Table 1: Solubility definition according to USP

Description forms (Solubility definition)	Parts of solvent required for one part of solute	Solubility range (mg/ml)	Solubility assigned (mg/ml)
Very Soluble (VS)	<1	>1000	1000
Freely soluble (FS)	From 1 to 10	100–1000	100
Soluble	From 10 to 30	33–100	33
Sparingly soluble (SPS)	From 30 to 100	10–33	10
Slightly soluble (SS)	From 100 to 1000	1–10	1
Very slightly soluble (VSS)	From 1000 to 10000	0.1–1	0.1
Practically insoluble (PI)	>10.000	<0.1	0.01

Importance of solubility enhancement:

Oral drug delivery is the most convenient and preferred route of administration due to its ease of administration, high patient compliance, cost effectiveness, least sterility contains and flexibility in the design of dosage form. Solubility is a vital parameter to attain desired drug concentration in systemic circulation for achieving necessary pharmacological response. Poorly water-soluble drugs generally require high dose to achieve therapeutic plasma concentrations after oral administration. For a drug molecule to be absorbed, should be in the form of aqueous solution at the site of absorption. Therapeutic effectiveness of drug depends on its solubility and bioavailability. Currently only 8% of new drug candidates have both high solubility and permeability. The basic aim of formulation and development section is to make that drug available at proper site of action within optimum dose. The two parameters Solubility and permeability are the deciding factors for in-vivo drug absorption, thus needs to be modified by various enhancement techniques.

Factors Affecting Solubility:

Solubility of a solute in a solvent is affected by many factors viz. physical form of the solid, nature, and composition of solvent as well as on temperature of system.⁴ The main factors that affect the solubility of a solute are:

a) Particle Size

b) Temperature

c) Pressure

d) Molecular Size

e) Nature of solute and solvent

f) Polymorphs

A .Particle Size:

As the particle becomes smaller, the surface area to volume ratio increases and the larger surface area allow a greater interaction with the solvent. Hence smaller the particle size greater the dissolution and thus higher the solubility. The effect of particle size on solubility can be described by the following equation.

Where,

S₀- Solubility of infinitely large particles,

S- Solubility of fine particles,

V- Molar volume,

γ- Surface tension of the solid,

r- Radius of the fine particle

B. Temperature:

Temperature affects solubility largely. In endothermic process, solubility increases with the increase in temperature, for example solubility of potassium nitrate increases with the increase in temperature and in exothermic process solubility decrease with the increase in temperature. For example, the solubility of calcium oxide decreases with the increase in temperature. For gaseous solutes, solubility decreases with the increase in temperature of the solution.

C. Pressure:

The solubility of gaseous solute increases with the increase in pressure. In case of solid and liquid solutes, decrease in pressure has practically no effect on the solubility.⁵

D. Molecular size:

Drug solubility depends upon the molecule size of the substance, larger the molecule poor the solubility of the substance, reason is larger molecules are more difficult to surround with solvent molecules in order to solvate the substance.

E. Nature of the solute and solvent:

Solubility of a solute in a solvent purely depends on polarity of the solute and solvent molecules. Generally, non-polar solute dissolves in non-polar solvents and vice versa. The polar solutes have a positive and a negative end to the molecule. If the solvent molecule is also polar in nature then the positive ends of solvent molecules will attract negative ends of solute molecules. This is known as dipole-dipole interaction. All molecules also have a type of intermolecular force much weaker than the other forces called London Dispersion forces where the positive nuclei of the atoms of the solute molecule will attract the negative electrons of the atoms of a solvent molecule. This gives the non-polar solvent a chance to solvate the solute molecules.

F. Polymorphs:

A crystal is in regular geometric arrangement or lattice made of atoms, ions and molecules, constantly repeated in three dimensions known as the unit cell. The ability of any substance to crystallize in more than one crystalline form is polymorphism. All crystals can crystallize in different polymorphic forms. These polymorphs can vary in melting point. Since the melting point of the solid is related to its solubility, the polymorphs will have different solubility. In polymorphs, the range of solubility differences is nearly about 2-3 folds only, due to relatively small differences in free energy.⁶

Techniques of solubility enhancement:

There are various techniques available to improve the solubility of poorly soluble drugs. Figure 2 highlights the various techniques of solubilization.

1. Particle size reduction

Size reduction is one of the oldest and widely used techniques for solubility enhancement. This technique is further sub-divided into several types viz. micronization, nano-suspension and sonocrystallization.

1.1 Micronization:

The particle size of poorly soluble drugs affects its bioavailability. Reduction in particle size leads to an increase in surface area, which may improve the dissolution properties of the drug and thus can allow wider approaches for formulation and delivery technologies. Micronization is a process, which increases the dissolution rate of drug but not the equilibrium solubility.⁷ However; conventional methods of size reduction like comminution and attrition have limited applications because they cause excessive physical stress on to the drug molecule, which induces degradation. The consequences of attrition are de-aggregation of solid particles. In addition, particles of sub-micron size are difficult to handle due to the development of static charge on the surface of particle, leading to contamination by flyaway powders. By contrast, the spray drying technique can offer good control over particle size and results in fast drying. Solid dispersions and micronized-coated particles can also be produced by spray drying.⁶ Spray drying of acid dispersed in acacia solution resulted in 50% improvement in solubility of salicylic acid.⁸ Recrystallisation with the help of liquid solvents and anti-solvents has been used to reduce the particle size of poorly soluble substances. The dependence upon these organic solvents during processing may increase the complexity of manufacture¹.Supercritical fluid (SCF) process is another novel solubilizing technology used for size reduction. It is based on manipulation of the pressure of SCFs and characteristics of gases diffusivity. The process is flexible and precise, which allows micronization of drug particles within narrow range to sub-micron levels. The most extensively used methods of SCF are rapid expansion of supercritical solutions (RESS) and gas antisolvent recrystallisation (GAS). Both these methods are employed in pharmaceutical industry using carbon dioxide as the SCF. In determination of polar compounds by RESS co-solvents such as methanol is required to solubilize the compound in the SCF. Co-solvents help to achieve extraction of the solvent and volatile materials, thus increasing the complexity of production. The use of CO₂ at high pressure causes significant scale-up and operation issues to arise, such as particle aggregation upon dispersion from nozzles and capillaries. This SCF method overcomes the shortcoming associated with precipitation with compressed antisolvent process (PCA), solution enhanced-dispersion by SCF (SEDS), supercritical antisolvent processes (SAS) and aerosol supercritical extraction system (ASES).

1.2 Nanosuspension

Nanosuspensions are the colloidal dispersion of drug particles stabilized by surfactants. They offer the advantage of increased dissolution rate due to larger surface area. This approach has been utilized for drugs like tarazepide, atovaquone, amphotericin B, paclitaxel and bupravaquone. The prime factor affecting particle size reduction is conversion of high-energy polymorph into low energy crystalline form, which may not be therapeutically active.^{7, 9}

1.2.1 Techniques for the production of nanosuspensions:

(a) Homogenization:

In this method, the suspension is forced under pressure through a valve containing nano aperture, which causes formation of water bubbles and finally collapses while coming out of valves. This mechanism cracks the particles. The homogenizers commonly used for particle size reduction in the pharmaceutical and biotechnology industries are conventional homogenizers, sonicators and high shear fluid processors.¹⁰

(b) Wet milling:

In this method, the drug is dispersed in aqueous surfactant solution and then subjecting the suspension to wet milling.¹¹The impaction of drug particles with milling media generates energy required for particle size reduction.

1.3 Sonocrystallisation:

This approach is based on crystallization using ultrasound. Sonocrystallisation utilizes ultrasound power characterized by a frequency range of 20–100 kHz for inducing crystallization. This method enhances the rate of nucleation and leads to size reduction and also controls size distribution of the active pharmaceutical ingredients (API).¹²

2. Modification of the crystal habit/ manipulation of solid state

The crystalline form of a drug is important with respect to its stability and bioavailability. Polymorphism can cause variations in solubility, melting point, stability and density of drug molecule. If a drug exists in multiple polymorphic forms, then the polymorph with the highest crystallinity is the most stable, has least amount of free energy, posses highest melting point and least solubility. By controlling the crystallization process, it is possible to create amorphous and metastable forms of drug. They offer the advantage of higher solubility but suffer from stability issues. One of the case highlighting the manipulation of crystal habit was withdrawal of ritonavir (Norvir®) capsules from the market in 1988. Polymorph of ritonavir was identified two years after the product was approved and marketed, which was less soluble and caused decrease in bioavailability of the drug.¹³This increased the significance of polymorphism in pharmaceutical industries. In case of eutectic mixtures with equilibrium phase diagram, there exists a correlation between the efficiency of emulsification and the region of enhanced water solubility.¹⁴ The dissolution of different solid forms of drug is in the order of amorphous > metastable polymorph > stable polymorph.

3. Dispersion of drug in carriers

In this technique, the drug is dispersed into different carriers for enhancement of solubility. This can be done by hot melt method, solvent evaporation, hot melt extrusion and melting solvent method.

3.1 Solid Dispersions:

This technique was first recognized in 1961 with an aim to increase the dissolution rate and absorption of drugs. In this method, the drug is dispersed in highly soluble solid hydrophilic matrix, which enhances the dissolution of the drug. This technique can yield eutectic mixtures and solid solution products.¹⁵ Eutectic mixtures are homogeneous dispersions of drug in carriers. Both the drug and carrier can be of crystalline or amorphous nature. Microcrystalline state of drug improves the wetting property and amorphous form contributes toward the enhanced solubilization. Some of the limitations of solid dispersion include manufacturing difficulties, poor stability and scale-up issues. By solid dispersion, using hydrophilic carriers the solubility of several drugs like etoposide, glyburide, itraconazole, ampelopsin, valdecoxib, celecoxib and halofantrine has been improved. The formulations of solid dispersion are also commercially available, one of them is the solid dispersion of griseofulvin and polyethylene glycol 8000 (Gris-PEG®). Different carriers used for solid dispersion are listed in Table 2 and 3. Following are the methods used for preparation of solid dispersions:

3.1 (a) Hot Melt method:

In this method, the prime requirement is the miscibility of drug and carrier in molten form.¹⁵ another necessary criteria is the thermo-stability of both drug and carrier. Presence of miscibility gap in the phase diagram, leads to a product that is not molecularly dispersed.

3.1 (b) Solvent Evaporation Method:

In this technique, solid solution is prepared by dissolving the drug and carrier in a common solvent and evaporating the solvent under vacuum.¹⁶ it is essential that both the drug and the carrier should be sufficiently soluble in the solvent. The drawback of this technique is that it shows negative effect of the solvent on the environment and leads to higher production cost due to extra facility required for removal of solvent. Because of the toxic nature of organic solvents used in this method, hot melt extrusion method is mostly preferred.^17,18

3.1 (c) Hot-melt Extrusion:

In pharmaceutical industry, melt extrusion technique was used as a manufacturing tool with the first application of HME in 1971.¹⁹ Melt extrusion of miscible components results in formation of amorphous solid solution whereas in case of an immiscible component the amorphous drug is dispersed in crystalline excipients.

3.1 (d) Melting–solvent method:

In this method, the drug is dissolved in liquid solvent and then incorporated into PEG melt, obtainable below 70⁰C. It is not necessary that the selected solvent and the dissolved drug will be miscible with the PEG melt. The liquid solvent used for the study can affect the polymorphic form of drug precipitated in the solid dispersion.

Table 2 Carriers for Solid Dispersions according to the generations

Class	Carrier
First generation Solid dispersion	Crystalline carriers including urea and sugars
Second generation Solid dispersion	Amorphous and polymeric carriers including: (i) Fully synthetic polymers such as Povidone (PVP), polyethylene glycols (PEG) and polymethacrylates. (ii) Natural and semi synthetic polymers such as hydroxypropylmethylcellulose (HPMC), ethyl cellulose, Hydroxy propylcellulose and starch derivates like cyclodextrins.
Third generation Solid dispersion	Surfactant carrier or a mixture of polymers and surfactants as inulin, Compritol 888 ATO, gelucire 44/14 and Poloxamer 407.

Table 3 - Carriers for Solid Dispersions according to the chemical class of compounds

Sr. No.	Chemical Class	Examples
1	Acids	Citric acid, Tartaric acid, Succinic acid
2	Sugars	Dextrose, Sorbitol, Sucrose, Maltose, Galactose, Xylitol
3	Polymeric Materials	Polyvinylpyrrolidone, PEG-4000, PEG-6000,Carboxymethyl cellulose, Hydroxypropyl cellulose, Guar gum, Xanthan gum, Sodium alginate, Methyl cellulose, HPMC, Dextrin, Cyclodextrins, Galactomannan
4	Surfactants	Polyoxyethylene stearate, Poloxamer, Deoxycholic acid, Tweens and Spans, Gelucire 44/14, Vitamin E TPGS NF
5	Miscellaneous	Pentaerythritol, Urea, Urethane, Hydroxyalkyl xanthines

4. Complexation:

Association between two or more molecules to form a non-bonded entity with a well-defined stiochiometry is called as complexation. It relies mainly on the weak forces like London forces, hydrogen bonding and hydrophobic interactions. The complexation techniques used for enhancement of solubility of poorly soluble drugs are staking complexation, inclusion complexation and co-crystallization. The complexing agents used are the coordination complexes (Hexamine cobalt III chloride), chelates (EDTA), metal olefin (ferrocene), inclusion complexes (cyclodextrins) and molecular complexes (polymers).²⁰

(a). Staking complexation:

The poor solubility of drugs can be increased/enhanced by formation of stacking complexes. It is a non-stoichiometric hydrotropic solubilization process. The agents used for staking complexation are nicotinamide, benzoic acid, salicylic acid, purine, caffeine, naphthalene and many more.²¹ Stacking complexation may occur between the molecules of same or different species (self-association or co-association). This type of complex is formed by the interaction between the planer hydrophobic regions of the complexing agent and the drug. When the exposure of hydrophobic regions to water is reduced, the complex is stacked arranged. The driving force contributing for this process is passive in nature. Finally, the drug and complexing agent may/may not have direct kinship towards each other but they interact to minimize their exposure to water.

(b). Inclusion complexation:

It is not always possible to achieve size reduction of all poorly soluble drugs by traditional micronization or nanosizing methods, especially In case of drugs with high dose products and those with higher melting points. For such drugs/compounds, solubilization via drug-cyclodextrin inclusion complexes is more appropriate.²² Cyclodextrins are a group of structurally related cyclic oligosaccharides that have biocompatible in nature and have non-polar cavity and hydrophilic external surface. Natural cyclodextrins consisting of 6, 7 and 8 D-glucopyranosyl units connected to α-1,4 glycosidic linkages are known as α, β, γ cyclodextrins, respectively²³. Of all these, β –cyclodextrin is mainly used for increasing the solubility of drugs with poor or limited aqueous solubility²⁴. Hydrophilic cyclodextrins like hydroxypropyl, methyl, hydroxypropyl derivatives of natural cyclodextrins are nontoxic in normal doses whereas the lipophilic derivatives are toxic. Hence, hydrophilic derivatives with improved aqueous solubility are preferred for pharmaceutical use²⁵. Lipophilic drug-cyclodextrin complexes and host-guest complexation, commonly known as inclusion complexes, are prepared by simply adding drug and excipient together, resulting in enhanced solubility. Cyclodextrin complexation is non-covalent interaction and occurs due to physical forces such as electrostatic interaction, Vander Waals forces, hydrophobic interaction, hydrogen bonding and release of enthalpy rich water molecules ²⁶.The drug (guest) molecule resides inside the structure of cyclodextrin and is protected from unfavorable environments. Due to complexation, there is fourfold increase in the bulk, which limits its application for potent drugs. This type of complexation can also be used in conjunction with hydrophilic polymers like HPMC to improve the solubilizing effect of CDs. This technique is one of the prominent strategy for enhancing the solubility of poor soluble drugs ²⁷.

(c). Co-crystallization:

Solubility enhancement through co-crystals or molecular complexes is one of the novel approaches. If the solvent forms at least two components crystal and is an integral part of the network structure, then it is termed as co-crystal. Whereas the condition when the solvent is not an integral part and does not participate directly in the network, is termed as clathrate (inclusion complex) ²⁶. A crystalline material consisting of two or more molecular species held together by non-covalent forces is called as co-crystal²⁵. These are more stable and exist as solids at room temperature. There are only three co-crystallizing agents (saccharin, nicotinamide and acetic acid) that are generally recognized as safe (GRAS). Co-crystallization of pharmaceutical active ingredient requires the use of sub-therapeutic amounts of drug substances such as aspirin or acetaminophen. Till today, 20 have been reported including the polymorphic co-crystals of caffeine and glutaric acid.²⁸ Co-crystals can be prepared either by evaporation of heteromeric solution or by grinding all the components together. Co-crystals can also be obtained by sublimation, growth from the melt and slurry preparation ²⁹. This significance of co-crystal and molecular complexes is increasing mainly for neutral compounds and those having weakly ionizable groups.

5. Solubilization by surfactant

The presence of surfactants lowers the surface tension and increase the solubility of drug in solvent. Solubility enhancement through surfactant can be done by formation of microemulsion and chemical modification. The use of surfactant in drug product may result in an incompatibility with drug delivery technologies. Micellar solubilization is an area of emerging investigation for improving the pharmaceutical formulations. It has been reported that the naturally secreted bile salts act as surfactants and enhance the dissolution rate of poorly soluble drugs, thereby increasing their bioavailability. However, the inadequate biliary secretion or insufficient exposure time leads to significant decrease in dissolution rate and absorption of drug.

(A). Micro emulsion:

Recently, the technique of micro emulsions and self-emulsifying systems have emerged as potential solubility enhancing technologies for the optimization of several methods of solubilizing active compounds using various synthetic MCTs and co-solvents in addition to non-ionic surfactants. Micro emulsions are thermodynamically stable homogenous, transparent dispersion of oil and water, stabilized by combination of surfactant and co-surfactant. The non-ionic surfactants, which are amphiphilic in nature, lead to higher degrees of solubilization and prevent the precipitation of drug out of the micro emulsion. Co-surfactants are used to increase the amount of drug being dissolved into the lipid base, as the minimum surfactant concentration required in most of the self-emulsifying systems is in excess of 30% w/w. One of the stable micro emulsion technology is Eurand’s Nanolipispheres^TM,which is colloidal suspensions of sub-micron sized drug particles in a solid lipid matrix. Stable powder can be obtained by drying the suspension. The droplet size of emulsion is a major factor, which affects the bioavailability of drug from its formulations, smaller droplet radii enhances the plasma levels of drugs, due to direct lymphatic uptake³⁰. As most of the SMEDDS (self-micro emulsifying drug delivery system) contains relatively high concentration of surfactants, their use in oral applications is limited and cannot be recommended for long-term use due to the potential of causing diarrhoea. This technique is being used by scientist for formulation and development purpose and for improving and enhancing the oral bioavailability of poorly soluble drugs³¹. The mechanism responsible for enhanced bioavailability and improved oral absorption of several drugs from these systems may be the increase in membrane fluidity facilitating transcellular absorption, opening of tight junction to allow paracellular transport, inhibiting P-glycoprotein to increase intracellular concentration and residence time by surfactants and the formation of mixed micelles containing the drug ³². Precipitation of drug occurs, if the micro emulsion is diluted below the critical micelle concentration of the surfactants, but sometimes these fine particles of the resulting precipitate can enhance the absorption.

(B). Chemical modifications:

Change in pH can be used as alternative technique for increasing the solubility of ionizable organic solutes. By adjusting the pH of the solution, the solubility can increase exponentially. This technique is applicable for drugs or compounds, which are either weak acid (low pKa) and/or weak base (high pKa). In case of hydrophobic and non-ionizable substances, change in pH of the solvent is not effective for solubility enhancements rather change in the dielectric constant of the solvent or use of co-solvents can improve the solubility to a greater extent. Another effective method of increasing the solubility and dissolution rates of acidic and basic drugs is salt formation^{33, 34}. An example in this regard is that an alkaloid base is slightly soluble in water, but on addition of acid, the pH of medium is reduced and the solubility of base is increased. This is due to the fact that that the base is converted to salt, which is relatively soluble in water. Similarly, the solubility of slightly soluble acid can be increased if the pH is increased by addition of alkali, due to salt formation.

6. Other Techniques:

Apart from the techniques discussed above, there are several other methods, which can improve or solve the problem of poor solubility of drugs, chemicals, NCEs etc. These methods are co–solvency, hydrotropy, use of solubilizing agent, Hydrophilic Solubilization Technology (HST), formation of Micro-emulsion drug delivery system and pH adjustment.

6.1. Co-solvency:

It is well known that addition of an organic co-solvent to water can dramatically change the solubility of drugs³⁵. Weak electrolytes and non-polar molecules have poor water solubility, which can be increased by altering the polarity of solvent. This process is known as co-solvency. Co-solvent system reduces the interfacial tension between the aqueous solution and hydrophobic solute. Most of the co-solvents have hydrogen donor and/or acceptor groups as well as small hydrocarbon regions. Their hydrophilic hydrogen bonding groups ensure water miscibility, while their hydrophobic hydrocarbon regions interfere with waters hydrogen bonding network, reducing the overall intermolecular attraction of water. Co-solvents reduce the ability of water to squeeze out the non-polar hydrophobic compounds thereby increasing the solubility. Seedher et.al; 2003 investigated that the aqueous solubility of celecoxib, rofecoxib and nimesulide could be enhanced significantly by using ethanol as the second solvent and PEG-400-ethanol had highest solubilization potentiality among the mixed solvent systems. Dimethylsulfoxide (DMSO) and dimethylacetoamide (DMA) have been widely used as co-solvents because of their large solubilization capacity and relatively low toxicity. Simply, co-solvents facilitate solubilization by making the polar environment of water non-polar like the solute³⁶.

6.2. Hydrotrophy:

Hydrotrophy is a technique where the increase in aqueous solubility is due to the presence of large amount of additives. The mechanism is similar to complexation involving weak interaction between the hydrotropic agents like sodium benzoate, sodium acetate, sodium alginate, urea and the solute. For example, solubilization of theophylline with sodium acetate and sodium alginate.

6.3. Solubilizing agents:

Use of solubilizing agent for solubility enhancement is one of the most reliable techniques. For example, solubilizing agent PEG 400 improved the solubility of hydrochlorothiazide³⁷, modified gum karaya (MGK), an excipient was evaluated as solubilizing carrier for dissolution enhancement of nimodipine³⁸. Solubilizing excipients/agents in the form of pH adjusters, co-solvents and surfactants can significantly improve the solubility and/or dissolution of poorly soluble drugs. pH adjustment depends on the pKa value of the drug and is generally regarded as safe (GRAS) buffering agent. pH in the range of 2-11 are acceptable for oral products, whereas for parenteral products, it is enviable to formulate close to the physiological pH because variations can result in painful injections. In co-solvent approach, the drug is mixed with a water-miscible organic solvent in which it has high solubility. The solubility of a non-polar drug is increased mainly due to the addition of co-solvents³⁹. Surfactants are also used as solubilizing agents to improve the dissolution of lipophilic drugs. Micellisation also results in enhanced solubility of poorly soluble drugs. Bit the major issue with the use of co-solvent and surfactant as solubilizing agents for parenteral products is the toxicity related with the excipients.

6.4. Hydrophilic Solubilization Technology (HST):

This technology consists of water-soluble pharmaceutical coating of lecithin and gelatin, which enhances the rate and extent dissolution of poorly soluble drugs. Figure 3 explains the drug release mechanism from HST. It is based on dual mechanism. Firstly, the coating acts as physical barrier preventing the aggregation of particles by reducing surface tension at the solid-liquid interface. Secondly, the formation of lecithin/gelatin micelles takes place followed by hydration, which increases the drug’s solubility and contribute to the dissolution enhancement. This technology is applicable for those drugs or systems that can be spray dried and granulated. For example: formulation of HST to cyclosporine in ratio of 1:1 to improve the dissolution and absorption of the drug ⁴⁰.

Figure 3: Composition and Drug Release Mechanism for HST

6.5. Micro-emulsion drug delivery system for Poorly Soluble Drugs:

Lipophilic Solubilization Technology (LST) is a process, which involves the formation of micro emulsion in contact with aqueous environment. The system consists of lipid/solvent drug reservoir and combination of surfactant and co-surfactant. The emulsion-solubilized drug is solubilized in the small intestine and absorbed resulting in improved oral bioavailability. This technology is suitable for drugs that act as a liquid at elevated or room temperature⁴⁰. The final formulation can be liquid, semi-solid or solid depending upon the properties of the ingredients used. Figure 4 shows release mechanism for LST.

Figure 4: Drug Release Mechanism for LST

6.6. pH Adjustment:

The solubility of weak electrolytes can be improved by pH adjustment in two ways- in situ salt formation and addition of buffers to the formulation. For example, Ketoprofen, a weak acid with pKa 4.6 was solubilized by adjusting the pH to a higher value. As most of the compounds are absorbed in intestine, solubilization at pH > 5 will be appropriate⁴¹. Combination of pH adjustment and cyclodextrin complexation can be used for solubilization of drugs with low water solubility⁴².

7. NANOTECHNOLOGY APPROACH FOR SOLUBILIZATION:

Most of the new and existing chemical entities have very low solubility and oral bioavailability. Enhancement by conventional micronization method leads to agglomeration, which decreases the effective surface area and finally the dissolution⁴¹. The use of novel nanotechnologies for solubilization continues to be optimized and refined to counteract the issues related to manufacturing scale-up, use of organic solvents and batch-to-batch reproducibility. Some of the nanotechnology-based approaches are discussed with examples. Table 4 enlists different nanotechnology approaches for improving solubility of hydrophobic drugs.

7.1 NANOCRYSTAL:

Diminishing the drug particles in the size range of 1-1000 nanometers is defined as nanocrystallization. Two methods for producing nanocrystals are bottom-up and top-down. The top-down methods (i.e. Wet Milling and High-pressure homogenization) start milling down from the macroscopic level. In bottom-up methods (i.e. Precipitation and Cryo-vacuum method) nanoscale materials are chemically made of atomic and molecular components. Commercial products developed by the NanoCrystal® technology are Rapamune® (sirolimus) tablets, Emend® (aprepitant) capsules, TriCor® (fenfi brate) tablets and Megace® ES (megestrol) oral suspension. Several companies in developing proprietary solubilization technologies like Baxter’s NanoEdge®, PharmaSol’s Nanopure® and SkyePharma’s Dissocube® technology, have adapted Microfluidization or high-pressure homogenisation along with steric stabilization. Several excipients like PVP, casein, glycerol, polyethylene glycol and polyvinyl alcohol acts as steric stabilizers to inhibit crystal growth and are generally regarded as safe. Various processes used to reduce drug particles are:

(i) Wet Milling:

This process is based on attrition, where the drug particle in contact with milling media generates energy to convert the crystals into nanoparticles. Limitation of this method includes contamination of product due to the abrasion occurring on grinding beads, only batch wise production is possible and variations in particle-size distribution.

(ii) High pressure homogenization:

This technique is based on the principle of cavitation forces high enough to disintegrate the microparticles to nanoparticles^43,44. In this method, a pre-suspension (containing drug in the micrometer range) is prepared by subjecting the drug to air jet milling in the presence of an aqueous surfactant solution. This pre-suspension is subjected to high-pressure homogenization, where it passes through a very small homogenizer gap of ~25 mm. Homogenisation either in water (Disso Cubes) or in non-aqueous media or water-reduced media (Nanopure) is done⁴⁵. High-pressure homogenization is suitable for both large and laboratory scale production and it creates negligible contamination of nanoparticles. The only limitation associated with this process is the use of very high pressure, which in some cases, can change the crystal structure and lead to increased amorphous fraction⁴³. This deviation in crystal form can cause instability and create quality control problems.

(iii) Precipitation:

In this method, the drug substance is dissolved in a solvent to prepare dilute solution and then injected into water, which acts as a bad solvent followed by continous stirring so that the substance precipitate as nanocrystals. The Nanocrystals obtained can be removed from the solution by filtering and air-drying.

7.6 COMMERCIALIZED NANOTECHNOLOGY: Some of the commercial nanotechnologies in practice to deliver poorly water-soluble drugs are as follows:

(i) Disso cubes:

Disso cubes is a patented technology currently owned by Skye Pharma Plc ^{43, 44, 53} It is based on piston–gap high-pressure homogenization. The advantages of this technology are ease of scale-up, little batch-to-batch variation and aseptic production for parenteral administration.

(ii) Nanoedge technology:

Nanoedge technology (Baxter Healthcare Corporation, Deerfield, IL) is a formulation toolbox for poorly water-soluble drugs⁵⁴. This technology is useful for those drugs and active compounds, which have high melting point and partition coefficients. It is based on direct homogenization, microprecipitation and lipid emulsions. In microprecipitation, the drug is dissolved in water-miscible solvent to form solution and mixed with a second solvent to form pre-suspension. Then energy is added (through sonication, homogenization, countercurrent flow homogenization, microfluidization) to the presuspension to form particles with average size of 400 nm to 2 μm⁵⁴. The suspension prepared by this technology can be administered directly as an injectable solution. It facilitates small particle sizes (<1000 nm), high drug loading (10–200 mg/mL), long-term stability (up to 2 years at room temperature or at low temperature as 5 °C), the elimination of co-solvents, reduced levels of surfactants, and the use of safe, well-tolerated surfactants.

(iii) Nanopure technology:

Nanopure technology (PharmaSol GmbH, Germany), is a method where the poorly water-soluble drugs are transferred to nanocrystals through high-pressure homogenization process^55,56. Powdered drug is dispersed in the surfactant solution and subjected to homogenization, where the strong forces disintegrate the coarse drug powder into nanoparticles with a mean diameter, typically between 200–600 nm. Alternative method involves the dispersion of drug into non-aqueous medium (PEG 600, Miglyol 812) or water-reduced mixture (e.g., water-ethanol) and homogenized in a piston-gap homogenizer. The machine suitable for the laboratory scale production is Micron Lab 40 (APV Deutschland GmbH). Non-aqueous dispersion media yield suspensions that can be directly filled in capsules.

(iv) Crititech technology:

Crititech Technology (CritiTech, Inc., Lawrence, KS) is based on PCA. This technology uses ultrasonic energy produced by converging–diverging nozzle or an electromechanical oscillator to shatter droplets into even droplets. This technique alone would not cause submicron particles to form because the droplets tend to coalesce immediately into larger drops. In the crititech procedure, the drug-laden solvent is sprayed into a flowing stream of supercritical carbon dioxide, which allows rapid mass transfer of solvent into the stream of supercritical carbon dioxide. This forces precipitation or crystallization to occur before the coalescence of droplets. The ultrasonic nozzle-based process is capable of producing discrete nanoparticles in a narrow size range⁵⁷. Moreover, crititech's proprietary particle-harvesting device allows continuous processing of compounds in closed systems with complete recovery of solvents and carbon dioxide for reuse or safe disposal.

(v) Nanocochleate technology:

Nanocochleate delivery vehicles (also known as bioral technology) are used for the delivery of therapeutic products⁵⁸. These molecules are stable phospholipid-cation precipitates composed of simple, naturally occurring materials such as phosphatidylserine and calcium. They consist of alternating layers of phospholipid and multivalent cations existing as stacked sheets, or continuous, solid, lipid bilayer sheets rolled up in a spiral configuration, with little or no internal aqueous space. Figure 5 highlights the composition of nanocochleate delivery vehicles. These nanocochleates have been used to mediate and enhance the oral bioavailability of a broad spectrum of important but difficult-to-formulate biopharmaceuticals, including compounds with poor water solubility, protein and peptide drugs and large hydrophilic molecules. Nanocochleate formulations are widely suitable to a broad range of therapeutic applications which include the oral delivery of amphotericin B (bioral amphotericin B); large DNA constructs and plasmids (bioral DNA vaccines and bioral gene therapy); peptide formulations; anti-inflammatory formulations (bioral aspirin); and peptide-based vaccines.

(vi) Controlled-flow cavitation (CFC) technology:

CFC (Five Star Technologies, Cleveland, OH) can be used to develop advanced materials for emerging applications and to design processes that enhance existing products and processes. It is based on hydrodynamic cavitation, which involves the formation, growth and implosive collapse of vapor bubbles into liquid created by fluctuations in fluid pressure. Figure 6 shows the composition of controlled flow cavitation reactor. In this process, parameters like size, density, speed of collapse, intensity of implosion and other energetics of cavitation bubble creation and collapse are controlled to generate the necessary energy dissipation levels and desired effects on the process medium^45, ⁵⁹. Table 5 enlists various examples of solubility enhancement using different techniques.

Figure 5: Composition of nanocochleate delivery vehicles

Figure 6: Controlled-flow cavitation reactor

CONCLUSION

Pharmaceutical and biotechnology industries continue to generate promising new candidates; however, these potential drugs create challenges for their successful development to commercial dosage forms and products. In particular, low solubility and bioavailability limits their therapeutic application, in addition to the requirement to mediate clinically relevant effects for an appropriate period. Solubilization of poorly soluble drugs continues to pose challenges for the pharmaceutical drugs. This review describes the multiple technologies available for the successful formulation of poorly soluble potential candidates. Cyclodextrin inclusion complexes, surfactant addition, particle size reduction, spray drying and solvent recrystallisation, possess significant limitations on the extent to which they may solubilize insoluble compounds. Recently nanoparticles technology in particular, is being applied to address these drug delivery challenges. Novel technologies, such as supercritical fluid processing, nanosizing and pH modification, present novel methods of solubilization that may allow greater opportunities to deliver poorly soluble drugs. Therefore, there is further need to explore and utilize these newer technologies to improve the effectiveness of the poorly soluble drugs in terms of pharmacokinetics, pharmacodynamics therapy as well as economy. By this article, we conclude that, solubility of the drug is the most important factor that controls the formulation and therapeutic efficacy of the drug, hence the most critical factor in the formulation development. Dissolution is the rate-determining step for oral absorption of the poor water-soluble drugs and solubility is the basic requirement for the formulation and development of different dosage form of different drugs. The various techniques described above can be used either alone or in combination to enhance the solubility of poorly soluble drugs.

ACKNOWLEDGEMENT

The authors are thankful to Director, University Institute of Pharmacy, Pt Ravi Shankar Shukla University Raipur, Chhattisgarh for providing necessary infrastructural facilities. The authors are also thankful to the Department of science and technology (DST-FIST), CCOST/MRP/2012 Endt. No. 1926 and UGC-MRP F. No. 42-706/2013 (SR) for providing financial assistance relating to this work.

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Received on 14.07.2013 Modified on 02.09.2013

Research J. Pharm. and Tech. 6(11): November 2013; Page 1258-1270

Company	Nanoparticulate Technologies	Description
Elan	NanoCrystal	NanoCrystal drug particles (<1,000 nm) produced by wet-milling and stabilised against agglomeration through surface adsorption of stabilisers; applied to NMEs eg aprepitant/reformulation of existing drugs eg. Sirolimus
Eurand	Biorise	Nanocrystals/amorphous drug produced by physical breakdown of the crystal lattice and stabilised with biocompatible carriers (swellable microparticles or cyclodextrins)
SkyePharma	IDD	Insoluble Drug Delivery: micro-nm particulate/droplet water-insoluble drug core stabilised by phospholipids; formulations are produced by high shear, cavitation or impaction
BioSante	CAP	Calcium Phosphate-based nanoparticles: for improved oral bioavailability of hormones/proteins such as insulin; also as vaccine adjuvant
American Bioscience	NAB	Nanoparticle Albumin-Bound technology: injectable suspension of biocompatible protein with drug improves solubility/removes need for toxic solvents; eg paclitaxel-albumin nanoparticles. Nanoparticle Albumin-Bound technology: injectable suspension of biocompatible protein with drug improvessolubility/removes need for toxic solvents; eg paclitaxel-albumin nanoparticles
Baxter	Nanoedge	Nanoedge technology: drug particle size reduction to nanorange by platforms including direct homogenisation, microprecipitation, lipid emulsions and other dispersed-phase technology
Nanostructuring Technologies
pSivida	BioSilicon	Drug particles are structured within the nano-width pores of biocompatible BioSilicon microparticles, membranes or fibres; gives controlled release/improves solubility of hydrophobic drugs
iMEDD	NanoGate	Silicon membrane with nano-width pores (10-100 nm) used as part of an implantable system for drug delivery and biofiltration
PharmaSol	NLC8	Nanostructured Lipid Carriers: nanostructured lipid particle dispersions with solid contents produced by high-pressure homogenisation; lipid-drug conjugate nanoparticles provide high-loading capacity for hydrophilic drugs for oral delivery

Drugs	Technique for solubility enhancement	Reference
Celecoxib, rofecoxib, meloxicam and nimesulide	By using solvents and mixed-solvent systems technique	57
Triflumizole and β Lapachone	Cyclodextrin complexation	58
Griseofulvin, mefenamic acid, nimesulide and ibuprofen	Surfactant-mediated dissolution and Solublization by surfactants	59-60
Valdecoxib, albendazole, celecoxib and ofloxacin	Solid Dispersion Technique and Surface solid dispersions	61-62
Nifedipine	Nanoparticles by high pressure homogenization	63
Acetyl salicylic acid	Particle size reduction and crystal habit modification	64
Meloxicam, caffeine and eflucimibe	Supercritical fluid technology	65-66
Ibuprofen, itraconazole and ketoconazole	Micronization	67
Spironolactone	Nanosuspension (Disso Cubes)	68
Theophylline	Cocrystallization	69
Nimodipine and clonixic acid	Microemulsion	70
Fluasterone and cyclosporin- A	Co-solvency, micellization and complexation.	71
Carbamazepin, danazol and carbamazepine	Spray freezing into liquid (SFL)	72-73
Nifedipine	Cogrinding	74
Dipyridamole	Recrystallization	75