SEMINAR ONSOLUBILITY ENHANCEMENT BY

1. ALTERATION IN pH OF THE SOLVENT SYSTEM2. COMLEXATION TECHNIQUES

CONTENTS:

Solubilization by pH

Handersson-Hasselbach equation

Solubilization by complexation Self association and stacking complexation

Inclusion complex

Solubilization using combination of pH and complexation

References

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SOLUBILIZATION

It is defined as the process of enhancement of solubility of a very slightly soluble or a insoluble drug to dissolve in a suitable solvent for desired formulation.

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SOLUBILIZATION BY pH

Drug should be dissolve in an aqueous media.

The ionized form of the drug has responsible for solubility of drug.

For weak acidic drugs, Lower pH Unionized form insoluble/ ppt.

Higher pH ionized form more soluble drug.

For weak basic drugs, Lower pH ionized form more soluble drug.

Higher pH Unionized form insoluble/ ppt.

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Dissociation constant for Acidic/Basic drug Dissociation constant for Acidic/Basic drug expressed by pKa values.expressed by pKa values.

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Lower pKaLower pKa Stronger the AcidStronger the Acid More ionization More ionization Higher pKaHigher pKa Stronger the Base Stronger the Base More More

ionizationionization

Handersson-Hasselbach Handersson-Hasselbach EquationsEquations

For weak Acid,

pH=pKa+log

For weak Base,

pH=pKa+log

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This equation helps to find out,

1) Solubility of a drug at particular pH.

2)Minimum pH range that must be maintain to prevent precipitation of the drug

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Weak acids:Weak acids:e.g. Nimesulide;51 fold increase in solubility by shifting pH from 1.2 to 8.4

Other examples: Aspirin, Phenytoin, Penicillin,

Cephalosporin, etc.

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Drugs showing enhancement in Drugs showing enhancement in solubility up on alteration in pH.solubility up on alteration in pH.

pHpH Solubility mg/mlSolubility mg/ml

1.21.2 0.700.70

6.26.2 0.860.86

7.47.4 4.104.10

8.48.4 43.9043.90

Weak bases:Weak bases:

Similar increase in solubility of Levemopamil HCl

by decreasing pH.

Other examples;

Morphine, Ephedrine,

Itraconazole, Flavopiridol, etc.

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Zwitter ion compounds: Pelrinone HCL; pH 3-5 Cationic form

pH 5-8 Neutral form

pH 8-11 Anionic form

Other examples;Loraxepam,Proteins,Amino acids, etc.

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Divalent compounds:

The solubilization of divalent acids/bases

is similar to that of monoprotic compound.

However due to ionization of second acid

group solubility increases up to 100 fold

for change in 1 pH unit.

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Solubilization by Complexation Solubilization by Complexation

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The mathematical description for

the equilibrium constant of a 1:1 complex

K1:1 = [SL] / [S] [L]

K1:1 is defined as equilibrium constant/

Stability constant/

Complexation constant.

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Self association and Stacking Complexation

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Complexes stacked can be homogeneous or mixed.

Examples of substances that interact in an aqueous media by stacking are,

Naphthalene,

Benzoic acid,

Pyrene,

Methylene blue,

Caffeine etc.

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Inclusion Complexes*

Inclusion of a nonpolar molecule or the nonpolar region of a molecule (guest) into the nonpolar cavity of another molecule or group of molecules ( host).

When the guest molecule enters the host molecule

the contact between water and the nonpolar

regions of both is reduced.

* Ref: Current perspectives of solubilization

potential for improved bioavailability

(C.A; 147 (16) 350123x: OCT; 2007)

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Cyclodextrins

These cyclic oligomers of glucose are relatively

soluble in water and have cavities large enough to

accept common nonpolar portion of the drugs.

Naturally occurring cyclodextrines obtained from

action of Bacillus marcerans amylase on starch to

form homogenous cyclic α,(1→4) linkage

glycoprotein.

6, 7, 8 glucopyranose units are termed α, β, γ,

respectively.

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The Natural Cyclodextrinsα-Cyclodextrin

Of somewhat limited value due to low complexation efficiency

with most drugs.

β-Cyclodextrin*

This cyclodextrin does usually possess rather good

complexation efficiency with drugs. However,

β-cyclodextrin, and its complexes have very limited aqueous

solubility.

*Ref: Process for the preparation of formulation of angiotension

converting enzyme inhibitor and product.

(C.A: 147(11) 243338z; SEP;2007)

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γ-Cyclodextrin

Favorable toxicological profile. However,

γ -cyclodextrin has frequently lower

complexation efficiency than β-cyclodextrin.

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Characteristics of CDsThe conventional thoughts:

CDs are not perfectly cylindrical, owing to lack of rotation about the bonds connecting the glucopyranose units

But are truncated cone shaped.

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β-Cyclodextrin:

Seven α-1,4-linked gluco- pyranose units form a cone with a hydrophilic outer surface and a lipophilic cavity in the center.

Cyclodextrin Derivatives of Pharmaceutical Cyclodextrin Derivatives of Pharmaceutical InterestInterest

RMβCD( Randomly methylated β-CD)

HPβCD( Hydroxy propyl β-CD)*

HPγCD(Hydroxy propyl γ-CD)

DMβCD( 2,4- dimethyl β-CD)**

SBEβCD( Sulfobutylether β-CD)

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*Ref: Complexation of ketoprofen with

Hydroxypropyl β-CD. The inclusion complex 0f KPF- 2 HPβ-CD could be formed

spontaneously and lower temp is benefit to the formation.

Hence, the solubility of KPF in aqueous solution increase.

**Ref: Novel approach for pharmaceutical

application of cyclodextrins. Among the natural CDs, bioadaptable γ-CD is particularly in

the addition, the multifunctional characteristic of DMβ-CD

allow alleviation of undesirable properties of drug molecules

through the formation of inclusion complexes.

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Complex formation

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From Frömming and Szejtli: Cyclodextrins in Pharmacy Kluwer Acad. Press, Dordrecht, 1994.

Release of drug molecule from the complex

Complexation of drugs by CDs does not interfere with their activity because complexation is a rapidly reversible process.

After administration, the drug is release from complex upon dilution.

Competitive displacement.

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Solubilization using combination of pH and Complexation*

The effect of pH on solubilization by complexation depends

entirely on the solute and the ligand.

If the ligand or the solute ionize with pH, the stability constant

typically decreases. However , even with a decrease in the

stability constant, author found that the combination of

ionization and complexation can be a powerful method for

solubilization.

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There is significantly increase the solubility of a

THIAZOLOBENZIMIDAZOLE derivative Combination of pH and

complexation via HPβ-CD.

* Combined effect of HPβ-CD and media pH on the solubility of

PROSTGLANDIN E 1.

Ref: C.A:147(13) 284709q; SEP; 2007

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Method for preparation of Cyclodextrin complex:

Grinding

Solid dispersion

Neutralization method

Kneading*

Co-Precipitation

Spray drying*

Freeze drying

Melting

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*Chlorthalidone is a practically insoluble in water. HPβ-CD used as

a host molecule to improve it’s solubility in water via inclusion

complex formation with the different ratio (1:1, 1:2). To form the CD

and chlorthalidone complex KNEADING, SPRAY DRYING methods

are used.

*Ref: C.A:147(13) 284708p; SEP; 2007

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Characterization of Inclusion Complexes

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Characterization in solid state:

1) Differential scanning calorimetry (DSC)2) X-ray Powder diffraction (XRPD)3) Fourier transform IR (FTIR)4) Scanning electron microscopy (SEM)5) Thermogravimetry (TG)

Characterization in solution state:

1) Solubility study2) TLC3) NMR4) UV studies

What are cyclodextrins used for?

To increase aqueous solubility of drugs.

To increase chemical stability of drugs.

To enhance drug delivery to and through biological membranes.

To increase physical stability of drugs.

To convert liquid drugs to microcrystalline powders.

To prevent drug-drug and drug-excipient interactions.

To reduce local irritation after topical or oral administration.

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Why are cyclodextrins better than organic solvents?

Why are cyclodextrins better than organic solvents?

Frequently less irritating after iv and im injection.

Frequently less toxic.

The drug does not precipitate after iv injection.* Example: Water soluble PROGESTERONE HPβ-CD complex for injectable formulations.

* Ref: C.A:147(17) 37141t; OCT; 2007

Can be used in solid dosage forms.

Frequently less irritating after iv and im injection.

Frequently less toxic.

The drug does not precipitate after iv injection.* Example: Water soluble PROGESTERONE HPβ-CD complex for injectable formulations.

* Ref: C.A:147(17) 37141t; OCT; 2007

Can be used in solid dosage forms.

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Parenteral solution containing diazepam 5 mg/ml

Parenteral solution containing diazepam 5 mg/ml

Valium:Diazepam

5.0 mgBenzylalcohol

15.7 mgEthanol

85.3 mgPropylene glycol

414.0 mgBenzoic acid

47.5 mgPurified water

ad 1.00 ml

About 45% water.

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CD formulation:

Diazepam 5.0 mg

HPCD 60.0 mg

Sodium chloride 6.0 mg

Purified water ad 1.00 ml

About 93% water.

Advantage of -Cyclodextrin: Advantage of -Cyclodextrin:

Liquid component can be transformed into a crystalline form

Volatile component can be stabilized against losses through

evaporation

Molecules can be protect against oxidation.

It can be used for taste and smell masking.

Incompatible drug can be mixed together if one of them is

protected by formation of Cyclodextrin complex.

Solubility in water as well as the rate of dissolution of poorly

soluble drug can be increased.

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Application of -cyclodextrin:

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Some cyclodextrin-containing products Some cyclodextrin-containing products

World-wide there are close to 30 cyclodextrin containing pharmaceutical products on the market and most of them are marketed in more than one country. Almost half of them contain the natural CD.

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NEWER APPROACH TO SOLUBILIZATION

Hydrophilic Solubilization Technology (HST)

Lipophilic Solubilization Technology (LST)

Zydis - Fast dissolve Technology

Qdis – A Fast dissolve dosage form

Supercritical Fluids in Solubilization

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REFERENCES1. Encyclopedia of Pharmaceutical technology, Volume 3, Edited By

James Swarbrick, 2458-2477

2. Encyclopedia of Pharmaceutical technology, Volume 18, Edited By

James Swarbrick, 172-207

3. Physical Pharmacy, Third edition, By Alfred Martin

4. The theory and practice of Industrial Pharmacy, By Leon Lachman

5. The Science and Pharmacy practice Remington vol:1

6. Journal of Pharmaceutical Science, vol. 96, No. 7, July 2007

7. Indian Journal of Pharmaceutical Science, May-June, 2006, 301-307

8. Drug development and Industrial pharmacy.2007,39(8), 856-873

9. www.SCOLR.com

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