Solubilization of Poorly Soluble Drugs: A Review

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Anil J Shinde

Anil J Shinde

Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Currently only 8% of new drug candidates have both high solubility and permeability1.

The solubility of a solute is the maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature2. In the other words the solubility can also define as the ability of one substance to form a solution with another substance3. The substance to be dissolved is called as solute and the dissolving fluid in which the solute dissolve is called as solvent, which together form a solution. The process of dissolving solute into solvent is called as solution, or hydration if the solvent is water4.

Solubility definitions3,4, 5:

Definition

Parts of solvent required for one part of solute

Very soluble

< 1

Freely soluble

1 - 10

Soluble

10 - 30

Sparingly soluble

30 - 100

Slightly soluble

100 - 1000

Very slightly soluble

1000 - 10,000

Insoluble

> 10,000

Process of solubilisation3:-

The process of solubilisation involves the breaking of inter-ionic or intermolecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion.

Step 1: Holes opens in the solvent

Holes opens in the solvent

Step2: Molecules of the solid breaks away from the bulk

Molecules of the solid breaks away from the bulk

Step 3:The freed solid molecule is intergrated into the hole in the solvent

The freed solid molecule is intergrated into the hole in the solvent

Factors affecting solubility:-

The solubility depends on the physical form of the solid, the nature and composition of solvent medium as well as temperature and pressure of system6.

Particle Size

The size of the solid particle influences the solubility because as a particle becomes smaller, the surface area to volume ratio increases. The larger surface area allows a greater interaction with the solvent. The effect of particle size on solubility can be described by3

image

Where,

S0is the solubility of infinitely large particles

Sis the solubility of fine particles

V is molar volume

g is the surface tension of the solid

r is the radius of the fine particle

Temperature

Temperature will affect solubility. If the solution process absorbs energy then the solubility will be increased as the temperature is increased. If the solution process releases energy then the solubility will decrease with increasing temperature7. Generally, an increase in the temperature of the solution increases the solubility of a solid solute. A few solid solutes are less soluble in warm solutions. For all gases, solubility decreases as the temperature of the solution increases2.

Pressure

For gaseous solutes, an increase in pressure increases solubility and a decrease in pressure decrease the solubility. For solids and liquid solutes, changes in pressure have practically no effect on solubility2.

Nature of the solute and solvent

While only 1 gram of lead (II) chloride can be dissolved in 100 grams of water at room temperature, 200 grams of zinc chloride can be dissolved. The great difference in the solubilities of these two substances is the result of differences in their natures2.

Molecular size

Molecular size will affect the solubility. The larger the molecule or the higher its molecular weight the less soluble the substance. Larger molecules are more difficult to surround with solvent molecules in order to solvate the substance. In the case of organic compounds the amount of carbon branching will increase the solubility since more branching will reduce the size (or volume) of the molecule and make it easier to solvate the molecules with solvent7.

Polarity

Polarity of the solute and solvent molecules will affect the solubility. Generally non-polar solute molecules will dissolve in non-polar solvents and polar solute molecules will dissolve in polar solvents. The polar solute molecules have a positive and a negative end to the molecule. If the solvent molecule is also polar, then positive ends of solvent molecules will attract negative ends of solute molecules. This is a type of intermolecular force known as dipole-dipole interaction. All molecules also have a type of intermolecular force much weaker than the other forces called London Dispersion forces where the positive nuclei of the atoms of the solute molecule will attract the negative electrons of the atoms of a solvent molecule. This gives the non-polar solvent a chance to solvate the solute molecules7.

Polymorphs

A solid has a rigid form and a definite shape. The shape or habit of a crystal of a given substance may vary but the angles between the faces are always constant. A crystal is made up of atoms, ions, or molecules in a regular geometric arrangement or lattice constantly repeated in three dimensions. This repeating pattern is known as the unit cell.The capacity for a substance to crystallize in more than one crystalline form is polymorphism. It is possible that all crystals can crystallize in different forms or polymorphs. If the change from one polymorph to another is reversible, the process is called enantiotropic. If the system is monotropic, there is a transition point above the melting points of both polymorphs. The two polymorphs cannot be converted from one another without undergoing a phase transition. Polymorphs can vary in melting point. Since the melting point of the solid is related to solubility, so polymorphs will have different solubilities3. Generally the range of solubility differences between different polymorphs is only 2-3 folds due to relatively small differences in free energy8.

Rate of solution:-

The rate of solution is a measure of how fast substances dissolve in solvents2.

Factors affecting rate of solution:

Size of the particles

When the total surface area of the solute particles is increased, the solute dissolves more rapidly because the action takes place only at the surface of each particle. Breaking a solute into smaller pieces increases its surface area and hence its rate of solution.

Temperature

For liquids and solid solutes, increasing the temperature not only increases the amount of solute that will dissolve but also increases the rate at which the solute will dissolve. For the gases, reverse is true.

Amount of solute already dissolved

When there is little solute already in solution, dissolution takes place relatively rapidly. As the solution approaches the point where no solute can be dissolved, dissolution takes place more slowly.

Stirring

With liquid and solid solutes, stirring brings fresh portions of the solvent in contact with the solute, thereby increasing the rate of solution.

Techniques Of Solubility Enhancement

There are various techniques available to improve the solubility of poorly soluble drugs. Some of the approaches to improve the solubility are9:

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. Eutectic mixtures

b. Solid dispersions

c. Solid solutions

D. Complexation

a. Use of complexing agents

E. Solubilization by surfactants:

a. Microemulsions

b. Self microemulsifying drug delivery systems

II. Chemical Modifications

I. Physical Modifications:-

A. Particle size reduction:

Particle size reduction can be achieved by micronisation and nanosuspension. Each technique utilizes different equipments for reduction of the particle size.

a. Micronization

The solubility of drug is often intrinsically related to drug particle size. By reducing the particle size, the increased surface area improve the dissolution properties of the drug. Conventional methods of particle size reduction, such as comminution and spray drying, rely upon mechanical stress to disaggregate the active compound. The micronisation is used to increased surface area for dissolution10.

Micronisation increases the dissolution rate of drugs through increased surface area, it does not increase equilibrium solubility11. Micronization of drugs is done by milling techniques using jet mill, rotor stator colloid mills etc. Micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug.

b. Nanosuspension

Nanosuspensions are sub-micron colloidal dispersion of pure particles of drug, which are stabilised by surfactants12. The advantages offered by nanosuspension is increased dissolution rate is due to larger surface area exposed, while absence of Ostwald ripening is due to the uniform and narrow particle size range obtained, which eliminates the concentration gradient factor.

Techniques for the production of nanosuspensions12:

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 processors13.

b) Wet milling:

Active drug in the presence of surfactant is defragmented by milling.

Other technique involves the spraying of a drug solution in a volatile organic solvent into a heated aqueous solution. Rapid solvent evaporation produces drug precipitation in the presence of surfactants.

The nanosuspension approach has been employed for drugs including tarazepide, atovaquone, amphotericin B, paclitaxel and bupravaquone. All the formulations are in the research stage. One major concern related to particle size reduction is the eventual conversion of the high-energy polymorph to a low energy crystalline form, which may not be therapeutically active one9, 14. Drying of nanosuspensions can be done by lyophilisation or spray drying.

Other techniques for reduction of the particle size:

1. Sonocrystallisation

Recrystallization of poorly soluble materials using liquid solvents and antisolvents has also been employed successfully to reduce particle size15. The novel approach for particle size reduction on the basis of crystallisation by using ultrasound is Sonocrystallisation.

Sonocrystallisation utilizes ultrasound power characterised by a frequency range of 20–100 kHz for inducing crystallisation. It’s not only enhances the nucleation rate but also an effective means of size reduction and controlling size distribution of the active pharmaceutical ingredients (API)16. Most applications use ultrasound in the range 20 kHz-5 MHz17.

2. Supercritical fluid process

Novel nanosizing and solubilization technology whose application has increased particle size reduction via supercritical fluid (SCF) processes18. A supercritical fluid (SF) can be defined as a dense noncondensable fluid19. Supercritical fluids are fluids whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Tp). Through manipulation of the pressure of SCFs, the favorable characteristics of gases- high diffusivity, low viscosity and low surface tension may be imparted upon liquids to precisely control the solubilisation of a drug with a supercritical fluid. SCFs are high compressible, allowing moderate changes in pressure to greatly alter the density and mass transport characteristics of fluid that largely determine its solvents power. Once the drug particles are solubilised within SCFs, they may be recrystalised at greatly reduced particle sizes. A SCF process allows micronisation of drug particles within narrow range of particle size, often to sub-micron levels. Current SCF processes have demonstrated the ability to create nanoparticulate suspensions of particles 5 to 2,000 nm in diameter.

The most widely employed methods of SCF processing for micronized particles are rapid expansion of supercritical solutions (RESS) and gas antisolvents recrystallisation (GAS), both of which are employed by the pharmaceutical industry using carbon dioxide (CO2) as the SCF18 due to its favourable processing characteristics like its low critical temperature (Tc = 31.1-C) and pressure (Pc = 73.8 bar)20.

RESS involves solubilising a drug or a drug-polymer mixture in SCF and subsequently spraying the SCF solution into a lower pressure environment via a conventional nozzle or capillary tube. The rapid expansion undergone by the solution reduces the density of the CO2, correspondingly reducing its solvent power and supersaturating the lower pressure solution. This supersaturation results in the recrystallisation and precipitation of pure drug or drug-polymer particles of greatly reduced size, narrow size distribution and high purity. The solubility of nifedipine has been improved by RESS21.

GAS processing requires the drug or drug-polymer mixture be solubilised via conventional means into a solvent that is then sprayed into an SCF; the drug should be insoluble in the SCF, while the SCF should be miscible with the organic solvent. The SCF diffuses into the spray droplets, causing expansion of the solvent present and precipitation of the drug particles.

The low solubility of poorly water-soluble drugs and surfactants in supercritical CO2 and the high pressure required for these processes restrict the utility of this technology in the pharmaceutical industry22.

3. Spray drying

Spray drying is a commonly used method of drying a liquid feed through a hot gas. Typically, this hot gas is air but sensitive materials such as pharmaceuticals and solvents like ethanol require oxygen-free drying and nitrogen gas is used instead. The liquid feed varies depending on the material being dried and is not limited to food or pharmaceutical products and may be a solution, colloid or a suspension. This process of drying is a one step rapid process and eliminates additional processing23. Spray drying of the acid dispersed in acacia solutions resulted in as much as a 50% improvement in the solubility of poorly water soluble salicylic acid24.

B. Modification of the crystal habit:

Polymorphism is the ability of an element or compound to crystallize in more then 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.

Generally, the anhydrous form of a drug has greater solubility than the hydrates. This is because the hydrates are already in interaction with water and therefore have less energy for crystal breakup in comparison to the anhydrates (i.e. thermodynamically higher energy state) for further interaction with water. On the other hand, the organic (nonaqueous) solvates have greater solubility than the nonsolvates.

Some drugs can exist in amorphous form (i.e. having no internal crystal structure). Such drugs represent the highest energy state and can be considered as super cooled liquids. They have greater aqueous solubility than the crystalline forms because they require less energy to transfer a molecule into solvent. Thus, the order for dissolution of different solid forms of drug is

Amorphous >Metastable polymorph >Stable polymorph

Melting followed by a rapid cooling or recrystallization from different solvents can be produce metastable forms of a drug.

C. Drug dispersion in carriers:

The solid dispersion approach to reduce particle size and therefore increase the dissolution rate and absorption of drugs was first recognised in 196125.The term “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-method26. Novel additional preparation techniques have included rapid precipitation by freeze drying27 and using supercritical fluids28 and spray drying29, often in the presence of amorphous hydrophilic polymers and also using methods such as melt extrusion30. The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone31, 32, polyethylene glycols33, Plasdone-S63034. 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 used34.

The solubility of etoposide35, glyburide36, itraconazole37, ampelopsin38, valdecoxib39, celecoxib40, halofantrine41 can be improved by solid dispersion using suitable hydrophilic carriers.

The eutectic combination of chloramphenicol/urea42 and sulphathiazole/ urea25 served as examples for the preparation of a poorly soluble drug in a highly water soluble carrier.

1. Hot Melt method

Sekiguchi and Obi25 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 can be achieved or not, depends on the degree of supersaturation and rate of cooling used in the process43. 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 Nakumara44 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 β-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 solvent43. The solvent can be removed by various methods like by spray-drying45 or by freeze-drying46. Temperatures used for solvent evaporation generally lie in the range 23-65 0C47,48.

The solid dispersion of the 5- lipoxygenase/cyclooxygenase inhibitor ER-34122 shown improved in vitro dissolution rate compared to the crystalline drug substance which was prepared by solvent evaporation49. These techniques have problems such as negative effects of the solvents on the environment and high cost of production due to extra facility for removal of solvents50. Due to the toxicity potential of organic solvents employed in the solvent evaporation method, hot melt extrusion method is preferred in preparing solid solutions26, 51.

3. Hot-melt Extrusion

Melt extrusion was used as a manufacturing tool in the pharmaceutical industry as early as 197152. 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 excipient53. The process has been useful in the preparation of solid dispersions in a single step.

4. Melting –solvent method

A drug is first dissolved in a suitable liquid solvent and then this solution is incorporated into the melt of polyethylene glycol, obtainable below 700C without removing the liquid solvent. The selected solvent or dissolved drug may not be miscible with the melt of the polyethylene glycol. Also polymorphic form of the drug precipitated in the solid dispersion may get affected by the liquid solvent used.

Carriers for Solid Dispersions26

Sr. No.

Chemical Class

Examples

1

Acids

Citric acid, Tartaric acid, Succinic acid

2

Sugars

Dextrose, Sorbitol, Sucrose, Maltose, Galactose, Xylitol

3

Polymeric Materials

Polyvinylpyrrolidone, PEG-4000, PEG-6000,

Carboxymethyl cellulose, Hydroxypropyl cellulose,

Guar gum, Xanthan gum, Sodium alginate, Methyl

cellulose, HPMC, Dextrin, Cyclodextrins,

Galactomannan

4

Surfactants

Polyoxyethylene stearate, Poloxamer,

Deoxycholic acid, Tweens and Spans,

Gelucire 44/14, Vitamine E TPGS NF

5

Miscellaneous

Pentaerythritol, Urea, Urethane,

Hydroxyalkyl xanthines

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. There are many types of complexing agents and a partial list can be found in below table.

List of Complexing Agents3

Sr.No.

Types

Examples

1

Inorganic

IB-

2

Coordination

Hexamine cobalt(III) chloride

3

Chelates

EDTA, EGTA

4

Metal-Olefin

Ferrocene

5

Inclusion

Cyclodextrins, Choleic acid

6

Molecular Complexes

Polymers

Staching complexation

Staching complexes are formed by the overlap of the planar regions of aromatic molecules. Nonpolar moieties tend to be squeezed out of water by the strong hydrogen bonding interactions of water. This causes some molecules to minimize the contact with water by aggregation of their hydrocarbon moieties. This aggregation is favored by large planar nonpolar regions in the molecule. Stached complexes can be homogeneous or mixed. The former is known as self association and latter as complexation. Some compounds that are known to form staching complexes are as follows:

Nicotinamide54, Anthracene, Pyrene, Methylene blue, Benzoic acid, Salicylic acid, Ferulic acid, Gentisic acid, Purine, Theobromine, Caffeine, and Naphthalene etc.

Higuchi and Kristiansen55 proposed a model according to which the compounds capable of undergoing stacking can be classified into two classes (classes A and B) based on their structure. The compounds in class A have higher affinity for compounds in class B than for those in class A and vice versa56.

Inclusion complexation

Inclusion complexes are formed by the insertion of the nonpolar molecule or the nonpolar region of one molecule (known as guest) into the cavity of another molecule or group of molecules (known as host). The major structural requirement for inclusion complexation is a snug fit of the guest into the cavity of host molecule. The cavity of host must be large enough to accommodate the guest and small enough to eliminate water, so that the total contact between the water and the nonpolar regions of the host and the guest is reduced.

The most commonly used host molecules are cyclodextrins. The enzymatic degradation of starch by cyclodextrin-glycosyltransferase (CGT) produces cyclic oligomers, Cyclodextrins. Cyclodextrins are non-reducing, crystalline, water soluble, cyclic, oligosaccharides. Cyclodextrins consist of glucose monomers arranged in a donut shape ring. Three naturally occurring CDs are α-Cyclodextrin, β-Cyclodextrin, and γ- Cyclodextrin. The complexation with cyclodextrins is used for enhancement of solubility58. Cyclodextrin inclusion is a molecular phenomenon in which usually only one guest molecule interacts with the cavity of a cyclodextrin molecule to become entrapped and form a stable association. The internal surface of cavity is hydrophobic and external is hydrophilic, this is due to the arrangement of hydroxyl group within the molecule.

Molecules or functional groups of molecules those are less hydrophilic than water, can be included in the cyclodextrin cavity in the presence of water. In order to become complex, the "guest molecules" should fit into the cyclodextrin cavity. The cavity sizes as well as possible chemical modifications determine the affinity of cyclodextrins to the various molecules.

The kinetics of cyclodextrin inclusion complexation has been usually analyzed in terms of a one-step reaction or a consecutive two-step reaction involving intracomplex structural transformation as a second step57. Cyclodextrins is to enhance aqueous solubility of drugs through inclusion complexation58. It was found that cyclodextrins increased the paclitaxel solubility by 950 fold59. Complex formation of rofecoxib60, celecoxib61, clofibrate62, melarsoprol63, taxol64, cyclosporin A65 etc. with cyclodextrins improves the solubility of particular drugs.

Factors affecting complexation66:

1. Steric effects

2. Electronic effects

a. Effect of proximity of charge to CD cavity

b. Effect of charge density

c. Effect of charge state of CD and drug

3. Temperature, additives and cosolvent effects

E. Solubilization by surfactants:

Surfactants are molecules with distinct polar and nonpolar regions. Most surfactants consist of a hydrocarbon segment connected to a polar group. The polar group can be anionic, cationic, zwitterionic or nonionic67. When small apolar molecules are added they can accumulate in the hydrophobic core of the micelles. This process of solubilization is very important in industrial and biological processes. The presence of surfactants may lower the surface tension and increase the solubility of the drug within an organic solvent15.

Microemulsion

The term microemulsion was first used by Jack H. Shulman in 1959. A microemulsion is a four-component 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. It is termed as microemulsion because of the internal or dispersed phase is < 0.1 μ droplet diameter. The formation of microemulsion is spontaneous and does not involve the input of external energy as in case of coarse emulsions. The surfactant and the cosurfactant alternate each other and form a mixed film at the interface, which contributes to the stability of the microemulsions68. 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 production15.

Advantages of microemulsion over coarse emulsion include its ease of preparation due to spontaneous formation, thermodynamic stability, transparent and elegant appearance, increased drug loading, enhanced penetration through the biological membranes, increased bioavailability69, 70, and less inter- and intra-individual variability in drug pharmacokinetics71.

II. Chemical Modifications:-

For organic solutes that are ionizable, changing the pH of the system may be simplest and most effective means of increasing aqueous solubility. Under the proper conditions, the solubility of an ionizable drug can increase exponentially by adjusting the pH of the solution. A drug that can be efficiently solubilized by pH control should be either weak acid with a low pKa or a weak base with a high pKa. Similar to the lack of effect of heat on the solubility of non-polar substances, there is little effect of pH on nonionizable substances. Nonionizable, hydrophobic substances can have improved solubility by changing the dielectric constant (a ratio of the capacitance of one material to a reference standard)72 of the solvent by the use of co-solvents rather than the pH of the solvent.

The use of salt forms is a well known technique to enhanced dissolution profiles73. Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs74.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).

Other techniques:-

1. Co-crystallisation:

The new approach available for the enhancement of drug solubility is through the application of the co-crystals, it is also referred as molecular complexes. If the solvent is an integral part of the network structure and forms at least two component crystal, 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)11. 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 forces75.

Co-crystals are more stable, particularly as the co-crystallizing agents are solids at room temperature. Only three of the co-crystallizing agents are classified as generally recognised as safe (GRAS) it includes saccharin, nicotinamide and acetic acid limiting the pharmaceutical applications11. Co-crystallisation between two active pharmaceutical ingredients has also been reported. This may require the use of subtherapeutic amounts of drug substances such as aspirin or acetaminophen76. At least 20 have been reported to date, including caffeine and glutaric acid polymorphic co-crystals77. Co-crystals can be prepared by evaporation of a heteromeric solution or by grinding the components together. Another technique for the preparation of co-crystals includes sublimation, growth from the melt, and slurry preparation78. The formation of molecular complexes and co-crystals is becoming increasingly important as an alternative to salt formation, particularly for neutral compounds or those having weakly ionizable groups.

2. Cosolvency:

The solubilisation of drugs in co-solvents is an another technique for improving the solubility of poorly soluble drug79. It is well-known that the addition of an organic cosolvent to water can dramatically change the solubility of drugs80.

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. Solvent used to increase solubility known as cosolvent. Cosolvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute. It is also commonly referred to as solvent blending81.

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. A different perspective is that by simply making the polar water environment more non-polar like the solute, cosolvents facilitate solubilization82. Solubility enhancement as high as 500-fold is achieved using 20% 2-pyrrolidone83.

3. Hydrotrophy:

Hydrotrophy designate the increase in solubility in water due to the presence of large amount of additives. The mechanism by which it improves solubility is more closely related to complexation involving a weak interaction between the hydrotrophic agents (sodium benzoate, sodium acetate, sodium alginate, and urea) and the solute84.

Example: Solubilisation of Theophylline with sodium acetate and sodium alginate

4. 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, nimodipine86. The aqueous solubility of the antimalarial agent halofantrine is increased by the addition of caffeine and nicotinamide87.

5. Nanotechnology approaches:

Nanotechnology will be 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 less88. 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 dissolution89 and the next step taken was Nanonisation90.

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.

Nanocrystallization is thought to be a universal method that can be applied to any drug91.

There are two distinct methods used for producing nanocrystals; ’bottom-up’ and ’top-down’ development92. 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.

a) Milling:

Nanoscale particles can be produced by wet-milling process93. In ball mills, particle size reduction is achieved by using both impact and attrition forces. The most common models are a tumbling ball mill and a stirred media mill. One problem of this method is the degradation of mill surfaces and subsequent suspension contamination.

b) High pressure homogenization:

In high pressure homogenization, an aqueous dispersion of the crystalline drug particles is passed with high pressure through a narrow homogenization gap with a very high velocity94. Homogenisation can be performed in water (DissoCubes) or alternatively in non-aqueous media or water-reduced media (Nanopure)90. The particles are disintegrated by cavitation and shear forces. The static pressure exerted on the liquid causes the liquid to boil forming gas bubbles. When exiting from the gap, gas bubbles collapse under normal air pressure. This produces shock waves which make the crystals collide, leading to particle disintegration. A heat exchanger should be used when operating on temperature sensitive materials because high pressure homogenization causes increase in the sample temperature95. The particle size obtained during the homogenization process depends primarily on the nature of the drug, the pressure applied and the number of homogenization cycles.

c) Precipitation:

In the precipitation method a dilute solution is first produced by dissolving the substance in a solvent where its dissolution is good96.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.

d) Cryo-vacuum method:

In the cryo-vacuum method the active ingredient to be nanonized is first dissolved in water to attain a quasi-saturated solution97. The method is based on sudden cooling of a solvent by immersing the solution in liquid nitrogen (-196 ºC). 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. 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 ºC 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. Immediately the drug substance suspension is converted into a true molecular solution. 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 nanoparticles98.

Nanotechnology approaches to improve the solubility of hydrophobic drugs99

Company

Nanoparticulate Technologies

Description

Elan

NanoCrystal

 

NanoCrystal drug particles (<1,000 nm) produced by wet-milling and stabilised against agglomeration through surface adsorption of stabilisers; applied to NMEs eg aprepitant/reformulation of existing drugs eg. sirolimus

Eurand

 

Biorise

Nanocrystals/amorphous drug produced by physical breakdown of the crystal lattice and stabilised with biocompatible carriers (swellable microparticles or cyclodextrins)

SkyePharma

 

IDD

Insoluble Drug Delivery: micro-nm particulate/droplet water-insoluble drug core stabilised by phospholipids; formulations are produced by high shear, cavitation or impaction

BioSante

 

CAP

Calcium Phosphate-based nanoparticles: for improved oral bioavailability of hormones/proteins such as insulin; also as vaccine adjuvant

American Bioscience

 

NAB

Nanoparticle Albumin-Bound technology: injectable suspension of biocompatible protein with drug improves solubility/removes need for toxic solvents; eg paclitaxel-albumin nanoparticles Nanoparticle Albumin-Bound technology: injectable suspension of biocompatible protein with drug improves solubility/removes need for

toxic solvents; eg paclitaxel-albumin nanoparticles

Baxter

 

Nanoedge

Nanoedge technology: drug particle size reduction to nanorange by platforms including direct homogenisation, microprecipitation, lipid emulsions and other dispersed-phase technology

Company

Nanostructuring Technologies

Description

pSivida

 

BioSilicon

Drug particles are structured within the nano-width pores of biocompatible BioSilicon microparticles, membranes or fibres; gives controlled release/improves solubility of hydrophobic drugs

iMEDD

 

NanoGate

Silicon membrane with nano-width pores (10-100 nm) used as part of an implantable system for drug delivery and biofiltration

PharmaSol

 

NLC8

Nanostructured Lipid Carriers: nanostructured lipid particle dispersions with solid contents produced by high-pressure homogenisation; lipid-drug conjugate nanoparticles provide high-loading capacity for hydrophilic drugs for oral delivery

Conclusion:

A drug administered in solution form immediately available for absorption and efficiently absorbed than the same amount of drug administered in a tablet or capsule form. 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. 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. It is now possible that to increase the solubility of poorly soluble drugs with the help of various techniques as mentioned above.

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About Authors: 

Mr. Kevin C. Garala

Kevin_C_Garala

M.Pharm(Pharmaceutics, IInd Year)

Mr. Anil J. Shinde

Mr. Anil J. Shinde

M.Pharm Lecturer in Pharmaceutics

Mr. Namdeo R. Jadhav

Mr. Namdeo R. Jadhav

M.PharmAsst. Professor in Pharmaceutics

Dr.Harinath N. More

Dr.Harinath N. More

M.Pharm,Ph.D, Professor & Principal

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