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\def\RunningAuthor{Amit B Patil et al.}
\firstPage{2895}
\articleType{Original Article}
\receivedDate{29.Jan.2020}
\acceptedDate{08.Feb.2020}
\revisedDate{04.Feb.2020}
\journalVolume{2020, 11}
\journalIssue{3}
\journalDoi{ijrps.v11i3.2374}
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\title{Formulation and Evaluation of fixed dose combination of Nootropic drugs}
\author{Priyavarshini~R,  
            Shweta~Betala, 
            Amit~B~Patil\textsuperscript{*}~\\[5pt]{Industrial Pharmacy, Department of Pharmaceutics, JSS College of Pharmacy, Mysuru JSS Academy of Higher Education and Research, Mysuru-570015, India}}

\begin{abstract}
Cognitive functions are the critical brain functions responsible for the effective learning and understanding in the humans. They are responsible for various functions like attention, memory, reasoning and in turn helps to improve knowledge. Cognitive impairment is majorly seen in elderly as the brain is prone to neuro degradation. It may also occur in young adults due to poor diet or exercise. Improving cognition is of utmost importance and can be done by the use of cognition enhancers like Nootropics. This class of drugs is said to act by various mechanisms, which in turn leads to the betterment of the neurotransmission in the brain. They may act on acetylcholine, Gamma Butyric Acid, on the beta amyloid receptor or on NMDA. This research emphasis on the enhancement of cognition along with treating various neurodegenerative diseases like dementia, Alzheimer's or Parkinson's. Nootropic drugs are chosen for this formulation as they exhibit a rationale in combination with each other since they follow distinctive route of mechanism to treat the diseases. They also show action by preventing the worsening of the disease and by curing the disease. As compared to other combination of nootropic, in this combination, the side effects are reduced of one in presence of the other and show a much higher bioavailability. They cross the blood brain barrier and central nervous system half-life is longer as compared to the systemic half-life owing to their efficacy and superiority over other nootropics when it comes to treating cognition Fixed dose combination of these nootropic drugs is desired and the dose can't be varied as they no longer show their effect if not used in the exact dose required. The dosage of this varied drug depends on the severity of the disease and patient condition. The research has helped to achieve the reduction in the total tablet mass from 1500 mg to 1420 mg with the use of few excipients. This made it easier for patients to swallow the tablet easily due to an oval shape of the tablet formulation.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Cognitive functions,\newline Croscarmellose sodium,\newline Fixed Dose Combination,\newline Neuro degradation,\newline Neurodegenerative disorder
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Amit~B~Patil~\\ Phone:\ +917975787977~\\  Email:\ amitbpatil@jssuni.edu.in
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
\textbf{Development and evaluation of fixed dose combination of nootropic drugs}

\textbf{Cognitive Function }encompasses reasoning, memory, attention and language and lead directly to the attainment of information and thus knowledge\unskip~\citep{688266:16286230}. Nevertheless, if cognitive performance is directly linked to these functions, other endogenous factors like mood and physical health can impact it tremendously classification of Cognitive functions in the Figure~\ref{f-752242d41d9b}.


\bgroup
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\makeatother 
\caption{\boldmath {Types of Cognitive functions}}
\label{f-752242d41d9b}
\end{figure*}
\egroup
\textbf{Maintenance of Healthy cognitive function}

Though cognitive decline is a natural process, certain activities can help maintain cognitive functioning of the brain.  

\textbf{Mental Activity }

If brain is not solicitated adequately, it would become dormant and cognitive decline would occur due to lack of intellectual stimulation. Training the brain to put to use with mental activity like playing Chess or video games can improve cognition.  

\textbf{Physical Activity }

As the body does some exercise, the blood circulation increases the brain achieves more oxygen leading to improvement in brain functioning \unskip~\citep{688266:16286229}. 

\textbf{Balanced Diet}

Diet affects cerebral health. Thus, a balanced diet is essential for the body and brain to function well. Diet that includes a good quantity of food containing Vitamin B and Vitamin C helps improve the cognitive functions \unskip~\citep{688266:16286234}.

\textbf{Decline of Cognitive Functions}

Cognitive functions can be impaired or declined by age. This may lead to many cognitive diseases like dementia, Alzheimer's, Parkinson's etc. Alzheimer's disease is the leading cause of death in the world.  Thus, it is highly important to maintain the normal cognitive functioning of the brain and delay brain aging

\textbf{Treatment of impaired cognitive functions}

Brain supplements and Cognition enhancers are used to treat and improve cognitive functions are mentioned in Table~\ref{tw-e729e2f0fbb0}.\unskip~\citep{688266:16286236,688266:16286226,688266:16286231}.


\begin{table*}[!htbp]
\caption{\boldmath {Brain supplements and Cognition enhancer} }
\label{tw-e729e2f0fbb0}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.10639999999999999\linewidth-2\tabcolsep}p{\dimexpr.3936\linewidth-2\tabcolsep}p{\dimexpr.0476\linewidth-2\tabcolsep}p{\dimexpr.4524000000000001\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{4}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Brain supplements }\\
\rowcolor{kwdboxcolor}S. No & \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{Drugs} & Function\\
\tblmidrule 
1. &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{Ginkgo (Ginkgo biloba') } &
  Improves blood flow to the brain, anti-inflammatory and has potent antioxidants protect brain cells from free radical damage.\\
2. &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{Bacopa (Bacopa monnieri)} &
  Improves memory, treat epilepsy and reduce anxiety\\
3. &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{American Ginseng (Panax quinquefolius)} &
  Comparing with Panax ginseng ,  American ginseng is considered superior excels as a cognitive enhancer. Quickly shows result for improve short-term memory.   \\
 &
   &
   &
  \\
\multicolumn{4}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack \textbf{Cognition enhancers}}\\
\textbf{S. No} &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{\textbf{Drugs}} &
  \textbf{Functions and uses }\\
1. &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{Amino Acid cognition enhancers } &
  \\
 &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{a. Tyrosine} &
  Acts as both a stress hormone and  neurotransmitter.\\
 &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{b. Tryptophan} &
  Tryptophan is the precursor of serotonin (the "happiness brain chemical") and the sleep hormone melatonin.\\
 &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{c. Taurine} &
  Taurine behaves much like the calming neurotransmitter GABA (gamma-aminobutyric acid) and, once in the brain, activates GABA receptors.\\
 &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{d. L-Theanine} &
  L-theanine is one of the most unique natural brain enhancers around. It's found mainly in tea and increases levels of the neurotransmitter's serotonin, dopamine, and GABA.\\
2. &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{Nootropics} &
  \\
 &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{a. Adderall and Ritalin} &
  Adderall and Ritalin are prescription stimulants for treating ADHD that increasing focus and energy. \\
 &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{b. Modafinil} &
  This is only medically approved uses are for narcolepsy, shift work sleep disorder, and obstructive sleep apnea.   \\
 &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{c. Racetams} &
  Racetam class of drugs show their effect on GABA. Its mechanism is not fully known. Theories include that they work by enhancing brain cell membrane fluidity improving the function of the neurotransmitter acetylcholine. \\
 &
  \multicolumn{2}{p{\dimexpr(.4412\linewidth-2\tabcolsep)}}{d. Choline Based Nootropic Drugs} &
  Choline is an essential nutrient for brain development, healthy brain cells, and neurotransmitter formation. It is a precursor of Ach. \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Solid oral Immediate release dosage form }

Solid oral dosage is preferable route of drug administration. Oral drug is convenient for systemic effect as well as Therapeutic effects. Oral dose is cost effective and easy for patient to take medication without any profession administrator. Immediate-release preparations These preparations are primarily intended to achieve fast onset of action for drugs such as analgesics, Antipyretics and coronary vasodilators. The release the drug once it is ingested orally. There is no delay in onset of action \unskip~\citep{688266:16286235}.  

\textbf{Nootropics}

Class of drugs aimed directly at promoting the efficiency of the essential brain integrative activity mechanisms. The most important features of nootropic are facilitation of learning, memory Consolidation. Their ability to increase or enhance resistance to learning impairments and several experimental types of brain hypoxia, and cerebral drug intoxications. They are also devoid of the usual psychotropic effects in that they cause neither stimulation nor sedation and in general have no locomotor effect.
    
\section{Materials and Methods}
 Citicoline

Piracetam 

Maize starch

Piracetam 

croscarmellose Sodium

Sodium Starch Glycolate

Microcrystalline Cellulose PH 101

Magnesium state 

Colloidal Silicon Dioxide

PVP K 30 

\textbf{Preformulation Studies}

The physicochemical properties of the drugs play an important role in the design of appropriate drug delivery systems. It would be possible to vary the formulation parameters according to the pre-formulation characteristics of the drug and other formulation excipients. An insight into such parameters allows the formulator to select various additives and formulation conditions for the successful, and effective drug delivery to the biological system. Critical information provided during the pre-formulation can enhance the rapid and successful introduction of new therapeutic entities for humans. Hence, pre-formulation studies are essential for proper designing of drug delivery systems. 

\textbf{Micromeritics of the drug }

This provides us with a knowledge about the physical and chemical properties of the API like its particle size, low property and compressibility. It helps in determining the bioavailability, stability and consistency of the material. The following are various tests performed to determine the characteristics of the drug. The results of which are given in Table~\ref{tw-ed11f11648d6}, \unskip~\citep{688266:16286227}.

\textbf{Bulk density, Tap density, Compressibility index }

It is important to improve the effectiveness of the roller compaction process and granules produced for milling. A tool to determine the void volume and predicting material segregation. Bulk volume was measured by taking weighed quantity  powder mix in measuring cylinder, Bulk volume is noted (Vb), and weight of the blend (M) was determined. The measuring cylinder containing known mass of powder blend was tapped for a fixed time and the tapped volume (Vt) occupied in the cylinder and the weight of the blend (M) was measured. From that bulk density, tapped density, Hausner's bulk ratio and Carr's index were calculated as follows,
\begin{eqnarray*}\style{font-size:11px}{Bulk\;Density(BD)=\left(\frac M{V_b}\right)\times100} \end{eqnarray*}

\begin{eqnarray*}\style{font-size:11px}{Tapped\;Density(T8)=\left(\frac M{V_t}\right)\times100} \end{eqnarray*}

\begin{eqnarray*}\style{font-size:11px}{\begin{array}{l}Compressibility\;Index\;or\;Carr's\;Index\;=\\\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\left(\frac{TD-BD}{TD}\right)\times100\end{array}} \end{eqnarray*}

\begin{eqnarray*}\style{font-size:11px}{Hausner's\;Ratio\;=\frac{TD}{BD}} \end{eqnarray*}
M- Mass of the blend taken 

Vb- Bulk Volume 

Vt- Tapped Volume 

\textbf{Angle of repose}

It determines how efficiently the blend would move from the Hopper to the die cavity in compression process. This ultimately leads to a prediction whether the blend would sit to the walls of the Hopper after processing. It is defined as the maximum angle that can be obtained between the free standing of a powder heap and the horizontal plane which is given by the equation. 
\begin{eqnarray*}\style{font-size:11px}{\theta\;=\tan^{-1}\left(\frac hr\right)} \end{eqnarray*}
where, \ensuremath{\theta } - Angle of repose 

h- Height of the powder heap from the horizontal base 

r-Radius of the base of the heap

\textbf{Sieve analysis}

It determines the particle size of the blend and ensures that a good ratio is established between the granules and the fines of the blend. Sieves are arranged according to the increasing mesh no. from 20,40,60,80 and 100. A measured quantity of blend is introduced into the top most sieve i.e. sieve no. 20. The sifter is allowed to be shaken on its own for 5 minutes at 20 power. The segregated granules and fines are weighed and calculated as,

 \%Blend retained on sieve = 
\begin{eqnarray*}\style{font-size:9px}{\left(\frac{Weight\;of\;blend\;retaines\;on\;that\;sieve}{Total\;weight\;of\;blend}\right)\times100} \end{eqnarray*}
\textbf{Solubility of the drug} \textbf{\space }

Solubility is the amount of solvent needed to dissolve 1 part of solute.  The solubility of and citicoline and Piracetam was tested in various buffer solutions and organic solvents according to British Pharmacopoeia(BP)  and According to BCS Class. According to British Pharmacopoeia the amount of solute/drug needed to dissolve 100 mg of the solute determines the solubility of the solute in that particular solvent. Whereas, for the determination of BCS class, we consider the highest dose of the drug to be solubilised in 250 ml of solvent when taken in a volumetric flask at room temperature. The results of solubility according to BP and BCS class\unskip~\citep{688266:16286228}. The results of solubility according to BP was performed and BCS is given inTable~\ref{tw-97c8f13604e4}.

The physical and chemical interactions between drugs, and excipients can affect the chemical nature, the stability, bioavailability of the drugs, therapeutic efficacy and safety. This study was carried out by triturating every ingredient mix and placing the mixture in equal proportion in 3 vials which are labelled and charged to various stability conditions for 15 days. 

The compatibility studies between Drug and excipients were examined for  Physical, and chemical parameters, Visual observation was carried out for determining any physical changes. Chemical degradation was determined by calculating the amount of relative substances (impurities) in the combinations. The result for physical and chemical degradation is given in Table~\ref{tw-c9577789a51a}.

\textbf{Linearity of the drugs using UV spectrophotometry}

Preparation of Stock Solution 

31.2mg of Citicoline was weighed and dissolved in 100ml demineralised water to produce the stock solution A. 31.2mg of Piracetam was weighed and dissolved in 100ml demineralised water to produce the slock solution B 

Preparation of sample solution of various concentrations 2ml, 3ml, 4ml, 5ml, and 6ml solution was withdrawn from Stock Solution A and diluted with distilled water to 50ml in a volumetric flask of 50ml to produce concentrations of 12.48ppm, 18.72ppm, 24.96ppm, 31.2ppm and 37.44ppm. 

Same was performed using stock solution B to produce various concentrations like 12.48ppm, 18.72ppm, 24.90ppm, 31.2ppm and 37.44ppm. The results are given in Tables~\ref{tw-48983c3d1b3e} and~\ref{tw-ebd045cea096} and Figures~\ref{f-24918caf7087} and~\ref{f-9e3f42aceb25}.

\textbf{Formulation of immediate release dosage}

The formulation is performed to find the best trial batch to optimise it. All trial batches are performed according to the results obtained by design of experiments, this would allow us to correlate the theoretical value with the one practically obtained.

\textbf{Design of Experiment}

Design of Experiment (DoE) was done using Design Expert Software; DoE Was performed using Box Benken method and trial batches were achieved. The responses for disintegration time and hardness was obtained.

 \textbf{Method of preparation}

The solid oral dosage form was prepared using the following procedure Drug and Excipients processed using wet granulation technique. In this, the drug, superdisintegrants and diluent were added into the Rapid Mixer Granulator. Through the binder addition Window, the binding solution was added upon continuous mixing. Later the damp mass is sieved from sieve no. 20 to obtain uniform sized granules.  Drying of granules was carried out using Fluidised Bed Dryer to achieve desired sized granules with acceptable flow properties. \% Moisture content in the granules was a mean of end point determination.  Superdisintegrants was added extra granularly for improved disintegration effect. Colloidal silicone dioxide and superdisintegrants was added into octagonal blender to carry out the pre lubrication stage of processing \unskip~\citep{688266:16286232}. Lubrication was done using Magnesium Stearate, where it was added to the pre lubricated blend in the octagonal blender. Lubrication gave a desired flow to the granules \unskip~\citep{688266:16286233}. The blend was compressed into tablet by the tablet compression machine.  Various IPQC tests like hardness, thickness, disintegration time were measured to obtain a desired tablet property.  The tablets were coated in conventional coating pan using ready mix coating material and a selected colour to obtain a desired formulation appearance.

Trial batch for binder/binding agent was performed and mentioned in Table~\ref{tw-39cef9b5d155}. 

\textbf{Various Trial Batches}


\begin{table*}[!htbp]
\caption{\boldmath {Trial batch (F1) For the study of binder/binding agent} }
\label{tw-39cef9b5d155}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1306\linewidth-2\tabcolsep}p{\dimexpr.3313\linewidth-2\tabcolsep}p{\dimexpr.21200000000000003\linewidth-2\tabcolsep}p{\dimexpr.3261\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No  & Materials used  & Quality (mg) & Category\\
\tblmidrule 
\multicolumn{4}{p{\dimexpr(.10000000000000001\linewidth-2\tabcolsep)}}{\cAlignHack Dry mix }\\
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 &
  Citicoline \mbox{}\protect\newline Piracetam \mbox{}\protect\newline Microcrystalline cellulose &
  522.5 \mbox{}\protect\newline 800 \mbox{}\protect\newline 52.5 &
  API \mbox{}\protect\newline API \mbox{}\protect\newline Diluent\\
\multicolumn{4}{p{\dimexpr(.10000000000000001\linewidth-2\tabcolsep)}}{\cAlignHack Binder}\\
4 \mbox{}\protect\newline 5 &
  Povidone (PVP K 30) \mbox{}\protect\newline Distilled water  &
  30 \mbox{}\protect\newline q. s &
  Binder \mbox{}\protect\newline Solvent to make a binding solution\\
\multicolumn{4}{p{\dimexpr(.10000000000000001\linewidth-2\tabcolsep)}}{\cAlignHack Prelubrication}\\
6 \mbox{}\protect\newline 7 &
  Croscarmellose Sodium \mbox{}\protect\newline Colloidal Silicon Dioxide &
  70 \mbox{}\protect\newline 10 &
  Superdisintegrant \mbox{}\protect\newline Prelubricating agent\\
\multicolumn{4}{p{\dimexpr(.10000000000000001\linewidth-2\tabcolsep)}}{\cAlignHack Lubrication}\\
8 &
  Magnesium Stearate   &
  15 &
  Lubricating Agent \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
The above batch was processed and compressed into tablets of total weight. Upon testing the tablet showed out hardness on much higher side. Thus, a new trial batch (F2) was taken where only water was used as the sole binding agent and Povidone is eliminated. Trial batch studies for the study of diluent is given in theTables~\ref{tw-497f11169798} and~\ref{tw-2441d6e237ff}.  


\begin{table*}[!htbp]
\caption{\boldmath {Trial batch (F2) using Microcrystalline cellulose} }
\label{tw-497f11169798}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.13620000000000001\linewidth-2\tabcolsep}p{\dimexpr.6103999999999999\linewidth-2\tabcolsep}p{\dimexpr.25340000000000003\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Material Used  & Quantity (mg)\\
\tblmidrule 
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Dry mix }\\
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 &
  Citicoline  \mbox{}\protect\newline Piracetam  \mbox{}\protect\newline Microcrystalline cellulose &
  522.5 \mbox{}\protect\newline  800  \mbox{}\protect\newline 82.5  \\
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Binder }\\
4 &
  Water  &
  q. s\\
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Pre lubrication }\\
5 \mbox{}\protect\newline 6 &
  Croscarmellose Sodium  \mbox{}\protect\newline Colloidal Silicon Dioxide &
  70 \mbox{}\protect\newline 10\\
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Lubrication }\\
7 &
  Magnesium Stearate &
  15\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Trial Batch (F3) using Maize starch} }
\label{tw-2441d6e237ff}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.14829999999999998\linewidth-2\tabcolsep}p{\dimexpr.45980000000000004\linewidth-2\tabcolsep}p{\dimexpr.3919\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Material Used  & Quantity (mg)\\
\tblmidrule 
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Dry mix }\\
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 &
  Citicoline  \mbox{}\protect\newline Piracetam  \mbox{}\protect\newline Maize starch &
  522.5  \mbox{}\protect\newline 800 \mbox{}\protect\newline  82.5\\
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Binder }\\
4 &
  Water &
  q. s\\
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Prelubrication }\\
5 \mbox{}\protect\newline 6 &
  Croscarmellose Sodium  \mbox{}\protect\newline Colloidal Silicon Dioxide &
  70 \mbox{}\protect\newline 10\\
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Lubrication }\\
7 &
  Magnesium Stearate &
  15\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
Use of diluent in both the batches enhanced the total tablet weight and upon testing the tablet showed out of acceptance limit range outcome for hardness and disintegration time (DT). Thus, new batches were carried out to study the effect of superdisintegrant on the DT and hardness and by removing diluent to reduce the tablet weight.

Trial batch for super disintegrants was performed for all batch and mentioned in Table~\ref{tw-906dbe7b1210}. 


\begin{table*}[!htbp]
\caption{\boldmath {Trial batches for the study of super disintegrants} }
\label{tw-906dbe7b1210}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.06379999999999999\linewidth-2\tabcolsep}p{\dimexpr.20040000000000003\linewidth-2\tabcolsep}p{\dimexpr.1148\linewidth-2\tabcolsep}p{\dimexpr.1174\linewidth-2\tabcolsep}p{\dimexpr.12959999999999999\linewidth-2\tabcolsep}p{\dimexpr.1182\linewidth-2\tabcolsep}p{\dimexpr.1226\linewidth-2\tabcolsep}p{\dimexpr.1332\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Materials & F3 \mbox{}\protect\newline (mg) & F4 \mbox{}\protect\newline (mg) & F5 \mbox{}\protect\newline (mg) & F6 \mbox{}\protect\newline (mg) & F7 \mbox{}\protect\newline (mg) & F8 \mbox{}\protect\newline (mg)\\
\tblmidrule 
\multicolumn{7}{p{\dimexpr(.8668000000000002\linewidth-2\tabcolsep)}}{\cAlignHack Dry mix} &
  \\
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 \mbox{}\protect\newline 4 \mbox{}\protect\newline 5 &
  Citicoline \mbox{}\protect\newline Piracetam \mbox{}\protect\newline Croscarmellose Sodium  \mbox{}\protect\newline Crospovidone \mbox{}\protect\newline Sodium Starch Glycolate &
  522.5 \mbox{}\protect\newline 800 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 &
  522.5 \mbox{}\protect\newline 800 \mbox{}\protect\newline 35 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 &
  522.5 \mbox{}\protect\newline 800 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 35 &
  522.5 \mbox{}\protect\newline 800 \mbox{}\protect\newline 35 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 &
  522.5 \mbox{}\protect\newline 800 \mbox{}\protect\newline 35 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 &
  522.5 \mbox{}\protect\newline 800 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 70\\
\cAlignHack  &
   &
   &
  Binder &
   &
   &
   &
  \\
6 &
  Water &
  q. s &
  q. s &
  q. s &
  q. s &
  q. s &
  q. s\\
\cAlignHack  &
   &
  \multicolumn{2}{p{\dimexpr(.2322\linewidth-2\tabcolsep)}}{\cAlignHack PreLubrication} &
   &
   &
   &
  \\
7 \mbox{}\protect\newline 8 \mbox{}\protect\newline 9 \mbox{}\protect\newline 10 &
  Croscarmellose Sodium \mbox{}\protect\newline Crospovidone \mbox{}\protect\newline Sodium Starch Glycolate \mbox{}\protect\newline Colloidal Silicon Dioxide &
  0 \mbox{}\protect\newline 35 \mbox{}\protect\newline 0 \mbox{}\protect\newline 12.5 &
  35 \mbox{}\protect\newline 0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 12.5 &
  0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 35 \mbox{}\protect\newline 12.5 &
  0 \mbox{}\protect\newline 0 \mbox{}\protect\newline 35 \mbox{}\protect\newline 12.5 &
  0 \mbox{}\protect\newline 70 \mbox{}\protect\newline 0 \mbox{}\protect\newline 12.5 &
  35 \mbox{}\protect\newline 70 \mbox{}\protect\newline 0 \mbox{}\protect\newline 12.5\\
\cAlignHack  &
   &
   &
  Lubrication &
   &
   &
   &
  \\
11 &
  Magnesium stearate &
  15 &
  15 &
  15 &
  15 &
  15 &
  15\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Optimization of working formula}

Optimisation of the trial batch was done according to the results obtained for the evaluation parameter mentioned in the results. The formula for optimised batch for uncoated tablets and coated tablets is given in Tables~\ref{tw-bdef0925c85d} and~\ref{tw-855623599b6e}.


\begin{table*}[!htbp]
\caption{\boldmath {working formula of optimised batch for uncoated tablets} }
\label{tw-bdef0925c85d}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1448\linewidth-2\tabcolsep}p{\dimexpr.53769999999999996\linewidth-2\tabcolsep}p{\dimexpr.3175\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S. No & Materials  & Quantity (mg)\\
\tblmidrule 
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Dry Mix}\\
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 &
  Citicoline \mbox{}\protect\newline Piracetam \mbox{}\protect\newline Croscarmellose Sodium &
  522.5 \mbox{}\protect\newline 800 \mbox{}\protect\newline 35\\
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Prelubrication}\\
4 \mbox{}\protect\newline 5 &
  Colloidal silicon dioxide \mbox{}\protect\newline Croscarmellose sodium &
  35 \mbox{}\protect\newline 12.5\\
\multicolumn{3}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Lubrication}\\
6 &
  Magnesium stearate  &
  15\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Working formula for coating of tablets of the optimised batch } }
\label{tw-855623599b6e}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1327\linewidth-2\tabcolsep}p{\dimexpr.6655999999999999\linewidth-2\tabcolsep}p{\dimexpr.20169999999999995\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Materials  & Quantity (\%)\\
\tblmidrule 
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 &
  Ready-mix coating materials(HPMC,Polypropylene glycol, polyethylene glycol, SLS,Titanium dioxide) \mbox{}\protect\newline Colour Sunset Yellow Supra \mbox{}\protect\newline Purified Water &
  10 \mbox{}\protect\newline 0.2 \mbox{}\protect\newline 89.80\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Evaluation parameters}

\textbf{The results of all the evaluation test is obtained }

\textbf{Weight variation}

This test was performed according to IP 2018. The process suggested that, selected twenty tablets randomly and weight each tablet on an electric weighing balance. Average the total weigh of the tablets. 

\textbf{Hardness}

The hardness of five individual tablet was tested using hardness test apparatus. Tablet was kept according to the longitudinal length and pressure was applied until a fracture is created. The result was noted in kilo poise (kp)

\textbf{Thickness}

The thickness of the tablet was measured using Vernier caliper. The result was measured in millimetre (mm).

\textbf{Disintegration time}

The test was performed according to IP. Randomly selected 6 tablets were added in the tubes of disintegration apparatus which is initially dipped in disintegration basket containing water as disintegrating solvent that has attained a temperature of 37\ensuremath{^\circ}C\ensuremath{\pm}2\ensuremath{^\circ}C. This basket was placed in the specialised water bath. The test was performed as the tubes moved vertical at 30\ensuremath{\pm}2 drops/minute and the time of disintegration of that tablet was noted in minutes. 

\textbf{Friability}

It is performed in Roche Friabilator. As the tablet weights more than 650mg, the total tablet taken, weighed equivalent to or greater than 6.5gm. The equipment was set at 25rpm for 4 mins. Initial weight of the tablets was obtained. After the test was performed, the tablets were weighed again to check the reduction in weight. This test is performed to know the strength of the tablet when stress or shear is utilised. \% friability is calculated a below and should not be more than 1 \%.

\%Friability = 

$\style{font-size:8px}{\begin{array}{l}\left[\frac{\left(Initial\;weight\;of\;tablet\right)-\left(Final\;weight\;of\;Tablet\right)}{Initial\;weight\;of\;tablet}\right]\\\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\times100\;\;\;\end{array}} $

\textbf{Stability studies}

Formulation was packed using ALU-ALU packing material. The integrity of the pack was tested using leak test where the pressure was set at 600 mm/Hg for 5 mins. The pack passed the leak test and hence it was chosen as packing material.

Evaluation was carried out at 40\ensuremath{^\circ}C /75\% RH as per ICH guidelines. Apart from initial analysis, the samples were evaluated for physio-chemical properties during stability studies at the mentioned stability conditions and intervals in the Table~\ref{tw-48983c3d1b3e}.The result for the stability lots is obtained in Table~\ref{tw-72ca9e370fd3}.


    
\section{Results and Discussion}
The Micromeritics of Citicoline and Piracetam was performed and the results obtained are as below


\begin{table*}[!htbp]
\caption{\boldmath {Micromeritics of Drugs} }
\label{tw-ed11f11648d6}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.37330000000000005\linewidth-2\tabcolsep}p{\dimexpr.3248\linewidth-2\tabcolsep}p{\dimexpr.3019\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Tests & Citicoline & Piracetam\\
\tblmidrule 
Bulk Density \mbox{}\protect\newline Tapped Density \mbox{}\protect\newline Carr's Index \mbox{}\protect\newline Hausner's Ratio &
  0.35gm/ml \mbox{}\protect\newline 0,55 gm/ml \mbox{}\protect\newline 36.36\% \mbox{}\protect\newline 1.57 &
  0.74 gm/ml \mbox{}\protect\newline 0.86 gm/ml \mbox{}\protect\newline 14.73\% \mbox{}\protect\newline 1.17\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Solubility Profile}


\begin{table*}[!htbp]
\caption{\boldmath {Determination of BCS classification of Citicoline and Piracetam} }
\label{tw-97c8f13604e4}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.25892\linewidth-2\tabcolsep}p{\dimexpr.16752000000000002\linewidth-2\tabcolsep}p{\dimexpr.17042\linewidth-2\tabcolsep}p{\dimexpr.18312000000000005\linewidth-2\tabcolsep}p{\dimexpr.22002\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Solvents used & Volume used to dissolve highest dose i.e. 500mg Citicoline & Volume used to dissolve highest dose i.e. 800 mg Piracetam & Observation & Result\\
\tblmidrule 
Demineralised water &
  250 ml &
  250 ml &
  Highly soluble &
  \multicolumn{1}{p{\dimexpr(.22002\linewidth-2\tabcolsep)}}{\multirow{5}{\linewidth}{Hence the solubility \mbox{}\protect\newline of these drugs in various solvents determines that they fall in the  \mbox{}\protect\newline BCS Class I~\mbox{}\protect\newline }}\\
0.1N HCL &
  250 ml &
  250 ml &
  Highly soluble &
  \\
4.5 pH Acetate buffer &
  250 ml &
  250 ml &
  Highly soluble &
  \\
6.8 pH Phosphate buffer &
  250 ml &
  250 ml &
  Highly soluble &
  \\
7.5 pH Phosphate buffer &
  250 ml &
  250 ml &
  Highly soluble &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Compatibility studies}


\begin{table*}[!htbp]
\caption{\boldmath {Physical chemical parameters observed for the drugexcipient compatibility studies} }
\label{tw-c9577789a51a}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2162777777777778\linewidth-2\tabcolsep}p{\dimexpr.08687777777777775\linewidth-2\tabcolsep}p{\dimexpr.22627777777777776\linewidth-2\tabcolsep}p{\dimexpr.078477777777777815\linewidth-2\tabcolsep}p{\dimexpr.08167777777777776\linewidth-2\tabcolsep}p{\dimexpr.07897777777777777\linewidth-2\tabcolsep}p{\dimexpr.07827777777777777\linewidth-2\tabcolsep}p{\dimexpr.076077777777777795\linewidth-2\tabcolsep}p{\dimexpr.07707777777777777\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Ingredient Mix & Ratio & Observation & \multicolumn{2}{p{\dimexpr(.16015555555555558\linewidth-2\tabcolsep)}}{\cAlignHack 60 {\textdegree}C} & \multicolumn{2}{p{\dimexpr(.15725555555555554\linewidth-2\tabcolsep)}}{40{\textdegree}C 75\% RH} & \multicolumn{2}{p{\dimexpr(.15315555555555557\linewidth-2\tabcolsep)}}{\cAlignHack RT}\\
\rowcolor{kwdboxcolor} &  &  & HUI & TUI & HUI & TUI & HUI & TUI\\
\tblmidrule 
Citicoline + Piracetam &
  1:1 &
  White to off White colour powder &
  BDL &
  BDL &
  BDL &
  BDL &
  BDL &
  BDL\\
Citicoline + Piracetam  \mbox{}\protect\newline Maize starch &
  1:1:1 &
  White to off White colour powder &
  BDL &
  BDL &
  BDL &
  BDL &
  BDL &
  BDL\\
Citicoline + Piracetam \mbox{}\protect\newline  croscarmellose Sodium &
  1:1:1 &
  White to off White colour powder &
  0.02 &
  0.02 &
  0.01 &
  0.01 &
  0.02 &
  003\\
Citicoline+Piracetam+  \mbox{}\protect\newline Sodium Starch Glycolate &
  1:1:1 &
  White to off White colour powder &
  0.05 &
  0.05 &
  0.05 &
  0.05 &
  0.02 &
  0.04\\
Citicoline+Piracetam+  \mbox{}\protect\newline Microcrystalline Cellulose PH 101 &
  1:1:1 &
  White to off White colour powder &
  0.04 &
  0.02 &
  0.03 &
  0.03 &
  0.04 &
  0.04\\
Citicoline+Piracetam+  \mbox{}\protect\newline Magnesium sterate  &
  1:1:1 &
  White to off White colour powder &
  0.04 &
  0.01 &
  0.02 &
  0.02 &
  0.02 &
  0.02\\
Citicoline+Piracetam+ \mbox{}\protect\newline Colloidal Silicon Dioxide &
  1:1:1 &
  White to off White colour powder &
  0.06 &
  0.03 &
  0.08 &
  0.13 &
  0.02 &
  0.03\\
Citicoline+ Piracetam  \mbox{}\protect\newline +PVP K 30 &
  1:1:1 &
  White to off White colour powder &
  0.02 &
  0.01 &
  0.03 &
  0.04 &
  0.01 &
  0.01\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Linearity of the drugs using UV spectrophotometry}


\begin{table*}[!htbp]
\caption{\boldmath {The linearity and regression equation of a Citicoline was obtained at \ensuremath{\lambda } max 271 nm} }
\label{tw-48983c3d1b3e}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1639\linewidth-2\tabcolsep}p{\dimexpr.4096\linewidth-2\tabcolsep}p{\dimexpr.4265\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Concentration (\ensuremath{\mu }g/ml)  & Absorbance at \ensuremath{\lambda }max 271 nm \\
\tblmidrule 
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 \mbox{}\protect\newline 4 \mbox{}\protect\newline 5 \mbox{}\protect\newline 6 &
  0 \mbox{}\protect\newline 12.48 \mbox{}\protect\newline 18.72 \mbox{}\protect\newline 24.96 \mbox{}\protect\newline 31.2 \mbox{}\protect\newline 37.44 &
  0 \mbox{}\protect\newline 0.2 \mbox{}\protect\newline 0.302 \mbox{}\protect\newline 0.405 \mbox{}\protect\newline 0.499 \mbox{}\protect\newline 0.604\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/6dbbf6cb-e7d5-47cb-b8c8-76ee59e45058-upicture2.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/6dbbf6cb-e7d5-47cb-b8c8-76ee59e45058-upicture2.png}{\includegraphics{images/6dbbf6cb-e7d5-47cb-b8c8-76ee59e45058-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Regression equation and linearity plot of Citicoline that proves its analytical linearity}}
\label{f-24918caf7087}
\end{figure}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {The linearity and regression equation an of Piracetam was obtained at \ensuremath{\lambda } max 210 nm } }
\label{tw-ebd045cea096}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1379\linewidth-2\tabcolsep}p{\dimexpr.4287\linewidth-2\tabcolsep}p{\dimexpr.4334\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Concentration (\ensuremath{\mu }g/ml)  & Absorbance at \ensuremath{\lambda }max 210nm\\
\tblmidrule 
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 \mbox{}\protect\newline 4 \mbox{}\protect\newline 5 \mbox{}\protect\newline 6 &
  0 \mbox{}\protect\newline 12.48 \mbox{}\protect\newline 18.72 \mbox{}\protect\newline 24.96 \mbox{}\protect\newline 31.2 \mbox{}\protect\newline 37.44 &
  0 \mbox{}\protect\newline 0.257 \mbox{}\protect\newline 0.382 \mbox{}\protect\newline 0.526 \mbox{}\protect\newline 0.63 \mbox{}\protect\newline 0.767\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/c6a4ce21-63fb-4303-88f3-7659ffa91582-upicture3.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/c6a4ce21-63fb-4303-88f3-7659ffa91582-upicture3.png}{\includegraphics{images/c6a4ce21-63fb-4303-88f3-7659ffa91582-upicture3.png}}{}
\makeatother 
\caption{\boldmath {Regression equation and linearity plot of Piracetam that proves its analytical linearity}}
\label{f-9e3f42aceb25}
\end{figure}
\egroup
\textbf{Micromeritics of all trial batches }


\begin{table*}[!htbp]
\caption{\boldmath {Bulkdensity (BD), Tapped density (TD) and Carr's Index (CI) is observed for all the trial formulations of the lubricated blend} }
\label{tw-5c1e91b82cdd}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0647\linewidth-2\tabcolsep}p{\dimexpr.14780000000000001\linewidth-2\tabcolsep}p{\dimexpr.09780000000000001\linewidth-2\tabcolsep}p{\dimexpr.08969999999999999\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Evaluation Parameter & F1 & F2 & F3 & F4 & F5 & F6 & F7 & F8\\
\tblmidrule 
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 \mbox{}\protect\newline  &
  BD (gm/cc) \mbox{}\protect\newline TD (gm/cc) \mbox{}\protect\newline CI (\%) &
  0.585 \mbox{}\protect\newline 0.675 \mbox{}\protect\newline 13.43 &
  0.595 \mbox{}\protect\newline 0.643 \mbox{}\protect\newline 7.620 &
  0.572 \mbox{}\protect\newline 0.621 \mbox{}\protect\newline 7.890 &
  0.524 \mbox{}\protect\newline 0.629 \mbox{}\protect\newline 16.69 &
  0.543 \mbox{}\protect\newline 0.691 \mbox{}\protect\newline 16.93 &
  0.520 \mbox{}\protect\newline 0.638 \mbox{}\protect\newline 18.49 &
  0.525 \mbox{}\protect\newline 0.651 \mbox{}\protect\newline 19.35 &
  0.525 \mbox{}\protect\newline 0.614 \mbox{}\protect\newline 14.49\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Post compression evaluation of above trial batches}


\begin{table*}[!htbp]
\caption{\boldmath {Total weight, thickness, hardness, disintegration time and friability results of all the formulation batches are obtained } }
\label{tw-79f80664344f}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.06109999999999999\linewidth-2\tabcolsep}p{\dimexpr.21150000000000002\linewidth-2\tabcolsep}p{\dimexpr.087\linewidth-2\tabcolsep}p{\dimexpr.09300000000000002\linewidth-2\tabcolsep}p{\dimexpr.08889999999999999\linewidth-2\tabcolsep}p{\dimexpr.0986\linewidth-2\tabcolsep}p{\dimexpr.09870000000000001\linewidth-2\tabcolsep}p{\dimexpr.08459999999999997\linewidth-2\tabcolsep}p{\dimexpr.08490000000000004\linewidth-2\tabcolsep}p{\dimexpr.09169999999999998\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.NO & Evaluation Parameter & F1 & F2 & F3 & F4 & F5 & F6 & F7 & F8\\
\tblmidrule 
1 \mbox{}\protect\newline 2 \mbox{}\protect\newline 3 \mbox{}\protect\newline 4 \mbox{}\protect\newline 5 &
  Total weight(mg) \mbox{}\protect\newline Thickness (mm) \mbox{}\protect\newline Hardness (kp) \mbox{}\protect\newline Disintegration time(mins) \mbox{}\protect\newline Friability (\%) &
  1500 \mbox{}\protect\newline 7.90 \mbox{}\protect\newline 39 \mbox{}\protect\newline 22 \mbox{}\protect\newline 0.73 &
  1500 \mbox{}\protect\newline 7.90 \mbox{}\protect\newline 30.5 \mbox{}\protect\newline 17 \mbox{}\protect\newline 0.69 &
  1385 \mbox{}\protect\newline 7.82 \mbox{}\protect\newline 15 \mbox{}\protect\newline 2 \mbox{}\protect\newline 0.55 &
  1420 \mbox{}\protect\newline 7.85 \mbox{}\protect\newline 24 \mbox{}\protect\newline 10 \mbox{}\protect\newline 0.49 &
  1420 \mbox{}\protect\newline 7.85 \mbox{}\protect\newline 29 \mbox{}\protect\newline 16 \mbox{}\protect\newline 0.65 &
  1420 \mbox{}\protect\newline 7.85 \mbox{}\protect\newline 26 \mbox{}\protect\newline 16 \mbox{}\protect\newline 0.78 &
  1455 \mbox{}\protect\newline 7.87 \mbox{}\protect\newline 24.5 \mbox{}\protect\newline 15 \mbox{}\protect\newline 0.65 &
  1525 \mbox{}\protect\newline 7.88 \mbox{}\protect\newline 35 \mbox{}\protect\newline 24 \mbox{}\protect\newline 0.52\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Stability Lots of Optimised Batch, its Evaluation and Process Parameters}

F4 was considered as the optimised batch for stability studied. This batch was processed for stability trials (ST) as ST 1, ST 2 and ST 3. Tablets were tested for post compression parameters and coating parameters after charged to temperature condition of 40{\textdegree}C/75\%RH.


\begin{table*}[!htbp]
\caption{\boldmath {Evaluation parameters of all the stability lots of batch size 2000 tablets} }
\label{tw-641f604ebb7b}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1335\linewidth-2\tabcolsep}p{\dimexpr.3468\linewidth-2\tabcolsep}p{\dimexpr.1765\linewidth-2\tabcolsep}p{\dimexpr.1861\linewidth-2\tabcolsep}p{\dimexpr.15709999999999999\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S. No & Parameters & ST 1 & ST 2 & ST 31\\
\tblmidrule 
1 &
  \multicolumn{4}{p{\dimexpr(.8664999999999999\linewidth-2\tabcolsep)}}{\cAlignHack Micromeritics of Lubricated Blend}\\
a \mbox{}\protect\newline c &
  Bulk Density (gm/cc) \mbox{}\protect\newline Tapped density (gm/cc) \mbox{}\protect\newline Carr's Index (\%) &
  0.579 \mbox{}\protect\newline 0.689 \mbox{}\protect\newline 15.87 &
  0.636 \mbox{}\protect\newline 0.762 \mbox{}\protect\newline 16.45 &
  0.651 \mbox{}\protect\newline 0.778 \mbox{}\protect\newline 16.25\\
d &
  \multicolumn{4}{p{\dimexpr(.8664999999999999\linewidth-2\tabcolsep)}}{\cAlignHack Sieve Analysis}\\
 &
  Below 40\% \mbox{}\protect\newline Above 60\% &
  17.41 \mbox{}\protect\newline 51.89 &
  14.0 \mbox{}\protect\newline 52.82 &
  15.0 \mbox{}\protect\newline 54.86\\
2 &
  \multicolumn{4}{p{\dimexpr(.8664999999999999\linewidth-2\tabcolsep)}}{\cAlignHack Compression Parameter}\\
\multicolumn{1}{p{\dimexpr(.1335\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{a \mbox{}\protect\newline b \mbox{}\protect\newline c \mbox{}\protect\newline d \mbox{}\protect\newline e \mbox{}\protect\newline f \mbox{}\protect\newline g \mbox{}\protect\newline h}} &
  \multicolumn{1}{p{\dimexpr(.3468\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{Description \mbox{}\protect\newline Punch Dimension weight(mg) \mbox{}\protect\newline (Average=1420 mg) \mbox{}\protect\newline (SD=Average \ensuremath{\pm}2\%) \mbox{}\protect\newline Weight variation (mg) \mbox{}\protect\newline Thickness (mm) \mbox{}\protect\newline Hardness (kp) \mbox{}\protect\newline (Acceptance =24-27 kp) \mbox{}\protect\newline Disintegration time (Not more than 15 minutes) \mbox{}\protect\newline Friability (\%) at 100 rotations}} &
  \multicolumn{3}{p{\dimexpr(.5197\linewidth-2\tabcolsep)}}{White to off colour oval shaped, uncoated tablets, plain on both sides.}\\
 &
   &
  \multicolumn{3}{p{\dimexpr(.5197\linewidth-2\tabcolsep)}}{22 \ensuremath{\times} 10 mm oval shaped, plain on both sides. }\\
 &
   &
   1419.0 \mbox{}\protect\newline 1422 \ensuremath{\pm}2\% \mbox{}\protect\newline 7.58-7.64 \mbox{}\protect\newline 19.00-27.00 \mbox{}\protect\newline 9 minutes 50 seconds \mbox{}\protect\newline 0.33 &
   1422.0 \mbox{}\protect\newline 1427 \ensuremath{\pm}2\% \mbox{}\protect\newline 7.57-7.63 \mbox{}\protect\newline 20.0-23.0 \mbox{}\protect\newline 9 minutes \mbox{}\protect\newline 0.33 &
   1418.0 \mbox{}\protect\newline 1423 \ensuremath{\pm}2\% \mbox{}\protect\newline 7.55-7.62 \mbox{}\protect\newline 24.0-28.0 \mbox{}\protect\newline 9 minutes 30 seconds \mbox{}\protect\newline 0.35 \mbox{}\protect\newline \\
3 &
  \multicolumn{4}{p{\dimexpr(.8664999999999999\linewidth-2\tabcolsep)}}{\cAlignHack Coating Parameters}\\
\multicolumn{1}{p{\dimexpr(.1335\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{a \mbox{}\protect\newline b \mbox{}\protect\newline c \mbox{}\protect\newline d \mbox{}\protect\newline e}} &
  \multicolumn{1}{p{\dimexpr(.3468\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Description \mbox{}\protect\newline Total weight (mg) \mbox{}\protect\newline Thickness (mm) \mbox{}\protect\newline Disintegration Time (minutes) \mbox{}\protect\newline (Acceptance: Not More Than 30 minutes)}} &
  \multicolumn{3}{p{\dimexpr(.5197\linewidth-2\tabcolsep)}}{Orange coloured, oval shaped, film coated tablets, plain on both sides.}\\
 &
   &
  1455.0 \mbox{}\protect\newline 7.59-7.78 \mbox{}\protect\newline 24.0-26.0 \mbox{}\protect\newline 10 minutes &
  1458.3 \mbox{}\protect\newline 7.62-7.72 \mbox{}\protect\newline 22.0-27.0 \mbox{}\protect\newline 9 minutes 37 seconds &
  1456.2 \mbox{}\protect\newline 7.65-7.80 \mbox{}\protect\newline 23.0-28.0 \mbox{}\protect\newline 9 minutes 45 seconds\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Assay and dissolution of the optimised batch and after 3 months it was kept for stability } }
\label{tw-72ca9e370fd3}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.10030000000000001\linewidth-2\tabcolsep}p{\dimexpr.2997\linewidth-2\tabcolsep}p{\dimexpr.2111\linewidth-2\tabcolsep}p{\dimexpr.1986\linewidth-2\tabcolsep}p{\dimexpr.1903\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{5}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Assay}\\
\tblmidrule 
S.NO &
  Specifications &
  Assay of Citicoline &
  Assay of Piracetam &
  Acceptance\\
1 &
  Optimised batch before charged to stability &
  97.12 &
  98.33 &
  90-110\%\\
2 &
  \multicolumn{4}{p{\dimexpr(.8997\linewidth-2\tabcolsep)}}{3 months after charged to stability }\\
A \mbox{}\protect\newline B &
  At 30{\textdegree}C/65\% RH \mbox{}\protect\newline At 40{\textdegree}C/75\% RH &
  102.15 \mbox{}\protect\newline 98.01 &
  96.18 \mbox{}\protect\newline 96.98 &
  90-110\% \mbox{}\protect\newline 90-110\%\\
\multicolumn{5}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Dissolution}\\
SL \mbox{}\protect\newline NO. &
  Specifications &
  dissolution of Citicoline &
  dissolution of Piracetam &
  \\
1 &
  \multicolumn{4}{p{\dimexpr(.8997\linewidth-2\tabcolsep)}}{Optimised batch before charged to stability}\\
A \mbox{}\protect\newline B &
  At 45 minutes  \mbox{}\protect\newline At 60 minutes &
  94.57-97.03 \mbox{}\protect\newline 94.29-98.11 &
  96.22-97.83 \mbox{}\protect\newline 95.58-99.20 &
  \\
2 &
  \multicolumn{4}{p{\dimexpr(.8997\linewidth-2\tabcolsep)}}{3 months after charged to stability}\\
A \mbox{}\protect\newline B &
  At 30{\textdegree}C/65\% RH \mbox{}\protect\newline At 40{\textdegree}C/75\% RH &
  102.28-105.80 \mbox{}\protect\newline 102.58-104.27 &
  98.42-101.09 \mbox{}\protect\newline 99.57-100.11 &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
Relative substances study determined the percentage of unknown and known impurities in the formulation which is recorded as highest unknown impurities and total unknown impurities are mentioned in Table~\ref{tw-4145e4094979}.


\begin{table*}[!htbp]
\caption{\boldmath {Values of total unknown impurities and highest unknown impurities } }
\label{tw-4145e4094979}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0909\linewidth-2\tabcolsep}p{\dimexpr.3796000000000001\linewidth-2\tabcolsep}p{\dimexpr.29159999999999997\linewidth-2\tabcolsep}p{\dimexpr.2379\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{4}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Relative Substances}\\
\tblmidrule 
S. \mbox{}\protect\newline No &
  Specification  &
  Highest unknown impurities  &
  Total unknown impurities \\
1 &
  Optimised batch before charged to stability &
  0.027 &
  0.033\\
2 &
  \multicolumn{3}{p{\dimexpr(.9091\linewidth-2\tabcolsep)}}{3 months after charged to stability}\\
A \mbox{}\protect\newline B &
  At 30{\textdegree}C/65 \%RH \mbox{}\protect\newline At 40{\textdegree}C/75\%RH &
  0.103 \mbox{}\protect\newline 0.106 &
  0.181 \mbox{}\protect\newline 0.191\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Micromeritics of Drugs}

The flow property and compressibility of the drug is studied by examination its bulk density, tapped density, Carr's index and Hauser's ratio. Thus, results obtained in table 8, 13 and 15 states that Citicoline and Piracetam have good compressibility index of 36.36\% and 14.73\%. This proves that they are good combinations and retain a good flow property which makes them non adhering substances.

\textbf{Solublity Profile}

According to British pharmacopoeia method testing and for the determination of BCS class.

The drugs when tested for solubility with the procedure given in the British pharmacopoeia, stated that Citicoline and Piracetam are soluble in demineralised water, 0.1 N HCL, 4.5 pH Phosphate buffer and pH 7.5 Phosphate buffer. Piracetam is also freely soluble in Ethanol. Citicoline and Piracetam are said to be BCS class I~drug, as they were soluble in all the buffer solution mentioned of varied pH\ensuremath{^{}}range (as they represent the various pH environment in the human alimentary route starting from mouth saliva to colon.)

Thus, the solubility of the drug, helps us to determine the solvent which can be used for analytical testing and other testing parameters to reduce the burden on the instruments and saves time.

\textbf{Drug Excipient compatibility studies}

Drug excipient compatibility studies resulted in insignificant colour change upon visual examination Table~\ref{tw-c9577789a51a}. Thus, there was no occurrence of any prominent physical changes. The value of all the impurity testing were within the acceptable limits as per each monography in IP. thus, no chemical degradation was observed over period of 15 days when charged to stability condition of 40{\textdegree}c/75\% RH,60{\textdegree}C and RT. This test allowed us to finalise the excipients for further processing. The excipients selected are, crospovidone, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate.

\textbf{Linearity plot of Citicoline and Piracetam}

Various concentration Tables~\ref{tw-48983c3d1b3e} and~\ref{tw-ebd045cea096} of Citicoline and Piracetam were used to determine the linearity of drug .Citicoline was tested at \ensuremath{\lambda } max of271 nm and Piracetam at 210 nm .The linearity graph obtained Figures~\ref{f-24918caf7087} and~\ref{f-9e3f42aceb25}stated that the R\ensuremath{^{2}} value of Citicoline and Piracetam is 0.9999 and 0.9992 respectively (acceptance criteria R\ensuremath{^{2 }}equivalent to 1).Thus, it is clear that the two drugs Citicoline and Piracetam are linear i.e. as there is an increase in concentration, the absorbance also increases linearity.

\textbf{Design of experiment}

Design of experiment (DoE) was performed. An experimental design was studied for the usage of superdisintegrants in various combination to optimise the best fit superdisintegeant to be used. Various tables and figures are shown in the previous section of results.

The best formulation is selected and the fourth formulation which contains only croscarmellose sodium in quantity of 70mg as compared to other super disintegration or when used in combination of other superdisintegration. The DT obtained is 10 minutes 16 sec and hardness are 24 kp of this formulation. Crospovidone and sodium starch glycolate is used in quantity of 0.5mg each. the desirability was 0.967 of the fourth response as compared 29 other responses. Thus, this design of formulation is a reliable with appreciable results.

\textbf{Micromeritic study of granules}

Bulk density, tapped density and carr's index was studied for the granules. The results obtained are mentioned in Tables~\ref{tw-ed11f11648d6}, \ref{tw-5c1e91b82cdd} and~\ref{tw-641f604ebb7b}. The results stated that the granules have good compressibility and flow property. the compressibility and flow property. The compressibility index ranges from 4.885 to 19.35, bulk density ranges from 0.512gm/ml to 0.623gm/ml and the tapped density ranges from 0.614gm/ml to 0.695gm/ml.

\textbf{Post compression evaluation of all trial batches}

The optimised formulation was evaluated for various parameters of disintegration time, tablet weight, hardness, friability and thickness the results are shown in the Table~\ref{tw-79f80664344f} were interpreted as below 

F1 formulation containing povidone (PVP K-30) as binder and microcrystalline cellulose as diluent, showed the hardness as 39 kp and disintegration time (DT) as 22 minutes. The tablet weight was found to be 1500 mg. hardness was said to be on a higher side and beyond the acceptance range (24-27kp), leading to hampering of the disintegration time. Thus, povidone (PVP K -30) was eliminated in the further formulations and demineralised water was used as the sole disintegration agent.

Formulation F2 contains maize starch as diluents. The tablets showed little change in hardness as compared to F1. The DT obtained was above the acceptance limit (acceptance: not more than 15 mins).To reduce the tablet weight and to improve the hardness and DT we considered the assay of and citicoline and Piracetam as 100\%, which lead to the removal of the diluents.

Formulation F3 to F8 were carried out using various combinations of super dis-integrategrants like croscarmellose sodium and sodium starch glycolate. Based on the box benken design obtained earlier, these formulations showed improved results for hardness disintegration time and reduction in tablet weight was achieved. Of these formulations, F4 was considered to have the most appreciable results of hardness as 24 kp (acceptance limit: 24-27), disintegration time as 10 minutes (NMT 15 minutes) and total tablet weight achieved was found to be 1420 mg.

Thus, F4 formulation containing croscarmelloses sodium in 35 mg+ 35 mg quantity (total 70 mg) proved to have the best results in design of experiments and when performed practically. It was optimised for further stability trials mentioned in Table~\ref{tw-72ca9e370fd3}.

 \textbf{Evaluation of stability lost and optimisation of process parameters}

 Formulation F4 was said to be optimised formulation. this formulation was optimised for larger batch size of 2000 tablets. These batches were then charged for stability. These batches were evaluated for micromeritics of granules, compression parameters and coating parameters. The results are observed in Table~\ref{tw-641f604ebb7b}. Optimisation of these process parameters helped for the development of tablet batches of larger batch sizes.

\textbf{Summary}

The objective for development of this formulation was to develop an immediate release formulation with optimum disintegration time and hardness that is able to release the drug immediately upon administration in the stomach at acidic pH.

Compatibility study done at accelerated stability results that the and citicoline and Piracetam are stable and compatible with all excipients. Povidone acted as a binder that enhanced the hardness and disintegration time to such an extent that it was out of acceptance limit. Considering 100 percent assay of the drugs, microcrystalline cellulose and maize starch was eliminated.

Study was carried out using various combinations of super disintegrants like Croscarmellose sodium, crospovidone and sodium starch glycolate. Box Benken design resulted in 17 different trials containing combination of the above super disintegrants based on the hardness and disintegration time these trials were evaluated.

Batch containing Croscarmellose sodium in the concentration of 35 mg intragranular and 35 mg extra granularly, should the best possible results. The total tablet weight also reduced from 1500 mg to 1420 mg. this batch was later optimised and changed to stability at 40{\textdegree}C/75\%RH, 30{\textdegree}C/60\%RH and 25{\textdegree}/60\%RH.

Evaluation test like hardness, thickness, disintegration time, weight variation and friability carried out for the stability batches showed appreciable results with acceptable range.  

Analytical chromatograms of assay and dissolution of optimised batch before and after 3 months stability showed that the drug content ranges from 101-105\% and 98-102\% of and citicoline and Piracetam respectively. The drug release obtained at 60 minutes time interval was equivalent to 100\% for both the drugs.

Relative substance testing was done for highest and total unknown Impurities. It was found to be within the acceptance limit.
    
\section{Conclusions}
Nootropic drugs when used in combination show a synergistic effect as the work by treating neuro degeneration using multiple mechanisms. The formulation used two nootropic drugs as Citicoline and Piracetam in a fixed dose combination. As the dose is fixed, the dosing frequency changes depending upon the severity of the condition. Croscarmellosesodium when used intragranular and extragranulary shows improved effect of disintegration as compared to crospovidone and sodium starch glycolate. Since, Croscarmellose sodium, works on the principle of wicking and swelling when used in tablet formulations.

Croscarmellose sodium when used in formulation F4 formulation showed a hardness as 24 kp when tested on hardness testing apparatus, disintegration time as 10 mins when tested on disintegration apparatus and total tablet weight as 1429 mg. F4 formulation was the best optimised formulation with a good reduction in tablet weight and size.Relative substance, dissolution and assay were the analytical parameters tested for these Formulations. Thus, a formulation with maximum possible reduction in tablet weight to achieve a swallowable shape of tablet and best possible disintegration time was developed to release the nootropic drugs for quicker absorption into the systemic circulation and show an immediate action upon administration. The tablet shows improvement by reduction drug excipient interaction and reduces the burden of processing and storage. 

\textbf{Conflict of Interest}

None.

\textbf{Funding Support}

None.
    

\bibliographystyle{pharmascope_apa-custom}

\bibliography{\jobname}
\end{document}
