INTRODUCTION:

Solubilisation of poorly soluble drugs is encountered as a challenge in screening studies of new chemical entities as well as its formulation development is obstacle. A number of methodologies can be adapted to improve solubility of poor water soluble drug and its bioavailability. Orally administered drugs undergo complete absorption only drug shows excellent solubility in gastric environment and ultimately shows better bioavailability if drug belong to BCS class II. Bioavailability is dependent on several factors, aqueous drug solubility and drug permeability across the biological membranes.

For BCS class III drugs permeability is the rate limiting step for the absorption and has limited bioavailability. Solubilized drug molecules only can be absorbed by the cellular membranes to subsequently reach the site of drug action (vascular system for instance). The drug must be present in the form of an aqueous solution at the site of absorption. Therefore drug solubility and its oral bioavailability remains one of most challenging aspects of drug development process. The solubility issue may lead to poor in vivo and in vitro characteristics and difficult to achieve predictable and reproducible in vivo/in vitro correlations because of solubility issues. There are numerous approaches available in literature to enhance the solubility of poorly water soluble drugs. The techniques are selected on the basis of certain aspects such as physicochemical properties of drug, excipients to be used and type of dosage form need to be developed. The generally used techniques for solubilisation of drug include chemical modification, pH adjustment, solid dispersion, complexation, co-solvency, micellar solubilisation, hydrotropy etc. Pharmaceutical analysis utilized hydrotropy technique to increase the water solubility of poorly water soluble drug molecule to preclude the use of organic and costlier solvent¹.

Solubility:

The term solubility is defined amount of solute that can be dissolved in a given solvent. Solubilization process occurs into three steps.

1. Breaking of inter ionic or inter molecular bonds in the solute.

2. Separation of solute molecule to provide space for the solute.

3. Interaction between the solvent & solute molecule or ions.

HYDROTROPY:

In 1916, Carl A. Neuberg coined the word ‘hydrotropy’. Hydrotropes possess the ability to increase the solubility of sparingly soluble and poorly soluble drugs in water.

It is a molecular phenomenon, adding a second solute (i.e. hydrotrope) helps to increase the aqueous solubility of poorly soluble drug. The presence of a excess quantity of one solute enhances the solubility of another solute^3,4.

Hydrotropic agents as ionic organic salts which has capacity to increase or decrease the solubility of solute in a given solvent through ‘salt in’ or ‘salt out’ effects, respectively. Salts which show ‘salt in effect’ of non electrolytes is called “hydrotropic salts” and the phenomenon is known as “hydrotropism”. They do not exhibit any colloidal properties but they improve solubility by forming weak interaction with solute molecules. A hydrotropic molecule interacts with a less water-soluble molecule as weak van der Waals interactions as π–π or dipole– dipole interaction.

Fig. 1: The structure of a hydrotropic agent

Hydrotropes are ampihilic in nature contains both hydrophobic and hydrophilic moieties. They contain a very small hydrophobic fraction. Generally larger is the hydrophobic part of an additive the better is the hydrotropic efficiency. Hydrotropic agents can be anionic, cationic or neutral, organic or inorganic & liquids or solids in nature (Fig. 2). Hydrotropic agents are freely soluble in organic solvents, which improve the aqueous solubility of organic substances by forming stack-type aggregation.

Mechanism of Hydrotropic solubilisation:

The enhancement of solubility by hydrotrope is based on the self-association of hydrotrope and the association of hydrotropes with solute. Various hypothetical and investigational efforts are being made to clarifying the mechanisms of hydrotrope.

The available proposed mechanisms can be abridged according to four designs:

a) It is also called as stacking. Self association of hydrotropes forms aggregates. It also attracts with the solute molecules inside the aqueous phase. So as concentration of hydrotropic agent increases, it results in increase in solubility.

b) Solute and hydrotropes interacts with each other and that formed complex shows higher aqueous solubility.

c) Intermolecular hydrogen-bonding changes the structure of the solvent. Hydrogen bonding results in altered solubility for the solute.

d) Hydrotropes act as a bridge to increase the solubility by accumulating around the hydrophobic solute but it is without interaction. Solubility is increased due to decrease in Gibbs energy^5,6.

Mixed Hydrotropy:

Mixed hydrotropy is a synergistic effect of a hydrotropic agent. An enhancement in solubility of a poorly water-soluble drug was observed by mixing two hydrotropic agents. Maheshwari et al and Jain et al was used in urea, sodium citrate & other mixture of hydrotropic agents to solubilize a poorly water soluble drugs. They reported the solvent system to carryout spectrophotometric analysis excluding the use of organic solvents.

Advantages of Hydrotropic solubilisation Techniques

1) It excludes the use of organic solvents, thus avoids the problem of residual solvent toxicity.

2) It is new, simple, cost effective, safe and environmental friendly method for the analysis (titrimetric and spectrophotometric analysis) of poorly water soluble drugs.

3) It only requires mixing of the drug and the hydrotrope in water.

4) Hydrotropy is superior in comparison to other solubilization method. The solubility is independent of pH. Hydrotrophy does not require emulsification.

5) It does not require chemical modification for lipohilic drugs.

6) Mixed hydrotropy has capacity to reduce the large concentration of hydrotropic agents need to produce increase in the solubility. The mixed hydrotrophy requires lower concentration of hydrotropic agents.

Pharmaceutical Applications of Hydrotropic Agents:

1) Quantitative estimations of poorly water-soluble drugs by using UV-Visible spectrophotometric analysis. It excludes the use of organic solvents.

2) Quantitative estimations of poorly water-soluble drugs by using titrimetric analysis.

3) Preparation of hydrotropic solid dispersion method of poorly water-soluble drugs.

4) Preparation of dry syrups for reconstitution for poorly water soluble drugs.

5) Preparation of injections as well as topical preparations of poorly water soluble drugs.

6) Hydrotropic solubilizers are also used as permeability enhancers.

7) The hydrotropy to give fast release of poorly water-soluble drugs use of suppositories.

8) The hydrotropic techniques are used in nanotechnology (by controlled precipitation).

9) The hydrotropic solubilization is also useful in extraction of active constituents from crude drugs.

Following table gives the highlights for the various studies carried out by various researchers for the development of analytical methods (Table I) and development of dosage form (Table II) with the outcome.

Table I: Different Hydrotropic Solubilization Studies for Various Poorly Water Soluble Drugs with respect to analytical method development

Drug Used	Hydrotropic Agents used	Outcome	Reference
Metronidazole	urea	Solubility of Metronidazole is increased by using hydrotropic agent as 8M urea. It is used as solvent for UV analytical method development.	Masthannamma S. K., Sravani K., Sridhar T. A., Naik Sankar, B. Siva⁷
Acyclovir	5M Urea solution	The selected wavelength for estimation drug (λmax) at 254 nm. Linearity was observed in the range of 10-100μg/ml	Aher B.O, Jain N.P., Jain U.N., Paithankar A.R., Bagul T.P., and Gaikwad S. S⁸
Tinidazole	8M urea	Developed a method for the estimation of bulk drug using as hydrotropic agent. Tinidazole showed maximum absorbance (λmax) at 318 nm method-A, (λmax) at 314-322 nm in method-B and 268 nm in method-C. At these wavelengths, hydrotropic agent & other tablet excipients did not shows any significant interference in the spectrophotometric assay. The developed methods were found to be linearity in the range of 5-25 μg/ml with correlation coefficients (R) of 0.999, 0.991 and 0.999^9.	M Masthannamma S. K., T. Ananta sridhar., B. Siva sankar naik.,T. Anil kumar⁹.
Etravirine	citric acid, sodium salicylate and sodium benzoate	The maximum absorbance (λmax) of Etravirine in hydrotropic agent was found at 259, 277,245nm respectively. Etravirine was found to be linearity in the concentration range of 1-5μg/ml.	Lurdhu Mary K. and Manohar babu S.¹⁰
Gliclazide	urea and sodium acetate	Novel spectrophotometric estimation of bulk drug by using mixed hydrotropic solubilization technique phenomenon using (λmax) at 225 nm. The method was linearity in the range of 2-105μg/ml	Rane J., Thakre V., Bakal R.L., Patil S.¹¹
Atenolol	5M ure	developed a Novel spectrophotometric estimation of bulk drug using hydrotropic solubilizing agent a. The selected wavelength (λmax) was 275 nm. Method was linearity in the range of 200-1000 μg/ml	Aher B.O., Jain N.P, Shinde G.S, Gayke Amol, Jadhav V. K, and Bankar K. A¹²
Fenofibric Acid	2M urea and 1M sodium citrate solution	Developed a UV Spectrophotometric Determination of by Using mixed Hydrotropy. was used as a hydrotropic solubilizing agents. Method-A involves the determination of fenofibric acid by standard absorbance method (λmax) at 299 nm. Method-B and Method-C involves the determination of fenofibric acid by first derivative spectrophotometry and second derivative spectrophotometry resp. The normal spectrum was derivatized to 1^st and 2^nd order derivative spectrum. The Beer’s concentration was found to be taken 5-30 μg/mL; Method-D involves the determination of fenofibric acid by area under curve in the range of (λmax) 275-316 nm.^[	V. Niraimathi, A. Jerad Suresh, A. Alageswaran¹³
Flupirtine Maleate	20 % sodium benzoate and niacinamide used as a mixed hydrotropic solubilizing agents	The UV spectrum of the drug in the range of 200-400nm on UV-visible spectrophotometer revealed that wavelength of maximum absorption (λmax) of Flupirtine was 304 nm. it was observed that the drug obeys beer’s law in the concentration range of 10-50 μg/ml (r= 0.999) at 304 nm.^[]	Shukla T, Neeraj Upmanyu , Pandey S. P., Yadav¹⁴
Telmisartan	Urea 20 M, Sodium Benzoate 2 M	The study showed that the solubility of Telmisartan is significantly enhanced i.e 19 times in Urea and 11 times in Sodium Benzoate. The standard calibration curves obeys Beer-Lambert’s law and linearity with concentration range of 5 - 20 μg/ml. Analysis of marketed tablets was found well within specified official label claim, (100.53% - 102.95%) of Telmisartan using both the hydrotropes.	Pal TK, Panda M, Roy C¹⁵
Zaltoprofen		UV spectrophotometric analysis of bulk drug by using mixed hydrotropic solubilizing agent was in the order of 20% Piperazine anhydrous >20% sodium salicylate >20% sodium benzoate > 10%sodium acetate > 10%PEG 600 shows enhancement in solubility are 90 folds and 1875.35 folds. The Beer-Lambert's law was obeyed in the concentration range of 15-75 µg/ml at the λmax of 339 nm. Aqueous solubility of Zaltoprofen was found to be 0.028 mg/ml.	Kate B. A., Phulzalke S. B., Deshmukh M.T.¹⁶
Miconazole	Sodium benzoate, niacinamide and urea	Developed a UV-Spectrophotometric determination of in bulk drug and pharmaceutical dosage form using hydrotropic solubilization technique using are the hydrotropic agents shows enhancement in solubility by 98.87 folds and 101.7 folds. This are increase in aqueous solubility of Miconazole in presence of large concentration of hydrotropes	Anu Kaushik, Jat Rakesh Kumar¹⁷
Lumafantrine	30% Tri sodium citrate dihydrate solution	Developed a UV-Spectrophotometric determination of in bulk drug and pharmaceutical dosage form using hydrotropic solubilization technique. The solubility studies showed that solubility of Lumafantrine was increased greater than 30 folds, when added to. The maximum absorbance (λ_max) of Lumafantrine in hydrotropic agent was found at The maximum absorbance(λ_max) of in hydrotropic agent was found at 332 nm.	Agrawal S. and M. Kasturi¹⁸
Diclofenac sodium	urea, PEG- 200, PEG-400, PEG-4000, PEG-6000 and sodium acetate	drug solubility was found to be enhanced by 2.31, 3.58, 3.80 and 3.90 folds the absorbance of hydrotropic agent at (λ_max) 276 nm and obeys Beer's Law in concentration range of 10-60 µg/ml^.	Khan Masheer A. Chourasia A¹⁹.
Telmisartan	Urea, PEG 4000 PEG 6000	UV-Spectrophotometric determination of in bulk drug and pharmaceutical dosage form using mixed hydrotropic solubilization technique. The mixed hydrotropic solution BD (shows 15737 folds improved solubility with wavelength of maximum absorption (λmax) of drug, 230 nm	Phulzalke S.B, Kate B.A, Bagade M. Y²⁰
Piroxicam	1.5 M Ibuprofen Sodium	Piroxicam solubility is significantly enahanced by using 1.5 M Ibuprofen Sodium as hydrotropic solution. The made standard solutions of Piroxicam follows Beerۥs law in the concentration range of 5-35 μg/ml.	Maheshwari RK, Prasad S, Pandey P, Wanare G²¹
Furosemide	40% urea, 40% sodium citrate, 40% sodium acetate, 40% sodium benzoate	Developed Aqueous Injection of Poorly Soluble Drug Using Mixed Hydrotropic Solubilization technique. The enhancement in the solubility of was carried out in distilled water, hydrotropic solutions. The aqueous solubility of furosemide was increased more than 488.42 times in hydrotropic blend BUCA2, 329. 16 times in hydrotropic blend BUCA3 and up to 200.46 fold in 40% sodium benzoate solution, 14.81 fold in 40% urea solution, 11.85 fold in 40% sodium citrate solution and 9.35 fold in 40% sodium acetate solution	Maheshwari R.K., Jawade S., Fouzdar A²²
Glipizide	tri-sodium citrate and urea solution	Developed a UV-Spectrophotometric determination of in bulk drug and pharmaceutical dosage form using hydrotropic solubilization technique. Solubility of Glipizide is increased by using as a hydrotropic agent. There was more than 28fold solubility enhanced in hydrotropic solution as compare with distilled water. The Glipizide shows the maximum absorbance(λmax) at 274.5 nm and linearity in the range of 5-40 μg/ml with correlation coefficient (r2) of 0.999	Patil C. D., Matore B. V. and Dhekale P. S.²³
Lurasidone hydrochloride	nicotinamide, sodium citrate, urea and sodium benzoate at concentration of 10, 20, 30, 40% w/v	The results indicate no changes in the wavelength of maximum absorbance (λ_max) of LRD in any of the solution and it was concluded there were no drug-hydrotrope interference.	Madan Jyotsana R., Pawar kiran T²⁴.

Table II Different Hydrotropic Solubilization Studies for Various Poorly Water Soluble Drugs with respect to formulation development

Drug	Hydrotropic Agents used	Outcome	Reference
Nevirapine	lactose, urea, citric acid and mannitol	All hydrotropes showed enhanced solubility for Nevirapine. The highest solubility was observed with lactose and citric acid at ration of 15:25. The solid dispersion was prepared by using solvent technique. No interaction between drug and hydrotrope, it is proved by XRD, DSC and FTIR studies.	Madan J. R., Kamate V. J., Dua K., Awasthi R.²⁵
Gatifloxacin	1.5 M metformin hydrochloride and 2.0 M sodium benzoate	Both hydrotropes showed improved aqueous solubility for gatifloxacin.	R.K. Maheshwari, h.m. Gupta, m. Singh, u. Ramchandani and s. p. Pandey²⁶.
Norfloxacin	Urea, Sodium Benzoate and Niacinamide	The norfloxacin loaded solid dispersions were prepared by a solvent evaporation technique using urea, sodium benzoate and a niacinamide hydrotropic mixture. The superior dissolution rate due to its reduced particle size may have contributed to the increased oral bioavailability. This study demonstrated that mixed-solvency may be alternative approaches for poorly soluble drugs to improve their solubility and oral bioavailability	Ravindra Kamblea, Sumeet Sharmaa, Piyush Mehtab²⁷
Aceclofenac	urea and sodium citrate and blends (urea + sodium citrate)	Aqueous injection of aceclofenac, using the mixed hydrotropic solubilization technique, was prepared with lyophilization process; The mixed hydrotropic solution containing ≥ 20% urea and 10% sodium citrate showed better solubility as compared to aceclofenac solubility in distilled water.	Rajesh Kumar Maheshwari and Arpna Indurkhya²⁸
carbamazepine	urea and nicotinamide	Both hydrotropes showed significant improvement in carbamazepine solubility (30-fold).	Avital Beig, David Lindley, Jonathan M. Miller, Riad Agbaria and Arik Dahan²⁹.
Ofloxacin	Lignocaine Hydrochloride, Niacinamide, Sodium benzoate, Sodium citrate,	Ofloxacin injection was developed using solubilizing agent like Lignocaine Hydrochloride, Niacinamide, Sodium benzoate, Sodium citrate. For synergistic enhancement of solubility various blends of solubilizers were tried to decrease the amounts of hydrotrope used. The study further extended for preparing dry powders for injection.	Pawar Prashant, Rawat S S, Mahajan YY, Galgatte UC, Maheshwari R K³⁰
Candesartan Cilexetil	urea, sodium acetate, sodium benzoate and sodium citrate at concentration of 10, 20, 30 and 40% w/v solutions	Significant enhancement in solubility was achieved with solutions containing sodium acetate, sodium benzoate, sodium citrate. This optimized combination was used for the preparation of solid dispersions by solvent evaporation technique with distilled water as solvent.	Jaya Singh, S. K. Umadevi, Sai Vardhan, Manisha Lachoriya, G. Rajeswari, B. Kasturibai³¹
Piroxicam	Sodium acetate, sodium benzoate and ascorbic acid	To enhance the aqueous solubility of poorly soluble drug Piroxicam by using hydrotropic solubilization technique. The hydrotrope in which drug showed highest solubility was further used to prepare mouth dissolving tablets, resulted in enhanced solubility and ultimately improves bioavailability.	Akhil sharma ³²
Gliclazide	Sodium Salicylate, Nicotinamide, Lactose, Sodium Acetate, Urea, Trisodium Citrate and Sodium Benzoate	Highest solubility was obtained with sodium salicylate and sodium benzoate at a ratio of 25:15. Using same ratio solid dispersions were prepared and formulated as Mouth dissolving tablet.	Jyotsana R. Madan, Virendra J. Kamate, Rajendra Awasthi and Kamal Dua³³

CONCLUSION:

Various organic solvents are used for the development of analytical methods for poorly water soluble drugs. The major drawback of such solvents is cost, toxicity and environmental hazards. To overcome these issues less costly hydrotropic agents have gain wide application for the development of analytical methods for routine analysis of marketed dosage form and developed dosage forms. The mixed hydrotropy approach suggests the minimum amount of the hydrotropic agents as a blend of two or more agents. Such blends results in lesser quantity as that of single hydrotropic agents. Similarly the hydrotropic agents are nowdays widely used to develop dosage forms as solid dispersion, mouth dissolving tablets, injections to improve therapeutic effectiveness and bioavailability for poorly water soluble drugs.

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Received on 28.01.2019 Modified on 21.02.2019

Research J. Pharm. and Tech. 2019; 12(7):3157-3162.

DOI: 10.5958/0974-360X.2019.00532.8