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\def\citeauthor{~Rabbani~Sk,
              ~Sujatha~S,
              ~Kudipudi~Harinadha~Baba}
\def\citetitle{\textbf{Formulation and Evaluation of Capecitabine Microspheres for Colorectal Cancer}}
\def\copyrightstmt{This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial- ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.}
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\def\RunningAuthor{Rabbani Sk et al.}
\firstPage{37}
\articleType{Original Article}
\receivedDate{15 Nov 2022}
\acceptedDate{08 Dec 2022}
\revisedDate{07 Dec 2022}
\journalVolume{3}
\journalIssue{1}
\journalDoi{fjphs.v3i1.338}
\copyrightYear{2023}
\eISSN{2583-116X}
\journalDoi{fjphs.v3i1.338}
\def\authorCount{3}
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\def\journalTitle{Future Journal of Pharmaceuticals and Health Sciences}

\title{\textbf{Formulation and Evaluation of Capecitabine Microspheres for Colorectal Cancer}}
\author{Rabbani~Sk\textsuperscript{*}\textsuperscript{1},  
            Sujatha~S\textsuperscript{1}, 
            Kudipudi~Harinadha~Baba\textsuperscript{2}~\\[5pt]{\textsuperscript{1}Department of Pharmaceutics, Narayana Pharmacy College, Chinthareddy Palem, Nellore - 524003, Andhra Pradesh, India}~\\{\textsuperscript{2}Department of Pharmaceutical Analysis, Narayana Pharmacy College, Chinthareddy Palem, Nellore - 524 003, Andhra Pradesh, India}}

\begin{abstract}
The present study aimed to formulate and evaluate Capecitabine microspheres for colorectal cancer, reduce dosing frequency, and improve patient compliance. Microspheres were prepared by emulsion solvent evaporation using polymers like ethyl cellulose (E.C.) and HPMC K-I00 in different ratios. The prepared microspheres were evaluated for flaw properties, percentage yield, drug entrapment efficiency, and \textit{in vitro } dissolution studies. Results showed that as the concentration of polymer ratio increases, it affects the particle size, percentage yield, and drug release from the microspheres. The percentage yield of F6 microspheres was up to 95.13\%. The release study was done with simulated intestinal fluid (SIF - pH 7.4) for 24 hours. It  showed that the drug was protected from being released in the physiological environment of the intestine and efficiently released in the colon (95.85\%). The optimized formulation F6 exhibited the drug release in a sustained manner arid following zero order, non-Fickian diffusion mechanism. An accelerated stability study was carried out for the optimized formulation. The results showed no significant changes in percentage drug entrapment efficiency, particle size, and \textit{in} \textit{vitro }controlled release of Capecitabine. The surface morphology analysis formulation F6 showed a spherical structure with smooth surface morphology. The prepared microspheres are promising drug delivery for sustained oral administration to target the colon and provide a better kinetic profile with improved bioavailability. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Colorectal Cancer,\newline Microspheres,\newline Controlled Release
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright{\Large$^\ast$}Corresponding Author\par Name:\ Rabbani~Sk~\\ Phone:\ 7842846913~\\  Email:\ rabbanishaik733@gmail.com
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\section{Introduction}
Colorectal cancer has been the 2nd most frequent cancer killer as a whole, as well as 3rd most frequent cause of lung cancer-related mortality with in united states, both in females and males. Colorectal drug delivery, like a safe and effective therapeutic colorectal cancer, will provide effective concentration like an anti-cancer advisor at receptor sites but also spare the traditional cells for lowered dote and lowered duration of treatment \unskip~\cite{1601862:26526222}. Its effective active targeting of opioids towards the colorectal through the digestive tract (GIT) did require a shield of such an opioid from degeneration and discharge within the stomach and intestine and afterward makes sure sustained release inside the proximal intestines.

Minimize a dose intensity and mitigate adverse effects compared with conventional medicine. Capecitabine is an orally administered chemotherapies agent used for the diagnosis of colon cancer and metastatic breast cancer. Capecitabine is just a prodrug that also proteolytic enzymes transformed about fluorouracil inside cancer, inhibiting DNA synthesis and slowing tumor cell expansion. However, it is quickly absorbed first from gastrointestinal trace its daily recommended dose has been huge \unskip~\cite{1601862:26526216}. Through being able to convert into the monitored, location-specific release dosage from 1st pass, various metabolic could be lessened bioavailability. 

\textbf{Methods of Preparation of Microspheres}

\textbf{Solvent Evaporation Method }

Floating TNNHI particulate recommended dose FONN could be prepared by solvent dispersion and vaporization to create an empty internal structure. A polymer has been absorbed inside an organic phase, and also the opioid must be either absorbed or instead distributed within polymer concentration. 

The solution containing the drug then is solubilized into such an aqueous medium usually contains ideal improver (surfactants/polymer) of about form oil-in-water emulsifiers. Just after the formation and stability of emulsifiers, an organic phase is vaporized by either raising the temperature under pressure or through constant stirring [Figure~\ref{f-42cf4fb28592}]. 

A solutes withdrawal results in polymer precipitation just at oil/water interaction like droplets, establishing cavity and therefore creating those porous of about conferring its hanging characteristics. Polymeric materials researched again for the advancement of specific processes encompass cellulose acetate, chitosan, eadragit, polyacrylates, polyvinyl acetate, carbopol, agar, polyethylene oxide but also polycarbonate \unskip~\cite{1601862:26526219}.


\bgroup
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\centering \makeatletter\IfFileExists{images/7ef7887e-f546-4b20-99c0-1f21226ed903-upicture1.png}{\includegraphics{images/7ef7887e-f546-4b20-99c0-1f21226ed903-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Solvent Evaporation}}
\label{f-42cf4fb28592}
\end{figure}
\egroup
\textbf{Ionotropic Gelation Method}

Ionotropic Gelation relies upon that capacity like poly electrolyte balance of about cross-link inside the existence of refute ions to make beads. Until its use of alginates. Gellan gum, chitosan, and carboxymethyl cellulose, again for encapsulation like a thug or even cellular, ionic gelation method, have already been broadly used for this purpose \unskip~\cite{1601862:26526212}. Its natural poly electrolyte supplements through spite, possessing property like covering upon that opioid core but also behaves as controlled release retardants including definite anions through with their chemical nature, such ions present shapes meshwork configuration through trying to also combine with polyvalent cations and stimulate gelatinization through directly binds primarily towards the anion slabs. Hydrogel beads have been generated by attempting to drop a drug-loaded polymeric solution into an aqueous phase like polyvalent ionic compounds. A schematic representation of the ionotropic gelling technique can be seen in Figure~\ref{f-c99b4fc5fc9b}.


\bgroup
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\centering \makeatletter\IfFileExists{images/c5bd5e08-5b78-4f89-a6d0-2247dfe7d1d3-upicture2.png}{\includegraphics{images/c5bd5e08-5b78-4f89-a6d0-2247dfe7d1d3-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Ionotropic Gelation}}
\label{f-c99b4fc5fc9b}
\end{figure}
\egroup
\textbf{Emulsion Solvent Diffusion Method}

Within an emulsion solvent evaporation technique, an attachment between both the opioid and also organic phase has been greater than those of the organic phase but rather appropriate solvent \unskip~\cite{1601862:26526213}. An opioid has been disintegrated within the organic phase, but also the solution has been distributed with an aqueous system generating emulsifiers droplets, although the organic phase has been miscible (Figure~\ref{f-c99b4fc5fc9b}). An organic phase dispersion progressively out from the emulsified raindrops more into the encompassing aqueous solution, and the aqueous medium dispersed in with the droplets through which opioid solidifies.
    
\section{Materials and Methods}
HPMC: Aqualon. usa, Coloroon Asia Pvt Ltd, Cellulose: Colorcon Asia Pvt. Ltd; Goa, Dichloromethane: Avantor performance, India (RFCL Ltd), Polyethylene Glycol: Alpha Chemika, Mumbai, PVA: Alpha Chenfika, Mumbai, HCI: Merck Specialties Pvt. Ltd; Mumbai, Sodium Hydroxide: Merck Specialties Pvt Ltd: Mumbai, Potassium di-hydrogen Phosphate: Merck Specialties Pvt. Ltd; Mumbai. The above materials, the best possible Pharma grade available, were supplied by the manufacturer for this research. All the reagents and chemicals used are of analytical grade.

\textbf{Methodology}

\textbf{Preparation of Capecitabine-Loaded Microspheres}

Microspheres have been prepared through the emulsion solvent diffusion technique until capecitabine is mildly soluble in water opioids. Polymeric materials ethyl cellulose and t-1pmc disintegrated through 20 ml like DCM \unskip~\cite{1601862:26526210}. Such polymeric materials but also opioids were also mixed thoroughly of about create a clear solution, after which 0.1\% of polyethylene glycol was added, which functions as an emulsifier. Therefore, the previous section solution has been solubilized by adding a drop at a time into the aqueous phase containing 160 ml of 0.4\% water, like PVA, as just an emulsifying agent. Dichloromethane has been excluded there at 35\ensuremath{^\circ}c through vaporization. Even as solutes were just being deleted, an emulsifying agent consistently maintained droplets of their globular setup but avoided through accumulating till the solutes were obliterated and the microspheres solidified just like secretive particulate. Eventually, solidified microspheres are cleaned of deionized water \unskip~\cite{1601862:26526217}. The obtained microspheres have been kept at room temperature and consequently held through desiccators. A similar procedure has been reproduced, such as all six formulations [Table~\ref{tw-32951f5a8197}].


\begin{table*}[!htbp]
\caption{\boldmath {Formulation of Capecitabine Microspheres} }
\label{tw-32951f5a8197}
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  \cAlignHack 1:1\\
\cAlignHack F2 &
  \cAlignHack 500 &
  \cAlignHack 600 &
  \cAlignHack 600 &
  \cAlignHack 1:1\\
\cAlignHack F3 &
  \cAlignHack 500 &
  \cAlignHack 900 &
  \cAlignHack 900 &
  \cAlignHack 1:1\\
\cAlignHack F4 &
  \cAlignHack 500 &
  \cAlignHack 200 &
  \cAlignHack 200 &
  \cAlignHack 2:1\\
\cAlignHack F5 &
  \cAlignHack 500 &
  \cAlignHack 400 &
  \cAlignHack 400 &
  \cAlignHack 2:1\\
\cAlignHack F6 &
  \cAlignHack 500 &
  \cAlignHack 600 &
  \cAlignHack 600 &
  \cAlignHack 2:1\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Kinetic Release Models with Their Equations} }
\label{tw-f38836ce0977}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.4978\linewidth-2\tabcolsep}p{\dimexpr.5022\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Model & \cAlignHack Equation\\
\tblmidrule 
\cAlignHack Zero-order kinetics &
  \cAlignHack Q - Q0-Kot \\
\cAlignHack First order kinetics &
  \cAlignHack Q=QO(1-e\ensuremath{^{-klt}})\\
\cAlignHack Higuchi square root model &
  \cAlignHack Qt=KH t1/2\\
\cAlignHack Hixson-Crowell's cube root model &
  \cAlignHack $3\sqrt{Qo}-3\sqrt{Qt} $=vKHCt \\
\cAlignHack Korsmeyer-peppas model &
  \cAlignHack $\frac{Qt}{Q\infty} $=Kktn \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Size Analysis} }
\label{tw-54ec736f18ef}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1502\linewidth-2\tabcolsep}p{\dimexpr.2626\linewidth-2\tabcolsep}p{\dimexpr.5871999999999999\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S. No & \cAlignHack Formulation & \cAlignHack Arithmetic Mean of Particle Size \\
\tblmidrule 
\cAlignHack 1. &
  \cAlignHack Fl &
  \cAlignHack 93 = 0.24\\
\cAlignHack 2. &
  \cAlignHack F2 &
  \cAlignHack 64+ 0.78\\
\cAlignHack 3. &
  \cAlignHack F3 &
  \cAlignHack 45\ensuremath{\pm}0.05\\
\cAlignHack 4. &
  \cAlignHack F4 &
  \cAlignHack 97+ 0.53\\
\cAlignHack 5. &
  \cAlignHack F5 &
  \cAlignHack 70\ensuremath{\pm}0.79\\
\cAlignHack 6. &
  \cAlignHack F6 &
  \cAlignHack 11 0 \ensuremath{\pm} 0.25 \\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Mean \ensuremath{\pm} S.D. of Three Determinations}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Carr's Index and Hausner's Ratio} }
\label{tw-26c9ea6e5751}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2028\linewidth-2\tabcolsep}p{\dimexpr.26119999999999997\linewidth-2\tabcolsep}p{\dimexpr.25450000000000003\linewidth-2\tabcolsep}p{\dimexpr.2815\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S. No & \cAlignHack Formulation & \cAlignHack Carr's Index & \cAlignHack Hausner's ratio\\
\tblmidrule 
\cAlignHack 1. &
  \cAlignHack Fl &
  \cAlignHack 14.13\ensuremath{\pm}0.31 &
  \cAlignHack 1.16\ensuremath{\pm}0.25\\
\cAlignHack 2. &
  \cAlignHack F2 &
  \cAlignHack 11.36\ensuremath{\pm}0.37 &
  \cAlignHack 1.12\ensuremath{\pm}0.26\\
\cAlignHack 3. &
  \cAlignHack F3 &
  \cAlignHack 14.07\ensuremath{\pm}0.41 &
  \cAlignHack 1.16\ensuremath{\pm}0.24\\
\cAlignHack 4. &
  \cAlignHack F4 &
  \cAlignHack 10.89\ensuremath{\pm}0.27 &
  \cAlignHack 1.23\ensuremath{\pm}0.26\\
\cAlignHack 5. &
  \cAlignHack F5 &
  \cAlignHack 14.85\ensuremath{\pm}0/6 &
  \cAlignHack 1.17\ensuremath{\pm}0.13\\
\cAlignHack 6. &
  \cAlignHack F6 &
  \cAlignHack 12.24\ensuremath{\pm}0.27 &
  \cAlignHack 1.14\ensuremath{\pm}0.16\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Mean \ensuremath{\pm} S.D. of Three Determinations}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Angle of Repose Mean \ensuremath{\pm} S.D. of Three Determinations} }
\label{tw-040a0f295ed6}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1772\linewidth-2\tabcolsep}p{\dimexpr.3772\linewidth-2\tabcolsep}p{\dimexpr.4456\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S. No & \cAlignHack Formulation & \cAlignHack Angle of Repose\\
\tblmidrule 
\cAlignHack 1. &
  \cAlignHack Fl &
  \cAlignHack 22.80\ensuremath{\pm}0.14\\
\cAlignHack 2. &
  \cAlignHack F2 &
  \cAlignHack 20.48\ensuremath{\pm}0.26\\
\cAlignHack 3. &
  \cAlignHack r3 &
  \cAlignHack 22.20\ensuremath{\pm}0.23\\
\cAlignHack 4. &
  \cAlignHack F4 &
  \cAlignHack 23.56\ensuremath{\pm}0.25\\
\cAlignHack 5. &
  \cAlignHack F5 &
  \cAlignHack 20.75\ensuremath{\pm}0.42\\
\cAlignHack 6. &
  \cAlignHack F6 &
  \cAlignHack 21.72\ensuremath{\pm}0.18\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Mean \ensuremath{\pm} S.D. of Three Determinations}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Drug Entrapment Efficiency} }
\label{tw-218bb0cd5b02}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1579\linewidth-2\tabcolsep}p{\dimexpr.24330000000000002\linewidth-2\tabcolsep}p{\dimexpr.2657\linewidth-2\tabcolsep}p{\dimexpr.3331\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S. No & \cAlignHack Formulation & \cAlignHack Drug Content  \mbox{}\protect\newline (mg)  & \cAlignHack Entrapment Efficiency  \mbox{}\protect\newline (\%) \\
\tblmidrule 
\cAlignHack 1.  &
  \cAlignHack Fl &
  \cAlignHack 40.55 \ensuremath{\pm}0.79 &
  \cAlignHack 81.10\ensuremath{\pm}0.01\\
\cAlignHack 2.  &
  \cAlignHack F2 &
  \cAlignHack 41.10 \ensuremath{\pm} 1.09 &
  \cAlignHack 82.20 \ensuremath{\pm} 1.03\\
\cAlignHack 3.  &
  \cAlignHack F3 &
  \cAlignHack 43.60 \ensuremath{\pm} 1.08 &
  \cAlignHack 87.20 \ensuremath{\pm} 0.05\\
\cAlignHack 4.  &
  \cAlignHack F4 &
  \cAlignHack 42.20 \ensuremath{\pm} 0.40 &
  \cAlignHack 84.40 \ensuremath{\pm} 0.07\\
\cAlignHack 5.  &
  \cAlignHack F5 &
  \cAlignHack 43.70 \ensuremath{\pm} 1.05 &
  \cAlignHack 87.40 \ensuremath{\pm}. 0.01\\
\cAlignHack 6.  &
  \cAlignHack F6 &
  \cAlignHack 44.95\ensuremath{\pm} 1.20  &
  \cAlignHack 89.30 \ensuremath{\pm} 0.05\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Mean \ensuremath{\pm} S.D. of Three Determinations}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Percentage Yield} }
\label{tw-5ad075d76ef2}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.22669999999999998\linewidth-2\tabcolsep}p{\dimexpr.3547\linewidth-2\tabcolsep}p{\dimexpr.4186000000000001\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S. No & \cAlignHack Formulation & \cAlignHack Percentage Yield\\
\tblmidrule 
\cAlignHack 1.  &
  \cAlignHack Fl &
  \cAlignHack 79.24 \ensuremath{\pm} 1.24 \\
\cAlignHack 2.  &
  \cAlignHack F2 &
  \cAlignHack 86.78 \ensuremath{\pm} 1.56\\
\cAlignHack 3.  &
  \cAlignHack F3 &
  \cAlignHack 94.88 \ensuremath{\pm} 1.31\\
\cAlignHack 4.  &
  \cAlignHack F4 &
  \cAlignHack 86.25\ensuremath{\pm} 1.21\\
\cAlignHack 5.  &
  \cAlignHack F5 &
  \cAlignHack 18.29 \ensuremath{\pm} 1.30\\
\cAlignHack 6.  &
  \cAlignHack F6 &
  \cAlignHack 95.13 \ensuremath{\pm} 1.37\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Mean \ensuremath{\pm} S.D. of Three Determinations}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Kinetic Modeling of Drug Release from F6} }
\label{tw-8e76ece1680a}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.09\linewidth-2\tabcolsep}p{\dimexpr.0911\linewidth-2\tabcolsep}p{\dimexpr.11700000000000001\linewidth-2\tabcolsep}p{\dimexpr.11\linewidth-2\tabcolsep}p{\dimexpr.1209\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}p{\dimexpr.121\linewidth-2\tabcolsep}p{\dimexpr.118\linewidth-2\tabcolsep}p{\dimexpr.112\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S.No & \cAlignHack (min) & \cAlignHack Time \mbox{}\protect\newline Log T & \cAlignHack Square  \mbox{}\protect\newline rout of  \mbox{}\protect\newline Time & \cAlignHack \%  \mbox{}\protect\newline C.R. & \cAlignHack \% Drug  \mbox{}\protect\newline Remaining  & \cAlignHack Lug  \mbox{}\protect\newline \%  \mbox{}\protect\newline C.R. & \cAlignHack Log  \mbox{}\protect\newline \% \mbox{}\protect\newline Drug  \mbox{}\protect\newline Remaining & \cAlignHack Square  \mbox{}\protect\newline root  \mbox{}\protect\newline Drug  \mbox{}\protect\newline Remaining\\
\tblmidrule 
\cAlignHack 1 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 100 &
  \cAlignHack 0 &
  \cAlignHack 2 &
  \cAlignHack 4.641\\
\cAlignHack 2 &
  \cAlignHack 2 &
  \cAlignHack 0.30 I~0 &
  \cAlignHack 1.4142 &
  \cAlignHack 09.56 &
  \cAlignHack 90.44 &
  \cAlignHack 0.9804 &
  \cAlignHack 1.95636 &
  \cAlignHack 4.4886\\
\cAlignHack 3 &
  \cAlignHack 4 &
  \cAlignHack 0.6020 &
  \cAlignHack 2.0 &
  \cAlignHack 19.25 &
  \cAlignHack 80.75 &
  \cAlignHack 1.2844 &
  \cAlignHack 1.9074 &
  \cAlignHack 4.32229\\
\cAlignHack 4 &
  \cAlignHack 6 &
  \cAlignHack 0.7781 &
  \cAlignHack 2.4494 &
  \cAlignHack 25.43 &
  \cAlignHack 74.57 &
  \cAlignHack 1.4053 &
  \cAlignHack 1.87256 &
  \cAlignHack 4.20908\\
\cAlignHack 5 &
  \cAlignHack 8 &
  \cAlignHack 0.9030 &
  \cAlignHack 2.8284 &
  \cAlignHack 3I.34 &
  \cAlignHack 68.66 &
  \cAlignHack 1.4960 &
  \cAlignHack 1.83670 &
  \cAlignHack 4.09481\\
\cAlignHack 6 &
  \cAlignHack 10 &
  \cAlignHack 1.0434 &
  \cAlignHack 3.1622 &
  \cAlignHack 36.72 &
  \cAlignHack 63.28 &
  \cAlignHack 1.5649 &
  \cAlignHack 1.80126 &
  \cAlignHack 3.98494\\
\cAlignHack 7 &
  \cAlignHack 12 &
  \cAlignHack 1.0791 &
  \cAlignHack 3.4241 &
  \cAlignHack 44.11 &
  \cAlignHack 55.89 &
  \cAlignHack 1.6445 &
  \cAlignHack 1.74733 &
  \cAlignHack 3.82335\\
\cAlignHack 8 &
  \cAlignHack 14 &
  \cAlignHack 1.1461 &
  \cAlignHack 3.741 &
  \cAlignHack 52.09 &
  \cAlignHack 47.91 &
  \cAlignHack 1.7167 &
  \cAlignHack 1.68042 &
  \cAlignHack 3.61196\\
\cAlignHack 9 &
  \cAlignHack 16 &
  \cAlignHack 12041 &
  \cAlignHack 4.9423 &
  \cAlignHack 6123 &
  \cAlignHack 39.77 &
  \cAlignHack 1.7798 &
  \cAlignHack 1.59955 &
  \cAlignHack 3.41338\\
\cAlignHack 10 &
  \cAlignHack 18 &
  \cAlignHack 1.2552 &
  \cAlignHack 4.2426 &
  \cAlignHack 68.75 &
  \cAlignHack 31.25 &
  \cAlignHack 1.8372 &
  \cAlignHack L49485 &
  \cAlignHack 3.14930\\
\cAlignHack 11 &
  \cAlignHack 20 &
  \cAlignHack 1.3010 &
  \cAlignHack 4.4721 &
  \cAlignHack 77.56 &
  \cAlignHack 22.44 &
  \cAlignHack 1.8896 &
  \cAlignHack 1.35102 &
  \cAlignHack 2.82059\\
\cAlignHack 12 &
  \cAlignHack 22 &
  \cAlignHack 1.3424 &
  \cAlignHack 4.6904 &
  \cAlignHack 86.45 &
  \cAlignHack 11.97 &
  \cAlignHack 1.9367 &
  \cAlignHack 1.13193 &
  \cAlignHack 2.38403\\
\cAlignHack 13 &
  \cAlignHack 24 &
  \cAlignHack 1.3302 &
  \cAlignHack 4.8989 &
  \cAlignHack 95.85 &
  \cAlignHack 4.15 &
  \cAlignHack 1.9815 &
  \cAlignHack 0.618048 &
  \cAlignHack 1.60700\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Regression Coefficients or Kinetic Release Model} }
\label{tw-69c6c102107b}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.4326\linewidth-2\tabcolsep}p{\dimexpr.5674\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Order of Kinetics & \cAlignHack Regression Coefficient (r\ensuremath{^{2}}) \\
\tblmidrule 
\cAlignHack Zero-order &
  \cAlignHack 0.9541\\
\cAlignHack First order &
  \cAlignHack  0.8027\\
\cAlignHack Higuchi release &
  \cAlignHack 0.9541\\
\cAlignHack Korsmeyer Peppas &
  \cAlignHack 0.7604\\
\cAlignHack Hixson Crowel &
  \cAlignHack 0.9081\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Accelerated Stability Studies or Optimized Formulations F6} }
\label{tw-61fdf9473e7e}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2287\linewidth-2\tabcolsep}p{\dimexpr.1946\linewidth-2\tabcolsep}p{\dimexpr.1821\linewidth-2\tabcolsep}p{\dimexpr.1946\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Parameters & \cAlignHack 0 Days & \cAlignHack 30 Days & \cAlignHack 60 Days & \cAlignHack 90 Days\\
\tblmidrule 
\cAlignHack Particle size &
  \cAlignHack 110.2 \ensuremath{\pm} 0.25 &
  \cAlignHack 110.2 \ensuremath{\pm} 0.31 &
  \cAlignHack 111.2 \ensuremath{\pm} 0.25 &
  \cAlignHack 112.2 \ensuremath{\pm} 0.23\\
\cAlignHack Entrapment Efficiency &
  \cAlignHack 89.30 \ensuremath{\pm} 0.05 &
  \cAlignHack 89.32 \ensuremath{\pm} 0.06 &
  \cAlignHack 89.32 \ensuremath{\pm} 0.05 &
  \cAlignHack 90.30 \ensuremath{\pm} 0.03\\
\cAlignHack \textit{In-Vitro} Drug Release &
  \cAlignHack 95.85 \ensuremath{\pm} 0.41 &
  \cAlignHack 95.92 \ensuremath{\pm} 0.46 &
  \cAlignHack 95.95 \ensuremath{\pm} 0.41 &
  \cAlignHack 96.85 \ensuremath{\pm} 0.42\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Evaluation of Prepared Floating Microspheres}

The prepared floating microspheres were evaluated for size analysis, Scanning electron microscopy (SEM), Bulk Density, Tapped Density, Carr's Index, and Hausner's ratio. Angle of Repose, Drug Content, Drug Entrapment Efficiency, buoyancy, and \textit{In }vitro dissolution studies \unskip~\cite{1601862:26526211}.

\textbf{Scanning Electron Microscopy}

Microsphere morphology has been researched using a scanning electron microscope (SEM). Specimens such as sem have been able to prepare by gently spattering on the double adhesive tape trapped to such an aluminum stub. Stubs were also painted for platinum to a width of about ten the under a kind of argon atmosphere using just a gold sputter component inside a high-vacuum evaporator. A scratch usually contains a film deposited and positioned within a scanning electron microscopy compartment. Specimens were also randomized searched, and photomicrographs were begun taking just at acceleration wattage like 20 kv, an initial depth of focus of 30' to enquire about the interior morphological characteristics microspheres were split into two parts items using a cutting \unskip~\cite{1601862:26526215}.

\textbf{Size Analysis of Microspheres}

The size of a microsphere's particles was resolute through optical microscopy \unskip~\cite{1601862:26526226}. A slight drop-like suspension has been positioned on such a glass beaker slide. Slide usually contains suspension microspheres has been assembled upon that phase of a magnifying glass, but also 300 particulate have been assessed, increasing an adjusted ocular micrometric. The method has been replicated three times for every batch able to prepare.

\textbf{Bulk Density and True Density}

Bulk density and tapped density have been assessed using high-density equipment. Specimens were put inside a 100 ml measuring cylinder. A cylinder has been corrected upon that bulk density equipment, and a timer "mob has been arranged, such as 100 toppings. High density and tapped density have been determined by calculating from the following formulae \unskip~\cite{1601862:26526224}. A tapped density has been selected by calculating, through gm per ml.

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{Bulk\;density=\frac{Bulk\;volume\;of\;microcapsules}{Weight\;of\;microcapsules}}} $

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{Tapped\;Density=\frac{Tapped\;mass\;of\;microcapsules}{Tapped\;volume\;of\;microcapsules}}} $

\textbf{The Measure of Powder Compressibility}

Using high-density equipment, Carr's index and Hausner's ratio have been ascertained from the tapped and bulk densities of such recognized poundage-like specimens. The following equations were used to determine carr's index and Hausner's ratio.

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{Carr's\;Index=\frac{Tapped\;Density}{Tapped\;density-bulk\;density}}} $

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{Hausner's\;Ratio=\frac{Bulk\;density}{Tapped\;density}}} $

\textbf{The Angle of Repose} \textbf{\space }

The flow characteristics of microcapsules were studied by measuring the angle of Repose employing the fixed funnel method. Such as suitable allowing components after which the tip of Repose will be less than 30\ensuremath{^\circ} \unskip~\cite{1601862:26526223}. The rise of Repose has been determined by calculating using the given equations.

O= tan\ensuremath{^{-1}}(h/r)

Where, H is the height; R is the radius of the cone.

\textbf{Drug Content and Entrapment Efficiency}

Microspheres similar to 50 mg of an opioid have been begun taking such as assessment. The quantity of opioids entrapped has been approximated by smashing microparticles and trying to extract aliquots like ph 7.4 PBS repetitively. An extricate transmitted to a 50 ml volumetric flask, and the volume was made using ph 7.4 PBS \unskip~\cite{1601862:26526214}. The solution has been filtrated, and the absorbance was recorded since appropriate dispersion spectrophotometrically about 239 nm against a suitable blank. The quantity of opioids encapsulated within microspheres has been determined by calculating even by following equations.

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{DEE=\frac{Amount\;of\;the\;drug\;actually\;present}{\;Theoretical\;drug\;load\;expected}\times100}} $

\textbf{Percentage Yield }

The prepared microspheres were collected and weighed. The measured Weight was divided by the total amount deli non-volatile components which were used for the preparation of the microspheres.

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{Percentage\;Yield\;(\%)=\frac{W1}{W2}\times100}} $

Where, W1 = Weight of microspheres; W2 = Total Weight of drug and polymer used in the formulation.

\textit{\textbf{In-Vitro }} \textbf{Release Study\textit{}}

Invitro drug release was investigated in simulated intestinal fluid (SIF -pH 7.4 phosphate buffer) until complete degradation \unskip~\cite{1601862:26526218}. A drug dissolution test like microspheres has been conducted using USP XXIII paddle kind of dissociation equipment (TDT-08L, electro lab India, Mumbai) at about 100 rpm 37\ensuremath{^\circ}c \ensuremath{\pm} 0.5\ensuremath{^\circ}c\_ microspheres (100 mg) have been weighed precisely but also packed through tea bags. Tea bags have been linked utilizing thread for a paddle and loaded into the dissociation equipment, usually containing a 900 ml-like dissolution medium. 

A specimen (10 ml) was forced to withdraw from the dissolution medium at intervals like 1 hr using just a pipette equipped with such a micro filter now at tips but also evaluated such as opioid through LTV spectrometer against a standard curve (r2 {\textgreater} 0\_99) acquired at = 239 nit!. 

Flawless sink affliction has been preserved during the dissolution rates period of study also with added of such an equal amount like fresh discharge moderate around the same temp \unskip~\cite{1601862:26526220}.

The cumulative amount of drug release = C x D.F. x D.M.

Where, C = concentration of drug at each time interval (pg/m1); D.F. = Dilution Factor is 100; DM = Dissolution Medium (900 ml).

\textbf{Kinetics of Drug Release (Model Dependent Methods)} \textbf{\space }

To investigate the mechanism of release of drugs from the prepared microspheres \unskip~\cite{1601862:26526221}, the release data were analyzed with the following mathematical release models [Table~\ref{tw-f38836ce0977}].

1. Cumulative percentage drug release Vs. \ensuremath{^{-}}4 (Higuchi's classical diffusion equation)

2. Time Vs. Cube root of Percentage drug remaining (Hixson - Crowell)

3. Log of cumulative percentage drug release Vs. log Time (Peppas exponential equation)

\textbf{Stability Studies}

Accelerated stability studies were performed for the final optimized formulation \unskip~\cite{1601862:26526209}. The prepared microspheres were selected for stability studies, which showed an appropriate balance between the drug content and the percentage release. The ready formulation was packed in aluminum foil and stored at 40 'Ct2T/75\%R.E1\ensuremath{\pm}55\ensuremath{^{1}}0RH temperatures per ICH guidelines \unskip~\cite{1601862:26526225}. As per the standard protocol, the samples must be analyzed at 0, 1. 2, 3, and 6 months' time points.
    
\section{RESULTS AND DISCUSSION}
\textbf{Drug Excipients Compatibility Studies}

The interaction studies [Table~\ref{tw-54ec736f18ef}] were to determine whether any interactions between drugs and the excipients used in the production of microspheres [Figure~\ref{f-9d5e0c83dae5}  and Figure~\ref{f-445f5da0f8d6}].


\bgroup
\fixFloatSize{images/cae6a9b7-8b0a-4b46-9c31-df579b3b3633-upicture3.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/cae6a9b7-8b0a-4b46-9c31-df579b3b3633-upicture3.png}{\includegraphics{images/cae6a9b7-8b0a-4b46-9c31-df579b3b3633-upicture3.png}}{}
\makeatother 
\caption{\boldmath {FTIR Spectrum of Capecitabine}}
\label{f-9d5e0c83dae5}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/b3508c03-97e0-4c45-bb17-c6ff777b2814-upicture4.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/b3508c03-97e0-4c45-bb17-c6ff777b2814-upicture4.png}{\includegraphics{images/b3508c03-97e0-4c45-bb17-c6ff777b2814-upicture4.png}}{}
\makeatother 
\caption{\boldmath {FTIR Spectrum of Drug and Polymer Mixture}}
\label{f-445f5da0f8d6}
\end{figure}
\egroup
\textbf{Differential Scanning Calorimetry (DSC)}

Medication excipient interactions are essential for, among other things, the release of the drug from the formulation. The physical and chemical interactions between the medication and the excipients utilized have been studied using DSC. Figure~\ref{f-8294c82bfeff}  shows the obtained DSC thermograms. It demonstrates that the drug's breakdown temperature was 121.84\ensuremath{^{o}}C and the formulation mixture was 122.20 \ensuremath{^\circ}C. It indicates there is no chemical interaction between Capecitabine and the polymer used.


\bgroup
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\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/e8781951-122b-4aee-9655-4592cef24f0b-upicture5.png}{\includegraphics{images/e8781951-122b-4aee-9655-4592cef24f0b-upicture5.png}}{}
\makeatother 
\caption{\boldmath {DSC Thermograms of (A) Pure Capecitabine and (B) Drug-Loaded Microspheres } (F6)}
\label{f-8294c82bfeff}
\end{figure}
\egroup
\textbf{Scanning Electron Microscopy (SEM)} \textbf{\space }

Scanning electron microscopy of optimized formulation F6 is shown in Figure~\ref{f-82612fee829f}. The view of the microspheres showed a spherical structure with a smooth surface morphology and discrete. The outer surface of the microspheres was smooth and showed some porous structure. 


\bgroup
\fixFloatSize{images/025edfa9-bc33-47bf-ba4f-8470bda62fab-upicture6.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/025edfa9-bc33-47bf-ba4f-8470bda62fab-upicture6.png}{\includegraphics{images/025edfa9-bc33-47bf-ba4f-8470bda62fab-upicture6.png}}{}
\makeatother 
\caption{\boldmath {Scanning Electron Micrographs of Microsphere Formulation F6 Size Analysis}}
\label{f-82612fee829f}
\end{figure}
\egroup
The average particle size of microspheres as determined by optical microscopy using a stage micrometer and ocular micrometer is shown in Table~\ref{tw-26c9ea6e5751}, and the units were analyzed in triplicate. All batches of microspheres were prepared by keeping the drug amount and solvent volume constant The particle size of floating microspheres varied between 45+0.05 to 110+0.25 tine. The results indicate that the mean particle size increases with increased concentration of polymers as the viscosity increases particle size increases. The formulation F6 showed a maximum particle size of I~I 0\ensuremath{\pm}0.25 um compared to other formulations. 

\textbf{Bulk Density and Tapped Density}

The prepared microspheres for all the formulations were evaluated for bulk density and tapped density by using bulk density apparatus, and the results are shown in Table~\ref{tw-040a0f295ed6}. 

The bulk density was found in the range of 0.933-0.984 gm/cm\ensuremath{^{\ensuremath{^{3}}}}. The tapped density ranged between 0.941- 0.99 gm/cm\ensuremath{^{3}}. 

\textbf{Size Analysis}

The average particle size of microspheres, as determined by optical microscopy using a stage micrometer and an ocular micrometer, is shown in Table~\ref{tw-54ec736f18ef}. The units were analyzed in triplicate. All batches of microspheres were prepared by keeping the drug amount and solvent volume constant. The particle size of floating microspheres varied between 45\ensuremath{\pm}0.05 to 110=0.25. The results indicate that the mean particle size increases with increased concentration of polymers; as the viscosity increases, particle size increases. The formulation F6 showed a maximum particle size of 110\ensuremath{\pm}0.25 \ensuremath{\mu}m compared to other formulations.

\textbf{The Angle of Repose }

All formulations Fl to F6 of microspheres were evaluated for angle of Repose (Table~\ref{tw-040a0f295ed6}); the rise of Repose of all the formulations was within the range of 20'-25\ensuremath{^\circ}; these values indicate that the prepared microspheres exhibited excellent flow properties. 

\textbf{Drug Content and Entrapment Efficiency}

The values of drug loading and entrapment efficiency \% are shown in Table~\ref{tw-218bb0cd5b02}. Drug content of the prepared formulations ranged between 40.55 \ensuremath{\pm} 10.79 to 44.95 \ensuremath{\pm} 24 mg, and drug entrapment efficiency varied from 81.10 \ensuremath{\pm} 0.01 to 89.30=0.05\%. This result indicated that the drug content and entrapment efficiency increased with the concentration of Ethylcellulose with the combination of HPMC K-100. Polymer concentration increases the viscosity of the solution. This was due to the ethyl cellulose showing good entrapment efficiency and the rank order of entrapment efficiency F6{\textgreater} F5{\textgreater} F3{\textgreater}F4{\textgreater} F2{\textgreater} Fl.

\textbf{Percentage Yield} \textbf{\space }

The percentage yield for the microspheres prepared by emulsion solvent evaporation was recorded in Table~\ref{tw-8e76ece1680a}, and it was determined by collected the microspheres and weighed. The measured Weight was divided by the total amount of all polymer components used to prepare the microspheres [Table~\ref{tw-69c6c102107b}]. The percentage yields of microspheres of all formulations were in the range of 79.24\ensuremath{\pm} 1.24 to 95.13\ensuremath{\pm}1.37\% [Table~\ref{tw-5ad075d76ef2}]. The formulation F6 showed a maximum percentage yield of 95.13 1.37\% compared to other formulations.

\textbf{Accelerated Stability Studies}

The most influential formulation's drug entrapment efficiency, particle size, and in vitro release research were assessed, and the results revealed no appreciable changes during storage. In the improved formulas, a foil made of aluminum wraps and seals F6. Table~\ref{tw-61fdf9473e7e}  displays the findings from stability studies.
    
\section{CONCLUSION}
The formulation of colon-targeted microspheres of the chemotherapeutic compound capecitabine utilizing the polymers E.C. and HPMC in combination was successful. The emulsion solvent evaporation method created spherical and freely flowing microspheres. The efficient formulations were found to have a strong recovery yield and percent drug entrapment due to the microspheres' good flow ability, which suggests that they may be handled and either filled into a capsule or crushed to tablet dose FCPMI. According to the study, the polymer concentration impacted the microspheres' release profile, and microspheres could delay the release of Capecitabine until it reached the colon. The produced microspheres provide potential as a colon-targeted delivery system since they have a higher kinetic profile and bioavailability.
    
\section{Acknowledgement}
I am heartly thankful to Dr. K. Harinadha Baba, M.Pharm., Ph.D., Principal, Narayana Pharmacy College,  for their kind encouragement and support during the research work and thankful to the management of Narayana Pharmacy College, Chinthareddypalem,  Nellore (Dist), Andhra Pradesh, India, for providing all the chemicals and facilities to do this research work. 

\textbf{Conflict of Interest}

The authors declare no conflict of interest, financial or otherwise.

\textbf{Funding Support}

The authors declare that they have no funding for this study.
    

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