Journal of Medical Pharmaceutical And Allied Sciences RESEARCH ARTICLE TECHNIQUES FOR SOLUBILITY ENHANCEMENT OF POORLY SOLUBLE DRUGS: AN OVERVIEW Deepshikha Sikarra, Vaibhav Shukla, Ankit Anand Kharia, Chatterjee D. P. Oriental College of Pharmacy, Bhopal, M.P., India, 46202211 www.jmpas.com Correspondence Vaibhav Shukla Assistant Professor Oriental College of Pharmacy, Bhopal E-Mail: vaibhav689@rediffmail.co m Keywords Solubility, solubility enhancement, nanonisation, poorly water soluble Accepted 22 Dec 2012 Reviewed 15 October 2012 Received 15 Dec 2012 Abstract A success of formulation depends on how efficiently it makes the drug available at the site of action. Solubility is the phenomenon of dissolution of solid in liquid phase to give a homogenous system. There are many techniques which are used to enhance the aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to increasing efficiency and/or reducing side effects for drugs. This is true for parenterally, topically and orally administered solutions. Hence various techniques are used for the improvement of the solubility of poorly water soluble drugs include hydrotrophy, use of salt form, use of precipitation inhibitors, alteration of pH of the drug micro-environment, solvent deposition, precipitation pH adjustment, co-solvency, micellar solubilization, super critical fluid techniques, solid dispersion, complexation, microemulsion, solid solution, eutectic mixture, selective adsorption on insoluble carriers, evaporative precipitation into aqueous solution, use of surfactants, use of amorphous, anhydrates, solvates and nanonisation. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 1 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com Introduction new chemical entities (NCEs) identified in the concentration of the solute in a saturated by many pharmaceutical companies are Solubility is defined in quantitative terms as solution at a certain temperature and in qualitative terms, it may be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. A saturated solution is one in which the solute is in equilibrium with the solvent. The solubility of a drug may be expressed as parts, percentage, molarity, molality, volume fraction, and mole fractionm. Due to this major reason Solubility enhancement is one of the important parameters which should be considered in formulation development of orally administered drug with poor aqueous solubility. Solubility is the characteristic physical property referring to the ability of a given substance, the solute, to dissolve in a solvent. Almost More than 90% drugs are orally administered. Drug absorption, sufficient & reproducible bioavailability, pharmacokinetic profile of orally administered drug substances is highly dependent on Solubility of that compound in aqueous medium. More than 90% of drugs are approved since 1995 have poor solubility. It is estimated that 40% of active combinatorial screening programs employed poorly water soluble. Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. Orally administered drugs on the Model list of Essential Medicines of the World Health Organization (WHO) are assigned BCS classifications on the basis of data available in the public domain. Of the 130 orally administered drugs on the WHO list 61 could be classified with certainty. 84% of these belong to class I (highly soluble, highly permeable), 17% to class II (poorly soluble, highly permeable), 24 (39%) to class III (highly soluble, poorly permeable) and 6 (10%) to class IV (poorly soluble, poorly permeable). The rate and extent of absorption of class II & class IV compounds is highly dependent on the bioavailability which ultimately depends on solubility. Due to this major reason Solubility enhancement is one of the important parameters which should be considered in formulation development of orally administered drug with poor aqueous Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 2 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com solubility. Solvent is a component which maximum quantity of solute that can capable to dissolve another substance to quantity forms major constituent of a solution & is form a uniformly disperse mixture at the molecular level. Solute is a substance that present in small quantity & dissolves in solvent. The solubility of a solute is the S. no. dissolve in a certain quantity of solvent or of solution at a specified temperature . In the other words, solubility can also define as the ability of one substance to form a solution with another substance (1). Table no.1: Descriptive terms for solubility (2) Descriptive terms Parts of solvent required dissolve one part of solute to 1. Very soluble Less than 1 2. Freely soluble More than 1 but less than 10 3. Soluble More than 10 but less than 30 4. Sparingly soluble More than 30 but less than 100 5. Slightly soluble More than 100 but less than 1000 6. Very slightly soluble More than 1000 but less than 10,000 7. Very very slightly soluble More than 10,000 or practically Insoluble Solubilization molecules of the solvent to provide space in breaking of inter-ionic or intermolecular between the solvent and the solute molecule The process of solubilization involves the bonds in the solute the separation of the Step 1: Holes opens in the solvent the solvent for the solute, interaction or ion. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 3 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com Step 2: Molecules of the solid breaks away from the bulk Step 3: The freed solid molecule is integrated into the hole in the solvent Fig. 1: Steps of solubilization process Factors Affecting Solubility The solubility depends on the physical form of the solid, the nature and composition of solvent medium, particle size, temperature, pressure, nature of the solute and solvent, molecular size polarity, polymorphs, rate of solution. Techniques for Solubility Enhancement Hydrotrophy Hydrotropic effect, the meaning is taken as the increase in saturation solubility of a substance in water by the addition of organic salts or also non-electrolytes, which of course must be physiologically compatible Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 4 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com for pharmaceutical application. The mode of nicotinamide, sodium citrate and sodium thought to be due to either an associate aqueous solubility of many poorly water- action of the hydrotropic substances is formation, in low concentrations to a formation of molecular complexes or in higher concentrations to the water structure being influenced. These hydrotropic substances are able to increase the number of hydrogen bridges in the water clusters. This makes the water more hydrophobic & thus it is a better solvent for non-polar drug However, the use of hydrotropic substances such as sodium benzoate, nicotinamide, urea, caffeine, sorbitol, etc. is limited due to the following factors: Slight increase of saturation up to solubility with high concentration of excipients. (e.g. 50% nicotinamide with a triple increase in the saturation solubility) acetate have been observed to enhance the soluble drugs. Hydrotropes are a class of amphiphilic molecules that cannot form well organized structures, such as micelles, in water but do increase the aqueous solubility of organic molecules. synergistic effects are Often observed strong when hydrotropes are added to aqueous surfactant or polymer solutions. A hydrotrope is a compound that solubilises hydrophobic compounds in aqueous solutions. Typically, hydrotropes consist of a hydrophilic part and a hydrophobic part (like surfactants) but the hydrophobic part is generally too small to cause spontaneous Hydrotropes do not self have aggregation. a critical concentration above which self-aggregation 'suddenly' starts to occur (as found for micelle- and vesicle-forming surfactants, Isotonicity is not reached. Individual effects of the excipients. which have a critical micelle concentration or CMC and a critical vesicle concentration, Hydrotropic solubilization is one of them. respectively Instead, some hydrotropes whereby addition of large amounts of a process, gradually increasing aggregation aqueous seem to self-aggregate at all, unless a Hydrotropy is a solubilization phenomenon aggregate in a step-wise self-aggregation second solute results in an increase in the size. However, many hydrotropes do not Concentrated aqueous hydrotropic solutions solubilisate solubility of another solute. has of sodium benzoate, sodium aciculate, urea, Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 been added. 5 Journal of Medical Pharmaceutical And Allied Sciences Hydrotropes Hydrotropes are are in use used in formulations to allow more (3). Use of Salt Form Salts have improved www.jmpas.com industrially. detergent simplest chemical reactions, involving either a proton transfer or a neutralization reaction between an acid and a base. Theoretically, every compound possessing acidic and/or solubility and dissolution characteristics in comparison to basic properties can participate in salt formation. the original drug. It is generally accepted Complex Salt Formation between the pKa value f the group and that as amines, frequently have higher aqueous that a minimum difference of 3 units of its counter ion is required to form stable salts. Alkali metal salts of acidic drugs like penicillin s and strong acid salts of basic drugs like atropine are water soluble than the parent drug3. Salt formation is frequently performed on weak acidic or basic drugs because it is a relatively simple chemical manipulation, which may alter the physicochemical, biopharmaceutical, and formulation, therapeutic properties of a drug without modifying the basic chemical structure. The ideal characteristics of a salt are that it is chemically stable, not hygroscopic, presents no processing problems, dissolves quickly from solid dosage forms (unless it is formed with the intent to delay dissolution and exhibits good bioavailability) Potentially Useful Salts: Salt formation is one of the Organic acid salt forms of basic drugs, such solubility than their corresponding inorganic salts. Acetic acid produced solubility higher than those observed with nay of the inorganic acids. Salts have improved solubility and dissolution characteristics in comparison to the original drug. It is generally accepted that a minimum difference of units between the pKa value f the group and that of its counter ion is required to form stable salts. Alkali metal salts of acidic drugs like penicillin s and strong acid salts of basic drugs like atropine are water soluble than the parent drug2. Salt Formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. Acidic or basic drug converted into salt having more solubility than respective drug. Ex. Aspirin, Theophylline, Barbiturates. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 6 Journal of Medical Pharmaceutical And Allied Sciences Use of Precipitation Inhibitor A significant increase in www.jmpas.com free drug concentration above equilibrium solubility results in super saturation, which can lead to drug precipitation or crystallization. This can be prevented by use of inert polymers such HPMC, PVP, PVA, PEG. Alteration of microenvironment pH of the drug This can be achieved in two ways- in situ salt formation, and addition of buffers to the formulation e.g. buffered aspirin tablets. Definition of PH: PH is the negative logarithm to the base 10 of the hydronium ion concentration. pH = - log [H3O+] For ionizable drugs, the aqueous solubility is strongly influenced by the pH of the solvent. Thus, the pH adjustment may be the most simple, economic and effective Way of increasing the aq. solubility of the drug. Solubilization by pH For a drug to be formulated in a liquid dosage form is generally required to be dissolved in an aqueous media. The ionized form of the drug is favored over unionized form to be solubilized in the aqueous solvent. For weakly acidic drugs /salt, o Lower pH unionized form o Higher pH ionized form insoluble/ precipitation more solubility For weakly basic drugs / salt, o Lower pH ionized form Higher pH unionized form more solubility o insoluble/precipitation(4) Solvent Deposition/ Evaporation In this method, the poorly aqueous soluble drug such as nifedipine is dissolved in an organic solvent like alcohol and deposited on an inert, hydrophilic, solid matrix such as starch or microcrystalline cellulose by evaporation of solvent. The carrier is then dispersed in the solution by stirring and the solvent is removed by evaporation under temperature and pressure. The resultant mass is then dried, pulverized, and passed through a sieve. The Increase in the dissolution rate is ascribed to the reduced particle size of the drug deposited Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 7 Journal of Medical Pharmaceutical And Allied Sciences on the carrier and enhanced wet ability of the particles brought about by the carrier. Precipitation In this method, the poorly aqueous soluble drug such as cyclosporine is dissolved in a suitable organic solvent followed by its rapid mixing with a non-solvent to effect precipitation of drug in nano size particles. The product so prepared is also called as hydrosol. Nano-suspension of Danazol and Naproxen were prepared by precipitation technique to improve their dissolution rate and oral bioavailability. The solution with the drug is then injected into water, which act as bed solvent. At the time of injection, the water has to be stirred efficiently so that the substance will precipitate as nanocrystals. Nano-crystals can be removed from the solution by filtering then dried in air. pH Adjustment Poorly water soluble drugs with parts of the molecule that can be protonated (base) or deprotonated (acid) may potentially be dissolved in water by applying a pH change. pH adjustment can in principle be used for both oral and parenteral administration. Upon intravenous administration the poorly www.jmpas.com soluble drug may be precipitate because blood is a strong buffer with Ph between 7.2 7.4. To assess the suitability of the approach, the buffer capacity and tolerability of the selected pH are important to consider. In the stomach the pH is around 1 to 2 and in the duodenum the pH is between 5-7.5, so upon oral administration the degree of solubility is also likely be influenced as the drug passes through the intestines. Ionizable compounds that are stable and soluble after pH adjustment are best suited. As per pH-partition hypothesis and Handerson- Hesselbatch equation, ionization of a compound is dependent on the pH of media and pKa of drug. 1.Advantages Simple to formulate and analyze. Simple to produce and fast track. Uses small quantities of compound, amenable evaluations. to high throughout 2.Disadvantages Risk for precipitation upon dilution with aqueous media having a pH at which the compound is less soluble. Intravenously this may lead to emboli, orally variability. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 it may cause 8 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com Tolerability and toxicity (local and of surfactants to improve the dissolution non physiological pH and extreme has systemic) related with the use of a pHs. As with all solubilized and dissolved performance of poorly soluble drug products also been successfully Surfactants can lower surface tension and improve the dissolution of lipophillic drugs systems, a dissolved drug in an in aqueous medium. less stable chemically compared to Traditional Surfactants aqueous environment is frequently formulations crystalline solid. The selected hydrolysis pH or may accelerate catalyze degradation mechanisms (5). other The addition of a water-miscible or partially miscible organic solvent (i.e. co-solvent to water) is a common and effective way by which to increase solubility of a non-polar drug. The technique is known as co- solvency. Examples of solvents used in cosolvent mixtures are PEG 300, propylene glycol or ethanol Solubility enhancement as high as 500-fold is achieved using 20% 2pyrrolidone. Surfactants are compounds Anionic Surfactant: Hydrophilic group carries a negative charge. E.g. SLS, Potassium laurate Cationic Surfactant: Hydrophilic group carries a positive charge. Co-Solvency Micellar Solubilization employed. E.g. Cetrimide, Benzalkonium Chloride (Zwitter-ion surfactant) Molecule carries both negative and positive charge. E.g. Ndodecyl-N, N-dimethylbetaine. Non Traditional Surfactants Nonionic Surfactant: Poloxamers (Pluronics) Hydrophile carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene groups. that have molecular structures with two distinct regions: A polar (hydrophilic) head group and a Non-polar (hydrophobic tail). The use E.g. Cetomacrogol (polyoxyethylated glycol monoethers), Spans and Tweens They can also be used to stabilize drug suspensions. When the concentration of surfactants exceeds their critical micelle concentration Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 9 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com (CMC, which is in the range of 0.05-0.10% may be recrystallized at greatly reduced occurs, entrapping the drugs within the offered for most surfactants), micelle formation micelles. This micellisation process is and generally used non-ionic known results as in enhanced solubility of poorly soluble drugs. Commonly surfactants include poly-sorbates, poly-oxy-ethylated castor oil, poly-oxy-ethylated glycerides, lauryl macro-glycerides and mono- and di- particle sizes. The flexibility and precision by SCF processes micronisation of drug particles within narrow ranges of particle size, often to submicron levels3. Novel nanoising has increased particle size reduction via supercritical fluid processes. Solid Dispersion often used to stabilize micro-emulsions and by Sekiguchi & Obi. The term suspensions into which drugs are dissolved. Super Critical Fluid Techniques The number of applications and Technologies involving supercritical fluids has also grown explosively. It has been known for more than a century that supercritical fluids (SCFs) can dissolve nonvolatile solvents, with the critical point of carbon-dioxide; the most widely used Supercritical fluid. It is used supercritical Solid dispersion, a concept firstly introduced solid dispersions refers to the dispersion of one or more active ingredients in an inert carrier in a solid state, frequently prepared by the melting (fusion) method, solvent method, or fusion solvent-method. certain nanoparticles, However, the definition can now be broadened to include microcapsules, microspheres and other dispersion of the drug in polymers prepared by using any one of the process6. In this technique, a poorly safe, soluble drug is dispersed in a highly soluble solvents dissolution of the drug. Solid dispersion environmentally friendly, and economical. Commonly and solubilization technology whose application fatty acid esters of low molecular weight polyethylene glycols. Surfactants are also allows include carbon dioxide, nitrous oxide, ethylene, propylene, propane, n-pentane, ethanol, ammonia, and water. Once the drug particles are solubilized within SCF, they solid hydrophilic matrix, which enhances the techniques can yield eutectic (non molecular level mixing) or solid solution (molecular level mixing) products. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 10 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com Carriers for Solid Dispersions 1. Acids: Citric Acid, Tartaric Acid, Succinic Acid. 2. Sugars: Sucrose, Dextrose, Sorbitol, Maltose, Galactose, Xylitol. 3. Polymeric Materials: Poly-vinyl- pyrollidone, PEG 4000 & 6000, Carboxy-mythyl cellulose, Hydroxypropyl-cellulose, Guar gum, Xanthan gum, Sodium Alginate, Dextrin, Cyclodextrin. 4. Surfactants stearate, Polyoxyethylene poloxamer, Deoxycholic acid, Tweens and Spans, Gelucire 44/14, Vitamine E TPGS NF. 5. Miscellaneous Hydroxyalkyl Urea, Xanthene, Urethane, Penta- erythritol Surface-active agents Mechanism of Increased Dissolution Rate by Solid dispersion 1. Reduction in particle size. 2. Solublization effect (use of carriers). 3 .Increased wettability and dispersibility by carriers 4. Formation of metastable dispersion with reduced lattice energy for faster dissolution. 5. Ex. Dissolution energy for furesamide is 17Kcal/mol while Dissolution energy for 1:2 furesamide:PVP co-precipitate is 7.3Kcal/mol. Advantages and Disadvantages of solid dispersion Advantages - Increase in dissolution rate & are extent of absorption and reduction in pre- adsorb onto the surfaces or interfaces liquid form of drug into solid form. Ex. substances that at low concentrations of a system and alter the surface or interfacial free energy and the surface and the interfacial tension. Surface-active agents have a characteristic structure, possessing both polar (hydrophilic) and nonpolar (hydrophobic) regions in the systemic metabolism. Transformation from Clofibrate & benzyl benzoate incorporated into PEG-6000 to give solid dispersion also avoidance of polymorphic changes so no bioavailability problems (as in case of nabilone & PVP dispersions. Disadvantages major problem is instability. There is change in crystallanity same molecule. The surface active & decrease in dissolution rate with aging. nature (6). supersaturated solution in solid dispersion carriers are said to be amphiphilic in Ex. Crystallization Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 of ritonavir from 11 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com system (main reason for withdrawal of large planar non-polar regions in the market. Moisture and temperature increases homogenous or mixed. The former is known ritonavir capsules [Norvir, Abbott] from deteriorating effect on solid dispersion than physical mixtures. molecule. as Stacked self-association complexation. complexes and the can be later as Complexation Inclusion Complex: An inclusion complex two or more molecules to form a no bonded molecule or the non-polar region of a Complexation is the association between entity with a well-defined stoichiometry. The two types of complexation that are useful for increasing the solubility of drugs in aqueous media are stacking and inclusion. Self-Association Complexation and Stacking Non-polar moieties tend to be squeezed out of water by the strong hydrogen bonding interactions of the water. This causes some molecules to minimize the contact with water by aggregation of their hydrocarbon moieties. This aggregation is favored by is produced by the inclusion of a non-polar molecule (known as the Guest) into the nonpolar cavity of another molecule or group of molecules (known as the Host). When the guest molecule enters the host molecule the contact between water and the non-polar regions of both is reduced. Thus, inclusion phenomena are the result of the same driving force that produces the micellization, Self-association, and stacking: namely the squeezing out from water of non-polar moieties. The most commonly used host molecules are the cyclodextrins. Structure of cyclodextrins Fig. 2: Structure of -Cyclodextrin with 7 glucose units. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 12 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com Glucose molecules are relatively soluble in decrease skin penetration. Lipophilic drug- accept non-polar portions of common drug as inclusion complexes, can be formed water and have cavities large enough to molecules. Complexation of drugs with cyclodextrins has been used to enhance aqueous solubility and drug stability. Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8 dextrose molecules ( , , cyclodextrin) bound in a 1, 4- configuration to form rings of various diameters. The ring has a hydrophilic exterior and lipophilic core in which appropriately sized organic molecules can form non-covalent inclusion complexes resulting in increased aqueous solubility and chemical stability. Derivatives of -cyclodextrin with increased water solubility (e.g. hydroxyl-propyl- - cyclodextrin HP- -CD) are most commonly used in pharmaceutical formulation. Cyclodextrin complexes have been shown to increase the stability, wettability and dissolution of the lipophilic insect repellent N, N-diethyl-m-toluamide (DEET) and the stability and photostability of sunscreens. Cyclodextrins are large molecules, with molecular weights greater than 1000Da, therefore it would be expected that they would not readily permeate the skin. Complexation with cyclodextrins has been variously reported to both increase and cyclodextrin complexes, commonly known simply by adding the drug and excipient together, resulting in enhanced drug solubilization. Cyclodextrins (CD) are a group of structurally-related cyclic oligosaccharides that have a polar cavity and hydrophilic external surface. Cyclodextrins consisting of 6, 7 and 8 D glucopyranosyl units connected to -1, 4 glycosidic linkages are known as , , , cyclodextrins, respectively. Hydrophilic cyclodextrins are nontoxic in normal doses while lipophilic ones may be toxic; hence, methyl, hydroxypropyl, sulfoalkylated and sulfated derivatives of natural cyclodextrins that possess improved aqueous solubility are preferred for pharmaceutical use (7). Micro Emulsions Micro-emulsions have been employed to increase the solubility of many drugs that are practically insoluble in water, along with incorporation of proteins for oral, parenteral, as well as percutaneous/ transdermal use. A micro-emulsion is an optically clear preconcentrate containing a mixture of oil, hydrophilic surfactant and hydrophilic solvent which dissolves a poor water soluble Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 13 Journal of Medical Pharmaceutical And Allied Sciences drug. Upon contact with www.jmpas.com water, the formulations spontaneously disperse (or self emulsifies ) to form a very clear emulsion of exceedingly small and uniform oil droplets containing the solubilized poorly soluble drug. Micro-emulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a co-surfactant with a droplet size usually in the range homogeneous of 20-200 systems, nm. which These can be prepared over a wide range of surfactant concentration and oil to water ratio, are all fluids of low viscosity. A self microemulsifying drug delivery system (SMEDDS) is an anhydrous system of micro-emulsions. It has also been referred to as micro-emulsion pre-concentrate by some researchers. It is composed of oil, surfactant and co-surfactant and has the ability to form o/w micro-emulsion when dispersed in aqueous phase under gentle agitation. The agitation required for the self-emulsification comes from stomach and intestinal motility. The surfactant can be non-ionic like polyoxy-ethylene surfactants e.g. Brij or sugar esters like sorbitan-mono-oleate (Span 80), cationic, or anionic like alkyl-tri-methylammonium bromide and sodium dodecyl- sulphate, or phospholipids zwitter (phosphatidylcholine) ionic like such as lecithin commercially available from soybean and eggs. Lecithin is very popular because it exhibits excellent biocompatibility. Combinations of ionic and non-ionic surfactants are also found to be effective. The major disadvantage of micro- emulsions is their high concentration of surfactant/co-surfactant, making them unsuitable for IV administration. Dilution of micro-emulsions below the critical micelle concentration of the surfactants could cause precipitation of the drug; however, the fine particle size of the resulting precipitate would still enhance absorption. Compared to macroemulsion pre-concentrates, micro- emulsion pre-concentrates remain optically clear after dilution and usually contain a higher amount of water soluble surfactant and a higher content of a hydrophilic solvent. These formulations are only administered orally due to the nature of the excipients. Solubilization using micro- emulsion pre-concentrates is suited to poorly soluble lipophilic compounds that have high solubility in the oil and surfactants mixtures. Most self-emulsifying systems are limited to administration in lipid-filled soft or hardshelled gelatin capsules due to the liquid Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 14 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com nature of the product. Interaction between the capsule shell and the emulsion should be considered so as to prevent the hygroscopic contents from dehydrating or migrating into the capsule shell. Emulsion droplet size is a major factor influencing bioavailability of drugs from emulsion formulations, with small droplet radii enhancing the plasma levels of drugs, in part due to direct lymphatic uptake. Since SMEDDS contain high concentration of surfactants, they should be limited to oral (8). Fig. 3: Phase diagram for continuous solid solutions b) Discontinuous Solid Solutions Exist at extremes of composition Solid Solution Two components crystallize together in homogenous one phase system. Particle size of drug in solid solution is reduced to its molecular size. Solid solutions shows faster dissolution rate than eutectic mixtures. More than 500 papers have been published on the subject and various materials are employed as drug carriers. Classification of solid solutions, according to extent of miscibility of two components; a) Continuous Solid Solution Two Fig. 4: Phase diagram for discontinuous solid solutions solids miscible in solid state in all According to criterion of molecular size of Here molecule in crystal lattice. Molecular size proportions a) Substitutional Solid solution Substitution of solvent molecule by solute two components should not differ by 15% < Ex. Anthracene- Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 15 Journal of Medical Pharmaceutical And Allied Sciences Acenapthacene, thiocynate. www.jmpas.com Ammonium-potassium In this b) Interstitial Solid solutions solute (guest) molecule occupies interstitial space in solvent (host) lattice. Solute molecule diameter should be less than 0.59 times than that of solvent. Owing to their large molecular size polymers favors formation of interstitial solid solution. Ex. Solid solution of digoxin, prednisolone acetate in matrix of PEG 600. Solvent (to dissolve the phase if on the Additives (co solvents or glycerol) Re-crystallization inhibitors Reasons of Solubility Enhancement in Solid Solution Reduction of particle size. The resulting enhanced surface area produces higher dissolution rate & bioavailability & dispersibility. Formation dispersions of the metastable Methods of Preparation Melting or Fusion method (Hot Melt Extrusion Technique) Electrostatic Spinning Method Novel ultra-rapid freezing particle Carrier (polymer or polymer blends ) methodology used) Carrier material enhances wettability Supercritical Fluid Technique Poorly water soluble drug depends effect on the drug. Fluidized Bed Coating Composition of the Solid Solution necessary, Carrier material has solubilization engineering process. Eutectic Mixture These systems are also prepared by fusion method. Eutectic melts differ from solid solutions in that the fused melt of solute m solvent show complete miscibility but negligible solid-solid solubility, i.e., such systems are basically intimately blended physical mixture components. Selective Carriers of Adsorption Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 two crystalline on Insoluble 16 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com A highly active adsorbent such as the the dissolution rate of poorly water soluble and The EPAS process utilizes rapid phase inorganic clays like bentonite can enhance prednisone by maintaining the concentration gradient at its maximum. The two reasons suggested for the rapid release of drugs from the surface of clays are- the weak physical bonding between the adsorbate, and hydration and swelling of the clay in the aqueous media. This study was concerned with solid dispersions, which were prepared following the dissolution method using a common solvent. The drugpolymer interactions were studied using DSC and IR techniques, as well as HPLC purity after storage in strength conditions. Neither significant interactions nor drugs such as griseofulvin, indomethacin separation to nucleate and grow nanoparticles and microparticles of lipophiic drugs. The drug is first dissolved in a low boiling point organic solvent. The solution is pumped through a tube where it is heated under pressure to a temperature above the solvent s boiling point and then sprayed through a fine atomizing nozzle into a heated aqueous solution. Surfactants are added to the organic solution on the aqueous solution to optimize particle formation and stabilization (10). degradation of the active ingredient was Use of Surfactant In addition, felodipine release from the solid enhancers and enhance both dissolution rate observed after storage at 40 °C for 3 months. dispersion systems was studied and the factors influencing release, such as the drugpolymer ratio, interactions, and polymer properties were investigated. HPMC was observed to promote a more significant retard and amore linear release of the active ingredient than HEC (9). Evaporative precipitation into aqueous solution Surfactants are very useful as absorption as well as permeability of drug. They enhance promoting dissolution wetting rate and primarily penetration by of dissolution fluid into the solid drug particles. The study enhancement showed of that solubility antimicrobial drug enrofloxacin using a series of co-solvents and surfactants. Aqueous solubility of enrofloxacin could be increased up to 26 times. Co-solvents alone produced only small increase in solubility. However, the Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 17 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com combined effect of co-solvents and buffer Based on these results, it can be concluded solubility could be attained. Ionic surfactants TPGS and solutol HS-15 resulted from a was synergistic and a large increase in were found to be much better solubilizing agents than nonionic surfactant. Amongst ionic surfactants, solubility was found to be very high in anionic surfactant, sodium dodecylsulphate as compared to the cationic surfactant, cetyltrimethylammonium bromide. Up to 3.8 mg/ml of enrofloxacin could be dodecylsulphate. dissolved in sodium Use of amorphs, anhydrates, solvates and metastable polymorphs Depending upon the internal structure of the solid drug, selection of proper form ofdrug with greater solubility is important. In general, amorphs are more soluble than metastable polymorhs, anhydrates are more soluble than hydrates and solvates are more soluble than non-solvates. Studied the mechanism responsible for solubility enhancement of Nifedipine solid dispersion, prepared using Vitamin E TPGS or Solutol HS-15, PEG1000, and lipocol C-10 of varying drug/polymer ratios by a fusion method. The solubility enhancement was found to be in the order of vitamin E TPGS > solutol HS-15 > lipocol C-10 > PEG1000. that enhanced solubility using vitamin E partial conversion of crystalline drug to the amorphous form, increase in wettability of the drug by water soluble polymers, better separation of drug particles, micellar solubilization of drug by high concentrations of surfactant polymers, and interaction between polymer and drug at the molecular level. Amorphous > Metastable polymorph > Stable polymorph> Micronization Micronization is reduction of particle size up to micron level Any problem related with the bioavailability of drug may be related with dissolution of drug and solubility of drug is dissolution of drug (11). affecting Micronization Micronization is reduction of particle size up to micron level Any problem related with the bioavailability of drug may be related with dissolution of drug and solubility of drug dissolution of drug. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 is affecting 18 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com In order to get better dissolution need to increase solubility and micronization is used as one of the solubilising solubility tool to increase Nanonisation It s a process whereby the drug powder is converted to nanocrystals of size 200600nm, e.g. amphotericin B. The main By micronization we get uniform production technologies currently in use to which is essential for developing a dispersion of drug nanocrystals in a liquid, As micronization occurs surface area There are three basic technologies currently size and a. Pearl milling and narrow particle size distribution produce drug nanocrystals yield as a product uniform dosage form typically water (called nanosuspension). increases with decreasing particle in use to prepare nanoparticles: observed solubility increased with b. Homogenisation in water (wet milling as accordance this equation c. Homogenization in non aqueous media or decreasing solubility increases and particle size in in a colloid mill) in water with water- miscible liquids. Log S/SO = 2( /2.303RTr) Where, S = the observed solubility, S0= Jalali et.al. prepared megestrol = surface acetate (MA) nanoparticles via a liquid Absolute Temperature, r = Radius of the particles had a mean size of 208 nm, and Following methods can range of 100 300 nm, whereas the raw MA Inherent equilibrium solubility, Energy of particle, R = Gas constant, T = precipitation technique. The prepared MA particles. 90% of the particles were distributed in the achieving Micronization be use for had a mean particle size of about 3.02 m, 1. Jet milling ranging widely from 0.2 m to 30 m. The 3. Microprecipitation & microcrystalization improved wettability as demonstrated by the 5. Supercritical fluid technology that particles were covered by a hydrophilic 7. Spray freeze dry (SFD) nanoparticles 2. Solid solution & eutectic mixtures freeze-dried MA nanoparticles exhibited 4. Controlled crystallization contact angle measurement result proving 6. Spray freezing into liquid layer. In dissolution achieved Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 rate tests, 100% the drug 19 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com dissolution within 5 min, while the raw MA is immediately available for absorption and suggesting that the dissolution property of of drug administered in a tablet or capsule did not dissolve completely after 120 min, MA nanoparticles enhanced (12). was significantly By this article we conclude that, solubility of the drug is the most important factor that controls the formulation of the drug as well as therapeutic efficacy of the drug, hence the most critical factor in the formulation development. Dissolution of drug is the rate determining step for oral absorption of the poor water soluble drugs and solubility is the basic requirement for the formulation and development of different dosage form of different drugs. The various techniques described above alone or in combination can be used to enhance the solubility of the drug. Solubility can be enhanced by many techniques and number of folds increase in solubility. Because of solubility problem of many drugs the bioavailability of them gets affected and hence solubility form. Solubility is a most important parameter for the oral bioavailability of poorly soluble drugs. Dissolution of drug is Conclusion also efficiently absorbed than the same amount enhancement becomes necessary. It is now possible that to increase the solubility of poorly soluble drugs with the help of various techniques as mentioned above. A drug administered in solution form the rate determining step for oral absorption of the poorly water soluble drugs, which can subsequently affect the in vivo absorption of drug. Currently only 8% of new drug candidates have both high solubility and permeability. Because of solubility problem of many drugs the bioavailability of them gets affected and hence solubility enhancement becomes necessary. Although salt formation, particle size reduction, etc. have commonly been used to increase dissolution rate of the drug, there are practical limitation with these techniques the desired bioavailability enhancement may not always be achieved. Therefore formulation approaches are being explored to enhance bioavailability of poorly water-soluble drugs. Solid dispersion is mainly used to mask the taste of the drug substances, and to prepare rapid disintegration oral tablets. Solid dispersion has also been used to produce sustained-release microspheres using tedious methods such as water-in-oil emulsions. Above review shows that, it is Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 20 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com now possible that to increase the solubility of poorly soluble drugs with the help of solid dispersion technique effectively. Also this method is practically simple & less tedious than other methods. 1. Aulton M.E. 2007. Dissolution & Solubility. In: Aulton ME, editor. The science of dosage form and design; 2nd ed, Philaadelphia: Churchill Livingstone, 7. 23-24. 2. Indian Pharmacopoeia, Ministry welfare, of Published health Government by the and of 1996. family India, controller publications, Delhi, Vol.1, P.1-7. of 3. Brahmankar D.M. and Jaiswal S.B. 2009. Biopharmaceutics and Pharmacokinetics- A Treatise. New Delhi, Vallabh Prakashan. P.349357. 4. Varun R.V. and Venkateshwarlu L., 2010. Solubility enhancement techniques. Int. J. Pharm. Sci. Rev. Res., 5(1), 28-39. 5. Purwa J. and Achhrish G. 2010. Solubility enhancement techniques with special Int. J. Pharm. Res., 1(1), 34-45. 6. Meera C.S. 2010. Review on various techniques of solubility enhancement of poorly soluble drugs with special. J. Pharm. Res., 3(10), 2494- 2501. References: Pharmaceutics; hydrotrophy. emphasis on 7. Anuj K. and Sangram K.S. 2011. Review on solubility enhancement techniques for hydrophobic drugs. Int. J. Comp. Pharm. 2(3). 25-36. 8. Stella V, Borchardt R, Hageman M, Oliyai R, Maag H and Tilley J 2007. Biotechnology: Pharmaceutical Aspects, Edition, vol 5(part 2), New York: Springer, pp.157-215. 9. Lindenberg M., Kopp S. and Dressman J. 2004. Classification of orally administered drugs on the WHO model medicines list of according biopharmaceutical essential to classification system. Eur. J. Pharm. Biopharm., 58; 2, 265-278. 10. Myrdal PB and Yalkowsky SH. 2006. Solubilization of Drugs in Aqueous Media. In: J Swarbrick, Editor. Encyclopedia of Pharmaceutical Technology, New York; Informa Healthcare: 3rd Ed. P.3314-3328. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 21 Journal of Medical Pharmaceutical And Allied Sciences www.jmpas.com 11. Rawat S. and Jain S.K. 2004. Solubility enhancement of celecoxib using ß-cyclodextrin complexes. Eur. J. Biopharm., 57: P.263-279. inclusion Pharm. 12. Jalali, M.B., Maleki N., Garjani, A. and Khandar, A.A. 2002. Enhancement of dissolution rate and anti-inflammatory effects of piroxicam using solvent deposition technique. Drug Dev. Ind. Pharm. 28, 681-686. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22 22