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\begin{document}


\def\RunningAuthor{Nabil Abdullah and Amit B Patil}
\firstPage{2499}
\articleType{Original Article}
\receivedDate{10 Oct 2020}
\acceptedDate{03 Nov 2020}
\revisedDate{20 Oct 2020}
\journalVolume{2020, 11 (SPL4)}
\journalDoi{ijrps.v11iSPL4.4505}
\copyrightYear{2020}
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\title{Application of DoE in polymers screening and optimization of \textit{in situ} topical film-forming solution for spray formulation}
\author{Nabil~Abdullah\textsuperscript{*}, 
            Amit~B~Patil~\\[5pt]{Department of Pharmaceutics sciences, JSS College of Pharmacy, Mysuru JSS Academy of Higher Education and Research, Mysuru, 570015, Karnataka, India}}

\begin{abstract}
DoE is a structured and organised method to determine the relationship between the effect of change in the concentration of the independent variables and its impact on the formulation, through establishing a mathematical model. Since the acceptance of the QbD approach by the regulatory authorities across the world, DoE has been widely implemented in the areas of screening and optimisation of the formulations by the pharmaceutical industries. The topical delivery of API still posses' limitations such as insufficient contact time, odd hours of application time, sticking to fabrics, formulation washing off, etc. To address these limitations, the researcher planned to develop an \textit{in situ} polymeric sprays that will form a transparent and flexible film, \& will not interfere with the applicant's routine. Polymers such as HPMC, Eudragit RS100, PVP K30, PVP K90, Carbopol, Propylene glycol, Soluplus, and pullulan whereas the plasticisers selected were sorbitol. Voriconazole, a second-generation triazole, was used as a model drug. The article is a technological demonstration, in which the screening of polymers as well as the optimised concentration of the polymeric will be selected through 3\ensuremath{^{2}} factorial design. The aim of the present article is also to establish the relationship between the software response and experimental values. The experiments were designed using 3\ensuremath{^{2}} factorial design which resulted in 9 trial runs. Each run was evaluated for drying time, viscosity, and stickiness. The resultant response surface Later the optimisation, to yield an optimised polymeric solution that can deliver a desired \textit{in situ} films. Based on ANOVA comparison of variability due to treatment, the significance of the regression model was evaluated. Other procedures such as DSC, FRIR, Stickiness, pH, diffusion studies were also performed on the selected formulation. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}DoE,\newline QbD,\newline 32 Full Factorial Design,\newline ANOVA,\newline In Situ Film,\newline Drying time,\newline viscosity
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Nabil~Abdullah~\\ Phone:\ ~\\  Email:\ nabilalbaheli1978@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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        \makeatother
        
    
\section{Introduction}
Polymeric films form an intact layer with the skin surface and hold the APIs for a longer duration of time by resisting any modification even by rubbing and washing \unskip~\citep{919012:20639506}. They are easy to apply and are devoid of any complications systemically observed in dosage and topical semi-solid formulations. Polymeric films are designed so that they produce desired effects, easy to apply with improved patient acceptance \unskip~\citep{919012:20639507}.

\textit{In situ} polymeric film solution is a novel approach that may produce the unconventional dosage formulae applied on the skin like ointments, creams, gels, spray, and patches. \textit{In situ} film polymeric solution spray is applied in the form of liquid which forms a transparent film \textit{in situ } after quick evaporation of the solvent. Polymeric solutions forming films are widely used in surgery, wound care and protection of skin. In surgery, these are used for sealing incisions without using sutures and act as tissue glue or as disinfectants during pre-operative preparation. Topical polymeric film solutions are also used for treating minor cuts, abrasions or for protecting the ostomy wound from surrounding body fluids, and they may or may not contain antimicrobial substances \unskip~\citep{919012:20639508}. 

Polymers are the base for film-forming solutions, and different types of polymers are used for the preparation of these solutions. Polymers can be used alone or in conjunction with other polymers to achieve the desired result. The polymers must have the ability to form a clear transparent film at skin temperature upon application. Film formation using polymeric solutions is a comparatively simple process as the polymer is already in the liquid state. Polymer chains start interpenetrating at a specifying concentration and viscosity when the droplets start vaporising from the substrate surface\ensuremath{^{9}}. The polymeric network formed on the substrate controls the release of the drug constituent by serving as an external reservoir. It reduces the excessive release of drug substance to the skin reservoir \unskip~\citep{919012:20639509}.

The research aims to design and characterise antifungal \textit{in situ} film-forming polymeric solution spray containing Voriconazole for topical drug delivery. The work focuses on a wider variety of polymers, on selecting suitable polymers and on characterising the properties of the resulting formulations so the production of this novel \textit{in situ} polymer solution spray as a dosing form can be focused on a broader technical basis. 
    
\section{Materials and Methods}
\textbf{Materials }

Voriconazole (API) was acquired from yarrow-chem products Mumbai, India. Polymers of various forms used were as Eudragit RS100 (Vikram Thermo India Ltd Mumbai), Polyvinyl pyrrolidine  K30, Polyvinyl pyrrolidine K 90, Carbopol, Sorbitol (Lobal Chemie laboratory reagats Mumbai), Hydroxypropyl Methylcellulose (Himedia Laboratories Pvt. Ltd Mumbai), Pullulan (Biodeal Pharmaceuticals Pvt. Ltd Himachal Pradesh), Soluplus (BASF, Mumbai), Propylene glycol (Sisco research laboratories Pvt. Ltd Mumbai) were founded as a pharmaceutical lab. The solvents and other chemicals used were of the pharmaceutical laboratory. 


\begin{table*}[!htbp]
\caption{\boldmath {Composition of placebo polymeric film solution with different solvents } }
\label{tw-3c85e5fd0199}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.1509\linewidth-2\tabcolsep}p{\dimexpr.2491\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulation Code & Polymers & Quantity (mg) & Ethanol (ml) & Hydroalcoholic (1:1ml)\\
\tblmidrule 
F1 &
  Polyvinyl pyrrolidine K30 &
  40 &
  20 &
  20\\
F2 &
  Polyvinyl pyrrolidine K 90  &
  40 &
  20 &
  20\\
F3 &
  Eudragit RS100 &
  40 &
  20 &
  20\\
F4 &
  Hydroxypropyl Methylcellulose  &
  40 &
  20 &
  20\\
F5 &
  Carbopol  &
  40 &
  20 &
  20\\
F6 &
  Propylene glycol  &
  40 &
  20 &
  20\\
F7 &
  Pullulan &
  40 &
  20 &
  20\\
F8 &
  Soluplus &
  40 &
  20 &
  20\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Composition of the Voriconazole solution spray by DoE \%W/V} }
\label{tw-2da96e6e1d23}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{LLLLL}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{Code Formulations }} & \multicolumn{4}{p{\dimexpr(\mcWidth{2}+\mcWidth{3}+\mcWidth{4}+\mcWidth{5})}}{Components }\\
\rowcolor{kwdboxcolor} & Voriconazole  & Eudragit RS100  & Sorbitol  & Ethanol purity  \mbox{}\protect\newline (96\%) upto (ml) \\
\tblmidrule 
F1 &
  1 &
  20 &
  2 &
  \multicolumn{1}{p{\dimexpr(\mcWidth{5})}}{\multirow{9}{\linewidth}{20 }}\\
F2 &
  1 &
  20 &
  3 &
  \\
F3 &
  1 &
  20 &
  2 &
  \\
F4 &
  1 &
  22 &
  3 &
  \\
F5 &
  1 &
  22 &
  4 &
  \\
F6 &
  1 &
  22 &
  4 &
  \\
F7 &
  1 &
  22 &
  4 &
  \\
F8 &
  1 &
  24 &
  2 &
  \\
F9 &
  1 &
  24 &
  3 &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Grading of transparency} }
\label{tw-e6f23356dfe1}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1765\linewidth-2\tabcolsep}p{\dimexpr.4835\linewidth-2\tabcolsep}p{\dimexpr.34\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}SI No. & Transparency & Grade\\
\tblmidrule 
1 &
  Completely &
  ++\\
2 &
  Acceptable &
  +\\
3 &
  Blurred &
  -\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Solubility Profile of Voriconazole} }
\label{tw-4b3ad9577713}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.16189999999999998\linewidth-2\tabcolsep}p{\dimexpr.4047\linewidth-2\tabcolsep}p{\dimexpr.4334\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Sr No. & Solvents  & Solubility (mg/ml) \\
\tblmidrule 
01 &
  pH 1.2 &
  1.823\\
02 &
  pH 6.8 &
  2.612\\
03 &
  pH 7.4 &
  3.431\\
04 &
  Ethanol &
  4.871\\
05 &
  Distilled Water &
  0.641\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {DSC data of Voriconazole + Eudragite RS 100} }
\label{tw-47f764e0602a}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.09219999999999999\linewidth-2\tabcolsep}p{\dimexpr.2278\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}SI. No. & Thermal Analysis & T\ensuremath{_{\text{\textordmasculine}}}\ensuremath{_{(\text{\textordmasculine}\ C\ )}} & T\ensuremath{_{m\ (\text{\textordmasculine}\ C\ )}} & T\ensuremath{_{c\ (\text{\textordmasculine}\ C\ )}} & Melting range\\
\tblmidrule 
1 &
  Voriconazole &
  130.95 c &
  133.67 c &
  138.67 &
  7.72\\
2 &
  Voriconazole +Eudragite RS100  &
  129.35 &
  133.63 &
  138.80 &
  7.26\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{T\ensuremath{_{\text{\textordmasculine}}} {\textendash} melt begins, T\ensuremath{_{m\ }} {\textendash} melting point,\ensuremath{_{}} T\ensuremath{_{c}}{\textendash} melting completion, DSC data collected at 10\ensuremath{_{\text{\textordmasculine}c}} /min.}
    
\item{Thermographs of DSC of pure Voriconazole show a sharpmelting endotherm at temperature 133.67.}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Functional groups of \textit{In situ} film-forming polymeric solution } }
\label{tw-e5fe4e10184d}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.26659999999999997\linewidth-2\tabcolsep}p{\dimexpr.25000000000000004\linewidth-2\tabcolsep}p{\dimexpr.2334\linewidth-2\tabcolsep}p{\dimexpr.25\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{3}{p{\dimexpr(.75\linewidth-2\tabcolsep)}}{\cAlignHack Frequency of drug (cm-1) } & {\multirow{2}{*}{Functional group }}\\
\rowcolor{kwdboxcolor}Voriconazole with Eudragite RS100 & Eudragite RS100 & Voriconazole  & \\
\tblmidrule 
1678 &
  1650 &
  1670  &
  C=N (Stretch) \\
1718 &
  1740  &
  1750 &
  C=O (Stretch) \\
1310 &
  - &
  1290  &
  C-F (Stretch) \\
1430 &
  1390  &
  1390  &
  C-N (Stretch) \\
3390 &
  3450-3550  &
  3100  &
  OH (Stretch) \\
2850 &
  2970  &
  - &
  CH2 (Stretch) \\
1650 &
  - &
  1590  &
  C=C (Stretch) \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Placebo polymeric film prepared with ethanol} }
\label{tw-e5e35c330897}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0889\linewidth-2\tabcolsep}p{\dimexpr.2912\linewidth-2\tabcolsep}p{\dimexpr.2199\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{SI No.}} & {\multirow{2}{*}{Formulation code}} & \multicolumn{3}{p{\dimexpr(.61989999999999995\linewidth-2\tabcolsep)}}{\cAlignHack Parameters}\\
\rowcolor{kwdboxcolor} &  & DT* (min) & Transparency & Stickiness (Yes/No)\\
\tblmidrule 
1 &
  Polyvinyl pyrrolidine K30  &
  19\ensuremath{\pm}0.4 &
  + &
  Yes\\
2 &
  Polyvinyl pyrrolidine K 90  &
  17\ensuremath{\pm}0.6 &
  + &
  Yes\\
3 &
  Eudragit RS100  &
  {\textless}1\ensuremath{\pm}0.5 &
  +++ &
  No\\
4 &
  Hydroxypropyl Methylcellulose  &
  21\ensuremath{\pm}0.8 &
  + &
  No\\
5 &
  Carbopol  &
  29\ensuremath{\pm}0.6 &
  - &
  Yes\\
6 &
  Propylene glycol  &
  18\ensuremath{\pm}0.8 &
  - &
  Yes\\
7 &
  Pullulan  &
  \multicolumn{3}{p{\dimexpr(.61989999999999995\linewidth-2\tabcolsep)}}{Film not formed}\\
8 &
  Soluplus  &
  \multicolumn{3}{p{\dimexpr(.61989999999999995\linewidth-2\tabcolsep)}}{Film not formed}\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{* Average of 6 readings}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Placebo polymeric film prepared with a hydroalcoholic solution (1:1)} }
\label{tw-2992a24e3acb}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.078900000000000015\linewidth-2\tabcolsep}p{\dimexpr.3211\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{SI No.}} & {\multirow{2}{*}{Formulation code}} & \multicolumn{3}{p{\dimexpr(.60\linewidth-2\tabcolsep)}}{\cAlignHack Parameters}\\
\rowcolor{kwdboxcolor} &  & DT* (min) & Transparency & Stickiness (Yes/No)\\
\tblmidrule 
1 &
  Polyvinyl pyrrolidine K30  &
  21\ensuremath{\pm}0.2 &
  - &
  Yes\\
2 &
  Polyvinyl pyrrolidine K 90  &
  40\ensuremath{\pm}0.6 &
  - &
  No\\
3 &
  Eudragit RS100  &
  9\ensuremath{\pm}0.5 &
  + &
  Yes\\
4 &
  Hydroxypropyl Methylcellulose  &
  34\ensuremath{\pm}0.8 &
  + &
  No\\
5 &
  Carbopol  &
  42\ensuremath{\pm}0.2 &
  - &
  Yes\\
6 &
  Propylene glycol  &
  38\ensuremath{\pm}0.4 &
  - &
  Yes\\
7 &
  Pullulan  &
  29\ensuremath{\pm}0.6 &
  - &
  Yes\\
8 &
  Soluplus  &
  27\ensuremath{\pm}0.4 &
  - &
  Yes\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{ * Average of 6 readings}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Various in situ-based variations of VOR with 3\ensuremath{^{2}}factorial designs} }
\label{tw-123c02dfd9c7}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.3246\linewidth-2\tabcolsep}p{\dimexpr.1236\linewidth-2\tabcolsep}p{\dimexpr.1518\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{Code of Formulation }} & \multicolumn{2}{p{\dimexpr(.2754\linewidth-2\tabcolsep)}}{Levels of coded factors } & \multicolumn{2}{p{\dimexpr(.40\linewidth-2\tabcolsep)}}{Responses }\\
\rowcolor{kwdboxcolor} & A & B & R1\# & R2\#\\
\tblmidrule 
F1 &
  -1 &
  -1 &
  29\ensuremath{\pm}0.02  &
  0.12\ensuremath{\pm}0.05 \\
F2 &
  0 &
  -1 &
  32\ensuremath{\pm}0.02  &
  0.12\ensuremath{\pm}0.07 \\
F3 &
  -1 &
  1 &
  33\ensuremath{\pm}0.09  &
  0.14\ensuremath{\pm}0.08 \\
F4 &
  1 &
  -1 &
  30\ensuremath{\pm}0.05  &
  0.13\ensuremath{\pm}0.09 \\
F5 &
  1 &
  1 &
  39\ensuremath{\pm}0.06  &
  0.13\ensuremath{\pm}0.04 \\
F6 &
  -1 &
  0 &
  42\ensuremath{\pm}0.04  &
  0.14\ensuremath{\pm}0.02 \\
F7 &
  0 &
  0 &
  90\ensuremath{\pm}0.05  &
  0.19\ensuremath{\pm}0.03 \\
F8 &
  0 &
  1 &
  93\ensuremath{\pm}0.07  &
  0.19\ensuremath{\pm}0.01 \\
F9 &
  1 &
  0 &
  92\ensuremath{\pm}0.03  &
  0.20\ensuremath{\pm}0.07 \\
Factors and their coding  &
  \multicolumn{4}{p{\dimexpr(.6753999999999999\linewidth-2\tabcolsep)}}{ -1 0 1}\\
A: polymers quantity (\%)  &
  \multicolumn{4}{p{\dimexpr(.6753999999999999\linewidth-2\tabcolsep)}}{ 20 22 24 }\\
B: Plasticizer quantity (\%)  &
  \multicolumn{4}{p{\dimexpr(.6753999999999999\linewidth-2\tabcolsep)}}{ 2 3 4}\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{\ensuremath{^{*}}Mean\ensuremath{\pm}SD; n=3}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {ANOVA for Drying time response (DoE) } }
\label{tw-6a2a22359997}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1258\linewidth-2\tabcolsep}p{\dimexpr.1542\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Source  & Sum of Squares & df  & Mean \mbox{}\protect\newline Square  & Value F  & p-value Prob {\textgreater} F & Conclusion \\
\tblmidrule 
Model  &
  20168.00  &
  4  &
  5042.00  &
  1260.50  &
  \textless\ 0.0001  &
  Significant \\
A-Polymer  &
  16380.50  &
  1  &
  16380.50  &
  4095.13  &
  \textless\ 0.0001  &
  Significant \\
B-Plasticizer  &
  162.00  &
  1  &
  162.00  &
  40.50  &
  \textless\ 0.0001  &
  Significant \\
A2  &
  3601.50  &
  1  &
  3601.50  &
  900.38  &
  \textless\ 0.0001  &
  Significant \\
B2  &
  24.00  &
  1  &
  24.00  &
  6.00  &
  0.0227  &
  Significant \\
Residual  &
  88.00  &
  22  &
  4.00  &
  -  &
  -  &
  - \\
Lack of Fit  &
  88.00  &
  4  &
  22.00  &
  -  &
  -  &
  - \\
Pure Error  &
  0.000  &
  18  &
  0.000  &
  -  &
  -  &
  - \\
Cor Total  &
  20256 &
  26  &
  - &
  - &
  - &
  -\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {ANOVA for Viscosity response (DoE) } }
\label{tw-4623cb142393}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.12459999999999999\linewidth-2\tabcolsep}p{\dimexpr.15540000000000001\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Source  & Sum of Squares & df  & Mean \mbox{}\protect\newline Square  & Value F  & p-value Prob {\textgreater} F & Conclusion \\
\tblmidrule 
Model  &
  0.025  &
  5  &
  4.961.3  &
  760.20  &
  \textless\ 0.0001  &
  Significant \\
A-Poly  &
  0.019  &
  1  &
  0.019  &
  2963.55  &
  \textless\ 0.0001  &
  Significant \\
B-Plasticizer  &
  6.722.4  &
  1  &
  6.722.4  &
  103.01  &
  \textless\ 0.0001  &
  Significant \\
AB  &
  3.333.5  &
  1  &
  3.333.5  &
  5.11  &
  0.0346  &
  Significant \\
A2  &
  4.446.3  &
  1  &
  4.446.3  &
  681.36  &
  \textless\ 0.0001  &
  Significant \\
B2  &
  3.130.4  &
  1  &
  3.130.4  &
  47.96  &
  \textless\ 0.0001  &
  Significant \\
Residual  &
  1.370.4  &
  21  &
  6.526.6  &
  - &
  - &
  -\\
Lack of Fit  &
  7.037.5  &
  3  &
  2.346.5  &
  6.33  &
  0.0040  &
  Significant \\
Pure Error  &
  6.667.5  &
  18  &
  3.70.6  &
  - &
  - &
  -\\
Cor Total  &
  0.025  &
  26  &
  - &
  -  &
  -  &
  - \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Evaluate the film-forming system according to different standards} }
\label{tw-d8131dddcc4a}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.09020000000000001\linewidth-2\tabcolsep}p{\dimexpr.18979999999999997\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{Sl. No}} & {\multirow{2}{*}{Formulation code}} & \multicolumn{5}{p{\dimexpr(.72\linewidth-2\tabcolsep)}}{Parameters}\\
\rowcolor{kwdboxcolor} &  & DT* (sec) & Transparency & Stickiness (Yes/No) & Structural features & Flexibility\\
\tblmidrule 
1 &
  F1 &
  29\ensuremath{\pm}0.02 &
  ++ &
  No &
  Smooth/weak &
  Non-flexibility\\
2 &
  F2 &
  32\ensuremath{\pm}0.02 &
  ++ &
  No &
  Smooth/weak &
  Non-flexibility\\
3 &
  F3 &
  33\ensuremath{\pm}0.09 &
  ++ &
  No &
  Smooth/weak &
  Non-flexibility\\
4 &
  F4 &
  30\ensuremath{\pm}0.05 &
  ++ &
  No &
  Smooth/weak &
  Non-flexibility\\
5 &
  F5 &
  39\ensuremath{\pm}0.06 &
  ++ &
  No &
  Soft/shiny film/ clear &
  Flexibility\\
6 &
  F6 &
  42\ensuremath{\pm}0.04 &
  ++ &
  No &
  White film residue after drying &
  Flexibility/ cracking\\
7 &
  F7 &
  90\ensuremath{\pm}0.05 &
  ++ &
  No &
  White film residue after drying \& hardness &
  Flexibility/ cracking\\
8 &
  F8 &
  93\ensuremath{\pm}0.07 &
  + &
  No &
  White film residue after drying \& hardness &
  Flexibility/ cracking\\
9 &
  F9 &
  92\ensuremath{\pm}0.03 &
  ++ &
  Yes &
  White film residue after drying \& hardness &
  Flexibility/ cracking\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{*Average of 6 readings }
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {pH test for the formulation} }
\label{tw-f5a536ea9a9f}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1205\linewidth-2\tabcolsep}p{\dimexpr.4793\linewidth-2\tabcolsep}p{\dimexpr.40019999999999996\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}No & Code of formulation & pH*\\
\tblmidrule 
1 &
  F1 &
  6.05 \ensuremath{\pm}0.2\\
2 &
  F2 &
  7.01 \ensuremath{\pm}0.5\\
3 &
  F3 &
  7.04 \ensuremath{\pm}0.3\\
4 &
  F4 &
  7.09 \ensuremath{\pm}0.1\\
5 &
  F5 &
  7.11 \ensuremath{\pm}0.4\\
6 &
  F6 &
  6.98 \ensuremath{\pm}0.3\\
7 &
  F7 &
  7.02 \ensuremath{\pm}0.2\\
8 &
  F8 &
  6.93 \ensuremath{\pm}0.2\\
9 &
  F9 &
  7.13 \ensuremath{\pm}0.3\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{\ensuremath{^{*}}Mean\ensuremath{\pm}SD; n=3}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Thickness measured for the formulation} }
\label{tw-1805d510d860}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.164\linewidth-2\tabcolsep}p{\dimexpr.45870000000000005\linewidth-2\tabcolsep}p{\dimexpr.3773\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}No. & Code of formulation & Thickness \\
\tblmidrule 
1 &
  F1 &
  0.01 \ensuremath{\pm}0.2\\
2 &
  F2 &
  0.01 \ensuremath{\pm}0.5\\
3 &
  F3 &
  0.02 \ensuremath{\pm}0.3\\
4 &
  F4 &
  0.02 \ensuremath{\pm}0.1\\
5 &
  F5 &
  0.08 \ensuremath{\pm}0.4\\
6 &
  F6 &
  0.08 \ensuremath{\pm}0.3\\
7 &
  F7 &
  0.09 \ensuremath{\pm}0.2\\
8 &
  F8 &
  0.12 \ensuremath{\pm}0.2\\
9 &
  F9 &
  0.14 \ensuremath{\pm}0.3\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{\ensuremath{^{*}}Mean\ensuremath{\pm}SD; n=3}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {WVP of polymeric films} }
\label{tw-cda8ecda81a9}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.33\linewidth-2\tabcolsep}p{\dimexpr.2719\linewidth-2\tabcolsep}p{\dimexpr.3981\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{Formulation Code}} & \multicolumn{2}{p{\dimexpr(.67\linewidth-2\tabcolsep)}}{WVP \mbox{}\protect\newline (g-mm/kpa-m\ensuremath{^{2}}) }\\
\rowcolor{kwdboxcolor} & 8\ensuremath{^{th}} hours & 24\ensuremath{^{th}} hours\\
\tblmidrule 
F1 &
  0.0025\ensuremath{\pm}0.3 &
  0.011\ensuremath{\pm}0.4\\
F2 &
  0.0025\ensuremath{\pm}0.2 &
  0.12\ensuremath{\pm}0.3\\
F3 &
  0.0045\ensuremath{\pm}0.1 &
  0.15\ensuremath{\pm}0.4\\
F4 &
  0.005\ensuremath{\pm}0.2 &
  0.016\ensuremath{\pm}0.1\\
F5 &
  0.0057\ensuremath{\pm}0.2 &
  0.0183\ensuremath{\pm}0.2\\
F6 &
  0.0052\ensuremath{\pm}0.3 &
  0.019\ensuremath{\pm}0.2\\
F7 &
  0.0075\ensuremath{\pm}0.1 &
  0.023\ensuremath{\pm}0.4\\
F8 &
  0.0083\ensuremath{\pm}0.3 &
  0.027\ensuremath{\pm}0.2\\
F9 &
  0.0112\ensuremath{\pm}0.3 &
  0.33\ensuremath{\pm}0.3\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{* Mean of 6 reading\ensuremath{\pm}S.D  }
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Moisture content Analysis \%} }
\label{tw-e55eaacc8514}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.4689\linewidth-2\tabcolsep}p{\dimexpr.5311\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulation Cod & Moisture Content\\
\tblmidrule 
F1 &
  1\ensuremath{\pm}0.11 \\
F2 &
  1\ensuremath{\pm}0.12 \\
F3 &
  1\ensuremath{\pm}0.10 \\
F4 &
  1.5\ensuremath{\pm}0.12 \\
F5 &
  1.5\ensuremath{\pm}0.12 \\
F6 &
  2\ensuremath{\pm}0.13 \\
F7 &
  2\ensuremath{\pm}0.12 \\
F8 &
  2.05\ensuremath{\pm}0.14 \\
F9 &
  2.5\ensuremath{\pm}0.11 \\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{* Mean of 6 reading \ensuremath{\pm}S.D}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Viscosity Analysis \%} }
\label{tw-d178bdb5f476}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.50\linewidth-2\tabcolsep}p{\dimexpr.50\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulation Cod & Moisture Content\\
\tblmidrule 
F1 &
  0.12\ensuremath{\pm}0.05 \\
F2 &
  0.12\ensuremath{\pm}0.07 \\
F3 &
  0.14\ensuremath{\pm}0.08 \\
F4 &
  0.13\ensuremath{\pm}0.09 \\
F5 &
  0.15\ensuremath{\pm}0.04 \\
F6 &
  0.14\ensuremath{\pm}0.02 \\
F7 &
  0.19\ensuremath{\pm}0.03 \\
F8 &
  0.19\ensuremath{\pm}0.01 \\
F9 &
  0.20\ensuremath{\pm}0.07 \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Mechanical properties of apolymeric film formed} }
\label{tw-93fac8f81cce}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulation cod & Width (mm) & Area of cross-section (cm\ensuremath{^{2}}) & Thickness (mm) & Max force (Kg) & Tensile strength Kg/cm\ensuremath{^{2}} & Elongation \%\\
\tblmidrule 
F5 &
  20\ensuremath{\pm}0.03 &
  0.04\ensuremath{\pm}0.08 &
  0.08\ensuremath{\pm}0.01 &
  1.08\ensuremath{\pm}0.05 &
  3\ensuremath{\pm}0.04 &
  5.71\ensuremath{\pm}0.03\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Mean value (\ensuremath{\pm}SD)}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Absorbance Values of \textit{In vitro} release study} }
\label{tw-0284128f9d88}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.13170000000000002\linewidth-2\tabcolsep}p{\dimexpr.3683\linewidth-2\tabcolsep}p{\dimexpr.25\linewidth-2\tabcolsep}p{\dimexpr.25\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}No. & Time (hours) & Absorbance & \%CDR\\
\tblmidrule 
1 &
  0 &
  0 &
  0\\
2 &
  15 &
  0.152\ensuremath{\pm}0.05 &
  5.14\\
3 &
  30 &
  0.197\ensuremath{\pm}0.02 &
  39.3\\
4 &
  60 &
  0.243\ensuremath{\pm}0.01 &
  38.9\\
5 &
  120 &
  0.287\ensuremath{\pm}0.05 &
  45.3\\
6 &
  180 &
  0.361\ensuremath{\pm}0.09 &
  55.97\\
7 &
  240 &
  0.433\ensuremath{\pm}0.02 &
  66.42\\
8 &
  300 &
  0.519\ensuremath{\pm}0.04 &
  78.99\\
9 &
  360 &
  0.623\ensuremath{\pm}0.04 &
  93.99\\
10 &
  420 &
  0.673\ensuremath{\pm}0.05 &
  101.30\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Mean value (\ensuremath{\pm}SD) n=3}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Storage stability data of the optimised formulation batch F5} }
\label{tw-1c6c268512a2}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1186\linewidth-2\tabcolsep}p{\dimexpr.2814\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}{\multirow{2}{*}{No}} & {\multirow{2}{*}{ Parameters }} & \multicolumn{3}{p{\dimexpr(.60\linewidth-2\tabcolsep)}}{Room temperature \mbox{}\protect\newline (30\ensuremath{\pm}2\ensuremath{^\circ}C) }\\
\rowcolor{kwdboxcolor} &  & 2 months & 3 months & 6 months\\
\tblmidrule 
1 &
  DT* (sec)  &
  44\ensuremath{\pm}0.03  &
  47\ensuremath{\pm}0.03  &
  48\ensuremath{\pm}0.03 \\
2 &
  Transparency  &
  ++  &
  ++  &
  ++ \\
3 &
  Stickiness (Yes/No)  &
  No &
  No &
  No\\
4 &
  Viscosity (cps)  &
  15.1\ensuremath{\pm}0.3  &
  15.4\ensuremath{\pm}0.3  &
  15.21\ensuremath{\pm}0.3 \\
5 &
  The volume of solution delivered by actuation (ml)  &
  0.289\ensuremath{\pm}0.021  &
  0.291\ensuremath{\pm}0.022  &
  0.292\ensuremath{\pm}0.021 \\
6 &
  Density (gm/ml)  &
  0.691\ensuremath{\pm}0.01  &
  0.686\ensuremath{\pm}0.03  &
  0.685\ensuremath{\pm}0.02 \\
7 &
  Spray angle  &
  81.63\ensuremath{\pm}0.07  &
  81.12\ensuremath{\pm}0.04  &
  80.72\ensuremath{\pm}0.04 \\
8 &
  Spray pattern  &
  Transparent, clear, spherical and uniform  &
  Transparent, clear, spherical and uniform  &
  Transparent, clear, spherical and uniform \\
9 &
  Folding Endurance  &
  Satisfactory  &
  Satisfactory  &
  Satisfactory \\
10 &
  Thickness  &
  0.08\ensuremath{\pm}0.01  &
  0.08.7\ensuremath{\pm}0.06  &
  0.08.7\ensuremath{\pm}0.10 \\
11 &
  Tensile strength (Kg/cm2)  &
  3\ensuremath{\pm}0.02  &
  2.7\ensuremath{\pm}0.05  &
  2.7\ensuremath{\pm}0.04 \\
12 &
  Elongation at break \%  &
  5.71\ensuremath{\pm}0.02  &
  5.41\ensuremath{\pm}0.07  &
  5.53\ensuremath{\pm}0.03 \\
13 &
  Water Vapor Permeability \mbox{}\protect\newline (g-mm/kpa-m2)  &
  0.0025\ensuremath{\pm}0.2  &
  0.0024\ensuremath{\pm}0.3  &
  0.0024\ensuremath{\pm}0.4 \\
14 &
  Surface pH study  &
  6.3\ensuremath{\pm}0.02  &
  6.4\ensuremath{\pm}0.01  &
  6.4\ensuremath{\pm}0.03 \\
15 &
  Moisture content (\%)  &
  1\ensuremath{\pm}0.12  &
  1.1\ensuremath{\pm}0.11  &
  1.1\ensuremath{\pm}0.14 \\
16 &
  CDR (\%)  &
  101.30  &
  100.47  &
  100.50 \\
 &
   &
   &
   &
  \\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{* Mean of 6 reading \ensuremath{\pm}S.D}
\end{tablenotes}
\end{threeparttable}

\end{table*}
\textbf{Procedures }

\textbf{Preparation of Voriconazole \textit{in situ} film}

Steps associated with the formulation of polymer in situ films, as shown in Figure and Composition of polymeric topical delivery formulations, as shown in Figure~\ref{f-3f2b7b1a831c}.

\textbf{Determination of solubility }

Voriconazole saturation solubility was measured in the pH 1.2 HCl, Phosphate pH buffer 6.8, Phosphate pH buffer 6.8, ethanol and distilled water. Each media was prepared, and excess samples were applied to 25 ml of each medium put in the conical 50 ml flask and held for 24 h for shaking on mechanical shake. After 24 h of shaking, 1 ml of aliquot was removed from each sample and filtered through No. 0.45 micron, whattman filter paper. Absorption has been calculated in the 200-400 nm range of visible UV spectrophotometer, and solubility measurements have been carried out \unskip~\citep{919012:20639510}. 

\textbf{Compatibility Studies of Voriconazole-Excipient}

\textbf{Differential Scanning Colorimetry (DSC)}

The pure drug (Voriconazole) and physical mixture with polymer (Eudragite RS100) thermal characteristics were done by differential calorimeter scanning (Shimadzu, japan, DSC-60) mention in the table and figure. Sample with about 5 mg was placed in aluminium pans for each sample on it, and DSC analysis was performed at a flow amount of 20 ml min\ensuremath{^{-1}}. Dynamic scans were rendered within the temperature range of 10 to 300 \ensuremath{^\circ} C in the nitrogen atmosphere at 10 \ensuremath{^\circ} C / min. Indium has been used as a standard reference for temperature adjustment \unskip~\citep{919012:20639511}.

\textbf{FTIR Spectral Analysis}

The pure drug (Voriconazole), polymer (Eudragite RS100) and their physical mixture of the Fourier {\textendash} transform (FTIR) spectra were recorded using a visible UV spectrophotometer (FTIR-8400S, Shimadzu, Kyoto, Japan) and mentioned in the table and figure. Disks of each sample (5 mg) were individually mixed with 200 mg of potassium bromide (spectrographic rank) and compressed into the disks using a hydraulic press (4000 cm\ensuremath{^{-1}} to 400 cm\ensuremath{^{-1}}) before scanning \unskip~\citep{919012:20639512}.

\textbf{Film Forming Capacity of Various Polymers}

The polymeric placebo films were prepared using the technique of solvent casting. The polymeric placebo films were prepared using various solvents such as ethanol, and hydroalcoholic solution. The purpose of the experiment was to research the impact of solvent on the film-forming capacity of the polymers without plasticisers. Solvent effects and film quality were studied in terms of transparency, film stickiness, and drying time. The different types of polymers like as Eudragit RS100, Polyvinyl pyrrolidine  K30, Polyvinyl pyrrolidine K 90, Hydroxypropyl Methylcellulose, Carbopol, Pullulan, Soluplus, Propylene glycol, were investigated for their film-forming ability given in Table~\ref{tw-3c85e5fd0199}. 

\textbf{DoE for optimising formulation}

For the optimisation of the formulated polymeric film, a full 3\ensuremath{^{2}} design factory was used. The concentration of polymer (X1 Eudragit RS100) and plasticiser (X2 sorbitol) was chosen as independent variables according to the literature review, and it is shown in Table~\ref{tw-2da96e6e1d23}, Viscosity (Y1) and dry time (DT \%) (Y2) were chosen as dependent variables, and API was a constant value. A statistical model is concerned with compositional response (degradation) Equation (1).

 Y = b\ensuremath{_{\ensuremath{^\circ}\ }} + b\ensuremath{_{1}}X\ensuremath{^{1}} + b\ensuremath{_{2}}X\ensuremath{_{2}} + b\ensuremath{_{3}}X\ensuremath{^{2}} + b\ensuremath{_{4}}X\ensuremath{^{2}}

It is proved that Y is the interaction response, whereas b0 is the arithmetic uncaring overreaction of the nine trails. The above interaction in the equation Y is the measurable result of preparation ingredient or different autonomous changes X and Y; b0 is the average arithmetic interaction; b1, b2 and b3 are the correlated coefficients for the elements X and Y.  Factorial design details are provided in the table. Variables representing each factor, with corresponding qualitative levels for each excipient, were included. DESIGN EXPERT\ensuremath{^{{\textsuperscript{\textregistered}} }} (version 10) software brought optimised formulation. In the standard container, the optimised formulation was filled in. Analyses for DSC, FTIR, water vapour permeability (VWP), moisture content, moister absorption, mechanical properties (folding capacity, thickness, elongation percentage, tensile strength), spray angle, spray pattern and \textit{In-vitro} \textit{\textbf{\space }}release studies were the optimisation formulation \unskip~\citep{919012:20639513}. 

\textbf{Characterisation of Voriconazole polymeric film formulations}

Typical control tests in topical film polymeric solutions are designed to optimise and improve the delivery system and formula proficiency.

\textbf{Drying} \textbf{ time (DT)}

The solution was sprayed on the skin surface, allowing drying and recording the time. In a normal environment, solution drying can be done, and the film is formed. 

\textbf{Morphological}\textbf{\space }\textbf{characterisation} \textbf{ of the films}

The outer surface of the dried films was evaluated for its stickiness/ smoothness by pressing and absorptive rubbing cotton wool under low manual pressure on the dry film, after pressing and rubbing of cotton wool, if the fibres from the cotton wool stick to the outer surface of the film then it was termed as sticky. If no fibres were found, the outer surface was said to be smooth \unskip~\citep{919012:20639514}. 

\textbf{Determination} \textbf{ of Transparency}

The transparency of the dried films forming was established by visual inspection and graded according to Table~\ref{tw-e6f23356dfe1}.  The films were also inspected for any bubble entrapment a deformation.  

\textbf{pH} \textbf{\space }

Digital pH meters were used to determine the pH of the polymeric spray solution. The phosphate buffer pH meter of 7.4 has been calibrated. The pH electrode was dipped to reach a pH of 20 ml of polymeric solution spray in a little beaker of glass. The pH was determined three times in every formula, and average values were estimated \unskip~\citep{919012:20639515}.

\textbf{Uniform} \textbf{ Thickness of Films}

The film-forming thickness was measured using a 0.01 mm precision handheld micrometre (Dial Gauge thickness 7301, Mitutoyo, Kanagawa, Japan). 

The thickness of the film samples was measured at 4 to 6 random points, and the mean value was used \unskip~\citep{919012:20639516}. 

\textbf{Viscosity} \textbf{\space }

The solutions were measured with Brookfield viscometer (Brookfield engineering laboratories, Inc., USA.) at a viscosity of 25 \ensuremath{\pm} 1 \ensuremath{^{\text{\textordmasculine}}}C. The spindle ULA S00 was rotated at 10 rpm, and 20 ml of the sample was taken in ULA cylinder. The torque readings were still higher than 10\%. Three measurements were taken, and the average was determined.

 AL= (W\ensuremath{_{t\ }} {\textendash} W\ensuremath{_{\text{\textordmasculine}}}) Dn. 

AL- the quantity of the sample given at each distribution, Wt- after distribution of formula weight, Wo- initial formulation weight before distribution, and Dn- density.

\textbf{Quantity of solution given for each actuation}

Amount of solution supplied with every operation. Using the volume of the polymeric film solution provided at each actuation was calculated \unskip~\citep{919012:20639518}.

 A\ensuremath{_{L}} = (W\ensuremath{_{t\ }} {\textendash} W\ensuremath{_{\text{\textordmasculine}}}) D\ensuremath{_{n.}}

Where, A\ensuremath{_{L}}- The quantity of solution given at every actuation, Wt- Weight after-action formulation, Wo- initial formulation weight before a performance, and Dn- formula's density.

\textbf{Density}

The dried and emptied Pycnometer was weighed and filled with the sample. The air bubble was permitted to rise to the top before inserting the stopper. The right value of the density was calculated by dividing the final liquid weight in Pycnometer \unskip~\citep{919012:20639517}.\textbf{\space }

\textbf{The angle of the spray}

The spray of solutions was stimulated flatly onto a white paper attached at 10 cm from the nozzle. A circle is formed on the paper, the radius of which is noted down. Radius from different directions was registered three times. The angle of spray (\ensuremath{\theta }) was calculated by
\begin{eqnarray*}Eq\;=\tan^{-1}\;(1/\;r) \end{eqnarray*}
Where 1- the distance between the paper and the nozzle, r- Median circular radius.

\textbf{The pattern of the spray}

For the study, the method used to impinge spraying on a piece of paper. 10 mg Methylene blue was dissolved in the polymeric film solution to facilitate visualization \unskip~\citep{919012:20639520}. 

\textbf{Folding Endurance}

Folding stamina was specific by repeated film folding at the same location until the film breaks. That indicates the film's brittleness. It is measured as the amount of folding endurance as the number of times when the film is plied without breaking. In the paper test, the folding endurance is the logarithm (to the base of ten) of the number of double folding parts necessary for breaking the test part under standardised conditions \unskip~\citep{919012:20639519}.
\begin{eqnarray*}F\;=\;\log_{10}\;d \end{eqnarray*}
Where F is the folding endurance; d the number of double folds. 

\textbf{Tensile strength}

The tensile strength was a film strength measurement and is calculated by dividing the maximum force required to break the films by the film cross-sectional area. To determine the peak load and tensile strength of the film, a universal test machine (International Equipment's, Mumbai) was used \unskip~\citep{919012:20639528}. The result is expressed in megapascals (MPa) and registered to a significant character.

$Tensile\;strength\;=\frac{(load\;at\;break)}{(original\;width)(original\;thickness)} $

\textbf{Elongation at break \%}

The per cent elongation was determined by dividing the elongation by the initial gauge length at the moment of the rupture and multiplying by 100. When using gauge marks or extensometers to define a particular section of the test. Tensile testing was used to determine the film peak charge, elongation at peak load. The tested film was determined as follows \unskip~\citep{919012:20639529}.

$Eb\;=\frac{L-L_0}{L_0}\times100 $

Where \textit{L} is the film's final length and where \textit{L\ensuremath{_{0\ }}}its original length.

\textbf{Water Vapor Permeability}

The permeability of the film samples to water vapour was calculated gravimetrically by the process. In WVP tests, films were chosen based on a lack of physical defects like cracks, bubbles and pinholes. Horizontally placed rectangular film samples (5 mm / 5 mm) on the WVP weighed in 10 ml beakers and filled with distilled water up to 1 cm below the picture. The beakers were set at 25\ensuremath{^{o}}C and 50 per percentage RH in the regulated humidity chamber with 1 m / min air current circulation. For a period of 8 and 24 hours, the cup was weighed every hour. The transmission rate of the water vapour (WVTR) was estimated from the slopes of the cup's steady-state portion of weight loss versus the time curve \unskip~\citep{919012:20639530}.\textbf{\space }

$WVPR\;=\frac W{A\ast t}(g/cm^{2}\ast\;24\;h) $

Where WVTR is the calculated rate of water vapour transmission (g / m\ensuremath{^{2}}s) through with a film, A was film surface area, and t was the time (h). 

\textbf{Moisture content}

The polymeric films (2 cm\ensuremath{^{2}}) were held for three days in a desiccator that contained activated silica and weighed (W\ensuremath{_{i}}) at room temp. The films were weighed periodically until we obtained a constant weight (W\ensuremath{_{f}}). The calculation of the (per cent) moisture content was based on the following equation \unskip~\citep{919012:20639532}.

$Moisture\;content\;(\%)=\frac{W_i-\;W_f}{W_i}\times100\; $

 Where W\ensuremath{_{i}} is the film's initial mass and W\ensuremath{_{f\ }} is the film's final weight. 

\textbf{In-vitro release review of cellophane membrane}

The modified Franz diffusion cell was used as a cellophane membrane for the permeation test. The cellophane membrane was immersed overnight in distilled water. Then it was soaked 24h before usage in pH 7.4 stock solution. The cellophane membrane was between the donor cell and the recipient cell. The spray of a polymeric solution was moved to the donor cell. The entire membrane surface was in contact with a receptor compartment containing 20 ml of pH 7.4 buffer of phosphate\ensuremath{^{19}}. The cell was agitated at 50 rpm on a magnetic stirrer and kept at 37\ensuremath{\pm}1 \ensuremath{^\circ} C. Every time 1 ml was withdrawn at intervals of 15, 30, 60, 120, 180, 240, 300, 360, and 420 min and replaced with the same fresh buffer of phosphate pH 7.4.

\textbf{Stability Studies}

Optimised formulation (batch F5) was kept away from the light for six months at 30 \ensuremath{\pm} 3 2C. And checked every tow month, Various measures including viscosity, the volume of solution delivered for every actuation, pH, angle of spray, the pattern of spray and in vitro experiments of drug release were subjected to the formulation. The study procedure used was identical to that mentioned previous section \unskip~\citep{919012:20639531}.
    
\section{Results and Discussion}
\textbf{Determination of solubility }

The results of Voriconazole's qualitative solubility in various solvents are shown in Table~\ref{tw-4b3ad9577713} and Figure~\ref{f-e644dca60943} below,


\bgroup
\fixFloatSize{images/07c310d1-5725-4934-835d-eb69ae8ce7e3-upicture1.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/07c310d1-5725-4934-835d-eb69ae8ce7e3-upicture1.png}{\includegraphics{images/07c310d1-5725-4934-835d-eb69ae8ce7e3-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Scheme of (VOR) in situ polymeric film}}
\label{f-3f2b7b1a831c}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/cb1e1962-4297-4bab-8640-711b146014e0-upicture2.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/cb1e1962-4297-4bab-8640-711b146014e0-upicture2.png}{\includegraphics{images/cb1e1962-4297-4bab-8640-711b146014e0-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Histogram representing the solubility of API in different solvents}}
\label{f-e644dca60943}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/c755885b-c710-45b2-b18c-790d54fed2ca-upicture3.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/c755885b-c710-45b2-b18c-790d54fed2ca-upicture3.png}{\includegraphics{images/c755885b-c710-45b2-b18c-790d54fed2ca-upicture3.png}}{}
\makeatother 
\caption{\boldmath {Thermographs of DSC: (A) Voriconazole pure (B) their physical combination (Voriconazole with Eudragite RS 100)}}
\label{f-458d3ea380a1}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/6a9f35ca-ccd4-4911-a470-2d9698d574a7-upicture4.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/6a9f35ca-ccd4-4911-a470-2d9698d574a7-upicture4.png}{\includegraphics{images/6a9f35ca-ccd4-4911-a470-2d9698d574a7-upicture4.png}}{}
\makeatother 
\caption{\boldmath {FT-IR Spectral of (I) Pure of Voriconazole, (II) Eudragite RS 100, (III) Physical mixture of (Voriconazole + Eudragite RS 100).}}
\label{f-f05346b7974e}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/0bd801ca-4256-4f8f-95b4-3f6d405581ab-upicture5.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/0bd801ca-4256-4f8f-95b4-3f6d405581ab-upicture5.png}{\includegraphics{images/0bd801ca-4256-4f8f-95b4-3f6d405581ab-upicture5.png}}{}
\makeatother 
\caption{\boldmath {Drying time of Ethanol polymeric film}}
\label{f-a83ae2bdec4e}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/8c288ff4-4543-4902-afe7-9e6ebaf1a19b-upicture6.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/8c288ff4-4543-4902-afe7-9e6ebaf1a19b-upicture6.png}{\includegraphics{images/8c288ff4-4543-4902-afe7-9e6ebaf1a19b-upicture6.png}}{}
\makeatother 
\caption{\boldmath {Drying time of the hydroalcoholic polymeric film}}
\label{f-69dea6a967aa}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/ef6bfd4f-6215-4464-959c-b4ee3803165c-upicture7.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/ef6bfd4f-6215-4464-959c-b4ee3803165c-upicture7.png}{\includegraphics{images/ef6bfd4f-6215-4464-959c-b4ee3803165c-upicture7.png}}{}
\makeatother 
\caption{\boldmath {Response surface plots of R1 Drying time (sec) of VOR based in situ polymeric film. }}
\label{f-e75f7fede19b}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/a474a8bd-4fbd-4992-b801-298516ee8222-upicture8.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/a474a8bd-4fbd-4992-b801-298516ee8222-upicture8.png}{\includegraphics{images/a474a8bd-4fbd-4992-b801-298516ee8222-upicture8.png}}{}
\makeatother 
\caption{\boldmath {The linear difference between occurrence and estimated drying time value (Y\ensuremath{_{1}}).}}
\label{f-2be1f614976b}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/d4201ecd-6441-4fe6-a912-7e353a7fc706-upicture9.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/d4201ecd-6441-4fe6-a912-7e353a7fc706-upicture9.png}{\includegraphics{images/d4201ecd-6441-4fe6-a912-7e353a7fc706-upicture9.png}}{}
\makeatother 
\caption{\boldmath {Overlay plot for optimisation of VOR based in situ polymeric films.}}
\label{f-bbf7b8061e0e}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/9407dbea-f2fa-4006-b366-b74842a3cad3-upicture10.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/9407dbea-f2fa-4006-b366-b74842a3cad3-upicture10.png}{\includegraphics{images/9407dbea-f2fa-4006-b366-b74842a3cad3-upicture10.png}}{}
\makeatother 
\caption{\boldmath {Response surface plots of R2 viscosity (cps) of VOR based in situ polymeric film}}
\label{f-6a55a8cd3cfb}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/9556d682-6fce-43aa-9197-683dd43ada27-upicture11.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/9556d682-6fce-43aa-9197-683dd43ada27-upicture11.png}{\includegraphics{images/9556d682-6fce-43aa-9197-683dd43ada27-upicture11.png}}{}
\makeatother 
\caption{\boldmath {The linear difference between occurrence and estimated viscosity value (Y\ensuremath{_{2)}}.}}
\label{f-de5dd8c1703e}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/e5910341-a862-4d4c-bfb3-361e9ef578dd-upicture12.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/e5910341-a862-4d4c-bfb3-361e9ef578dd-upicture12.png}{\includegraphics{images/e5910341-a862-4d4c-bfb3-361e9ef578dd-upicture12.png}}{}
\makeatother 
\caption{\boldmath {Overlay plot viscosity on VOR dependent in situ polymeric film optimisation}}
\label{f-2b0c4aec1fb4}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/2e77553f-5054-4f1b-a85b-a50673fdd8f6-upicture13.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/2e77553f-5054-4f1b-a85b-a50673fdd8f6-upicture13.png}{\includegraphics{images/2e77553f-5054-4f1b-a85b-a50673fdd8f6-upicture13.png}}{}
\makeatother 
\caption{\boldmath {Drying Time of Polymeric Film Formulations}}
\label{f-ad15ba089d76}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/ac10e701-4550-4452-a61f-f5091d2491a6-upicture14.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/ac10e701-4550-4452-a61f-f5091d2491a6-upicture14.png}{\includegraphics{images/ac10e701-4550-4452-a61f-f5091d2491a6-upicture14.png}}{}
\makeatother 
\caption{\boldmath {Drying Time In Situ Polymeric Film Forming Formulations}}
\label{f-f59a3b88c4cd}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/e4156145-f10f-45b2-ae37-e4ef75ee5be3-upicture15.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/e4156145-f10f-45b2-ae37-e4ef75ee5be3-upicture15.png}{\includegraphics{images/e4156145-f10f-45b2-ae37-e4ef75ee5be3-upicture15.png}}{}
\makeatother 
\caption{\boldmath {Measured pH for polymeric solution}}
\label{f-a073d2bad81b}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/2716da11-f114-4cc3-b6ea-bc75f0b43527-upicture16.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/2716da11-f114-4cc3-b6ea-bc75f0b43527-upicture16.png}{\includegraphics{images/2716da11-f114-4cc3-b6ea-bc75f0b43527-upicture16.png}}{}
\makeatother 
\caption{\boldmath {WVP of polymeric films}}
\label{f-a3dcb1ce69a1}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/b24e5fd3-3b7e-4f21-a852-00d44eeefc57-upicture17.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/b24e5fd3-3b7e-4f21-a852-00d44eeefc57-upicture17.png}{\includegraphics{images/b24e5fd3-3b7e-4f21-a852-00d44eeefc57-upicture17.png}}{}
\makeatother 
\caption{\boldmath {Moisture content \%}}
\label{f-70a162f56198}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/05e9e970-4614-45ca-b65c-97f2a09f374f-upicture18.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/05e9e970-4614-45ca-b65c-97f2a09f374f-upicture18.png}{\includegraphics{images/05e9e970-4614-45ca-b65c-97f2a09f374f-upicture18.png}}{}
\makeatother 
\caption{\boldmath {Viscosity content \%}}
\label{f-7ff26556b883}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/7eba739c-93bd-406c-bacb-e385f1ff922a-upicture19.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/7eba739c-93bd-406c-bacb-e385f1ff922a-upicture19.png}{\includegraphics{images/7eba739c-93bd-406c-bacb-e385f1ff922a-upicture19.png}}{}
\makeatother 
\caption{\boldmath {Spray pattern (F5)}}
\label{f-900c9dccca35}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/c499ffae-0fe2-45a9-a243-3ccfb068f732-upicture20.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/c499ffae-0fe2-45a9-a243-3ccfb068f732-upicture20.png}{\includegraphics{images/c499ffae-0fe2-45a9-a243-3ccfb068f732-upicture20.png}}{}
\makeatother 
\caption{\boldmath {Mechanical Properties for the film formed F5}}
\label{f-7b51ef8338aa}
\end{figure}
\egroup

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\fixFloatSize{images/32b8448c-4fe9-4225-98a3-993b2a417c1f-upicture21.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/32b8448c-4fe9-4225-98a3-993b2a417c1f-upicture21.png}{\includegraphics{images/32b8448c-4fe9-4225-98a3-993b2a417c1f-upicture21.png}}{}
\makeatother 
\caption{\boldmath {Cumulative Drug Release CDR\%}}
\label{f-346846a7c956}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/772fd933-3e56-4b8e-93e8-d3c1a9458540-upicture22.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/772fd933-3e56-4b8e-93e8-d3c1a9458540-upicture22.png}{\includegraphics{images/772fd933-3e56-4b8e-93e8-d3c1a9458540-upicture22.png}}{}
\makeatother 
\caption{\boldmath {In vitro diffusion cell using cellophane membrane }}
\label{f-e25a493e80d1}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/5c5f29c9-5a60-4216-860a-cc9f5c4e813a-upicture23.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/5c5f29c9-5a60-4216-860a-cc9f5c4e813a-upicture23.png}{\includegraphics{images/5c5f29c9-5a60-4216-860a-cc9f5c4e813a-upicture23.png}}{}
\makeatother 
\caption{\boldmath {Scheme result of (VOR) in situ polymeric film}}
\label{f-0792e4926002}
\end{figure}
\egroup
\textbf{Compatibility Tests of Voriconazole-Excipient}

\textbf{Differential Scanning Colorimetry Studies (DSC)}

Table~\ref{tw-47f764e0602a} and Figure~\ref{f-458d3ea380a1}  show the respective voriconazole DSC thermograms and their physical mixture (Voriconazole with Eudragite RS 100). 

Voriconazole thermogram exhibited a broad endothermic peak at 138.07 \ensuremath{^\circ}C related to the evolution of the sample's moisture. The prominent melting peak at 182.91 \ensuremath{^\circ}C manifested the natural crystalline state of polymer (Eudragite RS 100). The characteristic endothermic peaks of both drug and polymer were observed at their authentic locations in the case of a physical mixture, and there was almost no interaction between Voriconazole and polymer. 

\textbf{FTIR} \textbf{ Spectral Analysis}

FT-IR spectra of Voriconazole, polymer (Eudragite RS 100) and its physical mixture (Voriconazole + Eudragite RS 100), The range of OH Voriconazole FTIR generally exhibited stretching at 3200.09{\textendash}3046.04 cm\ensuremath{^{-1}}, C-N extending at 1510.28{\textendash}1451.28 cm\ensuremath{^{-1}}, and C-F at 1587.44{\textendash}1451.28 cm\ensuremath{^{-1}}, shown in Figure~\ref{f-f05346b7974e}, respectively. The Eudragite RS-100 FTIR spectrum showed a peak of 2953.9 cm{\textendash}1 due to the presence of O~{\textendash} H (carboxylic acid), 1450.7 cm{\textendash}1 due to the -CH2 bend, and 1731.2 cm{\textendash}1 due to the presence of C = O~(ester). The spectrum of the physical mixture of the drug (Voriconazole) and polymer (Eudragite RS 100) was identical, in a physical mixture of Voriconazole and polymer, no presence or disappearance of voriconazole peaks of the same characteristics as the ones listed in Table~\ref{tw-e5fe4e10184d}  and verified by the lack of chemical interactions between Voriconazole and polymer. 

\textbf{Characterisation of placebo film-forming polymers}

Characterisation of placebo polymeric film-forming solution with absolute ethanol it's given in Table~\ref{tw-e5e35c330897}  and Figure~\ref{f-a83ae2bdec4e}. 

Characterisation of placebo polymeric film of a film-forming solution with a hydroalcoholic solution it's given in Table~\ref{tw-2992a24e3acb}, Figure~\ref{f-69dea6a967aa}.

\textbf{DoE for optimising formulation}

A 3\ensuremath{^{2}}-level factorial, for optimisation of the formulation, complete factor design was used. The rates of the autonomous variables were based on the preliminary results of the batch. The low, medium and high rates were 20\%, 22\% and 24\% respectively for Eudragite RS100. Plasticiser was used at low (2\%), medium (3\%) and high (4\%) rates, respectively. Variable effect independently on Y1 (cps) viscosity and time of drying Y2 (seconds). The equation ANOVA indicated the model F values 760,20, P-value \textless\ 0,0001; showing the model to be significant. ANOVA for drying time and viscosity conclusion mentioned in Tables~\ref{tw-123c02dfd9c7}, \ref{tw-6a2a22359997} and~\ref{tw-4623cb142393}.  The reduced model was confounding, but the most important parameters influencing the response were screened (Eq. 1).  

2644 {\textendash} 254.42 X\ensuremath{_{1}} + 15 X\ensuremath{_{2}} + 6.12 X\ensuremath{^{1}} {\textendash} 2 X\ensuremath{^{2}}

The correlation coefficient was respectively 0.995 and 0.993 in the complete model and reduced form. Increased Eudragit RS 100 concentration increased drying time requires optimised formulation (Y1) development mention in Figures~\ref{f-e75f7fede19b}, \ref{f-2be1f614976b} and~\ref{f-bbf7b8061e0e}. The polynomial equation above shows a strong match of response variables at various levels.

For both the full model and reduction model the correlation coefficient value was 0.859 and 0.810 respectively. Y2 (Viscosity) was affected as a major factor by the increased concentration of polymers (Eq. 2). 2.44 {\textendash} 0.23 X\ensuremath{_{1}} + 0.00 + X\ensuremath{_{2}} + 0.01 + X\ensuremath{^{1 }} {\textendash} 2 X\ensuremath{^{2 }} note in Figures~\ref{f-6a55a8cd3cfb}, \ref{f-de5dd8c1703e} and~\ref{f-2b0c4aec1fb4}.

\textbf{Characterisation parameters related to polymeric film formulations}

Forms of evaluation films for all formulations such as drying time, transparency, stickiness, flexibility and structural characteristics. After analysing all the formulations, in terms of the film-shaped and unregulated from the negatives and defects present in some of the formulas are shown in Table~\ref{tw-d8131dddcc4a}  and in Figures~\ref{f-ad15ba089d76} and~\ref{f-f59a3b88c4cd} the best suitable. 

\textbf{pH}

pH measurements were made using a pH meter. For measuring pH, 20ml Spray for the solution was used. Results are shown in Table~\ref{tw-f5a536ea9a9f} and Figure~\ref{f-a073d2bad81b}. 

\textbf{Thickness}

The thickness of all formulations was between 0.01\ensuremath{\pm}0.03 to 0.08\ensuremath{\pm}0.02 their mention in Table~\ref{tw-1805d510d860}. 

\textbf{Water Vapor Permeability (WVP)}

The results of studies on the transmission rate of water vapour (WVTR) are shown in Table~\ref{tw-cda8ecda81a9}. And then in Figure~\ref{f-a3dcb1ce69a1}. Also, plasticiser addition was found to affect the permeability of polymer film as the experimental humidity conditions affected the WVTR, 25 per cent humidity conditions, and 50 per cent throughout the study were employed. 

All polymeric films showed low WVTR indicative of its hydrophobic character. A decrease in WVP is considered advantageous for application to skin targets.

\textbf{Moisture content }

Studies of the moisture content gave an insight concerning the stability of the film. The moisture content (percentage) of polymer films was low (1\ensuremath{\pm} 0.113 per cent, 1\ensuremath{\pm} 0.113 per cent, 1\ensuremath{\pm} 0.113 per cent, 1.5\ensuremath{\pm} 113 per cent, 1.5\ensuremath{\pm} 0.113 per cent, 2. \ensuremath{\pm} 113 per cent, 2\ensuremath{\pm}11 per cent, 2.05\ensuremath{\pm} 12 per cent, 2.5\ensuremath{\pm} 10 per cent) respectively, which may help preserve stability and prevent dryness and fragility during long-term storage, especially under dry co-storage, noted in Table~\ref{tw-e55eaacc8514} and Figure~\ref{f-70a162f56198}.

\textbf{Viscosity}

Formulations viscosity containing Eudragite RS100 as a polymer and glycerol as a plasticiser, formulations viscosity results were noted in Table~\ref{tw-d178bdb5f476}  and Figure~\ref{f-7ff26556b883} and sufficient spray capability is demonstrated. 

\textbf{Characterisation of Optimisation in situ film-forming solution spray formulation}

\textbf{Quantity of solution given for each actuation}

According to the equation given in the evaluation, the result will be as follows. 

For each actuation, the quantity of solution was 0.289\ensuremath{\pm}0.021 ml. 

$20ml\;=\frac{2.55-2.75}{0.691}=0.289\;ml $

\textbf{Density}

A pycnometer determined density, and the density value was estimated by measuring the resulting liquid weight into a pycnometer by amount.

$\begin{array}{l}31.07-\;44.9\;=\;13.83\\=\frac{13.83\;}{20}=0.691(gm/ml)\end{array} $

Density spray solution was 0.691(gm/ml).  

\textbf{Spray angle}

Spray angle was evaluated from local container spray and equation calculated by =tan\ensuremath{^{-1}} (1/ r). 

Where 1- the distance between the paper and the nozzle, r- Median circular radius. Average radius circle = 2.2 cm and distance of paper from nozzle was 15cm so, 

$\begin{array}{l}\tan^{-1}=\frac{15}{2.2}=6.8\;cm\\\tan^{-1}=81.63\end{array} $

spray angle was 81.63\ensuremath{^{0 }}\ensuremath{\pm}0.07

\textbf{Spray pattern}

It was observed that the formulation of the spray pattern was transparent, clear, spherical and uniform. After application of a clear transparent film, the drying time was 43 sec. 

The optimised formulation showed good sprayed properties. Figure~\ref{f-900c9dccca35} depicts an illustration of the films formed after drying (with the inclusion of methylene blue to improve visibility).

\textbf{Folding Endurance}

The values of folding endurance of formulation developed by the polymeric film were found in 80 folds which are considered adequate, elastic and reveal good film quality.

\textbf{Tensile strength}

Tensile strength was determined to define polymer film for its abrasion resistance and durability, the formula determined the tensile strength.

$Tensile\;strength\;=\frac{(1.08\;Kg)}{(2\;mm)(0.18mm)}=3\;Kg/cm^{2} $

The result mention in Table~\ref{tw-93fac8f81cce}. 

\textbf{Elongation at break \%}

Due to their abrasion resistance and durability, elongation at break was determined to characterise polymer film, noticed in Figure~\ref{f-7b51ef8338aa}.

$Elongation\;at\;break\;=\frac{74-70}{70}\times100=5.71\;\% $

\textbf{In vitro release study using cellophane membrane}

Studies of the release of the drug were performed \textit{in vitro} using a cellophane membrane in Franz diffusion cell. It includes a donor cell and a receiver compartment. The receptor compartment was filled in as a diffusion medium with 20ml of phosphate buffer pH 7.5 solution. In the receptor compartment, the prepared polymer solution was a spray, Magnetic beads used to stir the liquid constantly with 50 rpm, and 37\ensuremath{\pm}1 \ensuremath{^\circ}C held its temperature. 2ml receptor fluid sample was withdrawn at fixed intervals, and the same amount of 2ml phosphate buffer solution was replaced with the samples measuring their absorbance at 256 nm. The total volume of drug release transported in a formulation containing 22\% of Eudragite RS 100 and 1\% of Voriconazole was 101\ensuremath{\pm}0.07 per cent by measured from the slope of the linear portion of the curve found in Table~\ref{tw-0284128f9d88}  and Figures~\ref{f-346846a7c956} and~\ref{f-e25a493e80d1}.\textit{\textbf{\space }}

\textbf{Stability Studies}

Optimised formulation F5 batch short-term stability test was conducted at 30\ensuremath{\pm}2 \ensuremath{^\circ} C at room temperature for six months. Table~\ref{tw-1c6c268512a2}  Shows that pH, viscosity, performance volume, spray angle, spray pattern, folding endurance, thickness, tensile strength, break per cent elongation, density, and \textit{in vitro} release study the physical appearance of optimised formulation batch F5 remained unchanged through the study reference. 

\textbf{Discussion}

The polymeric film-forming solution was prepared by dissolving selected polymers in different solvents such as ethanol, hydroalcoholic solution (1:1) and distilled water. The films formed upon drying were subjected to various preliminary evaluation like drying time, transparency and stickiness. The films prepared using absolute ethanol solvent with plasticiser showed satisfactory results when considering the drying time and visual observation. The polymeric film solution prepared using sorbitol as a plasticiser, which was selected based on the exhaustive literature search performed. It can be concluded that, the polymeric solution that was prepared using as a solvent was considered to be unfit for the incorporation of the API because the film took a long time for drying and one of the formulations did not form a film. 

The polymeric film formed using ethanol as solvent F5 showed the best drying time and was considered as optimiser formulation. 

Formed films were prepared and evaluated. The drug used in these film formulations was Voriconazole. Out of 9\ensuremath{^{th}} formulations, 5\ensuremath{^{th}} formulation is best and gives aspired results from the evaluation conducted Figure~\ref{f-0792e4926002} .  
    
\section{Conclusions}
This study concludes that Voriconazole can form a topical in situ film-forming development by using a mixture of Eudragite RS100 and Sorbitol as plasticiser using the response surface method, and mentioned below results work. The impact of formulating variables on product properties can be easily predicted by using a 3\ensuremath{^{2}}-level factorial experimental design and quadratic mathematical equations developed. Based on the specifications of the product, such as Drying time (DT \%), Transparency, Stickiness, Structural features of the film formed, Viscosity, Spray angle, Spray pattern, Mechanical properties of the polymeric film formed and \textit{in vitro} using a cellophane membrane, the best batch of topical Voriconazole in situ film-forming would be 22\% Eudragite RS100 and 4\% Sorbitol. It can be concluded. 
\section*{Acknowledgement}The authors express a deep sense of gratitude towards the JSS Academy of Higher Education and Research, Mysuru, 570015, Karnataka, India. For the provision of obligatory facilities to carry out present research work.

\textbf{Conflict of Interest }

The authors declare that they have no conflict of interest for this study.

\textbf{Funding Support }

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

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