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\def\RunningAuthor{Anand S and Kumar K R}
\firstPage{6619}
\articleType{Original Article}
\receivedDate{10 Sep 2020}
\acceptedDate{14 Oct 2020}
\revisedDate{12 Oct 2020}
\journalVolume{2020, 11}
\journalIssue{4}
\journalDoi{ijrps.v11i4.3569}
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\def\journalTitle{International Journal of Research in Pharmaceutical Sciences}

\title{\textbf{Design, Development and Optimisation of Carvedilol Microemulsion by Pseudoternary Phase Diagram and Central Composite Design}}
\author{Anand~S\textsuperscript{*}\textsuperscript{1}, 
            Kumar~K~R\textsuperscript{2}~\\[5pt]{\textsuperscript{1}Centre for Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 085, India}~\\{\textsuperscript{2}Chemo India Formulations, Plot No. 2B \& 2C, Biotech Park Phase II, Lalgadi Malakpet, Hyderabad-500 078, India}}

\begin{abstract}
Aim of this study is to design and optimise carvedilol loaded microemulsion. Carvedilol microemulsion is prepared and optimised by Phase titration technique. The selections of material attributes for the formulation of microemulsion are chosen by building a pseudo ternary phase diagram with various concentration oils and surfactant. Optimisation of Carvedilol microemulsion formulation technique was carried out by Central composite Design with two centre points by using selected critical material attributes like the different concentration of oils, surfactants and evaluated for its effect on Critical quality attributes like PS nm, ZP mV, EE \%, PI, RI, \% Drug Content and Self emulsification time (sec). From this optimisation study data, selected Carvedilol Microemulsion is subjected to measure for its \textit{in vitro} drug release studies. CM9 formulation showed promising result in particle size, poly dispersibility index, entrapment efficiency and drug release studies. All the above data, it has been accomplished that CM9 was selected as an optimised Carvedilol microemulsion formulation.  
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Carvedilol,\newline Microemulsion,\newline Particle size,\newline Zeta potential,\newline Invitro drug release
\end{keywords}
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\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Anand~S~\\ Phone:\ ~\\  Email:\ anand.kar@gmail.com
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\section{Introduction}
Microemulsions [ME] are mixtures of hydrophobic, hydrophilic and amphiphilic sections that are macroscopically and optically isotropic.ME enhance the bioavailability of the drug. ME are homogenous, clear, thermodynamically constant dispersions of water \unskip~\citep{907796:20540479} and oil which is stabilised by a surfactant in combination to surfactant and their average droplet diameter lies in the range of within 10-140 micrometres \unskip~\citep{907796:20540478,907796:20540475,907796:20540481}. 

Direct (oil dispersed in water, o~/ w) and reversed (water dispersed in oil, w/o) are the two main types of microemulsions. ME is one of the potential and emerging drug carrier systems that help improve the release of drugs and improve the bioavailability of drugs that are poorly aqueous and soluble. The microemulsions demonstrate very rapid penetration of the active molecules, which is primarily due to the wide surface area of the internal phase, also decreasing the barrier property of their contents. The small droplets often have greater adherence in a regulated manner to membranes and transport drug molecules. MEs have been proposed to have a beneficial effect on drug absorption in a variety of ways, such as shielding the drugs from oxidation and enzymatic degradation and improving the membrane permeability and lymphatic transport. Also of importance is the composition of the interfacial layer of o~/ w~microemulsions, since it can influence the degree of solubilisation and the stabilisation of the structure. ow a day microemulsion is an emerging trade and having worldwide importance in a variety of technological applications \unskip~\citep{907796:20540484,907796:20540483}.

Carvedilol is a non-selective antagonist of beta-adrenergic receptors (\ensuremath{\beta }1, \ensuremath{\beta }2) and a regulator of alpha-adrenergic receptors (\ensuremath{\alpha }1). Carvedilol binds to beta-adrenergic receptors on cardiac myocytes reversibly. Inhibition of these receptors restricts the sympathetic nervous system from responding, resulting in reduced heart rate and contractility. In patients with heart disease, where the sympathetic nervous system is activated as a compensatory mechanism, this action is advantageous. Carvedilol alpha1 receptor blockade induces blood vessel vasodilatation. This inhibition corresponds to a decrease in peripheral vascular resistance and induces an antihypertensive reaction. Due to carvedilol's blockade of \ensuremath{\beta }1 receptors in the heart, there is no reflex tachycardia reaction. Carvedilol is graded as a BCS Class-II compound of low aqueous solubility and reasonable biomembrane permeability \unskip~\citep{907796:20540473,907796:20540482}. The central hypothesis of this research is to enhance the aqueous solubility the carvedilol formulating into microemulsion.
    
\section{Materials and Methods}
Carvedilol obtained as a contribution sample from Aurobindo Pvt. Ltd, Hyderabad. Arachis Oil, Castor Oil, Palm Oil, Sunflower Oil, Olive Oil, Corn oil, Tween 20 and 80, Span 20 and 80, Sodium Lauryl Sulphate, Poloxamer 188 and Polysorbates are obtained from Abitec corporation and Loba Chemie Pvt Ltd, Mumbai, Maharashtra, India.

\textbf{Methodology}

\textbf{Solubility studies}

By increasing the drug concentration, carvedilol's solubility has been evaluated in various oils such as Arachis Oil, Castor Oil, Palm Oil, Sunflower Oil, Olive Oil, and Corn Oil. Then it is allowed to dissolve until it is saturated to the equilibrium state in 10 ml of liquid. The solubility of the oil drug was estimated in mg/ml \unskip~\citep{907796:20540468}.

\textbf{FTIR analysis }

The chemical reaction between carvedilol and other ingredients such as oils, the surfactants used in the formulation, was calculated using FTIR tests. Studies have been carried out using the Potassium Bromide (KBr) pelletisation process for the carvedilol and microemulsion dispersion. Along with the KBr, narcotics (0.2 per cent) is grounded, and the mixture is then pressed with the aid of a mini KBr pellet press with a pressure of around 7 tons by shifting the press handle several times. The dispersion of the microemulsion was taken in a centrifuge tube and held for 40 minutes in a centrifuge at 15000 RPM., to eliminate the excess volume of oil, the supernatant solvent was siphoned from the centrifugal tube and traces were gathered and dried at 50\ensuremath{^{o}}C. Dried By fixing a resolution at 4cm\ensuremath{^{-1}} in the FTIR instrument (Bruker, Germany) fitted with the OPUS Spectrum programme, the dried microemulsion dispersion was stacked like a sandwich between a plane KBr pellet and scanned over a wavenumber scale of 4000 to 500 cm\ensuremath{^{-1}}. Samples were placed on the sample stage with a force gauge of 100 N and the reproducible contact between the sample and crystal holder for scanning is ensured \unskip~\citep{907796:20540490}.

\textbf{Identification of Drug by IR- spectrophotometric method}

Each chemical or drug's infrared spectrum contains details about the groups found in that unique chemical. A spectrophotometer for spectrum recording in the infra-red field consists of an optical device capable of producing 400-4000cm\ensuremath{^{-1}} monochromatic light and a resolution of 2cm\ensuremath{^{-1}} in the scanning range. To analyse liquid and semi-solid samples for IR analysis, attenuated complete reflection (ATR) is used. A microemulsion drop is placed directly on the (ATR) stage and scanned from 4000cm\ensuremath{^{-1}} to 400cm\ensuremath{^{-1}}. Bruker FTIR and ATR spectrophotometer (Germany) used the opus programme to collect the infrared spectrum of the drug sample \unskip~\citep{907796:20540490}. 

\textbf{Formulation of microemulsion }

To formulate the successful formulation of the microemulsion is mainly depends on the selection of oil excipients. There are many oil-based excipients presently available commercially. The selected excipients must possess properties required for the microemulsion system. There must be compatibility between drug and oil excipients used in microemulsion formulation. The surfactant and co-surfactant must have high HLB value and must be transparent to form a microemulsion. 

\textbf{Phase titration method}

The Spontaneous Emulsification Method (Phase Titration method) formulates microemulsions. It can be seen with the aid of phase diagrams, to prepare a microemulsion, a combination of fatty acids and oil is added a caustic solution. And a cosurfactant, and alcohol, is titrated with it until the system 


\begin{table*}[!htbp]
\caption{\boldmath {Different volumes of Surfactant and Co surfactant to prepare Smix ratio} }
\label{tw-41194b29c30d}
\def\arraystretch{1.1}
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\begin{tabulary}{\linewidth}{p{\dimexpr.1466\linewidth-2\tabcolsep}p{\dimexpr.3062\linewidth-2\tabcolsep}p{\dimexpr.26349999999999998\linewidth-2\tabcolsep}p{\dimexpr.2837\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S.NO & \cAlignHack Ratio of Smix & \cAlignHack Surfactant Volume (Span 80 in mL) & \cAlignHack Co surfactant Volume (Poloxamer 188 in mL)\\
\tblmidrule 
\cAlignHack 1. &
  \cAlignHack 1:1 &
  \cAlignHack 30 &
  \cAlignHack 30\\
\cAlignHack 2. &
  \cAlignHack 1:2 &
  \cAlignHack 20 &
  \cAlignHack 40\\
\cAlignHack 3. &
  \cAlignHack 1:3 &
  \cAlignHack 15 &
  \cAlignHack 45\\
\cAlignHack 4. &
  \cAlignHack 1:4 &
  \cAlignHack 12 &
  \cAlignHack 48\\
\cAlignHack 5. &
  \cAlignHack 2:1 &
  \cAlignHack 40 &
  \cAlignHack 20\\
\cAlignHack 6. &
  \cAlignHack 3:1 &
  \cAlignHack 45 &
  \cAlignHack 15\\
\cAlignHack 7. &
  \cAlignHack 4:1 &
  \cAlignHack 48 &
  \cAlignHack 12\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Composition of Carvedilol Microemulsion} }
\label{tw-c04f77ce164e}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2388\linewidth-2\tabcolsep}p{\dimexpr.2612\linewidth-2\tabcolsep}p{\dimexpr.20509999999999998\linewidth-2\tabcolsep}p{\dimexpr.29490000000000002\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulation code & Drug  \mbox{}\protect\newline (Carvedilol) (mg) & \multicolumn{2}{p{\dimexpr(.50\linewidth-2\tabcolsep)}}{\cAlignHack Ingredients \%w/w }\\
\rowcolor{kwdboxcolor} &  & \cAlignHack Olive oil  \mbox{}\protect\newline (ml) & \cAlignHack Span 80:Poloxamer (S\ensuremath{_{mix}}) 4:1 (ml)\\
\tblmidrule 
CM1  &
  20 &
  \cAlignHack 10 &
  \cAlignHack 90\\
CM2  &
  20 &
  \cAlignHack 20 &
  \cAlignHack 80\\
CM3  &
  20 &
  \cAlignHack 30 &
  \cAlignHack 70\\
CM4  &
  20 &
  \cAlignHack 40 &
  \cAlignHack 60\\
CM5  &
  20 &
  \cAlignHack 50 &
  \cAlignHack 50\\
CM6  &
  20 &
  \cAlignHack 60 &
  \cAlignHack 40\\
CM7  &
  20 &
  \cAlignHack 70 &
  \cAlignHack 30\\
CM8  &
  20 &
  \cAlignHack 80 &
  \cAlignHack 20\\
CM9  &
  20 &
  \cAlignHack 90 &
  \cAlignHack 10\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Solubility studies of carvedilol in various oils, surfactant and cosurfactant} }
\label{tw-ae8c02a0d1b9}
\def\arraystretch{1.1}
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\tbltoprule \rowcolor{kwdboxcolor}S.No & Oil & The solubility of Carvedilol (mg/ml.) & Surfactant & The solubility of Carvedilol (mg/ml.) & Cosurfactant & The solubility of Carvedilol (mg/ml.)\\
\tblmidrule 
1. &
  Arachis Oil &
  74.24\ensuremath{\pm}2.56 &
  Tween-20 &
  58.52\ensuremath{\pm}2.54 &
  Poloxamer188  &
  104.42\ensuremath{\pm}3.54\\
2. &
  Castor Oil &
  92.54\ensuremath{\pm}2.42 &
  Tween-80 &
  54.24\ensuremath{\pm}3.12 &
  Polysorbate20  &
  64.90\ensuremath{\pm}3.42\\
3. &
  Palm Oil &
  95.42\ensuremath{\pm}2.56 &
  SLS &
  52.66\ensuremath{\pm}3.24 &
  Polysorbate60  &
  77.72\ensuremath{\pm}3.62\\
4. &
  Sunflower Oil &
  65.46\ensuremath{\pm}2.94 &
  Span-20 &
  72.64\ensuremath{\pm}3.84 &
  Polysorbate80  &
  89.42\ensuremath{\pm}3.34\\
5. &
  Olive Oil &
  128.32\ensuremath{\pm}2.54 &
  Span-80 &
  82.42\ensuremath{\pm}3.62 &
  - &
  -\\
6. &
  Corn oil &
  80.54\ensuremath{\pm}2.40 &
  - &
  - &
  - &
  -\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/334b20a8-d648-486d-8925-380e3c5115f1-upicture1.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/334b20a8-d648-486d-8925-380e3c5115f1-upicture1.png}{\includegraphics{images/334b20a8-d648-486d-8925-380e3c5115f1-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Solubility studies of carvedilol in various (A) oils; (B) surfactant; (C) cosurfactant}}
\label{f-562e9504c112}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/8cbc4006-b853-44e1-a462-5f8311fbd342-upicture2.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/8cbc4006-b853-44e1-a462-5f8311fbd342-upicture2.png}{\includegraphics{images/8cbc4006-b853-44e1-a462-5f8311fbd342-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Standard calibration curve for Carvedilol in (A)7.4pH and (B) 1.2pH Hcl}}
\label{f-5e6daae20b78}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/ca8b2ef7-2516-4d1b-9014-9be8ee82bc0e-upicture3.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/ca8b2ef7-2516-4d1b-9014-9be8ee82bc0e-upicture3.png}{\includegraphics{images/ca8b2ef7-2516-4d1b-9014-9be8ee82bc0e-upicture3.png}}{}
\makeatother 
\caption{\boldmath {FTIR spectra of (A) Carvedilol and (B)Carvedilol microemulsion}}
\label{f-fb8bc71b1a8a}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Interpretation data of FTIR spectra of Carvedilol microemulsion} }
\label{tw-b04a2c6de03e}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.241\linewidth-2\tabcolsep}p{\dimexpr.2882\linewidth-2\tabcolsep}p{\dimexpr.2208\linewidth-2\tabcolsep}p{\dimexpr.25\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Wave numbers \mbox{}\protect\newline in cm-1 & Origin  & \multicolumn{2}{p{\dimexpr(.4708\linewidth-2\tabcolsep)}}{\cAlignHack Wavenumber in cm\ensuremath{^{-1}}}\\
\rowcolor{kwdboxcolor} &  & \cAlignHack Carvedilol  & \cAlignHack Carvedilol ME\\
\tblmidrule 
3600 - 3200  &
  O{\textendash}H alcohol(S)  &
  \cAlignHack 3337.84  &
  \cAlignHack 3344.70 \\
3200 - 2500  &
  O{\textendash}H Carboxylic (S)  &
  \cAlignHack 2922.82  &
  \cAlignHack 2994.70 \\
1750 - 1735  &
  C=O (S)  &
  \cAlignHack 1739.41  &
  \cAlignHack 1737.09 \\
3000 - 2500  &
  O{\textendash}H Carboxylic (S)  &
  \cAlignHack 2922.84  &
  \cAlignHack 2994.70 \\
3350 - 3050  &
  N-H (S)  &
  \cAlignHack 3337.84  &
  \cAlignHack 3344.70 \\
1580 - 1490  &
  -NH  &
  \cAlignHack 1505.86  &
  \cAlignHack 1503.22 \\
1470 - 1430  &
  C- H (S)  &
  \cAlignHack 1450.22  &
  \cAlignHack 1453.26 \\
1410 - 1260  &
  -OH  &
  \cAlignHack 1333.30  &
  \cAlignHack 1381.78\- \\
1300 - 1050  &
  C-O (S)  &
  \cAlignHack 1256.00  &
  \cAlignHack 1099.37 \\
900 {\textendash} 800  &
  -C-H (B) &
  \cAlignHack 851.30 &
  \cAlignHack 849.57\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Selected combination of oil, smix (4:1) and water for construction of Pseudo-ternary phase diagram} }
\label{tw-15ceef2bd421}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1713\linewidth-2\tabcolsep}p{\dimexpr.26799999999999997\linewidth-2\tabcolsep}p{\dimexpr.295\linewidth-2\tabcolsep}p{\dimexpr.2657\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulation code  & The ratio of Olive Oil: Smix(\%) & Water in (\%) consumed to give endpoint after titration & Visual \mbox{}\protect\newline Observation \\
\tblmidrule 
S1 &
  10:0 &
  0.0548 &
  Separation\\
S2 &
  9:1 &
  0.1207 &
  Turbid\\
S3 &
  8:2 &
  0.1646 &
  Turbid\\
S4 &
  7:3 &
  0.233 &
  Turbid\\
S5 &
  6:4 &
  0.3105 &
  Viscous gel\\
S6 &
  5:5 &
  0.3351 &
  Milk like\\
S7 &
  4:6 &
  0.3667 &
  Clear but turbid\\
S8 &
  3:7 &
  0.3693 &
  Transparent and clear\\
S9 &
  2:8 &
  0.3638 &
  Transparent and clear\\
S10 &
  1:9 &
  0.312 &
  Transparent and clear\\
S11 &
  0:10 &
  0.1103 &
  Turbid lightly\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/50ff5c96-5c3a-4956-9f29-b0c08943acec-upicture4.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/50ff5c96-5c3a-4956-9f29-b0c08943acec-upicture4.png}{\includegraphics{images/50ff5c96-5c3a-4956-9f29-b0c08943acec-upicture4.png}}{}
\makeatother 
\caption{\boldmath {Ternary Phase Diagrams Surfactant /co-surfactant ratio 4:1 (S1-S11)}}
\label{f-79e250967dd8}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Thermodynamic stability studies of Carvedilol Microemulsion formulations CM1-CM9} }
\label{tw-2cfbf2c480ab}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2164\linewidth-2\tabcolsep}p{\dimexpr.2791\linewidth-2\tabcolsep}p{\dimexpr.2545\linewidth-2\tabcolsep}p{\dimexpr.25\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulation & Heating Cooling Cycles (4\ensuremath{^{0}}C to 45\ensuremath{^{0}}C 72 hrs) & Freeze-Thaw Cycle  \mbox{}\protect\newline between -21\ensuremath{^{0}}C to -25\ensuremath{^{0}}C & Centrifugation \mbox{}\protect\newline (3500 rpm 48 hrs)\\
\tblmidrule 
CM1 &
  Separation of phase &
  Separation of phase &
  Separation of phase\\
CM2 &
  Stable  &
  Separation of phase &
  Separation of phase\\
CM3 &
  Stable  &
  Stable &
  Separation of phase\\
CM4 &
  Stable  &
  Stable  &
  Stable \\
CM5 &
  Stable  &
  Stable  &
  Stable \\
CM6 &
  Stable  &
  Stable  &
  Stable \\
CM7 &
  Stable  &
  Stable  &
  Separation of phase\\
CM8 &
  Separation of phase &
  Stable  &
  Separation of phase\\
CM9 &
  Separation of phase &
  Separation of phase &
  Separation of phase\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/37250da4-1dfb-43b4-b0b7-13c4b360336d-upicture5.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/37250da4-1dfb-43b4-b0b7-13c4b360336d-upicture5.png}{\includegraphics{images/37250da4-1dfb-43b4-b0b7-13c4b360336d-upicture5.png}}{}
\makeatother 
\caption{\boldmath {Particle Size and Zeta potential Report of CM9}}
\label{f-479f14a88489}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Optimisation of Carvedilol Microemulsion by Central composite design and evaluation of the effect of CMA and CPP on CQA} }
\label{tw-e1dd7f5922bd}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0924\linewidth-2\tabcolsep}p{\dimexpr.14519999999999998\linewidth-2\tabcolsep}p{\dimexpr.1413\linewidth-2\tabcolsep}p{\dimexpr.1426\linewidth-2\tabcolsep}p{\dimexpr.17849999999999998\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Run  & \cAlignHack Carvedilol \mbox{}\protect\newline (mg) & \multicolumn{2}{p{\dimexpr(.2839\linewidth-2\tabcolsep)}}{\cAlignHack CMA (Level Codes and its conc.)} & \multicolumn{3}{p{\dimexpr(.47849999999999994\linewidth-2\tabcolsep)}}{\cAlignHack CQA}\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack  & \cAlignHack X1 Oil Conc. & \cAlignHack X2 Smix Conc. & \cAlignHack Particle Size & \cAlignHack Zeta potential & \cAlignHack Entrapment Efficiency\\
\tblmidrule 
\cAlignHack CM1 &
  \cAlignHack 10 &
  \cAlignHack -1 &
  \cAlignHack -1 &
  \cAlignHack 5918.1\ensuremath{\pm}3.4 &
  \cAlignHack -14.7\ensuremath{\pm}1.4 &
  \cAlignHack 48.42\ensuremath{\pm}2.4\\
\cAlignHack CM2 &
  \cAlignHack 10 &
  \cAlignHack -1 &
  \cAlignHack 1 &
  \cAlignHack 1247.4\ensuremath{\pm}5.4 &
  \cAlignHack -21.3\ensuremath{\pm}1.6 &
  \cAlignHack 76.42\ensuremath{\pm}2.8\\
\cAlignHack CM3 &
  \cAlignHack 10 &
  \cAlignHack 1 &
  \cAlignHack -1 &
  \cAlignHack 2725.1\ensuremath{\pm}6.2 &
  \cAlignHack -17.4\ensuremath{\pm}1.6 &
  \cAlignHack 42.64\ensuremath{\pm}2.4\\
\cAlignHack CM4 &
  \cAlignHack 10 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 1734\ensuremath{\pm}3.6 &
  \cAlignHack -39.4\ensuremath{\pm}1.8 &
  \cAlignHack 73.80\ensuremath{\pm}2.6\\
\cAlignHack CM5 &
  \cAlignHack 10 &
  \cAlignHack 0 &
  \cAlignHack -1 &
  \cAlignHack 2264.2\ensuremath{\pm}3.0 &
  \cAlignHack -19.8\ensuremath{\pm}1.4 &
  \cAlignHack 68.42\ensuremath{\pm}2.8\\
\cAlignHack CM6 &
  \cAlignHack 10 &
  \cAlignHack -1 &
  \cAlignHack 0 &
  \cAlignHack 2147.0\ensuremath{\pm}3.4 &
  \cAlignHack -12.3\ensuremath{\pm}1.4 &
  \cAlignHack 56.42\ensuremath{\pm}2.4\\
\cAlignHack CM7 &
  \cAlignHack 10 &
  \cAlignHack 0 &
  \cAlignHack 1 &
  \cAlignHack 1036.6\ensuremath{\pm}3.8 &
  \cAlignHack -44.5\ensuremath{\pm}1.4 &
  \cAlignHack 92.40\ensuremath{\pm}2.6\\
\cAlignHack CM8 &
  \cAlignHack 10 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 1853.5\ensuremath{\pm}3.0 &
  \cAlignHack -38.4\ensuremath{\pm}1.2 &
  \cAlignHack 80.42\ensuremath{\pm}2.8\\
\cAlignHack CM9 &
  \cAlignHack 10 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1017.5\ensuremath{\pm}5.4 &
  \cAlignHack -64.4\ensuremath{\pm}1.4 &
  \cAlignHack 94.80\ensuremath{\pm}2.0\\
\cAlignHack CM10 &
  \cAlignHack 10 &
  \cAlignHack 1 &
  \cAlignHack 0 &
  \cAlignHack 1175.7\ensuremath{\pm}5.2 &
  \cAlignHack -41.2\ensuremath{\pm}1.6 &
  \cAlignHack 88.52\ensuremath{\pm}2.8\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Optimisation of Carvedilol Microemulsion and evaluation of the effect of CMA and CPP on other CQA} }
\label{tw-f8abc329f852}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1478\linewidth-2\tabcolsep}p{\dimexpr.1857\linewidth-2\tabcolsep}p{\dimexpr.2665\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Run & \multicolumn{4}{p{\dimexpr(.8522\linewidth-2\tabcolsep)}}{\cAlignHack Other CQA}\\
\rowcolor{kwdboxcolor} & PDI & RI & \% Drug Content & Self emulsification time (sec)\\
\tblmidrule 
CM1 &
  2.727 &
  1.442 \ensuremath{\pm}0.02 &
  80.54\ensuremath{\pm} 2.8 &
  42\ensuremath{\pm} 0.56\\
CM2 &
  0.739 &
  1.438 \ensuremath{\pm}0.02 &
  82.24\ensuremath{\pm} 3.2  &
  22\ensuremath{\pm} 0.32\\
CM3 &
  1.823 &
  1.498 \ensuremath{\pm}0.02 &
  80.94\ensuremath{\pm} 2.4 &
  30\ensuremath{\pm} 0.40\\
CM4 &
  0.969 &
  1.440 \ensuremath{\pm}0.02 &
  84.88\ensuremath{\pm} 3.6 &
  28\ensuremath{\pm} 0.26\\
CM5 &
  0.538 &
  1.466 \ensuremath{\pm}0.02 &
  85.42\ensuremath{\pm} 4.6 &
  26\ensuremath{\pm} 0.62\\
CM6 &
  3.481 &
  1.438 \ensuremath{\pm}0.02 &
  80.56\ensuremath{\pm} 2.4 &
  26 \ensuremath{\pm} 0.42\\
CM7 &
  0.659 &
  1.432 \ensuremath{\pm}0.02 &
  90.66\ensuremath{\pm} 4.2 &
  22\ensuremath{\pm} 0.42\\
CM8 &
  0.697 &
  1.458 \ensuremath{\pm}0.02 &
  84.68\ensuremath{\pm} 3.2 &
  27\ensuremath{\pm} 0.32\\
CM9 &
  0.591 &
  1.432\ensuremath{\pm}0.02 &
  96.80\ensuremath{\pm} 4.2 &
  19 \ensuremath{\pm} 0.26\\
CM10 &
  0.520 &
  1.482 \ensuremath{\pm}0.02 &
  89.42\ensuremath{\pm} 4.0 &
  21\ensuremath{\pm} 0.22\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/641e1e37-0b7a-44cc-9b24-b1a3cdd4a1b9-upicture6.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/641e1e37-0b7a-44cc-9b24-b1a3cdd4a1b9-upicture6.png}{\includegraphics{images/641e1e37-0b7a-44cc-9b24-b1a3cdd4a1b9-upicture6.png}}{}
\makeatother 
\caption{\boldmath {Prediction profiler Graph and Contour Graph showing (A, B) CMA effect on Particle Size ;(C, D) CMA effect on Zeta Potential; (E, F) CMA effect on Entrapment Efficiency}}
\label{f-3da02716e332}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/df576e34-6b25-4a88-b9fc-a242024c9787-upicture7.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/df576e34-6b25-4a88-b9fc-a242024c9787-upicture7.png}{\includegraphics{images/df576e34-6b25-4a88-b9fc-a242024c9787-upicture7.png}}{}
\makeatother 
\caption{\boldmath {SEM image of Microemulsion (CM9) at (A) 300\ensuremath{\mu }m and (B)100 \ensuremath{\mu }m}}
\label{f-7ac6eb33392c}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/52e1bc97-c6b8-43a4-91c2-11e459754f3e-upicture8.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/52e1bc97-c6b8-43a4-91c2-11e459754f3e-upicture8.png}{\includegraphics{images/52e1bc97-c6b8-43a4-91c2-11e459754f3e-upicture8.png}}{}
\makeatother 
\caption{\boldmath {Cumulative Invitro drug release profile of Microemulsion CM1-CM10}}
\label{f-bcd6dbfd0e16}
\end{figure*}
\egroup
turns transparent. Microemulsions with large visible spectrum transmissions can be produced with oils with longer chain lengths as the chain length of the surfactant has increased. Different alcohols are often observed to influence the development of microemulsions in various ways. The highest findings are achieved from short or branched alcohols in terms of the largest per cent transmittance combined with the wildest spectrum of oil concentrations (dispersed in water) \unskip~\citep{907796:20540480,907796:20540469,907796:20540477}.

\textbf{Screening of excipients based on solubility}

The option of excipients is dependent on drug, oil, surfactant. Co-surfactant solubility, drug solubility in various oils (Arachis Oil, Castor Oil, Palm Oil, Sunflower Oil, Olive Oil, Corn oil), Surfactants (Tween-20, Tween-80, Sodium lauryl Sulphate (SLS), Span-20, Span-80), co-surfactants (Poloxamer 188, Polysorbate 20, Polysorbate 60, Polysorbate 80)dissolution of an excess volume of drug in each vial containing 1 g of the chosen vehicle was determined. In a Sonicator bath kept at room temperature, the blends were shaken for 2 hours. Mixtures for 5min is centrifuged at 5000 rpm. The supernatant has been extracted and washed. The filtrate was sufficiently diluted with methanol, and UV-spectrophotometer measured drug concentrations in each liquid \unskip~\citep{907796:20540480}, surfactant and co-surfactant \unskip~\citep{907796:20540469,907796:20540477,907796:20540492}.

\textbf{Construction of pseudo-ternary phase diagrams }

Different volume ratios (1:1, 2:1, 3:1, 4:1, 1:2, 1:3, 1:4) of surfactants and co-surfactants (Smix) were combined in each group as shown in Table~\ref{tw-41194b29c30d}, and a stock of 10mL was prepared for each group. For a thorough analysis of the phase diagrams for the creation of microemulsions, these Smix ratios were chosen for increasing co-surfactant concentration concerning surfactant and increasing surfactant concentration concerning co-surfactant \unskip~\citep{907796:20540489,907796:20540487}.

\textbf{Preparation of Microemulsion systems}

As seen in Table~\ref{tw-c04f77ce164e}, a series of microemulsions were prepared using Olive oil as the oil, Span 80 as the surfactant, and Poloxamer as the co-surfactant. The quantity of prescription was kept stable in all formulations. Drugs were put in a beaker, correctly measured, and oil, surfactant, and co-surfactant were applied. The components were combined with a magnetic stirrer by gentle stirring, and the resulting mixture was positioned for size reduction in ultra-sonication for around 10-15 minutes. Then, once the substance had fully dissolved, the mixture was heated at 40\ensuremath{^{0}}C. Up for further application, the homogenous mixture was kept at room temperature \unskip~\citep{907796:20540476,907796:20540488}.

\textbf{Thermodynamic stability studies}

Thermodynamic stability tests, such as heating cooling stage, freeze-thaw stage and centrifugation, have been carried out following completion of all formulations \unskip~\citep{907796:20540488,907796:20540470}. 

\textbf{Characterisation of microemulsion}

\textbf{Phase separation study}

Accurately about 1 ml of drug-loaded microemulsion was added to100 ml of distilled water in a beaker at 37\ensuremath{^{0 }} C and vortexed for 2 min. the mixture was stored at 37\ensuremath{^{0}}C (Room Temperature) a period of 2 hrs and observed visually for any phase separation \unskip~\citep{907796:20540470}.

\textbf{Visual assessment}

The microemulsion was diluted with distilled water (100 ml) and softly blended with a magnetic stirrer. Roughly 100 \ensuremath{\mu }l of medication was filled. It is necessary to sustain the temperature at 37\ensuremath{^{0}}C. Slight white milk such as emulsion was the formulation CM1 was less transparent emulsion, which has a bluish-white colour. The CM2-CM9 formulations have a smooth, slightly bluish appearance with strong stability \unskip~\citep{907796:20540470,907796:20540471,907796:20540491}.

\textbf{Transmission test}

Light transmission from selected formulations of microemulsion as well as 50 times, 100 times and 200 times water dilution was tested by UV-Spectrophotometer at respective nm using water as a blank \unskip~\citep{907796:20540470,907796:20540471,907796:20540491}. 

\textbf{Scanning electron microscopy}

Scanning electron microscopy (SEM) is used to determine the Identified Optimised Microemulsions surface morphology, Using double adhesive tape, the samples were placed on alumina stubs and covered with gold in a HUS-5 GB vacuum evaporator. The sample was then observed in the Hitachi S-3000N SEM at 10KV acceleration voltage and 5000X magnification \unskip~\citep{907796:20540489,907796:20540487}.

\textbf{Particle size determination}

The average particle size of the microemulsion was calculated by dynamic light dispersion (DLS) at a dispersion angle of 173\ensuremath{^{o}}, and the temperature of the sample holder (Nanopartica SZ-100 HORIBA Scientific, Japan) was approximately 25\ensuremath{^{o}}C.,o ensure that the light scattering rate remained inside the instrument limit, the dispersion assay remained diluted to 1:2500 v / v with double distilled water \unskip~\citep{907796:20540489,907796:20540487}. 

\textbf{Zeta potential}

Zeta potential is the potential difference in the stationary phase of the fluid bound to the distributed particles in the dispersion medium. Zeta potential is primarily based on the stability of colloidal dispersion; zeta potential was calculated using a Zetasizer (Nanopartica SZ-100 HORIBA Science, Japan). The Zeta potential was then directly calculated by the Smolochowski equation using the equation as follows \unskip~\citep{907796:20540476,907796:20540488}.
\begin{eqnarray*}\style{font-family:'Times New Roman'}{\style{font-size:20px}{\boldsymbol\zeta\boldsymbol\;\boldsymbol=\boldsymbol\;\boldsymbol \ensuremath{\epsilon}\boldsymbol\ensuremath{\mu}\boldsymbol/\boldsymbol \ensuremath{\eta}}} \end{eqnarray*}
Where, \ensuremath{\zeta } - Zeta otential, \ensuremath{\mu} - Electrophoretic mobility; \ensuremath{\epsilon}- electric permittivity of the liquid; \ensuremath{\eta} is the viscosity of the liquid.

\textbf{Determination of \% drug content}

The oil based dispersed system of the drug was analysed spectrophotometrically for the drug content at wavelength 241nm with a proper dilution of formulations taking dichloromethane as a blank \unskip~\citep{907796:20540470,907796:20540471,907796:20540491}.

\textbf{Lyophilization of Microemulsion}

The procedure of lyophilisation is otherwise referred to as freeze-drying, involving freezing and then drying the microemulsion under high vacuum by applying ultra-low freezing temperatures in the range from -50 \ensuremath{^\circ} C to -80 \ensuremath{^\circ} C. The optimised microemulsion was added with 5\% of Mannitol, which functions as cryoprotectants. This dispersion was frozen at approximately -80 \ensuremath{^\circ} C and dried with Lyophilizer (Freeze Zone 2.5, Labconco, Labconco Company Czech Republic) at a chamber pressure of approximately 0.120 mBar for 48 hours. The dried microemulsion powder from the sample holders was extracted and processed for further use in desiccators \unskip~\citep{907796:20540486}.

\textit{\textbf{In-vitro}} \textbf{ drug release study}

In-vitro drug release from ME was used to measure the consistency of emulsifying property. The usp06 station, dissolution apparatus used to study the drug release from the oil in an aqueous medium, hard gelatin capsule containing lyophilised microemulsion and marketed Carvil tablet (mfg.: Zydus Cadila Healthcare, batch no.: 2053297) was performed in basket type dissolution apparatus. 900 ml of phosphate buffer pH (7.4) was used as dissolution media. The bath temperature as well as bowl temperature, was maintained about 37\ensuremath{\pm}0.5\ensuremath{^{0}}C and paddle allowed rotating 50 rpm. 5ml of the sample was withdrawn at time intervals 5, 10, 15, 20, 25, 30 min and dilution were made to 10ml. 5ml of fresh medium was replaced to dissolution jar. The diluted samples are analysed spectrophotometrically at 241nm for carvedilol, and their \% drug release was calculated \unskip~\citep{907796:20540472,907796:20540485,907796:20540474}.
    
\section{Results and Discussion}
\textbf{Solubility Studies}

To prepare microemulsion, the assortment of excipients is significant criteria should pharmaceutically suitable, ideal and compatible with the formulation. The elevated solubility of carvedilol in the oil phase is essential for microemulsion to keep up the carvedilol in solubilised form. High HLB (Hydrophilic Lipophilic Balance) surfactants and co-surfactants make a stable formulation. In this solubility studies, oils like Arachis oil, castor oil, palm oil, sunflower oil, olive oil and corn oil was selected and performed for the solubility studies. It shows that the solubility concentration of carvedilol was found to be 74.24\ensuremath{\pm}2.56, 92.54\ensuremath{\pm}2.42, 95.42\ensuremath{\pm}2.56, 65.46\ensuremath{\pm}2.94, 128.32\ensuremath{\pm}2.54, 80.54\ensuremath{\pm}2.40 mg/ml in oils. Surfactants like Tween-20, Tween-80, Sodium lauryl Sulphate (SLS), Span-20 and Span-80 was selected and performed for the solubility studies. It shows that the solubility concentration of carvedilol was found to be 58.52\ensuremath{\pm}2.54, 54.24\ensuremath{\pm}3.12, 52.66\ensuremath{\pm}3.24, 72.64\ensuremath{\pm}3.84, 82.42\ensuremath{\pm}3.62mg/ml in surfactant. Co-Surfactants like Poloxamer 188, Polysorbate 20, Polysorbate 60 and Polysorbate 80 was selected and performed for the solubility studies. 

It shows that the solubility concentration of carvedilol was found to be 104.42\ensuremath{\pm}3.54, 64.90\ensuremath{\pm}3.42, 77.72\ensuremath{\pm}3.62, 89.42\ensuremath{\pm}3.34mg/ml in cosurfactant. Olive oil, Span 80 and Poloxamer 188 were chosen from solubility studies as oil, surfactant and co-surfactant for microemulsion preparation. For the preparation of emulsion, all these excipients are pharmaceutically suitable and non-irritant, non-sensitising to eyes. A significant criterion for choosing components such as oil, surfactant and co-surfactant is the solubility of the poorly water-soluble substance in different excipients.

In contrast to other oils, the solubility of carvedilol was found to be greater in olive oil. For the production of the ideal formulation, olive oil was chosen as the oil process. As the surfactant, Tween 80 was chosen, and Poloxamer 188 was picked as the aqueous process as a co-surfactant and double-distilled water. The results are shown in Figure~\ref{f-562e9504c112} and Table~\ref{tw-ae8c02a0d1b9}.

\textbf{Calibration curve of Carvedilol}

The drug was observed for solubility, and the drug was identified with the help of UV and FTTR. the carvedilol exhibited absorption maxima at 241nm when 7.4 pH Phosphate buffer was used as a solvent which was same as mentioned in literature. The calibration curve was prepared diverse concentration of carvedilol like 0,5,10,15,20,25 \ensuremath{\mu}g/ml in 7.4pH phosphate buffer, and their absorbance was observed at 241 nm in UV spectrophotometer by keeping 7.4pH phosphate buffer as blank. XY linear plot was drawn by keeping concentration in \ensuremath{\mu}g/m on x-axis and absorbance on the y-axis, which shows a good linearity r\ensuremath{^{2}} value as 0.998. The calibration data infer the good purity if carvedilol and suitable for formulation. The calibration curve was prepared diverse concentration of carvedilol like 0,2,4,6,8,10 \ensuremath{\mu}g/ml in 1.2pH 0.1N hydrochloric acid, and their absorbance was observed at 255 nm in UV spectrophotometer by keeping 1.2 pH 0.1Nhydrochloric acid as blank. XY linear plot was drawn by keeping concentration in \ensuremath{\mu}g/m on x-axis and absorbance on the y-axis, which shows a good linearity r\ensuremath{^{2}} value as 0.997. The calibration data infer the good solubility and purity of carvedilol and suitable for formulation. The results are shown in Figure~\ref{f-5e6daae20b78}.

\textbf{Compatibility studies by FTIR analysis - Carvedilol and its Microemulsion formulation}

The key functional groups with wavenumbers are {\textendash}OH stretching of 3337.84 cm\ensuremath{^{-1}},2922.82 cm\ensuremath{^{-1}}, -NH Stretching of 3337.84 cm\ensuremath{^{-1}}, C-H Stretching of 1450.22 cm\ensuremath{^{-1}},-OH group of 1333.30 cm\ensuremath{^{-1}}, C-O Stretching of 1256.00 cm\ensuremath{^{-1}}, -C-H bending of 851.30 cm\ensuremath{^{-1}} in the Carvedilol drug; {\textendash}OH stretching of 3615.90cm\ensuremath{^{-1}},3394.00 cm\ensuremath{^{-1}},-N-H stretching of 3350.50 cm-\ensuremath{^{1}},1508.99 cm\ensuremath{^{-1}},-O-H group of 1342.64 cm\ensuremath{^{-1}},{\textendash}C-o stretching of 1239.04 cm\ensuremath{^{-1}},-C-H bending of 842.37 cm\ensuremath{^{-1 }} in Carvedilol Microemulsion respectively. The results are shown in Figure~\ref{f-fb8bc71b1a8a}  and Table~\ref{tw-b04a2c6de03e}. 

The best Carvedilol microemulsion formulations have shown same spectra as an isolated drug which demonstrates that the chemical structure of the drug doesn't change after converting to microemulsion and shows there is no interaction between the drug and excipients. From the data obtained from FTIR spectra, it was concluded that when compared to the carvedilol, the preferred functional group frequencies in the pure drug were reproducible in carvedilol microemulsion. It was verified that the drug and excipients used were found to be compatible with each other in the formulations. 

\textbf{Construction of Pseudo-ternary phase diagram}

Oil and precise Smix ratios as were extensively combined in various volume ratios from 1:9 to 9:1 in separate small glass test tubes for each phase diagram. Eleven different variations of oil and each Smix; 0:10, 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 9:1, 10:0 were created to cover the available ratios for the sample to delineate the phase boundaries specifically formed in the phase diagrams. Pseudo ternary step diagrams were developed using the water titration method to assess the presence of the microemulsion region. The olive oil was combined with various amounts of surfactant and cosurfactant (Smix) to create pseudo ternary phase diagrams, and the mixture was titrated with purified water until it turned turbid. Using data obtained from the aqueous titration process, pseudo ternary step diagrams were drawn. In the range of 5-95 per cent of the total volume at 5 per cent intervals, the quantity of water applied to offer water concentration. Visual evaluation was performed for every 5 per cent addition of water to the oil and Smix mixture, as seen in Table~\ref{tw-15ceef2bd421}. The surfactant and co-surfactant ratios (Span 80 and Poloxamer 188) used for titration were 1:1,1:2,1:3, 1:4, 2:1,3:1 and 4:1, respectively.By using the phase diagram, the composition of the microemulsion, as well as the phase behaviour of mixture, can be determined. For each Smix ratio the pseudo ternary phase diagram constructed separately, O/W microemulsion regions could be identified, and microemulsion could be optimised. Pseudo ternary phase diagram construction was constructed by using a surfactant, co-surfactant was incorporated in the ratio 1:1, and the pseudo ternary diagram was constructed. It was found that the region of microemulsion existence was very less. The increase in surfactant 2:1 concentration resulted in the development of a greater microemulsion region. Further concentration changes from 2:1 to 3:1 and 3:1 to 4:1 culminated in a much larger rise in the area of the microemulsion. Further increase in the concentration of surfactant and co-surfactant ratio from 4:1 to 5:1, resulting in the formation of gel-like microemulsion with less area of formulation of the microemulsion. On the other hand the increase in the cosurfactant and surfactant ratio from 1:1 to 1:2, 1:2 to 1:3 and 1:3 to 1:4, resulting in less microemulsion when compared to surfactant: co-surfactant ratio (4:1). These pseudo ternary phase diagrams were constructed with a combination of oil and Smix ratio from 1:9 to 9:1 like 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1. Each ratio of Smix and oil ratio represents a separate phase diagram individually. On which ratio of oil and Smix gives the highest region of microemulsion was identified and select that ratio for main formulation optimisation of microemulsion preparation. In this study, we found that 4:1 (Surfactant: co-surfactant) ratio gives a high region area for microemulsion preparation, so 4:1 Smix took as the optimised ratio for further microemulsion formulation. The results are shown in Figure~\ref{f-79e250967dd8}. 

\textbf{Thermodynamic stability studies}

Thermodynamic stability tests, tests such as heating-cooling cycle, freeze-thaw cycle and centrifugation, were conducted after completion of all formulations. Of the nine formulations, six formulations were chosen based on heating, cooling and centrifugation. Based on thermodynamic stability tests, six formulations were found to have been introduced and chosen for further characterisation. The Carvedilol Microemulsion formulations were named as CM1-CM9, out of these formulations CM2 to CM7 shows good stability in Heating cooling cycles; CM1, CM8, CM9 shows phase separation in heating and cooling cycles; CM3 {\textendash} CM8 shows no phase separation in Freeze-Thaw cycle; CM1, CM2, CM9 shows phase separation in Freeze-Thaw cycle; CM1-CM3 and CM7-CM9 show phase separation in Centrifugation; CM4-CM6 shows no phase separation in centrifugation. From the data shown in Table~\ref{tw-2cfbf2c480ab}, it shows that CM4-CM6 shows good Stability studies in all type of Stability studies. The results show the Carvedilol microemulsion (CM2-CM9) was less clear and transparent. 

\textbf{Optimisation of Phase titration technique for the preparation of Carvedilol Microemulsion (Central composite design)} \textbf{\space }

The central composite optimisation of carvedilol microemulsion and its result are shown in Tables~\ref{tw-e1dd7f5922bd} and~\ref{tw-f8abc329f852}; and Figures~\ref{f-479f14a88489} and~\ref{f-3da02716e332}  revealed the effect of CMA on CQA during the preparation of Carvedilol microemulsion. It was inferred from the data that a clear association occurred between particle size and Smix. From the data, it was verified that there was a decrease in microemulsion particle size by growing the concentration of Smix. The 'P' value was found to be \textless\ 0.05 for ANOVA when the Smix vs PS was executed in nm, which suggests a massive change in PS when increasing the Smix concentration. Of all formulations (CM1-CM10), CM9 displayed a target particle size of approximately 1017.5\ensuremath{\pm}5.4 nm at a high +1 Smix range (i.e. 4:1 portion of span 80 ratio: Poloxamer 188). The increase in the concentration of Smix in microemulsion preparation revealed a parallel rise in the strength of the zeta with a decrease in the particle size of the microemulsion, which verified the strong stability of the non-sedimentary microemulsion. The 'p' value was found to be \textless\ 0.05 by defining it in ANOVA; this indicated that there was a substantial improvement in ZP by increasing the concentration of Smix and oil. The CM9 formulation revealed that the zeta potential needed was approximate -64.4\ensuremath{\pm}1.4 mV at a high +1 Smix concentration level. A similar rise in the EE percentage indicated an increase in Smix concentration.CM9 formulation showed higher entrapment efficiency of about 94.80\ensuremath{\pm} 2.0\%. The other variables, like Polydispersity index (PI), Refractive index (RI), \% Drug Content and Self emulsification time (sec), was determined for all the formulation. Among all the formulation, microemulsion CM9 shown least PI of 0.591 (acceptance criteria are {\textless}7 for monodisperse condition)which shows good dispersibility of microparticles in phase and so that sedimentation rate if less for CM9 microemulsion; Cm  9 shows least Refractive index of about 1.432\ensuremath{\pm}0.02 which confirms the good transparency of microemulsion; Cm9 shows maximum carvedilol content of about 96.80\ensuremath{\pm} 4.2\%, it may result due to reduction in particle size which may enhance the encapsulation of drug in microparticles. The Self emulsification time for CM9 microemulsion was found very fast, i.e., 19 \ensuremath{\pm} 0.26 sec, it may be due to least particle size and concentration on Smix on the interface of oil and water. So that the water consumption for the formation of microemulsion was less and the endpoint for microemulsion was found to be short. From the optimisation results, it was concluded that the optimal formulation was found to be CM9. The polynomial equations were derived from central composite design coefficient values, provided by the CMA-based adjustments in the CQA, as follows:
\let\saveeqnno\theequation
\let\savefrac\frac
\def\dispfrac{\displaystyle\savefrac}
\begin{eqnarray}
\let\frac\dispfrac
\gdef\theequation{1}
\let\theHequation\theequation
\label{dfg-975deb6f210e}
\begin{array}{@{}l}PS\;=\;1448.32-1267.65X2\end{array}
\end{eqnarray}
\global\let\theequation\saveeqnno
\addtocounter{equation}{-1}\ignorespaces 
\vskip-1.5\baselineskip 
\let\saveeqnno\theequation
\let\savefrac\frac
\def\dispfrac{\displaystyle\savefrac}
\begin{eqnarray}
\let\frac\dispfrac
\gdef\theequation{2}
\let\theHequation\theequation
\label{dfg-da1caf4f3703}
\begin{array}{@{}l}\begin{array}{l}ZP=\;-36.2-12.45X1\\\;\;\;\;\;\;\;\;-13.05X2-10.1X1X2\end{array}\end{array}
\end{eqnarray}
\global\let\theequation\saveeqnno
\addtocounter{equation}{-1}\ignorespaces 
\vskip-1.5\baselineskip 
\let\saveeqnno\theequation
\let\savefrac\frac
\def\dispfrac{\displaystyle\savefrac}
\begin{eqnarray}
\let\frac\dispfrac
\gdef\theequation{3}
\let\theHequation\theequation
\label{dfg-a03dc8d8973e}
\begin{array}{@{}l}EE=\;80.02+17.35X2\end{array}
\end{eqnarray}
\global\let\theequation\saveeqnno
\addtocounter{equation}{-1}\ignorespaces 
From the optimisation, it was confirmed that all the practical values are correlated strongly with the predicted values, and the regression coefficient r2 value was found to be 0.995 when comparing the predicted vs observed values of PS, ZP and EE of carvedilol microemulsion CM9.

\textbf{Scanning Electron Microscopy (SEM) Evaluation}

Surface morphology and shape of microemulsion formulated with optimised parameters was observed for SEM studies. 

The study revealed that the microemulsion was mostly spherical, the particle surface had a distinctive smoothness, and the particle size, as shown by SEM, was in the micrometric range. The results of Carvedilol microemulsion shown in Figure~\ref{f-7ac6eb33392c}.

\textit{\textbf{In vitro}} \textbf{ drug release study}

The drug release profile for Lyophilized Carvedilol microemulsion particles was investigated in phosphate buffer (pH7.4) by packing in a gelatin capsule. It shows that droplet size decreased, the surface area increased, allowing more dissolution of the drug from microemulsion. The release of drug from formulation mainly depends on Smix: Oil ratio. When the concentration Smix increased in formulation result in smaller microdroplet was formed this result in enhancement of the dissolution profile of carvedilol. Thus, the carvedilol release from CM9microemulsion was found to be highest (100.74\ensuremath{\pm}2.80\%) at30 min than other formulation and marketed Carvil tablet, as shown in Figure~\ref{f-bcd6dbfd0e16}. With an increase in the Smix ratio in CM9, the release of the drug increases, and the successful distribution of the drug is partly due to the size of the microparticles and the polarity of the resulting oil droplets, which makes for a higher rate of drug release into the aqueous process. The solubilised drug, which is independent of the lipid digestion process, does not precipitate in the lumen and undergo rapid absorption. 
    
\section{Conclusion}
From the discusses optimisation study data, selected Carvedilol Microemulsion are subjected to measure for its \textit{in vitro} drug release studies and CM9 formulation showed promising result in particle size, poly dispersibility index, entrapment efficiency and in-vitro drug release studies. From all the above data, it has been accomplished that CM9 was selected as an optimised Carvedilol microemulsion formulation. 
    
\section{Acknowledgement}
The authors are thankful to all who have extended their constant support for the completion of the work.

\textbf{Conflict of Interest }

The authors declared no conflict of interest for this study.

\textbf{Funding Support}

The authors declared no funding support for this study.
    

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