An Exhaustive Review on Solubility Enhancement for Hydrophobic Compounds by Possible Applications of Novel Techniques

The combinatorial chemistry and high throughput screening increases the solubility of poorly water soluble compounds. The most challenging task in development of a formulation is the solubility of drug, availability at the site of action and stability of drug. Aqueous solubility of any therapeutically active substance is a key property as it governs dissolution, absorption and thus the in vivo efficacy. Among all newly discovered chemical entities about 40% drugs are lipophilic and these drugs are rejected by the pharmaceutical industry and will never benefit a patient because of its poor bioavailability due to low water solubility and/or cell membrane permeability. Drug efficacy can be severely limited by poor aqueous solubility and some drugs also show side effects due to their poor solubility. Therefore, drug release profiles are exhibited by such formulations for poorly soluble drugs to improve the solubility of such poorly soluble drugs. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption. Water is the solvent of choice for liquid pharmaceutical formulations. Most of drugs which are weakly acidic and basic show poor aqueous solubility hence various methods like, salt formation, co-solvency, micronization, addition of agent, solid dispersion, complexation etc., are some of the vital approaches routinely employed to enhance the solubility of poorly soluble drugs. This article reviews various methods used for improving the solubility of hydrophobic drugs and improve the drug release profiles which are exhibited by such formulations for poorly soluble drugs.

INTRODUCTION

The combinatorial screening programs employed by the pharmaceutical companies identified that about 40% of active New Chemical Entities (NCEs) are poorly water soluble. The two major obstacles in developing a therapeutic agent are Solubility and stability (Seedher and Sharma, 2007). Since 1995, more than 90% of drugs are approved as hydrophobic having poor solubility. A maximum amount of solute dissolved in a given solvent at a specified temperature defined as solubility (Patil et al., 2011). The substance which is to be dissolved is known as solute and the fluid (medium) in which the solute to be dissolve is known as solvent and the process of dissolving solute into solvent is called as solution. Descriptive terms for solubility are shown in (Table 1) (Beringer, 2005).

Table 1:	Solubility definitions (Rodier et al., 2005)

Table 2:	Biopharmaceutical classification system (BCS) (Malpani et al., 2009)

The poorly soluble agent have low water solubility hence they low bioavailability and absorption (Heimbach et al., 2007; Nourani et al., 2008; Vahedi, 2012). There are various techniques and formulations have been employed to overcome these limitations. Although, existing strategies such as complexing drugs by using Cyclodextrins (Vyas et al., 2008; Zhixun et al., 2006; Sangshetti et al., 2008) conjugation to dendrimers (Gupta et al., 2006), salt formation of ionizable drugs (Serajuddin, 2007) and the use of co-solvents (Akers, 2002; Strickley, 2004) have been shown to improve drug solubility. The World Health Organization (WHO) have classified BCS classification on the basis of data as 130 orally administer drug from which according to WHO list 61 could be classified as poorly soluble drug (Al Omari et al., 2009) (Table 2). Biopharmaceutical Classification System (BCS) many drugs belongs to Biopharmaceutics Classification System (BCS) class II (high permeability, low solubility) or IV (Low permeability, Low solubility) (Amidon et al., 1995; Porter and Charman, 2001). For the BCS class II drugs, the oral absorption is limited by the solubility or dissolution in gastrointestinal (GI) tract.

Solubilisation process: The breaking of inter-ionic or intermolecular bonds in the solute occurs mainly in the method of solubilisation. In solubilisation method the solvent provide space for the solute, interaction between solvent and the solute molecule or ion (Fig. 1).

FACTORS AFFECTING SOLUBILITY

Polymorphs: Absorption and bioavailability can also be enhanced by polymorphs as defined as the greater the solubility of the metastable form Blagden et al. (2007) and Ajazuddin et al. (2011). Polymorphs can vary in melting point. Since, the melting point of the solid is related to solubility, the capacity for a substance to crystallize in more than one crystalline form is polymorphism. It is possible that all crystals can crystallize in different forms or polymorphs. If the change from one polymorph to another is reversible, the process is called enantiotropy. If the system is monotropic, there is a transition point above the melting points of both polymorphs. So, polymorphs will have different solubility (Worthen, 2006; Noorizadeh and Farmany, 2011).

Particle size: The solubility of crystalline solids gets affected by particle size it is well describe in the documented (Hammond et al., 2007; Wu and Nancollas, 1998; Mosharraf and Nystrom, 1995).


Fig. 1:	Solubilisation process (Dabbagh and Taghipour, 2007; Sangshetti et al., 2008)

By reducing the particle size, the solubility of crystalline drugs can be increased to submicron levels, but the effect of solubility is trifling if the particle size is not reduced below 10 μm. The effect of particle size on solubility can be described by Chaumeil (1998):

Where:
S	:	The solubility of infinitely large particles
So	:	The solubility of fine particles
V	:	Molar volume
g	:	The surface tension of the solid
γ	:	The radius of the fine particle

Pressures: An increase in pressure increases solubility for gaseous solute. While decreases in pressure for solids and liquid solutes, changes in pressure have practically no effect on its solubility (Ain et al., 2009). There are various approaches to improve the solubility or to increase the available surface area for dissolution. These can be altered or modified by following the methods of Leaner and Dressman (2000).

Temperature: Solubility changes with the temperature. It is demonstrated by Pore and Kuchekar (2011), in solubilisation process energy get absorbs then the temperature will increased and their solubility will increases. If the temperature will increases enhance solubility decrease. A few solid solutes are less soluble in warm solutions (Lindenberg et al., 2004). The solubility of gases deceases with the increasing temperature.

METHOD FOR SOLUBILITY ENHANCEMENT

Physical modifications
Particle size reduction
Micronization: Surface area for dissolution can be increases by Micronization (Kawashima et al., 1975). Micronisation increases the dissolution rate of drug through increased surface area but does not enhanced equilibrium solubility. The increase in bioavailability after micronization of drugs, e.g., by jet or ball milling Example, danazol (Liversidge and Cundy, 1995), progesterone (Hargrove et al., 1989), or dioxin (Jounela et al., 1975).

Nanosuspension: Nanosuspensions are sub-micron colloidal dispersion of pure particles of drug, which are stabilized by the surfactants. (www.expresspharmapulse.com). Nanosuspensions in aqueous or non-aqueous vehicles can be produced by bottom-up (e.g., precipitation) or top-down (e.g., wet milling) processes (Rainbow, 2004; Douroumis and Fahr, 2006). High pressure homogenizers such as the piston gap homogenizer have proved to be a highly successful technology in nanosuspension formation.

Homogenization: Homogenization the required technique is used to reduce the globule size of a coarse emulsion (Amit et al., 2011), globule size is less than 100-200 nm (Davis et al., 1974). Brownian movement prevents creaming because of small globule size which also promotes good physical stability (Floyd, 1999; Chattopadhyay et al., 2011). There are so many method used to improve the dissolution of hydrophobic drugs. High-Pressure Homogenization (HPH) has been mostly used to reduce the particle size (Uchiyama et al., 2011; Grau et al., 2000). For example processing highly concentrated suspensions (Muller et al., 2001) and preparing emulsions (Tian et al., 2007). HPH has lot of advantages over other milling techniques as it is very simple, time saving and an organic solvent-free process. Therefore, HPH can be used to enhance the solubility of hydrophobic drugs such as PLH for which usage of organic solvents is limited (Al-Haj and Rasedee, 2009; Ajazuddin and Saraf, 2010b). This method having some advantages for Production of Solid Lipid Nanoparticles (SLNs) (Bhoyar et al., 2012; Ajazuddin and Saraf, 2010a). The objective of this study was to investigate solid lipid nanoparticles using Carbopol gel as gelling agent containing triamcinolone acetonide acetate (glucocorticoid compound) for transdermal iontophoretic delivery Solid Lipid Nanoparticles (SLN) (Mehnert and Mader, 2001; Muller et al., 2001) have been introduced to the literature as a carrier system for poorly water soluble pharmaceutical drugs (Ugazio et al., 2002; Westesen et al., 1997; Lokhande et al., 2006; Nourani et al., 2008) and cosmetic active ingredients.

Wet milling: Active drug in the presence of surfactant is defragmented by milling (Aulton, 2002). Other technique involves the spraying of a drug solution in a volatile organic solvent into a heated aqueous solution. Rapid solvent evaporation produces drug precipitation in the presence of surfactants.

MODIFICATION OF THE CRYSTAL HABIT (Hite et al., 2003)

Polymorphs: Polymorphism is the ability of compound to crystallize in more than one crystalline form. Different polymorphs of drugs are chemically identical, but they exhibit different physicochemical properties including solubility, melting point, density, texture, stability etc^.Generally, the anhydrous form of drug has greater solubility than the hydrates. This is because the hydrates are already in interaction with water and therefore, have less energy for crystal breakup in comparison to the anhydrites (i.e., thermodynamically higher energy state) for further interaction with water (Hammond et al., 2007; Chattopadhyay et al., 2011).

DRUG DISPERSION IN CARRIERS

Solid dispersion technique: The concept of solid dispersions was given by Sekiguchi and Obi (1961) who investigated the generation and dissolution performance of eutectic melts of a sulfonamide drug and a water-soluble carrier in the early 1960s (Tapas et al., 2011; Giri et al., 2010; Zhixun et al., 2006). Many of the drugs belongs to these techniques; can be categorized as class II according to the Biopharmaceutical Classification System (BCS). These drugs are poorly water soluble but once they are dissolved they get easily absorbed through the gastro-intestinal membrane. One of the approaches to enhance the dissolution rate is the use of solid dispersion. Some marketed formulation of solid dispersion shown in (Table 3).

Definition of solid dispersions: The two different components, generally a hydrophilic matrix and a hydrophobic drug mainly consist of solid dispersion (Chiou and Riegelman, 1971). These matrix are either crystalline or amorphous. In both particle (amorphous particles or crystalline particles) the drug can be dispersed molecularly (Ajazuddin et al., 2011). Solid dispersion is describing the most promising method to improve the oral bioavailability of hydrophobic drugs by preparing Lipid Nano Spheres (LNSs) (Amarji et al., 2007). There are different approaches which can be used for increasing the dissolution hydrophobic drugs of t he as given in the figure Fig. 2. That describes the approaches to Increase solubility/Dissolution (Verma, 2011; Patidar et al., 2010).

Table 3:	Marketed formulation of solid dispersion (Patel et al., 2010)


Fig. 2:	Approaches to increase solubility/dissolution (Verma, 2011)


Fig. 3:	Phase diagram of a simple eutectic mixture with negligible solid solubility, (Sharma et al., 2009).T A: M.P. of solid A (in °C), T B: M.P. of solid B (in °C ), TE: Eutectic point

Categories of solid dispersions
Simple eutectic mixtures: The two components which are completely miscible in a liquid state but only to a very limited extent in the solid state forms a simple eutectic mixture (Fig. 3) (Sharma et al., 2009). When, a composition E with a mixture of A and B is cooled, at first A and B crystallize out simultaneously, whereas when other compositions are cooled, one of the components starts to crystallize out while after that when composition E is further cooled one component starts to crystallize out before the others (Goldberg et al., 1966). Solid eutectic mixtures are usually prepared by rapid cooling of a co-melt of the two compounds in order to obtain a physical mixture of very fine crystals of the two components. When a mixture with composition E, consisting of a slightly soluble drug and an inert, highly water soluble carrier, is dissolved in an aqueous medium, the carrier will dissolve rapidly, releasing very fine crystals of the drug. Where T A-M.P. of solid A (in °C), T B-M.P. of solid B (in °C), TE-Eutectic Point.

Solid solution: Solid solutions of a poorly water soluble drug dissolved in a carrier with relatively good aqueous solubility are of particular interest as a means of improving oral bioavailability (Leaner and Dressman, 2000). Two components crystallize together in homogenous one phase system. Particle size of drug in solid solution is reduced to its molecular size. Solid solutions shows faster dissolution rate than eutectic mixtures. Solid solutions can be divided in two types, according to their miscibility (continuous versus discontinuous solid solutions) or, according to the way in which the solvate molecules are distributed in the solvendum (substitutional, interstitial or amorphous).

Miscibility types
Continuous: The continuous solid solution consists of totally miscible components both in liquid and solid state (Giri et al., 2010). The pure components in a solid state lattice energy as compare to continuous solid solution it is due to the higher heteromolecular bonding than the homomolecular one in a continuous solid solution (Fig. 4) shows the hypothetical phase diagram of a continuous solid solution.

Discontinuous solid solutions: Discontinuous solid solutions, the miscibility or solubility of one component is restricted in other (Fig. 5) shows a typical phase diagram of a discontinuous solid solution. α and β shows the regions of true solid solutions. The region labeled β is a solid solution of B in A that is component A would be regarded as the solvent and B as the solute. Similarly the region labeled β is a solid solution of A in B (Goldberg et al., 1965).

The way in which the solvate molecules are distributed in the solvendum
Substitutional crystalline solid solutions: A substitution crystalline solid dispersion is a type of solid solutions which is having a crystalline structure, in that the solute molecules substitute for solvent molecules in the crystal lattice. Substitution is only possible when the size of the solute molecules differs by less than 15% or so from that of the solvent molecules (Fig. 6) Substitutional solid solution.

Interstitial crystalline solid solutions: In interstitial solid solutions, dissolved molecules occupy the interstitial spaces between the solvent molecules in the crystal lattice. As in the case of substitutional crystalline solid solutions, the relative molecular size is a crucial criterion for classifying the solid solution type.


Fig. 4:	Hypothetical phase diagram of a continuous solid solution (Giri et al., 2010)


Fig. 5:	Hypothetical phase diagram of a discontinuous solid solution (Goldberg et al., 1965)


Fig. 6:	Substitutional solid solution (Maski et al., 2009)


Fig. 7:	Interstitial solid solution


Fig. 8:	Amorphous solid solution (Suryawanshi et al., 2010)

In the case of interstitial crystalline solid solutions, the solute molecules should have a molecular diameter that is no greater than 0.59 of the solvent molecule's molecular diameter Furthermore, the volume of the solute molecules should be less than 20% of the solvent (Fig. 7) Interstitial solid solution.

Amorphous solid solution: It is demonstrated, that drug with propensity to super cooling has more tendency to solidify as an amorphous form in presence of carrier (Nikhil, 2010). This is quite similar to simple eutectic mixtures but only difference is that drug is precipitated out in an amorphous form. Ex. Precipitation of sulfathiazole in crystalline urea (Fig. 8), amorphous solid solution (Table 4) and classification of Solid Dispersions according to Molecular arrangement (Gavali et al., 2011).

Table 4:	Classification of solid dispersions according to molecular arrangement (Sonpal et al., 2011)

A: Matrix in the amorphous state, C: Matrix in the crystalline state, A: Drug dispersed as amorphous clusters in the matrix, C: Drug dispersed as crystalline particles in the matrix, M**: Drug molecularly dispersed throughout the matrix

Glass solutions: Solute dissolves in glass carrier to form a homogeneous glassy system is known as glass solutions (Swarbrick, 2006; Kim et al., 2010). Glass suspensions are mixture in which precipitated particles are suspended in glass solvent. Different characteristics of glassy state are brittleness, transparency below the glass transition temperature. Lattice energy (barrier to rapid dissolution) is much lower in glass solution and suspension. Ex-Carriers for glass solution and suspension-citric acid, sugars (dextrose, sucrose and galactose), PVP, PEG and urea (British Pharmacopoeia, 2007; Van Drooge et al., 2004) (Table 4) Different carriers used for the preparation of solid dispersion (Naveen et al., 2010) (Fig. 9) Schematic picture of the variation of enthalpy (or volume) with temperature. TG-glass transition temp, T f-M.P. of material.

METHODS OF PREPARATION OF SOLID DISPERSIONS

Hot melt method: A process of transferring a powder blend of drug and carrier by a rotating screw, through the heated barrel of an extruder and pressing the melt through a die into a product of uniform shape is known as Hot-Melt Extrusion (HME) or fusion method (McGinity and Zhang, 2003).


Fig. 9:	Schematic picture of the variation of enthalpy (or volume) with temperature (Shujun et al., 2006) Tag: Glass transition temp, To: M.P. of material

HME was first introduced in the plastics industry in the mid-nineteenth century to apply polymeric insulation coatings to wires (Crowley et al., 2007). First applications of HME were realized as a manufacturing tool in the pharmaceutical industry (Chaudhuri, 2007).

Solvent evaporation method: The process which involve solubilization of drug and carrier in a volatile solvent which is later evaporated is termed as Solvent Evaporation Method (SEM). (Hasegawa et al., 1985; Lloyd et al., 1999; Lima et al., 2008). In this method, the thermal decomposition of drugs or carriers can be prevented, since organic solvent evaporation occurs at low temperature (Won et al., 2005; Gupta et al., 2008; Singh et al., 2011). Solvent evaporation method is popularly used for preparation of microsphere because of its simplicity, fast processing and reproducibility with minimum controllable process variables that can be easily implemented at the industrial level. Many studies have been done on solid dispersions of Meloxicam (Chokshi and Hossein, 2004; Leila et al., 2011), Naproxen and (Mullins and Macek, 1960), by solvent evaporation techniques.

Fusion method: A method in which a molten mixture of drug and carrier are cooled to solidification, is called as fusion method it is also called as solvent method in which precipitation of drug and carrier from a common solvent occur. Paracetamol solid dispersion with PEG 8000 was prepared by melt fusion method (Khan et al., 2011).

Melting solvent method: This involves dissolution of drug in a minimum amount of an organic solvent, which is then added to the molten carrier (Chiou and Riegelman, 1969; Gupta and Moorthy, 2007). Melting solvent method (melt evaporation) method is used to prepare spironolactone-polyethylene glycol 6000 solid dispersion without removing the solvent. They mention that 5-10% (w/w) of liquid compound could be incorporated into polyethylene glycol 6000 without significant loss of its solid property (Table 5). Some resent patent on solubility enhancement using solid dispersion technique (Schroeder, 2009; Ajazuddin and Saraf, 2011) has been shown in Table 5.

COMPLEXATION

Cyclodextrins (CD) is a group of cyclic oligosaccharides, known for their ability to form inclusion complexes with a variety of organic molecules (Saenger et al., 1984; Khan et al., 2001) Complexation by Cyclodextrins, especially the most commonly available β-Cyclodextrins, is widely used to increase the solubility of drug molecules which have limited solubilities in water (Abou-Auda et al., 2006).

Table 5:	Some resent patent on solubility enhancement using solid dispersion technique (Schroeder, 2009)

Table 6:	List of complexing agents

Cyclodextrins Can also be used to prevent drug-drug interaction, it Convert liquid drug in to microcrystalline powders, decreases volatility, modify gastrointestinal or ocular irritation and mask of objectionable taste or odor of drug. Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8 dextrose molecules (α, β, γ-Cyclodextrins) bound in a 1, 4-configuration to form rings of various diameters. The ring has a hydrophilic exterior and lipophilic core in which appropriately sized organic molecules can form noncovalent inclusion complexes resulting in increased aqueous solubility and chemical stability. Complexation is occurring between two or more molecules to form a nonbonded entity with a well defined stoichiometry. Complexation relies weak forces such as London forces, hydrogen bonding and hydrophobic interactions. The Inclusion complexes can induce modification of the physicochemical properties of the guest molecules, particularly in terms of water solubility and solution stability (Lyng et al., 2004). Complex Formation by Cyclodextrins shown in Fig. 10 (Khan et al., 2001). Different method are used to prepare inclusion complexes of a variety of drugs in order to improve their solubility and dissolution rate. E.g., Co-precipitation, kneading and solid dispersion methods (Shujun et al., 2006). There are many types of complexing agents and a partial list can be found in Table 6.

SOLUBILISATION BY SURFACTANTS

Surfactants are known to play a vital role in pharmacy because it have an ability to increase the solubility of poorly soluble drug in water (Gharaei-Fathabad, 2011; Moghaddam and Moghaddam, 2011).


Fig. 10:	Complex Formation by Cyclodextrins (Kawashima et al., 1975)

One of important property of surfactants is the formation of colloidal-sized clusters in solutions, called as micelles which is having a particular significance in pharmacy. Surfactant having the characteristic property of reducing the interfacial and surface tension using the same mechanism as chemical surfactant. Surfactants are the molecules with distinct no Polar Regions (Emara et al., 2002). Most surfactants consist of a hydrocarbon segment connected to a polar group. The polar group can be cationic, anionic, nonionic or zwitterionic. When small polar molecules are added they can accumulate in the hydrophobic core of the micelles. This technique of solubilization is very important in biological and industrial processes (Gavali et al., 2011). This work was investigated to develop the carvedilol tablets, allowing fast, reproducible and complete drug dissolution, by using surfactant.

Microemulsions: The concept of microemulsion was first introduced by Hoar and Schulman (1943). A monodispersion spherical droplets consisting of oil, surfactant, co-surfactant and aqueous phase, which is optically isotropic and thermodynamically stable with a droplet diameter within the range of 10-100 nm is defined as ‘microemulsion (Tenjarla, 1999; Yazdani and Hadianfard, 2012). Microemulsions could enhance the potential solubilization of hydrophobic drugs (Yin et al., 2009; Alexander et al., 2011a). Amongst the various drug delivery systems, the microemulsion system is considered as an ideal alternative for the oral delivery of lipophilic drug.

Self micro emulsifying drug delivery systems: For the improving solubility, dissolution and oral absorption of hydrophobic drugs ‘self- micro emulsifying drug delivery systems’ (SMEDDS) have been preferred (Breitenbach et al., 2002; Cui et al., 2005). SMEDDS is a isotropic mixtures of an oil, surfactant, co surfactant or (solubilizer) and drug. The basic principle of this system is its ability to form fine oil-in-water (o/w) microemulsions under gentle agitation following dilution by aqueous phases.

Self emulsifying drug delivery systems (SEDDS): An isotropic mixture of oils, surfactants, along with co-solvents/surfactants that have a unique ability of forming fine oil-in-water (o/w) micro emulsions upon moderate mixing of these ingredients in aqueous media, such as GI (Gastro Intestinal) fluids is termed as Self Emulsifying Drug Delivery Systems (SEDDS) (Agrawal et al., 2012). It is the most useful technology to improve the rate and extent of this poorly water soluble drug. SEDDS is a mixture of oil, surfactant and if necessary a solubiliser. Self emulsification is initiated under gentle agitation following contact with aqueous phase and forms a thermodynamically stable o/w microemulsion with particle diameter of 100 nm or less. They are reputed to improve the oral bioavailability of poorly water soluble drug (Obitte et al., 2008; Ajazuddin and Saraf, 2010b).

CHEMICAL MODIFICATIONS (Rytting et al., 2005)

Salt formation: For enhancement solubility and dissolution rates of acidic and basic drugs salt formation is the most common and effective method (Serajuddin, 2007). Salts of acidic and basic drugs have, in general, higher solubility than their corresponding acid or base forms. Salt formation to enhance the aqueous solubility is the most preferred approach for the development of liquid formulations for parenteral administration (Sweetana and Akers, 1996; Lakade and Bhalekar, 2010).

Co-crystallization: The crystalline material that consists of two or more molecular and electrical neutral species held together by non-covalent forces is termed as co-crystallization’ (Masuda et al., 2012). The non-ionizable drugs can be form due to the co crystal, which cannot undergo in salt formation (Childs et al., 2007). By the addition, for ionizable drugs, the number of suitable co crystal formers can exceed the number of suitable salt formers. For example, the ionizable drug piroxicam has more than 50 reported co crystal formers (Tran et al., 2010).

Co-solvent: Non-aqueous co-solvent systems have been evaluated for their potential use in the freeze-drying of pharmaceutical products. Co-solvents have been reported to affect the rate of the organic phase partitioning into the external aqueous phase and thus, influence the physicochemical properties and release kinetics of PLGA microspheres (Rudra et al., 2011; Singh et al., 2011).

Hydrotropic: For drug aqueous solubility ‘hydrotropic’ solubilization is an important technique (Shibata et al., 2009). Since 1916, New berg, was first suggested the term hydrotropic which is used to designate anionic organic salts which, at high concentrations, considerably increase the aqueous solubility of poorly soluble solutes. Hydrotropes dissolved in water which can produce high degree solubility enhancement of hydrophobic drugs (Trana et al., 2011). For enhancement of aqueous solubility of hydrophobic drugs ‘hydrotropic agents’ have been found to be more effective and hence can play important role for improving the oral bioavailability (Maheshwari and Jagwani, 2011; Alexander et al., 2011b) (Table 7). Hydrotropic is a molecular phenomenon where by adding a second solute (the hydrotropic) results in an increase in the aqueous solubility of poorly soluble solutes (Nidhi et al., 2011) (Table 8) provide the example of some drug which Enhance the solubility by using various technique.

Table 7:	Hydrotropic is a molecular phenomenon where by adding a second solute results in an increase in the aqueous solubility of poorly soluble solutes (Bobe et al., 2011)

Table 8:	Example of some drug which Enhance the solubility by this technique

CONCLUSION

The stability of the drug, its solubility and availability at the site of action, is very important particularly when the formulation is intended for oral administration. Solubility and dissolution can be subsequently affecting the in vivo absorption of drug. So, it is very important to improve the aqueous solubility drugs. By reviewing this article we conclude that, solubility is a most important parameter for the oral bioavailability of hydrophobic. Solubility is also the basic requirement for the formulation and development of different dosage form of different drugs. Solubility can be enhanced by many techniques and number of folds increase in solubility is reported too. Because due to the solubility and stability problem of many drugs the bioavailability of them gets affected and hence solubility enhancement becomes necessary. It is now possible that to increase the solubility of hydrophobic drugs with the help of various techniques as mentioned above.

ACKNOWLEDGEMENT

The authors would like to acknowledge the assistance provided by the Library of “Rugnta College of Pharmaceutical Sciences and Research, Kohka-kurud Road, Bhiali, C.G. (India) for collection of literature.

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