MALLA REDDY COLLEGE OF PHARMACYMAISAMMAGUDA, DHULAPALLY (POST VIA HAKIMPET),

SEC-BAD-14

PRESENTED BY:

K.SAI VANI

256213886014M.PHARM (PHARMACEUTICS)

GUIDED BY:

Mrs. Yasmin Begum

M.pharm

SOLUBILITY

SOLUBILITYDEFINITION: The term ‘solubility’ is defined as maximum amount of

solute that can be dissolved in a given amount solvent.

Solute is the substance being dissolved – powder Solvent is the dissolving agent – water

Solubility can also be defined quantitatively as well as qualitatively.

Quantitatively it is defined as the concentration of the solute

in a saturated solution at a certain temparature.

Qualitatively it may be defined as the spontaneous

interaction of two or more substances to form a homogenous molecular dispersion.

A saturated solution is one in which the solute is in equilibrium with solvent.

The solubility of drug is represented through various concentration expression such as parts,percentage,molarity,molality,volume fraction,mole fraction

IMPORTANCE OF SOLUBILITY Solubility is one of the important parameters to achieve desired

concentration of drug in systemic circulation for achieving required

pharmacological response. 

These poorly water soluble drugs having slow drug absorption leads

to inadequate and variable bioavailability and gastrointestinal

mucosal toxicity.

Most of the drugs(>40%) belongs to BCS class II (low solubility and

high permeability).

As for BCS class II drugs rate limiting step is drug release from the

dosage form and solubility in the gastric fluid, so increasing the

solubility in turn increases the bioavailability for BCS class II drugs.

BCS CLASSIFICATION:

TECHNIQUES TO IMPROVE SOLUBILITY: Solubility improvement techniques can be categorized into

physical modification, chemical modifications of the drug substance, and other techniques.

Physical Modifications —Particle size reduction like micronization and nano-suspension, modification of the crystal habit like polymorphs, amorphous form and co-crystallization, drug dispersion in carriers like eutectic mixtures, solid dispersions and solid solutions.

Chemical Modifications —Change of pH, use of buffer, derivatization, complexation, and salt formation.

Miscellaneous Methods —Supercritical fluid process, use of adjuvant like surfactant, solubilizers, cosolvency,hydrotropy etc.

PROCESS OF SOLUBILISATION:

Step 1 Step2

Step 3

Holes open in the solvent Molecules of the solid

breaks away fromthe bulk

The freed solid molecule is integrated

into the hole in the solvent

MICELLAR SOLUBILIZATION:

Micellar solubilizatiion: Surfactants can lower surface tension & improve the

dissolution of lipophilic drugs in the aqueous medium.

When the concentration of surfactants exceeds their critical micelle concentration (CMC, which is in a range of 0.05-0.10% for most surfactants), micelle formation occurs,entrapping the drugs within the micelles.

This process is known as micellisation and generally results in enhanced solubility of poorly soluble drugs.

MICELLAR SOLUBILIZATION: Micellar solubilization is a powerful alternative for

dissolving hydrophobic drugs in aqueous environments.

Surfactants are known to play a vital role in many processes of interest in both fundamental and applied science.

One important property of surfactants is the formation of colloidal-sized clusters in solutions, known as micelles, which have particular significance in pharmacy because of their ability to increase the solubility of sparingly soluble substances in water

Micelles are known to have an anisotropic water

distribution within their structure

Micellar systems can solubilize poorly soluble drugs and

thus increase their bioavailability

SURFACTANTS & MICELLES: Surfactants are amphiphilic molecules composed of a

hydrophilic or polar moiety known as head and a hydrophobic or nonpolar moiety known as tail.

The surfactant head can be charged (anionic or cationic), dipolar (zwitterionic), or non-charged (nonionic).

Ex: SDS, DTAB, Ethylene oxide, dioctanoyl phosphatidyl choline etc.

The surfactant tail is usually a long chain hydrocarbon residue and less often a halogenated or oxygenated hydrocarbon or siloxane chain.

A surfactant, when present at low concentrations in a system, adsorbs onto surfaces or interfaces significantly changing the surface or interfacial free energy

Surfactants usually act to reduce the interfacial free energy, although there are occasions when they are used to increase it.

When surfactant molecules are dissolved in water at concentrations above the critical micelle concentration (cmc), they form aggregates known as micelles.

In a micelle, the hydrophobic tails flock to the interior in order to minimize their contact with water, and the hydrophilic heads remain on the outer surface in order to maximize their contact with water.

The micellization process in water results from a delicate balance of intermolecular forces, including hydrophobic, steric, electrostatic, hydrogen bonding, and van der Waals interactions.

The determination of a surfactant cmc can be made by use of several physical properties, such as surface tension(γ), conductivity (κ) – in case of ionic surfactants, osmotic pressure (π), detergency, etc.

When these properties are plotted as a function of surfactant concentration (or its logarithm, in case of surface tension), a sharp break can be observed in the curves obtained evidencing the formation of micelles at that point

Another important parameter that characterizes micelles is the aggregation number, Nag, that corresponds to the average number of surfactant monomers in each micelle of a micellar solution.

Micelles are labile entities formed by the noncovalent aggregation of individual surfactant monomers. Therefore, they can be spherical, cylindrical, or planar (discs or bilayers).

Micelle shape and size can be controlled by changing the surfactant chemical structure as well as by varying solution conditions such as temperature, overall surfactant concentration, surfactant composition (in the case of mixed surfactant systems), ionic strength and pH

MICELLAR SOLUBILIZATION: An important property of

micelles that has particular significance in pharmacy is their ability to increase the solubility of sparingly soluble substances in water.

Solubilization can be defined as the spontaneous dissolving of a substance by reversible interaction with the micelles of a surfactant in water to form a thermodynamically stable isotropic solution with reduced thermodynamic activity of the solubilized material.

From the thermodynamic point of view, the solubilization can be considered as a normal partitioning of the drug between two phases, micelle and aqueous, and the standard free energy of solubilization (ΔGS º) can be represented by the following expression

ΔGS º= -RTlnP

where R is the universal constant of the gases, T is the absolute temperature, and P is the partition coefficient between the micelle and the aqueous phase.

Usually, the solubilization of a molecule by a surfactant can be evaluated based on two descriptors that are the molar solubilization capacity, χ, and the micelle water partition coefficient, P

The χ value is defined as the number of moles of the solute (drug) that can be solubilized by one mol of micellar surfactant, and characterizes the ability of the surfactant to solubilize the drug.

Where Stot is the total drug solubility, SW is the water drug solubility, Csurf is the molar concentration of surfactant in solution, and cmc is the critical micelle concentration.

The micelle-water partition coefficient is the ratio of drug concentration in the micelle to the drug concentration in water for a particular surfactant concentration, as follows:

Combining Equations we can relate the two solubility descriptors. Accordingly, for a given surfactant concentration

As can be seen, P is related to the water solubility of the compound, in contrary to χ . In order to eliminate the dependence of P on the surfactant concentration, a molar micelle-water partition coefficient (PM), corresponding to the partition coefficient when Csurf = 1 M, can be defined as follows

The lower is the cmc value of a given surfactant, the more stable are the micelles.

Hydrophilic drugs can be adsorbed on the surface of the micelle.

Drugs with intermediate Solubility should be located in intermediate positions within the micelle such as between the hydrophilic head group of Peo Micelles

In the Palisade Layer between the hydrophilic group and the first few carbon atoms of the hydrophobic group , that is the outer core.

Completely insoluble hydrophobic drugs may be located in the Inner Core of the micelle.

Examples of poorly soluble compounds that use micellar solubilization are

Anti-diabetic drugs, Gliclazide, Glipizide, Gluburide, Glimepride, Repaglinide, Pioglitazone,and Rosiglitazone.

HYDROTROPY:

HYDROTROPY:INTRODUCTION: The term Hydrotropic agent was first introduced by Neuberg(1916)

to designate anionic organic salts.

Hydrotropy is defined as a solubilisation process where by addition

of a large amount of second solute results in an increase in the aqueous solubility of another solute and the chemicals which are used in hydrotropy are called hydrotropes.

Ex: sodium benzoate, urea, sodium salicylate, ibuprofen sodium etc.

The chemical structure of the conventional Neuberg’s hydrotropic salts consists of two essential parts, an anionic group and a hydrotropic aromatic ring or ring system.

Hydrotropic agents are ionic organic salts.

Additives or salts that increase solubility in given solvent are said to “salt in” the solute & 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”.

Hydrotropic solutions do not show colloidal properties and involve a weak interaction between the hydrotropic agent and solute.

MECHANISM OF HYDROTROPIC ACTION: A hydrotrope is a compound that solubilises

hydrophobic compounds in aqueous solutions.

Typically, hydrotropes consist of a hydrophilic part and a hydrophobic part, but hydrophobic part is too small to cause self aggregation.

Hydrotropes do not have a critical concentration above which self aggregation 'suddenly' starts to occur.

Ex: Paracetamol with urea as hydrotropic agent.

SELECTION OF HYDROTROPES FOR POORLY WATER-SOLUBLE DRUGS:

The more is the concentration of hydrotrope, more is the aqueous solubility of poorly water-soluble drugs. Distilled water was used in making hydrotropic solutions.

To select suitable hydrotropes for various poorly water soluble drugs following method is used.(approx solubility can be determined)

25ml of H2O/Hydrotropic soln 50ml beaker Gross weight was

noted.(1)

Gross weight is same operation is Add drug and shake

noted (2) continued till excess

drug remain undissolved.

From the difference in two readings, solubility was determined.

Hydrotropic solubilisation study of various poorly water soluble drugs:

DRUG HYDROTROPIC AGENT

Cefprozil Potassium acetate, Potassiumcitrate, Sodium acetate, Sodiumcitrate, Urea

Hydrochlorothiazide Sodium acetate, urea

Paracetamol, Diclofenacsodium

urea

Theophylline Sodium salicylate

Salicylic acid Ibuprofen sodium, sodiumsalicylate

Furesamide Ibuprofen sodium

Chlorpropamide,Gatifloxacin

Ibuprofen sodium

Nifedipine Sodium salicylate

ketoprofen Urea, sodium salicylate.

DETERMINATION OF INTERFERENCE OF HYDROTROPIC AGENTS IN THE SPECTROPHOTOMETRIC ESTIMATION OF DRUGS:

The determination of interference of hydrotropic agents in the spectrophotometric estimation of the standard solutions of drugs were determined in distilled water alone and in the presence of the maximum concentration of the hydrotropic agent employed for spectrophotometric analysis.

The absorbances were recorded against respective reagent blanks at appropriate wavelengths

Enhancement ratios can be determined by the formula

Enhancement ratio = solubility in hydrotropic solution/ solubility in distilled water.

ADVANTAGES OF HYDROTROPIC SOLUBILIZATION TECHNIQUE:

Hydrotropy is suggested to be superior to other solubilization method, such as miscibility, micellar solubilization, co solvency 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

MIXED HYDROTROPY: Mixed hydrotropic solubilization technique is the

phenomenon to increase the solubility of poorly water-soluble drugs in the blends of hydrotropic agents which may give miraculous synergistic enhancement effect on solubility of poorly water soluble drugs.

Utilization of it in the formulation of dosage forms of water insoluble drugs and to reduce concentration of individual hydrotropic agent to minimize the side effects.

ADVANTAGES OF MIXED HYDROTROPIC SOLUBILIZATION: It may reduce the large total concentration of hydrotropic

agents necessary to produce modest increase in solubility by employing combination of agents in lower concentration.

It is new, simple, cost-effective, safe, accurate, precise and environmental friendly method for the analysis (titrimetric and spectrophotometric) of poorly water-soluble drugs titrimetric and spectrophotometric precluding the use of organic solvents.

It precludes the use of organic solvents and thus avoids the problem of residual toxicity, error due to volatility, pollution, cost etc

NOVEL PHARMACEUTICAL APPLICATIONS OF HYDROTROPIC SOLUBILIZATION:

Quantitative estimations of poorly watersoluble drugs by UV-Visible spectrophotometric analysis precluding the use of organic solvents.

Quantitative estimations of poorly watersoluble drugs by titrimetric analysis.such as ibuprofen, flurbiprofen and naproxen using sodium benzoate[29] .

Preparation of hydrotropic solid dispersions of poorly water-soluble drugs precluding the use of organic solvents. Such as felodipine[30] using poly ethylene glycol 6000 and poly-vinyl alcohol.

Preparation of injection of poorly water soluble drugs. The use of hydrotropic solubilizers as permeation enhancers. The use of hydrotropy to give fast release of poorly water-

soluble drugs from the suppositories. Application of mixed- hydrotropy to develop injection dosage

forms of poorly water-soluble drugs. Application of hydrotropic solubilization in nanotechnology

(by controlled precipitation). Application of hydrotropic solubilization in extraction of active

constituents from crude drugs (in pharmacognosy field). Hydrotropic solutions can also be tried to develop the

dissolution fluids to carry out the dissolution studies of dosage forms of poorly water soluble drugs.

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.

The various techniques described above alone or in combination can be used to enhance the solubility of the drug

Because of solubility problem of many drugs the bioavailability of them gets affected and hence solubility enhancement becomes necessary.

REFERENCES: International journal of pharmaceutical

sciences review and research,vol5,issue1, varun raj vemula, article007 nov-dec2010.

J pharm pharmaceutical sciences,CarlotaO. July2005.

Journal of drug delivery & therapeutics 2012,Md.Ali sajid.

International journal of drug development research, vol3, issue2, apr-jun2011

International journal of pharmaceutical research & bio-science.