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\def\RunningAuthor{Geethanjali K and Vaiyana Rajesh C}
\firstPage{1294}
\articleType{Original Article}
\receivedDate{28 Oct 2019}
\acceptedDate{27 Jan 2020}
\revisedDate{25 Jan 2020}
\journalVolume{2020, 11}
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\journalDoi{ijrps.v11i2.1984}
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\def\journalTitle{International Journal of Research in Pharmaceutical Sciences}

\title{Formulation and evaluation of self nano-emulsifying drug delivery system of ezetimibe for dissolution rate enhancement}
\author{Geethanjali~K\textsuperscript{*}, 
            Vaiyana~Rajesh~C~\\[5pt]{Department of Pharmaceutics, PSG College of Pharmacy, Coimbatore- 641 004, Tamilnadu, India}}

\begin{abstract}
The present study was aimed to develop a Self Nano Emulsifying Delivery System of Ezetimibe (EZM) for enhancing its dissolution rate. Ezetimibe is a cholesterol absorption inhibitor, being a lipophilic drug due to its low solubility EZM shows a low dissolution profile. The SNEDDS formulation consisted of excipients Cinnamon oil, Tween 80, PEG 400 as the Oil, Surfactant and Co-surfactant. Twelve formulations with different ratios of Oil, Surfactant and Co-surfactant were prepared. The liquid SNEDDS were then converted into Solid form by adsorption technique using Avicel PH 101 and Aerosil 200 as adsorbents. The liquid SNEDDS was characterised for Particle size, Emulsification time, Dispersibility, percentage transmittance, PCM, Centrifugation, Cloud Point and Freeze thaw cycle. The solid form was characterized for the flow property, SEM, Drug content and \textit{in-vitro} dissolution. Among the twelve formulations F6 formulation was found to have a particle size of 196 nm and PDI of 0.123. F6 formulation was selected as the best and it was made into solid by adsorption onto solid carriers. The F6 formulation consisted of the 25\% Cinnamon oil, 50\% tween 80 and 25\% PEG 400. The \textit{in-vitro} dissolution rate of the prepared formulation was compared with the marketed formulation. The \textit{in-vitro} dissolution data showed that the drug release at the end of 60 mins from marketed formulation was 63.75 \% and from SNEDDS formulation was 90.62 \%. The dissolution rate of the prepared SNEDDS was increased by 1.42 times than the marketed formulation. The increase in the dissolution rate shows that SNEDDS is a suitable drug delivery system to enhance the rate of dissolution of Ezetimibe.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Ezetimibe,\newline Self Nano emulsion,\newline Tween 80,\newline Cinnamon oil,\newline Solid Carrier
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Geethanjali~K~\\ Phone:\ +91- 7667279507~\\  Email:\ anjalik9795@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Ezetimibe is a lipid-reducing agent which specifically removes cholesterol and associated phytosterols from the intestinal absorption without influencing the absorption of fat-soluble nutrients, triglycerides or bile salts. As a BCS group II enzyme, Ezetimibe is a strongly lipophilic molecule with a log P value of 4.5 \unskip~\citep{680357:16093229,680357:16093234}. This displays a particularly unstable and weak dissolution profile in the gastrointestinal tract owing to its hydrophobicity. Formulation of BCS class II drugs as SNEDDS has shown to improve the solubility of drugs and thus increase the dissolution of drugs. Self Nano Emulsifying Drug Delivery Systems (SNEDDS) are preconcentrates of nanoemulsion or anhydrous forms of nanoemulsion. These systems are anhydrous isotropic mixtures of oil, surfactants and drugs that spontaneously form O/W nanoemulsions when they are introduced into aqueous phase under conditions of mild agitation \unskip~\citep{680357:16093233}. The purpose of this study was to design and evaluate different formulations of S-SNEDDS using various S mix ratios and adsorbent mixtures to achieve an enhancement in the dissolution rate of Ezetimibe.
    
\section{Materials and Methods}
Ezetimibe was provided as a gift sample from Medreich Limited, Bangalore, Karnataka, India. Cinnamon oil was brought from S.D. Fine Chemicals, India. Tween 80 (Polyoxyethylene 20 sorbitan mono-oleate), PEG 400 (Polyethylene glycol), Avicel PH 101 (Microcrystalline cellulose) was purchased from Sigma-Aldrich. Aerosil 200 was obtained from Biochemika reagents.

\textbf{Solubility study}

The solubility of Ezetimibe was found by a method of equilibrium solubility and saturation solubility using various oils, surfactants and co-surfactants. To determine the solubility an excess amount of the drug was introduced in to the tubes containing 1 ml of excipient. The vial was shaken continuously and vortexed using vortex mixer (REMI Equipment, Mumbai, India) for few minutes. The mixtures were then equilibrated at room temperature for 48 hrs. The samples were centrifuged (Eppendorf centrifuge 5415 R) at 5000 rpm for 10 mins. From the supernatant, the sample was then dissolved in ethanol to extract the drug and then suitably diluted with distilled water and the EZM dissolved in the oils were quantified using UV spectroscopy method \unskip~\citep{680357:16093228}.

\textbf{Screening of surfactants}

Different surfactants were screened for their emulsification efficiency. The surfactants used were tween 80, tween 20, span 80, span 20. The solubility was first determined by same procedure as used for oils. Emulsification ability was determined by adding 300 \ensuremath{\mu}l of the selected surfactant to 300 \ensuremath{\mu}l of the oil phase (1:1 ratio). The mixture was then heated to 50\ensuremath{^\circ}C and mixed to form a homogenized mixture. 25 \ensuremath{\mu}l of the mixture was then diluted to 25 ml with distilled water to form an emulsion. 

\textbf{Screening of co-surfactants}

Co-surfactants were selected on the basis of their efficacy to improve the emulsification ability of the chosen surfactants. Co-surfactants like PEG 400, glycerol were used. The mixtures of co-surfactant, surfactant and oil were prepared in the ratio of 1:2:3. It was mixed and heated to form a homogenous mixture. The \% transmittance of the mixtures was found out by the same procedure for surfactants \unskip~\citep{680357:16093228}.

\textbf{Pseudo ternary phase diagram}

The pseudo ternary phase diagram was plotted using the method of water titration. The surfactant and co-surfactant were mixed in different proportions (1:1, 2:1, 3:1, 1:2). To this oil phase was added to this in varying proportions. This mixture was then titrated with water until it turns clear or milky, translucent and free flowing. The values were then plotted in CHEMIX software to obtain the nano emulsion region \unskip~\citep{680357:16093230}. 

\textbf{Formulation of liquid-SNEDDS}

Formulations with varying concentrations of oil (20-30\%) and Surfactant and co-surfactant mixture (70-80\%) were prepared. The required quantity of tween 80 and PEG 400 were measured and added to a glass beaker. It was stirred continuously using a magnetic stirrer (2MLH, REMI Instrument). To this the oil was added and finally, the desired amount of EZM was weighed and added to the mixture. The stirring was continued for around 45 - 60 mins. It was then sonicated (Sonics-230 \ensuremath{\pm} 10V) for about 20 mins. The prepared L-SNEDDS was stored at room temperature (25\ensuremath{^\circ}C) in an air-tight container \unskip~\citep{680357:16093228}. The composition of the SNEDDS formulations are shown in Table~\ref{tw-7adca82146e7}.

\textbf{Characterization of L-SNEDDS }

\textbf{Particle Size and PDI}

Particle size or globule size determines the rate and extent to which the drug is released and was determined by using Malvern Zeta-sizer (MALVERN Zetasizer ZS90) \unskip~\citep{680357:16093230}. 

\textbf{Time for Emulsification}

Time for emulsification of the formulations was found out by adding 1 ml of the formulation to 900 ml of distilled water in USP dissolution apparatus II (LABINDIA DS 8000). Stainless steel paddle which rotates at 50 rpm provides the stirring. The time required for the formulation to completely disperse uniformly was noted which was the emulsification time \unskip~\citep{680357:16093230}. 

\textbf{Dispersibility test}

The dispersibility test was performed to find out the emulsification efficiency of the formulations. 0.5 ml of the formulation was added to 250 ml of distilled water in a dropwise manner. The test was done in a glass beaker kept on a magnetic stirrer with agitation at around 100 rpm and temperature was maintained at 37\ensuremath{\pm}0.5\ensuremath{^\circ}C. The solutions were then analysed visually for clarity using a grading system \unskip~\citep{680357:16093227}. 

Grade A {\textendash} nano emulsion forms rapidly within 1 min, has a clear or bluish appearance. 

Grade B {\textendash} nano emulsion forms within 2 mins, it is less clear and has a bluish appearance. 

Grade C {\textendash} fine milky emulsion forms within 2mins. 

Grade D {\textendash} emulsion was formed after 2 mins. dull, greyish white emulsion and slightly oily in appearance. 

Grade E {\textendash} emulsion was poorly formed which has large oil globules on the surface (more than 3mins).

\textbf{Percentage transmittance}

25 \ensuremath{\mu}l of EZM loaded L-SNEDDS was reconstituted with distilled water up to 25 ml to form a nano emulsion. It was observed visually for clarity. The \% transmittance of the samples was measured at 650 nm in UV-Vis spectrophotometer \unskip~\citep{680357:16093232}.

\textbf{Effect of dilution}

The samples were diluted 100 and 1000 times with water and 0.1 HCl. It was allowed to stand for 24 hours and viewed for any changes such as phase separation or precipitation of drug \unskip~\citep{680357:16093231}.

\textbf{Characterization of the F6 formulation}

\textbf{Phase Contrast Microscopy}

The morphology of the drug loaded F6 liquid SNEDDS was determined by Phase Contrast Microscopy (Leica S40, 230 \ensuremath{\pm} 10 V, 5 W). The morphology was determined by focusing the lens 10X and 40X. 

\textbf{Cloud point determination}

Cloud point evaluates the temperature effect on the phase behaviour of SNEDDS. The sample was diluted in the ratio of 1:250 with distilled water and heated. Cloud Point is the temperature at which there is a sudden appearance of cloudiness. The temperature was noted visually \unskip~\citep{680357:16093230}

\textbf{Centrifugation test }

The EZM SNEDDS sample was diluted to 100 times using distilled water and the samples were centrifuged (EPPENDROFF, 5415 R, Germany) at 4000 rpm for 30 mins. It was then examined for any instabilities \unskip~\citep{680357:16093227,680357:16093230}.

\textbf{Freeze-thaw cycle}

Freeze-thaw cycle involves the accelerated stability study of the formulations. It involves three freeze thaw cycles at temperatures -20\ensuremath{^\circ}C and +25\ensuremath{^\circ}C kept for 48 hrs. Any instability was observed in the formulation \unskip~\citep{680357:16093227}.

\textbf{Formulation of EZM loaded solid SNEDDS}

The optimized L-SNEDDS was transformed to solid SNEDDS with the use of porous solid carriers like adsorbents. Adsorption onto the solid carriers is the easiest way to convert the liquid into the solid. The liquid SNEDDS of about 1ml was taken in porcelain dish and different quantities of adsorbents like aerosil, avicel PH 101, lactose, mannitol etc. The adsorbent which had the highest adsorption capacity and good flow properties were chosen as the adsorbent. A combination of Avicel PH 101 and Aerosil 200 was selected for the study \unskip~\citep{680357:16093230}. The solid SNEDDS prepared by adsorption onto carriers were then filled into hard gelatine capsules. 

\textbf{Characterization of S-SNEDDS}

\textbf{Micromeritic properties of powders}

It is the study of the fundamental and derived properties of individual as well as a collection of particles. 

\textbf{Bulk Density}

Bulk density is the mass per unit volume of a loose powder bed, including the volume of all interparticle voids. Bulk density was calculated using the equation given below \unskip~\citep{680357:16093231}
\begin{eqnarray*}Bulk\;density\;=\;\frac M{V_0} \end{eqnarray*}
M - Mass in grams. 

Vo {\textendash} Untapped apparent volume in ml (bulk volume).

\textbf{Tapped Density}

Tapped density is the ratio of the mass of the powder to the volume of the powder occupied after it is tapped for a defined period of time. It is expressed in g/ml. It was calculated using the formula \unskip~\citep{680357:16093231}
\begin{eqnarray*}Tapped\;density\;=\;\frac M{V_f} \end{eqnarray*}
V\ensuremath{_{f}} {\textendash} the final tapped volume in ml. 

\textbf{Hausner's ratio}

The hausner's ratio predicts the propensity or flowabilty of a given powder sample to be compressed \unskip~\citep{680357:16093231}. It was determined by the formula
\begin{eqnarray*}Hausner\;ratio\;=\;\frac{V_0}{V_f} \end{eqnarray*}
\textbf{Carr's Index}

Carr's Index is an indication of the compressibility and flowability of a powder. It is expressed in percentage \unskip~\citep{680357:16093231}. It is calculated from the formula
\begin{eqnarray*}Carr's\;index\;=\;\frac{100(V_0-V_f)}{V_0} \end{eqnarray*}
\textbf{Angle of Repose}

The angle of repose is the angle produced by a heaped cone of a free standing powder. The determination of the angle was done by ``poured'' angle method \unskip~\citep{680357:16093231}. It is calculated by the formula
\begin{eqnarray*}\theta=\tan^{-1}\left(\frac hr\right) \end{eqnarray*}
Where, 

\ensuremath{\theta} is the angle. 

h - Height of the pile in cm

r {\textendash} Radius of the pile in cm

\textbf{FT-IR studies}

FT-IR studies was carried out for the drug and final physical mixture by the KBr press pellet technique.

\textbf{Scanning Electron Microscopy}

The size and morphological feature of solid SNEDDS were examined using scanning electron microscopy. The photograph was taken at acceleration voltage of 15KV. 

\textbf{Drug content}

Amount of sample equivalent to 10 mg of Ezetimibe is weighed and taken in a standard flask. A little quantity of ethanol is added to dissolve the drug and it is made up to 10 ml with distilled water. It is then further diluted to the desired concentration. Sample absorbance was measured by UV spectroscopy at 236 nm \unskip~\citep{680357:16093232}. 

\textit{\textbf{In-vitro}} \textbf{ dissolution}

The \textit{in-vitro} dissolution study was performed using USP dissolution apparatus II (LAB INDIA DS 8000). The dissolution test was performed in 0.05 M acetate buffer pH 4.5 with 0.45\% SLS \unskip~\citep{680357:16093236,680357:16093235}. Volume of the dissolution media was 500 ml. The stirring was provided by paddle rotating at 50 rpm with the temperature at 37\ensuremath{\pm}0.5\ensuremath{^\circ}C. Quantity of the solid formulation equivalent to 10 mg of the drug which was filled in a hard gelatine capsule was added into the medium. The samples were withdrawn at specific time intervals of 10, 20, 30, 45 and 60 min. Absorbance of the samples were then measured using UV spectrometer at 236 nm. 


\begin{table*}[!htbp]
\caption{\boldmath {Composition of Ezetimibe loaded liquid SNEDDS} }
\label{tw-7adca82146e7}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1958\linewidth-2\tabcolsep}p{\dimexpr.1696\linewidth-2\tabcolsep}p{\dimexpr.1805\linewidth-2\tabcolsep}p{\dimexpr.20700000000000003\linewidth-2\tabcolsep}p{\dimexpr.24709999999999997\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Formulation & \cAlignHack Oil (\%) & \cAlignHack Smix ratio & \cAlignHack Surfactant (\%) & \cAlignHack Co-surfactant (\%)\\
\tblmidrule 
\cAlignHack F1 &
  \cAlignHack 20 &
  \cAlignHack 1:1 &
  \cAlignHack 40 &
  \cAlignHack 40\\
\cAlignHack F2 &
  \cAlignHack 20 &
  \cAlignHack 2:1 &
  \cAlignHack 53.33 &
  \cAlignHack 26.66\\
\cAlignHack F3 &
  \cAlignHack 20 &
  \cAlignHack 3:1 &
  \cAlignHack 60 &
  \cAlignHack 20\\
\cAlignHack F4 &
  \cAlignHack 20 &
  \cAlignHack 1:2 &
  \cAlignHack 26.66 &
  \cAlignHack 53.33\\
\cAlignHack F5 &
  \cAlignHack 25 &
  \cAlignHack 1:1 &
  \cAlignHack 37.5 &
  \cAlignHack 37.5\\
\cAlignHack F6 &
  \cAlignHack 25 &
  \cAlignHack 2:1 &
  \cAlignHack 50 &
  \cAlignHack 25\\
\cAlignHack F7 &
  \cAlignHack 25 &
  \cAlignHack 3:1 &
  \cAlignHack 56.25 &
  \cAlignHack 18.75\\
\cAlignHack F8 &
  \cAlignHack 25 &
  \cAlignHack 1:2 &
  \cAlignHack 25 &
  \cAlignHack 50\\
\cAlignHack F9 &
  \cAlignHack 30 &
  \cAlignHack 1:1 &
  \cAlignHack 35 &
  \cAlignHack 35\\
\cAlignHack F10 &
  \cAlignHack 30 &
  \cAlignHack 2:1 &
  \cAlignHack 46.66 &
  \cAlignHack 23.33\\
\cAlignHack F11 &
  \cAlignHack 30 &
  \cAlignHack 3:1 &
  \cAlignHack 52.5 &
  \cAlignHack 17.5\\
\cAlignHack F12 &
  \cAlignHack 30 &
  \cAlignHack 1:2 &
  \cAlignHack 23.33 &
  \cAlignHack 46.66\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Percentage transmittance of different mixtures} }
\label{tw-41b8b7c857d5}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.43040000000000006\linewidth-2\tabcolsep}p{\dimexpr.2798\linewidth-2\tabcolsep}p{\dimexpr.2898\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Composition & \cAlignHack No. of flask inversions & \cAlignHack \% transmittance\\
\tblmidrule 
Cinnamon oil + Tween 20 &
  \cAlignHack 19 &
  \cAlignHack 95.67\\
Cinnamon oil + Tween 80 &
  \cAlignHack 19 &
  \cAlignHack 94.78\\
Clove oil + Tween 20 &
  \cAlignHack 16 &
  \cAlignHack 97.88\\
Clove oil + Tween 80 &
  \cAlignHack 16 &
  \cAlignHack 95.39\\
Cinnamon oil + Tween 20 + PEG 400 &
  \cAlignHack 17 &
  \cAlignHack 97.92\\
Cinnamon oil + Tween 80 + PEG 400 &
  \cAlignHack 11 &
  \cAlignHack 98.05\\
Clove oil + Tween 20 + PEG 400 &
  \cAlignHack 12 &
  \cAlignHack 96.22\\
Clove oil + Tween 80 + PEG 400 &
  \cAlignHack 18 &
  \cAlignHack 96.23\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Particle size and PDI of the formulations} }
\label{tw-c992cd79f5dd}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1473\linewidth-2\tabcolsep}p{\dimexpr.167\linewidth-2\tabcolsep}p{\dimexpr.1496\linewidth-2\tabcolsep}p{\dimexpr.1761\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Formulation & \cAlignHack Average Particle size (nm) & \cAlignHack PDI & \cAlignHack \% Transmittance & \cAlignHack Dispersibilty test (Grade) & \cAlignHack Dispersibility test result\\
\tblmidrule 
\cAlignHack F1 &
  \cAlignHack 273.7 &
  \cAlignHack 0.342 &
  \cAlignHack 97.18 &
  \cAlignHack A &
  \cAlignHack Pass\\
\cAlignHack F2 &
  \cAlignHack 250.6 &
  \cAlignHack 0.449 &
  \cAlignHack 98.43 &
  \cAlignHack A &
  \cAlignHack Pass\\
\cAlignHack F3 &
  \cAlignHack 203.4 &
  \cAlignHack 0.413 &
  \cAlignHack 98.26 &
  \cAlignHack A &
  \cAlignHack Pass\\
\cAlignHack F4 &
  \cAlignHack 389.6 &
  \cAlignHack 0.384 &
  \cAlignHack 94.80 &
  \cAlignHack A &
  \cAlignHack Pass\\
\cAlignHack F5 &
  \cAlignHack 428.8 &
  \cAlignHack 0.458 &
  \cAlignHack 95.33 &
  \cAlignHack A &
  \cAlignHack Pass\\
\cAlignHack F6 &
  \cAlignHack 196.1 &
  \cAlignHack 0.123 &
  \cAlignHack 98.95 &
  \cAlignHack A &
  \cAlignHack Pass\\
\cAlignHack F7 &
  \cAlignHack 264.9 &
  \cAlignHack 0.429 &
  \cAlignHack 97.37 &
  \cAlignHack A &
  \cAlignHack Pass\\
\cAlignHack F8 &
  \cAlignHack 384.0 &
  \cAlignHack 0.529 &
  \cAlignHack 92.55 &
  \cAlignHack B &
  \cAlignHack Pass\\
\cAlignHack F9 &
  \cAlignHack 509.0 &
  \cAlignHack 0.780 &
  \cAlignHack 90.07 &
  \cAlignHack B &
  \cAlignHack Pass\\
\cAlignHack F10 &
  \cAlignHack 443.0 &
  \cAlignHack 0.480 &
  \cAlignHack 94.70 &
  \cAlignHack B &
  \cAlignHack Pass\\
\cAlignHack F11 &
  \cAlignHack 307.4 &
  \cAlignHack 0.450 &
  \cAlignHack 93.33 &
  \cAlignHack C &
  \cAlignHack Fail\\
\cAlignHack F12 &
  \cAlignHack 640.3 &
  \cAlignHack 0.789 &
  \cAlignHack 91.80 &
  \cAlignHack C &
  \cAlignHack Fail\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Self emulsification time and dilution study of L-SNEDDS} }
\label{tw-5f754641d650}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.09309999999999997\linewidth-2\tabcolsep}p{\dimexpr.1532\linewidth-2\tabcolsep}p{\dimexpr.1922\linewidth-2\tabcolsep}p{\dimexpr.18069999999999997\linewidth-2\tabcolsep}p{\dimexpr.2027\linewidth-2\tabcolsep}p{\dimexpr.1781\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Formulation & \cAlignHack Self emulsification time (sec) & \multicolumn{2}{p{\dimexpr(.3728999999999999\linewidth-2\tabcolsep)}}{\cAlignHack Dilution study in water} & \multicolumn{2}{p{\dimexpr(.3808\linewidth-2\tabcolsep)}}{\cAlignHack Dilution study in 0.1N HCl}\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack  & \cAlignHack Drug precipitation & \cAlignHack Phase separation & \cAlignHack Drug precipitation & \cAlignHack Phase separation\\
\tblmidrule 
\cAlignHack F1 &
  \cAlignHack 49 &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No\\
\cAlignHack F2 &
  \cAlignHack 41 &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No\\
\cAlignHack F3 &
  \cAlignHack 46 &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No\\
\cAlignHack F4 &
  \cAlignHack 50 &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No\\
\cAlignHack F5 &
  \cAlignHack 58 &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No\\
\cAlignHack F6 &
  \cAlignHack 43 &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No\\
\cAlignHack F7 &
  \cAlignHack 48 &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack No\\
\cAlignHack F8 &
  \cAlignHack 83 &
  \cAlignHack No &
  \cAlignHack No &
  \cAlignHack Yes &
  \cAlignHack No\\
\cAlignHack F9 &
  \cAlignHack 85 &
  \cAlignHack No &
  \cAlignHack Yes &
  \cAlignHack No &
  \cAlignHack Yes\\
\cAlignHack F10 &
  \cAlignHack 92 &
  \cAlignHack No &
  \cAlignHack Yes &
  \cAlignHack No &
  \cAlignHack No\\
\cAlignHack F11 &
  \cAlignHack 129 &
  \cAlignHack No &
  \cAlignHack Yes &
  \cAlignHack No &
  \cAlignHack Yes\\
\cAlignHack F12 &
  \cAlignHack 132 &
  \cAlignHack Yes &
  \cAlignHack Yes &
  \cAlignHack Yes &
  \cAlignHack Yes\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Micromeritic properties of the powder} }
\label{tw-e39e9832eb5e}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1903\linewidth-2\tabcolsep}p{\dimexpr.2097\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.17790000000000003\linewidth-2\tabcolsep}p{\dimexpr.2221\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Bulk density \mbox{}\protect\newline (g/ml) & Tapped density (g/ml) & Hausner's ratio & Carr's index \mbox{}\protect\newline (\%) & Angle of repose (\ensuremath{\theta})\\
\tblmidrule 
0.24 &
  0.275 &
  1.12 &
  11.1 &
  31.06\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

    
\section{Results and Discussion}
\textbf{Solubility Study}

The amount of drug soluble in the excipients is an important criteria for the formulation of SNEDDS and its stability. The entire dose of the drug being used should be soluble in the excipients. The oil which had the highest solubilisation capacity for the drug was chosen as the oil phase. EZM was found to be highly soluble in cinnamon oil and clove oil. So these two oils were chosen as the oil phase for the further studies. The solubility of Ezetimibe in various excipients are shown Figure~\ref{f-5148cab4485c}.


\bgroup
\fixFloatSize{images/39c18a52-f234-4847-9729-7e6e73cbef84-upicture1.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/39c18a52-f234-4847-9729-7e6e73cbef84-upicture1.png}{\includegraphics{images/39c18a52-f234-4847-9729-7e6e73cbef84-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Ezetimibe solubility in various excipients}}
\label{f-5148cab4485c}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/98b25c17-dc99-4a0b-a54c-a38737d3aab7-upicture2.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/98b25c17-dc99-4a0b-a54c-a38737d3aab7-upicture2.png}{\includegraphics{images/98b25c17-dc99-4a0b-a54c-a38737d3aab7-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Pseudo Ternary Phase Diagram}}
\label{f-14832eb3605d}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/45152afa-6701-4251-a873-b2ab2e5d24dd-upicture3.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/45152afa-6701-4251-a873-b2ab2e5d24dd-upicture3.png}{\includegraphics{images/45152afa-6701-4251-a873-b2ab2e5d24dd-upicture3.png}}{}
\makeatother 
\caption{\boldmath {(a) Morphology of L-SNEDDS(10X);} (b) Morphology of L-SNEDDS(40X)}
\label{f-a3fb179646c2}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/cdb1f1dd-ff0c-4788-8b6e-5c7c075b8047-upicture4.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/cdb1f1dd-ff0c-4788-8b6e-5c7c075b8047-upicture4.png}{\includegraphics{images/cdb1f1dd-ff0c-4788-8b6e-5c7c075b8047-upicture4.png}}{}
\makeatother 
\caption{\boldmath {(a) FT-IR data for Ezetimibe; } (b) FT-IR data for physical mixture}
\label{f-75e619fa70ad}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/4ff70a0d-5dde-416d-b851-ee186ebb19dc-upicture5.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/4ff70a0d-5dde-416d-b851-ee186ebb19dc-upicture5.png}{\includegraphics{images/4ff70a0d-5dde-416d-b851-ee186ebb19dc-upicture5.png}}{}
\makeatother 
\caption{\boldmath {SEM Image for the F6 formulation}}
\label{f-37f1dee3df1d}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/5a20f28d-c279-48d2-8711-10c511ad9eea-upicture6.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/5a20f28d-c279-48d2-8711-10c511ad9eea-upicture6.png}{\includegraphics{images/5a20f28d-c279-48d2-8711-10c511ad9eea-upicture6.png}}{}
\makeatother 
\caption{\boldmath {\textit{In-vitro} dissolution data for F6 SNEDDS formulation and marketed formulation}}
\label{f-7f9fba1083da}
\end{figure}
\egroup
\textbf{Surfactants and co-surfactants screening}

The surfactant and co-surfactant were chosen on the basis of their HLB value, emulsifying ability and solubility of the drug in the excipients. The HLB value required for the formation of oil in water emulsion is 8-18. 

The surfactants with HLB value more than 10 showed good emulsification. NIS are preferred for oral administration as they can form a stable emulsion. NIS are least affected by changes in pH and ionic strength and are less toxic. The surfactant tween 80 with HLB value 15 showed more drug solubility (140 mg/ml) and emulsification efficiency. 

The drug was found to be freely soluble in PEG 400 (152 mg/ml) which had an HLB value of 11.4 and showed good emulsification ability. Tween 80 and PEG 400 had maximum emulsification efficiency with cinnamon oil and was chosen as the surfactant and co-surfactant respectively. The \% transmittance of the mixtures is shown in Table~\ref{tw-41b8b7c857d5}.

\textbf{Pseudo ternary phase diagram}

Self emulsification region was determined by the Pseudo ternary phase diagram. Phase diagrams says the relationship among the components of the emulsion and their phase behaviour. Surfactant and co-surfactant with different ratios were mixed with the oil in increasing concentration of 5\%. The nanoemulsion area shows the emulsification ability of the formulations. It is represented in the Figure~\ref{f-14832eb3605d}.

\textbf{Formulation of liquid-SNEDDS}

Formulations with different ratios of excipients were prepared according to the procedure. The amount of drug was kept constant for all the formulations. 

\textbf{Characterization of L-SNEDDS}

\textbf{Particle size and PDI}

The particle size or globule size of the formulations holds an important role in the stability of the nanoemulsion. The formulations with oil concentration of 20-25\% showed less particle size when compared to formulations with 30\% oil. The Particle size and PDI of the formulations are given in Table~\ref{tw-c992cd79f5dd}.

\textbf{Emulsification time}

The formulations which emulsified spontaneously within 1 minute were considered as good formulations. The formulations F1, F2, F3, F6, F7 showed good emulsification time. These formulations spontaneously formed emulsions when incorporated or introduced in aqueous media. Time for self emulsification is shown in Table~\ref{tw-5f754641d650}.

\textbf{Dilution study}

The formulations when diluted with water and 0.1 N HCl were observed for precipitation of drug and phase separation. In water, F9-F12 showed phase separation and F12 formulation also showed drug precipitation. In 0.1 HCl, drug precipitation was observed in formulations F8 and F12 and phase separation was observed in F9, F11 and F12. The result of the dilution study is shown in Table~\ref{tw-5f754641d650}.

\textbf{Dispersibility test}

The SNEDDS after administration should disperse completely in the GI fluids without any precipitation. The SNEDDS formulation which showed good clarity and dispersed completely were considered as pass (A or B grade). All the formulations from F1- F10 were A and B grade and these formulations passed the test for dispersibility. The grades of the formulations are mentioned in Table~\ref{tw-c992cd79f5dd}.

\textbf{Percentage transmittance}

Transmittance was measured to find out the clarity and transparency of the emulsions. The formulations with highest transmittance were considered as good emulsions and is given in table- 4. F1, F2, F3, F6, F7 formulations showed maximum transmittance and found to have more clarity compared to other formulations. The percentage transmittance of the formulations are given in Table~\ref{tw-c992cd79f5dd}.

\textbf{Characterization of the F6 formulation}

Based on the above evaluations and comparing the test result, F6 formulation was selected as the best formulation and further studies were carried out for the F6 formulation.

\textbf{Phase Contrast Microscopy}

The morphology of the liquid SNEDDS was examined by PCM. The Figure~\ref{f-a3fb179646c2}(a) and Figure~\ref{f-a3fb179646c2}(b) shows that spherical globules have been formed. 

\textbf{Cloud point determination}

Temperature is an important factor for the stability of nanoemulsion as changes in the phase behaviour can occur in higher temperatures when using non-ionic surfactants. The formulations which would remain as one phase transparent system and which a cloud point of above 37\ensuremath{^\circ}C was considered as an ideal formulation. The cloud point of the F6 formulation was found to be 76\ensuremath{^\circ}C which indicates that it is stable at physiological temperature.

\textbf{Centrifugation test}

The formulation F6 had no signs of precipitation or instabilities. Hence, L-SNEDDS was found to be stable after centrifugation.

\textbf{Freeze thaw cycle}

F6 formulation was kept in -20\ensuremath{^\circ}C and +25\ensuremath{^\circ}C for 48 hrs. The formulation showed no signs of phase separation and was found to be stable in these temperatures.

\textbf{Formulation and Characterization of S-SNEDDS}

\textbf{FT-IR Studies}~\textit{}

The characteristic peak was observed in the IR spectra of the drug [Figure~\ref{f-75e619fa70ad}(a)] and the physical mixture [Figure~\ref{f-75e619fa70ad}(b)]. This confirms that the molecule under the study has not undergone any characteristic changes which shows that there were no compatibilities observed within the components used.

\textbf{Micromeritic properties of powders}

The properties of the powder are mentioned in Table~\ref{tw-e39e9832eb5e}.

From the values of the micromeritic properties, it was found that the powder shows good flow properties according to the limits.

\textbf{Drug content}

Drug content of Ezetimibe was determined by using UV spectrophotometric method. The drug content of the formulation was found to be 98.5\% which falls within the pharmacopoeial (USP) limits of 93.0\%{\textendash}107.0\%.

\textbf{SEM}

The morphology of the powder formulation was found out by SEM. The irregular shaped granular particles indicates that the drug was enclosed in the solid powder formulation. Figure~\ref{f-37f1dee3df1d} shows the SEM image of the F6 solid powder formulation. 

\textit{\textbf{In-vitro}} \textbf{ dissolution}

The \textit{in-vitro} dissolution study for the F6 formulation was compared with the marketed formulation. The \textit{in-vitro} dissolution data for the prepared formulation and marketed formulation is represented in Figure~\ref{f-7f9fba1083da}. The \textit{in-vitro} dissolution data shows that the drug release at the end of 60 mins from marketed formulation was 63.75 \% and from the SNEDDS formulation was 90.62 \%. The data shows that the dissolution rate of the prepared SNEDDS was increased by 1.42 times than the marketed formulation.
    
\section{Conclusion }
In the present study, it was aimed to enhance the dissolution rate of the poorly water soluble drug Ezetimibe by formulating it in a self nano emulsified system. The data obtained from the study concludes that Ezetimibe can be converted into a self nanoemulsifying drug delivery system with the particle size in the nano range. Among the twelve formulations, F6 was chosen as the best formulation according to the results obtained from the evaluation test. F6 formulation showed a size of 196 nm and the PDI was 0.123. The F6 formulation consisted of the 25\% Cinnamon oil, 50\% tween 80 and 25\% PEG 400. \textit{In-vitro} dissolution study of the F6 formulation and Marketed formulation had a drug release of 90.62 \% and 63.75\% respectively at the end of 60 minutes. By comparing the \textit{in-vitro} dissolution data, the prepared S-SNEDDS formulation shows 1.42 times drug release than the conventional marketed formulation. 
    

\bibliographystyle{pharmascope_apa-custom}

\bibliography{\jobname}
\end{document}
