Introduction

1. Chemical Modifications:
   i) Use of salt forms
   ii) Co-crystallisation
   iii) Co-solvency
   iv) Hydrotrophy
   v) Solubilising agents
   vi) Nanotechnology
2. Physical Modifications:
   i) Particle size reduction
   a) Micronisation
   b) Nanosuspension
   c) Sonocrystallisation
   d) Supercritical fluid process
   ii) Modification of the crystal habit
   a) Polymorphs
   b) Pseudopolymorphs
   iii) Complexation – Use of complexing agents
   iv) Solubilisation by surfactants
   a) Microemulsions
   b) Self microemulsifying drug delivery system
   v) Drug dispersion in carriers

Use of Salt Forms

Salts have improved solubility and dissolution characteristics than the original drug. A minimum difference of 3 units between the pKa value of the group and that of its counter-ion is required to form stable salts. The solubility of alkali metal salts of acidic drugs (like penicillins) and strong acid salts of basic drugs (like atropine) in water is more than that of the parent drug. Factors influencing salt selection are physical and chemical properties of the salt, safety of counterion, therapeutic indications, and administration route.

Salt formation has the following limitations:

1) Salts of neutral compounds cannot be formed.
2) Salts of very weak bases or acids can be formed with much difficulty.
3) The salt may be hygroscopic, exhibit polymorphism, or has poor            processing characteristics.
4) Conversion of salt to free acid or base form of the drug on surface of solid dosage form prevents or retards drug release.
5) Precipitation of unionised drug in the gastrointestinal milieu that has     poor solubility.

Co-Crystallisation

With the application of co-crystals or molecular complexes, drug solubility can be improved. If the solvent forms an integral part of the network structure and at least two component crystal, it is termed as co-crystal. If the solvent does not directly involve itself in the network (as in open framework structures), it is termed as clathrate (or-inclusion complex). A co-crystal is a crystalline material consisting of two or more molecular and electrically neutral species bound by non-covalent forces.

Co-crystals are more stable as the co-crystallising agents are solids at room temperature. Only three co-crystallising agents, i.e., saccharin, nicotinamide and acetic acid, are recognised as safe (GRAS), thus limiting their pharmaceutical applications. Co-crystallisation may also occur between two active pharmaceutical ingredients by using sub-therapeutic amounts of drug substances (such as aspirin or acetaminophen). Co-crystals can be prepared by evaporating a heteromeric solution or by grinding the components together. Another technique of preparing co-crystals includes sublimation, growth from the melt, and slurry preparation. Formation of molecular complexes and co-crystals and their importance is increasing day-by-day as an alternative to salt formation, mainly for neutral compounds or those having weakly ionisable groups.

Cosolvency

Solubilising the drugs in co-solvents is another technique of solubility enhancement of poorly soluble drugs. Adding an organic cosolvent to water can change the drug solubility. Water solubility of weak electrolytes and non-polar molecules is poor and this can be improved by adding another solvent that alters the solvent polarity. This process is termed cosolvency, and the solvent used for increasing solubility is termed a cosolvent.

The system of cosolvent involves solvent blending in which the interfacial tension between the aqueous solution and hydrophobic solute is reduced. Cosolvents mostly have hydrogen bond donor and/or acceptor groups and small hydrocarbon regions. Their hydrophilic hydrogen bonding groups ensure water miscibility, and their hydrophobic hydrocarbon regions interfere with water’s hydrogen bonding network, thus reducing the intermolecular attraction of water. Cosolvents disrupt the water’s self-association, reduce water’s ability to squeeze out non-polar, hydrophobic compounds, and thus increase solubility. A different perception is that cosolvents facilitate solubilisation by making the polar water environment more non-polar like the solute. Solubility enhancement as high as 500 -fold is achieved by using 20% of 2 -pyrrolidone.

Hydrotrophy

Hydrotrophy is the increase in water solubility due to the presence of large amounts of additives. Its mechanism of improving solubility is closely related to complexation that involves a weak interaction between the hydrotrophic agents (e.g., sodium benzoate, sodium acetate, sodium alginate, and urea) and the solute. An example of hydrotrophy is solubilisation of theophylline with sodium acetate and sodium alginate.

Solubilising Agents

Solubility of poorly soluble drugs can also be improved by using solubilising materials. For example, PEG 400 is used for improving the solubility of hydrochlorothiazide; Modified Gum Karaya (MGK) was evaluated as a carrier for dissolution enhancement of nimodipine; addition of caffeine and nicotinamide for improving the aqueous solubility of halofantrine (antimalarial).

Nanotechnology Approaches

Nanotechnology is the study and use of materials and structures at the nanoscale level of approximately 100 nanometers  (nm) or less. For many new chemical entities of low solubility, enhancement of oral bioavailability by micronisation is not sufficient because the micronised product may undergo agglomeration, which decreases the effective surface area for dissolution.

Particle Size Reduction

Particle size reduction techniques by various milling processes are wellestablished and are a standard part of formulation development. Particle size of the drug is reduced by micronisation, nanosuspension, sonocrystallisation, etc. techniques. As particle size decreases, surface area of particle increases, and this increases the solubility.

Micronisation

Drug solubility is often intrinsically related to drug particle size. By reducing the particle size of the drug, its surface area is increased and its dissolution properties are improved. The conventional methods of particle size reduction (such as comminution and spray drying) rely on mechanical stress to disaggregate the active compound. Micronisation is used to increase the surface area for dissolution.

Nanosuspension

Nanosuspensions are sub-micron colloidal dispersion of pure drug particles, which are stabilised by adding surfactants. They offer the advantages of increased dissolution rate due to larger surface area exposed, and absence of Ostwald ripening due to the uniform and narrow particle size range obtained that eliminates the concentration gradient factor.

Sonocrystallisation

Recrystallisation of poorly soluble materials with liquid solvents and anti-solvents has been successfully employed for particle size reduction. Sonocrystallisation is a novel approach for particle size reduction that involves inducing crystallisation using ultrasound waves at a frequency range of 20-100kHz . This technique enhances the nucleation rate, is an effective means of size reduction, and also controls size distribution of the active pharmaceutical ingredients. In most cases, ultrasound waves are used in the range of 20 kHz-5 MHz  .

Supercritical Fluid Process

Application of novel nanosizing and solubilisation technology has increased the use of Supercritical Fluid (SCF) processes for particle size reduction. SCF is a dense non-condensable fluid with temperature and pressure greater than its critical temperature (Tc) and critical pressure (Tp). By manipulating the pressure of SCFs, the favourable properties of gases, like high diffusivity, low viscosity, and low surface tension, may be imparted upon liquids to control drug solubilisation with a supercritical fluid. SCFs are highly compressible, and allow moderate changes in pressure to alter the density and mass transport characteristics of fluid, which determine its solvent power.

Once the drug particles solubilise in SFs, they may be recrystallised at reduced particle sizes. SCF process allows micronisation of drug particles within a narrow range of particle size, often to sub-micron levels. The current SCF processes have the ability to create nanoparticulate suspensions of particles 5-2000nm in diameter. The most widely employed SCF processing methods for micronised particles are Rapid Expansion of Supercritical Solutions (RESS) and gas antisolvent recrystallisation (GAS). These methods are used by the pharmaceutical industries using carbon dioxide (CO₂) as the SCF due to its favourable processing characteristics like low critical temperature  (Tc = 31.10ºC) and pressure  Pc = 73.8 bar).

In the method of RESS, a drug or a mixture of drug and polymer is solubilised in SCF and this solution is sprayed through a conventional nozzle or capillary tube into a lower pressure environment. Rapid expansion the solution undergoes reduces CO₂ density and its solvent power, thus supersaturating the lower pressure solution. This supersaturation results in the recrystallisation and precipitation of pure drug or drug-polymer particles of greatly reduced size, narrow size distribution, and high purity.

For example, solubility of nifedipine has been improved by using RESS. In the GAS process, the drug or drugpolymer mixture is solubilised into a solvent via conventional means and then sprayed into a SCF; the drug should be insoluble in the SCF, and the SCF should be miscible with the organic solvent. The SCF diffuses into the spray droplets, causing expansion of the present solvent, and precipitation of the drug particles.