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Various Approaches for Enhancing Solubility of Drug Molecules

Assignment no: 1 Drug Delivery system I M.Pharm, (2012-2014) Industrial Pharmacy First semester

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

Kathmandu University
Dhulikhel, Kavre.

Submitted by: Achyut Bikram Thapa

Table of Content
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Solution and solubility ............................................................................................. 3 Methods of expressing solubility ............................................................................. 3 Biopharmaceutics classification system of drugs .................................................... 5 Types of solution...................................................................................................... 5 General consideration for solubility determination of solids in liquids ................... 6 Determination of solubility of solids in liquid ......................................................... 7 Process of solubalization of drugs ........................................................................... 8 Rate of solution ........................................................................................................ 9 Factors affecting the solubility of solids in liquids ................................................ 10 Methods of enhancing the solubility ...................................................................... 13 Conclusion ............................................................................................................. 21 References .............................................................................................................. 22

List of Tables Table 1: Descriptive terms for solubility ............................................................................ 4 Table 2: Types of solution .................................................................................................. 5

List of Figures Figure 1: Process of solubalization of solute in solvent ..................................................... 8 Figure 2: Process of absorption of drug from various dosage forms. ................................. 9 Figure 3: Solubility enhancement approaches for poorly soluble drug. ........................... 14

Various Approaches for Enhancing Solubility of Drug Molecules

1. Solution and solubility A solution can be defined as a system in which molecules of a solute (such as a drug or protein) are dissolved in a solvent vehicle. When a solution contains a solute at the limit of its solubility at any given temperature and pressure, it is said to be saturated. If the solubility limit is exceeded, solid particles of solute may be present and the solution phase will be in equilibrium with the solid, although under certain circumstances supersaturated solutions may be prepared, where the drug exists in solution above its normal solubility limit [1].

The solubility of a substance in a solvent at a given temperature and pressure, is the amount of substance that has passed into solution when equilibrium is attained between the solution and excess, i.e. undissolved substance. The solution that is obtained under these conditions is termed as saturated solution. It is possible to obtain solutions that are supersaturated. However, they are unstable and scratching the side of the container, the presence of dust, or the addition of undissolved solute will provide nuclei that readily lead to precipitation of the excess solute [2].

2. Methods of expressing solubility When quantitative data are available, solubilities are expressed in many ways. The British Pharmacopoeia expresses solubilities as the number of parts by volume of solvent required to dissolve one part by weight of a solid or one part by volume of a liquid. Unless otherwise specified, these solubilities apply at room temperature [2].

When special quantitative solubility tests are given in the compendia, these solubilities can be used as a criterion for assessing the purity of the compound. Whenever the exact solubility of a pharmaceutically important compound is not know or designated, the following descriptive terms (U.S.P. XVIII and N.F. XIII) can be used [3]:

Table 1: Descriptive terms for solubility Descriptive term Very soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Practically insoluble or insoluble Parts of solvent for 1 part of solute Less than 1 From 1 to 10 From 10 to 30 From 30 to 100 From 100 to 1000 From 1000 to 10,000 More than 10,000

The WHO defines the term high solubility for expression of solubility factor. An API is considered highly soluble when the highest dose recommended by WHO (if the API appears on the WHO Model List of Essential Medicines) or highest dose strength available on the market as a oral solid dosage form (if the API does not appear on the WHO Model List of Essential Medicines) is soluble in 250 ml or less of aqueous media over the pH range of 1.26.8. The pH-solubility profile of the API should be determined at 37 1 C in aqueous media. A minimum of three replicate determinations of solubility at each pH condition is recommended. Initial recommendations in the BCS Guidance suggested that the solubility should be measured over a pH range of 1.27.5. But successive scientific discussions and publications suggest that a pH range of 1.26.8 is more appropriate [4]. The reason for the 250-ml cut-off criterion for the dose: solubility ratio is that in pharmacokinetic bioequivalence studies, the API formulation is to be ingested with a large glass of water (8 ounces corresponds to about 250 ml). If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 17.5), solubility problems are not expected to hinder the uptake of the API in the small intestine [5].

3. Biopharmaceutics classification system of drugs The Biopharmaceutics Classification System (BCS) is based on aqueous solubility and intestinal permeability of the drug substance. It classifies the API into one of four classes [4]: Class 1: high solubility, high permeability Class 2: low solubility, high permeability Class 3: high solubility, low permeability Class 4: low solubility, low permeability As per the data collected, the drugs under class II and IV are requiring special attention during formulation of oral solid dosage form, or in liquid dosage form. Only about 8% of newer drugs fall under class I [6].

4. Types of solution Solutions may be classified based on the physical state of the components. Since there are three states of matter, i.e. solid, liquid and gas, nine different types of solution with two components are possible [2]. Table 2: Types of solution solute Gas Liquid Solid Gas Liquid Solid Gas Liquid Solid Solvent Gas Gas Gas Liquid Liquid Liquid Solid Solid Solid

5. General consideration for solubility determination of solids in liquids It is necessary to know the solubilities when preparing and dispensing medicines. Information of solubility is also necessary for separation of substances in quantitative and qualitative analysis [7]. The details of the determination of the solubility are affected markedly by the physical and chemical characteristics of the solute and solvent and by the temperature at which the solubility is determined. Accordingly, it is not possible to describe a universally applicable method, but in general, the following rules must be observed in solubility determinations [7]. a. The solvent and solute must be pure. b. A saturated solution must be obtained before any solution is removed for analysis. c. The method of separating a sample of saturated solution from undissolved solute must be satisfactory. d. The method of analyzing the solution must be reliable. e. Temperature must be adequately controlled. A saturated solution is obtained either by stirring excess of powdered solute with solvent for several hours at the required temperature until equilibrium has been attained, or by warming the solvent with an excess of the solute and allowing the mixture to cool to the required temperature. It is essential that some undissolved solid should be present at the completion of this stage in order to ensure that the solution is saturated [2].

A sample of the saturated solution is obtained for analysis by separating the solution from the undissolved solid. Filtration is usually used, but precautions should be taken to ensure that: a. It is carried out at the temperature of the solubility determination, in order to prevent any change in the equilibrium between dissolved and undissolved solute. b.Loss of a volatile component does not occur.

6. Determination of solubility of solids in liquid Different method of analysis may be applied to the saturated solution depending on the type of system involved. a. Shake flask method: According to Health and Human Services, Food and Drug Administration (HHS-FDA ) guidance, the determination of the equilibrium solubility should be carried out with the shake flask method (other methods such as acid or base titration are permitted when their ability to predict the equilibrium solubility is justified). The experiments should be carried out at a temperature of 371C. Further, a sufficient number of pH conditions should be chosen to cover the pH range of 17.5 and each determination should be carried out at least in triplicate. The buffer solutions given in the United States Pharmacopeia (USP) are appropriate for the tests, but other buffers are also allowed for these experiments. The pH value of each buffer solution should be checked before and after each experiment. Degradation of the API due to pH or buffer composition should be reported together with other stability data [5].

b. Heating: If one of the components is volatile and one is non-volatile, the amount of latter can be determined by heating to constant weight [2]. c. Conversion of solute: The solute is to an insoluble compound by chemical reaction and weight of this insoluble compound may be obtained after filtration and drying [2]. d. Volumetric analysis: This method is used especially for the compounds that exhibit the reactions with acids, alkalis, chlorides, etc. that readily determines the solubility [2]. e. Physical method: Physical measurements offer a further means of analysis. A measurement of electrical conductivity is suitable for sparingly soluble electrolytes, optical rotation may be used for optically active compounds, or a radioactive indicator method of analysis may be employed. For radioactive method, the test material is prepared in such a way that it

contains a know proportion of a radioactive indicator. A saturated solution is made and its level of radioactivity may be used to determine the concentration of solute [2].

7. Process of solubalization of drugs 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 [8]. Step 1: Holes opens in the solvent

Step2: Molecules of the solid breaks away from the bulk

Step 3: The freed solid molecule is integrated into the hole in the solv

Figure 1: Process of solubalization of solute in solvent The drugs are designed in different dosage form e.g. solid, liquid, semi solid, transdermal. API in class 1 and 3 of BCS are readily soluble and thus are of less importance in solubility considerations. Drugs in class 2 and 4 of BCS need special attention during formulation. Oral drug dosage forms undergo following pathway of solubalization before it reaches to blood circulation and finally to the site of action. Solid dosage forms of tablets and capsules undergo process of disintegration to result granules. These granules and coarse

powder is changed to fine particles by disaggregation of granular particles. Fine particles undergo process of dissolution and the drug particles gets to solution and eventually to blood after absorption.

Disintegration Tablets Capsules Rate of absorption solution [9]. There are different factors affecting the rate of solution, i.e. a. Size of the particles Dissolution of shell Granules Disaggregation

Powder (Coarse) Suspension

Fine particles

Dissolution Emulsion

Drug in solution Solution

Absorption from biological membrane

Drug in blood Figure 2: Process of absorption of drug from various dosage forms. 8. Rate of solution The measurement of speed by which the solute turns into solution is known as rate of

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

Different estimates shows about 50% of the new molecules developed with pharmacological importance are dropped due to poor solubility or insolubility. As the molecules are not soluble, they cannot make them bioavailable in sufficient quantity so could not produce desired level of pharmacological responses. In solid mainly following two factors causes the poor solubility in water [10] a. Strong intermolecular interactions that makes the solubilization expensive b. High lipophilicity 9. Factors affecting the solubility of solids in liquids The solubility depends on the physical form of the solid, the nature and composition of solvent medium as well as temperature and pressure of system [9]. a. 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 by following equation

Where, S is the solubility of infinitely large particles S0 is 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

b. 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 increases [9].

c. Pressure For gaseous solutes, an increase in pressure increases solubility and a decrease in pressure decreases the solubility. For solids and liquid solutes, changes in pressure have practically no effect on solubility [9].

d. 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 solubility of these two substances is the result of differences in their natures [9].

e. 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 solvent [11].

f. 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 molecules [11].

g. 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 energy [12].

10. Methods of enhancing the solubility To overcome the factors influencing the solubility, as discussed above, there are different techniques which are in practice are as follows [13] I. Physical Modification a. Particle size reduction i. Micronization ii. Nanosuspension iii. Sonocrystallization iv. Super critical fluid process v. Spray drying b. Modification of the crystal habit i. Polymorphs ii. Pseudopolymorphs c. Drug dispersion in carriers i. Eutectic mixtures ii. Solid dispersions iii. Solid solution d. Complexation i. Stacking complex ii. Inclusion complex e. Solubilization by surfactants i. Microemulsion ii. Self microemulsifying drug delivery system II. Chemical modification a. Change in pH b. Changing in salt form III. Other techniques

a. Co-crystallization b. Co-solvency c. Hydrotrophy d. Solubilizing agents e. Nanotechnologies The techniques to enhance the solubility are in practice from long ago and they have greatly contributed for improving the solubility of poorly soluble drug materials. Techniques like sonocrystallization, nanosuspension, solid dispersion; super critical fluid process, microemulsion, self-emulsifying drug delivery system etc are novel techniques. These techniques are under studies in recent years. From the side of formulation approaches, the solubility enhancement of poorly soluble drug can be represented as follows [14]

Figure 3: Solubility enhancement approaches for poorly soluble drug. Among the different techniques of improving the solubility of drug substances, some of the techniques appreciated and kept in further research are discussed in following paragraphs.

a. Self emulsifying drug delivery system

It is the drug delivery system designed with the use of surfactants of HLB value lesser than 12. In this system the drug molecules are mixed with oils like corn oil, soya bean oil, hydrogenated vegetable oil etc, surfactants like tween 80, sodium dodecyl benzene sulphonate etc, co-surfactants like polyoxyehtylated glycerides, D-alpha Tocopheryl polyethylene glycol 1000 succinate etc and cosolvents like ethanol, glycerine, polyethylene glycol etc, consistency builders like beeswax, tragacanth etc, polymers like ethyl cellulose, hydroxyl propyl methyl cellulose etc, and the preparations designed in soft gelatin capsules or in hard gelatin capsules [15]. There are certain advantages of this systemi. After reaching to gastric fluid and due to movement of gastro intestinal tract, the system get dissolve in gastric fluid, it forms oil in water emulsions, promoting the wide distribution and minimize the irritation, the formed emulsion is said as micro emulsion thus the system is somewhere called as self micro emulsifying drug delivery system. ii. Provides large interfacial surface area for partitioning of drug between oil and water. iii. Give physically stable formulation so easy to manufacture.

b. Solid dispersion techniques Chiou and Riegelman defined solid dispersion as the dispersion of one or more active ingredients in as inert excipient or matrix, where the active ingredients could exist in finely crystalline, solubilized or amorphous stage. The most commonly used hydrophilic base is polyvinylpyrrolidine K 30, polyethylene glycols, Plasdone-S630. Many times surfactants may also used in the formation of solid dispersion. Surfactants like Tween-80, Docusate sodium, Myrj-52, Pluronic-F68 and Sodium Lauryl Sulphate used [15].

c. Super critical fluid process Super critical fluid process is a novel nano sizing and solubilization technology whose application has increased particle size reduction using a supercritical fluid (SCF) [16].

A supercritical fluid (SCF) is a dense non-condensable fluid 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 SCF [17]. 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 re-crystallized 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 nano particulate 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 anti solvents recrystallisation (GAS), both of which are employed by the pharmaceutical industry using carbon dioxide (CO2) as the SCF [16]. CO2 is used as SCF due to its favourable processing characteristics like its low critical temperature (Tc = 31.1-C) and pressure (Pc = 73.8 bar) [18]. 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 RESS [19]. 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 industry [20].

d. Inclusion Complexes 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. 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 [21].

e. Sonocrystallization Recrystallization of poorly soluble materials using liquid solvents and antisolvents has also been employed successfully to reduce particle size [22]. The novel approach for particle size reduction based on crystallization by using ultrasound is Sonocrystallisation. It utilizes ultrasound power characterized by a frequency range of 20100 kHz for inducing crystallization. It not only enhances the nucleation rate but also controls size distribution of the active pharmaceutical ingredients (API) [23]. Most applications use ultrasound in the range 20 kHz-5 MHz [24].

f. Modification of Crystal habits

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 fewer than 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 [25].

g. Nanotechnology approaches Particle size reduction is the technique followed from past to increase the solubility of the poorly water soluble drugs, but only converting the drug in micro particle level doesnt solve the problem as it dont help to increase the saturation point of the respective drug. But if the same drug is produce in nano crystal form i.e. crystals of size below 2000 nm,

it help to improve the rate of absorption, bioavailability after oral administration, improves in dose proportionality, applicability to administer from any route of administration, reduction on required dose etc. The nano crystal can be formulated in nano suspension dosage form and also in tablet and capsule dosage form. The nano crystals of poorly water soluble drugs are dispersed in dispersion media comprising water, or non aqueous media, other polymeric media, salts, sugars etc and can be converted into above mentioned dosage forms [26].

h. 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 processing [27]. 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 acid [28].

i. 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 solute. Example: Solubilisation of Theophylline with sodium acetate and sodium alginate [29].

In addition to the above mentioned approaches some other approaches are made with certain modification in the existing solubility enhancement techniques, some techniques are given as follows-

i. Use of polyplasdone crospovidone In this system the poorly water soluble drugs are formulated with polyplasdone crospovidone while formulating the drug in tablet dosage form. The polyplasdone crospovidone is super disintegrant and after reaching to gastricfluid, helps to disintegrates as well improve the dissolution of poorly soluble drug in gastric fluid [30]. ii. Liquisolid techniques In this technique the poorly soluble drug molecule is embedded with non volatile solvent like polyethylene glycol, propylene glycol, tween 80, span 20 etc, carrier materials like methyl cellulose, ethyl cellulose, starch etc, coating materials like silica, aerosols, talc etc, and disintegrantt like sodium starch glycolaate, cross povidone etc, and formulated in tablet form, but certain part of liquid remains inside it and while compression of tablet the care and optimization of process should be made not to press out the present liquid [31]. iii. Designing of poorly water soluble drugs in controlled release dosage form In this technique, the poorly water soluble drugs are enclosed, adsorbed or incorporated in different polymers. After administration of this dosage form, it make available of the poorly water soluble drug at absorption site for prolong duration the bioavailability of respective drug get increases [32]. iv. Designing of poorly water soluble drugs in buccal drug delivery system The basic philosophy followed in this technique is to avoid the first pass effect and the possible destruction of active drug by gastric fluids after reaching to gastrointestinal tract. Thus the poorly water soluble drugs are made available for absorption from the mucosal layer of buccal cavity [33]. v. Floating granules In this technique, poorly water soluble drugs which are highly absorbed from the mucosal layer of stomach are taken in consideration. As those drugs which are highly absorbed from wall of stomach are retained

in stomach for prolong time the active drug available for absorption will available for prolong time thus the bioavailability of that drug become good so that may contribute for the reduction of dose of that drug also. In this method, the granules of poorly water soluble drugs are so designed that, the drug after oral administration get disintegrates in gastric fluid giving rises to granules which get float in gastric fluids available in stomach. This gives rise to the increase of drug available for absorption for prolong time and reduces the loss of undissolved drug in fecal matter due to movement of gastrointestinal tract [33].

11. Conclusion Solubility and permeability of APIs and dissolution characteristics of the dosage forms have direct effect on pharmacokinetic parameters. This in turn affects the pharmacological properties of the APIs. There are a number of problems associated with the new chemical entities bearing the pharmacological values. Among them solubility is one of the major parameter which directly influence the bioavailability of the drug and finally the pharmacological response of drug. To overcome this problem especially when the poorly water-soluble drugs are to be formulated as oral dosage forms, there are different techniques in practice. Some of them are in practice since long and some are newly introduced from research activities. The approaches of enhancing the solubility of poorly soluble drug molecules shows great promise for development of dosage forms using such APIs.

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