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\title{Evaluation and Ranking of Drug Release from Different Grades of Guar Gum, Acacia Gum and Polyvinyl Pyrrolidone as Cross-Linkers in Submicron Particles}
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             \author[1]{Negla Abdulghani Elsayed  Yagoub}

             \author[2]{Dr. Abubakar Osman Mohamed  Nur}

             \author[3]{Fadilah Sfouq  Aleanizy}

             \author[4]{Sarah  Ahmed}

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\date{\small \em Received: 1 January 1970 Accepted: 1 January 1970 Published: 1 January 1970}

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\begin{abstract}
        


Due to their unique properties, nanoparticles made of polysaccharides are promising carriers to deliver and protect the physiological properties of hydrophilic drugs. They have been successfully applied as drug delivery systems (83).Objective: The main goal of this research is to Improve Carbamazepine water solubility and drug release properties by nano sizing, and using guar gum, Acacia Gum and poly-vinylpyrrolidone, each of two viscosity grades, as crosslinking agents. Moreover, the study is extrapolated, utilizing composite index (CI) design and mathematical modelling, in an attempt to locate the most suitable set of the factors that affect nanoparticles produced with optimum specifications.

\end{abstract}


\keywords{polymer, Guar gum, acacia gum, polyvinyl pyrrolidine, carbamazepine, drug release, composite index.}

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\section[{Introduction a) Drug Release}]{Introduction a) Drug Release}\par
central reason for pursuing nanotechnology is to deliver drugs, hence understanding the manner and extent to which the drug molecules are released is important. The drug loading of the nanoparticles is generally defined as the amount of drug bound per polymer mass (usual moles of drug per mg polymer or mg drug per mg polymer); it could also be given as a percentage relative to the polymer.\par
Nanoparticles made of polysaccharides, due to their unique properties, are promising carriers to deliver and protect the physiological properties of hydrophilic drugs and have been successfully applied as drug delivery systems (1) As natural biomaterials, polysaccharides are stable, safe, nontoxic, hydrophilic, and biodegradable. 
\section[{b) Biological benefits of nanoparticles}]{b) Biological benefits of nanoparticles}\par
The property of nanoparticle formulations that make this approach highly beneficial is related to the surface properties imparted on nanometer-sized entities (2). Applying Nano-crystal Technology or one of the alternate nanoparticle formulation approaches to the many formulation and performance issues associated with poorly water-soluble compounds in the pharmaceutical industry provides many benefits. 
\section[{c) The Solubility Challenge}]{c) The Solubility Challenge}\par
It is estimated that \textasciitilde 40\% of active substances identified through combinatorial screening programs are difficult to formulate as a result of their lack of significant solubility in water (3, 4, and 5). In one sense, this is understandable. If a molecule must penetrate a biological membrane to be absorbed, the molecule generally must possess some hydrophobic or lipophilic characteristics. When these types of situations arise, a nanoparticle formulation approach has proven to be very useful and invaluable in all stages of drug development and has opened opportunities for revitalizing marketed products with suboptimal delivery. 
\section[{d) Guar gum}]{d) Guar gum}\par
Guar gum (GG) is galactomannan derived from Guar Cyamopsis tetragonolobuskernels which belong to family Leguminosae.\par
It is biocompatible, biodegradable, non-toxic, low-cost and amenable to chemical modifications, properties that make it an ideal material for developing drug delivery formulations (6). However, native guar gum has also shortcomings such as, uncontrolled rates of hydration, high swelling, thickening effect, instability upon storage, high susceptibility to microbial attack and the difficulty to control viscosity due to relative fast biodegradation (7).\par
Thermal treatment of guar gum at 70? for 10 minutes is an efficient tool to produce guar gum with desired properties for pharmaceutical processing and industries. The treatment has resulted in the production of treated guar gum with improved flowability, swellability, and compressibility. On the other hand, the method of drying seems to have a significant influence on the viscosity of the resultant treated guar powder and verification of such effect might necessitate a more collaborated extended study (8). 
\section[{e) Acacia Gum}]{e) Acacia Gum}\par
This is the dried exudate of the acacia tree (Acacia senegalor related species of Acacia Fam. Leguminosae. The gum is highly soluble in water. Physically, acacia is considered to be a complex, highly branched, globular molecule, which is closely packed rather than linear, thus accounting for its low viscosity. Rheologically, acacia gum solutions exhibit typical Newtonian behavior at concentrations up to 40\%. Above 40\%, solutions become pseudoplastic, as is shown by a decrease in viscosity with increasing shearing stress (9). 
\section[{f) Povidone}]{f) Povidone}\par
PVP is a water-soluble pharmaceutically acceptable polymer. Due to its ability to improve solubility and wettability of poorly soluble drugs, it is frequently used in solid dispersions to enhance solubility and dissolution rate (10, 11), Due to its hydrophilicity and rapid dissolution in an aqueous medium, PVP is very frequently applied as a carrier in immediate release dosage forms. PVP has a long history of use in human drug products and high molecular weight PVPs generally do not get absorbed in the GI tract. 
\section[{g) Carbamazepine (CBZ)}]{g) Carbamazepine (CBZ)}\par
One of the bad soluble active drug substances. Although Carbamazepinehas a high intestinal permeability, its bioavailability is limited by its low water solubility (0.11mgmL?1) (2).\par
5H-ibenz[b,f]azepine-5-carboxamide A white or almost white crystalline powder. It exhibits polymorphism that is very slightly soluble in water; sparingly soluble in alcohol and in acetone, and freely soluble in dichloromethane.\par
Carbamazepine is widely distributed throughout the body and is about 70 to 80\% bound to plasma proteins. It induces its own metabolism so that the plasma half-life may be considerably reduced after repeated dosage.\par
The mean plasma half-life of carbamazepine on repeated dosage is about 12 to 24 hours; it appears to be considerably shorter in children than in adults.\par
Carbamazepine is a dibenzazepine derivative with antiepileptic and psychotropic properties. It is used to control secondarily generalisedtonic-clonic seizures and partial seizures and in some primary generalized seizures. 
\section[{h) Composite index}]{h) Composite index}\par
A composite index is a grouping of equities, indexes or other factors combined in a standardized way, providing a useful statistical measure of overall market or sector performance over time, and it is also known simply as a "composite." Usually, a composite index has a large number of factors that are averaged together to form a product representative of an overall market or sector (12). 
\section[{II.}]{II.} 
\section[{Materials and Methods}]{Materials and Methods} 
\section[{Materials:}]{Materials:}\par
The Nano and submicron particles produced in our previous study (Evaluation of different grades of guar gum, acacia gum and polyvinyl pyrrolidone as cross-linkers in producing submicron particles) as in Table1 are used in this study  
\section[{b) Methods}]{b) Methods}\par
Collected submicron particles from all runs were subjected to the following qualifications. 
\section[{c) Particle size analysis}]{c) Particle size analysis}\par
By using particle size analyser 90, measurements of polydispersity (PD \%) were performed.\par
A specified amount of dry particles was completely dissolved in ethyl acetate, filtered and transferred to the instrument cell and subjected to the test. 
\section[{d) Entrapments efficiency of nanoparticles}]{d) Entrapments efficiency of nanoparticles}\par
Dried nanoparticles were dissolved in ethyl acetate (a common solvent for polymers and drug samples). The amount of entrapped carbamazepine that was present in the solution was measured spectrophotometrically at 287 nm (USP, 13).\par
Drug incorporation efficiency was expressed both as Drug Content (\% w/w), also referred to as drug loading in the literature, and Drug Entrapment (\%); represented by Eqs. (1) and (  {\ref 2}  
\section[{\%100}]{\%100}\par
(2) e) Nanoparticle drug release assessment All runs were subjected to drug release investigations where the amount of particles equivalent to 1 g of carbamazepine was weighed and transferred to a dissolution test beaker containing 1L of sodium lauryl sulphate. 3ml of each sample was filtered into 100 ml volumetric flask and the absorbance of the samples was determined at 287 nm against water as a blank \hyperref[b1]{(14)}. Making use of the drug calibration curve (as discussed next), the amount of carbamazepine was then estimated. The assay method was derived from the USP carbamazepine tablets dissolution test monograph (USP, 13).\par
(1) 
\section[{f) Calibration curve}]{f) Calibration curve}\par
From the reference standard Carbamazepine, 40 mg was accurately weighed and dissolved in 8 ml absolute methanol, 1 ml of this solution was taken and diluted to 10 ml. Serial dilutions were then carried out to obtain solutions of different drug concentrations. The absorbance of each concentration at 287nm was determined spectrophotometrically and a calibration curve was thus generated (USP,13). 
\section[{g) Composite index design}]{g) Composite index design}\par
A weighted composite index was generated for the data to designate a single score utilizing three constraints \hyperref[b2]{(15)}. This was done in order to select the optimized factors setting (polydispersity, Entrapment Efficiency and nanoparticle drug release rate at 60 mints) that could possibly yield the most desired properties for drug granules and tablets. The process of statistical composite index application was aided by the computer Excels program. 
\section[{III.}]{III.} 
\section[{Results}]{Results} 
\section[{a) Characterization of produced particles}]{a) Characterization of produced particles}\par
Table \hyperref[tab_1]{2} summarizes the polydispersity index (PDI \%) and entrapment efficiency (EE \%) properties of produced particles within different formulation runs. The Carbamazepine calibration curve and drug release profiles of different formulation runs are depicted in figures 1 and 2, respectively.    
\section[{Discussion a) Drug release Studies}]{Discussion a) Drug release Studies}\par
A central reason for pursuing nanotechnology is to enhance drug delivery, hence understanding the manner and extent to which the drug molecules are released is important. In order to obtain such information most release methods require that the drug and its delivery vehicle be separated \hyperref[b3]{(16,}\hyperref[b4]{17)}.\par
For the drug to be released from the Polymer particles, the Polymer undergoes degradation by hydrolysis or biodegradation through cleavage of its backbone ester linkage into oligomers and finally monomers \hyperref[b5]{(18)}. 
\section[{b) Calibration curve of standard carbamazepine}]{b) Calibration curve of standard carbamazepine}\par
The generated calibration curve for standard CBZ in solutions using the validated UV assay method shows high acceptable linear correlation regression between drug concentration and UV absorbance with a highly established correlation coefficient (R² = 0.9826) in the drug concentration range of 1-100µg/ml (Fig.  {\ref 1}). 
\section[{c) Effects on drug release characteristics}]{c) Effects on drug release characteristics}\par
The effect of different variables on drug release at 60min for different formulations has been studied. Fig 3  {\ref ,} showed the linear, quadratic and joined influences of polymer type, polymer grade, polymer load and stirring rate. Among the different variables investigated, the polymer grade has the predominant and significant effect on drug release over the other variables, it has a linear effect with p >0.05 which is the cutoff point. Polymer type (2) has less effect than the polymer grade(3) and when joining their linear effect (2 and3) it appears less than (2) and more than (3). Only the polymer type has a quadratic effect on drug release but it was a non-significant one. 
\section[{d) Relation between polymer (type, grade) and drug release}]{d) Relation between polymer (type, grade) and drug release}\par
Similar to what was found in a study done by Nur et al \hyperref[b6]{(19)} considering Guar gum, Treated Guar Gum, and Xanthan Gum, as drug fabricating polymers, different drug release profiles were also present in this study. This might be related to their dissimilar hydration and swelling attributes that determine the rate at which the surface viscous barrier (controlling gel) is being formed. These findings along with the effect of particle size and EE\% can explain the variation in CBZ release profile from the different gums. Moreover, the statistical work shown in fig 3 reveals the predominated effect of polymer grade (viscosity) as a significant effect over the other factors. Following is a discussion on the effect of different polymer grades on CBZ release.\par
Considering Native Guar gum, a fast release of 20\% to 40\% was observed immediately after the addition of loaded particles. This doesn't go along with Nur et al study and it's likely due to a fraction of CBZ present on the surface of the particles being immediately released upon coming in contact with the SLS medium.\par
However, native guar gum has also shortcomings such as uncontrolled rates of hydration, high swelling, thickening effect, instability upon storage, high susceptibility to microbial attack and the difficulty to control viscosity due to relative fast biodegradation \hyperref[b7]{(20)}. Various strategies were developed in order to overcome these issues, offering the opportunity to tailor the physical and chemical properties of guar gum thus yielding materials that may find a wide range of applications Regarding Treated Guar gum, the CBZ release was found to be delayed. Less than 30\% of the drug entrapped was released within 120 Min., This goes parallel with the results of Nur et al \hyperref[b8]{(21)}, which reported low hydration and swelling capabilities of the treated gum. Accordingly, this is reflected in the enhancement of drug release as a result of the delay in the formation of the gel layer that controls the drug release. Such a result is a good explanation of the poor release profile from the treated guar as for the particle in order to release the entrapped drug, the particle must be swollen to permit the drug release.\par
In Povidone K?? (Lower viscosity) the fastest and uniform release was shown with polymer concentration 1\% (R 9 \&R21) which has higher EE\%. This can be explained by the lower viscosity of the prepared emulsion producing small particles and the high hydrophilicity of povidonek30. All these parameters can increase drug dissolution, which is reported by a study published in ISP Pharmaceuticals (11). The study used low molecular weight PVPs as carriers in solid dispersions due to their higher aqueous solubility, lower viscosity in the diffusion boundary layer, and faster dissolution rate. the study revealed that solid dispersions of indomethacin from co-precipitation and spray drying processes showed faster release from PVP with low molecular weight (PVP K30) than those with high molecular weight (PVP K90) \hyperref[b9]{(22)}.\par
In our study, the release of CBZ from PVP K30 was very fast in R24. This is can be due to the lower EE\% which means that the drug is on the surface of particles not entrapped due to the emulsion's high viscosity as a consequence of increased polymer concentration (10\%). This high viscosity renders the drug from diffusing into a polymer molecule and crosslinking with it.\par
Another study, done by Bharali et al \hyperref[b10]{(23)}, investigated the characteristics of in vitro release of entrapped PVP at low loadings of the compound, which remains in the form of a molecular dispersion inside PVP particles. It was found that when the concentration of dye inside the core of the particle is very high, a part of it is associated or clustered, which has to be dissolved and released more slowly out of the particles. These phenomena appear clearly in our study in R 21 which has a higher EE\% of 52\% with a lower release rate.\par
Regarding Povidone k90 (High viscosity) High molecular weight grade PVP K90 dissolves in a large variety of organic solvents. However, due to its hydrophilicity, its moisture uptake level is high \hyperref[b11]{(24)} which may result in difficulties in its physical stability leading to drug crystallization in the carrier polymer caused by the plasticizing effect of absorbed water.\par
The drug release profile of the four runs (3,6,15,18) is strongly linked with EE\% as increase EE\% increase drug release, R 3 and R15 reached 90\% release in 60 minutes as shown in Table  {\ref 4}. The fastest one is in R15 (76\% release at 30 mins) can be attributed to the amount of CBZ entrapped (less than 50\%) and hence more drugs are on the particle surface leading to burst release (more than 30\% in the first 10 mints) (25)\par
With respect to Lower viscosity, Acacia gum showed the slowest release rate among runs, higher viscosity of acacia, large particle and higher polydispersity as seen in Table2 are the responsible factors. R2 small particle and high EE\% these results are not in accordance with relevant published work discussed above. As EE\% is a result of how a drug is cross-linked with a polymer, a decreased viscosity will lead to an increase in EE\% as less barrier is present, this was seen in R2 (1\%polymer concentration produces a solution of lower viscosity) even with large particle sizeR5 with smaller particles (1433.38) than R2 though with lower EE\% can be explained the same way.\par
Considering the higher viscosity of acacia gum runs, a fast release profile was observed which can be relied on for the burst release. More than 20\% to 47\% of drugs are released in the first 10 minutes with lower EE\%, which means the drug is on the particle surface and not entrapped as seen in R 11 and R 23 with less EE\%.\par
In R 8 and R 20 the EE\% is high; it has a fast release of 20 \% this can be explained by their small particle increasing drug solubility and accordingly enhancing drug release e) Effect of particle size on drug release Particle size distribution and morphology are the most important parameters of the characterization of particles. In a study done by (25), it has been found that particle size affects drug release. Smaller particles offer a larger surface area. As a result, most of the drugloaded onto them will be exposed to the particle surface leading to fast drug release, despite these findings present study found that the smallest particle of R19 (131.72) and R22 (168.25) have the slowest drug release. This may be contributed to the nature of treated guar gum used, thermal treatment of guar gum lead to new gum with odd properties due to degradation of the polymer chain. On the contrary, R1 (native guar) which has a particle size (769.81) showed fast drug release (41.83\%) in the first 10 minutes, which support the finding of Robinson (11). Such results can give us a good indication that drug release is mainly affected by polymer characteristics rather than particle size. When we go through the runs we find that R 5 \& R 3 have almost the same particle size (1.43 \& 1.45) but with different drug releases. R5 (lower viscosity Acacia gum) have 18.83\% of drug released in the first 10 minutes while R 3 (povidone lower viscosity) has 45.48\% of drug released in the first 10 minutes which support the above finding as seen in Table  {\ref 4}.\par
Polymer degradation can also be affected by particle size. For instance, the degradation rate of poly (lactic-co-glycolic acid) was found to increase with increasing particle size in vitro (26). 
\section[{f) Relation between EE\% and drug release}]{f) Relation between EE\% and drug release}\par
The fast drug release in first 10 minutes can be explained by the EE\%, as the drug on surface of the particle is released before the entrapped one. This finding appear in R 16 and R 4 (native Guar) with large particle size (3,600.58 \&26,450.88) and drug release 34.12\% \&50.20\% respectively It also ppear in povidone k90 R 12 and R 24 (release 33.66\% \& EE\% 11.49\%) (Maximum release 67.02\% and EE\% 12.88\%), respectively (Table  {\ref 4}).\par
A fast release of 20\% to 40\% was observed for native guar run just after the addition of loaded particles, likely due to a fraction of CBZ present on the surface of the particles being immediately released in contact with the simulated fluids. The CBZ released in the SLS medium over the total duration of the experiment reached 85 \%, indicating that the release of CBZ from the particles can also be controlled by pH. 
\section[{g) Optimization by composite indexing}]{g) Optimization by composite indexing}\par
Using composite index design as ranking tool prove to be effective in evaluating each factor in an equal way that help in making decision with strong statistical view.\par
Since the relative contribution of each individual constraint to the true composite score within each step was unknown, the decision was made to assign an arbitrary value of 1/3 to each of the three factors and, accordingly, each test result was transformed to a value between 0 and 0.33. Within each separate step, multilinear regression equations were applied for the three constraints in order to generate the composite index (CI) for each selected constraint including higher than and lower than ideal values. The run having the highest composite index would be considered as a batch fulfilling the constraints and consequently would be considered as an optimized one.\par
Table \hyperref[tab_2]{3} abridged the composite index scoring and the subsequent ranking of the different 24 runs based on the previously mentioned preset 3 constraints of (EE\%, PDI and R\% at 60 mints) in composite index are summarized in Table \hyperref[tab_2]{3}, The generated composite index scoring for Runs in this series has ranked R 8 as first run though it has R\% 28 at 60 min with increased EE\% and the smallest PDI( 0.3) lead to increase its efficiency in rank V. 
\section[{Conclusion}]{Conclusion}\par
It was found that Acacia gum has the more interesting properties in developing submicron particles like controlling drug release, and hence need to be studied further, while polymer viscosity has large impact on particles behavior.\begin{figure}[htbp]
\noindent\textbf{}\includegraphics[]{image-2.png}
\caption{\label{fig_0}}\end{figure}
   \begin{figure}[htbp]
\noindent\textbf{I} \par 
\begin{longtable}{P{0.04642392717815345\textwidth}P{0.2674902470741222\textwidth}P{0.053608582574772426\textwidth}P{0.2641742522756827\textwidth}P{0.05305591677503251\textwidth}P{0.11882314694408323\textwidth}P{0.04642392717815345\textwidth}}
\tabcellsep R9\tabcellsep 1000\tabcellsep PovidoneK30 lower viscosity\tabcellsep 1\%\tabcellsep Povidone\tabcellsep \\
\tabcellsep R10\tabcellsep 1000\tabcellsep G-treated\tabcellsep 10\%\tabcellsep Guar gum\tabcellsep \\
\tabcellsep R11\tabcellsep 1000\tabcellsep Acacia higher viscosity\tabcellsep 10\%\tabcellsep Acacia Gum\tabcellsep \\
\tabcellsep R12\tabcellsep 1000\tabcellsep PovidoneK30 lower viscosity\tabcellsep 10\%\tabcellsep Povidone\tabcellsep \\
\tabcellsep R13\tabcellsep 500\tabcellsep G-non treated\tabcellsep 1\%\tabcellsep Guar gum\tabcellsep \\
\tabcellsep R14\tabcellsep 500\tabcellsep Acacia lower viscosity\tabcellsep 1\%\tabcellsep Acacia Gum\tabcellsep \\
\tabcellsep R15\tabcellsep 500\tabcellsep PovidoneK30 lower viscosity\tabcellsep 1\%\tabcellsep Povidone\tabcellsep \\
\tabcellsep R16\tabcellsep 500\tabcellsep G-non treated\tabcellsep 10\%\tabcellsep Guar gum\tabcellsep \\
\tabcellsep R17\tabcellsep 500\tabcellsep Acacia lower viscosity\tabcellsep 10\%\tabcellsep Acacia Gum\tabcellsep \\
\tabcellsep R18\tabcellsep 500\tabcellsep PovidoneK90 higher viscosity\tabcellsep -10\%\tabcellsep Povidone\tabcellsep \\
Year 2022\tabcellsep R19 R20 R21 R22\tabcellsep 500 500 500 500\tabcellsep G-treated Acacia higher viscosity PovidoneK30 lower viscosity G-treated\tabcellsep 1\% 1\% 1\% 10\%\tabcellsep Guar gum Acacia Gum Povidone Guar gum\tabcellsep Year 2022\\
2\tabcellsep R23\tabcellsep 500\tabcellsep Acacia higher viscosity\tabcellsep 10\%\tabcellsep Acacia Gum\tabcellsep 3\\
Volume XXII Issue III Version I\tabcellsep \multicolumn{5}{l}{R24 a) Apparatus The following instruments were used in the experimental part of this study: 500 PovidoneK30 lower viscosity Instrument Specification and Source 10\% Analytical balance Reblab ®, Germany Zetasizer 90 plus Malvern Panalytical Ltds U.V. Spectrophotometer double beam UV-1800, Shimadzu, Japan Povidone Magnetic stirrer Stuart, England Scanning electron microscope Zeiss EVO LS10; Cambridge, United Kingdom}\tabcellsep Volume XXII Issue III Version I\\
D D D D )\tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep D D D D )\\
(\tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep (\\
Medical Research\tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep Medical Research\\
Global Journal of\tabcellsep Run\tabcellsep Stirring Rate\tabcellsep Polymer grade\tabcellsep Polymer load\tabcellsep Polymer type\tabcellsep Global Journal of\\
\tabcellsep R1\tabcellsep 1000\tabcellsep G-non treated\tabcellsep 1\%\tabcellsep Guar gum\tabcellsep \\
\tabcellsep R2\tabcellsep 1000\tabcellsep Acacia lower viscosity\tabcellsep 1\%\tabcellsep Acacia Gum\tabcellsep \\
\tabcellsep R3\tabcellsep 1000\tabcellsep Povidone K90 higher viscosity\tabcellsep 1\%\tabcellsep Povidone\tabcellsep \\
\tabcellsep R4\tabcellsep 1000\tabcellsep G-non treated\tabcellsep 10\%\tabcellsep Guar gum\tabcellsep \\
\tabcellsep R5\tabcellsep 1000\tabcellsep Acacia lower viscosity\tabcellsep 10\%\tabcellsep Acacia Gum\tabcellsep \\
\tabcellsep R6\tabcellsep 1000\tabcellsep Povidone K90 higher viscosity\tabcellsep 10\%\tabcellsep Povidone\tabcellsep \\
\tabcellsep R7\tabcellsep 1000\tabcellsep G-treated\tabcellsep 1\%\tabcellsep Guar gum\tabcellsep \\
\tabcellsep R8\tabcellsep 1000\tabcellsep Acacia higher viscosity\tabcellsep 1\%\tabcellsep Acacia Gum\tabcellsep \end{longtable} \par
  {\small\itshape [Note: B© 2022 Global Journals]} 
\caption{\label{tab_0}Table I :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{2} \par 
\begin{longtable}{P{0.1643646408839779\textwidth}P{0.34281767955801107\textwidth}P{0.34281767955801107\textwidth}}
Run No.\tabcellsep EE\tabcellsep PDI\\
R1\tabcellsep 52.3\%\tabcellsep 5.50\%\\
R2\tabcellsep 52.3\%\tabcellsep 0.52\%\\
R3\tabcellsep 52.3\%\tabcellsep 1.76\%\\
R4\tabcellsep 13.1\%\tabcellsep 0.37\%\\
R5\tabcellsep 13.1\%\tabcellsep 0.50\%\\
R6\tabcellsep 13.1\%\tabcellsep 0.43\%\\
R7\tabcellsep 52.3\%\tabcellsep 0.62\%\\
R8\tabcellsep 52.3\%\tabcellsep 0.30\%\\
R9\tabcellsep 52.3\%\tabcellsep 0.67\%\\
R10\tabcellsep 13.1\%\tabcellsep 0.39\%\\
R11\tabcellsep 12.5\%\tabcellsep 4.04\%\\
R12\tabcellsep 11.8\%\tabcellsep 0.40\%\\
R13\tabcellsep 39.6\%\tabcellsep 0.55\%\\
R14\tabcellsep 47.0\%\tabcellsep 0.44\%\\
R15\tabcellsep 45.0\%\tabcellsep 0.69\%\\
R16\tabcellsep 12.7\%\tabcellsep 0.38\%\\
R17\tabcellsep 13.1\%\tabcellsep 1.09\%\\
R18\tabcellsep 13.1\%\tabcellsep 1.04\%\\
R19\tabcellsep 52.3\%\tabcellsep 0.09\%\\
R20\tabcellsep 52.3\%\tabcellsep 0.38\%\\
R21\tabcellsep 52.3\%\tabcellsep 0.56\%\\
R22\tabcellsep 13.1\%\tabcellsep 1.74\%\\
R23\tabcellsep 13.1\%\tabcellsep 0.81\%\\
R24\tabcellsep 13.1\%\tabcellsep 16.64\end{longtable} \par
 
\caption{\label{tab_1}Table 2 :}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{3} \par 
\begin{longtable}{P{0.1944375\textwidth}P{0.125375\textwidth}P{0.10731249999999999\textwidth}P{0.0584375\textwidth}P{0.0945625\textwidth}P{0.065875\textwidth}P{0.0563125\textwidth}P{0.104125\textwidth}P{0.0435625\textwidth}}
\multicolumn{9}{l}{constraints for particles polydispersity index (PDI \%), entrapment efficiency (EE \%) and drug release at 60 min}\\
\tabcellsep \tabcellsep \tabcellsep \tabcellsep (\%Rel 60min )\tabcellsep \tabcellsep \tabcellsep \tabcellsep \\
Run No.\tabcellsep \multicolumn{3}{l}{Responses values}\tabcellsep \multicolumn{3}{l}{Transformed responses}\tabcellsep CI\tabcellsep Ranking\\
\tabcellsep PDI \%\tabcellsep EE \%\tabcellsep \%Rel 60min\tabcellsep PDI \%\tabcellsep EE \%\tabcellsep \%Rel 60min\tabcellsep \tabcellsep \\
R1\tabcellsep 5.50\tabcellsep 52.3\tabcellsep 70\tabcellsep 0\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.14\tabcellsep 7\\
R2\tabcellsep 0.52\tabcellsep 52.3\tabcellsep 73\tabcellsep 0\tabcellsep 0.14\tabcellsep 0.07\tabcellsep 0.21\tabcellsep 4\\
R3\tabcellsep 1.76\tabcellsep 52.3\tabcellsep 68\tabcellsep 0\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.14\tabcellsep 7\\
R4\tabcellsep 0.37\tabcellsep 13.1\tabcellsep 73\tabcellsep 0.16\tabcellsep 0\tabcellsep 0.07\tabcellsep 0.23\tabcellsep 3\\
R5\tabcellsep 0.50\tabcellsep 13.1\tabcellsep 15\tabcellsep 0\tabcellsep 0\tabcellsep 0\tabcellsep 0.00\tabcellsep 13\\
R6\tabcellsep 0.43\tabcellsep 13.1\tabcellsep 26\tabcellsep 0.04\tabcellsep 0\tabcellsep 0\tabcellsep 0.04\tabcellsep 12\\
R7\tabcellsep 0.62\tabcellsep 52.3\tabcellsep 5\tabcellsep 0\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.14\tabcellsep 7\\
R8\tabcellsep 0.30\tabcellsep 52.3\tabcellsep 28\tabcellsep 0.29\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.43\tabcellsep 1\\
R9\tabcellsep 0.67\tabcellsep 52.3\tabcellsep 45\tabcellsep 0\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.14\tabcellsep 7\\
R10\tabcellsep 0.39\tabcellsep 13.1\tabcellsep 6\tabcellsep 0.12\tabcellsep 0\tabcellsep 0\tabcellsep 0.12\tabcellsep 8\\
R11\tabcellsep 4.04\tabcellsep 12.5\tabcellsep 62\tabcellsep 0\tabcellsep 0\tabcellsep 0\tabcellsep 0.00\tabcellsep 13\\
R12\tabcellsep 0.40\tabcellsep 11.8\tabcellsep 73\tabcellsep 0.10\tabcellsep 0\tabcellsep 0.07\tabcellsep 0.17\tabcellsep 6\\
R13\tabcellsep 0.55\tabcellsep 39.6\tabcellsep 46\tabcellsep 0\tabcellsep 0\tabcellsep 0\tabcellsep 0.00\tabcellsep 13\\
R14\tabcellsep 0.44\tabcellsep 47.0\tabcellsep 28\tabcellsep 0.02\tabcellsep 0.08\tabcellsep 0\tabcellsep 0.10\tabcellsep 9\\
R15\tabcellsep 0.69\tabcellsep 45.0\tabcellsep 67\tabcellsep 0\tabcellsep 0.06\tabcellsep 0\tabcellsep 0.06\tabcellsep 11\\
R16\tabcellsep 0.38\tabcellsep 12.7\tabcellsep 73\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.07\tabcellsep 0.21\tabcellsep 5\\
R17\tabcellsep 1.09\tabcellsep 13.1\tabcellsep 60\tabcellsep 0\tabcellsep 0\tabcellsep 0\tabcellsep 0.00\tabcellsep 13\\
R18\tabcellsep 1.04\tabcellsep 13.1\tabcellsep 12\tabcellsep 0\tabcellsep 0\tabcellsep 0\tabcellsep 0.00\tabcellsep 13\\
R19\tabcellsep 0.09\tabcellsep 52.3\tabcellsep 8\tabcellsep 0\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.14\tabcellsep 7\\
R20\tabcellsep 0.38\tabcellsep 52.3\tabcellsep 37\tabcellsep 0.14\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.28\tabcellsep 2\\
R21\tabcellsep 0.56\tabcellsep 52.3\tabcellsep 46\tabcellsep 0\tabcellsep 0.14\tabcellsep 0\tabcellsep 0.14\tabcellsep 7\\
R22\tabcellsep 1.74\tabcellsep 13.1\tabcellsep 9\tabcellsep 0\tabcellsep 0\tabcellsep 0\tabcellsep 0.00\tabcellsep 13\\
R23\tabcellsep 0.81\tabcellsep 13.1\tabcellsep 73\tabcellsep 0\tabcellsep 0\tabcellsep 0.07\tabcellsep 0.07\tabcellsep 10\\
R24\tabcellsep 0.54\tabcellsep 13.1\tabcellsep 73\tabcellsep 0\tabcellsep 0\tabcellsep 0.07\tabcellsep 0.07\tabcellsep 10\end{longtable} \par
 
\caption{\label{tab_2}Table 3 :}\end{figure}
 			\footnote{B © 2022 Global JournalsEvaluation and Ranking of Drug Release from Different Grades of Guar Gum, Acacia Gum and Polyvinyl Pyrrolidone as Cross-Linkers in Submicron Particles} 		 		\backmatter  			 			 			  				\begin{bibitemlist}{1}
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