Sonocrystallization is a novel particle engineering technique to enhance solubility and dissolution of hydrophobic drugs and to study its effect on crystal properties of drug. Recrystallization of poorly soluble materials using liquid solvents and antisolvents has also been employed successfully to reduce particle size by using ultrasound. Sonocrystallization utilizes ultrasound power characterized by a frequency range of 20–100 kHz for inducing crystallization. Most applications use ultrasound in the range 20 kHz-5 MHz. Melt sonocrystallization (MSC) is promising technique of sonocrystallization to obtain porous, amorphous material with high stability.

Supercritical fluid method4,10,11,12
A supercritical fluid (SCF) can be defined as a dense noncondensable fluid is a novel nanosizing and solubilisation technology. A SCF process allows the micronization of drug particles within sub micron levels. Supercritical fluids are fluids whose temperature and pressure are greater than critical temperature (Tc) and critical pressure (Tp). At near-critical temperature, SCFs are highly compressible, allowing moderate changes in pressure to greatly alter the density and mass transport characteristics of a fluid that largely determine its solvent power. Once the drug particles are solubilised within SCF, they may be recrystallised at greatly reduced particle size. Carbon dioxide and water are the most commonly used supercritical fluids. The SCF process can create nanoparticulate suspensions of particles 5–2000 nm in diameter.

Spray freezing into liquid and lyophilization4
This technique involves atomizing an aqueous, organic, aqueous-organic cosolvent solution, aqueous organic emulsion or suspension containing a drug and pharmaceutical excipients directly into a compressed gas (i.e. carbon dioxide, helium, propane, ethane), or the cryogenic liquids (i.e. nitrogen, argon or hydrofluroethers). The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders. The dissolution rate is enhanced from the SFL (Spray freezing into liquid) powder containing amorphous nanostructured aggregates with surface area and excellent wettability.

Evaporative precipitation into aqueous solution4
This process utilizes rapid phase separation to nucleate and grow nanoparticles and microparticles of lipophilic drugs. The solution is pumped through a tube where it is heated under pressure to a temperature above the solvent’s boiling point and then sprayed through a fine atomizing nozzle into a heated aqueous solution. Surfactants are added to the organic solution on the aqueous solution to optimize particle formation and stabilization.

Use of surfactant4
Surface active agents (surfactants) are substances which at low concentrations, adsorb onto the surfaces or interfaces of a system and alter the surface or interfacial free energy and the surface or interfacial tension. Surface active agents have a characteristic structure, possessing both polar (hydrophilic) and non-polar (hydrophobic) regions in the same molecule. Thus, surfactants are said to be amphipathic in nature. Depending on their charge characteristics the surface-active molecules may be anionic, cationic, zwitterionic (ampholytic) or non-ionic. Various surfactants like Polyglycolized glyceride (Labrasol), Tweens, Spans, Polyoxyethylene stearates and synthetic block copolymers like Poly (propylene oxide)-poly (ethylene oxide) – poly (propylene oxide), Poly (beta-benzyl-Laspartate), b-poly (ethylene oxide) etc used as carrier for solubility and dissolution enhancement. Improvement of drug solubility by using the amphiphilic surfactants is due tolowering of surface tension between drug and solvent, improvement of wetting characteristics and micellar solubilization of the drugs. To get any substantial solubility enhancement, the surfactant concentration must be at least above the critical micelle concentration (CMC). The CMC will depend upon the surfactant itself and the ionic strength of the media. The amount of surfactant needed depends on the CMC and the degree to which the compound partitions into the surfactant micelles.

Use of co-solvent4,13
Cosolvent addition is a highly effective technique for enhancement of solubility of poorly soluble drugs. It is well-known that the addition of an organic cosolvent to water can dramatically change the solubility of drugs. Weak electrolytes and nonpolar molecules have poor water solubility and it can be improved by altering polarity of the solvent. This can be achieved by addition of another solvent. This process is known as cosolvency. Solvent used to increase solubility is known as cosolvent. Cosolvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute. The use of mixed solvent system is often necessary in pharmaceuticals when a drug is poorly soluble. Co-solvents such as ethanol, propylene glycol, glycerin, sorbitol and polyoxyethylene glycols, dimethylsulfoxide, ethanol and N, N dimethyl formamide can be used.

Hydrotropy method4,14,15
Hydrotropy is a solubilization phenomenon whereby addition of large amount of a second solute results in an increase in the aqueous solubility of another solute. The term “Hydrotropy” has been used to designate the increase in aqueous solubility of various poorly water soluble compounds due to the presence of a large amount of additives. The mechanism by which it improves solubility is more closely related to complexation involving a weak interaction between the hydrotrophic agents and the solute. Solute consists of alkali metal salts of various organic acids. Hydrotropic agents are ionic organic salts. Specific examples include ethanol, aromatic alcohols like resorcinol, urea, sodium ascorbate, pyrogallol, catechol, a- and b-naphthols and salicylates, alkaloids like caffeine and nicotine, ionic surfactants like diacids, SDS (sodium dodecyl sulphate) and dodecylated oxidibenzene. Hydrotropy is used for solubility enhancement of different class of drugs such as anti?tumor, anti?viral, anti?inflammatory, antipyretic and analgesic drugs, xanthine derivatives etc. Hydrotropy issuccessfully applied for solubility enhancement of nimesulide, riboflavin, nifedipine, xanthine derivatives like theophylline and caffeine.

Use of salt forms4
A major improvement in solubility and dissolution rate can be achieved by forming a salt. Salts of acidic and basic drugs have, in general, higher solubilities than their corresponding acid or base forms. For solid dosage forms, dissolution rates of salt forms of several weakly acidic compounds under gastrointestinal (GI) pH conditions were much higher than those of their respective free acid forms. This may be attributed the higher dissolution rate of a salt to its higher solubility (relative to the free acid form) in the aqueous diffusion layer surrounding the solid. Alkali metal salts of acidic drugs like penicillins and strong acid salts of basic drugs like atropine are more water soluble than the parent drug.

Solvent deposition4
In this technique drug is dissolved in a solvent like methylene chloride to produce a clear solution. The carrier is then dispersed in the solution by stirring and the solvent is removed by evaporation under temperature and pressure. The resultant mass is then dried, pulverized, and passed through a sieve. The increase in the dissolution rate is ascribed to the reduced particle size of the drug deposited on the carrier and enhanced wettability of the particles brought about by the carrier. Succesfully solubility of aceclofenac has increase by solvent deposition technique using lactose.

Solubilizing agents4
Solubilizing materials like superdisintegrants such as crospovidone, crosscarmellose sodium and sodium starch glycolate used as solubilizing agents in many formulation which increase the solubilty and dissolution rate of poorly water soluble drugs. The superdisintegrants acts as hydrophilic carrier for poorly water soluble drug. PEG 400 used to improve the solubility of hydrochlorthiazide. Modified gum karaya (MGK), a developed excipient was evaluated as carrier for dissolution enhancement of poorly soluble drug nimodipine. The aqueous solubility of the antimalarial agent halofantrine was increased by the addition of caffeine and nicotinamide.

Modification of the crystal habit4
Polymorphism is the ability of an element or 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. Broadly polymorphs can be classified as enantiotrope and monotropes on the basis of thermodynamic properties. In the case of an enantiotropic system, one polymorphs form can change reversibly into another at a definite transition temperature below the melting point, while no reversible transition is possible for monotrope. Once the drug has been characterized under one of this category, further study involves the detection of metastable form of crystal. Metastable forms are associated with higher energy and thus higher solubility. Similarly the amorphous form of drug is always more suited than crystalline form due to higher energy associated and increase surface area. Generally, the anhydrous form of a 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 anhydrates (i.e. thermodynamically higher energy state) for further interaction with water. On the other hand, the organic (nonaqueous) solvates have greater solubility than the nonsolvates. Some drugs can exist in amorphous form (i.e. having no internal crystal structure). Such drugs represent the highest energy state and can be considered as super cooled liquids. They have greater aqueous solubility than the crystalline forms because they require less energy to transfer a molecule into solvent. Thus, the order for dissolution of different solid forms of drug is amorphous > metastable polymorph > stable polymorph. Melting followed by a rapid cooling or recrystallization from different solvents can produce metastable forms of a drug.

The new approach available for the enhancement of drug solubility is through the application of the co-crystals, also referred as molecular complexes. A co-crystal may be defined as a crystalline material that consists of two or more molecular (and electrically neutral) species held together by non-covalent forces. Co-crystals are more stable, particularly as the co-crystallizing agents are solids at room temperature. Only three of the co-crystallizing agents are classified as generally recognized as safe (GRAS) which includes saccharin, nicotinamide and acetic acid limiting the pharmaceutical applications. Co-crystals can be prepared by evaporation of a heteromeric solution or by grinding the components together. Another technique for the preparation of co-crystals includes sublimation, growth from the melt, and slurry preparation. The formation of molecular complexes and co-crystals is becoming increasingly important as an alternative to salt formation, particularly for neutral compounds or those having weakly ionisable groups.

The most common complexing ligands are cyclodextrins, caffeine, urea, polyethylene glycol, N methylglucamide. Considerable increase in solubility and dissolution of the drug has been achieved by the use of cyclodextrins. Cyclodextrins are non-reducing, crystalline, water soluble, cyclic, oligosaccharides. Cyclodextrins consist of glucose monomers arranged in a donut shape ring. Three naturally occurring cyclodextrins are α-Cyclodextrin, β-Cyclodextrin, and γ- Cyclodextrin. The complexation with cyclodextrins is used for enhancement of solubility. Cyclodextrin inclusion is a molecular phenomenon in which usually only one guest molecule interacts with the cavity of a cyclodextrin molecule to become entrapped and form a stable association. The internal surface of cavity is hydrophobic and external is hydrophilic; this is due to the arrangement of hydroxyl group within the molecule. Molecules or functional groups of molecules those are less hydrophilic than water, can be included in the cyclodextrin cavity in the presence of water. In order to become complex, the "guest molecules" should fit into the cyclodextrin cavity. The cavity sizes as well as possible chemical modifications determine the affinity of cyclodextrins to the various molecules.



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