Solubility Enhancement – Eminent Role in Poorly Soluble DrugsABSTRACT Among all newly discovered chemical substances about 40% drugs are lipophilic and fail to reach market due to their poor water solubility. The solubility behavior of drugs remains one of the most challenging aspects in formulation development. Solid dispersions have better potential for improving drug solubility among other. Solid dispersions have been employed to enhance the dissolution rates of poorly water - soluble drugs. The approaches included and described are fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, di-electric concepts, electro static spinning method and super critical fluid technology. The present review is devoted to production of solid dispersions, various carriers used and the advantageous properties of solid dispersion. KEYWORDS: Solid dispersion, solubility, eutectic mixture, poorly soluble,etc; INTRODUCTION: The BCS (Biopharmaceutics Classification System) is a scientific framework for classifying a drug substance based on its aqueous solubility and intestinal permeability. It is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration. When combined with the in vitro dissolution characteristics of the drug product, the BCS takes into account three major factors: solubility, intestinal permeability, and dissolution rate, all of which govern the rate and extent of oral drug absorption from IR solid oral-dosage forms1. According to the Biopharmaceutics Classification System, drug substances are classified as follows: Class I - high permeability, high solubility o Example: metoprolol o Those compounds are well absorbed and their absorption rate is usually higher than excretion. Class II - high permeability, low solubility o Example: glibenclamide o The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found. Class III - low permeability, high solubility o Example: cimetidine o The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied. Class IV - low permeability, low solubility o Example: hydrochlorothiazide o Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected. d). In addition micronization is a high-energy process. h is the thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound. Consideration of the modified Noyes-Whitney equation provides some hints as to how the dissolution rate of Even very poorly soluble compounds might be improved to minimize the limitations to oral availability: dC = AD. the bioavailability may be enhanced by increasing the solubility and dissolution rate of the drug in the gastro-intestinal fluids. Optimizing the wetting characteristics of compound surface. Use of co-solvents or surfactants to improve dissolution rate pose problems.) dt h Where. use of surfactant and use of pro. Improve apparent solubility of drug under physiologically relevant conditions. The poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastro-intestinal fluids often cause insufficient bioavailability. epigastric distress due to high alkalinity.C. Cs is the solubility of the compound in the dissolution medium. such as patient compliance and commercialization. Consequently poor solubility results in low bioavailability. D is the diffusion coefficient of the compound. However sodium and potassium salts of weak acids dissolve more rapidly than the free salts. Potential disadvantages of salt forms include high reactivity with atmospheric carbon dioxide and water resulting in precipitation of poorly water-soluble drug. surface properties and electrostatic charges. the formed fine powders showing poor wettability and . The solubility/dissolution behavior of a drug is key determinant in oral bioavailability. (Cs . Ensure sink condition for dissolution f).drug however all these techniques have certain limitations. C is the concentration of drug in the medium at time t. morphology. To increase the dissolution rate from equation the following approaches are available. the main one being the limited opportunity to control important characters of the final particle such as size. and present formulators with considerable technical challenges. in general includes micronization. To decrease the boundary layer thickness e). Even though particle size reduction increases the dissolution rate. Improvement of oral bioavailability of poor water-soluble drugs remains one of the most challenging aspects of drug development. The techniques/ approaches that have commonly been used to overcome drawbacks associated with poorly water-soluble drugs. Micronization has several disadvantages. which causes disruptions in the drug s crystal lattice. resulting in the presence of disordered or amorphous regions in the final product. c). A is the surface area available for dissolution. dC/dt is the rate of dissolution.Poorly water-soluble drug candidates often emerge from contemporary drug discovery programs. Especially for class II substances according to the Biopharmaceutics Classification System (BCS). a). shape. To increases the surface area available for dissolution by: b). Decreasing the particle size of drug. salt formation. the carrier will dissolve rapidly. The large surface area of the resulting suspension should result in an enhanced dissolution rate and thereby improved bioavailability. Fig: Phase diagram of simple eutectic mixture with negligible solid solubility . SOLID DISPERSIONS Simple Eutectic Mixtures No review of solid dispersions would be complete without a brief description of eutectic mixtures. When. A simple 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. Solid dispersion technique has come into existence to eliminate all these problems. highly water soluble carrier. one of the components starts to crystallize out before the other. Solid eutectic mixtures are usually prepared by rapid cooling of a comelt of the two compounds in order to obtain a physical mixture of very fine crystals of the two components. whereas when other compositions are cooled. a mixture of A and B with composition E is cooled. When a mixture with composition E. which are the corner stone of this approach to improving bioavailability of poorly soluble compounds. consisting of a slightly soluble drug and an inert.flow properties. releasing very fine crystals of the drug. A and B crystallize out simultaneously. is dissolved in an aqueous medium. the selection of the carrier has an ultimate influence on the dissolution characteristics of the dispersed drug. Therefore.The concept of solid dispersions was originally proposed by Sekiguchi and Obi. absorption and therapeutic efficacy of drugs in dosage forms. Solid dispersions represent a useful pharmaceutical technique for increasing the dissolution. CLASSIFICATION: The solid dispersions may also be called solid-state dispersions. Since the dissolution rate of a component from a surface is affected by the second component in a multiple component mixture. who investigated the generation and dissolution performance of eutectic melts of a sulfonamide drug and a water-soluble carrier in the early 1960s. The term solid dispersion refers to the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (fusion). as first used by Mayerson and Gibaldi. solvent. a water-soluble carrier results in a fast release of the drug from the matrix. . The term “co-precipitates” has also been frequently used to refer to those preparations obtained by the solvent methods. and a poorly soluble or insoluble carrier leads to a slower release of the drug from the matrix. or melting-solvent method. STRATEGIES FOR SOLUBILITY ENHANCEMENT Various strategies investigated by several investigators include fusion (melting). extruding method. use of surfactant. the fusion process does not require an organic solvent but since the melting of sparingly water-soluble drug and water-soluble polymer entails a cooling step and solid pulverizing step. Many investigators studied SD of meloxicam. To overcome this problem Nakano et al have described a method conceptualizing the formation of a SD as the solid-to-solid interaction between a sparingly water soluble drug. This process employs melting of the mixture of the drug and carrier in metallic vessel heated in oil bath. prepared SD of etoricoxib using PEG and PVP as a carriers by solvent evaporation method where carriers along with drug were dissolved . the sparingly water soluble drug can be made amorphous to have never been achieved by any dry process heretofore known. felodipine. This method is reported to produce SD with 0% apparent crystallinity. Solvent evaporation method: The solvent-based process uses organic solvent to dissolve and intimately disperse the drug and carrier molecule. naproxen. wherein SD(s) of troglitazone. Suhagic et al. instead of heating the system to the extent that the two materials are melted . Fusion method: The fusion process is technically the less difficult method of preparing dispersions provided the drug and carrier are miscible in the molten state. atenolol. immediately after fusion.polyvinyl pyrrolidone (PVP) have been prepared by closed melting point method. These findings suggest that the above-mentioned technique can be employed successfully for improvement and stability of solid dispersions of poor water drugs. Decomposition should be avoided and is affected by fusion time and rate of cooling. unlike conventional production method. This method involves controlled mixing of water content to physical mixtures of troglitazone PVP by storing at various equilibrium relative humidity levels (adsorption method) or by adding water directly (charging method) and then mixer is heated. the sample are poured onto a metallic plate which is kept at ice bath. A modification of the process involves Spray congealing from a modified spray drier onto cold metal surface. electro static spinning method and super critical fluid technology. nilvadipine and water soluble polymer which. On the other hand. Another modification of the above method. melt agglomeration process. and nimesulide using solvent evaporation technique. rofecoxib. spray drying technology. comprises mixing a sparingly water soluble drug and water soluble polymer together under no more than the usual agitation force with heating within the temperature region not melting them. a time consuming multiple stage operation is required. solvent evaporation. Large volumes of solvents are generally required which can give rise to toxicological problems. lyophilization (freeze drying). In addition. The effect of screw revolution speed and water content on the preparation of SD(s) should be investigated. is now used to process cereals and functionalize food materials.. Larger particles results in densification of agglomerates while fine particle cause complete adhesion to the mass to bowl shortly after melting attributed to distribution and coalescence of the fine particles.tetrahydrocannabinol containing inulin based solid dispersions with improved incorporation of . frozen and sublimed to obtain a lyophilized molecular dispersion. The extruder consists of a hooper. Lyophillization has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent.tetrahydrocannabinol in inulin. improved wetting and improved bioavailability. Badry et al. suggested spray freeze-drying as a potential alternative to the above-mentioned process to produces 9. Binder (carrier). Betageri et al. Hot melt extrusion approach represent the advantageous mean of preparation of SD(s) by using the twin screw hot melt extruder where only thermo stable components are relevant. such as tissue products from animal proteins. a kneading screw and heaters. The prepared SD(s) exhibited improved dissolution attributed to decreased crystallinity. Nakamichi et al. high screw speed high feed rate processes in comparison with low screw speed low feed rate processes caused an increase in extrudate radius and porosity and decrease in mechanical .. barrel. a die.. studied that presence of kneading paddle element of screw results in super saturation on dissolution testing while slow revolution rate of screw and addition of the suitable amount of water increased rate of dissolution although no super saturation occurred.in procedure) or by spraying a dispersion of drug in molten binder on the heated excipient (sprayon procedure) by using a high shear mixer. Drooge et al. Topalogh et al. since these parameters have profound impact on the quality of SD(s).in 2-propanol to get a clear solution followed by solvent evaporation and finally dispersion was collected. The physical mixture is introduced into the hopper that is forwarded by feed screw and finally is extruded from the die. and Fathy et al. Extruding method: The extruding method was originally designed as an extraction/casting method for polymer alloys in plastic industry. Melt agglomeration process: This technique has been used to prepare SD where the binder acts as a carrier. drug and excipients are heated to temperature above the melting point of the binder (melt. Lyophillization technique: Freeze-drying involves transfer of heat and mass to and from the product under preparation. 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. have successfully investigated the potential applications of lyophilization in manufacturing of SD(s). The operating conditions and dryer design depends upon the drying characteristics of the product and require powder specifications. The role of methylparaben and sorbitol has also been investigated as plasticizer in preparation of SD(s) in extrusion method. The process allows production of fine. indomethacin/lacidipine/nefidipine/ piroxicam/ tobutamide and polyvinylpyrrolidone(PVP). It is an established method that is initiated by atomizing suspensions or solutions into fine droplets followed by a drying process. prepared SD(s) of loperamide with PEG 6000 by this technique wherein solutions containing different concentrations of PEG 6000 and constant amount of loperamide were spray dried. controlled pore glass and porous cellulose is appreciated to formulate solid . The prepared SD(s) exhibited higher dissolution rates than that of pure crystalline loperamide.strength and drug release rate from the matrix attributed to the expansion promoted under certain extrusion conditions. During extrusion carbon dioxide is transformed in gaseous phase. a plasticizer can be added to the formulation. it is simple and cost effective. Carbon dioxide can act as temporary plasticizer. as it is 30-50 times less expensive than freeze-drying. Chouhan et al 58 studied the suitability of this technique for preparation of SD(s) of glibenclamide polyglcolized glycerides. Today. also improvement in the therapeutics efficacy of amorphous glibenclamide in SD(s) was observed. The role of porous materials such as calcium silicate. As a consequence carbon dioxide escapes from extrudate and does not appear in final product. itraconazole and HPMC 2910/Eudragit e 100 or a mixture of Eudragit E 100-PVP vinyl acetate 64 to improve solubility and dissolution rate of poor water soluble drugs. spray drying finds great utility in pharmaceutical industry because of the rapid drying and specific characteristics such as particle size and shape of the final product. The spray drying technique is a useful method to obtain spherical particle and narrow distribution. resulting solid particles. After spray drying. Spray drying: The manufacture of milk powder was one of the first applications of spray drying when the method was developed in 1920. the dispersions were dried at 400C under vacuum until constant weight. Solvent used was dichloromethane. In addition. environmental pollution and operational safety as well as corporate problems such as capital investment. This study revealed the improvement in solubility and dissolution rates. Typically. Rankell et al. To reduce the melt viscosity in the extrudate and to be able to decrease temperature settings. Tanno et al. Some other investigators also reported improvement in solubility and dissolution rate. conventional plasticizer such as triacetin or polyethylene glycol is used in concentration range of 5-30 % weight of the extrudate that lowers the processing temperature. described a process for producing the SD(s) of poorly watersoluble drugs using water-soluble polymer dispersion and/ or water-soluble polymer solution and the plasticizer solution by using 4-nozzle spray gun. dust free powder as well as agglomerated one to precise specifications. The frequent use of the organic solvent in spray drying pose problems such as residues in products. This method has already been used successfully to prepare SD(s) of traconazole and hydroxypropylmethylecellulose(HPMC). is a clear liquid surfactant with a HLB of 14. The presence of water and polar water-miscible solvent. a partially water-miscible solvent. These are available in various molecular weights and PEO/PPO ratios.poly(ethylene oxide) (PEOPPO-PEO) block polymers. Solid dispersions using pluronic F-68 (a type of poloxamer) as a carrier were studied for improving the dissolution and bioavailability of ABT-963. When used in relatively high quantities. The amphiphilic poly (ethylene oxide)-poly (propylene oxide).and triglycerides and of mono. detergents. organic solvents and surfactants . porous materials control polymorphs and stabilizes meta-stable crystals in SD(s) under sever storage conditions. Moreover. Improvement in solubility. Labrasol. Surfactant: The utility of the surfactant systems in solubilization is well known. di. Gelucire 44/14 and gelucire 50/13 are two examples of this synthetic group where 44 and 50 represent melting point. while 14 and 313 represent HLB values of gelucire respectively. known as poloxamer or pluronics represent another class of surfactants. porous silica has been reported to improve solubility and dissolution rates of indomethacin and tolbutamide. of same chemical nature as gelucire.PVP were studied.dosages forms because they confer special characteristics such as decrease of melting point and a decrease in the crystallinity of drug entrapped in pores. Recently a new class of surfactant known as Gelucires are introduced which identify by melting points and HLB values. by forming a lipid matrix.and di. poloxamer imparts sustained-release properties to solid dosage forms. A significant increase of oral bioavailability compared with conventional capsule formulation was also reported. In addition. gelling agents.soluble compound. Therefore. Solid dispersions of piroxicam with labrasol have also resulted in improved solubility and dissolution when compared with pure drug. dispersing agents.fatty acid esters of polyethylene glycol (PEG) derived from natural vegetable fatty acids and having amphiphilic character. emulsifying agents and solubilizing agents. a poorly water. an anionic surfactant and cationic surfactant affect domain of the PEOPPO-PEO block copolymer self-assembly. a non. Surfactant reduces hydrophobicity of drug by reducing interfacial or surface tension because of these unique property surfactants have attracted the attention of investigators for preparation of solid dispersions. Results showed that the solid dispersion substantially increased the in vitro-dissolution rate of ABT-963. dissolution and stability was observed. Gelucires with low HLB can be employed to decrease the dissolution rate of drugs and higher HLB ones for fast release.PEG 6000gelucire 44/14. Gelucire is a saturated polyglycolized glyceride consisting of mono-.gelucire 44/14 and UC-781.ionic surfactant. Gelucire is a widely use in the formulation of semi-solid dispersions. These block polymers are extensively used in the pharmaceutical industry as defoaming agents. and hence offer a large variety of physico-chemical properties. Solid dispersions of antiviral agent uc-781-polyethylene glycol 6000. and experimental proofs of concept are abundant in the scientific literature for a plethora of model compounds from very different areas such as drugs and pharmaceutical compounds. Wong et al compared the SD(s) of felodipine prepared by conventional solvent evaporation (CSE) and supercritical antisolvent precipitation (SAS) methods. The use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete. a commonly used surfactant.e. Conventional methods. has also been evaluated as carrier in formulation of solid dispersions for a poorly watersoluble drug. However the particle sizes of the SD(s) from SAS process were maintained for 6 h due to the increased solubility of felodipine. it poses no danger to the patient. in 1879. particles from gas-saturated Solution (PGSS). Super critical fluid (scf) technology: This technology has been introduced in the late 1980s and early 1990s.should be used with great care for preparation solid dispersion while using in combination with poloxamer. explosives and energy materials. polymers and biopolymers. gas anti-solvent (GAS) and precipitation with a compressed fluid anti-solvent (PCA) are process of micronization. i. Supercritical fluids used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. Inutec SPI has low viscosity and stability effect on emulsion and suspension. supercritical anti-solvent (SAS). Since the first experiences of Hannay et al. . even though a small amount of carbon dioxide remains trapped inside the polymer. solvent evaporation and hot melt method often result in low yield. The SAS process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing concurrently. Inutec SPI. These methods use. Solution enhanced dispersion by supercritical fluids (SEDS) and/or dispersing fluid: GAS. Solution enhanced dispersion by supercritical fluids (SEDS). The reason for this depression is the solubility of the lighter component (dense gas) in the forming phase (heavier component). 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. Polysorbate also ensues complete release of drug in metastable finely dispersed state having large surface area. SCFs either as solvent: rapid expansion from supercritical solution (RESS) or antisolvent: gas anti-solvent (GAS). studied that polysorbate. Spray drying. superconductors and catalyst precursors dyes and biomolecules such as proteins and peptides. a number of techniques have been developed and patented in the field of SCF-assisted particle design. Hemant et al. SEDS. Dissolution properties of SD(s) made up of itraconazole and Inutec SPI were improved in comparison to pure itraconazole or physical mixtures with Inutec SPI4. high residual solvent content or thermal degradation of the active substance. supercritical anti-solvent (SAS). results in improvement of dissolution and bioavailability of poorly water soluble drug attributed to solubilization effect of surface active agent. aerosol solvent extraction system (ASES). The particle sizes of the SD(s) from CSE process increased at 1h after dispersed in distilled water. 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. and Sheen et al. Moreover. SD(s) form the SAS process showed a high dissolution rate of over 90% within 2 h showing the potential applications of SCF technology in preparation of SD(s). .