1. INTRODUCTION:

The phenomenon of hydrotropy, i.e., the increase in the solubility of sparingly soluble compounds in aqueous solutions was first reported by Neuberg in 1916^[1]. Hydrotropes are the organic salts (Booth et al., 1949; Balasubramanian et al.,1989; kim et al., 2010^[2-3]. The use of hydrotropes in industrial applications is attractive because of an easy recovery of the solutes from the solution by controlled dilution with water and high selectivity (Goel et al., Bhawsar et al., 2011)^[4]. Solubility do not show any appreciable increase even after the addition of a hydrotrope in the aqueous phase but continued addition of the hydrotrope beyond a certain concentration level called the Minimum Hydrotrope Concentration (MHC) (Jain et al., 2010; Travis et al., 2007) the solubility of petroleum and petrochemical compounds present in the aqueous phase was found to increase significantly (Senthil et al., 2009; Deepak et al., 2008, Gibson et al., Nidhi et al., 2011)^[5-8].

petrochemical compounds could be attributed to the formation of organized assemblies of hydrotrope molecules at critical concentrations (Jayakumar et al., 2013)^[9-12]. This increase is presumably through a self-aggregation process because of their amphiphilic nature and varies with the nature of the petroleum and petrochemical compounds (Maheshwari et al., 2006; Rathore et al., 2013; Niraimathi et al., 2017; Mishra et al., 2013)^[13-15]. The increasing trend is maintained only up to a certain concentration of hydrotrope, beyond which there is no appreciable increase in the solubility of petroleum and petrochemical compounds in the aqueous phase (Behera et al., 2010; Bernard et al., 2013; Chavan et al., 2014; Evstigneev et al., 2007). The concentration of hydrotrope corresponding to this condition is termed as the Maximum Hydrotrope Concentration (C_max)^[16-21].

The characteristics of hydrotropes are surface active, non-toxic and high selectivity (Ferreira et al., 1996; Bhole et al., 2006; Nair et al., 2010; Revathi et al., 2010) ^[22-25]. The advantages of hydrotropy technique are, easy recovery of dissolved solutes, reuse of hydrotrope solution and absence of emulsification problems (Madhusudhan et al., 2000)^[26]. The main property of the hydrotropes is related to the MHC (Minimum Hydrotropic Concentration), which means the concentration at which hydrotrope molecule begins to aggregate, i.e. forming new microenvironments with different properties as those of the hydrotropes in relatively dilute solutions (Saha et al., 2006)^[27-28]. Solubility do not show an appreciable increase even after the addition of hydrotrope in the aqueous phase but on subsequent increase in the concentration of hydrotrope, the solubility of the organic compound present in aqueous phase increases significantly (Arias et al., 1995) ^[29]. The increase in the solubility of organic compounds when present in water could be due to the formation of organized assemblies of hydrotrope molecules at critical concentrations (MHC) (Ezquerra et al., 2006)^[30].

Hydrotropic solutions of sodium salicylate and resorcinol were employed as solubilizing agent to analyze slightly water soluble antibacterial drugs like theophylline by spectrophotometric estimation (Yamanaka et al., 2014)^[31-32]. There was a tremendous increase in the solubility of theophylline in 7.5 M sodium salicylate and 5.5 M resorcinol solutions. Therefore, it was thought worthwhile to solubilize the drug with the help of sodium salicylate and resorcinol solutions to carry out the estimation (Lauerma et al., 1994; Yamanaka et al., 2014)^[33-35].

2. MATERIALS AND METHODS:

All the chemicals used were of analytical grades and are bought from Sisco Research Laboratories Pvt. Ltd., Mumbai, India. Theophylline tablets were purchased from the local market.

2.1 Determination of interference of hydrotropic agent in the spectroscopic estimation of drugs

Shimadzu UV-visible spectrophotometer (Model - UV 1800, λ_max= 274 nm) with 1 cm matched silica cells was used for spectrophotometric analysis. For determination of interference of hydrotropic agents in the spectrophotometric estimation of theophylline, the absorbance of the standard solutions of drug was determined in distilled water and with the maximum concentration of the hydrotropic agent employed in the present investigation for the purpose of spectrophotometric analysis. The absorbance was recorded against respective reagent peaks at the appropriate wavelength.

2.2 Preparation of stock solution of theophylline in distilled water

Theophylline was accurately weighed (50mg) and transferred to a 500mL volumetric flask. Distilled water (450mL) was added and flask was shaken vigorously to dissolve the drug. After complete dissolution of drug, the volume was made up to the mark with distilled water to get 1mg/mL stock solution.

2.3 Preparation of stock solution of theophylline in sodium salicylate solution:

Theophylline was accurately weighed (50mg) and transferred to a 500mL volumetric flask and 100mL of 7.5 M sodium salicylate solution was added and drug was dissolved in this solution. After complete dissolution of drug, due distilled water was used to make up the volume and to get the stock solution of 1mg/mL.

2.4 Preparation of stock solution of theophylline in resorcinol solution:

Theophylline was accurately weighed (50mg) and transferred to a 500mL volumetric flask and 100mL of 5.5 M resorcinol solution was added and drug was dissolved in this solution. After complete dissolution of drug, distilled water in required amount was used to make up the volume and to get the stock solution of 1mg/mL.

2.5 Estimations of drug in distilled water alone and in the presence of hydrotropic:

solubilizing agents:

All the stock solutions were suitably diluted with distilled water to get various standard solutions containing 5, 10, 15, 20, 25, 30 and 35μg/mL of drug. Absorbance value of theophylline solution was noted at 274nm against respective peak. These values of absorbance of standard solutions were used to obtain a regression equation for the estimation of solubility of drugs in distilled water alone and in the presence of sodium salicylate and resorcinol solutions of respective dilutions (Table 1). Calibration curve has been plotted from the absorbance values obtained for the concentration.

The concentration of theophylline in supernatant liquid was analyzed using U-V spectrophotometer (Shimazdu Model: 1800) at 274 nm (Figure -1).

Figure 1: λ_maxgraph for Theophylline pure drug

2.6 Equilibrium solubility determinations at room temperature:

For equilibrium solubility determination at room temperature, the method used by Maheshwari et al. was employed. Enough excess amount of drug was added to screw-capped 30mL glass vials containing distilled water and the solution of a hydrotropic agent separately. The vials were shaken mechanically for 12 hrs at room temperature (28 ± 1ºC) in Orbital Flask Shaker (Remi Laboratory Instruments, Mumbai, India). The solutions were allowed to equilibrate for the next 24 hrs and then centrifuged for 5 minutes at 2000rpm using a centrifuge (Remi Laboratory Instruments, Mumbai, India). The supernatant liquid of each vial was filtered through Whatman’s filter paper # 41.

Filtrates of saturated solutions of drug; Theophylline was analyzed by spectrophotometric analysis, measuring the absorbance of appropriately diluted solutions with distilled water against respective peaks at their appropriate wavelengths. Equilibrium solubility of drug in distilled water and with hyrdrotropic solubilizing agents was determined by interpolation on the calibration curve. Solubilities so determined have been reported in Table 1.

Solubility enhancement ratio was also determined (Table 1) by the following formula.

Enhancement ratio = Solubility of drug in hydrotropic solution/Solubility of drug in distilled water

Table1: Regression equation and equilibrium solubilities of selected drug in distilled water and in sodium salicylate and resorcinol solutions

Drug	Solvent used	Beer’s range (μg/ml)	Temperature (^oC )	Regression equation	R²	Std. Error	Std. Dev.	Solubility 10 ² S, mol/L	SER
Theophylline	Distilled water	5 - 30	28 ± 2°C	y = 4.58 + 0.02 x	0.973	2.189	0.812	4.63	-
	Distilled water + Sodium salicylate	5 - 30	28 ± 2°C	y = 9.744 + 89.55 x	0.949	2.358	0.942	104.231	22.51
	Distilled water	5 - 30	28 ± 2°C	y = 4.58 + 0.02 x	0.973	2.189	0.812	4.63	-
	Distilled water + resorcinol	5 - 30	28 ± 2°C	y = 5.078 + 8.81 x	0.956	3.042	0.936	30.270

SER: Solubility Enhancement Ratio; R²: Regression coefficient

3. RESULTS AND DISCUSSION:

There is a significant enhancement in the aqueous solubility of selected poorly water-soluble drugs have been observed in the presence of large amounts of hydrotropic agents. It was thought worthwhile to make use of hydrotropic solubilization techniques in the development of new spectrophotometric methods for the analysis of poorly water-soluble drugs. Preliminary drug solubility studies of theophylline were determined in distilled water and 7.5 M sodium salicylate solution at 28 ± 1°C. While the solubility enhancement ratio (SER) of theophylline was found to increase by 22.51 times in 7.5 M sodium salicylate solution as compared to the solubility in distilled water, whereas the SER of theophylline was found to increase by 6.53 times in 5.5 M resorcinol solution as compared to the solubility in distilled water. The proposed methods are validated statistically and the corresponding values of the statistical parameters such as standard deviation, standard error and regression coefficient are reported in table 1.

Insight into the mechanism of hydrotropic solubilization and solubilization capacity of hydrotropes can be obtained from the effect of hydrotrope concentration.

4. CONCLUSIONS:

Like theophylline, other poorly water soluble drugs can also be subjected to analysis by using hydrotropic solubilisation method. The hydrotropic solubilization technique can also be used for titrimetric and spectrophotometric estimations of poorly water-soluble drugs from their bulk drug samples and solid dosage forms precluding the use of organic solvents providing simple, economic, eco-friendly, safe (free from toxicity) and accurate analytical methods. The proposed technique would be economical, convenient and safe. The developed formulations would be definitely cheaper when compared to market formulations which use costly additives/excipients. Further, the proposed hydrotropic agents are known to be safe, hence toxicities/safety related issues may not raise concern, suggesting the adaptability for large scale manufacturing i.e. Industrial feasibility.

5. CONFLICT OF INTERESTS:

There are no conflicts of interest.

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Received on 20.12.2019 Modified on 08.02.2020

Research J. Pharm. and Tech. 2021; 14(2):793-796.

DOI: 10.5958/0974-360X.2021.00138.4