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
Alteration of pH of the drug microenvironment
III. Use of complexing agents E. Polymorphs b.
.Salt formation B. Solubilization by surfactants a. Self microemulsifying drug delivery systems
II. Modification of the crystal habit a.The size of solid drug particles range from 1 to 10 microns. Micronization b. Drug dispersion in carriers a.Solubility Enhancement Techniques
Solubility is important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response. Solid solutions b. Physical Modifications:
A. Nanosuspension B. Micronization: Micronization of drugs is done by spray drying or by use of attrition methods (fluid energy or jet mill). Pseudopolymorphs C. Chemical Modifications:
A . Particle size reduction a. Techniques can be classified as follows:
I. Others I. Solid dispersions c. Microemulsions b. Complexation a.Physical Modification
A. Eutectic mixtures D. Particle size reduction a. There are various techniques available to improve the solubility of poorly soluble drugs.
All ODT formulations prepared using nanosuspensions showed a higher dissolution rate compared with the ODT prepared with the coarse. which are stabilized by surfactants.Yuichi Tozuka et al . and high shear fluid processors.Nanocrystals produced from the process are of size (200-600) nm. Three types of homogenizers are commonly used for particle size reduction in the pharmaceutical and biotechnology industries: conventional homogenizers. 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.et al . F. sonicators. 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. Different nanocrystal formulations were prepared using a high pressure homogenization technique and poloxamer 188 as a stabilizer. b) Wet milling: Active drug in the presence of surfactant is defragmented by milling. Nanosuspension: Nanosuspension is sub-micron colloidal dispersion of pure particles of drug. At near-critical temperatures.
Other techniques for reduction of the particle size:
Supercritical Fluid  Recrystallization Supercritical fluids (e. studied on the effectiveness of a-glucosyl hesperidin (Hsp-G) as a novel grinding aid for the preparation of drug nanoparticles by dry grinding. small changes in pressure or temperature result in large changes in density Once the drug are solubilised within SCF .g. carbon dioxide) are fluids whose temperature and pressure above its critical point. The dissolution profile of glibenclamide from the ground mixtures of glibenclamide/ Hsp-G showed dramatic improvement from that of untreated drug crystals.
b. Techniques for the production of nanosuspension are as follows: a) Homogenization: The suspension is forced under pressure through a valve that has nano aperture. no distinct liquid and gas phases exist. and dissolve materials like a liquid. Lai. 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. It can effuse through solids like a gas. It was evident that all poorly water-soluble drugs used in this study formed nanoparticles after the ground mixtures were dispersed into distilled water. This causes bubbles of water to form which collapses as they come out of valves. SCFs are highly compressible. This mechanism cracks the particles.
. studied piroxicam dissolution rate in novel orally disintegrating tablets (ODT) using Nanocrystals. there may be recrystallization at greatly reduced particle sizes.
studied on spray-drying of enteric polymers from aqueous solutions to produce pHresponsive micro particles.
Mohamed A et al . Broadly polymorphs can be classified as enantiotropes and monotropes based on thermodynamic properties. and release was rapid and complete at small intestinal conditions. was sufficient to eradicate the ammonium residues. Once the drug has been characterized under one of this category. Modification of the crystal habit Polymorphism is the ability of an element or compound to crystallize in more than one crystalline form. and lipocol C-10 of varying
. prepared using Vitamin E TPGS or Solutol HS-15. stability etc. Moreover. Amorphous >Metastable polymorph >Stable polymorph
Rajebahadur M.Spray drying : 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 air is then exhausted with the moisture. Metastable forms are associated with higher energy and thus higher solubility. while no reversible transition is possible for monotropes. In bicarbonate media. texture. safety. Similarly the amorphous form of drug is always more suited than crystalline form due to higher energy associated and increase surface area. The microparticles loaded with the model drug prednisolone. one polymorphs form can change reversibly into another at a definite transition temperature below the melting point. PEG1000. and environmental benefits. but they exhibit different physicochemical properties including solubility. Different polymorphs of drugs are chemically identical. emulsion. further study involves the detection of metastable form of crystal. This new microparticle preparation concept obviates the need for organic solvent and utilizes spray-drying techniques. the solutions were then spray-dried. slurry. studied the mechanism responsible for solubility enhancement of Nifedipine solid dispesion. were spherical and small in size (2±5 lm). melting point. The feed may be solution. The approach involves the neutralization and generation of water-soluble salt forms of enteric polymers.
B. It involves bringing together a highly dispersed liquid and a sufficient volume of hot air to produce evaporation and drying of liquid droplets. Incubating the microparticles for three hours at 70° C and 130° C for the Eudragit S and L products respectively. gel or paste. The methacrylic acid polymers (Eudragit L and EudragitS) were added separately to aqueous solutions of ammonium hydrogen carbonate. The air supplies the heat for evaporation and conveys the dried product to the collector. In the case of an enantiotropic system. density. The approach therefore offers economic. drug release from these spray-dried microparticles was faster compared to microparticles produced from conventional emulsion solvent evaporation methods. the particles were gastroresistant. et al .
The solubility enhancement was found to be in the order of vitamin E TPGS > solutol HS-15 > lipocol C-10 > PEG1000. Novel additional preparation techniques have included rapid precipitation by freeze drying and using supercritical fluids and spray drying. The resultant solid mass was then milled to reduce the particle size. Cooling leads to supersaturation. Surfactants like Tween-80. This enabled them to produce a solid solution of the highly lipophilic -carotene in the highly water soluble carrier polyvinylpyrrolidone. and interaction between polymer and drug at the molecular level. The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone. solvent method. Drug dispersion in carriers The term ³solid dispersions ´ refers to the dispersion of one or more active ingredients in an inert carrier in a solid state. Docusate sodium. 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. 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. Sulphathiazole and urea were melted together and then cooled in an ice bath. Many times surfactants may also used in the formation of solid dispersion. increase in wettability of the drug by water soluble polymers. this usually leads to a product that is not molecularly dispersed. C.drug/polymer ratios by a fusion method. The solvent can be removed by various methods like by spray-drying or by freeze-drying. often in the presence of amorphous hydrophilic polymers and also using methods such as melt extrusion. Plasdone-S630.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. 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. micellar solubilization of drug by high concentrations of surfactant polymers. frequently prepared by the melting (fusion) method. Hot Melt Method Sekiguchi and Obi used a hot melt method to prepare solid dispersion. or fusion solvent-method. Another important requisite is the thermostability of the drug and carrier. Pluronic-F68 and Sodium Lauryl Sulphate used.
. polyethylene glycols. Different methods of drug dispersion in carriers are as follows: 1.
2. Myrj-52. better separation of drug particles. Based on these results. Temperatures used for solvent evaporation generally lie in the range 23-65° C. When there are miscibility gaps in the phase diagram. but due to solidification the dispersed drug becomes trapped within the carrier matrix.
whereas extrusion of an immiscible component leads to amorphous drug dispersed in crystalline excipient.
Sebastian Bialleck et al . it is only limited to drugs with a low therapeutic dose e. The process has been useful in the preparation of solid dispersions in a single step.the weak physical bonding between the adsorbate. N methylglucamide. The drug is either dispersed or dissolved in the starch melt. pea starch. Complexation relies on relatively weak forces such as London forces. Also the liquid solvent used may affect the polymorphic form of the drug. carboxymethyl cellulose sodium. polyethylene glycol.3. and hydration and swelling of the clay in the aqueous media.
Karavas E.g. urea. which is then evaporated until a clear. and hydroxypropylmethyl cellulose (HPMC) as carriers in felodipine solid
. The two reasons suggested for the rapid release of drugs from the surface of clays are. 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. solvent free film is left. caffeine. low porosity and small surface area. From a practical standpoint. Pellets were produced based on four different starches (corn starch. paracetamol. which precipitates as the solid dispersion. It is possible that the selected solvent or dissolved drug may not be miscible with the melt of the polyethylene glycol. hydroxyethyl cellulose (HEC). Complexation: Complexation is the association between two or more molecules to form a nonbonded entity with a well defined stichiometry. The resulting pellets exhibit a large mechanical stability. The most common complexing ligands are cyclodextrins. studied the use of three modified celluloses. et al. the combination of starch. Drug loadings of up to 80% are achievable. The 5 ±10% (w/w) of liquid compounds can be incorporated into polyethylene glycol6000 without significant loss of its solid property. phenazon and tramadol-HCl) and various additives. It has been reported that melt extrusion of miscible components results in amorphous solid solution formation. hydrogen bonding and hydrophobic interactions. four different active ingredients (ibuprofen. potato starch and waxy corn starch). indomethacin and prednisone by maintaining the concentration gradient at its maximum. active ingredient and additives. 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. Hot-melt Extrusion Melt extrusion was used as a manufacturing tool in the pharmaceutical industry as early as 1971. prepared starch-based pellets by hot-melt extrusion. D. below 50 mg. The drug release rate is controlled by the particle size. . The film is further dried to constant weight.
The drug-polymer interactions were studied using DSC and IR techniques..
Kamal dua et al studied on Molecular Modeling of Inclusion Complex of Aceclofenac with
Cyclodextrins. interactions. surfactant and cosurfactant. Shulman in 1959. The addition of surfactant. thermodynamically stable emulsion. 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. and polymer properties were investigated.dispersion systems. as well as HPLC purity after storage in strength conditions. E. results in the formation of an optically clear. which is predominately soluble in the internal phase unlike the cosurfactant.cyclodextrins and several of their derivatives are unique in having the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility.
Srinivasan Shanmugam et al. 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.thiazide diuretics. isotropic. 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. There are several examples of drugs with improved bioavailability due to such phenomenon. which were prepared following the dissolution method using a common solvent. A microemulsion is a fourcomponent system composed of external phase. barbiturates and a number of NSAIDs. Thus the molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate. Neither significant interactions nor degradation of the active ingredient was observed after storage at 40 °C for 3 months. studied on solid self-nanoemulsifying drug delivery system (SSNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein. such as the drug-polymer ratio. This study was concerned with solid dispersions. felodipine release from the solid dispersion systems was studied and the factors influencing release. Solubilization by surfactants: Microemulsion The term microemulsion was first used by Jack H. 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. such as Tweens (polysorbates) and Labrafil (polyoxyethylated oleic glycerides).The objectives of study was to prepare solid self-nanoemulsifying drug delivery system
. Non-ionic surfactants. with high hyrophile-lipophile balances are often used to ensure immediate formation of oil-in-water droplets during production. internal phase.and gamma. In addition. the outside of the host molecule is relatively hydrophilic.
S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo. Thus. Co-
. The bioavailability study performed in rabbits resulted in enhanced values of Cmax and AUC for S-SNEDDS. The droplet size analyses revealed droplet size of less than 100 nm. Seedhar N et al. Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. The solid state characterization of S-SNEDDS by SEM. 2) addition of buffers to the formulation e.g buffered aspirin tablets. Barbiturates
B) Alteration of pH of the drug microenvironment: This can be achieved in two way 1) in situ salt formation. Aqueous solubility of enrofloxacin could be increased up to 26 times. Theophylline. as oil phase for the delivery of bioactive carotenoid lutein.g. and XRPD revealed the absence of crystalline lutein in the S-SNEDDS.(S-SNEDDS)containing phosphatidylcholine (PC). and the solubility of the base is increased as the pH continues to be reduced. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. the reason being that a salt is formed (e. They enhance dissolution rate primarily by promoting wetting and penetration of dissolution fluid into the solid drug particles. but if the pH of medium is reduced by addition of acid. Tribasic calcium phosphate). which is relatively soluble in water (e.An alkaloid base is. The enhancement of Cmax for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP). The reason for this increase in solubility is that the base is converted to a salt. DSC. by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil 200) as the inert solid carrier.74-folds or 11.
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. respectively The relative BA of S-SNEDDS compared with CP or LP was 2.  studied solubility enhancement of antimicrobial drug enrofloxacin using a series of co-solvents and surfactants. generally.
II) Chemical modification:
A) Use of salt forms: The use of salt forms is a well known technique to enhanced dissolution profiles.g. slightly soluble in water.The solubility of slightly soluble acid increased as the pH is increased by addition of alkali. an endogenous phospholipid with excellent in vivo solubilization capacity. Aspirin.79-folds. and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. respectively.
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. Wang et al. aqueous-organic cosolvent solution.e. This can be achieved by addition of another solvent. nitrogen. reducing the overall
. argon or hydrofluroethers). as in open framework structures. 3) Co-crystallization: The new approach available for the enhancement of drug solubility is through the application of the cocrystals. instability and stabilization of the lyophilized formulation. then it is termed as clathrate (inclusion complex). ethane). If the solvent is an integral part of the network structure and forms at least two component crystals.solvents alone produced only small increase in solubility. the combined effect of co-solvents and buffer was synergistic and a large increase in solubility could be attained. cetyltrimethylammonium bromide. helium. Their hydrophilic hydrogen bonding groups ensure water miscibility. organic. sodium dodecylsulphate as compared to the cationic surfactant. Most cosolvents have hydrogen bond donor and/or acceptor groups as well as small hydrocarbon regions. If the solvent does not participate directly in the network itself. Up to 3. However. while their hydrophobic hydrocarbon regions interfere with waters hydrogen bonding network.e. 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. This process is known as cosolvency. stresses. aqueous organic emulsion or suspension containing a drug and pharmaceutical excipients directly into a compressed gas (i. co2. Ionic surfactants were found to be much better solubilizing agents than non-ionic surfactant. The dissolution rate is remarkably enhanced from the process. Amongst ionic surfactants. powder containing amorphous nanostructured aggregates with surface area and excellent wettability. propane. or the cryogenic liquids (i. then it may be termed as co-crystal.8 mg/ml of enrofloxacin could be dissolved in sodium dodecylsulphate
2) Spray freezing into liquid and lyophilization: This technique involves atomizing an aqueous. Cosolvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute. solubility was found to be very high in anionic surfactant.
4) Cosolvency: Weak electrolytes and nonpolar molecules have poor water solubility and it can be improved by altering polarity of the solvent. it is also referred as molecular complexes.  reported the challenges associated with lyophilization of solid protein pharmaceuticals. He identified and discussed many critical issues like drying.
propylene glycol. For many new chemical entities of very low solubility. and glycerol. Etman et al. Tween 80. 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. a nanoparticle with a structure that is mostly crystalline. sorbitol and mannitol. Brij 58. which leads to decreased effective surface area for dissolution and the next step taken was Nanonisation. By disrupting waters self-association. Nanotechnology refers broadly to the study and use of materials and structures at the nanoscale level of approximately 100 nanometers (nm) or less. oral bioavailability enhancement by micronisation is not sufficient because micronized product has the tendency of agglomeration. and precipitation.intermolecular attraction of water. PEG 400 is improving the solubility of hydrochlorthiazide85. nimodipine. Several salts with large anions or cations that are themselves very soluble in water result in ³salting in´ of non electrolytes called ³hydrotropic salts´ a phenomenon known as ³hydrotropism´. Nanocrystal A nanocrystal is a crystalline material with dimensions measured in nanometers. sodium benzoate. and two enhancers. Solute consists of alkali metal salts of various organic acids. 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. thus increasing solubility. a recently developed excipient was evaluated as carrier for dissolution enhancement of poorly soluble drug. polyethelene glycol 400. two hydrotropic salts. 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. Based on the solubility data. Hydrotropic agents are ionic organic salts. The nanocrystallization is defined as a way of diminishing drug particles to the size range of 1-1000 nanometers. hydrophobic compounds. There are two distinct methods used for producing
.. turbidity. Additives or salts that increase solubility in given solvent are said to ³salt in´ the solute and those salts that decrease solubility ³salt out´ the solute. three sugars sucrose.
7) Nanotechnology approaches: Nanotechnology is used to improve drugs that currently have poor solubility.studied solubility of etodolac in four different co-solvents. The aqueous solubility of the antimalarial agent halofantrine is increased by the addition of caffeine and nicotinamide. sodium salicylate. ethanol. Modified gum karaya (MGK). cosolvents reduce waters ability to squeeze out non-polar.
. Precipitation: In the precipitation method a dilute solution is first produced by dissolving the substance in a solvent where its dissolution is good.nanocrystals. Precipitation and Cryo-vacuum method). . ¶bottom-up¶ and ¶top-down¶ development.The admixture of an aqueous solution of a polymer induces precipitation of the drug substance. NanoMorph The NanoMorph technology is to convert drug substances with low water-solubility from a coarse crystalline state into amorphous nanoparticles. large surface area to mass ratio.e. The solvent must be completely frozen before the vessel is removed from the liquid nitrogen. Using this technology the coarse crystalline drug substances are transformed into a nanodispersed amorphous state. nanoparticles .g. high reactivity. which acts as a bad solvent. It leads to the preparation of amorphous nanoparticles. A suspension of drug substance in solvent is fed into a chamber. In bottom-up methods (i. have unique physicochemical properties such as ultra small and controllable size. nanoscale materials are chemically composed from atomic and molecular components. Zhang at al. the water has to be stirred efficiently so that the substance will precipitate as nanocrystals. and functionalizable structure. e.g. 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 ºC. These properties can be applied to facilitate the administration of antimicrobial drugs. At the time of injection. The method is based on sudden cooling of a solvent by immersing the solution in liquid nitrogen (-196 ºC). The method yields very pure nanocrystals since there is no need to use surfactants or harmful reagents. where it is rapidly mixed with another solvent. without any physical milling or grinding procedures. from a powder that is micron sized. so they will remain crystalline. Nanostructured biomaterials. Cryo-vacuum method: In the cryo-vacuum method the active ingredient to be nanosized is first dissolved in water to attain a saturated solution. e. Next the solvent is removed by sublimation in a lyophilization chamber where the temperature is kept at constant -22 ºC and the pressure is lowered to 10-2 mbar. studied on development of nanoparticles for antimicrobial drug delivery. Nanocrystals can be removed from the solution by filtering and then dried in air. spray-drying. The polymer keeps the drug substance particles in their nanoparticulate state and prevents them from aggregation or growth. This leads to a fast nucleation of the dissolved substance at the edges of the ice crystals. Milling and High pressure homogenization) start milling down from macroscopic level. The top-down methods (i. The solution with the drug is then injected into water. Cryo-assisted sublimation makes it possible to remove the solvent without changing the size and habit of the particles produced. Water redispersable dry powders can be obtained from the nanosized dispersion by conventional methods.e. L.
which can subsequently affect the in-vivo absorption of drug. Dissolution of drug is the rate determining step for oral absorption of the poorly water soluble drugs. Because of solubility problem of many drugs.
. Conclusion: Solubility is a most important parameter for the oral bioavailability of poorly soluble drugs.overcoming some of the limitations in traditional antimicrobial therapeutics. In recent years. 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. 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.
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