A Review on Solid Dispersion and Carriers Used Therein for Solubility Enhancement of Poorly Water Soluble Drugs

A large number of hydrophilic and hydrophobic carriers in pharmaceutical excipients are available today which are used for formulation of solid dispersions. Depending on nature of carriers the immediate release solid dispersions and/or controlled release solid dispersions can be formulated. Initially crystalline carriers were used which are transformed into amorphous solid dispersions with enhanced properties. The carriers used previously were mostly synthetic one. Recent trend towards the use of natural carriers have replaced the use of synthetic carriers. This review is the overview of various synthetic, natural, semisynthetic, modified natural hydrophilic carriers used for formulation of solid dispersions.


Introduction
Absorption of drug and its therapeutic effectiveness get affected by solubility which is a significant physicochemical factor. Poor aqueous solubility can leads to failure in formulation development process. The main reason behind inadequate bioavailability of drug is its low dissolution rate and low solubility in aqueous medium. 1 A large number of hydrophilic carriers are explored today which have shown significant results for solubility enhancement. Nowadays, most of the drug substances were innovated but the venture to improve the solubility and dissolution of hydrophobic drug substances remain one of the trickiest tasks in drug development. Dissolution of drug in aqueous medium like gastric fluid is important to get better absorption and bioavailability for orally administered drug. Therefore, to progress bioavailability of poorly water soluble compounds like biopharmaceutical classification system class II and IV drugs, polymer matrix of various origin can be used. Various solubility enhancement methods have been introduced to triumph over this problem. 1 There are several techniques for solubility enhancement which can be categorized into physical modification, chemical modifications for the drug substance, and other techniques 2 which are listed in Table 1.
One of the most promising and efficient techniques for solubility enhancement is solid dispersion formulation. According to Chiou and Riegelman, solid dispersion systems can be defined as 'the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting [fusion], solvent, or meltingsolvent method' . The drug is hydrophobic in nature whereas matrix is hydrophilic. Solid dispersion can be classified as simple eutectic mixtures, solid solutions, glass solutions and glass suspensions, amorphous precipitation in a crystalline carrier, compound or complex formations. 3 However, several modifications have been done in classification systems by various researchers which will be discussed in the following.

Classification of solid dispersions
On the basis of recent advancement in solid dispersion, they can be classified as:

First generation solid dispersion
The solid dispersions which could be prepared by using crystalline carriers are categorized as the first generation solid dispersions. 6 Examples of used crystalline carriers are urea and sugars. 7 In this type, thermodynamically stable crystalline solid dispersion get formed which releases the drug slowly. 6 The dissolution rate is faster in case of amorphous solid dispersions (ASDs) as compared to crystalline sold dispersions. The first reported solid dispersion was eutectic mixture or monotectic mixture. In case of eutectic mixture melting point of dispersion is lower than the melting point of carrier and drug the melting point of drug and carrier are constant in case of monotectic mixture. In cooling process of eutectic mixture, the drug and carrier will crystallize simultaneously therefore it is preferred over the monotectic mixture. 8 At the specific composition in eutectic mixture where drug crystallizes out is referred as eutectic point, and the mixture consists of fine crystals of two components. 6 Small particle size will results in increased specific surface area which generally improves rate of dissolution and oral absorption of poorly water soluble drugs. 3 Moreover, the number of studies having exact eutectic composition in solid dispersion is very limited. 8 Based on the extent of miscibility between the two components or the crystalline structure of solid solution they are of two kinds. One is continuous [or isomorphous, complete, unlimited] solid solutions and the other discontinuous [or restricted, partial, limited, complete] solid solutions. They can also be classified into two groups-substitutional solid solutions in which the solute molecule substitutes the solvent molecule in the crystal lattice of the solid solvent. Whereas, in case of interstitial solid solutions, the solute molecule occupies the interstitial space of the solvent lattice. 3 The disadvantage of first generation solid dispersion is forming crystalline solid dispersion as they were prepared using crystalline carriers like urea and sugars. Crystalline solid dispersions were more thermodynamically stable which lowers their dissolution rate as compared to amorphous one. 9 Okonogi et al 10 has studied the effect of urea and mannitol on crystallinity of ofloxacin. The higher solubility and dissolution rate were observed in case of urea based solid dispersions than mannitol based solid dispersions because urea reduced the crystallinity of ofloxacin more than mannitol proved by PXRD and DSC results.

Second generation solid dispersion
These contain amorphous carriers like PVP, PEG, cellulose derivatives, etc. 7 Second generation solid dispersions were found more effective than first generation solid dispersions (SD) because of their thermodynamic stability. 9 According to the physical state of drug, ASDs can be classified as amorphous solid suspensions and amorphous solid solutions [glass solutions]. Amorphous solid suspensions consist of two separate phases while amorphous solid solutions contain molecularly homogenous mixture of both the drug and amorphous carriers. Amorphous carriers can be synthetic polymer or natural polymer. 8 Amorphous solid suspensions can be formulated in case of drugs with limited carrier solubility or high melting point. In case of second generation solid dispersions because of forced solubilization of the drug in the carrier the drug is in its supersaturated state. 9 Due to increase in chain length or molecular weights of polymers the aqueous solubility of polymers get decrease and viscosity get increased. Prevention of recrystallization of drugs in manufacturing, storage and dissolution process can be achieved by using high viscosity polymers. Moreover, the use of high viscosity polymer can delay the dissolution rate of drug in aqueous medium. The major problem regarding second generation solid dispersion is drug precipitation and recrystallization which affect the in vitro or in vivo drug release. 8

Third generation solid dispersion
The dissolution profile of drug can be improved using third generation solid dispersions which consists of carriers having surface activity or emulsifying properties. 9 Use of special type of carrier for formulation of solid dispersions will overcome precipitation and recrystallization problems. Use of surfactant or emulsifiers not only improve the dissolution profile of drug but also improves physical and chemical stability of drug in solid dispersion. Examples of these carriers are inulin, Gelucire, poloxamer, etc. 8 The physical and chemical stability of solid dispersion get enhanced by preventing nucleation and agglomeration. 9 The selection of surface active agent or another polymer is based on dissolution or stability profile of drug, i.e. surfactant is used when faster dissolution is required while polymer with higher Tg may be used when prevention of re-crystallization is needed. 8,11 Fourth generation solid dispersion These type of dispersions can be referred as controlled release solid dispersions (CRSD). It contain poorly water soluble drug with a short biological half life. 8 The carrier used are either water soluble carrier or water insoluble carrier. 7 Solubility enhancement and extended release of drug in controlled manner are the two targets in CRSD. 8 The water soluble carriers used in CRSD are ethyl cellulose, Eudragit RS, Eudragit RL, HPC, etc. 7 On the basis of physical state and molecular arrangement of active pharmaceutical ingredient (API) and carrier, binary solid dispersions can be divided into six distinct systems as follows: Meng et al have classified solid dispersions into six groups Class C-C, Class C-A, Class A-C, Class A-A, Class M-C, Class M-A based on physical state and molecular arrangement of both API and carrier ( Table 2). Further efforts are needed to shape a clear classification system and correlate it with the performance of solid dispersion in terms of solubility and stability. 12 The aim of this article is to update on information regarding hydrophilic carriers used in solubility enhancement by using various solid dispersion methods. Here, hydrophilic carriers were classified on the basis of its origin like synthetic hydrophilic carrier, natural hydrophilic carriers, modified natural hydrophilic carriers

Mechanisms of incorporation of drug into polymer
Carriers used in solid dispersions are polymers. When drug and polymer are in intimate contact then drug occupy void spaces between polymeric chain and makes polymer chain relatively flexible. For example, in case of hot melt extrusion process, polymer is allowed to heat up to some extent that the heat given is responsible for loosening of polymer chain and incorporation of drug molecule into it. While in spray drying method the solvent used in process is responsible for weak cohesive inter and intra molecular interactions of polymer chain and resulting in formation of solvent polymer interactions. After this, drug molecules dissolved in solvent are incorporated into the loosened polymer chains. Antiplasticization effect is observed when the mechanical properties of substance changes into stiff and brittle when another substance is added. In another way it can be explained as, compound with low Tg of resulting mixture would fall somewhere in between the Tg's of both compounds. In this case drug undergoes antiplasticization. Where as polymer undergoes plasticization as its Tg decreases. 13 Drug release mechanism from solid dispersion Dissolution performance of solid dispersion after its oral administration in the form of tablet, capsules, etc. will give proper idea about ultimate success. One of the successful approaches for enhancement of solubility of poorly soluble drug is conversion of crystalline form of drug to an amorphous from. For successful solid dispersion formulation major keys are supersaturation state maintenance and amorphous form stabilization. The problem regarding solid dispersions is precipitation of supersaturated drug which will ultimately affect its bioavailability. 13 Increases stability and solubility of drug in medium is observed due to particle size reduction and reduced agglomeration. 14 In supersaturating drug delivery system such as solid dispersion spring like effect is observed due to enhancement of dissolution rate of drug. At the stage of supersaturation decrease in dissolution rate is observed due to drug precipitation. Furthermore in such system parachute like effect is observed on dissolution profile of drugs when precipitation inhibitors are added. 12 Drug controlled release and carrier controlled release are two types of mechanisms involved in drug release from immediate release solid dispersions. While in case of CRSD diffusion and erosion drug release mechanisms are observed depending on characteristics of polymer and the miscibility of the drug and carrier. 8 If the carrier is soluble in the dissolution medium then the release of ASD is dissolution controlled mechanism while in case of insoluble carrier diffusion controlled mechanism is observed. 15

Carriers used in solid dispersion
Carriers plays major role in formulation of solid dispersion. 16 They can be hydrophilic or hydrophobic or water swellable. Depending on their characteristics they can be used as release retardant or release enhancers. 8 Also the dissolution characteristics of drug molecules are depend on nature of carriers. 17 The criteria for selection of carrier are as follows: • It should be water soluble or swellable, soluble in variety of solvents. • It should be economical, pharmacologically inert, non-toxic. • It should be heat stable.
• Chemically compatible with drug.
The better chemical stability of solid dispersion was observed in case of solid dispersions which are formulated using solvent based methods as compared to fusion based methods. Solvent based methods include spray drying, coprecipitation, etc. While hot melt extrusion, KinetiSol® dispersing technology, etc. comes under fusion based methods. 18 Hydrophilic carriers used in solid dispersion are classified on the basis of their origin. Table 3 shows list of synthetic hydrophilic carriers. In recent years, polymers those are derived from plant origin are getting tremendous interest because of their diverse pharmaceutical applications and also easy availability, biocompatibility, non-toxic nature, chemically inertness they are preferred over the synthetic ones. Demand for these substances is increasing and new sources are being developed. Polysaccharide, one of the most abundant industrial raw materials and have been the subject of intensive research due to their sustainability, bio-safety and bio-degradability. The natural gums are metabolic by-products of plants obtained from various parts of plant like seed, fruit, incised trunk (gummy exudate), etc. 52 Various natural hydrophilic carriers used till date are given in Table 4.
Natural gum polysaccharides are promising   71 Generally natural carriers on modification using heating method will leads to change in its physical characteristics like viscosity, density, swelling index, water holding capacity, flow properties etc. Due to changes in these characteristics the improved results were obtained in case of modified natural carriers. 4 Carboxymethylation of natural carriers increases their hydrophilicity and makes them more soluble in aqueous systems. 71 Various modified hydrophilic carriers and semi synthetic carriers used are shown in Table 5 and Table 6.

Advantages of solid dispersions
The main objective behind formulation of solid dispersions is to enhance solubility of drug and thereby enhancement of its in vitro dissolution rate and bioavailability as well as developing controlled release solid dispersions. 87 The factors affecting drug solubility are its particle size, porosity, wettability, etc. 9 Various advantageous properties of solid dispersions are showed in Figure 1.

Characterization of solid dispersions
Solid dispersions are mainly known for their use in dissolution rate and bioavailability enhancement. The enhanced dissolution rate can be examined by using  Table 7.

Conclusion
New chemical entities are mostly the poorly water soluble drugs. To overcome poor solubility problem, solid dispersions can be prepared using hydrophilic carriers. These carriers can be of synthetic or of natural origin. Major problem regarding solid dispersions is its stability which can also be overcome by using newly coming carriers and use of optimized manufacturing techniques. Industrial and academic research work have solving the scalability problem of solid dispersions. There are still several carriers which are not investigated so far. Therefore, studies on such carrier materials should be done for solubility enhancement.

Ethical Issues
Not applicable.  85 Microwave induced fusion method Raloxifene HCL Increased solubility as well as in vitro drug dissolution HPMC: MESOPOROUS SILICA (ternary ASD) 86 Hot melt extrusion Indomethacin Enhanced dissolution rate and physical stability

Conflict of interests
There is no conflict of interest. To study physical and chemical interactions between drug and polymer during its manufacturing and storage period