Even though a great deal of time, money, and effort goes into identifying and developing new medicinal products, the successful candidates frequently have poor physicochemical qualities, such as low solubility, stability, dissolution rate, etc. [1]. Solubility is an important physicochemical property that affects both medication absorption and therapeutic effectiveness. Inadequate solubility in water can result in formulation development failure. [2]. Pharmaceuticals are divided into four basic classifications by the US Food & Drug Administration (FDA) according to the BCS, which is based on their permeability and solubility (Table 1) [3]. Biopharmaceutics classification system (BCS) class II medications, such as phenytoin, danazol, and nifedipine, and BCS class IV drugs, such as furosemide, taxol, and hydrochlorothiazide, are examples of drugs with low solubility [4].

Table 1: Biopharmaceutical Classification System [3]

The amount of the solute present in a saturated solution at a specific temperature is known as its solubility. When it comes to quality, solubility is the ability of two or more substances to spontaneously combine and form a homogenous molecular dispersion. A solution is considered saturated when there is an equilibrium between the solute and solvent. The solubility of a medicine can be expressed in terms of parts, percentages, molarity, molality, volume fraction, and mole fraction; all are valid. The term "drug solubility" refers to the maximum amount of a drug's solute that may dissolve in a solvent at a specific temperature, pH, and pressure [5]. The solubility ranges from Very soluble (i.e., completely miscible) in water, like ethanol, to Very slightly soluble in water, like silver chloride [6].

Table 2: Definitions of Solubility [6,7].

Factors that affect solubility: - [6]

· Nature of solute and solvent

· Size of particle

· Molecular size

· Temperature

· Pressure

Methods to enhance solubility: - [8,9,10]

Chemical Modifications:

1. Salt Formation

2. Co-crystallization

3. Co-solvency

4. Hydrotropes

5. Use of novel solubilizer

6. Nanotechnology

Physical Modifications:

1. Particle size reduction

a. Micronization

b. Nanosuspension

2. Modification of the crystal habit

a. Amorphous form

b. Polymorphs

3. Complexation

a) Kneading method

b) Co-precipitate method

4.Inclusion Complex Formulation Based Techniques

5. Solubilization by surfactants

6. Drug dispersion in carriers

a) Solid solution

b) Solid dispersions

-Melting / Fusion Method

-Solvent Evaporation Method

-Hot Melt Extrusion

c) pH adjustment

d) Supercritical fluid process

e) Liqui solid technique

Chemical Modification: -

1. Salt Formation: The most popular and efficient way to enhance the solubility and dissolution of basic and acidic medications is to produce salt. Drugs that are basic or acidic can be transformed into salt, which is more soluble than the original drug. Ex: Barbiturates, Theophylline, and Aspirin [8].

2. Co- crystallisation: Multicomponent crystal that forms between two compounds that are solids under ambient conditions, where at least one component is an acceptable ion or molecule" is definition of a co-crystal. By reducing the interfacial tension, the mechanism of co solvency facilitates the dissolving of a non-polar solute. The physical states of the constituents are the only distinction between solvates and cocrystals.[10]

3. Co-solvency: Co-solvent can be used to improve the solubility of medications that are poorly soluble in water in pharmaceutical liquid formulations. Cosolvents are miscible solvent mixes that are frequently added to water to drastically alter the solubility of medications that are not very soluble in water [9].

4. Hydrotropes: A high concentration of a second solute is added to a third solute to boost its aqueous solubility through a process known as hydrotrophy. More specifically, complexation—a weak interaction between hydrotropic substances such sodium alginate, sodium acetate, sodium benzoate, and urea and poorly soluble drugs—is linked to the process by which it increases solubility. Many salts with big anions or cations that are also exceptionally soluble in water—a phenomenon known as "hydrotropism"—are what induce the "salting in" of non-electrolytes known as "hydrotropic salts." The hydrotropic agent and the solute have a weak interaction in hydrotropic solutions, which are non-colloid [3]. Because the solvent is independent, hydrotropy is the most crucial tool for the other solubilization techniques, including micellar solubilization, spray drying, salting, and miscibility [11]. They are practically insoluble in the framework but totally soluble in water. Because of their amphiphilic structure, hydrotropes are surface dynamic and completely arranged in a watery manner. When hydrotropes are dissolved in water, their characteristics include being inexpensive, simple to employ, nonlethal, nonreceptive, and temperature-insensitive.  The other noteworthy characteristics of hydrotropes include their dissolvable nature, which is pH-free, their high selectivity, and the absence of emulsification [12].

5. Use of novel solubilizer: Drugs that ar1e poorly soluble can also be made more soluble by using a range of solubilizing agents. For example, the solubility of SS is being improved using conventional solubilizers such polysorbates, PEG 400 Sepitrap, Soluplus Povacoat, and dendrimers [10].

6. Nanotechnology: Using elements in the 1-100 nanometer range, nanotechnology has the potential to bring back many of the pre-clinically promising candidates that were "beached" because they were not water soluble, in addition to revolutionary therapeutic advances. Due to recent advancements in nanotechnology, scientists are attempting to address this issue by creating medications with the assistance of nanocarriers. When creating drug delivery systems, nanoemulsions, dendrimers, micelles, liposomes, solid lipid nanoparticles, polymeric nanoparticles, inorganic nanoparticles, carbon nanotubes, MOFs, and other similar materials are most frequently used [13].

1. Particle size reduction:

The drug's particle size determines how soluble it is. Because they have a lower surface area, large particles interact with the solvent less. Reducing the size of the drug's particles is one way to increase its surface area, which enhances its dissolution ability [14].

a. Micronization: Because micronization increases surface area, it decreases drug particle size while speeding up drug dissolution. Drugs are micronized using milling procedures such rotor stator colloid mills and jet mills. Progesterone, spironolactone, diosmin, griseofulvin, and fenofibrate were all synthesized using these techniques. In just 30 minutes, the solubility of micronized fenofibrate increased by more than ten times, from 1.3% to 20% [15].

b. Nanosuspension: Submicron colloidal dispersions of medication particles in an aqueous phase that are colloidally stabilized with the help of surfactants are known as nanosuspensions. Nanosuspensions are used in conjunction with lipidic systems to produce medications that are insoluble in organic solvents and water. The ideal substances to make into nanosuspensions are those with high dose strengths, high log p values, and high melting points. The ideal plasma level is reached faster and the rate of saturation of the active component increases when the nanosuspension is administered orally or intravenously (IV). In a nanosuspension, solid particles have a size distribution between 200 and 600 nm [13].

2. Modification of the crystal habit

a. Amorphous form: The solid has no stable internal structure in this state. They were arranged as in liquid at random. It is also known as freeze liquid form, and it is made via lyophilization, quick precipitation, etc. [8] The drug's amorphous form is preferable to its crystalline version. As a result of increased surface area and high related energy [3]. In nature, they are less stable than isotropic ones. Their solubility is high, and their melting point is not sharp. Order for dissolving various medication types in solid form [8]. The arrangement of several solid medication forms:-

Amorphous > Metastable Polymorph > Stable [8,3].

b. Polymorphs: The ability of a solid material to exist in two or more distinct crystalline forms with various lattice configurations is known as polymorphism. Different crystalline forms are called polymorphs. Drugs in crystalline form have the identical chemical structure, but they differ in their physiochemical characteristics, such as stability, solubility, texture, melting point, and density [3]. This phenomenon exclusively affects organic substances, as inorganic materials are typically characterized by a single crystal structure. For instance, chloramphenicol palmitate comes in three polymorphs: A, B, and C. Form B has the highest bioavailability, while Form A is inactive. Different polymorphs frequently have different physical characteristics, such as solubility, melting temperature, density, crystal structure, and optical and electrical qualities. The least stable, highest melting point, and lowest Gibbs energy are all represented by the stable polymorph. The remaining polymorph is referred to as the metastable form, and it has a lower melting temperature, a higher gibbs energy, and a high solubility in water. The metastable form has a thromodynamic tendency to change into the stable form due to its higher energy. It should be highlighted that a metastable form cannot be classified as unstable because it will stay stable for years if it is kept dry. There are several techniques for analyzing polymorph, including TGA, SEM, DSC (differential scanning microscopy, optical calorimetry), and crystallography [8].

       
           
       
Fig 2. Classification of Internal structure of compound [8]

The most popular methods in the pharmaceutical industry for improving the bioavailability and solubility of medications with low water solubility. The process by which two or more molecules associate to generate non-bonded molecules is known as complexation. Hydrophobic contacts and hydrogen bonding are examples of relatively weak forces that complexation operates on. Several substances that induce complexation are referred to as chelates, including polymers, cyclodextrins, inclusion complexes, EGTA, and EDTA (ethylene diamine tetra acetic acid) [6]. A drug's solubility can be increased by complexing with other molecules or ions. Certain chemicals can become more soluble through complexation with metal ions or salt production, for instance [16].

a) Kneading method: This method involves turning the drug carriers into a paste with water, mixing the paste with the drug compound, and pressing it for a predetermined amount of time. The pressed mixture is then dried and sieved [14].

b) Co-precipitation technique: The medication is dissolved in an organic solvent and the carrier is dissolved in water in the coprecipitation method. Lastly, the organic drug solution is mixed with the aqueous carrier solution, and anti-solvent is added to cause the dissolved components to precipitate simultaneously. To eliminate any remaining traces of organic solvent, the precipitate is filtered, washed, and evaporated. The precipitate is then sized and dried [17].

4.Inclusion Complex Formulation Based Techniques

More successfully than any other solubility augmentation strategy, the aqueous solubility, dissolution rate, and bioavailability of drugs that are just weakly water-soluble have been enhanced. These are produced when nonpolar molecules most often cyclodextrin cannot dissolve into the surrounding molecule. The most commonly employed host molecules are cyclodextrins. When a nonpolar molecule or a nonpolar portion of a molecule is integrated into the cavity of another molecule or collection of molecules, referred to as the host, inclusion complexes are produced [18]. Drug molecules can be incorporated into the disc's hollow to alter the physicochemical and biological properties of poorly soluble medicines. The hollow, lipophilic core cavity of CDs allows lipophilic molecules to be attached through a range of intermolecular interactions [13].

5.Solubilization by surfactants

Hydrophilic substances possessing a hydrophobic tail are known as surfactants. They exist at the interface between systems, and they modify the tension across the interface. They exist in inadequate concentration. The primary objective of the surfactant is to reduce the interfacial tension between the two systems to an extremely low level, hence facilitating the dispersion process that occurs during the microemulsion production process. To fit the right shape, it delivers the microemulsion with the right lipophilic character. Both polar and nonpolar groups can be combined into a single molecule by a surfactant. A surfactant molecule is chosen by considering its hydrophilic lipophilic balance (HLB) value. The kind of emulsion formation (whether o/w or w/o) is suggested by this HLB value [14,19]. The formulations self-emulsify when they come into contact with water, creating a small, homogeneous emulsion of tiny, transparent oil droplets that contain the weakly soluble drug that has been solubilized. Microemulsions have been used to integrate proteins for oral, parenteral, and intravenous delivery as well as to increase the solubility of several drugs that are almost insoluble in water. Three types of microemulsions can be distinguished according to their composition:

 • Oil-in-water microemulsions in which the oil droplets are distributed throughout the aqueous phase.

• Water-in-oil microemulsions: these involve the dispersion of water droplets inside the continuous oil phase.

• Bi-continuous microemulsions, in which the system contains a mixture of water and oil microdomains [5].

An oil-in-water (o/w) microemulsion is the best formulation since it is designed to improve solubility by dissolving molecules with low water solubility into an oil phase solubility. [3] The best method for solubilizing a poorly soluble molecule is to reduce the interfacial tension that exists between the solvent and solute surfaces. Many surfactants, such as polyglycolized glyceride, Tweens, polyoxyethylene stearates, spans, and some co-polymers, such as polypropylene oxide and polyethylene oxide, are effectively employed as excipients or carriers in solubility enhancement [6].

       
           
       
Fig 3. Microemulsion [5]

a) Solid Solution:It is the result of the blending of two crystalline solids to create a new one. In a homogeneous one-phase solution, the two components crystallize simultaneously, producing a mixed crystal. It is therefore expected to produce higher dissolution rates than basic eutectic systems [29]     

b) Solid dispersions: Sekiguchi and Obi created a workable technique in 1961 that allows for the improvement of bioavailability of medications that are not very water soluble while overcoming many of the restrictions. This process later named solid dispersion involves melting the physical mixes of the medications to create a eutectic combination of the pharmaceuticals with water-soluble carriers [20]. "Dispersion of one or more active ingredients at molecular to microcrystalline level in an inert carrier or matrix at solid state" is the definition of solid dispersion. Solid dispersion is prepared using physiologically inert carriers, which can be either readily water-soluble or water-insoluble for formulations requiring quick or modified release, respectively [17]. Solid dispersion improves the solubility, dissolving rate, and oral bioavailability of weakly water-soluble medicines by reducing their particle size and increasing their surface area [9]. A solid dispersion is a matrix consisting of a minimum of two substances: a medication that is poorly soluble and a solvent carrier that is primarily hydrophilic [21]. The medication is disseminated in a solid state using an inert water-soluble carrier in solid dispersion [22]

       
           
       
Fig no 4: solid dispersion technique [28]

• Melting/Fusion Method: An active agent and a carrier are physically combined and heated to the point of melting. After vigorously agitating the melted physical combination to quickly solidify it in an ice bath or liquid nitrogen, it is ground and sieved to the appropriate particle size. Rapid cooling that causes super saturation and solidification can be used to achieve the molecular dispersion of a dispersed medication [17,23]. 
• Solvent Evaporation Method: The most effective technique for increasing the solubility of medications that are poorly soluble in water is solvent evaporation, particularly for thermolabile components [13]. The main advantage of the solvent evaporation technique is that thermal disintegration of medications or carriers can be prevented because organic solvents evaporate at low temperatures [18]. This process permits the mixing of the drug and carrier with the help of a solvent, which also has the benefit of utilizing carriers with extraordinarily high melting points, in contrast to the melting method, which uses heat to do the mixing [13].

Hot-Melt Extrusion: The production of commercial products on the market demonstrates the well-established usage of HME for increasing the solubility and dissolution rate of weakly water-soluble medicines through dispersion or distribution in appropriate carriers [24]. One of the most popular methods for creating Amorphous Solid Dispersions (ASDs) is hot metal extrusion (HME), particularly the twin-screw method using Meltrex™ as an example [25]. A feed hopper, barrel, extrusion screws, torque sensors, heating and cooling systems, and dies are typically found in hot-melt extruders. The HME equipment's modular components allow for process customization to meet different raw material requirements and produce desired results [30]. The SD technology has advanced, and numerous commercial items created with it have been effectively introduced in a variety of medical fields, including oncology, transplant medicine, HIV infection treatment, and others [27].

       
           
       
Figure: - Twin screw hot-melt extrusion and the associated manufacturing variables impacting product properties [28].