Assignment I Solubility

8/22/2019 Assignment I Solubility

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The assignment on

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


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Table of Content

1. Solution and solubility ............................................................................................. 32. Methods of expressing solubility ............................................................................. 33. Biopharmaceutics classification system of drugs .................................................... 54. Types of solution...................................................................................................... 55. General consideration for solubility determination of solids in liquids ................... 66. Determination of solubility of solids in liquid ......................................................... 77. Process of solubalization of drugs ........................................................................... 88. Rate of solution ........................................................................................................ 99. Factors affecting the solubility of solids in liquids ................................................ 1010. Methods of enhancing the solubility ...................................................................... 1311. Conclusion ............................................................................................................. 2112. References .............................................................................................................. 22

List of Tables

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

List of Figures

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


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Various Approaches for Enhancing Solubility of Drug Molecules

1. Solution and solubilityA solutioncan 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 besaturated. 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 solubilityWhen 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]:


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Table 1: Descriptive terms for solubility

Descriptive term Parts of solvent for 1 part of solute

Very soluble Less than 1

Freely soluble From 1 to 10

Soluble From 10 to 30

Sparingly soluble From 30 to 100

Slightly soluble From 100 to 1000

Very slightly soluble From 1000 to 10,000

Practically insoluble or insoluble 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].


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3. Biopharmaceutics classification system of drugsThe 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 solutionSolutions 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 SolventGas Gas

Liquid Gas

Solid Gas

Gas Liquid

Liquid Liquid

Solid Liquid

Gas SolidLiquid Solid

Solid Solid


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5. General consideration for solubility determination of solids in liquidsIt 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 solutemust 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 toprevent any change in the equilibrium between dissolved and undissolved solute.

b.Loss of a volatile component does not occur.


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6. Determination of solubility of solids in liquidDifferent 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 alsoallowed for

these experiments. The pH value of each buffer solution should bechecked before and

after each experiment. Degradation of the API due to pHor 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


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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 drugsThe 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 lessimportance 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


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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

Dissolution of shell Disaggregation

Absorption from biological

membrane

Figure 2: Process of absorption of drug from various dosage forms.

8. Rate of solutionThe measurement of speed by which the solute turns into solution is known as rate of

solution [9].

There are different factors affecting the rate of solution, i.e.

a. Size of the particles

Tablets

Capsules

Powder

Coarse

Suspension

Granules

Drug in solution

Solution

Fine particles

Emulsion

Dissolution

Drug in blood

Rateofabsor

ption


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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. TemperatureFor 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 dissolvedWhen 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 expensiveb. High lipophilicity9. 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
http://www.pharmainfo.net/tablet-evaluation-tests/dissolutionhttp://www.pharmainfo.net/tablet-evaluation-tests/dissolutionhttp://www.pharmainfo.net/tablet-evaluation-tests/dissolutionhttp://www.pharmainfo.net/tablet-evaluation-tests/dissolution


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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. TemperatureTemperature 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. PressureFor 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 solventWhile 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 thesolubility of these two substances is the result of differences in their natures [9].

e. Molecular sizeMolecular 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


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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. PolarityPolarity 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 intermolecularforce 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. PolymorphsA 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


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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 solubilityTo overcome the factors influencing the solubility, as discussed above, there are different

techniques which are in practice are as follows [13]

I. Physical Modificationa. Particle size reduction

i. Micronizationii. Nanosuspension

iii. Sonocrystallizationiv. Super critical fluid processv. Spray drying

b. Modification of the crystal habiti. Polymorphs

ii. Pseudopolymorphsc. Drug dispersion in carriers

i.

Eutectic mixturesii. Solid dispersions

iii. Solid solutiond. Complexation

i. Stacking complexii. Inclusion complex

e. Solubilization by surfactantsi. Microemulsion

ii. Self microemulsifying drug delivery systemII. Chemical modification

a. Change in pHb. Changing in salt form

III. Other techniques


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a. Co-crystallizationb. Co-solvencyc. Hydrotrophyd. Solubilizing agentse. 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


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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 likepolyoxyehtylated 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 system-

i. After reaching to gastric fluid and due to movement of gastrointestinal 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 andwater.

iii. Give physically stable formulation so easy to manufacture.

b. Solid dispersion techniquesChiou 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 processSuper critical fluid process is a novel nano sizing and solubilization technology whose

application has increased particle size reduction using a supercritical fluid (SCF) [16].


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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 to2,000 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.


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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 ComplexesInclusion 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. SonocrystallizationRecrystallization 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


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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 approachesParticle 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,


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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 dryingSpray 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. HydrotrophyHydrotrophy 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-
http://en.wikipedia.org/wiki/Medicationhttp://en.wikipedia.org/wiki/Solventhttp://en.wikipedia.org/wiki/Ethanolhttp://en.wikipedia.org/wiki/Oxygenhttp://en.wikipedia.org/wiki/Nitrogenhttp://en.wikipedia.org/wiki/Solutionhttp://en.wikipedia.org/wiki/Colloidhttp://en.wikipedia.org/wiki/Suspension_%28chemistry%29http://en.wikipedia.org/wiki/Suspension_%28chemistry%29http://en.wikipedia.org/wiki/Colloidhttp://en.wikipedia.org/wiki/Solutionhttp://en.wikipedia.org/wiki/Nitrogenhttp://en.wikipedia.org/wiki/Oxygenhttp://en.wikipedia.org/wiki/Ethanolhttp://en.wikipedia.org/wiki/Solventhttp://en.wikipedia.org/wiki/Medication


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i. Use of polyplasdone crospovidoneIn this system the poorly water solubledrugs 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 techniquesIn this technique the poorly soluble drug molecule isembedded with non volatile solvent likepolyethylene 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 formulatedin 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 formIn 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 systemThebasic 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 granulesIn this technique, poorly water soluble drugs which arehighly absorbed from the mucosal layer of stomach are taken in consideration.

As those drugs which are highly absorbed from wall of stomach are retained


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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.ConclusionSolubility 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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Organization (WHO Technical Report Series, No. 937), 2006, Annex 7. 378-379.

5. Proposal to waive in vivo bioequivalence requirements forWHO Model List ofEssential Medicines immediate-release, solid oral dosage forms. In: WHO Expert

Committee on Specifi cations for Pharmaceutical Preparations. Fortieth report.

Geneva, World Health Organization (WHO Technical Report Series, No. 937), 2006,

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Assignment I Solubility