30V\\
Collision Energy &
  6V\\
Cone gas &
  60L/hr\\
Scan Time &
  0.50sec\\
Source Temperature &
  120\ensuremath{^\circ}C\\
Desolvation gas  &
  800L/h\\
Desolvation Temperature &
  400\ensuremath{^\circ}C\\
Resolution &
  22000\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
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\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/93adb238-0699-44d6-bbeb-34b42170f895-upicture2.png}{\includegraphics{images/93adb238-0699-44d6-bbeb-34b42170f895-upicture2.png}}{}
\makeatother 
\caption{\boldmath {HPLC chromatogram hydrolytic of the stress degradation studies showing degradation under oxidation and different hydrolytic conditions with the drug as well as the blank acid chromatogram}}
\label{f-a977217009f9}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Comparative HPLC retention time data of hydrolytic as well as oxidative conditions} }
\label{tw-2bf6e80953f9}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
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\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{Peak \mbox{}\protect\newline No.}} & \multicolumn{2}{p{\dimexpr(.22058888888888887\linewidth-2\tabcolsep)}}{\cAlignHack Acidic} & \multicolumn{2}{p{\dimexpr(.2326888888888889\linewidth-2\tabcolsep)}}{\cAlignHack Basic} & \multicolumn{2}{p{\dimexpr(.21748888888888885\linewidth-2\tabcolsep)}}{\cAlignHack Neutral} & \multicolumn{2}{p{\dimexpr(.22328888888888887\linewidth-2\tabcolsep)}}{\cAlignHack Oxidative}\\
\rowcolor{kwdboxcolor} & Ret. Time (min)  & RRT & Ret. Time (min)  & RRT & Ret. Time (min)  & RRT & Ret. Time (min)  & RRT\\
\tblmidrule 
ALB3 &
  14.686 &
   &
   &
   &
   &
   &
   &
  \\
ALB4 &
  15.934 &
  16.310 &
  0.559 &
   &
   &
   &
   &
  \\
ALB5 &
   &
  16.559 &
  0.567 &
  17.794 &
  0.609 &
   &
  17.794 &
  0.609\\
ALB6 &
  17.358 &
   &
   &
   &
   &
   &
   &
  \\
ALB7 &
  18.800 &
  18.807 &
  0.644 &
   &
   &
   &
   &
  \\
ALB8 &
  19.283 &
  19.283 &
  0.660 &
  19.253 &
  0.659 &
   &
  19.253 &
  0.659\\
ALB9 &
  20.034 &
  20.976 &
  0.718 &
   &
   &
   &
   &
  \\
ALB10 &
  20.988 &
   &
   &
   &
   &
   &
   &
  \\
ALB11 &
  21.287 &
   &
   &
  21.307 &
  0.730 &
   &
  21.307 &
  0.730\\
ALB12 &
  22.716 &
  22.631 &
  0.775 &
  22.753 &
  0.778 &
   &
   &
  \\
ALB13 &
  23.577 &
   &
   &
   &
   &
   &
   &
  \\
ALB14 &
  26.451 &
  0.899 &
   &
   &
   &
   &
  26.427 &
  0.904\\
Drug &
  29.412 &
  1.000 &
  29.200 &
  1.0000 &
  29.243 &
  1.0000 &
   &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Comparative data showing HPLC and LC-HRMS peaks for hydrolytic and oxidative conditions } }
\label{tw-14e5d8be89de}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.098\linewidth-2\tabcolsep}p{\dimexpr.1263\linewidth-2\tabcolsep}p{\dimexpr.09739999999999998\linewidth-2\tabcolsep}p{\dimexpr.1303\linewidth-2\tabcolsep}p{\dimexpr.098\linewidth-2\tabcolsep}p{\dimexpr.12940000000000001\linewidth-2\tabcolsep}p{\dimexpr.09059999999999999\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}p{\dimexpr.11\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{Peak}} & \multicolumn{2}{p{\dimexpr(.22369999999999997\linewidth-2\tabcolsep)}}{\cAlignHack Acidic HPLC} & \multicolumn{2}{p{\dimexpr(.2283\linewidth-2\tabcolsep)}}{\cAlignHack Acidic HRMS} & \multicolumn{2}{p{\dimexpr(.22\linewidth-2\tabcolsep)}}{\cAlignHack Oxidative HPLC} & \multicolumn{2}{p{\dimexpr(.23\linewidth-2\tabcolsep)}}{\cAlignHack Oxidative HRMS}\\
\rowcolor{kwdboxcolor} & Ret. Time (min) & RRT & Ret. Time (min) & RRT & Ret. Time (min) & RRT & Ret. Time (min) & RRT\\
\tblmidrule 
ALB1 &
   &
   &
  11.075 &
  0.4324 &
  5.002 &
  0.1713 &
  11.075 &
  0.4324\\
ALB2 &
   &
   &
   &
   &
   &
   &
  12.287 &
  0.4797\\
ALB3 &
  14.686 &
  0.4993 &
  12.278 &
  0.4793 &
   &
   &
  13.107 &
  0.5117\\
ALB4 &
  15.934 &
  0.5418 &
  13.145 &
  0.5132 &
   &
   &
   &
  \\
ALB5 &
   &
   &
   &
   &
  17.794 &
  0.6094 &
  14.565 &
  0.5686\\
ALB6 &
  17.358 &
  0.5902 &
  15.649 &
  0.6109 &
   &
   &
   &
  \\
ALB7 &
  18.8 &
  0.6392 &
  16.452 &
  0.6423 &
   &
   &
  16.529 &
  0.6453\\
ALB8 &
  19.283 &
  0.6556 &
  16.678 &
  0.6511 &
  19.253 &
  0.6593 &
  16.669 &
  0.6508\\
ALB9 &
  20.034 &
  0.6812 &
  17.716 &
  0.6916 &
   &
   &
   &
  \\
ALB10 &
  20.988 &
  0.7136 &
   &
   &
   &
   &
   &
  \\
ALB11 &
  21.287 &
  0.7238 &
   &
   &
  21.307 &
  0.7297 &
  18.877 &
  0.7370\\
ALB12 &
  22.716 &
  0.7723 &
  20.003 &
  0.7809 &
   &
   &
   &
  \\
ALB13 &
  23.577 &
  0.8016 &
  20.726 &
  0.8091 &
   &
   &
   &
  \\
ALB14 &
  26.451 &
  0.8993 &
  22.996 &
  0.8978 &
   &
   &
   &
  \\
ALB15 &
   &
   &
   &
   &
   &
   &
  24.314 &
  0.9492\\
Drug &
  29.412 &
  1.0000 &
  25.615 &
  1.0000 &
   &
   &
   &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Data showing the presence and absence of peak under different conditions} }
\label{tw-14e63b2f3f3a}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1959\linewidth-2\tabcolsep}p{\dimexpr.1875\linewidth-2\tabcolsep}p{\dimexpr.19860000000000003\linewidth-2\tabcolsep}p{\dimexpr.22219999999999995\linewidth-2\tabcolsep}p{\dimexpr.19580000000000005\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Peak No.  & \cAlignHack Acidic & \cAlignHack Basic & \cAlignHack Neutral & \cAlignHack Oxidative\\
\tblmidrule 
ALB1 &
  + &
  - &
  - &
  +\\
ALB2 &
  - &
  - &
  - &
  +\\
ALB3 &
  + &
  - &
  - &
  +\\
ALB4 &
  + &
  + &
  + &
  -\\
ALB5 &
  - &
  + &
  + &
  +\\
ALB6 &
  + &
  - &
  - &
  -\\
ALB7 &
  + &
  + &
  - &
  -\\
ALB8 &
  + &
  - &
  - &
  +\\
ALB9 &
  + &
  + &
  + &
  +\\
ALB10 &
  + &
  + &
  - &
  -\\
ALB11 &
  + &
  - &
  - &
  +\\
ALB12 &
  + &
  - &
  + &
  -\\
ALB13 &
  + &
  + &
  + &
  -\\
ALB14 &
  + &
  - &
  - &
  -\\
ALB15 &
  - &
  - &
  - &
  +\\
Drug &
  + &
  + &
  + &
  -\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{- Peaknot present }
    
\item{+ Peak is present}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\bgroup
\fixFloatSize{images/829ddca2-7528-49e8-a29d-cd3546154a46-upicture3-u1.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/829ddca2-7528-49e8-a29d-cd3546154a46-upicture3-u1.png}{\includegraphics{images/829ddca2-7528-49e8-a29d-cd3546154a46-upicture3-u1.png}}{}
\makeatother 
\caption{\boldmath {Mass spectra for the fraction separated (Drug peak, ALB1 and ALB2) when samples subjected to LC-HRMS studies}}
\label{f-cc54a261c6c5}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/e36e33db-9890-4c38-9682-9c817bad2309-upicture.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/e36e33db-9890-4c38-9682-9c817bad2309-upicture.png}{\includegraphics{images/e36e33db-9890-4c38-9682-9c817bad2309-upicture.png}}{}
\makeatother 
\caption{\boldmath {Mass spectra for the fraction separated (ALB3-ALB6) when samples subjected to LC-HRMS studies}}
\label{f-3c413fcf7167}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/d0e30f1b-afe4-481f-b947-3e0371a605a6-upicture3-u3.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/d0e30f1b-afe4-481f-b947-3e0371a605a6-upicture3-u3.png}{\includegraphics{images/d0e30f1b-afe4-481f-b947-3e0371a605a6-upicture3-u3.png}}{}
\makeatother 
\caption{\boldmath {Mass spectra for the fraction separated (ALB7-ALB9) when samples subjected to LC-HRMS studies}}
\label{f-ddac709f7dfb}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/e9aa7aed-35d3-4e5d-9218-b6074c48d599-upicture3-u4.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/e9aa7aed-35d3-4e5d-9218-b6074c48d599-upicture3-u4.png}{\includegraphics{images/e9aa7aed-35d3-4e5d-9218-b6074c48d599-upicture3-u4.png}}{}
\makeatother 
\caption{\boldmath {Mass spectra for the fraction separated (ALB10-ALB13) when samples subjected to LC-HRMS studies}}
\label{f-cc6f9f00cd74}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/36ac30b1-676c-4362-9a81-749f54cfb84b-upicture3-u5.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/36ac30b1-676c-4362-9a81-749f54cfb84b-upicture3-u5.png}{\includegraphics{images/36ac30b1-676c-4362-9a81-749f54cfb84b-upicture3-u5.png}}{}
\makeatother 
\caption{\boldmath {Mass spectra for the fraction separated (ALB15-ALB16, Drug peak) when samples subjected to LC-HRMS studies}}
\label{f-512bf2e45dcb}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/8331eacb-5aeb-42a4-9192-7885c932ae56-upicture4-u1.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/8331eacb-5aeb-42a4-9192-7885c932ae56-upicture4-u1.png}{\includegraphics{images/8331eacb-5aeb-42a4-9192-7885c932ae56-upicture4-u1.png}}{}
\makeatother 
\caption{\boldmath {Fragmentation pattern of the LC fraction separated of all the samples subjected to LC-HRMS studies (Peak ALB1-ALB3)}}
\label{f-45ad16240b12}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/eaabacd9-1a17-4a44-8638-b7667d1cf1a7-upicture4-u2.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/eaabacd9-1a17-4a44-8638-b7667d1cf1a7-upicture4-u2.png}{\includegraphics{images/eaabacd9-1a17-4a44-8638-b7667d1cf1a7-upicture4-u2.png}}{}
\makeatother 
\caption{\boldmath {Fragmentation pattern of the LC fraction separated of all the samples subjected to LC-HRMS studies (Peak ALB4-ALB6)}}
\label{f-abca60f42c0b}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/1e86a275-c8e7-45d8-8d25-ff0abb1370da-upicture4-u3.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/1e86a275-c8e7-45d8-8d25-ff0abb1370da-upicture4-u3.png}{\includegraphics{images/1e86a275-c8e7-45d8-8d25-ff0abb1370da-upicture4-u3.png}}{}
\makeatother 
\caption{\boldmath {Fragmentation pattern of the LC fraction separated of all the samples subjected to LC-HRMS studies (Peak ALB7-ALB9)}}
\label{f-d9a2d90a7d4b}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/7a48d1e1-cb65-491b-98c8-492f93d22da0-upicture4-u4.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/7a48d1e1-cb65-491b-98c8-492f93d22da0-upicture4-u4.png}{\includegraphics{images/7a48d1e1-cb65-491b-98c8-492f93d22da0-upicture4-u4.png}}{}
\makeatother 
\caption{\boldmath {Fragmentation pattern of the LC fraction separated of all the samples subjected to LC-HRMS studies (Peak ALB10-ALB13)}}
\label{f-fe02840548a4}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/4e9be370-c97a-4776-85a3-e131a7ecf4c8-upicture4-u5.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/4e9be370-c97a-4776-85a3-e131a7ecf4c8-upicture4-u5.png}{\includegraphics{images/4e9be370-c97a-4776-85a3-e131a7ecf4c8-upicture4-u5.png}}{}
\makeatother 
\caption{\boldmath {Fragmentation pattern of the LC fraction separated of all the samples subjected to LC-HRMS studies (Peak ALB15-ALB16, drug peak)}}
\label{f-9e60a7e352da}
\end{figure*}
\egroup
Anything made by humans is subject to decay with time, and pharmaceuticals are no exception. The drugs decompose to degradation products (DPs) on storage, and the presence of the latter in pharmaceutical products beyond certain limits is not only quality but also a safety issue for the regulatory agencies. This is because DPs may be more potent and/or more toxic than the drug.

Keeping in mind the above, the project was undertaken to study the behavior of the drug (ALB) under different conditions when in the solution state. No report exists in literature providing such a comprehensive study of degradation behaviour in the solution state. 
    
\section{Materials and Methods}
\textbf{Reagents and chemicals}

Pure albendazole (ALB), was obtained from Mahalaxmi Chemicals (Hyderabad, India). Analytical reagent (AR) grade boric acid (H\ensuremath{_{3}}BO\ensuremath{_{3}}) was purchased from s.d. Fine-chem Ltd. (Boisar, India), while sodium carbonate (Na\ensuremath{_{2}}CO\ensuremath{_{3}}) was sourced from Rankem (Avantor Performance Materials, Maharashtra, India). Buffer salts and all other chemicals of AR grade were bought from s.d. Fine-chem Ltd. (Boisar, India). HPLC grade ACN and methanol were procured from Fischer Scientific (Mumbai, India). Water for HPLC studies was obtained from the ELGA water purification unit (Bucks, England).

\textbf{Apparatus and equipment}

Separation behavior of the drugs and degradation products was studied using a Prominence liquid chromatography system that was equipped with a photodiode detector (SPD-M20A), and the same was controlled by CBM 20 A software, version 3 (all from Shimadzu, Kyoto, Japan). The column used was Inertsil ODS-3 C-18 (250 nm x 4.6 nm, i.d., particle size 5 \ensuremath{\mu}).  

A pH/Ion analyzer (Seven Easy, Mettler Toledo, Schwerzenbach, Switzerland) was used to check and adjust the pH of buffer solutions. Other small equipments were sonicator (YJ 5200 DT, Citizen Scale India Pvt. Ltd., India), precision analytical balance (XP 205 and AG204, Mettler Toledo, Schwerzenbach, Switzerland) and autopipettes (Eppendorf, Hamburg, Germany). LC-MS/TOF studies were carried out on a system in which AQUITY UPLC (I Class, Waters Corporations, USA) was hyphenated to XEVO G2XS QTOF spectrometer (Waters Corporations, USA). It was controlled using Masslynx (version 4.0). The column used was XBridge C18-5\ensuremath{\mu}-4.6*250mm.

\textbf{Solution State Stress Degradation Studies}

The stressors, choice of their concentration, and preparation of samples were based on the protocol described in the publication \unskip~\citep{621492:14611907,621492:14611917,621492:14611921,621492:14611922}. As the drug, namely albendazole \unskip~\citep{621492:14611903}, was slightly soluble in water but more so under acidic conditions, so the method of preparation of drug samples for ALB was varied according to the conditions as given in Table~\ref{tw-ed14c0fb3333}. The stock solution was not prepared, but the drug was added to a mixture of diluent and stressor. The concentration of ALB was 2 mg/ml. 

The drug was kept at 80 \ensuremath{^\circ}C for 72 hrs. For hydrolytic, along with study, the effect of thermal stress also. In the oxidative study, the study was conducted with 15\% H\ensuremath{_{2}}O\ensuremath{_{2}} for 7 d at room temperature. Parallel blanks were kept for all the stress conditions. The optimized stress conditions for the drugs are enlisted in Table~\ref{tw-66c0bbdd013c}. The stress samples were withdrawn at suitable time intervals and diluted with the suitable anti stressor (50:50 v/v) before analysis by HPLC. The final concentration of the drug in all the samples was 1mg/ml for injection in HPLC.

\textbf{Method Optimization}

To achieve satisfactory separation of the drugs from the degradation products (DPs) in the stressed samples, the composition of the mobile phase including the ratio of polar to the non-polar component, buffer concentration, pH, flow rate, column temperature, and injection volume were suitably optimized. Various possible permutations and combinations were used \unskip~\citep{621492:14611910,621492:14611918,621492:14611917}. A desirable separation and resolution were obtained using 10 mM potassium dihydrogen orthophosphate buffer (pH 3.0), which was run in a gradient mode (Table~\ref{tw-e41c40d036d1}) at a flow rate of 1 ml/min. The column temperature was set at 25\ensuremath{^\circ}C. The analysis was performed using the PDA detector and the wavelength finally selected was 254 nm and 295 nm.

\textbf{MS Studies on the Drugs}

The elucidation of the mass fragmentation pathway of the drug was achieved with the help of MS/TOF. The studies were performed in ESI positive mode \unskip~\citep{621492:14611908,621492:14611918}. The instrument parameters were first optimized to get the molecular ion peak of the drugs. The same was subsequently modified to get the complete fragmentation profile of each drug. The instrument parameters, at which mass studies were done for all the drugs, are listed in Table~\ref{tw-0368827293e4}. 

\textbf{LC-MS Studies on the Degradation Products}

The stressed samples were subjected to LC-MS/TOF analyses \unskip~\citep{621492:14611908} using the optimized MS/TOF parameters listed in Table~\ref{tw-0368827293e4}. The optimized method was used with the replacement of buffer with ammonia buffer\unskip~\citep{621492:14611910}. For internal calibration, Leucine Enkephalin was injected through a diverter in a specific segment near the peak of interest. 
    
\section{Results and Discussion}
\textbf{HPLC-PDA method}

The HPLC chromatograms for the degradation of ALB under different stress conditions are shown in Figure~\ref{f-a977217009f9}. They showed that the drug eluted at a retention time of 30 min when the samples were analyzed at 254 nm using the optimized method. The drug was reduced to 15 degradation products (ALB1-ALB15) under different solution-state stress conditions, as shown in Table~\ref{tw-2bf6e80953f9}. The products were formed upon degradation by both the hydrolytic as well as the oxidative conditions. The peak at around 19.283 min (ALB8) was present in almost every sample, as supported by LC-HRMS data. The peak at around 17.5 min (ALB5, ALB6) was present in almost every sample, but after analysis of LC-HRMS the sample, it was found that peak in the oxidative condition has different patterns, thus given a separate number. The peak at RT around 15.593 (ALB4) and another peak at 22.800 min (ALB12) were observed under all the hydrolytic conditions. The peak at 14.686 (ALB3), ALB2 (observed in LC-HRMS), ALB15 (observed in LC-HRMS) are exclusively present under degradation in oxidative conditions. The peak at RT 23.577 (ALB13) is present only under acidic conditions. Finally, the drug in oxidative condition was completely degraded while under hydrolytic conditions, it was present in a sufficient amount. 

\textbf{LC-HRMS method}

The comparative charts of RRT (Relative retention time) of HPLC-PDA and LC-HRMS data are compiled in Table~\ref{tw-14e5d8be89de}. The data of HRMS supports the HPLC-PDA data, so in all sixteen degradation products are separated. Other peaks are also seen in the chromatogram, but they can be due to H\ensuremath{_{2}}O\ensuremath{_{2,\ }}blank of the other components (solvent, salts) used to carry out the study. The comparative data includes only acidic and oxidative conditions as all the peaks are covered under the two. Some of the peaks in LC-HRMS are there, which are not in HPLC-PDA as the LC used in HRMS is UPLC, thus causing more refined separation.

The compiled Table~\ref{tw-14e63b2f3f3a} shows the comparison of all the conditions with respect to the degradation products formed. This comparative data shows the interrelation of the formation of various degradation products in more than one condition \unskip~\citep{621492:14611916,621492:14611918,621492:14611919}.

The mass spectrum of the drug and the degradation products separated by LC is shown in Figures~\ref{f-cc54a261c6c5}, \ref{f-3c413fcf7167}, \ref{f-ddac709f7dfb}, \ref{f-cc6f9f00cd74} and~\ref{f-512bf2e45dcb} and the detailed fragmentation is highlighted in Figures~\ref{f-45ad16240b12}, \ref{f-abca60f42c0b}, \ref{f-d9a2d90a7d4b}, \ref{f-fe02840548a4} and~\ref{f-9e60a7e352da}.
    
\section{Conclusion}
 The systematic solution state degradation studies of drug albendazole were studied. Degradation products in all the stressed samples were separated by an optimized HPLC- PDA system at 254 nm. Overall degradation products were formed under every condition-acidic, neutral, basic, and oxidative. The oxidative products were formed readily in 2 h as well as the basic hydrolysis was also achieved in 6 h at 0.1 N NaOH. The hydrolytic condition for neutral as well as acidic was taking a long time of 72 h. The hydrolysis at -NH end, oxidation at -S (mono- and di- are possible). The alkylation of aliphatic -N is also seen in some of the products formed as supported by ALB4, ALB5, and ALB15 peaks in HRMS data. The study emphasized the care to be taken while manufacturing and storing the dosage form so as to prevent the formation of degradation products that are toxic or otherwise unwanted. The study has been further carried out using the drug in combination with other drugs of the above category.\textbf{\space }
    

\bibliographystyle{pharmascope_apa-custom}

\bibliography{\jobname}
\end{document}
