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\def\citeauthor{~Pindukuri~Chakrapani,
              ~Bharath~Kumar~A,
              ~Prakash~Reddy~PK}
\def\citetitle{\textbf{Formulation and Evaluation of Ocular \textit{In-Situ} Gels of Besifloxacin}}
\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{Pindukuri Chakrapani et al.}
\firstPage{160}
\articleType{Original Article}
\receivedDate{20 Aug 2022}
\acceptedDate{07 Sep 2022}
\revisedDate{05 Sep 2022}
\journalVolume{1}
\journalIssue{4}
\journalDoi{ijebr.v1i4.392}
\copyrightYear{2022}
\eISSN{2583-5254}
\journalDoi{ijebr.v1i4.392}
\def\authorCount{3}
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\def\journalTitle{International Journal of Experimental and Biomedical Research}

\title{\textbf{Formulation and Evaluation of Ocular \textit{In-Situ} Gels of Besifloxacin}}
\author{Pindukuri~Chakrapani\textsuperscript{*}\textsuperscript{\href{https://orcid.org/0000-0002-0293-0338}{\XeTeXLinkBox{\includegraphics[height=7pt]{orcid-logo-pharmascope.pdf}}}},  
            Bharath~Kumar~A, 
            Prakash~Reddy~PK~\\[5pt]{Department of Pharmaceutics, Mahathi College of Pharmacy, Chinnatipa Samudram, Madhanapalle-517 325, Andhra Pradesh, India}}

\begin{abstract}
Besifloxacin, a fourth-generation broad-spectrum antibiotic indicated for infective ophthalmitis, is intended to be released over a sustained period using ion-sensitive ocular \textit{in situ} gels, which were the focus of the current work. The present analysis concludes that designing and creating oral \textit{in-situ} gels of Besifloxacin requires a careful selection of polymers and medication. According to I.R. and U.V. investigations, the polymer is chosen, sodium alginate and HPMC were compatible with pefloxacin. It was found that the two polymers' different concentrations had an impact on the gel's viscosity, spreadability, and drug release. Gel formulations demonstrated good stability and uniformity. However, the gel formula, which showed the most significant percentage of drug release and favorable rheological characteristics, ended up being the formula of choice. Based on \textit{in vitro} release investigations. Formulation F3 gives better and quicker patient improvement. When compared to other formulations, the F3 formulation is the most optimal. There is room for additional pharmacokinetic research because the outcomes of the studies that have already been done are encouraging. With this prolonged drug delivery system, the medicine's bioavailability can also be increased, benefiting patient efficacy, compliance, and therapeutic usefulness.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Ocular,\newline In situ,\newline Besifloxacin,\newline Ophthalmitis
\end{keywords}
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\makeatletter{\raggedright{\Large$^\ast$}Corresponding Author\par Name:\ Pindukuri~Chakrapani~\\ Phone:\ +91 6305500347~\\  Email:\ panichakra66@gmail.com
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\section{Introduction}
Ophthalmic drug distribution is complex because the eye's specific architecture limits drug absorption into the deeper tissues. The disadvantages of the available ophthalmic medication delivery methods, such as inserts, ointments, and suspensions, were patient compliance issues, impaired vision, and heterogeneity \unskip~\cite{1635738:26743802}. 

Due to slower drainage from the cornea, increasing a drug formulation's viscosity in the precorneal region can boost bioavailability. Several approaches for in-situ gelling devices have been investigated to address this issue. Ion activation, pH, and temperature can all activate these systems. 

\textit{In-situ} gels are created from polymers that experience phase transition due to environmental physicochemical change. They are quickly injected into the conjunctival sac of the eye as a solution \unskip~\cite{1635738:26743790}. 

The polymer modifies its structure to form a gel when it comes into contact with the lachrymal fluid. Due to the gel formation, this delivery system has a long retention time and is as simple to use as an ophthalmic solution. 

Ion-sensitive in-situ gels can produce a gel on the ocular surface by cross-linking with the cations found in tear fluid. Buffers can be manufactured at the ideal pH for ocular delivery and can be precisely and quickly injected at room temperature \unskip~\cite{1635738:26743793}.
    
\section{Materials and Methods }
Besifloxacin was obtained from Aurobindo Pharma Ltd, Hyderabad, India, as a gift sample, HPMC E50, sodium alginate, K4M. Other chemicals came from Mumbai's S.D. Fine Chemicals. Analytical-grade materials and solvents were also used.

\textbf{Preparation of \textit{In situ} gel}

The necessary amounts of HPMC- E 50 LV/HPMC- K4M and sodium alginate were dissolved in water while continuously stirring. The dispersion process was used to create the polymeric solution. Besifloxacin solution was continuously stirred into the polymeric solution [Table~\ref{tw-f7b0d87118f2}]. Agents for preservation and isotonicity were introduced \unskip~\cite{1635738:26743791}. The solution's pH was determined to be 6.3{\textendash}6.5.


\begin{table*}[!htbp]
\caption{\boldmath {Formulation Design of In situ Gelling System} }
\label{tw-f7b0d87118f2}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.4234\linewidth-2\tabcolsep}p{\dimexpr.09600000000000005\linewidth-2\tabcolsep}p{\dimexpr.07510000000000003\linewidth-2\tabcolsep}p{\dimexpr.069999999999999964\linewidth-2\tabcolsep}p{\dimexpr.0651\linewidth-2\tabcolsep}p{\dimexpr.06709999999999997\linewidth-2\tabcolsep}p{\dimexpr.06909999999999998\linewidth-2\tabcolsep}p{\dimexpr.07409999999999998\linewidth-2\tabcolsep}p{\dimexpr.06009999999999999\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Ingredients (mg)  & F1 & F2 & F3 & F4 & F5 & F6 & F7 & F8\\
\tblmidrule 
Drug &
  2 &
  2 &
  2 &
  2 &
  2 &
  2 &
  2 &
  2\\
Sodium Alginate &
  500  &
  1000  &
  1000 &
  500 &
  1500 &
  500 &
  - &
  -\\
HPMC K15M &
  500  &
  1000 &
  500 &
  1000 &
  500 &
  1500  &
  500 &
  1000\\
Ethylcellulose &
  - &
  - &
  - &
  - &
  - &
  - &
  1000 &
  500\\
Calcium carbonate &
  2000  &
  2000  &
  2000  &
  2000  &
  2000  &
  2000  &
  2000 &
  2000\\
Methylparaben &
  198 &
  198 &
  198 &
  198 &
  198 &
  198 &
  198 &
  198\\
Distilled water  \mbox{}\protect\newline (up to 100ml) &
  Q.S &
  Q.S &
  Q.S &
  Q.S &
  Q.S &
  Q.S &
  Q.S &
  Q.S\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Evaluation Parameters}

\textbf{Evaluation of Gels}\ensuremath{^{}}

Gels were evaluated for their clarity, pH, viscosity, spreadability, skin irritation test, drug content, in vitro diffusion, and in vivo studies by using standard procedure. All analyses were carried out in triplicate, and average values were reported \unskip~\cite{1635738:26743796}. 

\textbf{Clarity}

Visual inspection was used to assess the clarity of different formulations under the black and white background \unskip~\cite{1635738:26743794}, and It was given the following grades: turbid (+), transparent (+), and apparent (+++).

\textbf{P.H.}

In 25 ml of purified water, 2.5 grams of gel were precisely weighed and mixed 82. Digital pH meters were used to measure the pH of the dispersion \unskip~\cite{1635738:26743797}. (Systronics \ensuremath{\mu} pH system 362). 

\textbf{Homogeneity}

All developed. After being placed in the container, the appearance of the gels and the presence of any aggregate were checked for homogeneity \unskip~\cite{1635738:26743792}.

\textbf{Spreadability}

Glass slide and wooden block measuring tools were used to determine it. The excess sample was put for the spreadability test between two glass slides and squeezed to a uniform thickness for 5 minutes with a 1000 g weight. 50 g of weight was put into the pan \unskip~\cite{1635738:26743789}. The spreadability was measured by the Time it took to separate the two slides or when the upper glass slide moved over the bottom plates (S). Spreadability was determined using the following formula:

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{S=ML/T}} $

Where, 

S = Spreadability

M = Weight tide to upper slide 

L = Length moved on the glass slide 

T = Time taken to separate the slide from each other

\textbf{Viscosity Measurement}

The viscosity of the gels was measured using a Brookfield DV-II + Pro viscometer and a tiny sample adaptor with the spindle number SC4-18/13R. The torque applied to the gel ranged from 10\% to 100\%. The "Local" software was used to determine the viscosity \unskip~\cite{1635738:26743798}.

\textbf{Drug Content}

The Besifloxacin 50 cc of phosphate buffer 6.8 was used to dissolve 100 mg of gel. The volumetric flask holding the gel solution was agitated on a mechanical shaker for two hours to obtain complete drug solubility. This solution underwent filtering and spectrophotometer estimation \unskip~\cite{1635738:26743799}. 

\textbf{Extrudability}

The Pfizer hardness tester was used to conduct the extrudability test. The aluminum tube was filled with 15gm of gel. To adequately secure the line, the plunger was adjusted. For 30 seconds, 1 kg/cm2 of pressure was applied. The weighing was done on the gel that was extruded. At three equally spaced locations along the tube, the process was repeated. A test was conducted in triplicates \unskip~\cite{1635738:26743801}. 

\textbf{Through Dialysis Sac }

The device is a cylindrical glass tube with an internal diameter of 22 mm and a height of 76 mm that was opened on both ends. One end of the line was fixed to the dialysis sac, which had previously been soaked in water for 15 minutes, and 100 mg of the gel formulation equivalent to 1 mg of besifloxacin was evenly disseminated on the surface. The preparation now fills the inner circumference of the tube. The assembly was adjusted so that the lower end of the line carrying the gel barely touched (1-2 mm depth) the surface of the diffusion medium, which was a 250 ml beaker containing 200 ml of phosphate buffer with a pH of 6.8 that was kept at 37.2 C in a water bath. The contents were swirled using a magnetic stirrer at a speed of 100 10 rpm. The dialysis sac is a barrier between the gel phase and water (the sink phase). At intervals of 1, 2, 3, 4, 6, 8, 10, and 12 hours, 5 ml of the receptor fluid was taken. A spectrophotometer set at 280 nm was used to estimate the release of the medication, and 5 ml of pH 6.8 phosphate buffer was changed immediately after each estimate \unskip~\cite{1635738:26743788}.

\textbf{Drug Release Kinetics for Prepared Besifloxacin \textit{In-situ } Gel}

Data from the in vitro release was plotted in several kinetics models to evaluate the kinetics of release \unskip~\cite{1635738:26743795,1635738:26743800}.

\textbf{Zero Order Equation}

The graph was drawn as percent medication release vs. days.

$C=K_0t $

First Order Equation

Log cumulative\% medication remaining was used to depict the graph against Time in days.

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{Log\;C\;=\;\log\;C_0\;-\;Kt\;/2.3}} $

\textbf{Higuchi Kinetics}

The cumulative \% drug release vs. square root of Time was used to produce the graph.

$Q=Kt^{1/2} $

\textbf{Korsmeyer{\textendash}Peppas Equation}

To evaluate the drug release mechanism, which was then plotted as log cumulative\% drug release vs. Time in Peppa's equation.

$\style{font-family:'Times New Roman'}{\style{font-size:8px}{\begin{array}{l}Mt/\;Ma\;=\;Kt^\Elzrtln\;\\Log\;Mt/\;Ma=\;Log\;K+\;n\;\log t\end{array}}} $

\textbf{Stability Study }

Besifloxacin \textit{In-situ } Gel Stability tests were run on the formulas developed for this investigation [Table~\ref{tw-67ad915eeaf4}]. Stability research on the best formulation of F3 was carried out following ICH recommendations under various humidity and temperature conditions for 3 or 6 months.


\begin{table}[!htbp]
\caption{\boldmath {Stability Study Storage Condition} }
\label{tw-67ad915eeaf4}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.3247\linewidth-2\tabcolsep}p{\dimexpr.6753\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Study  & Storage Condition \\
\tblmidrule 
Long term  &
  25\ensuremath{^{o}}C + 2\ensuremath{^{o}}C/60\%RH+ 5\% RH\\
Intermediate  &
  30\ensuremath{^{o}}C+ 2\ensuremath{^{o}}C/65\%RH+ 5\% RH\\
Accelerated  &
  40\ensuremath{^{o}}C+ 2\ensuremath{^{o}}C/75\%RH+ 5\% RH\\
\tblbottomrule 
\end{tabulary}\par 
\end{table}
The samples were withdrawn after 3 and 6 months and were analyzed for their Clarity; Spreadability; Viscosity; Drug content, and \textit{In-vitro} drug release. The results revealed no significant changes in Clarity, Spreadability, Drug content, and In-vitro drug release for F3 formulation.
    
\section{Results and Discussion}
\textbf{Pre-Formulation Studies}

The first stage in creating any formulation is to conduct pre-formulation investigations. 

The main objective of this investigation was to determine whether the medicine was compatible with the polymers that were being employed.


\begin{table*}[!htbp]
\caption{\boldmath {FTIR Spectrum Data for Pure Besifloxacin} }
\label{tw-fc522aefad90}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.223\linewidth-2\tabcolsep}p{\dimexpr.2613\linewidth-2\tabcolsep}p{\dimexpr.22069999999999997\linewidth-2\tabcolsep}p{\dimexpr.295\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.4843\linewidth-2\tabcolsep)}}{\cAlignHack IR absorption bands (cm\ensuremath{^{-1}}) } & Bond  & Functional Group\\
\rowcolor{kwdboxcolor}Observed Peak & Characteristic Peak &  & \\
\tblmidrule 
3009.0 &
  3000-3100 &
  O-H strech &
  Monometric alcohol\\
1338.0 &
  1330-1540 &
  C-H Bend in plane &
  Alkanes\\
1225.4 &
  800-1300 &
  -C-O strech &
  Alcohol, ethers\\
1005.4 &
  800-1300 &
  -C-O strech &
  Alcohol, ethers\\
999.1 &
  800-1300 &
  -C-O strech &
  Alcohol, ethers\\
877.5 &
  800-1300 &
  -C-O strech &
  Alcohol, ethers\\
805.3 &
  800-1300 &
  -C-O strech &
  Alcohol, ethers\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {I.R. Spectrum Data for Pure Sodium Alginate, HPMC K15M and Ethyl Cellulose} }
\label{tw-1a2e3fd2026f}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.25\linewidth-2\tabcolsep}p{\dimexpr.2635\linewidth-2\tabcolsep}p{\dimexpr.22529999999999998\linewidth-2\tabcolsep}p{\dimexpr.2612\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.5135\linewidth-2\tabcolsep)}}{\cAlignHack I.R. absorption bands (cm\ensuremath{^{-1}}) } & Bond  & Functional Group\\
\rowcolor{kwdboxcolor}Observed peak & Characteristic peak  &  & \\
\tblmidrule 
3009.0 &
  3000-3100 &
  O-Hstrech &
  Monometric alcohol\\
3005.0 &
  3000-3100 &
  O-Hstrech &
  Monometric alcohol\\
1500.0 &
  1330-1540 &
  C-H Bend in plane &
  Alkanes\\
1153.3 &
  800-1300 &
  -C-Ostrech &
  Alcohol,ethers\\
1111.3 &
  800-1300 &
  -C-Ostrech &
  Alcohol,ethers\\
1005.4 &
  800-1300 &
  -C-Ostrech &
  Alcohol,ethers\\
999.1 &
  800-1300 &
  -C-Ostrech &
  Alcohol,ethers\\
805.3 &
  800-1300 &
  -C-Ostrech &
  Alcohol,ethers\\
754.5 &
  600-1500 &
  C-Clstrech &
  Alkanes\\
657.0 &
  600-1500 &
  C-Clstrech &
  Alkanes\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {I.R. Spectrum Data for Mixture of all Ingredients} }
\label{tw-d7598da69961}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2275\linewidth-2\tabcolsep}p{\dimexpr.2613\linewidth-2\tabcolsep}p{\dimexpr.2209\linewidth-2\tabcolsep}p{\dimexpr.2903\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.48879999999999995\linewidth-2\tabcolsep)}}{\cAlignHack I.R. absorption bands (cm\ensuremath{^{-1}})} & Bond  & Functional group\\
\rowcolor{kwdboxcolor}Observed peak  & Characteristic peak  &  & \\
\tblmidrule 
3135.6 &
  3010-3330 &
  N-Hstrech &
  Aromatic ring\\
2981.3 &
  2500-3000 &
  C-Hstrech &
  Alkens aromatic ring\\
2861.2 &
  2650-2880 &
  C-Hstrech &
  Alkens aromatic ring\\
1547.8 &
  1660-1580 &
  C=Ostrech &
  Alkenes\\
976.6 &
  800-1300 &
  C-Cstrech &
  Alcohols, ethers\\
845.3 &
  800-1300 &
  C-Cstrech &
  Alcohols, ethers\\
687.4 &
  600-1500 &
  C-Clstrech &
  Alkanes\\
612.4 &
  600-1500 &
  C-Clstrech &
  Alkanes\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Values of Created Gel's Evaluation Metrics} }
\label{tw-82681249d56e}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.07599999999999998\linewidth-2\tabcolsep}p{\dimexpr.06210000000000002\linewidth-2\tabcolsep}p{\dimexpr.17189999999999998\linewidth-2\tabcolsep}p{\dimexpr.115\linewidth-2\tabcolsep}p{\dimexpr.103\linewidth-2\tabcolsep}p{\dimexpr.102\linewidth-2\tabcolsep}p{\dimexpr.11\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulations & Clarity & Ph & Homogeneity & Spreada- bility \mbox{}\protect\newline (G.Cm/S) & Viscosity (Cps) & \%Drug & Skin irritation & Extrudability\\
\tblmidrule 
F1 &
  + &
  6.3 &
  Good &
  18.07 &
  9122 &
  101.46 &
  - &
  +\\
F2 &
  + &
  6.3 &
  Good &
  25.45 &
  8776 &
  98.74 &
  - &
  +\\
F3 &
  ++ &
  6.9 &
  Good &
  18.70 &
  9223 &
  99.13 &
  - &
  ++\\
F4 &
  + &
  6.4 &
  Good &
  27.27 &
  8824 &
  97.29 &
  - &
  +\\
F5 &
  + &
  6.7 &
  Good &
  18.07 &
  8954 &
  98.65 &
  - &
  +\\
F6 &
  + &
  6.6 &
  Good &
  22.72 &
  8874 &
  99.48 &
  - &
  +\\
F7 &
  + &
  6.4 &
  Good &
  19.12 &
  9257 &
  99.67 &
  - &
  +\\
F8 &
  + &
  6.4 &
  Good &
  18.94 &
  9783 &
  99.64 &
  - &
  +\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Note: + Satisfactory, + + Good, + + + Excellent}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {\textit{In-vitro} Drug Release of Besifloxacin} }
\label{tw-5594c7089bfb}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.13299999999999999\linewidth-2\tabcolsep}p{\dimexpr.108\linewidth-2\tabcolsep}p{\dimexpr.096\linewidth-2\tabcolsep}p{\dimexpr.103\linewidth-2\tabcolsep}p{\dimexpr.11\linewidth-2\tabcolsep}p{\dimexpr.11\linewidth-2\tabcolsep}p{\dimexpr.11\linewidth-2\tabcolsep}p{\dimexpr.11\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Time (hrs)  & \multicolumn{8}{p{\dimexpr(.867\linewidth-2\tabcolsep)}}{\cAlignHack Cumulative \% Drug Released}\\
\rowcolor{kwdboxcolor} & F1 & F2 & F3 & F4 & F5 & F6 & F7 & F8\\
\tblmidrule 
1 &
  21.47 &
  15.84 &
  20.16 &
  19.81 &
  18.99 &
  19.64 &
  22.83 &
  15.94\\
2 &
  28.49 &
  22.42 &
  30.56 &
  26.77 &
  25.55 &
  26.04 &
  36.81 &
  28.48\\
3 &
  35.86 &
  33.51 &
  37.37 &
  31.47 &
  31.65 &
  33.90 &
  51.56 &
  43.22\\
4 &
  43.66 &
  43.91 &
  49.12 &
  37.60 &
  42.84 &
  45.85 &
  64.78 &
  57.73\\
6 &
  51.66 &
  52.60 &
  58.66 &
  44.51 &
  50.62 &
  54.33 &
  79.27 &
  72.51\\
8 &
  58.22 &
  59.77 &
  64.45 &
  51.92 &
  58.93 &
  61.93 &
  80.12 &
  81.34\\
10 &
  72.49 &
  71.45 &
  77.06 &
  63.28 &
  71.04 &
  74.75 &
  89.13 &
  90.34\\
12 &
  80.82 &
  81.33 &
  96.08 &
  72.77 &
  78.38 &
  83.77 &
  90.57 &
  95.56\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Kinetic Values Obtained from In-Vitro Released Data of Formulation F1-F8} }
\label{tw-c4a17b03e9ae}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1465\linewidth-2\tabcolsep}p{\dimexpr.17349999999999998\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Code & Zero-order & First order & Higuchi & \multicolumn{2}{p{\dimexpr(.36\linewidth-2\tabcolsep)}}{Peppas}\\
\rowcolor{kwdboxcolor} & R\ensuremath{^{2}} & R\ensuremath{^{2}} & R\ensuremath{^{2}} & R\ensuremath{^{2}} & N\\
\tblmidrule 
F1 &
  0.972 &
  0.981 &
  0.995 &
  0.990 &
  0.518\\
F2 &
  0.979 &
  0.991 &
  0.991 &
  0.985 &
  0.668\\
F3 &
  0.977 &
  0.987 &
  0.988 &
  0.992 &
  0.576\\
F4 &
  0.973 &
  0.975 &
  0.993 &
  0.990 &
  0.490\\
F5 &
  0.977 &
  0.990 &
  0.994 &
  0.987 &
  0.580\\
F6 &
  0.977 &
  0.990 &
  0.993 &
  0.986 &
  0.592\\
F7 &
  0.965 &
  0.969 &
  0.992 &
  0.988 &
  0.659\\
F8 &
  0.983 &
  0.990 &
  0.984 &
  0.989 &
  0.803\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {The \textit{In-Vitro} Drug Release Profile of F3 During Stability Tests } }
\label{tw-b66e5a7fda16}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.20370000000000005\linewidth-2\tabcolsep}p{\dimexpr.13889999999999993\linewidth-2\tabcolsep}p{\dimexpr.2287\linewidth-2\tabcolsep}p{\dimexpr.2143\linewidth-2\tabcolsep}p{\dimexpr.2144\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Time (hours) & \multicolumn{4}{p{\dimexpr(.7963\linewidth-2\tabcolsep)}}{\cAlignHack Cumulative \% Drug Release (X\ensuremath{\pm}S.D)*}\\
\rowcolor{kwdboxcolor} & Initial & 1 month \mbox{}\protect\newline (25\ensuremath{^{0}}C- 60\%RH) & Two month \mbox{}\protect\newline (40\ensuremath{^{0}}C-70\%RH) & Three month \mbox{}\protect\newline (60\ensuremath{^{0}}C-80\%RH)\\
\tblmidrule 
0 &
  0 &
  0 &
  0 &
  0\\
1 &
  20.16 &
  19.53 &
  20.64 &
  19.94\\
2 &
  30.56 &
  28.34 &
  31.42 &
  29.46\\
3 &
  37.37 &
  36.46 &
  37.96 &
  35.46\\
4 &
  49.12 &
  48.92 &
  51.24 &
  47.92\\
6 &
  58.66 &
  58.65 &
  60.67 &
  58.64\\
8 &
  64.45 &
  65.12 &
  64.94 &
  63.79\\
10 &
  77.06 &
  78.64 &
  77.64 &
  75.94\\
12 &
  96.08 &
  97.34 &
  96.92 &
  95.38\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{*Mean \ensuremath{\pm} S.D, n=3}
\end{tablenotes}
\end{threeparttable}

\end{table*}
\textbf{Drug-Polymer Compatibility}

To study the possible interactions between the Drug and excipient formulation. The prominent peaks obtained for the combinations were nearly identical to the medications. 

Pure materials' I.R. spectra did not significantly differ from one another. Besifloxacin as well a mixture of polymer and drug [Figure~\ref{f-64a3f7e124fe}, Figure~\ref{f-1612f67a241a}  and Figure~\ref{f-fff32255361f}] [Table~\ref{tw-fc522aefad90}, Table~\ref{tw-1a2e3fd2026f}  and Table~\ref{tw-d7598da69961}].


\bgroup
\fixFloatSize{images/9e2f65aa-dabb-4788-bfe4-e6d960271d36-upicture1.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/9e2f65aa-dabb-4788-bfe4-e6d960271d36-upicture1.png}{\includegraphics{images/9e2f65aa-dabb-4788-bfe4-e6d960271d36-upicture1.png}}{}
\makeatother 
\caption{\boldmath {FT-IR Spectra of Pure Besifloxacin}}
\label{f-64a3f7e124fe}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/6a8f86ca-32a9-4baf-953c-fb7a56a5684a-upicture2.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/6a8f86ca-32a9-4baf-953c-fb7a56a5684a-upicture2.png}{\includegraphics{images/6a8f86ca-32a9-4baf-953c-fb7a56a5684a-upicture2.png}}{}
\makeatother 
\caption{\boldmath {FT-IR Spectra of Pure Sodium Alginate, HPMC K15M and Ethyl Cellulose}}
\label{f-1612f67a241a}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/97286750-60fc-4239-b259-422833f7eb3c-upicture3.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/97286750-60fc-4239-b259-422833f7eb3c-upicture3.png}{\includegraphics{images/97286750-60fc-4239-b259-422833f7eb3c-upicture3.png}}{}
\makeatother 
\caption{\boldmath {FT-IR Physical Mixture of all Ingredients (Formulation F3)}}
\label{f-fff32255361f}
\end{figure}
\egroup
\textbf{Evaluation of Gels}

\textbf{Clarity}

All gels were found to be translucent viscous. All gels were free from the presence of particles [Table~\ref{tw-82681249d56e}].

\textbf{P.H.}

The pH value of all developed formulations gels (F1-F8) was 6.2 {\textendash} 6.9.

\textbf{Homogeneity}

All fully formed (F1-F8) gels displayed excellent uniformity and were lump-free. The prepared materials were considerably more transparent and clear [Table~\ref{tw-82681249d56e}].

\textbf{Spreadability}

The spreadability rating shows that a tiny amount of shear can quickly spread the gel [Table~\ref{tw-82681249d56e}]. Indicating Spreadability of HPMC K4Mcontaining Besifloxacin gel was good as compared to other gel Spreadability of gels in the range of 18.07-27.27g.cm/sec. 

\textbf{Viscosity Measurement}

Using a Brookfield viscometer, the viscosity of variously prepared Besifloxacin gels was evaluated. Every system of prepared gels' rheological behavior was investigated [Table~\ref{tw-82681249d56e}]. The proportion of the solid fraction, which creates the structure, to the liquid fraction determines the consistency of a gel system. The range of viscosity for variously designed gels was 8776 to 9826 centipoises.

\textbf{Drug Content}

The percentage drug content of 97.24 to 101.46\% of all created gel formulations was discovered to fall within this range [Table~\ref{tw-82681249d56e}]. It was determined that the formulations' drug content percentages were satisfactory. Consequently, the techniques used to make gels were deemed appropriate. 

\textbf{Extrudability}

When applying the gel and ensuring that the patient accepts it, the extrusion of the gel from the tube is crucial. A sufficient consistency is necessary to extrude the gel from the line since high-consistency gels may not do so, while low-viscosity gels may flow easily [Table~\ref{tw-82681249d56e}]. It was discovered that HPMC gel compositions have good extrudability. Although the extrudability of other gels was satisfactory. 

\textbf{Skin Irritation}

Patient accepts lack of skin irritation in gel formulation. A test for skin irritation was run, but no skin reddening occurred. It was discovered that none of the gel formulations caused outrage [Table~\ref{tw-82681249d56e}]. Thus, observations suggest that these gels are suitable for topical use.

\textit{\textbf{In-Vitro}} \textbf{ Drug Diffusion Studies}

Purified water was used as the dissolution medium for the \textit{in-vitro} drug release investigations. The findings were tabulated and graphically depicted by placing Time (hrs) on the X-axis and Cumulative percentage drug release on the Y-axis [Table~\ref{tw-5594c7089bfb} \& Figure~\ref{f-ea5715036193}].


\bgroup
\fixFloatSize{images/2dce088d-8b1e-4f0f-804e-100db21a101d-upicture4.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/2dce088d-8b1e-4f0f-804e-100db21a101d-upicture4.png}{\includegraphics{images/2dce088d-8b1e-4f0f-804e-100db21a101d-upicture4.png}}{}
\makeatother 
\caption{\boldmath {Comparative Diffusion Profile of F1 to F8 Formulations}}
\label{f-ea5715036193}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/6ded5eb8-fc0d-4f35-a772-f3bc8a20e455-upicture5.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/6ded5eb8-fc0d-4f35-a772-f3bc8a20e455-upicture5.png}{\includegraphics{images/6ded5eb8-fc0d-4f35-a772-f3bc8a20e455-upicture5.png}}{}
\makeatother 
\caption{\boldmath {The \textit{In-Vitro} Drug Release Profile of F3 During Stability Tests}}
\label{f-2f8b3d1c9c94}
\end{figure}
\egroup
\textit{\textbf{In Vitro}} \textbf{ Drug Release Kinetics for Besifloxacin \textit{In-Situ }Gel}

To compare the dissolving profiles of the best formulation F3, various model-dependent techniques (Zero order, First order, Higuchi, and Korsemayer-Peppas plots) were used. According to the output of these models, the formulation F3 follow Peppas is the model that fits data the best. This is a result of a previously established fact based on the fitted R2 value. Formulation F3 has a Korsemayer-Peppas release exponent (n) value of 0.576, which is more than 0.45 and indicates non-fickian diffusion [Table~\ref{tw-c4a17b03e9ae}].

\textbf{Stability Data}

The chosen formulation The F3 formulation was kept in storage for three months at 40\ensuremath{^\circ}C + 2\ensuremath{^\circ}C / 75\% 5\% R.H. Following storage, samples were examined for 1, 2 and three months [Figure~\ref{f-2f8b3d1c9c94} and Table~\ref{tw-b66e5a7fda16}].
    
\section{CONCLUSION }
The current analysis concludes that designing and creating oral in-situ gels of Besifloxacin requires a careful selection of polymers and medication. According to I.R. and U.V. investigations, the polymer chosen, sodium alginate, and HPMC were discovered to be compatible with the medication besifloxacin. It was found that the two polymers' different concentrations had an impact on the gel's viscosity, flowability, or drug release. Gel formulations demonstrated good durability or uniformity. But, a gel formula that exhibited the highest percentage of drug release and favorable rheological characteristics ended up being the formula of choice. Formulation F3 gives better and quicker patient improvement. There is room for additional pharmacokinetic research because the outcomes of the studies that have already been done are encouraging. When compared to other formulations, the F3 formulation is the most optimal. Based on in vitro release investigations, the formulations of the Besifloxacin gels used in this inquiry were found to be satisfactory, according to the thesis's results. With this prolonged drug delivery system, the medicine's bioavailability can also be increased, benefiting patient efficacy, compliance, and therapeutic usefulness.
    
\section{Acknowledgement}
I want to thank my esteemed Management \& Principal (PK Prakash Reddy), Department of Pharmaceutics, Mahathi College of Pharmacy, Chinnatipa samudram, Madhanapalle-517 325, Andhra Pradesh, India.

\textbf{Funding Support}

The authors declare that they have no funding for this study.\textbf{\space }

\textbf{Conflict of Interest}

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