You are hereDIFFERENT METHODS OF ENHANCEMENT OF SOLUBILIZATION AND BIOAVAILABILITY OF POORLY SOLUBLE DRUGS: A RECENT REVIEW

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


About Authors:
Patel Chirag J*, Asija Rajesh, Asija Sangeeta
Maharishi Arvind Institute of Pharmacy, Department of Pharmaceutics,
Jaipur, Rajasthan.
*chirag.bangalore@gmail.com

ABSTRACT
Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. The insufficient dissolution rate of the drug is the limiting factor in the oral bioavailability of poorly water soluble compounds. This review discusses BCS classification, carriers for solubility enhancement and different techniques for solubility enhancement.Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include micronization, nanonization, sonocrystallization, supercritical fluid method, spray freezing into liquid and lyophilization, evaporative precipitation into aqueous solution, use of surfactant, use of co-solvent, hydrotropy method, use of salt forms, solvent deposition, solubilizing agents, modification of the crystal habit, co-crystallisation, complexation and drug dispersion in carriers.Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.With the advent of combinatorial chemistry and a high throughput screening, the number of poorly water soluble compounds has increased solubility. A success of formulation depends on how efficiently it makes the drug available at the site of action.The purpose of this review article is to describe the techniques of solubilization for the attainment of effective absorption with improved bioavailability.


Reference Id: PHARMATUTOR-ART-1424

INTRODUCTION
When an active agent given orally, it must first dissolves in gastric and/or intestinal fluids before it can permeate the membranes of the GI tract to reach systemic circulation. Therefore, a drug with poor aqueous solubility will typically exhibit dissolution rate limited absorption, and a drug with poor membrane permeability will typically exhibit permeation rate limited absorption. Hence, two areas focus on improving the oral bioavailability of active agents include:
1. Enhancing solubility and dissolution rate of poorly water-soluble drugs
2. Enhancing permeability of poorly permeable drugs1.

The solubility is defined as a maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature2. Almost More than 90% drugs are orally administered. Drug absorption, bioavailability, pharmacokinetic profile of orally administered drug substances is highly dependent on solubility of that compound in aqueous medium. More than 90% of drugs are approved since 1995 have poor solubility. It is estimated that 40% of active new chemical entities (NCEs) identified in combinatorial screening programs employed by many pharmaceutical companies are poorly water soluble3. Solvent is defined asthe component which forms major constituent of a solution and is capable to dissolve another substance to form a uniformly disperse mixture at the molecular level.Soluteis defined as asubstance that present in small quantity and dissolves in solvent2.


Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Oral drug delivery is the simplest and easiest way of administering drugs due to its convenience, good patient compliance, greater stability, accurate dosage and easy production. Drug solubility is the maximum concentration of the drug dissolved in the solvent under specific condition of temperature, pH and pressure. It is important to improve the solubility and/or dissolution rate for poorly soluble drugs because these drugs possess low absorption and bioavailability. As solubility is an important determinant in drug liberation hence it plays a key role in its bioavailability. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption4.

Table 1: Solubility description table5

Definition

Parts of solvent required for one part of solute

Very Soluble

< 1

Freely soluble

1 – 10

Soluble

10 – 30

Sparingly soluble

30 – 100

Slightly

100 – 1000

Very slightly soluble

1000 – 10,000

Insoluble

> 10,000

BCS CLASSIFICATION4,6

Class I: High permeability and solubility.
Formulation independent:
The bioavailability of class I compounds is determined only by delivery of the drug solution to the intestine.
Examples: Loxoprofen , Benzapril, Sumatriptan etc.

Class II: High permeability but low solubility
Formulation dependent:
The bioavailability of class II compounds is limited by drug solubility/dissolution.
Examples: Aceclofenac , Valsartan, Nimesulide, Loratadine etc.

Class III: Low permeability but high solubility
Dependent on barrier properties:
The bioavailability of class III compounds is limited by intestinal permeability.
Examples: Atropine, Gabapentine, Topiramate etc.

Class IV: Low permeability and low solubility
Formulation and barrier properties dependent:
The bioavailability of class IV compounds is limited both by solubility/dissolution and intestinal permeability.
Examples: Hydrochlorthiazide, Meloxicam, Furosemide etc.

TECHNIQUES FOR SOLUBILITY ENHANCEMENT
There are various techniques available to improve the solubility of poorly soluble drugs. Some of the approaches to improve the solubility are
Micronization
4,8
Particle size reduction leads to increase in the effective surface area resulting in enhancement of solubility and dissolution velocity of the drug. Micronization technique is used to improve dissolution rates of drugs into the biological environment, in order to improve the oral bioavailability. Particle size reduction methods include recrystallization of the solute particles from solutions using liquid antisolvents, along with labor intensive techniques like crushing, milling, grinding, freeze drying and spray-drying. The rapid expansion of supercritical solutions (RESS) is an alternative technique for the micronization of particles using supercritical carbon dioxide to quickly and naturally reduce the particle sizes of various drugs. Micronization has some limitations; micronization of sparingly or poorly soluble drugs is by no means a guarantee of better dissolution and absorption. A hydrophobic powder with small particle size leads to aggregation, making it difficult to disperse. The particles float on the dissolution medium because of entrapped air. It is difficult to remove or wet these particles. All these effects, in fact, reduce the rate of dissolution.

Nanonization2,4,8
Various nanonization strategies have emerged to increase the dissolution rates and bioavailability of numerous drugs that are poorly soluble in water. Nanonization broadly refers to the study and use of materials and structures at the nanoscale level of approximately 100 nm or less. Nanonization can result in improved drug solubility and pharmacokinetics, and it might also decrease systemic side-effects. For many new chemical entities with very low solubility, oral bioavailability enhancement by micronization is not sufficient because micronized product has the tendency to agglomerate, which leads to decrease effective surface area for dissolution, the next step is nanonization. There are different techniques used for nanonization of drug including Wet milling, Homogenization, Emulsification-solvent evaporation technique, Pear milling, Spray drying etc. There are many examples of nanonization of drugs.
A.   
Nanocrystals:
The term drug nanocrystals imply a crystalline state of the discrete particles, but depending on the production method they can also be partially or completely amorphous. Drug nanocrystals can be produced by bottom up technologies (precipitation methods) or alternatively by top down technologies (size reduction methods). The at present most industrially feasible methods are the top down technologies, all products on the market are made by size reduction.

B.     Nanosuspension:
Nanosuspensions are sub-micron colloidal dispersion of pure particles of drug, which are stabilised by surfactants. Nanosuspension technology solved the problem of drugs which are poorly aqueous soluble and less bioavailability. Stability and bioavailability of the drugs can be improved by the Nanosuspension technology. Nanosuspensions are prepared by using wet mill, highpressure homogenizer, emulsion?solvent evaporation, melt emulsification method and super critical fluid techniques. Nanosuspensions can be delivered by oral, parenteral, pulmonary and ocular routes.

C.    Nanoemulsion:
Nanoemulsions are a nonequilibrium, heterogeneous system consisting of two immiscible liquids in which one liquid is dispersed as droplets in another liquid. Emulsions with nanoscopic droplet sizes (typically in the range of 20–200 nm) are often referred to as submicron emulsions. Nanoemulsions are composed of oil droplets dispersed in an aqueous medium and stabilized by surfactant molecules. The methods used for the production of nanoemulsions include HPH, microfluidization, ultrasonication and spontaneous emulsification. Commercial products that are nanoemulsions include Estrasorb and Flexogan.

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