SOLID DISPERSION- STRATEGY TO ENHANCE SOLUBILITY AND DISSOLUTION OF POORLY WATER SOLUBLE DRUGS

Improving oral bioavailability of drugs those given as solid dosage forms remains a challenge for the formulation scientists due to solubility problems. Over the years a variety of solubilization techniques have been studied and widely used, as maximum drugs are poorly water soluble in pharmaceutical field. The enhancement of dissolution rate and oral bioavailability is one of the greatest challenges in the development of poorly water soluble drugs. Solid dispersions have attracted many researchers as an efficient means of improving the dissolution rate and hence the bioavailability of a range of poorly water-soluble drugs. The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic inert carrier or matrix and a hydrophobic drug. Solid dispersion can form either a eutectic mixture or solid solution or glass solution or amorphous precipitation in a crystalline carrier or compound or complex formation. The focus of this review article is on the advantages, limitations, various methods of preparation and characterization of the solid dispersion.


INTRODUCTION
Oral drug delivery is the most popular, simplest and easiest way for drugs administration. When a drug is administered orally, it must dissolve in gastric and/or intestinal fluids in order to permeate the membranes of the GI tract to reach systemic circulation 1 . 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. Maximum drugs have poor solubility 2 . Hence, pharmaceutical research that focus on improving the oral bioavailability of active agents by enhancing solubility and dissolution rate of poorly water-soluble drugs 3 . The term solid dispersion refers to a group of solid products consisting of a hydrophilic matrix and a hydrophobic drug. The matrix can be amorphous or crystalline in nature. Solid dispersion need not necessarily exist in the micronized state. A fraction of the drug might molecularly disperse in the matrix, thereby forming a solid dispersion 4 . When the solid dispersion comes in contact of aqueous media, the carrier dissolves and the drug release as a fine colloidal particle, resulting enhanced surface area. This results in higher dissolution rate and bioavailability of poorly water soluble drugs 5 . In addition, in solid dispersion a portion of drug dissolves immediately to saturate gastro intestinal tract fluid and excess drug precipitates as fine colloidal particles or only globules of submicron size. Solid dispersion technologies are particularly promising for improving the oral absorption and bioavailability of BCS Class II drugs 6 . BCS takes into account three major factor; solubility, intestinal permeability and dissolution rate, all of which govern the rate extent of oral drug absorption from solid oral-dosage forms 7 . It classifies drugs into four classes as shown in Table 1.

TYPES OF SOLID DISPERSION 1. Eutectic mixtures
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. These systems are usually prepared by melt fusion method. When the eutectic mixture is exposed to water, the soluble carrier dissolves leaving the drug in a microcrystalline state which gets solubilized rapidly. The increase in surface area is mainly responsible for increased rate of dissolution 14 . Examples of this type include phenacetin-phenobarbital, Chloramphenicol-urea, griseofulvin-succinic acid, and paracetamol-urea.

. Solid solution
These consist of a solid solute dissolved in a solid solvent. The particle size of the drug in the solid solution is reduced to its molecular size. Solid solutions are comparable to liquid solutions, consisting of just one phase irrespective of the number of components. These systems are generally prepared by solvent evaporation or co-precipitation method, in which solute and carrier are dissolved in a common volatile solvent such as alcohol 15 . Solid solution differs from eutectic mixture in a way that the drug is precipitated out in an amorphous form in solid dispersion/solution while it is in crystalline form in eutectics. Solid solution can generally be classified according to the extent of miscibility between the two components or the crystalline structure of the solid solution asi). Continuous Solid Solutions: In this system, the two components are miscible or soluble at solid state in all proportions. Although it is theoretically possible but no established solid solution of this kind has been shown to exhibit faster dissolution properties. The presence of a small amount of the soluble carrier in the crystalline lattice of the poorly soluble drugs may also produce a dissolution rate faster than the pure compound with similar particle size 16 .   The solute (guest) molecule occupies the interstitial space of the solvent (host) lattice. It usually forms only a discontinuous (limited) solid solution. The size of the solute is critical in order to fit into the interstices. It was found that the apparent diameter of the solute molecules should be less than that of the solvent in order to obtain an extensive interstitial solid solution of metals 19 .

3) Glass solution
It is a homogenous system in which a glassy or a vitreous carrier solubilized drug molecules in its matrix. By an abrupt quenching of the melt, the glassy or vitreous state is usually obtained. It is characterized by transparency and brittleness below the glass transition temperature. On heating, it softens progressively without a sharp melting point 20 .

4) Compound or complex formation
This system is characterized by complexation of two components in a binary system during solid dispersion preparation. Rate of dissolution and gastrointestinal absorption can be increased by the formation of a soluble complex with low association constant 21 .

PREPARATION OF SOLID DISPERSIONS 1. Fusion method
First solid dispersions created for pharmaceutical application were prepared by the fusion method. It is also referred as the melt method only when the starting materials are in crystalline state. Drug and carrier mixture of eutectic composition is molten at temperature above its eutectic temperature. Then molten mass is solidified on an ice bath and pulverized to a powder. The solidification is often performed on stainless steel plates to facilitate rapid heat loss. A modification of the process involves spray congealing from a modified spray drier onto cold metal surfaces 22 .

Freeze-drying method:
This method consists of dissolving the drug and carrier in a common solvent, which is immersed in liquid nitrogen until it is fully frozen. Then, the frozen solution is further lyophilized. An important advantage of freeze drying is that the drug is subjected to minimal thermal stress during the formation of the solid dispersion. Furthermore the risk of phase separation is minimized as soon as the solution is vitrified 23 .

Spray-drying:
This method consists of dissolving or suspending the drug and carrier, then spraying it into a stream of heated air flow to remove the solvent. Due to the large specific surface area offered by the droplets, the solvent rapidly evaporates and the solid dispersion is formed within seconds, which may be fast enough to prevent phase separation 24 .

Dropping method:
It is a new procedure for producing round particles from melted solid dispersions. This method does not use organic solvents and, therefore, has none of the problems associated with solvent evaporation. A solid dispersion of a melted drug carrier mixture is pipetted and then dropped onto a plate, where it solidifies into round particles. The size and shape of the particles can be influenced by factors such as the viscosity of the melt and the size of the pipette. This method also avoids the pulverization and compressibility difficulties 25 .

Solvent evaporation method:
The solvent evaporation method consists of the solubilization of the drug and carrier in a volatile solvent that is later evaporated such as ethanol, chloroform, mixture of ethanol and dichloromethane. The solvent evaporation process uses organic solvents, the agent to intimately mix the drug and carrier molecules. Vacuum evaporation may be used for solvent removal at low temperature and also at a controlled rate. More rapid removal of the solvent may be accomplished by freezedrying. The difficulties in selecting a common solvent to both drug and carrier may be overcome by using an azeotropic mixture of solvent in water 26 .
ISSN: 2456-8058 53 CODEN (USA): UJPRA3 Figure 6: Solvent evaporation method 6. Supercritical fluid methods In this method carbon dioxide is used as an antisolvent for the solute but as a solvent with respect to the organic solvent. In these technique drug and carrier are dissolved in a common solvent leads to particle formation vessel through a nozzle using carbondioxide 27 . In addition the ability of carbon dioxide to plasticize and swell polymers can also be exploited and the process can be carried out near room temperature. Moreover, supercritical fluids are used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. The temperature condition used in this process is fairly mild (35-75°C), which allows handling of heat sensitive biomolecules, such as enzymes and proteins. The use of this method reduces residual solvent content, particle size without any degradation 28 .

Co-precipitation method
In this method non-solvent is added drop wise to the drug and carrier solution, under constant stirring. In the course of the non-solvent addition, the drug and carrier are co-precipitated to form micro particles. At the end, the resulted micro particle suspension is filtered and dried 29 . 8. Hot melt extrusion method: In this method extruder is utilized for intense mixing of components. The components of the extruder are barrel, hopper, a kneading screw, heating jacket, and a die. Physical mixture of both the carrier and drug is introduced into the hopper then passed through screw and finally it is extruded from the die. The product produced by this method can easily be handled because any shape can be adopted 30 .

CHARACTERIZATION 1. Microscopic Methods
These methods are used to determine size and observe morphology of solid dispersion. In scanning electron microscopy sample coated by gold or palladium -using vacuum evaporator examined at accelerating voltage with suitable magnification 31 .

Spectroscopic methods a. FTIR spectroscopy
This is used to check interaction between drug and carrier used in formulation of solid dispersion. Appearance and disappearance of peak indicate interaction between two compound and degradation of drug 32 . b. UV visible Spectroscopy Spectra of pure drug and dispersed drug are scanned. Calculation of molar extinction provides evidence of any decomposition 33 .
c. X-ray diffraction spectroscopy This is used to study quantitatively the concentration of crystalline compound in mixture. It is efficient tool in studying physical nature of solid dispersion. Intensity of X-ray diffraction (or reflected) from sample is measured as function of diffraction angle. Compound or complex formation can be detected by change in spectra of pure drug 34 .

Thermal Methods
These methods include exposure of sample to different temperature condition. Studying physicochemical interaction between drug and carrier is based on principle of change in thermal energy as function of temperature 35 .

a. Thaw Melting Method
In this method samples are frozen heated and suddenly converted from solid state to liquid state. Thaw point and melting point can be noted. A limitation of this method is that it depends upon subjective observation, therefore not highly reproducible 36 .

b. Cooling curve Methods
In this method prepared physical mixtures are heated and homogeneous melt temperature of each mixture is noted. Limitations of this method include time consuming process, it requires relatively large amount of sample and not suitable for heat sensitive material 37 . c. Differential Thermal Analysis (DTA) In this study the temperature difference that develops between a sample and an inert reference material is measured, at identical heat treatments. Phase transitions or chemical reactions can be followed by absorption or evolution of heat 38 .

d. Differential Scanning Calorimetry (DSC)
This technique it is used to observe fusion and crystallization events, glass transition temperatures, oxidation, as well as other chemical reactions 39 .

Dissolution Studies
Carried out at physiological temperature by using type II USP dissolution apparatus. Dissolution profile of solid dispersion or compressed tablet made from solid dispersion is determined by comparison between dissolution profile of pure drug, physical mixture and solid dispersion gives idea about dissolution rate. Effect of different carrier and their different proportion on dissolution rate of solid dispersion is main characterization tool 40 .