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\def\RunningAuthor{Swetha M. et al. }
\firstPage{544}
\articleType{Original Article}
\receivedDate{04 Jan 2020}
\acceptedDate{08 Oct 2020}
\revisedDate{05 Oct 2020}
\journalVolume{2021, 12}
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\journalDoi{ijrps.v12i1.4116}
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\title{\textit{\textbf{Invitro }} \textbf{Designing of Fluvastatin Chrono Formulation}}
\author{Swetha~M.\textsuperscript{*}\textsuperscript{1},  
            Suresh~Kumar~J.N.\textsuperscript{2}, 
            Satyavathi~D.\textsuperscript{3}~\\[5pt]{\textsuperscript{1}Hits college of pharmacy, JNTUH affiliated, Hyderabad, Telangana, India}~\\{\textsuperscript{2}Narsaraopeta institute of pharmaceutical sciences, JNTUH affiliated, Guntur- 522601, Andhra Pradesh, India }~\\{\textsuperscript{3}Brilliant college of pharmacy, JNTUH affiliated Hyderabad, Telangana, India}}

\begin{abstract}
The objective was to improve fluvastatin prescribed pulsatile release formulation to get the disintegrative and ruptured lag-time mechanism with a fixed time delay which matches the chronotherapeutics (hypercholesteroidal disorder). Pre formulation studies UV, FTIR (Drug excipient compatibility), solubility studies and flow properties were evaluated for blend and drug. All the values were within the limit. 12 core tablets were prepared with two novel disintegrants, i.e. ludiflash, lycoat in different concentrations after doing the post-compression parameters \& drug release F8 was optimized \& then coated with PH sensitive polymers HPMC K200M \& Ethylcellulose in different concentrations. An evaluation was carried out for all six formulations, and all the values were within the limit. Based on In-vitro dissolution studies, swelling index and rupture test C5F8 is optimized and compared with the marketed product for 10 hours. As per the ICH guidelines optimized formulation (C5F8), stability tests were conducted for three months and was found to be stable. Optimized formulation (C5F8) contains 3:2 polymers (HPM K200M: Ethylcellulose) demonstrates an outstanding pulsatile drug delivery relative to the branded version (Lexcol XL) compared to all other formulations.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Chrono therapeutics,\newline fluvastatin,\newline ludiflash,\newline lycoat,\newline HPMC K200M and Ethylcellulose
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Swetha~M.~\\ Phone:\ 9701118007~\\  Email:\ swethabodire@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Oral controlled drug delivery system is found to be advantageous and convenient to the patients. In Pulsatile drug delivery, the medication is released from these devices at a fixed or adjustable speed. In Chrono formulation, the drug is released after a predetermined lag time based on Circadian rhythm and Chronological behavior of the patient. \unskip~\citep{900922:20479546,900922:20479547}

Many conditions demand pulsatile release like, 


  
  \begin{enumerate}
  \item \relax Body works with the rhythm of the circadian. For examples. Hormone isolation, stomach acid secretion and gastric emptying.
  \item \relax The time lag is necessary for medicines which are weakened by the medium of gastric acids (for example, peptide). 
  \item \relax The pharmaceutical substances that are metabolized in the first place, resulting in lower bio availability, a shift in substance and metabolite status and the probability of food drug interactions, require postponement of the medication as much as practicable. \unskip~\citep{900922:20479540,900922:20479531,900922:20479532}
  \end{enumerate}
  Time-controlled drug delivery systems are pulsative devices, which are based on physiological conditions such as pH, metabolites, GI motility. These are designed as pellets or mini-tablets with different coating techniques to release the drug in the pulsatile model. In present work compression coating (without solvent) is selected to design pulsatile release of fluvastatin. Fluvastatin is an anti-hyperlipidemic agent, which is a reductase (statin) antagonist of hydroxyl methylglutaryl-CoA (HMG-CoA). Fluvastatin reduces blood lipid levels and prevents cardiovascular disease. \unskip~\citep{900922:20479544} Fluvastatin is a BCS-Class II therapeutic agent which lowers LDL, triglycerides and improves HDL concentrations. \unskip~\citep{900922:20479533}
    
\section{Materials and Methods}
\textbf{Materials}

Fluvastatin, Ludiflash \& Lycoat were purchased from BMR chemicals, polymers, and other excipients were laboratory chemicals of HITS College of pharmacy. 

\textbf{Solubility test}

Solubility was determined by the shake-flask method. The excess quantity of fluvastatin was mixed with various solvents. The samples were placed in a mechanical shaker at 37\ensuremath{^\circ}C and 100 rpm for 24 Hours. 

The upper layer was separated and filtered through Whatman filter paper, and the filtrate was diluted, and Spectrophotometrically assayed at 292 nm, and values were tabulated below in Table~\ref{tw-a47a32130542}.\unskip~\citep{900922:20479541}

\textbf{UV spectrum of fluvastatin}

Fluvastatin crude powder analyzed with UV spectroscopic at the range of 200-400 cm-1, and maximum absorption (\ensuremath{\lambda } max) was determined, results were shown in Figure~\ref{f-cbc1a412d999}, \unskip~\citep{900922:20479536}

\textbf{FTIR} \textbf{\space }

FTIR was performed for the physical mixture of fluvastatin and formulation to check the compatibility of fluvastatin and polymers. And results were shown in Figure~\ref{f-1494da08b26b} \& Figure~\ref{f-df5abd83c6c3}. \unskip~\citep{900922:20479536}

\textbf{Pre-compression o} \textbf{f core tablets of fluvastatin}

Pre-compression parameters like Bulk Density, tapped density, Compressibility Index, Hausner's Ratio and Angle of Repose were performed for all the formulations (blend), and the values were found to be within limits. Results were discussed. \unskip~\citep{900922:20479535,900922:20479548,900922:20479537}

\textbf{Formulation of core tablets}

As per Table~\ref{tw-3fb30f0e299e}, all drug \& excipients are blended and punched with 6mm punch.

\textbf{Coating of the core tablet by Compression coating method}

From polymer blend, half quantity of polymer was measured and placed in a die cavity, and the middle core tablet was placed, and the remaining polymer was poured over the core tablet and punched. Table~\ref{tw-080eb287af60}, \unskip~\citep{900922:20479534}

\textbf{Evaluation of tablets (coated \& uncoated)}

All the evaluation tests (Hardness Test, Thickness Of Coated Tablet, Weight Variation, Friability, Disintegration Test) for core and coated tablets as per the standard procedures from the book. Three measurements were taken and reported on average. The result was shown in Table~\ref{tw-d0bf55260899}. \unskip~\citep{900922:20479550}.

\textbf{Drug Content}

From each formulation, ten tablets were selected and powdered. From this powder equivalent to 100mg was weighed accurately and dissolved by sonication for 5 minutes with 5ml methanol in 100ml volumetric flask and Volume made up to 100ml by using phosphate buffer 7.4 and absorbance was measured at 292 nm and values are tabulated in Table~\ref{tw-d0bf55260899}. \unskip~\citep{900922:20479545}

\textit{\textbf{In- Vitro}} \textbf{ Dissolution Studies of Compressed Coated Tablets}

Compressed coated Fluvastatin tablets dissolution carried out through using pH 1.2, Phosphate 6.8 and Phosphate 7.4 buffers till 10 Hours, 2 hrs, 3 hrs, and 5 hrs respectively at 37\ensuremath{^{0}}C and 50 rpm by using USP dissolution apparatus. Every one hour sample of 1ml was collected and diluted up to 10 ml with pH medium, and the sample is analyzed for absorbance through ultra visible Spectroscopy at 292 nm. \% drug release vs t (time) plotted on the graph and results are shown in Table~\ref{tw-1e2749040d6c} \& Figure~\ref{f-3a130a80a82c}. \unskip~\citep{900922:20479542}\ensuremath{^{}}

\textbf{Swelling Index}

In containers loaded by 10 ml of 1.2 buffer and Phosphate 7.4 buffers, the Percentage swelling strength of tablets was determined. Tablets have been withdrawn from containers, weighted and again weighed in the medium at fixed intervals, lined with tissue paper until the external surface of the tablet has begun to break. The Percentage of swelling was determined, and results were tabulated in Table~\ref{tw-436ce01a7c41}. \unskip~\citep{900922:20479550,900922:20479539}

Percentage swelling = [(Wet tablet weight at time {\textendash}dry tablet weight) / dry tablet weight] \ensuremath{\times} 100

\textbf{Rupture Test}

The breakage test was performed with USP paddle two systems on closed tablets. The other criteria here were similar to the in-vitro process of dissolution by using pH 1.2, Phosphate 6.8 and Phosphate 7.4 buffers. Noted the time where the outer layer started to rupture. The results are shown in Table~\ref{tw-cd5e46e87b40}, \unskip~\citep{900922:20479543}

\textit{\textbf{Drug release Kinetics}}

Drug release kinetics found to be good for all formulations out of 6 formulation data of formulation C5F8 was best explained by Higuchi equation, as the plot showed highest linearity (\textit{r2 }= 0.656), followed by zero-order equation (\textit{r2 }= 0.862). As the drug release was best fitted in Higuchi kinetics, indicating that the rate of drug release is diffusion. The result was shown in Figure~\ref{f-e9ff12bcef2a}.\textit{}

\textbf{Comparative Study between optimized formulation and marketed product\ensuremath{^{x19 }}}

Dissolution tests were separately carried out for Optimized formulation (C5F8) and marketed product (LEXCOL-XL) for 10 hrs with dissolution USP type 2 apparatus in 900 ml of 0.1N HCL at 37\ensuremath{\pm}0.5\ensuremath{^\circ}C \& 50 RPM for 2 hr followed by 3 hrs in Phosphate 6.8 and Phosphate 7.4 buffer. Every one-hour 1ml samples are collected from each vessel on an hourly basis and diluted to 10ml with media, and absorbance was measured spectroscopically at 292nm. The retired specimen was replaced immediately with a fresh buffer counterpart. The data obtained for dissolution was compared to the time in a percentage of medicines released. The result was shown in Figure~\ref{f-3503d3fa50b3}. \unskip~\citep{900922:20479549}

\textbf{Stability Studies}

As for the ICH guidelines for the optimized formulation of fluvastatin compressed coated tablets sealed in an aluminium foiled cover stored for three months and monthly, physic-chemical properties were evaluated. The result was shown in Table~\ref{tw-8a7e4ee40d90}. \unskip~\citep{900922:20479538}
    
\section{Results and Discussion}
\textbf{Flow Properties of Fluvastatin}

From the flow properties of pure fluvastatin, it was observed that fluvastatin has good flow property. 


\begin{table*}[!htbp]
\caption{\boldmath {Formulation of Core Tablets} }
\label{tw-3fb30f0e299e}
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  \cAlignHack 61 &
  \cAlignHack 58 &
  \cAlignHack 55 &
  \cAlignHack 52 &
  \cAlignHack 61 &
  \cAlignHack 58 &
  \cAlignHack 55 &
  \cAlignHack 52 &
  \cAlignHack 61 &
  \cAlignHack 58 &
  \cAlignHack 55 &
  \cAlignHack 52\\
\cAlignHack Mg.stearate &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3\\
\cAlignHack Talc &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3 &
  \cAlignHack 3\\
\cAlignHack Total wt (mg) &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Composition of compression coated tablets} }
\label{tw-080eb287af60}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.175\linewidth-2\tabcolsep}p{\dimexpr.1299\linewidth-2\tabcolsep}p{\dimexpr.1151\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.1471\linewidth-2\tabcolsep}p{\dimexpr.1529\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack  Formulation & \cAlignHack  C1F8 & \cAlignHack C2F8 & \cAlignHack C3F8 & \cAlignHack C4F8 & \cAlignHack C5F8 & \cAlignHack C6F8\\
\tblmidrule 
\cAlignHack Core &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150 &
  \cAlignHack 150\\
\cAlignHack HPMC K200M &
  \cAlignHack 250 &
  \cAlignHack -- &
  \cAlignHack 175 &
  \cAlignHack 100 &
  \cAlignHack 150 &
  \cAlignHack 75\\
\cAlignHack Ethylcellulose &
  \cAlignHack -- &
  \cAlignHack 250 &
  \cAlignHack 75 &
  \cAlignHack 150 &
  \cAlignHack 100 &
  \cAlignHack 175\\
\cAlignHack Total weight &
  \cAlignHack 400 &
  \cAlignHack 400 &
  \cAlignHack 400 &
  \cAlignHack 400 &
  \cAlignHack 400 &
  \cAlignHack 400\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Solubilitystudies of fluvastatin} }
\label{tw-a47a32130542}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.5124\linewidth-2\tabcolsep}p{\dimexpr.4876\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Solvents & \cAlignHack Solubility(mg/ml)\\
\tblmidrule 
\cAlignHack 0.1N HCL &
  \cAlignHack 0.102\ensuremath{\pm}0.36\\
\cAlignHack 6.8pH Buffer &
  \cAlignHack 0.275\ensuremath{\pm}0.04\\
\cAlignHack 4.5pH Buffer &
  \cAlignHack 0.168\ensuremath{\pm}0.01\\
\cAlignHack 7.4pH Buffer &
  \cAlignHack 0.147\ensuremath{\pm}0.10\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Evaluation of compressed tablets of fluvastatin} }
\label{tw-d0bf55260899}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1241\linewidth-2\tabcolsep}p{\dimexpr.1807\linewidth-2\tabcolsep}p{\dimexpr.1752\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Formula  & \cAlignHack Avg. wt  & \cAlignHack Hardness  & \cAlignHack Friability  & \cAlignHack Thickness & \cAlignHack Drug content\\
\rowcolor{kwdboxcolor}\cAlignHack  & \cAlignHack (mean\ensuremath{\pm} D, mg) & \cAlignHack (mean\ensuremath{\pm} D) & \cAlignHack (\%) & \cAlignHack  & \cAlignHack (\%)\\
\tblmidrule 
\cAlignHack C1F8 &
  \cAlignHack 400.26\ensuremath{\pm}0.52 &
  \cAlignHack 7.56\ensuremath{\pm}0.62 &
  \cAlignHack 0.26\ensuremath{\pm}0.02 &
  \cAlignHack 6.85\ensuremath{\pm}0.21 &
  \cAlignHack 89.56\ensuremath{\pm}0.02\\
\cAlignHack C2F8 &
  \cAlignHack 399.85\ensuremath{\pm}0.36 &
  \cAlignHack 7.15\ensuremath{\pm}0.52 &
  \cAlignHack 0.25\ensuremath{\pm}0.14 &
  \cAlignHack 7.42\ensuremath{\pm}0.30 &
  \cAlignHack 90.15\ensuremath{\pm}0.26\\
\cAlignHack C3F8 &
  \cAlignHack 399.74\ensuremath{\pm}0.20 &
  \cAlignHack 8.01\ensuremath{\pm}0.41 &
  \cAlignHack 0.54\ensuremath{\pm}0.64 &
  \cAlignHack 7.10\ensuremath{\pm}0.52 &
  \cAlignHack 95.25\ensuremath{\pm}0.05\\
\cAlignHack C4F8 &
  \cAlignHack 398.45\ensuremath{\pm}0.02 &
  \cAlignHack 7.65\ensuremath{\pm}0.26 &
  \cAlignHack 0.61\ensuremath{\pm}0.65 &
  \cAlignHack 6.48\ensuremath{\pm}0.10 &
  \cAlignHack 97.56\ensuremath{\pm}0.20\\
\cAlignHack C5F8 &
  \cAlignHack 399.12\ensuremath{\pm}0.30 &
  \cAlignHack 7.49\ensuremath{\pm}0.63 &
  \cAlignHack 0.26\ensuremath{\pm}0.32 &
  \cAlignHack 6.95\ensuremath{\pm}0.02 &
  \cAlignHack 97.12\ensuremath{\pm}0.32\\
\cAlignHack C6F8 &
  \cAlignHack 397.56\ensuremath{\pm}0.26 &
  \cAlignHack 7.26\ensuremath{\pm}0.25 &
  \cAlignHack 0.31\ensuremath{\pm}0.25 &
  \cAlignHack 6.47\ensuremath{\pm}0.06 &
  \cAlignHack 95.16\ensuremath{\pm}0.52\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {In-Vitro Dissolution Studies of Coated Tablets} }
\label{tw-1e2749040d6c}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1305\linewidth-2\tabcolsep}p{\dimexpr.1412\linewidth-2\tabcolsep}p{\dimexpr.1388\linewidth-2\tabcolsep}p{\dimexpr.1495\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.14\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Time (hrs) & \cAlignHack C1F8  & \cAlignHack C2F8  & \cAlignHack C3F8  & \cAlignHack C4F8  & \cAlignHack C5F8  & \cAlignHack C6F8 \\
\tblmidrule 
\cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0\\
\cAlignHack 1 &
  \cAlignHack 6.45\ensuremath{\pm}0.21 &
  \cAlignHack 8.56\ensuremath{\pm}0.26 &
  \cAlignHack 1.58\ensuremath{\pm}0.21 &
  \cAlignHack 0.59\ensuremath{\pm}0.48 &
  \cAlignHack 0.26\ensuremath{\pm}0.48 &
  \cAlignHack 0.79\ensuremath{\pm}0.26\\
\cAlignHack 2 &
  \cAlignHack 15.86\ensuremath{\pm}0.02 &
  \cAlignHack 17.59\ensuremath{\pm}0.32 &
  \cAlignHack 4.78\ensuremath{\pm}0.32 &
  \cAlignHack 1. 97\ensuremath{\pm}0.26 &
  \cAlignHack 1.48\ensuremath{\pm}0.82 &
  \cAlignHack 2.56\ensuremath{\pm}0.47\\
\cAlignHack 3 &
  \cAlignHack 25.27\ensuremath{\pm}0.52 &
  \cAlignHack 26.62\ensuremath{\pm}0.52 &
  \cAlignHack 13.15\ensuremath{\pm}0.45 &
  \cAlignHack 4.26\ensuremath{\pm}0.49 &
  \cAlignHack 3.26\ensuremath{\pm}0.15 &
  \cAlignHack 5.74\ensuremath{\pm}0.52\\
\cAlignHack 4 &
  \cAlignHack 34.68\ensuremath{\pm}0.62 &
  \cAlignHack 35.65\ensuremath{\pm}0.14 &
  \cAlignHack 24.59\ensuremath{\pm}0.45 &
  \cAlignHack 10.65\ensuremath{\pm}0.10 &
  \cAlignHack 7.49\ensuremath{\pm}0.28 &
  \cAlignHack 9.65\ensuremath{\pm}0.48\\
\cAlignHack 5 &
  \cAlignHack 44.09\ensuremath{\pm}0.12 &
  \cAlignHack 44.68\ensuremath{\pm}0.15 &
  \cAlignHack 36.78\ensuremath{\pm}0.26 &
  \cAlignHack 22.48\ensuremath{\pm}0.25 &
  \cAlignHack 12.15\ensuremath{\pm}0.39 &
  \cAlignHack 30.26\ensuremath{\pm}0.52\\
\cAlignHack 6 &
  \cAlignHack 53.50\ensuremath{\pm}.23 &
  \cAlignHack 53.71\ensuremath{\pm}0.25 &
  \cAlignHack 48.97\ensuremath{\pm}0.56 &
  \cAlignHack 40.56\ensuremath{\pm}0.96 &
  \cAlignHack 39.74\ensuremath{\pm}0.26 &
  \cAlignHack 48.75\ensuremath{\pm}0.48\\
\cAlignHack 7 &
  \cAlignHack 62.91\ensuremath{\pm}0.20 &
  \cAlignHack 62.74\ensuremath{\pm}0.56 &
  \cAlignHack 61.16\ensuremath{\pm}0.25 &
  \cAlignHack 58.64\ensuremath{\pm}0.23 &
  \cAlignHack 72.26\ensuremath{\pm}0.47 &
  \cAlignHack 67.24\ensuremath{\pm}0.36\\
\cAlignHack 8 &
  \cAlignHack 72.32\ensuremath{\pm}0.32 &
  \cAlignHack 71.77\ensuremath{\pm}0.62 &
  \cAlignHack 73.35\ensuremath{\pm}0.21 &
  \cAlignHack 76.72\ensuremath{\pm}0.14 &
  \cAlignHack 97.27\ensuremath{\pm}0.80 &
  \cAlignHack 85.73\ensuremath{\pm}0.15\\
\cAlignHack 9 &
  \cAlignHack 81.73\ensuremath{\pm}0.02 &
  \cAlignHack 85.8\ensuremath{\pm}0.78 &
  \cAlignHack 85.54\ensuremath{\pm}0.36 &
  \cAlignHack 94.82\ensuremath{\pm}0.02 &
  \cAlignHack  &
  \cAlignHack 97.85\ensuremath{\pm}0.26\\
\cAlignHack 10 &
  \cAlignHack 91.14\ensuremath{\pm}0.06 &
  \cAlignHack 96.83\ensuremath{\pm}0.02 &
  \cAlignHack 97.73\ensuremath{\pm}0.15 &
  \cAlignHack  &
  \cAlignHack  &
  \cAlignHack \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Swelling Index} }
\label{tw-436ce01a7c41}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1412\linewidth-2\tabcolsep}p{\dimexpr.1388\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}\cAlignHack Time (hr) & \cAlignHack C1F8 & \cAlignHack C2F8 & \cAlignHack C3F8 & \cAlignHack C4F8 & \cAlignHack C5F8 & \cAlignHack C6F8\\
\tblmidrule 
\cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0 &
  \cAlignHack 0\\
\cAlignHack 1 &
  \cAlignHack 76\ensuremath{\pm}0.32 &
  \cAlignHack 84\ensuremath{\pm}0.32 &
  \cAlignHack 72\ensuremath{\pm}0.26 &
  \cAlignHack 79\ensuremath{\pm}0.23 &
  \cAlignHack 68\ensuremath{\pm}0.26 &
  \cAlignHack 74\ensuremath{\pm}0.65\\
\cAlignHack 2 &
  \cAlignHack 84\ensuremath{\pm}0.21 &
  \cAlignHack 96\ensuremath{\pm}0.52 &
  \cAlignHack 88\ensuremath{\pm}0.32 &
  \cAlignHack 86\ensuremath{\pm}0.65 &
  \cAlignHack 86\ensuremath{\pm}0.03 &
  \cAlignHack 86\ensuremath{\pm}0.56\\
\cAlignHack 3 &
  \cAlignHack 89\ensuremath{\pm}0.26 &
  \cAlignHack 106\ensuremath{\pm}0.74 &
  \cAlignHack 102\ensuremath{\pm}0.15 &
  \cAlignHack 99\ensuremath{\pm}0.26 &
  \cAlignHack 102\ensuremath{\pm}0.02 &
  \cAlignHack 94\ensuremath{\pm}0.21\\
\cAlignHack 4 &
  \cAlignHack 96\ensuremath{\pm}0.28 &
  \cAlignHack 124\ensuremath{\pm}0.850 &
  \cAlignHack 126\ensuremath{\pm}0.24 &
  \cAlignHack 104\ensuremath{\pm}0.21 &
  \cAlignHack 138\ensuremath{\pm}0.21 &
  \cAlignHack 114\ensuremath{\pm}0.25\\
\cAlignHack 5 &
  \cAlignHack 99\ensuremath{\pm}0.65 &
  \cAlignHack 134\ensuremath{\pm}0.59 &
  \cAlignHack 139\ensuremath{\pm}0.1 &
  \cAlignHack 126\ensuremath{\pm}0.02 &
  \cAlignHack 161\ensuremath{\pm}0.33 &
  \cAlignHack 126\ensuremath{\pm}0.56\\
\cAlignHack 6 &
  \cAlignHack 114\ensuremath{\pm}0.54 &
  \cAlignHack 102\ensuremath{\pm}0.52 &
  \cAlignHack 102\ensuremath{\pm}0.25 &
  \cAlignHack 101\ensuremath{\pm}0.36 &
  \cAlignHack 124\ensuremath{\pm}0.36 &
  \cAlignHack 104\ensuremath{\pm}0.36\\
\cAlignHack 7 &
  \cAlignHack 106\ensuremath{\pm}0.58 &
  \cAlignHack 94\ensuremath{\pm}0.65 &
  \cAlignHack 91\ensuremath{\pm}0.29 &
  \cAlignHack 94\ensuremath{\pm}0.02 &
  \cAlignHack 102\ensuremath{\pm}0.21 &
  \cAlignHack 82\ensuremath{\pm}0.26\\
\cAlignHack 8 &
  \cAlignHack 91\ensuremath{\pm}0.63 &
  \cAlignHack 69\ensuremath{\pm}0.31 &
  \cAlignHack 56\ensuremath{\pm}0.28 &
  \cAlignHack 76\ensuremath{\pm}0.32 &
  \cAlignHack 86\ensuremath{\pm}0.09 &
  \cAlignHack 62\ensuremath{\pm}0.03\\
\cAlignHack 9 &
  \cAlignHack 66\ensuremath{\pm}0.21 &
  \cAlignHack 32\ensuremath{\pm}0.26 &
  \cAlignHack 24\ensuremath{\pm}0.65 &
  \cAlignHack 50\ensuremath{\pm}0.26 &
  \cAlignHack 54\ensuremath{\pm}0.01 &
  \cAlignHack 39\ensuremath{\pm}0.25\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Rupture test} }
\label{tw-cd5e46e87b40}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.4627\linewidth-2\tabcolsep}p{\dimexpr.5373\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Formulation & \cAlignHack Time (hrs)\\
\tblmidrule 
\cAlignHack C1F8 &
  \cAlignHack 1.2\ensuremath{\pm}0.26\\
\cAlignHack C2F8 &
  \cAlignHack 1.0\ensuremath{\pm}0.53\\
\cAlignHack C3F8 &
  \cAlignHack 3.1\ensuremath{\pm}0.45\\
\cAlignHack C4F8 &
  \cAlignHack 5.0\ensuremath{\pm}0.74\\
\cAlignHack C5F8 &
  \cAlignHack 6.2\ensuremath{\pm}0.85\\
\cAlignHack C6F8 &
  \cAlignHack 5.2\ensuremath{\pm}0.23\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Accelerated stability studies for C5F8 formulation } }
\label{tw-8a7e4ee40d90}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2687\linewidth-2\tabcolsep}p{\dimexpr.23339999999999996\linewidth-2\tabcolsep}p{\dimexpr.2499\linewidth-2\tabcolsep}p{\dimexpr.248\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Evaluation parameters & \cAlignHack After 30 days & \cAlignHack After 60 days & \cAlignHack After 90 days\\
\tblmidrule 
\cAlignHack Colour and appearance &
  \cAlignHack No change &
  \cAlignHack No change &
  \cAlignHack No change\\
\cAlignHack Hardness &
  \cAlignHack 7.49\ensuremath{\pm}0.13 &
  \cAlignHack 7.49\ensuremath{\pm}0.15 &
  \cAlignHack 7.49\ensuremath{\pm}0.14\\
\cAlignHack \% Drug content &
  \cAlignHack 97.12\ensuremath{\pm}0.32 &
  \cAlignHack 97.12\ensuremath{\pm}0.17 &
  \cAlignHack 97.12\ensuremath{\pm}0.12\\
\cAlignHack \% Drug release &
  \cAlignHack 97.27\ensuremath{\pm}0.80 &
  \cAlignHack 97\ensuremath{\pm}0.80 &
  \cAlignHack 96.9\ensuremath{\pm}0.01\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/2d7b2ffb-e46b-4590-a871-42736ae548a9-upicture1.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/2d7b2ffb-e46b-4590-a871-42736ae548a9-upicture1.png}{\includegraphics{images/2d7b2ffb-e46b-4590-a871-42736ae548a9-upicture1.png}}{}
\makeatother 
\caption{\boldmath {UV spectra of fluvastatin at 292 nm}}
\label{f-cbc1a412d999}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/dd68851b-c0f3-4f7f-9460-9531c20257f1-upicture2.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/dd68851b-c0f3-4f7f-9460-9531c20257f1-upicture2.png}{\includegraphics{images/dd68851b-c0f3-4f7f-9460-9531c20257f1-upicture2.png}}{}
\makeatother 
\caption{\boldmath {FTIR of Pure Drug (Fluvastatin)}}
\label{f-1494da08b26b}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/2b89c7fc-9d5f-43e5-b901-855e2a871421-upicture3.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/2b89c7fc-9d5f-43e5-b901-855e2a871421-upicture3.png}{\includegraphics{images/2b89c7fc-9d5f-43e5-b901-855e2a871421-upicture3.png}}{}
\makeatother 
\caption{\boldmath {FTIR of Fluvastatine Formulation}}
\label{f-df5abd83c6c3}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/77c0eb1a-2c0f-44ff-9fea-112c32900880-upicture4.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/77c0eb1a-2c0f-44ff-9fea-112c32900880-upicture4.png}{\includegraphics{images/77c0eb1a-2c0f-44ff-9fea-112c32900880-upicture4.png}}{}
\makeatother 
\caption{\boldmath {In vitro dissolution studies}}
\label{f-3a130a80a82c}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/630935cf-decd-467c-959c-82794e216f7c-upicture5.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/630935cf-decd-467c-959c-82794e216f7c-upicture5.png}{\includegraphics{images/630935cf-decd-467c-959c-82794e216f7c-upicture5.png}}{}
\makeatother 
\caption{\boldmath {Drug Release Kinetics}}
\label{f-e9ff12bcef2a}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/1190834d-e88e-403a-9c22-ad2cb0870ef6-upicture6.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/1190834d-e88e-403a-9c22-ad2cb0870ef6-upicture6.png}{\includegraphics{images/1190834d-e88e-403a-9c22-ad2cb0870ef6-upicture6.png}}{}
\makeatother 
\caption{\boldmath {Comparison of optimized batch}}
\label{f-3503d3fa50b3}
\end{figure*}
\egroup
\textbf{Solubility studies}

From the Table~\ref{tw-a47a32130542}, fluvastatin has a higher solubility in 6.8 pH buffer than the other buffers.

\textbf{UV spectrum of Fluvastatin}

Wavelength of Fluvastatin maximum absorption (\ensuremath{\lambda } max) was 292 nm.

\textbf{FTIR Studies (Drug - Excipients Compatibility) }

Based on the above FTIR spectrums, there is no incompatibility between the drug and excipients. In the above spectrum fluvastatin has shown peaks at 3403.89 cm\ensuremath{^{-1}} due to O{\textendash}H stretching); 2960 and 2877 cm\ensuremath{^{-1}} due to C{\textendash}H stretching; and 1711.25 cm\ensuremath{^{-1}} due to stretching of ester and lactone carbonyl functional groups; 1230,1115.9 and 1006.4cm\ensuremath{^{-1}}(C-O stretching of esters and anhydrides). These peaks were commonly observed in both formulation and fluvastatin. There is no incompatibility problem. 

\textbf{Pre-compression evaluation of core tablet of Fluvastatin}

Pre-compression studies, bulk density, Hauser ratio, Carr's index, tapped density, and Angle of Repose were evaluated. The value of bulk density and tapped density was within a limit from 0.3-0.4 gm/ml. The value of the Hausner ratio was found to be in the range of 1.14-1.17. The value of carr's index was found to be 11.36 to 14.63 \%, and the angle of repose for all the formulations was found to be in the range of 25.41\ensuremath{^\circ}-31.15\ensuremath{^\circ} which ensure good flow Property.

\textbf{Evaluation of core tablet}

Weight variation, Thickness, Hardness, Friability, Drug content, Disintegration, \textit{Percentage drug release}, swelling index, rupture time, acid uptake studies etc. Weight variation was found to be uniform, and Hardness ranged between 3.20 to 3.78 kg/cm\ensuremath{^{2}}. Friability ranges from 0.04-0.52\%. The values of drug content were found to be 86.29-97.39\%. The values of disintegration were found to be 22- 112 sec.

\textbf{Cumulative per cent drug release of core Fluvastatin tablets}

All 12 formulations have shown good post compression parameters which are suitable for coating out if 12 formulations F8 has a good drug release within 20 min with excellent drug content, i.e. 98.22\ensuremath{\pm}0.06.

Based on in-vitro dissolution studies of core tablets out of all formulations F8 is showing good dissolution, i.e. 99.63\ensuremath{\pm}0.28 at 20 min.

\textbf{Evaluation of compressed tablets of fluvastatin}

All six formulations were evaluated for percentage drug release in PH 1.2,6.8 \& 7.4 buffers the values were tabulated. After 5 hrs of lag time, drug release is stated for all six formulations in PH 7.4 Phosphate buffer based on data C5F8 shown good release, i.e. 97.27\ensuremath{\pm}0.80 at 8th hour\textbf{.}

\textbf{Swelling Index}

The swelling studies of the pulsatile tablet during 9 hrs studies were found to have very good sustaining efficacy. The Percentage swelling at the end of 5\ensuremath{^{th}} hour of C5F8 formulation was found to be 161\ensuremath{\pm}0.33. So an increase in the concentration of polymer will decrease the \% water uptake capacity and increase the Lag-time. 

\textbf{Rupture test}

All six formulations\textbf{\space }are subjected to rupture test, and the rupture test was carried out using USP paddle two apparatus at 37\ensuremath{^\circ}C, the time at which the outer polymer coating starts to rupture is called as rupture time. The rupture time of formulations was found to be in a range between 1 and 6.2hr

\textbf{Drug release Kinetics data}

Drug release kinetics found to be good for all formulations out of 6 formulation data of formulation C5F8 was best explained by Higuchi equation, as the plot showed highest linearity (\textit{r2 }= 0.656), followed by zero-order equation (\textit{r2} = 0.862). As the drug release was best fitted in Higuchi kinetics, indicating that the rate of drug release is diffusion. The result was shown in Figure~\ref{f-e9ff12bcef2a}
    
\section{Conclusion }
According to my work I~am concluding that Fluvastatin Chrono formulation can be considered and be evaluated further as it is found to be better compared to conventional formulations, as the drug release is at a peak after the lag time, mimicking the Circadian rhythm.

\textbf{Funding Support}

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

\textbf{Conflict of Interest}

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

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