DIFFERENT METHODS OF ENHANCEMENT OF SOLUBILIZATION AND BIOAVAILABILITY OF POORLY SOLUBLE DRUGS: A RECENT REVIEW

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Drug dispersion in carriers4,16-19
A.    Solid solution:
A solid solution is a binary system comprising of a solid solute molecularly dispersed in a solid solvent. Since the two compartments crystallize together in a homogeneous one phase system, solid solutions are also called as molecular dispersion or mixed crystals. Because of reduction in particle size to molecular level, solid solutions show greater aqueous solubility and faster dissolution than eutectics and solid dispersion. They are generally prepared by fusion method whereby physical mixture of solute and solvent are melted together followed by rapid solidification. Such systems, prepared by fusion are called as melts e.g. griseofulvin- succinic acid. The griseofulvin from such solid solution dissolves 6 to 7 times faster than pure griseofulvin. Mechanism of solid solution for solubility enhancement is when the binary mixture exposed to water, the soluble carrier dissolves rapidly leaving the insoluble drug in a state of microcrystalline dispersion of very fine particles, and when the solid solution, which is said to be in a state of randomly arranged solute and solvent molecules in the crystal lattice, is exposed to the dissolution fluid, the soluble carrier dissolves rapidly leaving the insoluble drug stranded at almost molecular level.

B.     Eutectic mixtures:
When the eutectic mixture is exposed to water, the soluble carrier dissolves leaving the drug in microcrystalline state which solubilizes rapidly. Eutectic mixture differs from solid solution in that the fused melt of solute-solvent show complete miscibility but negligible solid-solid solubility i.e. such system are basically intimately blended physical mixture of two crystalline components. A simple eutectic mixture consists of two compounds which are completely miscible in the liquid state but only to a very limited extent in the solid state. Solid eutectic mixtures are usually prepared by rapid cooling of a co melt of the two compounds in order to obtain a physical mixture of very fine crystals of the two components. The large surface area of the resulting suspension should result in an enhanced dissolution rate and thereby improved bioavailability.

C.    Solid dispersion:
Solid dispersion (SD) technique has been widely used to improve the dissolution rate, solubility and oral absorption of poorly water-soluble drugs. Solid dispersion is defined as the dispersion of one or more active ingredients in an inert excipient or matrix (carrier), where the active ingredients could exist in finely crystalline, solubilised or amorphous state. Once the solid dispersion is exposed to aqueous media and the carrier dissolve, the drug is released as very fine to colloidal particles. Because of greatly enhanced surface area obtained in this way, the dissolution rate and the bioavailability of poorly water-soluble drugs are expected to be high. The enhanced solubility and dissolution rate of drugs from solid dispersions is based on following mechanisms:
a.       Reduction in particle size provides large surface area.
b.      Particles with improved wettability and dispersibility of drug.
c.       Particles with higher porosity.
d.      Drugs in amorphous state.
e.       Solubilizing effect on the drug by water soluble carrier.
f.       Formation of metastable dispersion.

Various pharmaceutical approaches for the preparation of solid dispersion include co-precipitation, lyophilization, spray drying, melting solvent method, melt extrusion method, solvent evaporation, fusion and powder mixing methods.

CARRIERS FOR SOLUBILITY ENHANCEMENT2,4,16-20
Carriers, which are soluble and dissolve in water at a fast rate, are widely used in pharmaceutical formulations to enhance solubility and dissolution of drugs. Various carriers are used for solubilty enhancement listed mentioned in the table 2.

Table 2: List of carriers used for solubility enhancement

Sr. no.

Category

Examples of carrier

1

Surfactants

Deoxycholic acid, tweens, spans, polyoxyethylene stearate, renex, poloxamer 188.

2

Hydrotrops

Urea, sodium acetate, nicotinamide, sodium benzoate, sodium salicylate, sodium-o-hydroxy benzoate.

3

Insoluble or enteric polymer

Eudragit L100, Eudragit S100, Eudragit RL,

Eudragit RS, Hydroxy propyl methyl cellulose phthalate.

4

Acids

Citric acid, succinic acid.

5

Sugars

Dextrose, sucrose, galactose, sorbitol, maltose, mannitol, lactose.

6

Polymeric materials

Povidone (PVP), polyethylene glycol (PEG), cyclodextrin,

hydroxypropyl methyl cellulose, methyl cellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose.

7

Miscellaneous

Microcrystalline cellulose, dicalcium phosphate, silica gel, sodium chloride.

CONCLUSION
The solubility of the drug is the factor that controls the formulation of the drug as well as therapeutic efficacy of the drug, hence the most critical factor in the formulation development. There are various available techniques, alone or in combination can be used to enhance the solubility of the drug. A drug administered in solution form immediately available for absorption and efficiently absorbed than the same amount of drug administered in a solid dosage form such as tablet or capsule. Solubility is a most important parameter for the oral bioavailability of poorly soluble drugs. Dissolution of drug is the rate determining step for oral absorption of the poorly water soluble drugs, which can subsequently affect the in vivo absorption of drug. Currently only 8-10% of new drug candidates have both high solubility and permeability. Because of solubility problem of many drugs the bioavailability of them gets affected and hence solubility enhancement becomes necessary. It is now possible that to increase the solubility of poorly soluble drugs with the help of various techniques as mentioned above. Numerous technological advancements have been introduced for solubility and dissolution enhancement of poorly water soluble drugs.

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