Neethu ppt

GUIDED BY

Mrs. YASMEEN BEGUM ASST PROFESSOR (M.pharm)

TECHNIQUES TO IMPROVE SOLUBILITY

PRESENTED BY

C.R.NEETHU256213885003M.Pharm (Analysis)

MALLA REDDY COLLEGE OF PHARMACYMaisammaguda, 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 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.

SALT FORMATION

W H O I S S A LT ?WHAT IS SALT ?

Ionic compound – formed when the hydrogen ion, H+ from an acid is replaced by

a metal ion or an ammonium ion, NH4+

Na+

NH4+

H Cl

Metal ions

Ammonium ion

Na+ Cl-

NH4+Cl-

replace

replace

Ammonium chloride

Sodium chloride

IDEAL CHARACTERISTICS OF SALT FORMATION

chemically stable.

not hygroscopi

c.

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

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 membran

e

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.

ANALYTICAL TECHNIQUES

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 is administered for its anti-inflammatory, antipyretic, analgesic effects, and to inhibit intraoperative mitosis.

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

Acetonitrile: is a polar solvent that used to crystallize the Flurbiprofen-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[hydroxymethyl]aminometha

ne

The equation reaction

reactants product

Flurbiprofen-Tris salt

Solvent

ANALYTICAL METHODS

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

Mel

ting

poin

t

137.640C

129.030C

Mel

ting

poin

t

Melting point

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

A dramatic change from

160oC

until

260oC

A dramatic change from

160oC

until

260oC

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