PHAR 505

Assignment On Solubility Enhancement Techniques

Submitted to: Dr. Panna Thapa, HoD Pharmacy Department, Dean of School of Science

Submitted by: Kiroj Rajbanshi M. Pharm. 1st Year 1st Sem.

Submission date: 18/11/11

Solubility Enhancement Techniques

Solubility is important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response. There are various techniques available to improve the solubility of poorly soluble drugs. Techniques can be classified as follows:

I. Physical Modifications:
A. Particle size reduction a. Micronization b. Nanosuspension B. Modification of the crystal habit a. Polymorphs b. Pseudopolymorphs C. Drug dispersion in carriers a. Solid solutions b. Solid dispersions c. Eutectic mixtures D. Complexation a. Use of complexing agents E. Solubilization by surfactants a. Microemulsions b. Self microemulsifying drug delivery systems

II. Chemical Modifications:

A .Salt formation B. Alteration of pH of the drug microenvironment

III. Others I.Physical Modification

A. Particle size reduction a. Micronization: Micronization of drugs is done by spray drying or by use of attrition methods (fluid energy or jet mill).The size of solid drug particles range from 1 to 10 microns.

Yuichi Tozuka et al [1], studied on the effectiveness of a-glucosyl hesperidin (Hsp-G) as a novel grinding aid for the preparation of drug nanoparticles by dry grinding. Poorly water-soluble drugs and Hsp-G were mixed at a weight ratio of 1/5 and ground for 60 min by a vibrational ball mill. It was evident that all poorly water-soluble drugs used in this study formed nanoparticles after the ground mixtures were dispersed into distilled water. The dissolution profile of glibenclamide from the ground mixtures of glibenclamide/ Hsp-G showed dramatic improvement from that of untreated drug crystals. The area above the time-curve of plasma glucose concentrations using the ground mixture of glibenclamide/Hsp-G was 6-fold higher than that using untreated glibenclamide.

b. Nanosuspension: Nanosuspension is sub-micron colloidal dispersion of pure particles of drug, which are stabilized by surfactants.Nanocrystals produced from the process are of size (200-600) nm. Techniques for the production of nanosuspension are as follows: a) Homogenization: The suspension is forced under pressure through a valve that has nano aperture. This causes bubbles of water to form which collapses as they come out of valves. This mechanism cracks the particles. Three types of homogenizers are commonly used for particle size reduction in the pharmaceutical and biotechnology industries: conventional homogenizers, sonicators, and high shear fluid processors. b) Wet milling: Active drug in the presence of surfactant is defragmented by milling. F. Lai.et al [2], studied piroxicam dissolution rate in novel orally disintegrating tablets (ODT) using Nanocrystals. Different nanocrystal formulations were prepared using a high pressure homogenization technique and poloxamer 188 as a stabilizer. All ODT formulations prepared using nanosuspensions showed a higher dissolution rate compared with the ODT prepared with the coarse, and conclude that the improvement in dissolution rate is mainly caused by the increased surface-to-volume ratio due to the submicron dimension of the drug particles.

Other techniques for reduction of the particle size:

Supercritical Fluid [4] Recrystallization Supercritical fluids (e.g. carbon dioxide) are fluids whose temperature and pressure above its critical point, no distinct liquid and gas phases exist. It can effuse through solids like a gas, and dissolve materials like a liquid. At near-critical temperatures, SCFs are highly compressible, small changes in pressure or temperature result in large changes in density Once the drug are solubilised within SCF , there may be recrystallization at greatly reduced particle sizes.

Spray drying [3]: Spray drying is the continuous transformation of feed from a fluid state into dried particulate form by spraying the feed into a hot drying medium. The feed may be solution, slurry, emulsion, gel or paste. It involves bringing together a highly dispersed liquid and a sufficient volume of hot air to produce evaporation and drying of liquid droplets. The air supplies the heat for evaporation and conveys the dried product to the collector; the air is then exhausted with the moisture.

Mohamed A et al [5], studied on spray-drying of enteric polymers from aqueous solutions to produce pHresponsive micro particles. The approach involves the neutralization and generation of water-soluble salt forms of enteric polymers. The methacrylic acid polymers (Eudragit L and EudragitS) were added separately to aqueous solutions of ammonium hydrogen carbonate; the solutions were then spray-dried. Incubating the microparticles for three hours at 70 C and 130 C for the Eudragit S and L products respectively, was sufficient to eradicate the ammonium residues. The microparticles loaded with the model drug prednisolone, were spherical and small in size (25 lm). Moreover, the particles were gastroresistant, and release was rapid and complete at small intestinal conditions. In bicarbonate media, drug release from these spray-dried microparticles was faster compared to microparticles produced from conventional emulsion solvent evaporation methods. This new microparticle preparation concept obviates the need for organic solvent and utilizes spray-drying techniques. The approach therefore offers economic, safety, and environmental benefits.

B. Modification of the crystal habit Polymorphism is the ability of an element or compound to crystallize in more than one crystalline form. Different polymorphs of drugs are chemically identical, but they exhibit different physicochemical properties including solubility, melting point, density, texture, stability etc. Broadly polymorphs can be classified as enantiotropes and monotropes based on thermodynamic properties. In the case of an enantiotropic system, one polymorphs form can change reversibly into another at a definite transition temperature below the melting point, while no reversible transition is possible for monotropes. Once the drug has been characterized under one of this category, further study involves the detection of metastable form of crystal. Metastable forms are associated with higher energy and thus higher solubility. Similarly the amorphous form of drug is always more suited than crystalline form due to higher energy associated and increase surface area. Amorphous >Metastable polymorph >Stable polymorph

Rajebahadur M. et al [6], studied the mechanism responsible for solubility enhancement of Nifedipine solid dispesion, 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. Based on these results,it can be concluded that enhanced solubility using vitamin E TPGS and solutol HS-15 resulted from a 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. C. Drug dispersion in carriers The term solid dispersions [8] 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. Novel additional preparation techniques have included rapid precipitation by freeze drying and using supercritical fluids and spray drying, often in the presence of amorphous hydrophilic polymers and also using methods such as melt extrusion. The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone, polyethylene glycols, Plasdone-S630. Many times surfactants may also used in the formation of solid dispersion. Surfactants like Tween-80, Docusate sodium, Myrj-52, Pluronic-F68 and Sodium Lauryl Sulphate used. Different methods of drug dispersion in carriers are as follows: 1. Hot Melt Method Sekiguchi and Obi used a hot melt method to prepare solid dispersion. Sulphathiazole and urea were melted together and then cooled in an ice bath. The resultant solid mass was then milled to reduce the particle size. Cooling leads to supersaturation, but due to solidification the dispersed drug becomes trapped within the carrier matrix. A molecular dispersion achievement depends on the degree of supersaturation and rate of cooling used in the process. An important requisite for the formation of solid dispersion by the hot melt method is the miscibility of the drug and the carrier in the molten form. When there are miscibility gaps in the phase diagram, this usually leads to a product that is not molecularly dispersed. Another important requisite is the thermostability of the drug and carrier.

2. Solvent Evaporation Method Tachibana and Nakumara were the first to dissolve both the drug and the carrier in a common solvent and then evaporate the solvent under vacuum to produce a solid solution. This enabled them to produce a solid solution of the highly lipophilic -carotene in the highly water soluble carrier polyvinylpyrrolidone. An important prerequisite for the manufacture of a solid dispersion using the solvent method is that both the drug and the carrier are sufficiently soluble in the solvent. The solvent can be removed by various methods like by spray-drying or by freeze-drying. Temperatures used for solvent evaporation generally lie in the range 23-65 C.

3. Hot-melt Extrusion Melt extrusion was used as a manufacturing tool in the pharmaceutical industry as early as 1971. It has been reported that melt extrusion of miscible components results in amorphous solid solution formation, whereas extrusion of an immiscible component leads to amorphous drug dispersed in crystalline excipient. The process has been useful in the preparation of solid dispersions in a single step.

Sebastian Bialleck et al [7], prepared starch-based pellets by hot-melt extrusion. Pellets were produced based on four different starches (corn starch, pea starch, potato starch and waxy corn starch), four different active ingredients (ibuprofen, paracetamol, phenazon and tramadol-HCl) and various additives. The resulting pellets exhibit a large mechanical stability, low porosity and small surface area. The drug is either dispersed or dissolved in the starch melt. Drug loadings of up to 80% are achievable. The drug release rate is controlled by the particle size, the combination of starch, active ingredient and additives. 4. Melting solvent Method 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 glycol6000 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. From a practical standpoint, it is only limited to drugs with a low therapeutic dose e.g. below 50 mg. D. Complexation: Complexation is the association between two or more molecules to form a nonbonded entity with a well defined stichiometry. Complexation relies on relatively weak forces such as London forces, hydrogen bonding and hydrophobic interactions. The most common complexing ligands are cyclodextrins, caffeine, urea, polyethylene glycol, N methylglucamide. Selective Adsorption on Insoluble Carriers: A highly active adsorbent such as the inorganic clays like bentonite can enhance the dissolution rate of poorly water soluble drugs such as griseofulvin, indomethacin and 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.

Karavas E. et al. [9], studied the use of three modified celluloses, carboxymethyl cellulose sodium, hydroxyethyl cellulose (HEC), and hydroxypropylmethyl cellulose (HPMC) as carriers in felodipine solid

dispersion systems. This study was concerned with solid dispersions, which were prepared following the dissolution method using a common solvent. The drug-polymer interactions were studied using DSC and IR techniques, as well as HPLC purity after storage in strength conditions. Neither significant interactions nor degradation of the active ingredient was observed after storage at 40 C for 3 months. In addition, felodipine release from the solid dispersion systems was studied and the factors influencing release, such as the drug-polymer ratio, interactions, and polymer properties were investigated. HPMC was observed to promote a more significant retard and a more linear release of the active ingredient than HEC Molecular Encapsulation with Cyclodextrins: The beta- and gamma- cyclodextrins and several of their derivatives are unique in having the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility. These bucket shaped oligosaccharides produced from starch are versatile in having a hydrophobic cavity of size suitable enough to accommodate the lipophilic drug as guests; the outside of the host molecule is relatively hydrophilic. Thus the molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate. There are several examples of drugs with improved bioavailability due to such phenomenon- thiazide diuretics, barbiturates and a number of NSAIDs.

Kamal dua et al[10] studied on Molecular Modeling of Inclusion Complex of Aceclofenac with

Cyclodextrins. Aceclofenac is very slightly soluble in water and therefore an attempt has been made to prepare inclusion complexes of aceclofenac with -cyclodextrin ( -CD) and to explore the possibility of its molecular arrangement using molecular modeling and structural designing. Such molecular-modeling studies can be employed as an additional tool to support the formation of stable molecular inclusion complexation of any water insoluble drug complexed with cyclodextrins. E. Solubilization by surfactants: Microemulsion The term microemulsion was first used by Jack H. Shulman in 1959. A microemulsion is a fourcomponent system composed of external phase, internal phase, surfactant and cosurfactant. The addition of surfactant, which is predominately soluble in the internal phase unlike the cosurfactant, results in the formation of an optically clear, isotropic, thermodynamically stable emulsion. Non-ionic surfactants, such as Tweens (polysorbates) and Labrafil (polyoxyethylated oleic glycerides), with high hyrophile-lipophile balances are often used to ensure immediate formation of oil-in-water droplets during production.

Srinivasan Shanmugam et al.[11], studied on solid self-nanoemulsifying drug delivery system (SSNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein.The objectives of study was to prepare solid self-nanoemulsifying drug delivery system

(S-SNEDDS)containing phosphatidylcholine (PC), an endogenous phospholipid with excellent in vivo solubilization capacity, as oil phase for the delivery of bioactive carotenoid lutein, by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil 200) as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. The droplet size analyses revealed droplet size of less than 100 nm. The solid state characterization of S-SNEDDS by SEM, DSC, and XRPD revealed the absence of crystalline lutein in the S-SNEDDS. The bioavailability study performed in rabbits resulted in enhanced values of Cmax and AUC for S-SNEDDS. The enhancement of Cmax for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP), respectively The relative BA of S-SNEDDS compared with CP or LP was 2.74-folds or 11.79-folds, respectively. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. Thus, S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo.

II) Chemical modification:

A) Use of salt forms: The use of salt forms is a well known technique to enhanced dissolution profiles. Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs.An alkaloid base is, generally, slightly soluble in water, but if the pH of medium is reduced by addition of acid, and the solubility of the base is increased as the pH continues to be reduced. The reason for this increase in solubility is that the base is converted to a salt, which is relatively soluble in water (e.g. Tribasic calcium phosphate).The solubility of slightly soluble acid increased as the pH is increased by addition of alkali, the reason being that a salt is formed (e.g. Aspirin, Theophylline, Barbiturates

B) Alteration of pH of the drug microenvironment: This can be achieved in two way 1) in situ salt formation, 2) addition of buffers to the formulation e.g buffered aspirin tablets.

III) Other techniques

1) Use of surfactants: Surfactants are very useful as absorption enhancers and enhance both dissolution rate as well as permeability of drug. They enhance dissolution rate primarily by promoting wetting and penetration of dissolution fluid into the solid drug particles. Seedhar N et al. [12] studied solubility enhancement of 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 combined effect of co-solvents and buffer was synergistic and a large increase in solubility could be attained. Ionic surfactants were found to be much better solubilizing agents than non-ionic 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 dissolved in sodium dodecylsulphate

2) Spray freezing into liquid and lyophilization: This technique involves atomizing an aqueous, organic, aqueous-organic cosolvent solution, aqueous organic emulsion or suspension containing a drug and pharmaceutical excipients directly into a compressed gas (i.e. co2, helium, propane, ethane), or the cryogenic liquids (i.e. nitrogen, argon or hydrofluroethers). The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders use of acetonitrile as the solvent increases drug loading and decreases the drying time for lyophilization. The dissolution rate is remarkably enhanced from the process, powder containing amorphous nanostructured aggregates with surface area and excellent wettability. Wang et al. [13] reported the challenges associated with lyophilization of solid protein pharmaceuticals. He identified and discussed many critical issues like drying, stresses, instability and stabilization of the lyophilized formulation. 3) Co-crystallization: The new approach available for the enhancement of drug solubility is through the application of the cocrystals, it is also referred as molecular complexes. If the solvent is an integral part of the network structure and forms at least two component crystals, then it may be termed as co-crystal. If the solvent does not participate directly in the network itself, as in open framework structures, then it is termed as clathrate (inclusion complex). A co-crystal may be defined as a crystalline material that consists of two or more molecular (and electrically neutral) species held together by non-covalent forces.

4) Cosolvency: Weak electrolytes and nonpolar molecules have poor water solubility and it can be improved by altering polarity of the solvent. This can be achieved by addition of another solvent. This process is known as cosolvency. Cosolvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute. Most cosolvents have hydrogen bond donor and/or acceptor groups as well as small hydrocarbon regions. Their hydrophilic hydrogen bonding groups ensure water miscibility, while their hydrophobic hydrocarbon regions interfere with waters hydrogen bonding network, reducing the overall

intermolecular attraction of water. By disrupting waters self-association, cosolvents reduce waters ability to squeeze out non-polar, hydrophobic compounds, thus increasing solubility. Etman et al.[14],studied solubility of etodolac in four different co-solvents; ethanol, propylene glycol, polyethelene glycol 400, and glycerol, three sugars sucrose, sorbitol and mannitol, two hydrotropic salts; sodium benzoate, sodium salicylate, and two enhancers; Tween 80, Brij 58. Based on the solubility data, a trial has been done to propose a formulation (100 mg/3ml) for parenteral use in an aqueous solvent blend and formulation was tested physically for color, turbidity, and precipitation. 5) Hydrotrophy: Hydrotrophy is a solubilisation process whereby addition of a large amount of second solute results in an increase in the aqueous solubility of another solute. Solute consists of alkali metal salts of various organic acids. Hydrotropic agents are ionic organic salts. Additives or salts that increase solubility in given solvent are said to salt in the solute and those salts that decrease solubility salt out the solute. Several salts with large anions or cations that are themselves very soluble in water result in salting in of non electrolytes called hydrotropic salts a phenomenon known as hydrotropism. Hydrotrophy designate the increase in solubility in water due to the presence of large amount of additives.

6) Solubilizing agents: The solubility of poorly soluble drug can also be improved by various solubilizing materials. PEG 400 is improving the solubility of hydrochlorthiazide85. Modified gum karaya (MGK), a recently developed excipient was evaluated as carrier for dissolution enhancement of poorly soluble drug, nimodipine. The aqueous solubility of the antimalarial agent halofantrine is increased by the addition of caffeine and nicotinamide.

7) Nanotechnology approaches: Nanotechnology is used to improve drugs that currently have poor solubility. Nanotechnology refers broadly to the study and use of materials and structures at the nanoscale level of approximately 100 nanometers (nm) or less. For many new chemical entities of very low solubility, oral bioavailability enhancement by micronisation is not sufficient because micronized product has the tendency of agglomeration, which leads to decreased effective surface area for dissolution and the next step taken was Nanonisation. Nanocrystal A nanocrystal is a crystalline material with dimensions measured in nanometers; a nanoparticle with a structure that is mostly crystalline. The nanocrystallization is defined as a way of diminishing drug particles to the size range of 1-1000 nanometers. There are two distinct methods used for producing

nanocrystals; bottom-up and top-down development. The top-down methods (i.e. Milling and High pressure homogenization) start milling down from macroscopic level, e.g. from a powder that is micron sized. In bottom-up methods (i.e. Precipitation and Cryo-vacuum method), nanoscale materials are chemically composed from atomic and molecular components. Precipitation: In the precipitation method a dilute solution is first produced by dissolving the substance in a solvent where its dissolution is good. The solution with the drug is then injected into water, which acts as a bad solvent. At the time of injection, the water has to be stirred efficiently so that the substance will precipitate as nanocrystals. Nanocrystals can be removed from the solution by filtering and then dried in air. Cryo-vacuum method: In the cryo-vacuum method the active ingredient to be nanosized is first dissolved in water to attain a saturated solution. The method is based on sudden cooling of a solvent by immersing the solution in liquid nitrogen (-196 C). Rapid cooling causes a very fast rise in the degree of saturation based on the decrease of solubility and development of ice crystals when the temperature drops below 0 C. This leads to a fast nucleation of the dissolved substance at the edges of the ice crystals. The solvent must be completely frozen before the vessel is removed from the liquid nitrogen. Next the solvent is removed by sublimation in a lyophilization chamber where the temperature is kept at constant -22 C and the pressure is lowered to 10-2 mbar. Cryo-assisted sublimation makes it possible to remove the solvent without changing the size and habit of the particles produced, so they will remain crystalline. The method yields very pure nanocrystals since there is no need to use surfactants or harmful reagents. NanoMorph The NanoMorph technology is to convert drug substances with low water-solubility from a coarse crystalline state into amorphous nanoparticles. A suspension of drug substance in solvent is fed into a chamber, where it is rapidly mixed with another solvent.The admixture of an aqueous solution of a polymer induces precipitation of the drug substance. The polymer keeps the drug substance particles in their nanoparticulate state and prevents them from aggregation or growth. Water redispersable dry powders can be obtained from the nanosized dispersion by conventional methods, e.g. spray-drying. Using this technology the coarse crystalline drug substances are transformed into a nanodispersed amorphous state, without any physical milling or grinding procedures. It leads to the preparation of amorphous nanoparticles. L. Zhang at al. [15], studied on development of nanoparticles for antimicrobial drug delivery. Nanostructured biomaterials, nanoparticles , have unique physicochemical properties such as ultra small and controllable size, large surface area to mass ratio, high reactivity, and functionalizable structure. These properties can be applied to facilitate the administration of antimicrobial drugs, thereby

overcoming some of the limitations in traditional antimicrobial therapeutics. In recent years, encapsulation of antimicrobial drugs in nanoparticle systems has emerged as an innovative and promising alternative that enhances therapeutic effectiveness and minimizes undesirable side effects of the drugs. Conclusion: Solubility is a most important parameter for the oral bioavailability of poorly soluble drugs. Dissolution of drug is the rate determining step for oral absorption of the poorly water soluble drugs, which can subsequently affect the in-vivo absorption of drug. Because of solubility problem of many drugs, the bioavailability of them gets affected and hence solubility enhancement becomes necessary which can be improved with the help of various techniques as mentioned above.

References:
[1] Yuichi Tozuka et al, A novel application of a-glucosyl hesperidin for nanoparticle formation of active pharmaceutical ingredients by dry grinding, European Journal of Pharmaceutics and Biopharmaceutics, 2011, 79, 3,559565

[2] F. Lai .et al, Nanocrystals as tool to improve piroxicam dissolution rate in novel orally Disintegrating tablets, European Journal of Pharmaceutics and Biopharmaceutics, 2011,79,3, 552558 [3]Swarbrick J et al, Spray drying and Spray Congealing of Pharmaceuticals; Encyclopedia of Pharmaceutical Technology, Marcel Dekker, 1992, 207-221. [4] http://en.wikipedia.org/wiki/Supercritical fluid (site visited on 15/11/10) [5] Mohamed A et al, Spray-drying enteric polymers from aqueous solutions: A novel, economic, and environmentally friendly approach to produce pH-responsive microparticles, European Journal of Pharmaceutics and Biopharmaceutics,2011,79,2, 432439

[6] Rajebahadur M. et al, Mechanistic study of solubility enhancement of Nifedipine using Vitamin E TPGS or Solutol HS-15, Informaworld Drug Delivery, May 2006, 13, 3, 201-206.

[7] Sebastian Bialleck et al, Preparation of starch-based pellets by hot-melt extrusion, European Journal of Pharmaceutics and Biopharmaceutics, 2011, 79, 2,440448 [8] http://www.pharmainfo.net/reviews/solid-dispersions-overview (sited on 12/11/11) [9]Karavas E.et al, Hydrophilic matrices as carriers in Felodipine solid dispersion systems , European Colloid and Interface Science XV, 2001, 118, 149-152.

[10] Kamal dua et al,Molecular Modeling of Inclusion Complex of Aceclofenac with Indian Journal of Novel Drug delivery Jan-Mar, 2011,3(1), 58-60

-Cyclodextrins ,

[11] Srinivasan Shanmugam et al, Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein, European Journal of Pharmaceutics and Biopharmaceutics , 2011,2, 250257

[12]. Seedhar N. et al, Various solvent systems for solubility enhancement of enrofloxacin, Indian J Pharm. Sci., 2009, 71, 1, 82-87.

[13] Wang W. et al, Lyophilization and development of solid protein, Int. J. Pharm., 2000, 203, 24-30. [14] Etman M.A. et al, Solubilization of etodolac for pareteral administration, Indian J. Pharm. Sci.,2001, 63, 459- 467. [15] Zhang et al, Development of Nanoparticles for Antimicrobial Drug Delivery, Current Medicinal Chemistry, 2010, 17, 585-594 [16] Purwa jain et al, solubility enhancement techniques with special emphasis on hydrotrophy, international journal of pharma professional research

[17] Brahmankar D.M. et al, Biopharmaceutics and Pharmacokinetics 2007, 15-35. [18] www.pharmatext.org/whitepaper/solubilty enhancement technique