Neethu ppt

GUIDED BY

Mrs. YASMEEN BEGUM

ASST PROFESSOR

(M.pharm)PRESENTED BY

C.R.NEETHU

256213885003

M.Pharm (Analysis)

MALLA REDDY COLLEGE OF PHARMACY

Maisammaguda, Dhulapally (post via

Hakimpet),

Sec-bad-14

CONTENTS

INTRODUCTION

SOLUBILITY

SALT FORMATION

CO-SOLVENCY

ANALYTICAL TECHNIQUES

CONCLUSION

INTRODUCTION

• Therapeutic effectiveness of a drug depends

upon the bioavailability and ultimately upon

the solubility of drug molecules.

• Solubility is one of the important parameter to

achieve desired concentration of drug in

systemic circulation for pharmacological

response to be shown.

• Currently only 8% of new drug have both high

solubility and permeability.

SOLUBILITY • Solubility is the maximum quantity of

solute that can dissolve in a certain

quantity of a solvent or solution at a

constant temperature and specified

pressure.

Process of solubilization

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 solvent.

TECHNIQUES TO IMPROVE

SOLUBILITY:

Solubility improvement techniques can be categorized into 3 types:

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

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

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

Metal ions

Ammonium

ion

replace

replace

Ammonium chloride

Sodium chloride

IDEAL CHARACTERISTICS OF

SALT FORMATION

chemically stable.

not hygroscopic.

presents no processing problems.

dissolves quickly from solid dosage

forms.

SALT FORMATION

Salt formation is one of the simplest chemical

reactions, involving either a proton transfer or a

neutralization reaction between an acid and a base.

The salt form of a drugs is usually more soluble than

parent drug .

An alkaloidal base is slightly soluble in water, But if

the pH of medium is reduced by addition of acid, the

solubility of the base increases. The reason for this

increase in solubility: as the pH continues to reduce,

the base is converted to a salt, which is relatively more

soluble in water.

Examples include Atropine , Bupivacaine, etc.

The solubility of slightly soluble acid is increased as the pH is

increased by addition of alkali, the reason being that a salt is

formed.

Examples include Aspirin , Theophylline , Barbiturates .

Compound Solubility (mg/ml)

Naproxen 0.07

Naproxen Na 266

Tolmetin 0.1

Tolmetin Na 163

Bupivacaine 0.05

Bupivacaine HCl 175

Salts have improved solubility and dissolution characteristics in

comparison to the original drug.

It is generally accepted that a minimum difference of 3 units between

the pKa value of the group and that of its counter ion is required to

form stable salts.

Alkali metal salts of acidic drugs like penicillin’s and strong acid

salts of basic drugs like atropine are water soluble than the parent

drug

Salt formation is frequently performed on weak acidic or basic

drugs because it is a relatively simple chemical manipulation, which

may alter the physicochemical formulation, biopharmaceutical,

and therapeutic properties of a drug without modifying the basic

chemical structure.

Use of Salt Form

CO-SOLVENCY

• The solubility of a poorly water soluble drug can be

increased by the addition of a water miscible solvent

in which the drug has a good solubility. This whole

procedure is known as co-solvency and the solvent is

called co-solvents.

• Co-solvents are mixtures of water and one or more

water miscible solvents used to create a solution with

enhanced solubility for a poorly water soluble drug.

• It is commonly referred to as solvent blending.

Characteristics of Co-Solvents

Non toxic.Non

irritant.

Able to solubilize

the drug in given

solvent.

Able to cross the

membrane

GLYCERINE

SORBITOL

PEG

ETHYL CARBAMATE

DIMETHYL ACETAMIDE

GLYCOFUROL

SOME EXAMPLES OF CO-SOLVENTS

Mechanism responsible for solubility enhancement

through co-solvency is by

Reducing the interfacial tension (polarity

differences) between the aqueous solution and

hydrophobic solutes.

Reducing the contact angle between solid and

liquid.

Co-solvents can increase the solubility of a nonpolar

drug up to several orders of magnitude compared to its

aqueous solubility.

MECHANISM OF CO-SOLVENT :

Solubilization by Co-solvents:

• Weak electrolytes and non polar molecules have

poor aqueous solubility. Their solubility in water

is increased by addition of water miscible solvents

in which drug has good solubility .

• The cosolvents such as propylene glycol,

polyethylene glycol, ethanol, glycerin aid in

solubilizing the drug in aqueous vehicle.

• The solubilizing effect by cosolvency primarily

dependent upon the polarity of drug with respect

to solvent and cosolvent.

Several analytical techniques were used for the

purpose of salt identification and solubility

dissolution rates investigations, these techniques

included NMR, FT-IR, and TLC.

Analysis for salt formation confirmation, XRD

characterization of the salt material, thermal

analysis included DSC, TGA, and HPLC.

For qualification and quantification of the new

crystals pH-solubility studies and finally intrinsic

dissolution rate studies.

The role of counter-ion in salt formation to improve the

solubility of poorly water soluble drugs in the case of

Flurbiprofen and Tris(hydroxymethyl)amino methane

• This study shows the role of salt formation in

improving the solubility and dissolution rates of

Flurbiprofen, which is one of the poorly water

soluble drugs.

• Tris[hydroxymethyl]aminomethane was used as

a counter-ion and the Flurbiprofen-Tris salt was

crystallized from acetonitrile as solvent.

Flurbiprofen: is a non-steroidal anti-inflammatory drug(NSAID) that readily forms carboxylic acid salts. It isadministered for its anti-inflammatory, antipyretic, analgesiceffects, and to inhibit intraoperative mitosis.

Tris[hydroxymethyl]aminomethane: was used as acounter-ion .

Acetonitrile: is a polar solvent that used to crystallize theFlurbiprofen-Tris salt .

MSc presentation project 24

EXAMPLE :

The Flurbiprofen and Tris [hydroxy methyl]amino methane were

combined to prepare an soluble salt, which was then precipitated

and yield the final product.

MSc presentation project

- +3

Acetonitrile

Flurbiprofen Tris[hydroxymethy

l]aminomethane

The

equation

reaction

reactants product

Flurbiprofen-

Tris salt Solvent

Differential Scanning Calorimetric (DSC)

Thermo Gravimetric Analysis (TGA)

High Pressure Liquid Chromatography (HPLC)

Ultra Violet spectroscopy (UV)


Analytical methods:

Differential Scanning Calorimetric (DSC)


The DSC curve in Flurbiprofen shows a

sharp endothermic peak representing

the melting point of pure Flurbiprofen

at (113.950C). The sharpness of the

peak and absence of any others within

the temperature range of the

experiment indicates that this material

is reasonably pure.

The DSC curve in Flurbiprofen-Tris salt

which formed by using acetonitrile as

solvent gave a two exothermic peaks at

temperatures of 129.030C - 137.640C

indicating a polymorphic crystalline

internal structure for the Flurbiprofen-

Tris salt.

Several experiments were attempted to resolve and identify all obtained

peaks by once changing the N2 gas flow rate for a better expansion for

the DSC curve.

113.950C

137.640C

129.030C

Pure

Flurbiprofen

Flurbiprofen-Tris

salt

Analytical methods:

Thermo Gravimetric Analysis (TGA)


For Flurbiprofen and its salt, the weights of the samples were steady

until 160oC, and then a dramatic change happened from 160oC until

260oC.

• The weight loss of the Flurbiprofen was 1.637mg (54.5%).

• The weight loss of the Flurbiprofen-Tris salt was 1.966mg

(50.3%).

The weight is steady until

160oC

The weight is steady until

160oC

The weight loss of the

Flurbiprofen is 1.637mg

(54.5%)

The weight loss of the

Flurbiprofen-Tris salt is 1.966mg

(50.3%)

Analytical methods:

High Pressure Liquid Chromatography (HPLC)


Flurbiprofen-Tris saturated

salt

Conc. Using HPLC (mol/ml)

Saturated salt 1 5.43477E-04



The mean of saturated salt 5.10500E-04

Conc. (ppm) Conc. Of

Flurbiprofen

(mol/ml)

Conc. Of

Flurbiprofen-Tris

salt (mol/ml)

10 3.97100E-05 2.84643E-05

25 1.01118E-04 6.97923E-05

50 2.10014E-04 1.32468E-04

75 3.05400E-04 2.05545E-04

100 4.08564E-04 2.75064E-04

The figure shows a linear relationship between

the concentration and the peak area for both

the Flurbiprofen and the Flurbiprofen-Tris salt.

Both compounds were soluble, but the

Flurbiprofen-Tris salt had lower solubility based

on its sigma value, when compared to the sigma

value of Flurbiprofen

The HPLC calibration curve equations for

Flurbiprofen-Tris allowed calculation of the

amount of salt that has been dissolved in

water at a ratio of 1:1 (water:salt).

Analytical methods:

Ultra Violet spectroscopy (UV)


Flurbiprofen-Tris saturated

salt

Conc. Using UV (mol/ml)

Saturated salt 1 527.2689301



The mean of saturated salt 495.81908

Conc. (ppm) Conc. Of

Flurbiprofen

(mol/ml)

Conc. Of

Flurbiprofen-Tris

salt (mol/ml)

0.1 3.47976E-07 2.73695E-07

0.2 8.59704E-07 6.29499E-07

0.3 1.26909E-06 8.48455E-07

0.4 1.47378E-06 1.04004E-06

0.5 1.92410E-06 1.25900E-06

0.6 2.74287E-06 1.61480E-06

0.7 3.07037E-06 1.97061E-06

0.8 3.35694E-06 2.21693E-06

0.9 3.64351E-06 2.49063E-06

1.0 3.93008E-06 2.73695E-06

The figure shows a linear relationship for the absorbances of Flurbiprofen and the Flurbiprofen-

Tris salt. The overall absorbance of Flurbiprofen-Tris salt was lower than that for Flurbiprofen.

The UV calibration curve equations

for Flurbiprofen-Tris allowed

calculation of the amount of salt that

has been dissolved in water at a ratio

of 1:1 (water:salt).

CONCLUSION

The aqueous solubility of drug is often a limiting factor in developing most

desirable dosage form.Hence, Increasing the water solubility of insoluble or

slightly soluble compounds is of major concern for pharmaceutical

researchers.

A highly solubilized formulation is desired to minimize

dissolution limited absorption.

Newly developed techniques could bridge the gap between dissolution and

absorption for many such drugs.Research in this area still continues to be

promising and challenging for optimization of the drug delivery

Neethu ppt

Documents

Transcript of Neethu ppt