Hydrotropy: A Promising Tool for Solubility Enhancement

 

G. Kalyani1, P. Bhuvaneswari1, B. Hemalatha*1, K. Padmalatha2

1Department of Pharmaceutics, Vijaya Institute of Pharmaceutical Sciences for Women, Vijayawada.

2Department of Pharmacology, Vijaya Institute of Pharmaceutical Sciences for Women, Vijayawada.

*Corresponding Author E-mail:

 

ABSTRACT:

Solubility is one of the key parameters to attain desired concentration of drug in systemic circulation to show pharmacological response. Various methods are engaged to augment the aqueous solubility of poorly water-soluble drugs and hydrotropic solubilisation is one of them. Hydrotropy is defined as a solubilization process whereby addition of a large amount of second solutes results in an increase in the aqueous solubility of another solute and chemicals which are used in the hydrotropy are called hydrotropes like sodium benzoate, sodium citrate, urea, niacinamide etc. Based on advantages like the high selectivity, independent of pH and cheap, easy availability makes this technique more prevailing than other solubilisation methods. Mixed hydrotropy is a solubilisation technique to augment the water solubility of poorly water soluble drugs by the way of different ratio of blends of hydrotropic agents which gives synergistic augmentation effect. The purpose of this review article is to illustrate the need for solubility, hydrotropic solubilisation, mechanism of action of hydrotrope, classification of hydrotropes, advantages and mixed hydrotropic technique of solubilisation for improving the solubility which in turn helps to attain absorption and improved bioavailability.

 

KEYWORDS: Hydrotropy, Hydrotropes, solubility, Mixed hydrotropy, Solubilisation.

 

 


1. INTRODUCTION:

The present major problem in the pharmaceutical industry was related to strategies that enhance the aqueous solubility of drugs, as nearly 40% of the recently discovered drug candidates experience from poor aqueous solubility. Solubility is one of the key characters to achieve required pharmacological response. Therapeutic effectiveness of a drug relies upon the bioavailability and eventually was attributed to solubility of drug moiety1. Currently, various formulation technologies were existing to augment solubility and dissolution profile to boost oral bioavailability. In addition to these technologies, ʻhydrotropyʼ was one of the familiar methods accessible for resolving solubility problems2.

 

1.1 Need of solubility:

About 40% of novel chemical entities upcoming from discovery were inadequately bioavailable. Poor bioavailability applies strong limits to the performance of a drug by the requirement to administer a much upper dose than strictly required from a pharmacologic viewpoint3. This could provoke important side effects otherwise generate troubles related to the cost of treatment. Poor bioavailability might as well obligate the formulator to opt the injection route rather than the oral route. For superior oral bioavailability drug should be soluble in gastro-intestinal fluids i.e., aqueous soluble as well as possess permeability properties for good membrane diffusion in turn to arrive at the bloodstream 4. The crucial plan of the further formulation and development section was to formulate that drug obtainable at appropriate site of action within optimum dose5. Hydrotropic agents had been found to be efficient to augment aqueous solubility of numerous hydrophobic drugs and thus can play important role in getting improved oral bioavailability6.

 

1.2 Expressing Solubility and Concentration:

The Solubility was typically expressed by variety of concentration that was by Quantity per quantity, Percentage, Parts, Molarity, Molality, Mole fraction, Milliequivalents and normal solutions 7. This will as well provide details in term of parts of solvent needed for 1 part of solute as made cleared in U. S pharmacopeia which was shown in Table 1.

 

Table 1: Expression for approximate solubility

Descriptive terms

Relative amounts of solvents to dissolve 1 part of solute

Very soluble

Less than 1

Freely soluble

From 1 - 10

Soluble

From 10 - 30

Sparingly soluble

From 30 – 100

Slightly soluble

From 100 – 1000

Very slightly soluble

From 1000 – 10000

Insoluble or practically insoluble

More than 10,000

 

Descriptive terms:

Wide-ranging parameters affecting solubility were particle size, shape along with surface area, physicochemical properties of drugs, and physical forms of drugs, solvents, pH of the medium, temperature as well as use of surfactants. The pharmacopoeia lists solubility in terms of dissolve 1g of solute8. If accurate solubilities were not identified, the pharmacopoeia gives common terms to depict a specified range. These descriptive terms were listed in Table 1.

 

1.3 Mechanism of solubility:

The term ‘solubility’ was defined as maximum quantity of solute that can be dissolved in a given quantity of solvent. It can as well be described quantitatively as well as qualitatively. Quantitatively it was defined as the concentration of the solute in a saturated solution at a certain temperature. In qualitative terms, solubility might be defined as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion. A saturated solution was one in which the solute was in equilibrium with the solvent9.

 

1.4 Process of solubilisation:

The process of solubilisation entails the breaking of inter-ionic or intermolecular bonds in the solute, the separation of the molecules of the solvent to give space in the solvent for the solute, interaction linking the solvent and the solute molecule or ion10.

 

Figure No - 1: Process of Solubilisation

 

2. Hydrotropy and hydrotropic agents:

The term hydrotropic agent was foremost introduced by Neuberg (1916) to designate anionic organic salts which, at elevated concentrations amplify the aqueous solubility of poorly soluble solutes. Hydrotropy was a solubilization phenomenon whereby addition of huge quantity of second solute results in an increase in the aqueous solubility of another solute11. However, the term had been used in the literature to assign non-micelle-forming substances, either liquids or solids, organic or inorganic, able of solubilising insoluble compounds12.

 

A. Mechanism of action of hydrotrope:

The chemical structure of the conventional Neuberg’s hydrotropic salts (proto-type, sodium benzoate) consists normally of two vital parts, an anionic group along with a hydrophobic aromatic ring or ring system. The anionic group was involved in bringing about elevated aqueous solubility, which is a prerequisite for a hydrotropic substance13. The kind of anion or metal ion have a minor effect on the phenomenon. On the other hand, planarity of the hydrophobic part had been highlighted as a significant factor in the mechanism of hydrotropic solubilization. Solute consists of alkali metal salts of a variety of organic acids14. Hydrotropes have both hydrophobic and hydrophilic fractions in them. In comparison to surfactant, they have a very little hydrophobic fraction. The effectiveness of hydrotrope solubilization depends on the balance linking hydrophobic plus hydrophilic part of hydrotrope. The larger is the hydrophobic part of an additive, the better is the hydrotropic efficiency; the presence of the charge on the hydrophilic part is less significant15. Hydrotropic agents can be anionic, cationic or neutral, organic or inorganic and liquids or solids in nature. These were freely soluble organic compounds which augment the aqueous solubility of organic substances by forming stack-type aggregation16.

 

Figure No - 2: Structure of a Hydrotropic Agent

 

Hydrotropic agents were ionic organic salts. Additives or salts that augment solubility in given solvent were said to “salt in” the solute and those salts that reduce solubility “salt out” the solute. Numerous salts with large anions or cations that are themselves very soluble in water outcome in “salting in” of non electrolytes called “hydrotropic salts” a phenomenon known as “hydrotropism”. Hydrotropic solutions do not show colloidal properties as well as engage a weak interaction between the hydrotropic agent and solute17. A hydrotropic molecule interacts with a less water-soluble molecule via weak vander Waals interactions such as π–π or attractive dipole–dipole interaction18. The mechanism involved in hydrotropy is related to complexation which engages interaction between lipophilic drugs and the hydrotropic agents for instance urea, nicotinamide, sodium alginate, sodium benzoate etc19.

 

B. Self-association of hydrotropes:

Minimum hydrotropic concentration (MHC), is a critical concentration at which hydrotrope molecules start to aggregate, i.e. self-aggregation potential. Solubilization power of hydrotropes was governed by their self-aggregation potential20. This potential depends upon their amphiphilic features and the nature of the solute molecule. Hydrotropes strongly interact with the solute to generate the complexes and these complexes would then lead to higher aqueous solubility21.

 

C. Classification of hydrotropes18:

Table 2: Classification of Hydrotropes

Category

Examples

Aromatic anionics

Sodium benzoate

Sodium salicylate

Sodium benzene sulphonate

Sodium benzene disulphonate

Sodium cinnamate

Sodium 3-hydroxy-2-naphthoate

Sodium para toluene sulphonate

Sodium cumene sulphonate

Aromatic cationics

Para amino benzoic acid hydrochloride

Procaine hydrochloride

Caffeine

Aliphatics and linear anionics

Sodium alkanoate

 

D. Characteristics of hydrotropes17:

1.   Completely soluble in water and practically insoluble in system.

2.   Hydrotropes are surface active and aggregate in aqueous solution because of their amphiphilic structure.

3.   Must not generate any temperature when dissolved in water.

4.   Cheap plus easy availability14.

5.   Non toxic as well as non reactive15.

6.   Insensitive to temperature effects, when dissolved in water.

7.   The solvent character being independent of pH, high selectivity, as well as the absence of emulsification were the other distinctive advantages of hydrotropes 18.

 

E. Advantages of hydrotropic solubilisation19:

1.   This process does not require emulsification, highly selective and solvent character was independent of pH. Thus it was preferred over other solubilisation methods such as cosolvency, micellar solubilisation.

2.   It mainly involves the mixing of hydrotrope and drug directly into solvent which is water.

3.   It does not need chemical alteration of hydrophobic drugs, employ organic solvents, or preparation of emulsion system12.

 

Hydrotropes had the capability to amplify the solubility of poorly water soluble drug moreover this tendency was greatest when concentration of hydrotropes was sufficient to form the associated structures. Minimum hydrotrope concentration was referred to concentration of hydrotrope at which self association occurs. 

 

F. Hydrotropes as coupling agents:

Hydrotropes were well known as 'coupling agents’; Stig E Friberg said that the addition of hydrotropes in to a turbid liquid with relatively high water content causes the liquid to become transparent. The traditional explanation has been that the hydrotrope molecule acts as a 'coupling agent'; it serves as a link between the nonpolar and polar spaces in the liquid21.

 

G. Difference between hydrotropy and other cosolvency methods:

Hydrotropy was different from simple phase mixing, or the cosolvency process, and also from salting-in action. While the self-aggregation phenomenon of hydrotropes is reminiscent of surfactant self assemblies, there were significant differences. Solubilization of hydrotropes was characterized by the relatively elevated concentrations of the hydrotrope required and the larger amounts of solute solubilised, compared with that in micellised surfactants. Further, hydrotropes often exhibit selective ability to solubilise guest molecules than micellised surfactants22. Surfactants have long hydrocarbon chains, whereas, hydrotropes were characterized by a short, bulky hydrocarbon groups. The aggregation numbers found in the case of hydrotrope aggregates was lesser compared to those originated in the case of micelles. Hydrotropes have a tendency to form loose aggregates while long chain surfactants tend to form micelles by comparing the aggregation behaviors of two linear alkyl benzene sulfonates.

 

H. Selection of hydrotropes for poorly water-soluble drugs:

It is manifested from the literature survey that more is the concentration of hydrotrope; more is the aqueous solubility of poorly water-soluble drugs. Hence greatly concentrated solutions of hydrotropic agents were utilized in the present investigations. Distilled water was used in preparing hydrotropic solutions23.

 

2 M niacinamide (2 M NM), 2 M sodium benzoate (2 M SB), 2 M sodium salicylate (2 M SS), 10 M urea (10 M UR), 4 M sodium acetate (4 M SA) and 1.25 M sodium citrate (1.25 M SC) were employed as hydrotropic solutions. In order to choose appropriate hydrotropes (for sufficient enhancement in solubility) for various poorly water soluble drugs, following method (an approximate solubility determination method) was used. Twenty five ml of distilled water/hydrotropic solution was taken in a 50 ml glass bottle and gross weight (including the cap) was noted. Then, few mg (by visual observation) of fine powder of drug was transferred to the bottle. The bottle was shaken vigorously (by hand). When drug got dissolved, more drugs (few mg by visual observation) were transferred to the bottle and again the bottle was shaken vigorously. Same operation was repeated till some excess drug remained undissolved (after constant vigorous shaking for 10 minutes).

 

Table 3: Hydrotropic solubilisation study of various poorly soluble drugs

Drug

Hydrotropic agent

Cefprozil

Potassium acetate, Potassium citrate, Sodium acetate, Sodium citrate, Urea

Hydrochlorothiazide

Sodium acetate, Urea

Paracetamol, Diclofenac sodium

Urea

Theophylline

Sodium salicylate

Salicylic acid

Ibuprofen sodium, sodium salicylate

Furesamide

Ibuprofen sodium

Chlorpropamide, Gatifloxacin

Ibuprofen sodium

Nifedipine

Sodium Salicylate

Ketoprofen

Urea, Sodium citrate

 

After that again gross weight was noted. From the difference in two readings (of weight), an approximate solubility was determined and solubility enhancement ratios (solubility in hydrotropic solution/solubility in distilled water) were calculated for all selected drugs for all six hydrotropic solutions. When the determined solubility enhancement ratio was at least 5, such hydrotropic solution was selected for that drug23.

 

I. Methods to measure the solubility:

To determine solubility of solids in liquids following two steps are used.

 

1) Preparation of saturated solution:

Solubility indicates the maximum amount of a substance that can be dissolved in a solvent at a specified temperature. Such a solution was known as saturated. Solubility is measured either in grams per 100g of solvent (g/100g) or number of moles per 1 L of the solution.

 

2) Analysis of saturated solution:

Once the saturated solution was ready its analysis was carried out to verify the solubility. It depends upon the nature of the solute as well as correctness of the method employed24.

Following methods are used for analysis.

a)   Evaporation method

b)   Volumetric method

c)   Gravimetric method

d)   Instrumental method

 

J. Determination of interference of hydrotropic agents in the spectrophotometric estimation of drugs:

A UV-Visible recording spectrophotometer with 1cm matched silica cells was engaged for spectrophotometric determinations. For determination of interference of hydrotropic agents in the spectrophotometric estimation of the standard solutions of drugs were determined in distilled water alone as well as in the presence of the maximum concentration of the hydrotropic agent used for spectrophotometric analysis. The absorbances were recorded against respective reagent blanks at appropriate wavelengths. Titrimetric analysis method employed for determining equilibrium solubility at room temperature. Enhancement ratios in solubilities were determined by following formula.

 

Enhancement ratio = Solubility in hydrotropic solution ÷ Solubility in distilled water

 

3. Mixed Hydrotropy25:

It is a solubilisation technique to augment the water solubility of poorly water soluble drugs by means of different ratio of blends of hydrotropic agents which gives synergistic augmentation effect. The major advantage of this technique is that it decreases the concentration of individual hydrotropic agents which directly lessens the side effects of individual hydrotropic agent (in place of using a large concentration of one hydrotrope a blend of, say, 5 hydrotropes can be employed in 1/5th concentrations reducing their individual toxicities.

 

3.1 Advantages of mixed hydrotropic solubilisation:

1.   It may perhaps lessen the huge total concentration of hydrotropic agents essential to produce modest enhance in solubility by employing combination of agents in lower concentration.

2.   It is novel, simple, cost-effective, safe, accurate, precise and environmental friendly method for the analysis (titrimetric and spectrophotometric) of poorly water-soluble drugs precluding the use of organic solvents26.

3.   It precludes the use of organic solvents and therefore avoids the difficulty of residual toxicity, error owing to volatility, pollution, cost etc.

 

4. CONCLUSION:

By means of this study we could conclude that, Solubility was the most vital physical characteristic of a drug for its oral bioavailability, formulation development of different dosage form of different drugs and for quantitative analysis. Solubility can be improved by many techniques among them hydrotropy is of very much significance. Hydrotropy was defined as a solubilisation process whereby adding up of a large amount of second solute consequences in an augment in the aqueous solubility of another solute and the chemicals which were used in hydrotropy were called hydrotropes. For example sodium benzoate, urea, sodium salicylate and ibuprofen sodium etc. In current situation this method was getting lot of values and may be proved the most excellent method in future.

 

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Received on 16.09.2021         Modified on 04.12.2021

Accepted on 07.01.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech. 2022; 12(2):146-150.

DOI: 10.52711/2231-5713.2022.00025