Strategies for improving hydrophobic drugs solubility and bioavailability

Solubility

Solubility is defined as the concentration of the solute in a saturated solution at a certain temperature .The solubility of a drug can be expressed as parts, percentage, molarity, molality, volume fraction, and mole fraction. Solubility of drug means the maximum concentration of the drug solute dissolved in the solvent under specific condition of temperature, pH and pressure that relates more closely to the bioavailability rate.^[9]

Official pharmacopoeia classify the solubility with the solvent used for quantification and have defined the criteria as given in below table.^[10]

Mechansm of solubilization^[11]

The mechanism of solubilisation involves the breaking of weak wander wall forces of molecules such as intermolecular bonds in the solute the separation of the molecules of the solvent which provide space in the solvent for solute, interaction between the solvent and the solute molecule or ion.

Causes for poor oral absorption

Possible Causes for Poor Oral Absorption of Any drug is said to be when:

Aqueous solubility <100μg/ml

High crystal energy (melting point >2000 C)

Poor dissolution: Intrinsic dissolution rate <0.1 mg/cm2/min

High molecular weight: (>500), Self-association and aggregation.^[12]

Factors affecting solubility

Molecular size:^[20]

Larger molecule shows less solubility because they are more difficult to surround with solvent molecules in order to solvate the substance. In case of organic compounds as the carbon branching increases the solubility gets increased since more branching will reduce the size of the molecule and make it easier to solvate the molecules with solvent.

Need of solubility enhancement:^[22]

About 40-50% of new drug applications of new chemical entities are rejected because of poor solubility and thus poor biopharmaceutical properties and pharmacological response such as membrane penetration, gastric fluid absorption and poor oral bioavailability.

Different approaches used to improve api solubility and thus bioavailability^[23], ^[24], ^[25]

API having good solubility requires oral formulations as well as prerequisite for parenteral administration forms, as injectables or subcutaneous injection, hence the API should be in solubilized form. Different approaches to solubility enhancement are available which are as.

Co-solvency

The co-solvency is the process in which solubility of poorly soluble drugs in water can be increased by mixing it with some water miscible solvent which is known as co-solvent. Cosolvent acts by reducing the interfacial tension between the aqueous solution and hydrophobic solute of the system. Hydrophilic hydrogen-bonding groups confirms water miscibility, while their hydrophobic hydrocarbon regions interfere with waters hydrogen bonding network, reducing the overall intermolecular attraction of water.^[26]

Complexation

Stacking and inclusion complex: Association between two or more molecules to form a non-bonded entity with a well-defined stoichiometry is called as Complexation, which involves relatively weak forces such as London forces, hydrogen bonding and hydrophobic interactions are involved. There are two types such as Stacking complexes, introducing non-polar part of drug and complexing agent which shows exclusion of the non-polar area from contact with water, reducing total energy of the system. This complex can be homogeneous or mixed, but results in clear solution. Second is Inclusion complexes, by inserting the nonpolar molecule or the nonpolar region of one molecule into the cavity of another molecule or group of molecules. Cyclodextrins (CD) are a group of cyclic oligosaccharides contains three major cyclodextrins α, ß and γ-CD are composed of six, seven, and eight D-(+) - glucopyranose units. Cyclodextrins have a hydrophilic exterior and ahydrophobic internal cavity which form complex with drug and improve the solubility and bioavailability of poorly soluble drug. R- cyclodextrin derivative with increased water solubility (e.g. hydroxypropyl-R-cyclodextrin HP-R-CD) are most commonly used in pharmaceutical formulation. ^[29], ^[30], ^[31]

Particle size reduction

The solubility is directly proportional to the drug particle size as a particle becomes smaller, the surface area increases and thus larger surface will available for direct contact and interaction with solvent.^[32]

High-pressure homogenization

In this method water or alternatively in nonaqueous media or water-reduced media dispersion of the crystalline drug particles is passed under high pressure through a narrow homogenization gap with a very high velocity. The particles are disintegrated by stepwise in which, Boiling of a liquid due to static pressure exerted on the liquid results in formation of gas bubbles, gas bubbles collapse under normal air pressure which produces shock waves and crystals undergo collision, lastly disintegration of particle. ^[34]

Examples: Drugs such as Cefixime Trihydrate, Albendazole, Aphidicolin, Azithromycin, Fenofibrate and Valsartan solubility were improved by High Pressure Homogenization method and formulated in nanosuspension. ^[32], ^[35], ^[36], ^[37], ^[38]

Cryogenic method

In this method nanostructured amorphous drug particles are created with high degree of porosity at very low- temperature. The Type of injection device (capillary, rotary, pneumatic, and ultrasonic nozzle), location of nozzle (above or under the liquid level), and the composition of cryogenic liquid (hydrofluoroalkanes, N2, Ar, O2, and organic solvents) describes the Cryogenic inventions. After cryogenic processing, the drugs are powdered by various drying processes like spray freeze drying, atmospheric freeze drying.^[39]

Spray Freezing onto Cryogenic Fluids. Here drug and the carrier (mannitol, maltose, lactose, inositol) are dissolved in water and atomized above the surface of a boiling agitated fluorocarbon refrigerant. Sonication probe can be placed in the stirred refrigerant to enhance the dispersion of the aqueous solution.^[40]

Spray Freezing into Cryogenic Liquids (SFL). This technology forms amorphous nanostructured aggregates of drug powder having good surface area and wettability. It incorporates direct liquid-liquid encroach between the automatized feed solution and cryogenic liquid to provide intense atomization into microdroplets and significantly faster freezing rates.^[41]

Spray Freezing into Vapor over Liquid (SFV/L). Cryogenic fluid vapors freezes the drug solution with subsequent removal of frozen solvent and produces fine drug particles with high wettability. The drug becomes supersaturated as the solvent freezes and fine drug particles may nucleate and grow.^[42]

Ultra-Rapid Freezing (URF). A novel cryogenic technology that creates nanostructured drug particles with large surface area and adequate surface morphology by using solid cryogenic substances. Utilizing drugs solution to the solid surface of cryogenic substrate results into rapid freezing and subsequent lyophilization which forms micronized drug powder with enhanced solubility.^[43]

Lyophilisation monophase solution technique is also suitable alternative procedure that could overcome demerits of the conventional freeze-drying. In this technique, TBA, which is miscible with water in any proportion, was used as an organic cosolvent to solubilize the hydrophobic drug while the hydrophilic carrier was dissolved in water then the mixed isotropic solution was lyophilized. TBA possesses a high vapor pressure (41.25 mm Hg at 25^OC), a high melting point (24^OC) and has a low toxicity. All these factors contribute TBA as an ideal freeze-drying medium that could be removed rapidly and completely by freeze-drying. Lyophilization monophase solution technique was used to enhance the dissolution rate of the poorly soluble drugs; budesonide, salmeterol, ketoprofen and nitrendipine by complexation with βCD and HPβCD.^[44]

Liquisolid compacts

The liquisolid technique is a novel concept where a liquid converted into free flowing, readily compressible and apparently dry powder by means of simple physical blending with selected carrier and coating material. The layer of a liquid will formed on the particle surface. This layer redially adsorbed by the fine coating particles. Thus, the liquid material converted to an apparently dry, free flowing, and compressible powder.^[45]

pH adjustment

May potentially dissolve in water by applying a pH change approach can be applied for Poor water soluble drug, for this according to nature of a drug and the buffer capacity of the selected pH are important to consider. The excipients that increase environmental pH of drug within the dosage form which should have higher than pKa of weekly acidic drugs increase the solubility of that drug, whereas the excipients which are alkaline in nature (alkalyzing agents) may increase the solubility of weekly basic drugs.^[49]

Examples: Flufenamic acid, Mefenamic acid, Niflumic acid, Diclofenac sodium and Meclofenamic sodium.^[50]

Precipitation

In this method dilute solution is prepared by dissolving the drug substance in a solvent and this solution of drug is then poured with the help of injected into the water with stirring so that the substance will precipitate as nanocrystals. The obtained nanocrystals can be removed from the solution by membrane filtration and then dried in air.^[51]

Example: JNJ-25894934 New molecule entity,^[52] Pioglitazone.^[53] ultrafine Rifampicin particles,^[54] Fenofibrate-loaded nanoparticles by precipitation method,^[55], Curcumin using HPMC K 15M by Solvent Change Precipitation Method ^[56] etc.

Manipulation of solid state/polymeric alteration

Drug that exhibits different crystalline forms and may have different properties is known as Polymorphs. They may have different physical and chemical stability, shelf-life, melting point, vapor pressure, intrinsic solubility, dissolution rate, morphology, density and biological activities as well as bioavailability. Therefore metastable form is the most stable crystalline polymorphs. Polymorphism showing drugs have different physicochemical properties such as melting point, density, stability and drug solubility because such as properties depend on the escaping tendency of the molecules from a particular crystalline structure. The metastable forms have many advantages of higher solubility but have poor stability. Hence stabilizers added to stabilize and to prevent to crystal growth in the formulation. Eg: Withdrawal of ritonavir (Norvir®) capsules containing its polymorph from the market because a less soluble and less bioavailable.^[57]

Hydrotrophy

In this method, large amount of second solute are added in excess which results in an increase in the aqueous solubility of another solute. Solute may be alkali metal salts of various organic acids, ionic organic salts. Sometimes addition of additives or salts that increase solubility in given solvent are said to “salt in” the solute and those salts that decrease solubility in given solvent are said to “salt out” the solute. Various water soluble salts with large anions or cations are added in solvents result in “salting in” of non-electrolytes called “hydrotropic salts” a phenomenon known as “hydrotropism”. Hydrotropic solutions involve a weak interaction between the hydrotropic agent and solute which are wander wall types in nature. Hydrotrophy increases solubility of API in water due to the presence of large amount of additives called hydrotropic agents like sodium benzoate, sodium acetate, sodium alginate, urea and the poorly soluble drugs.^[58]

Solid dispersion

In solid dispersion method one or more active ingredients/API/Drugs (hydrophobic) are incorporated into in an inert carrier or matrix which are hydrophilic in nature are added at solid state and can be prepared in various ratios by various methods such as the melting (fusion), solvent, or melting-solvent method. Solid dispersion refers to a group of solid products consisting of atleast two different components such as hydrophilic matrix in crystalline or amorphous nature and a hydrophobic drug can be molecularly dispersed in amorphous particles or in crystalline particles. Commonly low cost green-eco-friendly solvents used for solid dispersions include water, methanol, ethanol, chloroform, DMSO, acetic acid etc. ^[60], ^[61] Solid dispersion again classified into six categories; solid solution, eutectic mixtures, glass suspensions, amorphous precipitates, complex and above combinations.

Microemulsion and self-emulsifying system

A microemulsion is an optically clear pre-concentrate containing a mixture of oil, hydrophilic surfactant and hydrophilic solvent, which dissolves a poorly water-soluble drug. The formulation spontaneously self emulsifies upon contact with water to form a very clear emulsion having small and uniform oil droplets containing the solubilized poorly soluble drug. Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a co-surfactant with a droplet size usually in the range of 20-200 nm. SMEDDS is an anhydrous system of microemulsions. It is composed of oil, surfactant and cosurfactant and has the ability to form o/w microemulsion when dispersed in aqueous phase under gentle agitation. The mixture of oil, surfactant, co-surfactant, one or more hydrophilic solvents and cosolvent forms a transparent isotropic solution that is known as the self-emulsifying drug delivery system (SEDDS). Self-emulsifying drug delivery systems (SEDDS) and self micro-emulsifying drug delivery systems (SMEDDS) are isotropic solutions of oil and surfactant which form oil-in-water microemulsions on mild agitation in the presence of water. These novel colloidal formulations on oral administration behave like oil-in-water microemulsions. Compared with ready-to-use microemulsions, the SEDDS and SMEDDS have been shown to improve physical stability profile in long-term storage. ^[62] Various paper had reported the Microemulsion and self-emulsifying study on Drugs like resveratrol, ^[63] Fexofenadine Hydrochloride. ^[64] Olmesartan Medoxomil, ^[65] Loratadine etc. ^[66]

Solubilization using surfactants

Surfactants are molecules contain both polar and non-polar regions. Most of surfactants are of hydrocarbon nature containing hydrocarbon segment connected to a polar group. The polar group can be anionic, cationic, zwitterionic or nonionic which accumulate small polar molecules into hydrophobic core of the micelles when they are mixed together and solublization of drug achieve. It is the natural process in pharmaceutical industry and widely used. The surfactants form micelle when the surfactants are added more than their critical micelle concentration (CMC, which is in the range of 0.05–0.10% for most surfactants); formed micelle will entrap the drugs within the micelles. Solubilizing materials used are includes superdisintegrants such as crospovidone, crosscarmellose sodium and sodium starch glycolate used as solubilizing agents in many formulations, which increase the solubility and dissolution rate of poorly water-soluble drugs. Example: Repaglinide solubilized by using surfactants such as SDS,CTAB, Tween-80, SDS+Tween- 80,CTAB+Tween-80 ^[67]

Micronization

Micronization is another conventional technique for the particle size reduction and improves solubility by increased surface area by decreasing particle size. For micronization of drugs various mills can be used such as jet mill, rotor stator colloid mills and so forth butmicronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug.^[68] Domperidone was dissolved in appropriate solvent (acetone and methanol 1:1 v/v), and the stabilizing agents such as Soluplus® or PEG6000 was dissolved in water (as nonsolvent). The nonsolvent was poured rapidly into the drug solution under stirring by a homogenizer, and the resultant was freeze dried.^[69]

Nanocrystallization

The drugs particle size reduces to 1-1000 nanometers by two distinct methods used for producing nanocrystals; ‘bottom-up’ and ‘top-down’ development. The top- down methods start milling down from macroscopic level, e.g. from a powder that is micron sized. In bottom-up methods nanoscale materials are chemically composed from atomic and molecular components.^[70]

Examples: Griseofulvin,^[71] Sirolimus, Aprepitant, Fenofibrate, Megestrol acetate, Nabilone, Ketoprofen, Cyclosporine, Spironolacton, Itraconazole. Etc^[72]

Nanosuspension

This technology is applied for drugs which are insoluble in both water and oils. Hence nano sized drug particles produced by miles and are stabilized by surfactants in a system for either oral and topical use or parenteral and pulmonary administration. Nanosuspension particles have particle size distribution near about one micron with an average particle size ranging between 200 and 600 nm.^[73]

Neutralization

Drug is added in alkaline solution like sodium hydroxide, ammonium hydroxide. To dissolve the joined drug solution of β-Cyclodextrin is then added. After few seconds the clear solution obtained under agitation is neutralized using HCl solution until reaching the equivalence point. At this moment, the appearance of a white precipitate could be appreciated, corresponding to the formation of the inclusion compound. The precipitate is then filtered and dried.^[74]

Example: Rebamipide neutralization with microfluidization for rebamipide nanosuspensions formulation to improve solubility.^[75]

Salt formation

This method is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. Dissolution rates of salt forms of several weakly acidic compounds under gastrointestinal (GI) pH conditions were much higher than those of their respective free acid forms. Alkali metal salts of acidic drugs like penicillins and strong acid salts of basic drugs like atropine are more water soluble than the parent drug.^[76]

Examples: Benexate in Benexate saccharinate monohydrate and Benexate cyclamate salt, Itraconazole in Itraconazole dihydrochloride salt, Diclofenac is available in five novel salts formation with the bases 2-amino-2- methyl-1, 3-propanediol, 2-amino-2-methylpropanol, tert-butylamine, benzylamine and deanol, Aceclofenac in Aceclofenac triethanolamine, Diphenhydramine in Diphenhydramine hydrochloride, Ketoconazole in Ketoconazole Dihydrochloride, Agomelatine in Agomelatine Sulfonate etc. ^[77], ^[78], ^[79]

Solvent deposition

This technique utilizes the solvent like methylene chloride to dissolve the drug and produce a clear solution. Then by stirring the carrier is dispersed in the solution and the solvent is removed by evaporation under temperature and pressure. The resultant mass is then dried, pulverized, and passed through a sieve. The increase in the dissolution rate by the reduced particle size of the drug deposited on the carrier and enhanced wettability of the particles brought about by the carrier.^[80]

Sonocrystallization

Melt sonocrystallization is newer particle engineering technique. In this method by applying ultrasound energy in range of 20 to 100 kHz crystallization process is achieved. Ultra sound energy was tradionally introduced in pharmaceutical industry to increase the solubility of sparingly soluble drug. Ultrasound influences the initial nucleation stage of crystallisation. Cavitation is an important phenomenon of ultrasonication. In sonocrysatllization the energy of ultrasound causes repeated compression and expansion. After several cycles the bubble forms, grows and collapses. Due to bubble collapses, the energy is produced. Applying ultrasound to crystallization results in:

Nucleation at the lowest level of super saturation where the tendency of the compound to re-dissolve in the solution is overcome by crystallization.

Narrowing of the metastable zone width.

Narrow particle size distribution.

Low level of cooling necessary to achieve crystallization.

Highly repeatable and predictable crystallization.

Polymorph control.^[85]

Examples: Rosiglitazone, ^[86] flurbiprofen ^[87]

Spherical agglomeration

It is a particle engineering technique, a process of crystallization, agglomeration and Spheronization, which convert fine crystal in spherical shape particle. This technique is important for improving the flow property, wettability and dissolution rate of poorly soluble drug. For production of spherical crystal , parameter like amount and mode of addition of spherical liquid, temperature and agitation speed must be optimize in this technique.^[88] Examples: Simvastatin.^[89]

Spray drying

Drug is dissolved in suitable solvent and the adequate amount of carrier material like β-cyclodextrin, Aerosol 200 is dissolved in water. Solutions are then mixed by the process of sonication or other suitable method to produce a clear solution, which is then spray dried. It gives the dried powder which is more soluble as well as more stable.^[90]

Nowadays spray drying with solid dispersion technique widely used for drug solublization such as Atorvastatin Calcium, Griseofulvin.^[91]