The solubility of drug molecule is one of the most challenging aspect in formulation development. It is crucial to ensure the right concentration of a drug gets into the bloodstream so the bioavailability of the drug causes the desired pharmacological response. Therefore, using a variety of techniques to improve solubility helps drug companies launch a poorly soluble drug compound.
Solubility Enhancement Techniques
Solubility enhancement opportunities using conventional approaches include:
• Addition of surfactant,
• Addition of solubilizing agent,
• Co-solvency,
• Salt formation,
• pH adjustment,
• Particle size reduction,
• Complexation,
• Hydrotropy,
• Solid dispersion etc.
Particle Size Reduction
The solubility of drug is often intrinsically related to drug particle size. Particle size reduction can be achieved by Micronization and Nano-suspension. Micronization increases the dissolution rate of drugs through increased surface area and Nano-suspensions are sub-micron colloidal dispersion of pure particles of drug also increase the dissolution rate is due to larger surface area exposed.
Addition of Solubilizing Agents
The solubility of poorly soluble drug can also be improved by various solubilizing materials. For example: PEG 400 is improving the solubility of hydrochlorothiazide.
Addition of Surfactants
Surfactants improve the drug solubility by avoiding recrystallization. A surfactant can interact with both polar and nonpolar molecules and the highly charged complex better interacts with water and is therefore soluble.
Co-solvency
It is well-known that the addition of an organic co-solvent to water can dramatically change the solubility of drugs.
Salt Formation
It is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. Acidic or basic drug converted into salt having more solubility than respective drug. For example: Aspirin, Theophylline, Barbiturates.
pH adjustment
pH dependent solubility most commonly exhibited by ionizable drugs. Wherein weakly acidic drugs are more soluble at pH> higher than pKa (ionization constant) and weakly basic drugs are soluble at pH lower than pKa.
Hydrotropy
It designate to increase in solubility in water due to presence of large amount of additives. It improves solubility by Complexation involving weak interaction between hydrophobic agents (Sodium benzoate, sodium alginate, urea etc.) & solute.
Complexation
Complexation is the association between two or more molecules to form a non-bonded entity with a well-defined stochiometry. Complexation relies on relatively weak forces such as London forces, hydrogen bonding and hydrophobic interactions. Examples of complexing agents are: EDTA, Cyclodextrins etc.
Solid Dispersion
The term solid dispersion refers to the dispersion of one or more active ingredients in a highly soluble carrier. It is prepared by the melt (fusion) method and solvent evaporation technique. Resulting a high surface area is formed and increase the dissolution rate.
Novel solubility enhancement techniques include
- Spherical crystallization (SC) technique using the spherical agglomeration (SA) method
- Nanotechnology approach for formulating drug compounds as nanoparticles with high specific surface areas
- Particle engineering technique for modifying the physicochemical and biopharmaceutical properties of drug compound
Processing Technologies for Poorly Soluble Compounds
- Spray Drying
- Fluid-Bed Processing
- Roller Compaction
- Hot Melt Extrusion
- Particle Size Reduction
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