Because of high-energy involved, it causes disruptions in the drugs crystal lattice, resulting in the presence of amorphous regions in the final product. All poorly water-soluble drugs are not suitable for improving their solubility by salt formation. Potential disadvantages of salt forms include high reactivity with atmospheric carbon dioxide and water resulting in precipitation of poorly water-soluble drug, epigastric distress due to high alkalinity. Even though use of co solvent to improve dissolution rate pose problems such as patient compliance, toxicity of organic solvents.

Solid dispersion, which was introduced in the early 1970s, is essentially a multicomponent system having drug dispersed in and around hydrophilic carriers⁴. Solid dispersion technique has been used for a wide variety of poorly water soluble drugs such as nimesulide, ketoprofen, tenoxicam, nifedipine, nimodipine, ursodeoxycholicacid, meloxicam, naproxen, rofecoxib, felodipin atenolol and albendazole. Various hydrophilic carriers such as polyethylene glycols, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, eudragits and chitosans, gums, sugars, and urea have been investigated for improvement of dissolution characteristics and bioavailability of poorly aqueous soluble drugs⁵. Solid dispersion can be prepared by various methods such as solvent evaporation and melting method⁶. Here, a drug is thoroughly dispersed in a water soluble carrier by suitable method of preparation. The mechanism by which the solubility and the dissolution rate of the drug is increased include: firstly, the particle size of the drug is reduced to submicron size or to molecular size in the case where solid solution is obtained. Secondly, the drug is changed from crystalline to amorphous form, the high energetic state which is highly soluble and finally, the wettability of the drug particle is improved by the dissolved carrier⁷.

Various strategies are investigated for solid dispersion preparation which include fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electrostatic spinning method and super critical fluid technology^8-16. These methods deal with the challenge of mixing a matrix and a drug, preferably on a molecular level, while matrix and drug are generally poorly miscible. One of the major hurdles in the development of solid dispersions is the lack of suitable manufacturing techniques that could be scaled up to commercial production. Only a few products have been marketed so far e.g., Gris-PEG (Novartis, Griseofulvin in PEG), Cesamet (Lily, Nabilone in PVP), Sporanox (Janssen Pharmaceutica/J&J, Itraconazole in HPMC and PEG 20000 sprayed on sugar spheres)¹⁷.

Various issues that impeded the commercial development of solid dispersions include: Inability to scale benchtop formulations to manufacturing-sized batches, Difficulty to control physicochemical properties, Difficulty in delivering solid dispersion formulations as tablet or capsule dosage forms and Physical and chemical instability of the drug and/or the formulation itself.

PROBLEMS WITH CONVENTIONAL SOLID DISPERSION MANUFACTURING METHODS:

With conventional solid dispersion preparation techniques, problem of demixing (partially or complete) and formation of different phases is observed. Generally, phase separation can be prevented by maintaining a low molecular mobility of matrix and drug during preparation which can be achieved by keeping the mixture at an elevated temperature thereby maintaining sufficient miscibility for as long as possible. The extent of phase separation can be minimized by a rapid cooling procedure¹⁸. Conventional methods like solvent evaporation and hot melt method often result in low yield, high residual solvent content or thermal degradation of the active substance. Another important limitation of solid dispersions is the inherent stability problems i.e. recrystallization of drug. However, the use of polymers with a high glass transition temperature for solid dispersions is often sufficient to prevent recrystallization¹⁹. Polymers improve the physical stability of amorphous drugs in solid dispersions by increasing the glass transition temperature of the miscible mixture, thereby reducing the molecular mobility at regular storage temperatures or by interacting specifically with functional groups of the drugs. An obstacle of solid dispersion technology in pharmaceutical product development is that a large amount of carrier i.e., more than 50% to 80% wt/wt was required to achieve the desired dissolution. Recently, use of combined carriers or use of surfactants with higher HLB value has reduced amount required for hydrophilic carrier and hence lower weight final product can be formulated. Thermosensitive drugs and carriers may be destabilized during the melting or solvent-facilitated melting process since high melting temperatures are usually applied which can be avoided by use of CO₂ as a plasticizer and hot melt extrusion process. The soft and tacky properties of solid dispersion powders result in poor flowability, mixing property and compressibility which may complicate the operations and render poor reproducibility of physicochemical properties of final products. The problem in the solvent evaporation process is that it is hard to remove the solvent from the coprecipitates to an acceptable level because the coprecipitates become more and more viscous during the drying process which prevents further evaporation of the residual solvent.

CONVENTIONAL METHODS WITH NEWER APPROACHES:

Solid dispersions of poorly water soluble drugs can be prepared by mainly two approaches namely; Melting and Solvent evaporation. But both of them are having certain inherent problems regarding process scale-up, economy, residual organic solvent and thermal stability of drugs. For efficient processing of thermolabile drugs and easy removal of organic solvent, various new approaches have been tried which is shown in Table 1.

Melting: It consists of melting the drug with the carrier followed by cooling and pulverization of the obtained product. A common approach is that suspending the active drug in a previously melted carrier, instead of using both drug and carrier in the melted state reducing therefore the processing temperature. To cool and solidify the melted mixture, several processes such as ice bath agitation, stainless steel thin layer spreading followed by a cold draught, solidification on petri dishes at room temperature inside a dessicator, spreading on plates placed over dry ice, immersion in liquid nitrogen and storage in a dessicator were used^20-24. But this method can’t be used for thermolabile drugs and the incomplete miscibility between drug and carrier because of the high viscosity of a polymeric carrier in the molten state, is another limitation of this process. When drug and matrix are incompatible two liquid phases or a suspension can be observed in the heated mixture, which results in an inhomogeneous solid dispersions. This can be prevented by incorporation of surfactants. To overcome above mentioned limitations techniques like hot melt extrusion, Meltrex^TM, Melt agglomeration and closed melting point method have been developed^25-28.

TABLE 1: SOLID DISPERSION FORMULATION STRATEGIES:

CONVENTIONAL METHODS	1. Melting 2. Solvent Evaporation
NEWER APPROACHES	1. Melting	1. Hot-Melt Extrusion 2. Meltrex^TM 3. Melt Agglomeration 4. Closed Melting Point Method
	2. Solvent Evaporation	1 Spray Drying, 2.Lyophilization, 3.Fluid Bed Drying, 4. Electrostatic Spinning Method
	3. Use Of Super Critical Fluids 4. Cryogenic Technology 5. Use Of Surfactant 6. Surface Solid Dispersion 7. Sustained Release Solid Dispersion 8. Hot Melt Encapsulation 9. Spraying On Sugar Beads Using A Fluidized Bed Coating System

1. Hot melt extrusion: In a hot-melt extrusion process, the drug carrier mixture is simultaneously melted, homogenized and then extruded using melt extruder and shaped as tablets, granules, pellets, sheets, sticks or powders. Hot-stage extrusion consists of the extrusion, at high rotational speed, of the drug and carrier, previously mixed, at melting temperature for a small period of time. The resulting product is then collected after cooling at room temperature and milled. A reduction in processing temperature can be achieved by the association of hot-stage extrusion with the use of carbon dioxide as a plasticizer which broadens the application of hot-stage extrusion to thermally labile compounds. Solid dispersions of para amino salicylic acid/ethylcellulose, itraconazole/PVPand itraconazole/ethylcellulose were successfully prepared by this technique^29-31. Polymers such as polyvinyl pyrollidone (PVP), hydroxypropylmethyl cellulose (HPMC), polymethacrylate polymers (e.g., Eudragit EPO), poly(ethyleneoxides) (PEO) and HPMC acetate succinate were successfully used during HME to form solid dispersions of itraconazole, nicardipine, nifedipine and indomethacin. A plasticizer is required in order to reduce the viscosity of the mixture in the extruder and therefore to lower the process temperature settings. Typically, conventional plasticizers are used in a concentration range of 5–30 wt % of the extrudable mass to produce large mass. CO₂ is also used as a plasticizer. Where carbon dioxide is absorbed between the polymer chains causing an increase of free volume and a decrease in chain entanglement. Carbon dioxide acts as a molecular lubricant that reduces melt viscosity. Carbon dioxide acted as plasticizer for itraconazole/EC 20 cps, reducing the processing temperature during the hot stage extrusion process³¹. The macroscopic morphology changed to a foam-like structure due to expansion of the carbon dioxide at the extrusion die. This resulted in increased specific surface area, porosity, hygroscopicity and improved milling efficiency.

2. Meltrex: Meltrex^TMa melt extrusion technology, is a patented solid dispersion manufacturing process on the basis of the melting process. This Meltrex^TM is considered to be an efficient and specialized technology embedding poorly soluble drugs as solid dispersion/solid solution into a biocompatible polymer matrix. The crucial elements in the Meltrex^TM technology is the use of a special twin screw extruder and the presence of two independent hoppers in which the temperature can vary over a broad temperature range. This process permits a reduced residence time of the drug in the extruder, allowing a continuous mass flow and avoiding thermal stress to the drug and excipients. Additionally, it is possible that the application of this technique to protect drugs susceptible to oxidation and hydrolysis by complete elimination of oxygen and moisture from the mixture^[^26]. However, it can be used to tailor drug dissolution profiles. This melt extrusion technology has the advantage of being a solvent and dust-free process which allows for a clean processing environment with a reduction in environmental pollution, explosion proofing and residual organic solvents. The therapeutic advantages of Meltrex^TMas applied to drug formulations include improved dissolution kinetics, enhanced bioavailability and therefore efficacy, improved safety and the ability to tailor-make release profiles.

3. Melt agglomeration: Melt agglomeration allows the preparation of solid dispersions in conventional high shear mixers or rotary processor³². In this technique, binder acts as a carrier. Solid dispersions are prepared either by heating binder, drug and excipient to a temperature above the melting point of the binder (melt in procedure) or by spraying a dispersion of drug in molten binder on the heated excipient (spray on procedure) by using a high shear mixer.The rotary processor might be preferable to the high melt agglomeration because it is easier to control the temperature and because a higher binder content can be incorporated in the agglomerates. It has been investigated that the melt in procedure gives a higher dissolution rates than the spray on procedure with PEG 3000, poloxamer 188 and gelucire 50/13 attributed to immersion mechanism of agglomerate formation and growth. In addition the melt in procedure also results in homogenous distribution of drug in agglomerate.

4. Closed melting point method: Closed melting point method involves controlled mixing of water content to physical mixtures of drug and hydrophilic carrier by storing them at various relative humidity conditions or by adding water directly and then mixture is heated. This method is reported to produce solid dispersion with no crystallinity. Solid dispersion of troglitazone with polyvinylpyrrolidone k30 had been reported by this method.

Solvent evaporation: Solvent evaporation method uses organic solvent e.g., ethanol, chloroform or a mixture of ethanol and dichloromethane to dissolve and intimately disperse the drug and carrier molecule which is later evaporated and the resulting films are pulverized and formulated in to particular dosage form. Identification of a common solvent for both drug and carrier can be problematic and complete solvent removal from the product can be a lengthy process. Various solvent evaporation processes include vacuum drying, heating of the mixture on a hot plate, slow evaporation of the solvent at low temperature, the use of a rotary evaporator, a stream of nitrogen, spray-drying, freeze-drying and the use of supercritical fluids (SCF)^33-40. Spin-coated films is a new process to prepare solid dispersions by the solvent evaporation method which consists of dissolving drug and carrier in a common solvent that is dropped onto a clean spinning substrate⁴¹. This process is indicated to moisture sensitive drugs since it is performed under dry conditions. Drooge DJV et alsuggested spray freeze-drying as a potential alternative to the above-mentioned process to produce tetrahydrocannabinol containing inulin based solid dispersions with improved incorporation of tetrahydrocannabinol in inulin⁴². Van Drooge et al. prepared an alternative solid dispersion by spraying a povidone and diazepam solution into liquid nitrogen, forming a suspension that was then lyophilized⁴³. Solvent evaporation technique have some drawbacks like residual organic solvent and inefficient powder characteristics of final product. To overcome these hurdles, various new solvent removal technique have been approached such as spray drying, freeze drying, fluid bed drying and electrostatic spinning method.

1. Spray drying: This mostly used solvent evaporation technique consists of dissolving or suspending the drug and carrier in organic solvent and then spraying it into a stream of heated air flow to remove the organic solvent. Drying and micronizing are processed simultaneously to produce amorphous drug/carrier powders which are further formulated with other excipients into dosage forms. It is simple and cost effective as it is 30-50 times less expensive than freeze-drying. The frequent use of the organic solvent in spray drying pose problems such as residues in final product, environmental pollution and operational safety. Spray drying usually yields drug in the amorphous state, however sometimes the drug may (partially) crystallized during processing.

2. Lyophilization: Freeze drying involves transfer of heat and mass to and from the product under preparation. Here, the drug and carrier are codissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion. Benifits of freeze drying are minimal thermal stress given to the drug and low risk of phase separation. Limitation of this technique is that low sample temperatures are required to be maintained which slows down the process. But this technique is poorly exploited for solid dispersion preparation due to low freezing temperature of most organic solvents.

3. Fluid Bed Drying: The preformulation pulverization of the solid dispersion melt/congealed slabs is more challenging because they are usually semisolid and waxy in nature and difficult to micronize. The soft and tacky properties of solid dispersion powders result in poor flowability, mixing property and compressibility which may complicate the operations and render poor reproducibility of physicochemical properties of final product. Fluid bed drying can be used for organic solvent removal from drug carrier solution/ melt where solution is spray dried against hot air flow leading to formation of free flowing micronized final product which can be directly compressed or filled in to hard gelatin capsules.

4. Electrostatic spinning method: Previously used in polymer industry, this technique now is being applied for drug nanofibers formation by combining two technologies namely; Solid dispersion and Nanotechnology. Electrostatic spinning is a process in which solid drug fibers are produced from a polymeric fluid stream solution or melt under application of a strong electrostatic field over a conductive capillary attaching to a reservoir containing a polymer solution or melt and a conductive collection screen. Here, a liquid stream of a drug/polymer solution is subjected to a potential between 5 and 30 kV. When electrical forces overcome the surface tension of the drug/polymer solution at the air interface, fibers of submicron diameters are formed. As the solvent evaporates, the formed fibers can be collected on a screen to give nanofibers. This electospun fibers can be incorporated in to hard gelatin capsules. The fiber diameters depend on surface tension, dielectric constant, feeding rate and electric field strength⁴⁴.Itraconazole/HPMC nanofibers have been prepared using this technique. This process is restricted to a limited type of matrices, because only a few high molecular weight materials are fiber forming materials. Benefit of this technique is that it can be used for both immediate release and controlled release formulations by using water soluble and insoluble polymers respectively.

RECENT TECHNOLOGIES:

Recently, super critical fluid technology and cryogenic technology are of greater interest in the field of solid dispersion formulation. These are mainly applied for thermolabile compounds forming formulation with excellent water solubility due to free flowing porous final product but having problems of costlier instruments and processing.

1. Super Critical Fluid Technology: The use of super critical fluid, substances existing as a single fluid phase above their critical temperature and critical pressure, was shown to be efficient in obtaining solid dispersions. This fluid possesses the penetrating power typical of a gas and the solvent power typical of a liquid which ensured a very fine dispersion of the hydrophobic drug in the hydrophilic carrier. Carbon dioxide (CO₂) is the most commonly used SCF because it is chemically inert, non-toxic and non-flammable. Owing to its mild critical temperature (31.06 ⁰C) and critical pressure (73.8 bar), CO₂ is suitable to treat heat-sensitive APIs like peptides, steroids and DNA with relatively low energy costs. Supercritical carbon dioxide is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains trapped inside the polymer, it poses no danger to the patient. 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. The use of processes using SCF reduces particle size, residual solvent content, without any degradation, and often results in high yield. Depending on the formulation and processing parameters, supercritical fluid-based processes can yield particles containing drug in an amorphous or crystalline form. These methods use SCFs either as solvent (e.g., rapid expansion from supercritical solution (RESS)) or as antisolvent (e.g.gas antisolvent (GAS), supercritical antisolvent (SAS), solution enhanced dispersion by supercritical fluids (SEDS)) and/or as dispersing fluid (GAS, SEDS, particles from gas-saturated solution (PGSS)⁵¹.

Three key process concepts^45-51:

1. Precipitation from supercritical solutions

Rapid expansion of supercritical solution (RESS);

2. Precipitation from saturated solutions using SCF as an antisolvent

Gas antisolvent (GAS), Precipitation with compressed antisolvent (PCA), Supercritical antisolvent (SAS), Aerosol solvent extraction system (ASES)and Solution enhanced dispersion by supercritical fluids (SEDS) process and

3. Precipitation from gas-saturated solutions

Particles from gas-saturated solutions (PGSS).

In the supercritical fluid antisolvent techniques, carbon dioxide is used as an antisolvent for the solute but as a solvent with respect to the organic solvent. The SAS process involves the spraying of the solution of the solute and of the organic solvent into a continuous supercritical phase flowing concurrently⁴⁸. SCF is inable to dissolve moderate to highly polar compounds. Such compounds can be easily dissolved in suitable organic solvents and SCFs can be used as antisolvents to precipitate the solids. This procedure has been termed as “solution-enhanced dispersion by supercritical fluids” (SEDS)⁵⁰. Depending on the method by which solution and SCF are introduced and mixed into each other, different applications have been described. These includes PCA, GAS, SAS, ASES, and SEDS. In one study, solid dispersions of felodipine in HPMC and surfactants, such as poloxamer 188, poloxamer 107 and polyoxyethylene hydrogenated castor oil were prepared using GAS technique⁵². In aerosol solvent extraction system (ASES),the solution is sprayed through atomization nozzle into a chamber filled with SCF where expansion of solution occurs within the fine droplets of solvent being sprayed, thus creating supersaturation and precipitation of solids as fine particles⁴⁹. The PCA differs from the GASprocess in that much higher mass transfer rate and efficient crystallization are achieved by supplying compressed antisolvent into solution being sprayed⁴⁷. In one study, supercritical CO₂ as the antisolvent to prepare solid dispersions of phenytoin and PVP K30 from their solutions in acetone or acetone/ethanol mixture by using PCA and conventional spray-drying process⁵³. During RESS process, the SCF is diffused through a bed of solid solute⁴⁵. As the fluid diffuses through the bed, the solid solute dissolves in it, causing an extremely rapid nucleation and precipitation of high-energy solids. Drug substances such as indomethacin, nifedipine, carbamezapine, naproxen, and nitrendipine have been processed using this technology to generate drug products with highly reproducible physicochemical properties⁵⁴. The processing equipment can be totally enclosed, free of moving parts, and constructed from easily maintained high-grade stainless steel. Particle formation in a light-free, oxygen-free, and possibly moisture-free atmosphere minimizes their confounding effect during scale-up.

2. Cryogenic Technologies: Cryogenic technologies involve the rapid freezing of single solvent or co-solvent based solutions containing drug, hydrophilic carrier and stabilizing excipients by either spraying on or into a cryogenic liquid or applying the solution onto a cryogenic substrate⁵⁵. The frozen material is then lyophilized to remove the solvent by sublimation, thus yielding a freely flowing powder of high surface area. Examples of these processes include spray-freeze-drying, spray-freezing into a halocarbon refrigerant vapor, spray-freezing into halocarbon refrigerant, spray freezing onto liquid nitrogen, and ultra-rapid freezing. Solid dispersions can also be obtained by the ultra-rapid freezing of a solution containing the pharmaceutical ingredients⁵⁶. Firstly, the feed solution is dispersed through an injection device (capillary, rotary, pneumatic or ultrasonic nozzle) in a cryogenic medium (N₂, Ar, O₂, hydrofluoroalkanes or organic solvents). Then frozen particles are freeze-dried to remove the organic solvent⁵⁷. Due to the liquid–liquid collision, dispersion beneath the surface of refrigerant may considerably reduce particle size. Williams et al. have prepared sub-micron particles of carbamazepine/ Poloxamer 407/PVP K17 solid dispersion by injecting the feed solution in liquid nitrogen through a submerged insulating nozzle (spray-freezing into Liquid, SFL)⁵⁸. The large surface area and direct contact with the cooling agent result in even faster vitrification, thereby decreasing the risk of phase separation to a minimum. Moreover, spray freeze drying offers the potential to customize the size of the particle to make them suitable for further processing or applications like pulmonary or nasal administration.

NEWER FORMULATION APPROACHES:

Solid dispersion formulation involves dispersion of poorly water soluble drug throughout hydrophilic carriers like polyethylene glycol (PEG400, PEG4000, PEG6000), polyvinyl pyrrolidone (PVP K 30, PVP K 90). But now a days, use of hydrophilic polymers like hydroxy propyl methyl cellulose, surfactants such as gelucires, polysorbate 80, sodium dodecyl sulphate, Labrasol, poloxamer, Inutec SPI, Vitamin E TPGS and Synperonic® F127 have been tried for their solubility enhancement effect which will also reduce amount of hydrophilic carrier required in solid dispersion formulation.

1. Use of Surfactant: Use of surface-active and self-emulsifying carriers for solid dispersion of poorly water-soluble drugs are of great interest in recent years. Surfactants have been reported to cause solvation/plasticization and reduction of melting point of the active pharmaceutical ingredients. Surfactants are also reported to prevent recrystallization of amorphous drug of solid dispersion. Because of the rapid dissolution of the water-soluble carriers than the drugs, drug-rich layers were formed over the surfaces of dissolving plugs, which prevented further dissolution of drug from solid dispersions. Therefore, surface-active or self-emulsifying agents including bile salts, lecithin, lipid mixtures, Gelucire 44/14 and Vitamin E TPGS NF were used as additional additives, acting as dispersing or emulsifying carriers for the liberated drug to prevent the formation of any water-insoluble surface layer⁵⁹. Various surfactants have been tried for various purposes in solid dispersion like gelucires, polysorbate 80, sodium dodecyl sulphate, labrasol, poloxamer, Inutec SPI, Vitamin E TPGS and Synperonic® F127. Gelucires are the saturated polyglycolized glycerides consisting of mono-,di- and tri-glycerides and of mono- and di-fatty acid esters of polyethylene glycol. Gelucires with low HLB can be employed to decrease the dissolution rate of drugs and higher HLB ones for fast release. Gelucire 44/14 listed in the European Pharmacopoeia as laurylmacrogolglycerides and in the US Pharmacopoeia as lauroylpolyoxyglycerides. Gelucire 44/14 has commonly been used in solid dispersion for the bioavailability enhancement of various drugs⁶⁰. Vitamin E TPGS (NF) is prepared by the esterification of the acid group of d-R- tocopheryl acid succinate by PEG 1000. A commonly used surfactant, Polysorbate 80, when mixed with solid PEG has also been reported to be an alternative surface-active carrier. Polysorbate 80 is liquid at room temperature; it forms a solid matrix when it is mixed with a PEG because it incorporates within the amorphous regions of PEG solid structure. The PEG-polysorbate carriers have been found to enhance dissolution and bioavailabilityof drugs through the solid dispersions⁶¹. Incorporation of 5% (wt/wt) phosphatidylcholine resulted in enhanced dissolution rate of nifedipine from a PEG-based solid dispersion. Pulverized solid dispersions in PEG containing varying amounts of ionic and nonionic surfactants, including sodium dodecyl sulfate and Polysorbate 80 gave increased dissolution rate of drug. Labrasol is a clear liquid surfactant with a HLB of 14. Solid dispersions of piroxicam with labrasol have also resulted in improved solubility and dissolution when compared with pure drug⁶². The amphiphilic poly (ethylene oxide)-poly (propylene oxide)- poly (ethylene oxide) (PEO-PPO-PEO) block polymers, known as poloxamer or pluronics represent another class of surfactants⁶³. These are available in various molecular weights and PEO/PPO ratios and hence offer a large variety of physicochemical properties. When used in relatively high quantities, poloxamer imparts sustained-release properties to solid dosage forms. Inutec SPI, a derivative of inulin prepared by the reaction between isocyanates and the polyfructose backbone in the presence of a basic catalyst such as a tertiary amine or lewis acid, has also been evaluated as carrier in formulation of solid dispersions for a poorly water soluble drug⁶⁴. Dissolution properties of SD(s) made up of itraconazole and Inutec SPI were improved in comparison to pure itraconazole or physical mixtures with Inutec SPI. Sheen et al studied that polysorbate 80, a commonly used surfactant, results in improvement of dissolution and bioavailability of poorly water soluble drug attributed to solubilization effect of surface active agent⁶⁵. The ability of Synperonic® F127, the ABA block copolymer of polyoxyethylene-polyoxypropylene polyoxyethylene (PEO-PPO-PEO) to adsorb on to hydrophobic surfaces and the extent and mechanism of adsorption has been extensively investigated by modifying the surface of polystyrene particles⁶⁶.

2. Surface solid dispersion: This is another approach for solubility enhancement in which instead of molecularly dispersing drug with the carrier, fine drug particles are adsorbed over hydrophilic inert carrier particles. Deposition of the drug on the surface of an inert carrier leads to reduction in the particle size of the drug ,thereby providing faster rate of drug dissolution⁶⁷. This is because more surface area of drug is exposed to dissolution fluid by adsorbing over hydrophilic carrier. Various hydrophilic materials with high surface area can be utilized to deposit the drug on their surface. Dissolution rate of griseofulvin was increased by depositing it on the surface of disintegrant such as Primogel, Starch, Nymcel⁶⁸. In other study, nifedipine was deposited on the surface of superdisintegrant such as Ac-Di-Sol, Kollidon, and Explotab to increase its dissolution⁶⁹.

3. Sustained release solid dispersion: Solid dispersion technique can also be used to develope sustained release formulation by using water-insoluble or slower dissolving carriers instead of conventional hydrophilic polymers. Another approach is a membrane-controlled SR tablet containing solid dispersion of drug. Since the release of drug from such diffusion controlled system is driven by the gradient of the drug concentration resulting from penetration of water, it may have a risk for the recrystallization of drug because of contacting solid dispersion to water penetrated into the system for longer period. Disintegration-controlled matrix tablet (DCMT) of nilvadipine, hydrogenated soybean oil as wax and low-substituted hydroxypropylcellulose as a disintegrant has been reported⁷⁰. Wax layer effectively limits the penetration of water into the tablet and the disintegrant contained in solid dispersion granules is gradually swollen by the penetrated water and then the granules are separated from the DCMT which is a rate-limiting step for nilvadipine to release from DCMT.

NEWER DOSAGE FORMS STUDIED:

Generally solid dispersion of poorly water soluble drugs are being developed as tablets and capsule dosage forms. Recently, direct filling of hot melt mass of drug and hydrophilic carrier in to hard gelatin capsule had been approached. Also drug-carrier solution or melt had been coated on non-pariel sugar beads for production of granular final product which can be easily directly compressed in to tablet.

1. Hot melt encapsulation: Direct filling of hard gelatin capsules with the lipid melt of drug with carrier and subsequent cooling/hardening will reduce problem associated with the processing of the waxy mass of solid dispersions. Volumetric filling of molten mass into hard gelatin capsules and subsequent banding or sealing of filled capsules are carried out in a continuous fashion. Qualifill capsule filler can be used. Lipid based carriers and excipients such as PEG, polyoxyethylene–polyoxypropylene (Poloxamer), poly(oxyethylene), Gelucires ® and lipid surfactants are well suited for this technology. The filling of hard gelatin capsules has been reported in molten dispersions of Triamterene-PEG 500 using a Zanasi LZ 64 capsule filling machine^[71]. In this dosage form, water-soluble carrier dissolve more rapidly than the drug resulting in drug-rich layers formed over the surface of dissolving plugs which will prevented further dissolution of the drug. To overcome this, a surfactant must be mixed with the carrier to avoid formation of a drug-rich surface layer (eg, polysorbate 80 with PEG, phosphatidylcholine with PEG). Another limitation of this method is that the temperature of the molten solution should not exceed 70^o C because it might melt the hard gelatin capsule shell.

2. Spraying on sugar beads using a fluidized bed coating system: The approach involves spraying drug carrier solution onto the granular surface of excipients or sugar spheres to produce either granules ready for tableting or drug-coated pellets for encapsulation in one step. Here drug and hydrophilic carrier are dissolved in common organic solvent to produce solution which is coated over sugar bead and then solvent is evaporated to form solid solution of drug in carrier adsorbed over sugar beads. Kennedy and Niebergalldescribed a hot-melt fluid-bed method whereby non-pareils could be coated with PEGs with molecular weights between 1450 and 4600⁷². Itraconazole solid dispersion with HPMC is (Sporanox oral capsules, Janssen Pharmaceutica, Titusville, NJ) coated on sugar sphere by evaporation of organic solvents (Ethanol and dichloromethane) where HPMC acts as a stabilizer to inhibit recrystallization of the itraconazole⁷³. This technique can be used to deposit solid dispersions on non-pareils and may find application in the manufacturing and scaling up of solid dispersion formulations in the future. The method can be applied for both controlled- and immediate-release solid dispersion preparations.

FUTURE PROSPECTS:

Despite many advantages of solid dispersion, issues related to preparation, reproducibility, formulation, scale up, and stability limited its use in commercial dosage forms for poorly water-soluble drugs. One major focus of future research will be identification of new surface-active carriers and self-emulsifying carriers for solid dispersion. Only a small number of such carriers are currently available for oral use. Some carriers that are used for topical application of drug only may be qualified for oral use by conducting appropriate toxicological testing. One limitation in the development of solid dispersion system may be the inadequate drug solubility in carriers, so a wider choice will increase the success of dosage form development. Research should also be directed toward identification of vehicles or excipients that would retard or prevent crystallization of drugs from supersaturated systems. Many of the surface-active and self-emulsifying carriers are lipidic in nature, so potential roles of such carriers on drug absorption, especially on their p-glycoprotein-mediated drug efflux, will require careful consideration. Solid dispersion strategy should be explored for development of extended-release dosage forms by use of slower dissolving carriers.

CONCLUSION:

The solubility of drugs in aqueous media is a key factor highly influencing their dissolution rate and bioavailability following oral administration. The solid dispersion method is one of the effective approaches to achieve the goal of solubility enhancement of poorly water-soluble drugs. Various techniques described in this review are successfully used for the preparation of SD(s) in the bench and lab scale and can be used at industrial scale also. Some products have been marketed using technologies like the surface-active carriers. Various methods have been tried recently to overcome the limitation and make the preparation practically feasible. The problems involved in incorporating formulation into dosage forms have been gradually resolved with the advent of alternative strategies like spraying on sugar beads and direct capsule filling.

REFERENCES:

1. Guidance for Industry : Bioavailability and Bioequivalence Studies for Orally Administered Drug Products. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation andResearch (CDER). FDA, 2002.

2. GL Amidon et al. A theoretical basis for a biopharmaceutical drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995 ;12(3):413-420.

3. Prajapati BG and Patel MM. Conventional and alternative pharmaceutical methods to improve oral bioavailability of lipophilic drugs. Asian journal of pharmaceutics 2007;1(1):1-8.

4. Chiou WL and Riegelman S. Pharmaceutical application of solid dispersion systems. J Pharm Sci 1971;73:1281-1303.

5. Leuner C and Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 2000;50:47-60.

6. Vilhelmsen T et al. Effect of a melt agglomeration process on agglomerates containing solid dispersions. Int J Pharm 2005;303:132–142.

7. Craig DQM. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm 2002;231:131–144.

8. Vippagunta SR et al. Factors affecting the formation of eutectic solid dispersions and their dissolution behavior. J Pharm Sci 2006;96:294–304.

9. Karavas E et al. Effect of hydrogen bonding interactions on the release mechanism of felodipine from nanodispersions with polyvinylpyrrolidone. Eur J Pharm Biopharm 2006;63:103–114.

10. Betageri GV and Makarla KR. Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. Int J Pharm 1995;126:155-160.

11. Seo A et al. The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer. Int J Pharm 2003;259:161–171.

12. Egakey M, Soliva M and Speiser P. Hot extruded dosage forms. Pharm Acta Helv 1971;46:31-52.

13. Pokharkar VB et al. Development, characterization and stabilization of amorphous form of a low Tg drug. Powder Technol 2006;167:20–25.

14. Serajuddin ATM et al. Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drugs from solid dispersions. J Pharm Sci 1988;77:414–417.

15. Konno H and Taylor LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci 2006;95:2692–2705.

16. Sethia S and Squillante E. Physicochemical characterization of solid dispersions of carbamazepine formulated by supercritical carbon dioxide and conventional solvent evaporation method. J Pharm Sci 2002;91:1948–1957.

17. Dhirendra K et al. Solid Dispersions: A Review. Pak. J Pharm Sci 2009;22(2):234-246.

18. Sekiguchi K and Obi. Studies on Absorption of Eutectic Mixture. I. A comparison of the behaviour of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem Pharm Bull 1961;9:866-872.

19. Taylor LS and Zografi G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res 1997;14:1691–1698.

20. Chiou WL and Riegelman S. Preparation and dissolution characteristics of several fast-release solid dispersions of griseofulvin. J Pharm Sci 1969;58:1505–1510.

21. Li FQ et al. In vitro controlled release of sodium ferulate from Compritol ATO-based matrix tablets. Int J Pharm 2006;324:152–157.

22. Timko RJ and Lordi NG. Thermal characterization of citric acid solid dispersions with benzoic acid and phenobarbital. J Pharm Sci 1979;68:601–605.

23. Yao WW et al. Thermodynamic properties for the system of silybin and poly(ethylene glycol) 6000. Thermochim Acta 2005;437:17–20.

24. Lin CW and Cham TM. Effect of particle size on the available surface area of nifedipine from nifedipine-polyethylene glycol 6000 solid dispersions. Int J Pharm 1996;127:261–272.

25. Vervaet C, Baert L and Remon JP. Extrusion-spheronisation a literature review. Int J Pharm 1995;116:131-146.

26. Breitenbach J and Lewis J. Two concepts, one technology: controlled release and solid dispersion with meltrex. In Modified-Release Drug Delivery Technology. Marcel Dekker.2003:125–134.

27. Passerini N et al. Preparation and characterisation of ibuprofen-poloxamer 188 granules obtained by melt granulation. Eur J Pharm Sci 2002;15:71–78.

28. Hasegawa S et al. Effects of water contents in physical mixture and heating temperature on crystallinity of troglitazone- PVP K 30 solid dispersions prepared by closed melting method. Int J Pharm 2005;302:103-112.

29. Verreck, G. et al. Hot stage extrusion of p-amino salicylic acid with EC using CO2 as a temporary plasticizer. Int J Pharm 2006;327:45–50.

30. Verreck G et al. The effect of pressurized carbon dioxide as a temporary plasticizer and foaming agent on the hot stage extrusion process and extrudate properties of solid dispersions of itraconazole with PVP-VA 64. Eur J Pharm Sci 2005;26: 349–358.

31. Verreck G et al. The effect of supercritical CO2 as a reversible plasticizer and foaming agent on the hot stage extrusion of itraconazole with EC 20 cps. J Supercrit Fluids 2007;40:153–162.

32. Vilhelmsen T et al. Effect of a melt agglomeration process on agglomerates containing solid dispersions. Int J Pharm 2005;303:132–142.

33. Wang X et al. Solid state characteristics of ternary solid dispersion composed of PVP VA64, Myrj 52 and itraconazole. Int J Pharm 2005;303:54–61.

34. Desai J et al. Characterization of polymeric dispersions of dimenhydrinate in ethyl cellulose for controlled release. Int J Pharm, 2006;308:115–123.

35. Lloyd GR et al. A calorimetric investigation into the interaction between paracetamol and polyethlene glycol 4000 in physical mixes and solid dispersions. Eur J Pharm Biopharm 1999;48:59–65.

36. Ceballos A. et al. Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets. II Farmaco 2005;60:913–918.

37. Prabhu S et al. Novel lipid-based formulations enhancing the in vitro dissolution and permeability characteristics of a poorly water-soluble model drug, piroxicam. Int J Pharm 2005;301;209–216.

38. Weuts I et al. Salt formation in solid dispersions consisting of polyacrylic acid as a carrier and three basic model compounds resulting in very high glass transition temperatures and constant dissolution properties upon storage. Eur J Pharm Sci 2005;25:387–393.

39. Drooge DJV et al. Characterization of the Mode of Incorporation of Lipophilic Compounds in Solid Dispersions at the Nanoscale Using Fluorescence Resonance Energy Transfer (FRET). Macromol Rapid Commun 2006;27:1149–1155.

40. Won DH et al. Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process. Int J Pharm. 2005;301:199–208.

41. Konno H and Taylor LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci 2006;95:2692–2705.

42. Drooge DJV et al. Characterization of the Mode of Incorporation of Lipophilic Compounds in Solid Dispersions at the Nanoscale Using Fluorescence Resonance Energy Transfer (FRET). Macromol Rapid Commun 2006;27:1149–1155.

43. Drooge DJV et al. Characterization of the molecular distribution of drugs in glassy solid dispersions at the nanometer scale, using differential scanning calorimetry and gravimetric water vapour sorption techniques. Int J Pharm 2006;310: 220–229.

44. Deitzel JM et al. The effect of processing variables on the morphology of electrospun nanofibers and textiles. Polym 2001;42:261-272.

45. Turk M et al. Micronization of pharmaceutical substances by Rapid Expansion of Supercritical Solutions (RESS): a promising method to improve bioavailability of poorly soluble pharmaceutical agents. J Supercrit Fluids 2002;22:75–84.

46. Corrigan OI et al. Comparative physicochemical properties of hydrocortisone–PVP composites prepared using supercritical carbon dioxide by the GAS anti-solvent recrystallization process, by coprecipitation and by spray drying. Int J Pharm 2002;245:75–82.

47. Fusaro FM et al. Dense gas antisolvent precipitation: A comparative investigation of the GAS and PCA techniques. Eng Chem Res 2005;44:1502–1509.

48. Badens Elisabeth et al. Comparison of solid dispersions produced by supercritical antisolvent and spray-freezing technologies. Int J Pharm 2009;377:25–34.

49. Ruchatz F, Kleinebudde P and Muller BW. Residual solvents in biodegradable microparticles. Influence of process parameters on the residual solvent in microparticles produced by the Aerosol Solvent Extraction System (ASES) process. Int J Pharm Sci 1997;86:101–105.

50. Majerik V et al. Bioavailability enhancement of an active substance by supercritical antisolvent precipitation. J Supercrit Fluids 2007;40:101–110.

51. Juppo AM, Boissier C and Khoo C. Evaluation of solid dispersion particles prepared with SEDS. Int J Pharm 2003;250:385–401.

52. Won DH et al. Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation. Int J Pharm 2005;301:199–208.

53. Muhrer G et al. Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water-soluble drug: Generation of drug microparticles and drug-polymer solid dispersion. Int J Pham 2006;308:69–83.

54. Subramanian B, Rajewski RA and Snavely K. Pharmaceutical processing with supercritical carbon dioxide. J Pharm Sci 1997;86:885–890.

55. Majerik V et al. Novel particle engineering techniques in drug delivery: review of formulations using supercritical fluids and liquefied gases. Hun J Ind Chem 2004;32:41–56.

56. Rogers TL, Johnston KP and Williams RO. Solution-based particle formation of pharmaceutical powders by supercritical or compressed fluid CO2 and cryogenic spray-freezing technologies. Drug Dev Ind Pharm 2001;27:1003–1015.

57. Hu J, Johnston KP and Williams RO. Rapid dissolving high potency danazol powders produced by spray freezing into liquid process. Int J Pharm 2004;27:145–154.

58. Williams RO et al. Process for production of nanoparticles and microparticles by spray freezing into liquid. World Patent 02/060411,2002.

59. Serajuddin ATM et al. Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions. J Pharm Sci 1988;77:414-417.

60. Barker SA et al. An investigation into the structure and bioavailability α-tocopherol dispersions in Gelucire 44/14. J Controlled Release 2003;91:477–488.

61. Serajuddin ATM, Sheen PC and Augustine MA. Improved dissolution of a poorly water soluble drug from solid dispersions in poly (ethylene glycol)-polysorbate 80 mixture J Pharm Sci 1990;79:463–464.

62. Yukse N et al. Enhanced bioavailability of piroxicam using Gelucire 44/14 and Labrasol: in vitro and in vivo evaluation. Eur J Pharm Biopharm 2003;56:453-459.

63. Newa M et al. Preparation, characterization and in vivo evaluation of ibuprofen binary solid diseprsion with poloxamer 188. Int J Pharm 2007;243:228-237.

64. Van MG. et al. Evaluation of Inutec SP1 as a new carrier in the formulation of solid dispersions for poorly soluble drugs. Int J Pharm 2006;316:1–6.

65. Sheen PC et al. Bioavailability of a poorly water-soluble drug from tablet and solid dispersion in humans. J Pharm Sci 1991;80:712-714.

66. Rouchotas C, Cassidy OE and Rowley G. Comparison of surface modification and solid dispersion techniques for drug dissolution. Int J Pharm 2000;195:1–6.

67. Dixit RP and Nagarsenker MS. In Vitro And In Vivo Advantage Of Celecoxib Surface Solid Dispersion And Dosage Form Development. Indian J Pharm Sci 2007;69(3):370-377.

68. Law SL and Chiang CH. Improving dissolution rate of griseofulvin by deposition on disintegrants. Drug Develop Ind Pharm 1990:16;137-147.

69. Yen SY et al. Investigation of dissolution enhancement of nifedipine by deposition on superdisintegrants. Drug Develop Ind Pharm 1997:23;313-317.

70. Tanaka N et al. Development of novel sustained-release system, disintegration controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine. J Contr Release 2005;108:386–395.

71. Walker SE et al. The filling of molten and thixo formulations into hard gelatin capsules. J Pharm Pharmacol 1980;32:389-393.

72. Kennedy JP and Niebergall PJ. Development and optimization of a solid dispersion hot bed fluid bed coating method. Pharm Dev Technol 1996;1:51–62.

73. Gilis PA et al. Beads having a core coated with an antifungal and a polymer. US patent 5633015, 1997.

74. Zhang F and McGinity JW. Properties of hot-melt extruded theophylline tablets containing poly(vinyl acetate). Drug Dev Ind Pharm 2000;29(6):938–948.

75. Nakamichi K et al. The role of the kneading paddle and the effects of screw revolution speed and water content on the preparation of solid dispersions using a twin-screw extruder. Int J Pharm 2002;241:203–211.

76. Seo A et al. The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer. Int J Pharm 2003;259:161-171.

77. Ambika AA, Mahadik KR and Paradkar A. Spray-dried amorphous solid dispersion of simavastatin. Pharm Research 2005;54:37-43.

78. Paradkar A et al. Characterization of curcumin-PVP solid dispersion obtained by spray drying. Int J Pharm Sci 2004;271:281-286.

79. Zhang F and McGinity JW. Properties of hot-melt extruded theophylline tablets containing poly(vinyl acetate). Drug Dev Ind Pharm 2000;29(6):938–948.

80. Verreck G et al. Preparation and characterization of nanofibers containing amorphous drug dispersions generated by electrostaticspinning. PharmRes 2003;20:810-817.
81. Wnek GE et al. Release of tetracycline hydrochloride from electrospun poly(ethylene-co-vinyl-acetate), poly(lactic acid) and a blend. J Control Release 2002;81:57-64.

81. Rogers TL et al. A novel particle engineering technology: spray-freezing into liquid. Int J Pharm 2002b;242:93–100.

82. Yu Z et al. Preparation and characterization of microparticles containing peptide produced by a novel process: spray freezing into liquid. Eur J Pharm Biopharm 2002;54:221–228.

83. Iqbal Z, Babar A and Muhammad A. Controlled-release Naproxen using micronized Ethyl Cellulose by wet granulation and solid dispersion method. Drug Dev Ind Pharm 2002; 28: 129-134.

84. Law SL et al. Dissolution and absorption of nifedipine in poly (ethylene glycol) solid dispersion containing phosphatidylcholine. Int J Pharm 1992;84:161-166.

Received on 10.11.2009

Accepted on 08.01.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(1): Jan. –Feb. 2010, 14-22

STARATEGY	DRUG	REFERENCE NO.
1. Hot Melt Extrusion	Para amino salicylic acid Itraconazole Theophylline	29 31 74
2. Meltrex	Verapamil Nifedipine Itraconazole	26 75 30
3. Melt Agglomeration	Diazepam	76
4. Closed Melting Point Method	Troglitazone	28
5. Spray Drying	Loperamide Simvastatin Curcumin	38 77 78
6. Lyophilization	Diazepam Glyburide	43 79
7. Spray Freeze Drying	Tetrahydrocannabinol	42
8. Electrostatic Spinning	Itraconazole Felodipine Tetracycline	80 41 81
9. RESS	Griseofulvin Nifedipine	45 54
10. GAS	Hydrocortisone Felodipine	46 52
11. PCA	Phenytoin	53
12. SAS	Oxeglitazar	48
13. SEDS	Oxeglitazar	50
14.SFL	Danazole Carbamazepine Insulin	57 82 83
15.Use Of Surfactant	Gelucire 44/14 - α tocoferol Labrasol – Piroxicam Poloxamer 188 – Ibuprofen Inutec SPI – Itraconazole Synperonic - Phenylbutazole	60 62 63 64 66
16. Surface Solid Dispersion	Celecoxib Griseofulvin Nifedipine	67 68 69
17. Sustained Release Solid Dispersion	Nivaldipine Naproxen	70 84
18. Hot Melt Encapsulation	Triamterene Nifedipine	71 85
19. Spraying Coating On Sugar Beads	Saperconazole, Itraconazole	73