Assignment on

Techniques for enhancement of solubility of drug molecules

Prepared By: Sajan Maharjan M.Pharm, 1st Semester Kathmandu University Dhulikhel, Kavre, Nepal.

Submitted To: Professor Panna Thapa MPharm PhD Dean, KU School of Science Kathmandu University Dhulikhel, Kavre, Nepal.

Introduction
According to IUPAC, solubility may be defined as The analytical composition of a saturated solution, expressed in terms of the proportion of a designated solute in a designated solvent, is the solubility of that solute. The solubility may be expressed as a concentration, molality, mole fraction, mole ratio, etc. Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. The solubility of a substance fundamentally depends on the solvent used as well as on temperature and pressure. The extent of solubility of a substance in a specific solvent is measured as the saturation concentration where adding more solute does not increase its concentration in the solution. The extent of solubility ranges widely, from infinitely soluble (fully miscible) such as ethanol in water, to poorly soluble, such as silver chloride in water. Extensive use of solubility from different perspective has led to solubility being expressed in various manners. It is commonly expressed as a concentration, either by mass (g of solute per kg of solvent, g per dL (100 mL) of solvent), molarity, molality, mole fraction, or other similar descriptions of concentration. The maximum equilibrium amount of solute that can dissolve per amount of solvent is the solubility of that solute in that solvent under the specified conditions. Based on solubility, all drugs can be divided into four classes: class Ihigh soluble and high permeable, class IIlow soluble and high permeable, class IIIlow soluble and high permeable and class IVlow soluble and low permeable.

Importance of Solubility Solubility plays a major role for oral dosage forms and parenteral formulations. Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as generic development.

More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. These poorly water soluble drugs having slow drug absorption leads to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. For orally administered drugs, solubility is the most important rate limiting parameter to achieve their desired concentration in systemic circulation for pharmacological response. So, Problem of solubility is a major challenge for formulation scientist. The improvement of drug solubility thereby its oral bio-availability remains one of the most challenging aspects of drug development process especially for oral-drug delivery system. There are numerous approaches available and reported in literature to enhance the solubility of poorly water-soluble drugs. The techniques are chosen on the basis of certain aspects such as properties of drug under consideration, nature of excipients to be selected, and nature of intended dosage form. Techniques for Solubility enhancement Solubility enhancement techniques can be categorized as follows:

Solubility enhancement techniques

Physical modifications

Chemical modifications

Miscellaneous methods

Particle size reduction Modification of crystal habit Solid dispersions Cryogenic techniques

pH adjustment Complexation Salt formation

Supercritical fluid process Cosolvency Hydrotrophy Miceller solubilization

Physical modifications 1) Particle size reduction: The solubility of drug is often intrinsically related to drug particle size; as a particle becomes smaller, the surface area to volume ratio increases. The larger surface area allows greater interaction with the solvent which causes an increase in solubility. Nowadays Particle size reduction can be achieved by micronisation and nanosuspension. Each technique utilizes different equipments for reduction of the particle size. In micronization the solubility of drug is often intrinsically related to drug particle size. By reducing the particle size, the increased surface area improves the dissolution properties of the drug. 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. These processes were applied to griseofulvin, progesterone, spironolactone diosmin, and fenofibrate. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy. Nanosuspension is another technique which is sub-micron colloidal dispersion of pure particles of drug, which are stabilized by surfactants. Nanosuspensions are produced by homogenization and wet milling process. The nanosuspension approach has been employed for drugs including tarazepide, atovaquone, amphotericin B, paclitaxel and bupravaquon. The advantages offered by nanosuspension is increased dissolution rate which is due to larger surface area exposed. Advantages: Liquid forms can be rapidly developed for early stage testing (pre-clinical) that can be converted into solids for later clinical development. Typically, low excipient to drug ratios is required. Formulations are generally well tolerated provided that strong surfactants are not required for stabilisation. Generally, crystal forms are chemically and physically more stable than amorphous particles. Disadvantages: Due to the high surface charge on discrete small particles, there is a strong tendency for particle agglomeration. Developing a solid dosage form with a high pay load without encouraging agglomeration may be technically challenging. Technically, development of sterile intravenous formulations is even more challenging.

2) Modification of crystal habit (Crystal engineering): Crystal engineering techniques are developed for the controlled crystallization of drugs to produce high purity powders with well-defined particle size distribution, crystal habit, crystal form

(crystalline or amorphous), surface nature, and surface energy. By manipulating the crystallization conditions (use of different solvents or change in the stirring or adding other components to crystallizing drug solution), it is possible to prepare crystals with different packing arrangement; such crystals are called polymorphs. Polymorphs for the same drug may differ in their physicochemical properties such as solubility, dissolution rate, melting point, and stability. Most drugs exhibit structural polymorphism and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf-life under a variety of real-world storage conditions. A classic example of the importance of polymorphism on bioavailability is that of chloramphenicol palmitate suspensions. It was shown that the stable polymorph of chloramphenicol palmitate produced low serum levels, whereas the metastable polymorph yielded much higher serum levels when the same dose was administered. Crystal engineering approach also involves the preparation of hydrates and solvates for enhancing the dissolution rate. During the crystallization process, it is possible to trap molecules of the solvent within the lattice. If the solvent used is water, the resultant crystal is a hydrate; if any other solvent is used, it is referred to as solvate.The dissolution rate and solubility of a drug can differ significantly for different solvates. For example, glibenclamide has been isolated as pentanol and toluene solvates, and these solvates exhibited higher solubility and dissolution rate than two nonsolvated polymorphs. It is possible for the hydrates to have either a faster or slower dissolution rate than the anhydrous form. The most usual situation is for the anhydrous form to have a faster dissolution rate than the hydrate. For example, the dissolution rate of theophylline anhydrate was faster than its hydrate form. Traditional crystallization methods include sublimation, crystallization from solutions, evaporation, thermal treatment, desolvation, or grinding/milling. These are being replaced with novel methods of crystal engineering such as Super Critical Fluid(SCF) technologies to produce pharmaceutical solids with desired dissolution rate and stability. Melt sonocrystallization is yet another emerging technology that uses ultrasonic energy to produce porous fast dissolving particles for hydrophobic drug molecules. Based on these exciting reports, it appears that crystal engineering techniques need to be exploited more for enhancing the dissolution rate of poorly soluble drugs.

3) Solid dispersions: Solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone(PVP), polyethylene glycols (PEGs), Plasdone-S630. Surfactants like Tween-80, docusate sodium, sodium lauryl sulphate (SLS),etc. The solubility of hydrophobic drugs like celecoxib, halofantrine, and ritonavir can be improved by

solid dispersion using suitable hydrophilic carriers like celecoxib with povidone (PVP) and ritonavir with gelucire. Solid dispersions are prepared by using several methods: i. Hot-Melt Method (Fusion Method): In this method, the physical mixture of a drug and a water-soluble carrier are heated directly until the two melts. The melted mixture is then cooled and solidified rapidly in an ice bath with rigorous stirring. The final solid mass is then crushed, pulverized, and sieved, which can be compressed into tablets with the help of tableting agents. The main advantages of this direct melting method is its simplicity and economy. An important requirement for the formation of solid dispersion by the hotmelt method is the miscibility of the drug and the carrier in the molten form and also the thermostability of both the drug and the carrier. ii. Solvent Evaporation Method: In this method both the drug and the carrier are dissolved in a common solvent and then the solvent is evaporated under vacuum to produce a solid solution. The main advantage of the solvent evaporation method is that thermal decomposition of drugs or carriers can be prevented because of the low temperature required for the evaporation of organic solvents. The disadvantages associated with this method are the higher cost of preparation, the difficulty in completely removing the organic solvent, the possible adverse effect of the supposedly negligible amount of the solvent on the chemical stability of the drug, the selection of a common volatile solvent, and the difficulty in reproducing crystal forms iii. Hot-Melt Extrusion: Hot-melt extrusion is essentially the same as the fusion method except that intense mixing of the components is induced by the extruder. HME technique is utilized in the formulation development of poorly water-soluble because of the enhanced dissolution properties, absorption and therapeutic efficacy. High-shear forces resulting in high local temperature in the extruder is a problem for heat sensitive materials. However, compared to the traditional fusion method, this technique offers the possibility of continuous production, which makes it suitable for large-scale production. 4) Cryogenic Techniques: Cryogenic techniques have been developed to enhance the dissolution rate of drugs by creating nanostructured amorphous drug particles with high degree of porosity at very low-temperature conditions. Cryogenic inventions can be defined by 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). After cryogenic processing, dry powder can be obtained by various drying processes like spray freeze drying, atmospheric freeze drying, vacuum freeze drying, and lyophilisation Some of the important techniques are: a) Spray Freezing onto Cryogenic Fluids: At first, the drug and the carrier (mannitol, maltose, lactose, inositol, or dextran) 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 [28]. b) Spray Freezing into Cryogenic Liquids (SFL): In this technique, it incorporates direct liquid-liquid impingement between the automatized feed solution and cryogenic liquid to provide intense atomization into microdroplets and consequently significantly faster freezing rates. The frozen particles are then lyophilized (process of removal of solvent) to obtain dry and free- flowing micronized powders [29]. c) Spray Freezing into Vapor over Liquid (SFV/L): In this technique at first, Freezing of drug solutions in cryogenic fluid vapours and subsequent removal of frozen solvent produces fine drug particles with high wettability. During SFV/L the atomized droplets typically start to freeze in the vapor phase before they contact the cryogenic liquid. As the solvent freezes, the drug becomes supersaturated in the unfrozen regions of the atomized droplet, thus fine drug particles may nucleate and grow. [30]. d) Ultra-Rapid Freezing (URF): The most novel cryogenic technology is Ultra-rapid freezing. In this technology creates nano-structured drug particles with greatly enhanced surface area and desired surface morphology by using solid cryogenic substances. Application of drugs solution to the solid surface of cryogenic substrate leads to instantaneous freezing and subsequent lyophilization (for removal of solvent) forms micronized drug powder with improved solubility. Ultra rapid freezing prevents the phase separation and the crystallization of the pharmaceutical ingredients

Chemical modifications 1. pH adjustment: Poorly water soluble drugs with parts of the molecule that can be protonated (base) or deprotonated (acid) may potentially be dissolved in water by applying a pH change. pH adjustment principle be used for both oral and parenteral administration. Upon intravenous administration the poorly soluble drug may be precipitated because blood is a strong buffer with pH between 7.2 7.4. To assess the suitability of the approach, the buffer capacity and tolerability of the selected pH are important to consider. In the stomach the pH is around 1 to 2 and in the duodenum the pH is between 5-7.5, so upon oral administration the degree of solubility is also likely be influenced as the drug passes through the intestines. Ionizable compounds that are stable and soluble after pH adjustment are best suited. The compound types may be acids or bases or zwitterionic. It can also be applied to crystalline as well as lipophilic poorly soluble compounds. Solubilized excipients that increase environmental pH within a dosage form, such as a tablet or capsule, to a range higher than pKa of weakly-acidic drugs increases the solubility of that drug, those excipients which act as alkalizing agents may increase the solubility of weakly basic drugs.The solubility of the poorly soluble drug is increased compared to water alone, so if compounds can permeate through the epithelium orally, the fraction of orally

absorbed drug may be increased. pH adjustment is also frequently combined with co-solvents to further increase the solubility of the poorly soluble drug. Advantages: Simple to formulate and analyse. Simple to produce and fast track. Uses small quantities of compound. Disadvantages: Risk for precipitation upon dilution with aqueous media having a pH at which the compound is less soluble. Intravenously this may lead to emboli, orally it may cause variability. Tolerability and toxicity (local and systemic) related with the use of a non physiological pH and extreme pHs. As with all solubilized and dissolved systems, a dissolved drug in an aqueous environment is frequently less stable chemically compared to formulations crystalline solid. The selected pH may accelerate hydrolysis or catalyze other degradation mechanisms. 2. Complexation: Inclusion complex formation technique is used precisely to improve the aqueous solubility, dissolution rate, and bioavailability of poorly water soluble drugs among all the solubility enhancement techniques. Inclusion complexes are prepared by the insertion of the non-polar molecule or the non-polar region of one molecule (known as guest) into the cavity of another molecule or group of molecules (known as host). The most commonly used host molecules are cyclodextrins. Cyclodextrins (CD) are a group of structurally-related cyclic oligosaccharides that have a polar cavity and hydrophilic external surface. Derivatives of -cyclodextrin (e.g. hydroxypropyl--cyclodextrin HP--CD) are most commonly used in pharmaceutical formulation for increased water solubility. The surface of the cyclodextrin molecules makes them water soluble, but the hydrophobic cavity provides a microenvironment for appropriately sized non-polar molecules. Based on the structure and properties of drug molecule it can form 1 : 1 or 1 : 2 drug cyclodextrin complex as illustrated in Figure below:

3. Salt formation: Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. Most salts of organic compoundsare formed by the addition or removal of a proton to form an ionized drug molecule, which is then neutralized with a counter ion. Ephedrine Hydrochloride, for example, is prepared by addition of a proton to te basic secondary nitrogen atom on ephedrine, resulting in a protonated drug molecule, which is neutralized with a chloride anion. In general, organic salts are more water soluble than corresponding unionized molecule, and hence offer a simple means of increasing dissolution rates and possibly improving bioavailability. During synthesis, salts are usually formed in organic media to improve yield as well as purity. Some of tge problems commonly encountered in evaluating salt forms include poor crystallinity, various degree of solvation or hydration, hygroscopicity, instability due to an unfavourable pH in the crystalline microenvironment. Miscellaneous methods 1. Super Critical Fluid (SCF) Process: Supercritical fluids are fluids whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Tp), allowing it to assume the properties of both a liquid and a gas. At near-critical temperatures, SCFs, are highly compressible allowing moderate changes in pressure to greatly alter the density and mass transport characteristics of the fluid that largely determine its solvent power. Once the drug particles are solubilised within the SCF (usually carbon dioxide), they may be recrystallised at greatly reduced particle sizes. The low operating conditions (temperature and pressure) make SCFs attractive for pharmaceutical research. The flexibility and precision offered by SCF processes allows micronisation of drug particles within narrow ranges of particle size, often to submicron levels. Current SCF processes have demonstrated the ability to create nanoparticulate suspensions of particles 52,000 nm in diameter. Several methods of SCF processing have been developed such as Precipitation with compressed antisolvent process (PCA), Solution enhanced dispersion by SCF (SEDS), Supercritical antisolvent processes (SAS), Rapid expansion of supercritical solutions (RESS), Gas anti solvent recrystallization (GAS), Aerosol supercritical extraction system (ASES

2. Cosolvency: The solubility of poorly soluble drugs in water can be increased by mixing it with some water miscible solvent in which the drug is readily soluble.This phenomenon is known as cosolvency and the solvent used in combination are known

as cosolvent. Weak electrolytes and nonpolar molecules are poorly water soluble.This can be improved by altering polarity of the solvent. Cosolvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute. It is also commonly referred to as solvent blending. 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 inter molecular attraction of water. By disrupting water self-association, cosolvents reduce waters ability to squeeze out non-polar, hydrophobic compounds, thus increasing solubility. Most of the cosolvent mixture consist of water,alcohol,glycerine,propylene glycol etc. Advantages: Simple and rapid to formulate and produce.

Disadvantages: With all excipients, the toxicity and tolerability related with the level of solvent administered has to be considered. Uncontrolled precipitation occurs upon dilution with aqueous media. The precipitates may be amorphous or crystalline and can vary in size. As with all solubilized forms, the chemical stability of the insoluble drug is worse than in a crystalline state.

3. Hydrotrophy: Hydrotrophy is a solubilisation process, whereby addition of a large amount of second solute, the hydrotropic agent results in an increase in the aqueous solubility of first solute. Hydrotropic agents are ionic organic salts, consists of alkali metal salts of various organic acids. 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. The mechanism by which it improves solubility is more closely related to complexation involving a weak interaction between the hydrotrophic agents like sodium benzoate, sodium acetate, sodium alginate, urea, and the poorly soluble drugs. The hydrotropes are known to self-assemble in solution. The classification of hydrotropes on the basis of molecular structure is difficult, since a wide variety of compounds have been reported to exhibit hydrotropic behaviour. Specific examples may include ethanol, aromatic alcohols like resorcinol, pyrogallol, catechol, and naphthols and salicylates, alkaloids like caffeine and nicotine, ionic surfactants like diacids, SDS (sodium dodecyl sulphate), and dodecylated oxidibenzene. The aromatic hydrotropes with anionic head groups are mostly studied compounds. They

are large in number because of isomerism and their effective hydrotrope action may be due to the availability of interactive pi () orbital. Advantages of Hydrotropic Solubilization Technique: Hydrotropy is suggested to be superior to other solubilization method, such as miscibility, micellar solubilization, cosolvency and salting in, because the solvent character is independent of pH, has high selectivity and does not require emulsification. It only requires mixing the drug with the hydrotrope in water. It does not require chemical modification of hydrophobic drugs, use of organic solvents, or preparation of emulsion system.

4. Miceller solubilization: The use of surfactants to improve the dissolution performance of poorly soluble drug products is probably the basic, primary, and the oldest method. Surfactants reduce surface tension and improve the dissolution of lipophilic drugs in aqueous medium. They are also used to stabilise drug suspensions. When the concentration of surfactants exceeds their critical micelle concentration (CMC, which is in the range of 0.050.10% for most surfactants), micelle formation occurs which entrap the drugs within the micelles. This is known as micellization and generally results in enhanced solubility of poorly soluble drugs. Surfactant also improves wetting of solids and increases the rate of disintegration of solid into finer particles. Commonly used nonionic surfactants include polysorbates, polyoxyethylated castor oil, polyoxyethylated glycerides, lauroyl macroglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene glycols. Surfactants are also often used to stabilize microemulsions and suspensions into which drugs are dissolved. Examples of poorly soluble compounds that use Micellar solubilization are antidiabetic drugs, gliclazide, glyburide, glimepiride, glipizide, repaglinide, pioglitazone, and rosiglitazone.

Conclusion Solubility of the drug is the most important factor that controls the formulation of the drug as well as therapeutic efficacy of the drug, hence the most critical factor in the formulation development. Dissolution of drug is the rate determining step for oral absorption of the poorly water soluble drugs and solubility is also the basic requirement for the formulation and development of different dosage form of different drugs. The various techniques described above alone or in combination can be used to enhance the solubility of the drug. Solubility can be enhanced by many techniques and number of folds increase in solubility. Because of solubility problem of many drugs the bioavailability of them gets affected and

hence solubility enhancement becomes necessary. It is now possible to increase the solubility of poorly soluble drugs with the help of various techniques as mentioned above. References The theory and practice of industrial pharmacy by Leon Lachman, Herbert A. Lieberman and Joseph L. Kanic , 3rd edition. Article Review on Drug Solubility: Importance and Enhancement Techniques by Ketan T. Savjani, Anuradha K. Gajjar, and Jignasa K. Savjani. Review article on International Journal of Pharmaceutical Sciences Review and Research on the topic SOLUBILITY ENHANCEMENT TECHNIQUES by Varun Raj Vemula, Venkateshwarlu Lagishetty, Srikanth Lingala. Article on International Journal of Therapeutic Applications, Volume 6, 2012, on topic SOLUBILITY ENHANCEMENT OF POORLY HYDROPHILIC DRUGS BY USING DIFFERENT NEWER TECHNIQUES: A REVIEW by Varshney, H. M, Chatterjee, A.