Indomethacin Solubilisation In Aqueous Solutions Of Poloxomar Biology Essay

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The increased solubilisation of hydrophobic indomethacin for the incorporation into the core of the micelles formed by copolymer surfactant Pluronic P103 in aqueous solutions has been examined using HPLC. Pluronic ABA block copolymer (also known as 'poloxamers') P103 consist of hydrophilic shells of poly-ethylene oxide (PEO) and hydrophobic core of poly-propylene oxide (PPO) blocks arranged in a structure of EOx-POy-EOx where 2x=33.75 and y=59.74. This arrangement results in a non-ionic amphiphlic copolymer structure which can be utilized as an effective surfactant. It is the difference in hydrophobicity and preferences in making bond with water molecules between these two structures, which help to form micelles and the water insoluble substances like indomethacin assemble into micelles in aqueous solutions above the critical micelle concentration (CMC). Due to this enhanced ability to form stable micellar system in aqueous solutions, these surfactants are widely studied as drug delivery system for poor water soluble drugs.

Contents v

1.Introduction 1

2. Methods and materials 4

2.1 Methods 4

2.1.1 Molecular process of solubilisation 4

2.1.2 Solubilisation 8

2.1.3 HPLC method 9

2.1.4 Indomethacin 11

2.1.5 Sugar as additives 13

2.2 Materials 14

2.3 Solubilisation experiments 14

3. Results and Discussion 16

3.1 Solubilisation for polymer solution 16

3.2 Solubilisation for polymer with sugar additives 20

3.3 Calibration curve 23

3.4 HPLC measurement 24

4. Conclusion 25

5. Future Aspects 26

6. References 27

Tables

Figures

Introduction

It is now believed in Pharmaceutical science that for more effective and substantial development of existing and yet undiscovered drugs, improvement of their delivery system is extremely important. This can be easily understood by the fact that about 50% of the drugs still show very limited to negligible solubility in biological fluids when they are administered and absorbed. As a result for couple of decades, a tremendous attraction was arisen for finding the effective drug delivery system which means design of technologically optimal vehicles for the administration of drugs. Among all the drug delivery systems, a major subset which is based on ABA block copolymer attracted significant attention as they appear to be very promising. They are the amphiphilic poly (ethylene oxide)-poly(propylene oxide) block copolymers who can aggregate and form stable nanoscopic (˃100 nm) structure named micelle above a certain concentration called the critical micelle concentration (CMC) to be used as carriers and hydrosolubilizers in aqueous solutions for the poorly water soluble drugs [1].

Poloxamer (trademark name Pluronic) P103 is one of the multifunctional and environmental friendlier block copolymer that can be used as an effective drug delivery system. This is very less toxic and approved by FDA and EPA as thermo-viscosifying materials and to find applications as direct and indirect food additives, pharmaceutical ingredients and agricultural products [2]. This is a non-ionic tri-block amphiphilic copolymer that contains one hydrophobic PPO unit sandwiched between two side hydrophilic PEO units. When a hydrophobic drug like indomethacin together with this poloxamer placed in an aqueous solution this comparative hydrophobic and hydrophilic characteristic takes charge. The PEO-PPO-PEO chains take the form of small strands and above certain concentration, the hydrophobic centres come together surrounding the hydrophobic indomethacin for strong hydrophobic attraction to form the core of a stable carrier system called micelle. Whereas the attached hydrophilic PEO side arms are kept in the mobile state of water solution as they are stretched outside from the particle surface. These side arms provide stability to the carrier system by showing repulsive characteristic among them, through a steric mechanism of stabilization involving both enthalpic and entropic contribution [3]. For this type of surface activity, the hydrophobic parts together with indomethacin keep themselves away from the exposure of water molecules and the hydrophilic parts find themselves in the middle of the surface of water and hydrophobic parts, like a covering/partition. In this way the triblock copolymers self assemble surrounding the hydrophobic organic compound in aqueous solution to form a miceller system and help to transfer the hydrophobic compound to aqueous system through creating a dispersed hydrophobic environment. As a result the apparent solubility of hydrophobic compound in aqueous solution is increased [4][5].

The block copolymers are termed as surfactant because they reduce the interfacial tension between water and the hydrophobic compound by taking place in between them and help the immiscible hydrophobic particle to disperse in the aqueous solvent. This type of dispersion only takes place when the micelles are formed and they are formed when the concentration of the surfactant reaches the critical micelle concentration (CMC) which is dependent on that particular surfactant system, temperature, pH and additives. Although CMC is defined as a single concentration point, the micellization process for pluronics normally take place in a broad concentration range that is referred to as aggregation concentration range (ACR). The limiting aggregation concentration (LAC) is the point at which the surfactant reaches saturation, which would correspond to the more conventional CMC.

Additives like sugar can also influence the CMC of a particular surfactant system and influence the solubilisation of a hydrophobic drug compound as well [6][7]. By obstructing the iceberg formation around the non-polar part of the surfactant the carbohydrate molecules help to increase the attraction among the hydrophobic core molecules to form micelles. As a result the aggregation number of the surfactant increases and CMC of the surfactant system decreases.

The goal of our work is to find out the enhancement gradient of the solubilisation of a hydrophobic drug compound Indomethacin using the aqueous and sucrose solution of non-ionic tri-block copolymeric surfactant Pluronic P103.

2. Methods and materials

2.1 Methods

2.1.1 Molecular process of solubilisation

The formation of micelle is required to use the polymeric surfactant as a solubility enhancement and an efficient drug delivery system. So for understanding the solubilisation characteristic it is important to understand the structure of Poloxamer and formation of micelle. We know the molecular structure of Poloxamer P103 is

The hydrophobic poly-propylene oxide (PPO) block of Poloxamer is placed in between two side-arms of hydrophilic poly-ethylene oxide (PEO) blocks where x=17 and y=62.As they have higher the number of PPO than PEO they normally show lower CMC value which makes the micelle more stable [10].

The block copolymer shows surface activity because of the differing solvent preferences of the PEO and PPO blocks. At low temperatures both of PPO and PEO blocks are soluble in water. However when the temperature of the system increased the PPO block shows increasing hydrophobicity and this leads to phase separation of the surfactant [12]. This important phenomenon may be described using works of two groups of workers.

Almgren et al. proposed that in low temperature the PPO and PEO blocks form ice like network with water molecules using the hydrogen bonds [13]. But in high temperature the highly ordered structure of water molecules around hydrocarbon chain is eliminated when the polymer molecules assemble together to contact the hydrocarbon tails of each other. The release of these water molecules with ordered arrangement causes the increase in entropy, and hence, the decrease in free energy.

Three types of energy changes may be introduced in the 'free energy of mixing' for the formation of micelles. They are (1) negative enthalpy change for the formation of highly ordered hydrogen bond around the polymer molecules with water molecules, (2) positive entropy change for the combinatorial contribution of the polymer chains and (3) negative entropy change for the increased structuring of water molecules. For the formation of micelle, the change of free energy of mixing can be calculated by the following relation

where the concentration of monomer is constant corresponding to the CMC. represents the standard enthalpy change and represents the standard entropy change associated with the formation of micelles. For non-ionic polymer it was examined that decreases with the increase in temperature from positive value to negative one and increases with temperature from negative toward positive. It describes that in low temperature region, the large negative entropy change overcomes positive enthalpy change causes the negative free energy, while the negative enthalpy change is more prevailing in high temperature region [14].

Figure 1: Formation of micelle of tri-block co-polymer from unimer molecules.

Using neutron scattering Finney and Soper demonstrated that there is no bond formed between water and non polar hydrophobic part. Karlstorm proposed that the reason of increase in hydrophobicity of PEO block for the increase in temperature is the change in conformation of the PEO block [15]. In low temperature, for the backbone -O-C-C-O- the two polar conformations in trans-gauche-trans position is preferred which form bonds with water molecules. As there are only two conformations, they are of low energy levels and also of low probability [15]. But in high temperature, the less polar conformations of about 23 are favoured which interact with water molecules less favourably. For being less polar, they are of high energy level and high probability. So the loss of water molecules from the hydrogen bonds in higher temperature, allow PEO parts to come together and form micelles.

It has been observed that the pendant methyl group of PPO blocks create more strain on water structure than those noticed in the case of PEO blocks in much lower temperatures [16]. The PPO blocks shows more hydrophobicity than the PEO blocks and loses hydration spheres more readily resulting in greater interaction between the PPO blocks on different chains. On the other hand the more hydrophilic PEO blocks remain in the bonds with water molecules and create a difference in phase preferences.

As a result like all amphiphilic molecules, the copolymers attach themselves using their hydrophobic PPO parts to form the core of their aggregates and disperse in water by stretching the PEO blocks outside the core to water. As the core of the aggregates is hydrophobic, water insoluble compounds like indomethacin can easily be incorporated into the core. In this way water insoluble hydrophobic particles can be transferred into the aqueous solution and the apparent solubility of the particle can be increased. This type of enhancement of solubility is called solubilisation.

2.1.2 Solubilisation

Critical micelle concentration of a surfactant plays a significant role in solubilisation of water insoluble hydrophobic compounds. When the concentration of polymer in aqueous solution reaches CMC, the hydrophobic parts of unimer molecules come to the contact of each other to form hydrophobic core of micelle and the hydrophobic compound like indomethacin starts to be incorporated into the core. This helps to increase the apparent solubility of hydrophobic compound which is less soluble in water and this process is called 'Solubilisation'. Normally below CMC the unimers of surfactant have little, if any, ability to increase the solubility of the compound. In every miceller system with solute, there is a dynamic equilibrium between the solute molecules inside the micelle and those of soluble in water solution [17]. Paterson et al, describes this dynamic equilibrium following the relation

Where Sa and Sw are the solubility (mol/L) of indomethacin in aqueous solution with poloxamer and without poloxamer respectively. The constant P is called partition coefficient. As we know micelles are introduced in the system after CMC the partition coefficient can be described as [17]

= 1+Kunimer Cs where Cs

where Cs

where Cs is the concentration of surfactant in aqueous phase and Kunimer is the equilibrium constant that describes the interaction between the unimers and solute. Kmicelle is another constant represents the interaction between the micelles and solute. It is not possible to find the exact description of equilibrium as the system of micelle has no well defined initial and final state. But if the system is a homogenous solution an acceptable relation of solubilisation can be reached using the above relation. Normally in solubilisation the size of the micelle core increases and CMC decreases due to the incorporation of solute molecules and increase in aggregation number [18]. From the equation it is explained that the solubility of indomethacin has a clear break at CMC and above CMC the gradient of the solubility line starts to increase [18]. Before CMC as there is very little attraction remain in between unimer surfactants and solute molecule, the gradient of the line keeps very low.

2.1.3 HPLC method

High performance liquid chromatography (HPLC) is widely used technique for analysis in pharmaceutical industries as it is highly sensitive within wider linear dynamic range, the amount of sample needed for experiment is minute and the instrumentation for separation, identification and quantification is simple [19][20]. It is known that if (a) the mobile phase flow rate and the pressure in the detector is constant, (b) all the samples are eluted without decomposition, reaction or irreversible adsorption and (c) the detector is linear, the peak area is proportional to the concentration of the component contained in the injected sample with respect to time [21]. This can be described following the relation given as

C = RF- A

where RF is a proportionality constant. Peak areas on the chromatogram were measured with an integrator which represents a number that is proportional to the area for each peak. For identifying the peak of the solute, increasing the accuracy and measuring the concentration of indomethacin in aqueous solution of polymer, a calibration curve was introduced within the working range of the experiment, recommended by FDA. Here a series of peak areas were plotted in a graph against the corresponding known concentrations of the solute near the expected concentrations in the unknown. Most solutes give a linear calibration curve for certain ranges which are referred to as the linear dynamic range. Using this curve in linear dynamic range a regression line equation can be calculated that shows a relation of peak areas with the corresponding concentrations of solute.

where

              x and y are the variables.

              m = The slope of the regression line

              b = The intercept point of the regression line and the y axis.

              n = Number of values or elements

Using the R-squared coefficient calculation of linear regression in Microsoft Excel, the slope and the intercept can be easily calculated and in doing so the concentration related to different peak areas of different polymer solutions can be determined. We have used the reverse phase HPLC method to separate polar compound of indomethacin from other solutes in the solution. It is generally easier, faster and more reproducible than other and solutes are eluted in order of their polarity, the most polar being eluted first [22]. The hydrophobic surface of the bonded phase attracts the less polar part of the mobile phase to form a layer at the silica surface of column and the partitioning of solutes occurs between this layer and the mobile phase [22].

2.1.4 Indomethacin

Indomethacin is a member of the non-steroidal anti inflammatory drugs (NSAIDS), used to reduce pain/swelling involved in osteoarthritis, rheumatoid arthritis, bursitis, tendinitis, ankylosing spondylitis and headaches [23]. The chemical structure of indomethacin is

Figure 3: indole acetic acid derivative 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid

It has been observed that indomethacin is poorly soluble in water and highly permeable (class 2) acidic drug. After oral administration the absorption of drugs in circulatory system, depends on three rate determining steps (1) disintegration of drugs in gastrointestinal tract, (2) dissolution of drugs in gastrointestinal fluids and (3) absorption of drugs across gastrointestinal membrane into the circulatory system. But for poor solubility of indomethacin the rate determining step is normally the dissolution of drug resulting in low and erratic bio availability in gastrointestinal fluids [24]. They also keep prolonged contact with the mucosa of the gastrointestinal tract which causes irritating side effects.

So for increasing the bio availability of this widely used antirheumatic agent many techniques of solubilisation have been tried over the years like using adsorbents, hydrotopes and cosolvents, preparing coprecipitate, preparing coprecipitate liquisolid compacts, first releasing microparticles and compression with buffers etc. We have studied block copolymer P103 as a drug carrier system because it shows promising for both increasing the rate of dissolution and preventing the high permeability of the drug compound which leads to high bio-availability of drug into the body.

2.1.5 Sugar as additives

It has been observed that sugar has the ability to be used with the polymer to decrease the CMC and used as a taste mask for drug while administered. The addition of sugar into the aqueous solution of Poloxamer favours the formation of water matrix structure due to hydrogen bonding and more structured the water matrix, more the decrease in CMC. Originally micelle is formed due to the hydrophobic attraction and the mutual repulsion of hydrophilic part of the surfactant creates strain in the formation of micelle [8][9]. It is believed that for the hydrophobic attraction, an iceberg like structure is most probably formed surrounding the non-polar tails of the surfactant molecules [25]. When sugar is added with the surfactant, water-water interaction was replaced by the water-sugar interaction for the presence of carbohydrate. The formation of iceberg around the non-polar part is blocked and the hydrophobic PPO blocks can easily come closer to form micelle. As a result more surfactant molecules take part in aggregation which lowers the CMC [26]. The lowering of CMC is in favour of carbohydrate induced phasing out of the amphiphiles accompanied by a favourable miceller growth. But in the same time for the increase in attraction of indomethacin with the micelle core results in increase of the number of hydrophobic compound incorporated with surfactant molecules which will increase the solubility of indomethacin.

2.2 Materials

Pluronic P103 surfactant was obtained from BASF corporation. It was used as received. The molecular formula of pluronic P103 is

And average molecular mass is 4950. The molecular formula of indomethacin is C19H16ClNO4 and molecular weight is 357.79 gm (99% grade). This was purchased from Sigma-Aldrich Company and was also used as received. The polymer solutions were prepared using distilled water. For standard solutions methanol (HPLC grade) and glacial acetic acid (laboratory reagent grade) were obtained from Fisher Chemicals and used as received. For sucrose solution sucrose was obtained from VWR international Ltd, Poole, England whose molecular formula is C12H22O11 and molecular mass is 342.30. This was used without any modification.

2.3 Solubilisation experiments

The stock solution of Poloxamer was prepared by weighing 5.002gm in a 100 ml volumetric flask and adding distilled water up to the mark. Using this stock solution, seven solutions of different concentrations of 0.5%, 0.75%, 0.875%, 1%, 1.25%, 1.625% and 1.75% were prepared in 20ml volumetric flasks. For all of them concentrated solutions of indomethacin were prepared by adding excess of it into these solutions. The flasks were sealed by plastic caps and kept on a vibrator instrument with medium speed for 24 hours at room temperature. The saturated solutions were then injected into a HPLC machine (Philips PU4100) and related chromatograms were obtained from attached UV detector (PYE Unicam PU 4025). The column used was a PS Phase Separation column where silica was used as stationary phase. The flow rate of HPLC was kept between 1 to 1.5 ml/minutes.

The mobile phase was prepared by a mixture of 75% methanol, 24.85% water and 0.15% glacial acetic acid. For calibration curve a stock solution of standard was prepared by weighing 5.03 gm of indomethacin in a 100 ml volumetric flask and adding mobile phase solution up-to the mark. It was then kept on a magnetic stirrer with speed of 30 rpm for an hour. When the solution became transparent a series of mobile phase solutions of different concentrations of 0.0032%, 0.005%, 0.01%, 0.02% and 0.03% were prepared by adding mobile phase solutions up-to the mark in different 20 ml volumetric flasks. The known solutions were well shaken and kept still for some time so that no bubbles could be present. Using the syringe, the solutions were injected into the HPLC machine with flow rate of 1 ml/min.

For preparing the molar stock solution of sucrose, 85.575 gm of it was carefully weighed and added in a 250 ml volumetric flask and made it up to the mark using distilled water. It was then well shaken to make it homogenous solution and by weighing 5.02 gm of Poloxamer was added to the solution. It was kept on the stirrer machine with 40 rpm speed for 2 hours in room temperature. It was then removed and using this stock solution a number of solutions of different concentrations of 0.5%, 0.625%, 0.75%, 0.875%, 1% and 1.25% were prepared in 20ml volumetric flasks. Indomethacin was added sufficiently to each solution to make saturated solutions and kept them on the vibrator machine for about one day in room temperature. After that, the solutions were removed and kept still for some time to ensure the bubbles to settle down. They were filtered using the syringe filter and again kept still for some time. The solutions were then injected into the HPLC machine with flow rate of 1 ml/min.

During all of the injections any sign of bubbles in the injection or in the mobile phase was carefully observed and if found they were removed. All the experiment was carried out at room temperature. Between two injections the syringe was carefully washed using water and mobile phase solution respectively.

3. Results and Discussion

3.1 Solubilisation for polymer solution

Critical micelle concentration plays an important role in the solubilisation of indomethacin in the aqueous solution of poloxamer.

Figure 4: Indomethacin solubility enhancement ratio (s'/s) as a function of P103 surfactant concentration in mmol/dm3 and the blue dots represents the experimental data.

The solubilisation of the hydrophobic compound is clearly introduced with a sharp break at CMC of the surfactant. Before the break at CMC, there was more or less no change in solubilisation of indomethacin. Because there is usually no existence of micelle in the solution below CMC and unimers of surfactant have little attraction with the hydrophobic compound. The solubilisation below the CMC was expressed by the relation

= 1+Kunimer Cs where Cs < CMC

Kunimer represents the attraction of unimer with the solute which is very negligible. So from the relation above solubilisation of the compound is approximately 1. That means there is no noticeable change in the gradient of the line of solubilisation. At first for the introduction of surfactant the unimers take place on the surface of water and create a partition in the interface between water and hydrophobic parts of the surfactant. The hydrophilic PEO units are attracted to the water molecule by creating an ice like structure keeping the hydrophobic parts away from the interface. This helps to decrease the free energy of the system. As the concentration of the surfactant increases below CMC, the surfactant unimers go to the interface to reduce the free energy of the system.

Table 1: Results of peak area, concentration% and enhanced solubilisation ratio s'/s of indomethacin in relation with P103 concentration in mmol/dm3 in the aqueous solution.

P103 Concentration mmol/dm3

Peaks Area

Indomethacin

Concentration %

Solubilisation

s'/s

0

283172

0.006731

1

1

307926

0.007367

1.094

1.5

686017

0.017067

2.535

1.75

771002

0.019248

2.859

2

868642

0.021753

3.232

2.5

1104784

0.027812

4.132

3

1349357

0.034087

5.064

3.25

1413317

0.035728

5.308

Figure 5: Peak area for indomethacin as a function of P103 surfactant concentration in mmol/dm3 and the red dots represents the experimental data.

When the surfactant concentration reaches CMC at 1mmol/dm-3 a sharp change in the solubilisation gradient is observed in the graph. There are no more unimers attached with the surface of water instead they start to attract each other by the interaction of hydrophobic parts. As a result they start to aggregate to form micelles with their hydrophobic parts in the core surrounding the hydrophobic indomethacin. The formation of core leads to bonding of the hydrophilic PEO parts with water molecules to form an ice like structure. This phenomenon of micelle formation helps to reduce the free energy of the system. Actually CMC is the concentration of the surfactant while it is in the bulk of the system. Surfactants divide into bulk and interface while CMC represents the concentration of the surfactant in the bulk. As normally the concentration of surfactant in interface is negligible, the CMC represents the concentration of the surfactant in the system.

Figure 6: Concentration% of indomethacin as a function of P103 surfactant concentration in mmol/dm3 and the blue dots represents the experimental data.

When the surfactant concentration increases above CMC, the apparent solubility of indomethacin also increases dramatically. The gradient of the partition coefficient or solubilisation line maintains a trend of continuous enhancement with the increase of the concentration of surfactant. This illustrates the fact that for the increase of surfactant concentration above CMC there is a continuous rise in the rate of micelle formation surrounding the solute to obtain the favourable free energy change in the system. More the surfactant added to the solution more the affinity between the solute and the miceller aggregates and more the enhancement of apparent solubility of the indomethacin drug in the aqueous solution. We can demonstrate this solubility enhancement above CMC with the relation

where Cs

In comparison to the attraction between the micelle and the solute, the attraction of unimer with the solute is very negligible. Using this relation it can easily be understood that above CMC the solubilisation is mainly dependent on the formation of micelle surrounding indomethacin and there is a good linear relationship is maintained between the concentration of polymer and the solubility of indomethacin above CMC.

In the whole experiment saturated solutions were used for the measurement of solubility. As the experiment was carried out at room temperature there was no effect assured for the change in the temperature. We can assume that the concentration-absorption relationship obeyed the Beer-Lambert law for the absorbance.

3.2 Solubilisation for polymer with sugar additives

For adding sucrose in the aqueous solution of Poloxamer P103, we have observed a remarkable increase in the solubilisation of indomethacin. For 1 mmol/dm3 of polymer sucrose solution the solubilisation enhancement is 3.139-1.261=1.878 from using only the poloxamer solution.

Figure 7: Indomethacin solubility enhancement ratio (s'/s) as a function of P103 surfactant concentration in mmol/dm3 in molar solution of sucrose and the blue dots represents the experimental data.

Figure 8: Peak area for indomethacin as a function of P103 surfactant concentration in molar solution of sucrose and the red dots represents the experimental data.

Figure 9: Concentration% of indomethacin as a function of P103 surfactant concentration in mmol/dm3 in molar solution of sucrose and the blue dots represents the experimental data.

Table 2: Results of peak area, concentration% and enhanced solubilisation ratio s'/s of indomethacin in relation with P103 concentration in mmol/dm3 in the molar solution of sucrose.

Sol mmol/dm3

Peak Area

Indomethacin Con %

Solubilisation

1

844321

0.021129

3.139

1.25

989474

0.024853

3.692

1.5

1301471

0.032858

4.882

1.75

1403820

0.035484

5.272

2

1564158

0.039598

5.883

2.25

1755001

0.044494

6.61

The solubilisation graph illustrates a linear relation with the increase in the concentration of Poloxamer solution which indicates superior enhancement of solubility of drug compound in the aqueous solution. This could be the result of the formation of enhanced water matrix with the hydrophilic parts of the polymer which helps to further reduce the free energy and form strong hydrogen bond with the water molecules. The carbohydrate molecules can avoid the formation of iceberg around the hydrophobic parts of the polymer which need to come closer to form micelle.

3.3 Calibration curve

The results of peak area for calibration curve were not observed to be in quite a straight line. So for reducing errors, the square of R which is the correlation co-efficient of linear regression equation was measured using the Microsoft Excel and used to find the slope and intercept of calibration curve. By using this calibration curve the concentration of different unknown solutions of Poloxamer were measured quite precisely and used in the experiment.

Table 3: Results of peak area for different standard concentrations of indomethacin in mobile phase solution and corresponding slope and intercept for the calibration curve.

Concentration

Peak Area

0.0032

123935

0.005

170815

0.01

468291

0.02

854947

0.03

1144204

 

 

Slope

38975544

Intercept

20811.97

Figure 10: Peak area for indomethacin as a function of known concentration% in the aqueous solution of sucrose and the blue dots represents the experimental data.

3.4 HPLC measurement

HPLC-UV measures a very small concentration of a solution. So the weighing of Poloxamer P103 gel was carried out slowly and carefully. The solutions were well shaken and kept still after shaking to make sure they were homogenous and no bubbles could present in any part of the experiment. For every concentration more than one chromatogram were taken and the average of the results were plotted in the graph. There was no dilution carried out in the polymer solutions because there could be a delay in the micelle deformation which would results in wrong solubilisation in the HPLC [11]. There were differences observed in the HPLC chromatograms for the same concentration of solution may be for the high sensitivity to minute concentration differences.

4. Conclusion

The critical requirement of improving the bioavailability of many poor water soluble drugs like indomethacin can be successfully achieved using Poloxamer P103 as a drug carrier system. It has certainly displayed a comprehensible enhancement in the solubilisation property of indomethacin with the increase in the concentration of polymer. This commercially available Polymer has shown very low toxicity and is approved by Food and Drug Administration which make it more attractive. One of the problem could be associated with the use, is the dissociation of micelle when the concentration of surfactant reaches below CMC in biological environment. This can be resolved by using direct radical cross linking of a reactive monomer in the miceller cores [27] or using additives like sugar which helps to reduce the CMC and increase solubility. Using sugar as an additive can decrease the probability of dissociation of micelles in dilution and maintain an excellent balance between the carrying the drug with stability and releasing the drug effectively to the site of action.

5. Future Aspects

In pharmaceutical science, this impressive solubilisation enhancement of the drug using copolymer P103 can play an important role. The solubilisation of drugs using many other procedures can be compared with this copolymer. There can be some researches carried out to examine more thermodynamic characteristics of Poloxamer that would provide more effective ways to use it as drug carrier system and to remove any deficiencies. Using sugar for enhancing the solubilisation capability can be tested for compatibility and any toxicity issues. Some other additives like salts of sodium chloride can be tried to enhance the properties of the polymer. Pluronic P103 can be used with many other drugs like protein drugs as an effective carrier system to enhance their adsorption and stability. The most important has to do with the low stability of the self-assembled polymers upon dilution in the bloodstream.

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