Vol - 4, Issue - 2, Apr 2013 ISSN: Dhumal et al PHARMA SCIENCE MONITOR

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1 PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES METHOD FOR ENHANCEMENT OF SOLUBILITY: A REVIEW S. G. Dhumal*, J. K. Patil, S. P. Pawar, N. K. Jadhav, P. A. Patil Department of Quality Assurance, P.S.G.V.P. Mandal s College of Pharmacy, Shahada, Dist- Nandurbar , Maharashtra (INDIA) ABSTRACT Improving oral bioavailability of drugs, those given as solid dosage forms remains a challenge for the formulation scientists due to solubility problems. The problem can be solved by different technological approaches during the pharmaceutical product development like solid dispersion, micronisation, micelle formation, novel techniques like lyophilisation, floating granules are some of the vital approaches routinely employed to enhance the solubility of poorly soluble drugs. Many techniques have been exercised to improve oral bioavailability of drugs. Among them, solid dispersion has attracted an attention of the researchers. The present review is devoted to various traditional and novel techniques for enhancing drug solubility to reduce the percentage of poorly soluble drug candidates ignored from the development. Keywords: Solubility, Bioavailability, Solid dispersion, Micro emulsion, Lyophilisation. INTRODUCTION The progress in treatment of diseases has been evident within upsurge in development of new drugs. An estimated 40% of these drugs are poorly water soluble. Although most of the drugs have encouraging experimental data obtained in vitro and in vivo, there results have been disappointing. The attributes include; 1. Poor absorption, rapid degradation, and lamination (peptides and protein) resulting in insufficient concentration, 2. Drug distribution to other tissues with high drug toxicities (anticancer drugs), 3. Poor solubility of drugs, and 4. Fluctuations in plasma levels owing to unpredictable bioavailability. Poor aqueous solubility is the predominant problem particularly associated with combinatorial chemistry and high throughput screening (HTS). Rate of absorption is most IC Value

2 prominently limited by poor solubility of drug than its permeability through intestinal mucosa. So, poorly soluble drug can be defined as the drug having dissolution rate so less that, release and therefore uptake can t be completed within the time taken for the drug, that not only to defeats transit time of absorption site but also longer exposure arrive problems of decomposition. There are two parameters useful for identifying poorly soluble drugs. One is its aqueous solubility should be less than 100 µg/ml and another is dose : solubility ratio. Dose : solubility ratio can be defined as volume of gastrointestinal fluids necessary to dissolve the administered dose. Biopharmaceutical Classification System (BCS) classifies drug Products in to following categories: TABLE 1: BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS) Class Solubility Permiability IV Circulation Rate of Absorbtion Class I High High Can be good Gastric emptying Class II Low High Good Dissolution Class III High Low Poor Permiability Class IV Low Low Poor Dissolution and Permiability High solubility of refers largest dose of drug should be soluble in 250 ml of water having ph range 1.0 to7.5,while highly permeability refers drug should pass 90 per cent of the administered dose through absorption membrane. Over 40% new chemical entities and 27.70% WHO essential drugs fall in class II and class IV. If such a drug administered orally, it should be administered in large dose to get desired bioavailability. In case of cancer and HIV treatment more dose treatment is required and in case of arthritis, diabetes and hypertension low dose formulation should be essential. So this challenge is in front of formulation scientist can be solved by various techniques as discussed follows. 1 The enhancement of oral bioavailability of such poorly water soluble drugs remains one of the most challenging aspects of drug development. The development of solid IC Value

3 dispersions as a practically viable method to enhance bioavailability of poorly watersoluble drugs overcame the limitations of previous approaches such as salt formation, solubilization by cosolvents, and particle size reduction. Studies revealed that drugs in solid dispersion need not necessarily exist in the micronized state. A fraction of the drug might molecularly disperse in the matrix, thereby forming a solid dispersion. 2 when the solid dispersion is exposed to aqueous media, the carrier dissolves and the drug releases as fine colloidal particles. The resulting enhanced surface area produces higher dissolution rate and bioavailability of poorly water-soluble drugs. In addition, in solid dispersions, a portion of drug dissolves immediately to saturate the gastrointestinal tract fluid, and excess drug precipitates as fine colloidal particles or oily globules of submicron size. In spite of these advantages, only 2 products have been marketed since the development of this technology 4 decades ago. The limitations of this technology have been a drawback for the commercialization of solid dispersions. The limitations include, 1. Laborious and expensive methods of preparation, 2. Reproducibility of physicochemical characteristics, 3. Difficulty in incorporating into formulation of dosage forms, 4. Scale-up of manufacturing process, and 5. Stability of the drug and vehicle. 3 SOLUBILITY: The solubility of a substance at a given temperature is defined as the concentration of the dissolved solute, which is in equilibrium with the solid solute. Solubility of molecules depends on H-bond donor and acceptor properties of the molecule and of water and crystal lattice of molecule. Effects of these factors can be well explained by following equation S = f (Crystal packing energy + Cavitation energy + Solvation energy) Where, IC Value

4 Crystal packing energy is the energy require for breaking crystal lattice to interact solute molecules with the solvent molecules, Cavitation energy is the energy required to form cavity within the solvent, Salvation energy is the energy released after favorable interactions between solute and solvent. Cavitation energy can be fulfilled by use of surfactants and crystal packing energy by amorphism or polymorphism of solute. Therefore together with surface area, the saturation solubility is a key factor in the dissolution rate of drug. It depends on physiochemical properties of drug such as, crystalline form, lipophilicity and pka. DISSOLUTION: Dissolution composed of two consecutive stages; 1. An artificial reaction results in the liberation of solute molecules from the solid phase, 2. Followed by transport of these molecules away from the interface into the bulk of the liquid phase under the influence of diffusion or convection. 4 The overall rate of mass transport that occurs during dissolution will be determined by the rate of slowest stage. In the absence of chemical reaction between solute and solvent then the slowest stage is usually the diffusion of dissolved solute across the static boundry of layer of liquid that exist at a solid-liquid interface. The dissolution rate of a solid in a liquid may be described quantitatively by the Noyes-Whitney equation: dm/dt = KA (Cs - C) Where, m = the mass of solute that has passed into solution in time t, dm/dt represents the rate of dissolution, K is the intrinsic dissolution rate or simply the dissolution rate constant. A is the surface area of undissolved solid in contact with the solvent, IC Value

5 Cs is the concentration of solute required to saturate the solvent at the experimental temperature, C is the solute concentration at time t. TABLE 2: FACTORS INFLUENCING THE DISSOLUTION Terms in Noyes-Whitney equation Factors affecting equation parameters A, surface area of undissolved solid Size of solute particles, dispersibility of powdered solid in dissolution medium, porosity of solid particles Cs, solubility of solid in dissolution medium Temperature, Nature of dissolution medium, Molecular structure of solute, Crystalline form of solid, Presence of other compounds C, concentration of solute in solution at time (t) Volume of dissolution medium, Process that removes solute from the dissolution medium K, dissolution rate constant Thickness of boundry layer, diffusion coefficient of solute in the dissolution TECHNIQUES OF SOLUBILITY ENHANCEMENT: There are various techniques available to improve the solubility of poorly soluble drugs. Some of the approaches to improve the solubility are; I. Physical Modifications A. Particle size reduction by Micronization B. Modification of the crystal habit a. Polymorphism b. Nanosuspensions C. Drug dispersion in carriers a. Solid Dispersions (SD) b. Complexation D. Solubilisation by surfactants a. Microemulsions b. Self microemulsifying drug delivery systems IC Value

6 II. Chemical Modifications a. Prodrugs b. Salt formation c. Liquid-solid compacts. 5 SOLID DISPERSIONS: The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles. Therefore, based on their molecular arrangement, six different types of solid dispersions can be distinguished. They are described in Table 2. Moreover, certain combinations can be encountered, i.e. in the same sample; some molecules are present in clusters while some are molecularly dispersed. Moreover, not the preparation method but the molecular arrangement governs the properties of solid dispersions. TABLE 3: POORLY SOLUBLE DRUGS WITH HYDROPHILIC CARRIERS Sr. No. Carrier Drug 1. Poloxamer 407, B-cyclodextrine Tadalafil 2. Polyethylene glycol (PEG) Griseofulvin 3. Polyvinylpyrrolidone (PVP) Flufeenamic acid 4. Hydroxypropylmethylcellulose Albendazole, (HPMC) Benidipine 5. Sorbitol Prednisolone 6. Urea Ofloxacin Categories of Solid Dispersions: A. Simple eutectic mixtures B. Solid solutions a. According to their miscibility IC Value

7 i. Continuous ii. Discontinuous solid solutions b. According to the way in which the solvate molecules are distributed in the solvent i. Substitutional crystalline solid solutions ii. Interstitial crystalline solid solutions iii. Amorphous solid solutions C. Glass solutions D. Amorphous precipitation in a crystalline carrier Simple eutectic mixtures: When a mixture of A and B with composition E is cooled, A and B crystallize out simultaneously, whereas when other compositions are cooled, one of the components starts to crystallize out before the other. Solid eutectic mixtures are usually prepared by rapid cooling of a co-melt of the two compounds in order to obtain a physical mixture of very fine crystals of the two components. When a mixture with composition E, consisting of a slightly soluble drug and an inert, highly water soluble carrier, is dissolved in an aqueous medium, the carrier will dissolve rapidly, releasing very fine crystals of the drug. The large surface area of the resulting suspension should result in an enhanced dissolution rate and thereby improved bioavailability. 6 Figure 1 Phase diagram for a eutectic system IC Value

8 Solid solutions: i) Continuous solid solutions: In a continuous solid solution, the components are miscible in all proportions. Theoretically, this means that the bonding strength between the two components is stronger than the bonding strength between the molecules of each of the individual components. Solid solutions of this type have not been reported in the pharmaceutical literature to date. 7 ii) Discontinuous solid solutions: In the case of discontinuous solid solutions, the solubility of each of the components in the other component is limited. A typical phase diagram is shown in Fig. 2 show the regions of true solid solutions. In these regions, one of the solid components is completely dissolved in the other solid component. Note that below a certain temperature, the mutual solubilities of the two components start to decrease. Due to practical considerations it has been suggested by Goldberg that the term solid solution should only be applied when the mutual solubility of the two components exceeds 5%. Whether or not a given solid solution can be utilized as a dosage form strategy will depend not only on the mutual solubilities of the two components but also on the dose of the drug component. 8 The upper limit for the mass of a tablet or capsule is about 1 g. Assuming that the solubility of the drug in the carrier is 5%, doses of above 50 mg would not be feasible with this strategy. Obviously, if the drug solubility in the carrier is significantly higher than 5%, larger doses can be entertained. IC Value

9 Figure 2 Phase diagram for a discontinuous solid solution b. According to the way in which the solvate molecules are distributed in the solvent i) Substitutional crystalline solid solutions: Classical solid solutions have a crystalline structure, in which the solute molecules can either substitute for solvent molecules in the crystal lattice or into the interstices between the solvent molecules. 9 Figure 3 Substitutional crystalline solid solution ii) Interstitial crystalline solid solutions: In interstitial solid solutions, the dissolved molecules occupy the interstitial spaces between the solvent molecules in the crystal lattice (Fig. 4). As in the case of substitutional crystalline solid solutions, the relative molecular size is a crucial IC Value

10 criterion for classifying the solid solution type. In the case of interstitial crystalline solid solutions, the solute molecules should have a molecular diameter that is no greater than 0.59 of the solvent molecule's molecular diameter. Furthermore, the volume of the solute molecules should be less than 20% of the solvent. 10 Figure 4 Interstitial crystalline solid solution iii) Amorphous solid solutions: In an amorphous solid solution, the solute molecules are dispersed molecularly but irregularly within the amorphous solvent (Fig.5). Using Griseofulvin in citric acid, Chiou and Riegelman were the first to report the formation of an amorphous solid solution to improve a drug's dissolution properties. Other carriers that were used in early studies included urea and sugars such as sucrose, dextrose and galactose. More recently, organic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and various cellulose derivatives have been utilized for this purpose. Polymer carriers are particularly likely to form amorphous solid solutions as the polymer itself is often present in the form of an amorphous polymer chain network. In addition, the solute molecules may serve to plasticizer the polymer, leading to a reduction in its glass transition temperature. IC Value

11 Figure 5 Amorphous solid solution Glass solutions and glass suspensions: Chiou and Riegelman first introduced the concept of formation of a glass solution as another potential modification of dosage forms in increasing drug dissolution and absorption. A glass solution is a homogenous, glassy system in which a solute dissolves in a glassy solvent. The familiar term glass however, can be used to describe either a pure chemical or a mixture of chemicals in a glassy or vitreous state. The glassy or vitreous state is usually obtained by an abrupt quenching of the melt. It is characterized by transparency and brittleness below the glass transition temperature Tg. On heating, it softens progressively and continuously without a sharp melting point. 11 METHODS OF PREPARATION OF SOLID DISPERSIONS: Melting method: The melting or fusion method, first proposed by Sekiguchi and Obi involves the preparation of physical mixture of a drug and a water-soluble carrier and heating it directly until it melted. The melted mixture is then solidified rapidly in an ice-bath under vigorous stirring. The final solid mass is crushed, pulverized and sieved. Appropriately this has undergone many modifications in pouring the homogenous melt in the form of a thin layer onto a ferrite plate or a stainless steel plate and cooled by flowing air or water IC Value

12 on the opposite side of the plate. In addition, a super- saturation of a solute or drug in a system can often be obtained by quenching the melt rapidly from a high temperature. Under such conditions, the solute molecule is arrested in the solvent matrix by the instantaneous solidification process. The quenching technique gives a much finer dispersion of crystallites when used for simple eutectic mixtures. However many substances, either drugs or carriers, may decompose during the fusion process which employs high temperature. It may also cause evaporation of volatile drug or volatile carrier during the fusion process at high temperature. Some of the means to overcome these problems could be heating the physical mixture in a sealed container or melting it under vacuum or in presence of inert gas like nitrogen to prevent oxidative degradation of drug or carrier. 12 Solvent method: In this method, the physical mixture of the drug and carrier is dissolved in a common solvent, which is evaporated until a clear, solvent free film is left. The film is further dried to constant weight. The main advantage of the solvent method is thermal decomposition of drugs or carriers can be prevented because of the relatively low temperatures required for the evaporation of organic solvents. However, some disadvantages are associated with this method such as 1) The higher cost of preparation. 2) The difficulty in completely removing liquid solvent. 3) The possible adverse effect of traces of the solvent on the chemical stability 4) The selection of a common volatile solvent. 5) The difficulty of reproducing crystal form. 6) In addition, a super saturation of the solute in the solid system cannot be attained except in a system showing highly viscous properties. 13 Melting solvent method (Melt evaporation): IC Value

13 It involves preparation of solid dispersions by dissolving the drug in a suitable liquid solvent and then incorporating the solution directly into the melt of polyethylene glycol, which is then evaporated until a clear, solvent free film is left. The film is further dried to constant weight. The 5 10% (w/w) of liquid compounds can be incorporated into polyethylene glycol 6000 without significant loss of its solid property. It is possible that the selected solvent or dissolved drug may not be miscible with the melt of the polyethylene glycol. Also the liquid solvent used may affect the polymorphic form of the drug, which precipitates as the solid dispersion. This technique possesses unique advantages of both the fusion and solvent evaporation methods. From a practical standpoint, it is only limited to drugs with a low therapeutic dose e.g. below 50 mg. Melt extrusion method: The drug/carrier mixture is typically processed with a twin-screw extruder. The drug/carrier mixture is simultaneously melted, homogenized and then extruded and shaped as tablets, granules, pellets, sheets, sticks or powder. The intermediates can then be further processed into conventional tablets. An important advantage of the hot melt extrusion method is that the drug/carrier mix is only subjected to an elevated temperature for about 1 min, which enables drugs that are somewhat thermo labile to be processed. 14 Solid dispersion obtained by this method is composed of active ingredient and carrier, and prepare by hot-stage extrusion using a co-rotating twin-screw extruder. The concentration of drug in the dispersions is always 40% (w/w). The screw- configuration consist of two mixing zones and three transport zones distribute over the entire barrel length, the feeding rate is fix at 1 kg/h and the screw rate is set at 300 rpm. The five temperature zones are set at 100, 130, 170, 180, and 185ºC from feeder to die. 15 The extrudates are collected after cooling at ambient temperature on a conveyer belt. Samples are milled for 1 min with a laboratory-cutting mill and sieve to exclude particles >355µm. IC Value

14 Figure 6 Screw and kneading elements Figure 7 Extrusion screw geometry Lyophilisation Technique: Freeze-drying involves transfer of heat and mass to and from the product under preparation. This technique was proposed as an alternative technique to solvent evaporation. Lyophilisation has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion. Melt Agglomeration Process: IC Value

15 This technique has been used to prepare SD wherein the binder acts as a carrier. In addition, SD(s) 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 16. A rotary processor has been shown to be alternative equipment for melt agglomeration. 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. The effect of binder type, method of manufacturing and particle size are critical parameters in preparation of SD(s) by melt agglomeration. Since these parameters results in variation in dissolution rates, mechanism of agglomerate formation and growth, agglomerate size, agglomerate size distribution and densification of agglomerates. It has been investigated that the melting method gives a higher dissolution rates than the spray method 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. 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. 17 By Using Surfactant: The utility of the surfactant systems in solubilization is well known. Adsorption of surfactant on solid surface can modify their hydrophobisity, surface charge, and other key properties that govern interfacial processes such as flocculation/dispersion, floatation, wetting, solubilization, detergency, and enhanced oil recovery and corrosion inhibition. Surfactants have also been reported to cause solvation/plasticization, manifesting in reduction of melting the active pharmaceutical ingredients, glass transition temperature and the combined glass transition temperature of solid dispersions. Because of these IC Value

16 unique properties, surfactants have attracted the attention of investigators for preparation of solid dispersions. 18 Electrospinning: Electrospinning is a process in which solid fibers are produced from a polymeric fluid stream solution or melt delivered through a millimeter-scale nozzle. This process involves the 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. Upon increasing the electrostatic field strength up to but not exceeding a critical value, charge species accumulated on the surface of a pendant drop destabilize the hemispherical shape into a conical shape (commonly known as Taylor s cone). 19 Beyond the critical value, a charged polymer jet is ejected from the apex of the cone (as a way of relieving the charge built-up on the surface of the pendant drop). The ejected charged jet is then carried to the collection screen via the electrostatic force. The Coulombic repulsion force is responsible for the thinning of the charged jet during its trajectory to the collection screen. The thinning down of the charged jet is limited by the viscosity increase, as the charged jet is dried. This technique has tremendous potential for the preparation of nanofibres and controlling the release of biomedicine, as it is simplest, the cheapest, this technique can be utilized for the preparation of solid dispersions in future. 20 Super Critical Fluid (SCF) Technology: This technology has been introduced in the late 1980s and early 1990s, and experimental proof of concept are abundant in the scientific literature for a plethora of model compounds from very different areas such as drugs and pharmaceutical compounds, polymers and biopolymers, explosives and energy materials, superconductors and catalyst precursors dyes and biomolecules such as proteins and peptides. From the very beginning of supercritical fluid particle generation research, the formation of biocompatible polymer and drug-loaded biopolymer micro-particles for pharmaceutical applications has been studied intensively by a number of researcher groups CFs IC Value

17 either as solvent: rapid expansion from supercritical solution (RESS) or antisolvent: gas antisolvent (GAS), supercritical antisolvent (SAS), solution enhanced dispersion by supercritical fluids (SEDS) and/or dispersing fluid: GAS, SEDS, particles from gassaturated solution (PGSS). Conventional methods, i.e. Spray drying, solvent evaporation and hot melt method often result in low yield, high residual solvent content or thermal degradation of the active substance 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. Different acronyms were used by various authors to denote micronization processes: aerosol solvent extraction system (ASES), precipitation with a compressed fluid antisolvent (PCA), gas anti-solvent (GAS), solution enhanced dispersion by supercritical fluids (SEDS) and supercritical anti-solvent (SAS). 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 use of supercritical carbon dioxide is advantageous as it 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. Moreover, supercritical fluids are used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. 21 CONCLUSION Solubility of the orally administered drugs is one of the rates limiting parameter in order to achieve their desired concentration in systemic circulation for desired therapeutic response. Problem of solubility is a major challenging step for formulation scientists in new chemical entity development. Various techniques, described in this review alone or in combination can be successfully used to enhance the solubility of hydrophobic drugs or BCS class II drugs for improving their dissolution rate and ultimately improves IC Value

18 bioavailability, but successful improvement is mainly depends on selection of method. The techniques of solubility are chosen on the basis of certain aspects such as properties of drug under consideration, nature of excipients to be selected and nature of intended dosage form. Among all the solubility enhancement techniques super critical fluid, cryogenic and inclusion complex formation are most attractive techniques to resolve the solubility problems of hydrophobic drugs such as Tadalafil, Simvastatin, Fenofibrate, Atorvastatin, Clopidogrel, Glipazide, Rosuvastatin, Acyclovir, Meloxicam etc. In future these novel methods become a most acceptable way to enhance the bioavailabiity. REFERENCES 1. Ahire BR, Rane BR, Bakliwal SR and Pawar SP: Solubility enhancement of poorly water soluble drug by solid dispersion techniques. International Journal of Pharmaceutical Technology Research 2011; 2: Saffon N, Uddin R, Hasan N and Bishwajt K: Enhancement of oral bioavalability and solid dispersion: A Review. Journal of Applied Pharmaceutical Science 2011; 7: Sharma DK, and Joshi SB: Solubility enhancement strategies for poorly watersoluble drugs in solid dispersions: A Review. Asian Journal of Pharmaceutics 2007; 1: Verma S and Rawat A: Solid dispersion: A strategy for solubility enhancement. International Journal of Pharmaceutical Technology Research 2011; 3: Arora SC and Sharma PK: Development, characterization and solubility study of solid dispersion of Cefixime trihydrate by solvent evaporation method. International Journal of Drug Development & Research 2010; 2: Chaudhari PD: Current trends in solid dispersions techniques. Pharmainfo Net 2006; 4: IC Value

19 7. Arunachalam A and Karthikeyan M: Solid dispersions: A review. Current Pharmaceutical Research 2010; 3: Craig DQM: The mechanisms of drug release from solid dispersions in watersoluble polymers. International Journal of Pharmaceutics 2002; 2: Janssens S and Mooter GVD: Review: physical chemistry of solid dispersions. Journal of Pharmacy and Pharmacology 2009; 61: Liu L and Wang X: Improved dissolution of Oleanolic acid with ternary solid dispersions. American Association of Pharmaceutical Scientists 2007; 8: Papageorgiou GZ and Bikiaris D: Effect of physical state and particle size distribution on dissolution enhancement of Nimodipine/PEG solid dispersions prepared by melt mixing and solvent evaporation. American Association of Pharmaceutical Scientists 2006; 8: Patidar K, Soni M, Sharma KD and Jain KS: Solid Dispersion: Approaches, technology involved unmet need & challenges. Drug Invention Today 2010; 2: Pouton CW: Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system. Journal of Pharmaceutical Science 2006; 29: Urbanetz NA: Stabilization of solid dispersions of Nimodipine and Polyethylene glycol Journal of Pharmaceutical Science 2006; 28: Noyes AA and Whitney WR: The rate of solution of solid substances in their own solutions. Journal of American Chemistry Science 1897; 19: Leuner C and Dressman J: Improving drug solubility for oral delivery using solid dispersion. Europian Journal of Pharmaceutical and Biopharmaceutics 2000; 50: IC Value

20 17. Sekiguchi K and Obi N: Studies on absorption of eutectic mixtures, A comparison of the behaviour of eutectic mixtures of Sulphathiazole and that of ordinary Sulphathiazole in man. Chemical Pharmaceutis 1961; 9: Chiou WL and Riegelman S: Pharmaceutical applications of solid dispersion systems. Journal of Pharmaceutical Science 1971; 60: Vasconceleos T: Solid Dispersion as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 2007; 12: Chowdary PR and Hymavathi R: Enhancement of dissolution rate of Meloxicam. Indian Journal of Pharmaceutical Science 2001; 5: Rao MG: Preparation and evaluation of solid dispersions of naproxen. Indian Journal of Pharmaceutical Science 2005; 1: For Correspondence: S. G. Dhumal dhumalsameer07@gmail.com IC Value