A recent review on enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications

About Authors:
Tarun Garg, Ajay Bilandi,
Seth G.L.Bihani S.D.college of technical education,
Sri Ganganagar

The aim of this review is to improve the solubilization and bioavailability of poorly soluble drugs by using various approaches like physical, chemical and others modifications or techniques. The solubility of a solute is the maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Drug efficacy can be severely limited by poor aqueous solubility and some drugs also show side effects due to their poor solubility. There are many techniques which are used to enhance the aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to increasing efficiency and/or reducing side effects for certain drugs. This is true for parenterally, topically and orally administered solutions. Physical modifications techniques like media milling/ nanocrystal technology, cryogenic technology, supercritical fluid process, modification of the crystal habit,complexation, micellar technologies, chemical modifications, other techniques like co-crystallization, cosolvency, hydrotrophy are used for increase the solubility of very soluble drugs like dolargin, loperamide, tubocurarine, doxorubicin, ibuprofen, griseofulvin, diazepam, naproxen, carbamazepine, nifedipine, phytosterol etc.

Refernce Id: PHARMATUTOR-ART-1153

Solubilization of poorly soluble drugs is a frequently encountered challenge in screening studies of new chemical entities as well as in formulation design and development [1,2]. A number of methodologies can be adapted to improve solubilization of poor water soluble drug and further to improve its bioavailability. Orally administered drugs completely absorb only when they show fair solubility in gastric medium and such drugs shows good bioavailability. Bioavailability depends on several factors, drug solubility in an aqueous environment and drug permeability through lipophilic membranes being the important ones [3]. The techniques generally employed for solubilization of drug includes micronization, chemical modification, pH adjustment, solid dispersion, complexation, co?solvency, micellar solubilization, hydrotropy etc. Actually, only solubilized drug molecules can be absorbed by the cellular membranes to subsequently reach the site of drug action (vascular system for instance). Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption [4-7].  As Solubility & permeability is the deciding factor for the in-vivo absorption of the drug, these can be altered or modified by enhancement techniques like [8]. Poorly soluble compounds belongs to class II of BCS, also present many in vitro formulation obstacles, such as severely limited choices of delivery technologies and increasingly complex dissolution testing with limited or poor correlation to the in vivo absorption. Recently more than 40% NCEs (new chemical entities) developed in Pharmaceutical Industry are practically insoluble in water. These poorly water soluble drugs are allied with slow drug absorption leading to inadequate and variable bioavailability and gastrointestinal mucosal toxicity [9]. Therefore, the improvement of drug solubility thereby its oral bio-availability remains one of most challenging aspects of drug development process especially for oral drug delivery system.  These in vivo and in vitrocharacteristics and the difficulties in achieving predictable and reproducible in vivo/in vitro correlations are often sufficiently difficult to develop formulation on many newly synthesized compounds due to solubility issues [10,11]. Although pharmaceutical companies have been able to overcome difficulties with very slightly soluble drugs, those with aqueous solubility of less than 0.1 mg/ml present some unique challenges. This review thus begins with discussion regarding the traditional approaches to drug solubilisation include Ph adjustment, cosolvency and particle size reduction. While microemulsion and self-emulsifying systems are novel approaches.These drugs are particularly good candidates for advanced solubilization technologies developed by companies specializing in drug delivery. Traditional approaches to drug solubilisation include particle size reduction, pH adjustment and addition of surfactants and cosolvents, while microemulsion and self-emulsifying systems are novel approaches. There are numerous approaches available and reported in literature to enhance the solubility of poorly water soluble drug. The techniques are chosen on the basis of certain aspects such as properties of drug under consideration, nature of excipients to be selected and nature of intended dosage form. This review is intended to discuss the various traditional and novel techniques for solubility enhancement of hydrophobic drugs for oral pharmaceutical formulation.

The process of solubilisation involves the breaking of intermolecular or inter-ionic bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion [12]. Solubilisation process occurs into three steps. (Fig. 1).

The solubility depends on the nature and composition of solvent medium, the physical form of the solid as well as temperature and pressure of system. Consider a lot of factor, which affects the solubility like-

(1) Particle Size
The size of the solid particle influences the solubility because as a particle becomes smaller, the surface area to volume ratio increases of the particle. The larger surface area allows a greater interaction with the solvent. The effect of particle size on solubility can be described

Where, S0 is the solubility of infinitely large particles, S is the solubility of fine particles, V is molar volume, r is the radius of the fine particle and γ is the surface tension of the solid. 

As the temperature is increased than the solution process absorbs energy and the solubility will be increased but if the solution process releases energy then the solubility will decrease with increasing temperature. A few solid solutes are less soluble in warm solutions. For examples all gases, solubility decreases as the temperature of the solution increases.

(3) Pressure
For solids and liquid solutes, changes in pressure have practically no effect on solubility but for gaseous solutes, an increase in pressure, increases solubility and a decrease in pressure, decrease the solubility.

(4) Nature of the solute and solvent
Only 1 gram of lead (II) chloride can be dissolved in 100 grams of water at room temperature while 200 grams of zinc chloride can be dissolved. The great difference in the solubility’s of these two substances is the result of differences in their natures. 


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