A Saminar on PH partition theory, Slides of Pharmacy

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A SEMINAR ON

pH PARTITION THEORY

By

S.JHANSI RANI

DEPARTMENT OF INDUSTRIAL PHARMACY

UCPSC

CONTENTS

• INTRODUCTION

• pH-PARTITION THEORY
• DRUG pKa AND GASTROINTESTINAL pH
• LIPOPHILICITY AND DRUG ABSORPTION
• DEVIATIONS FROM THE pH PARTITION THEORY
• A UNIFYING HYPOTHESIS
• CONCLUSION
• REFERENCES

PHYSICOCHEMICAL PROPERTIES OF DRUG

SUBSTANCES:

1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudo polymorphism
5. Salt form of the drug
6. Lipophilicity of the drug
7. pka of the drug and pH
8. Drug stability

pH PARTITION THEORY:

• The theory states that for drug compounds of molecular weight greater than 100, which are primarily transported across the biomembrane by passive diffusion, the process of absorption is governed by:

1. The dissociation constant (pka) of the drug.
2. The lipid solubility of the unionized drug ( a function of drug K O/W

3. The pH at the absorption site.

DIAGRAM SHOWING THE TRANSFER OF DRUG

ACROSS THE MEMBRANE:

DRUG pka AND GASTROINTESTINAL pH:

• The fraction of drug in solution that exist in the unionized form is a function of both dissociation constant of the drug and the pH of the solution.
• The dissociation constant is often expressed for both acids and bases as pka (the negative logarithm of the acidic dissociation constant.)
• It is customary to express the dissociation constants of both acidic and basic drugs by pka values. The lower the pka of an acidic drug,the stronger the acid i.e., greater the proportion of ionized form at a particular pH. The higher the pka of a basic drug, the stronger the base.

i.e., for weak acids: pH = pka + log [IDC/UDC] % drug ionized = [ pH-pka /1+ pH-pka ]* For weak bases: pH = pka + log [UDC/IDC] % drug ionized = [ pka-pH /1+ pka-pH ]* when the concentration of ionized and unionized drug becomes equal, the second term of the equation becomes zero (since log1 = 0) and thus pH = pka. The pka is the characteristic of the drug.

• A barrier that separates the aqueous solutions of different ph such as GIT and plasma then the theoretical ratio R of drug concentration on either side of the membrane can be given by the equation
• For weak acids: R a

= C

GIT

/C

Plasma

pH GIT-pka / 1+ pH plasma-pka For weak bases: R =C GIT

/C

Plasma

pka-pH GIT / 1+ pka-pH plasma

• Most acid drugs are predominantly unionized at the low pH of gastric fluids and may be absorbed from the stomach as well as from the intestine.
• Very weak acid (pka>8) such as phenytoin, theophylline are essentially unionized throughout the GIT.
• The ionization of weak acids with pka values ranging from about 2.5 - 7. is sensitive to changes in ph. More than 99% of the weak acid aspirin (pka=3.5) exist as unionized drug in gastric fluids at pH=1. on the other hand, only about 0.1% of aspirin is unionized at pH 6.5 in the fluids of small intestine.
• Despite of unfavorable ratio of unionized to ionized drug, aspirin and most weak acids are well absorbed in the small intestine.A large surface area and a relatively long residence time in the small intestine are contributing factors.

• These factors minimize the need for a large fraction of the drug to be in an unionized form in the small intestine.
• Strong acids (di sodium cromoglycate) are ionized throughout the GIT and are poorly absorbed.

Comparison of gastric absorption at pH 1 and pH

8 in the rat

pka %absorbed at pH= %absorbed at pH= Acids 5 - sulfosalicylic Thiopental <2.

0 46 0 34 Bases Aniline Quinine

6 0 56 18

• Most weak bases are poorly absorbed, if at all, in the stomach since they are largely ionized at low pH.
• Codeine, a weak base with a pka of about 8 will have only 1 of every million molecules in the non ionized form in gastric fluid at pH 1.
• The pH range of the intestine from duodenum to the colon is about 5-8. weakly basic drugs (pka<5), such as dapsone, diazepam are essentially unionized throughout the intestine. Stronger bases such as mecamylamine and guanethidine are ionized throughout the GIT and tend to be poorly absorbed.

Comparison of intestinal absorption in rat at several pH

values

pka pH=4^ pH=5^ pH=7^ pH= ACIDS Salicylic Benzoic

64 62 35 36 30 35 10 5 BASES Aniline Quinine

40 09 48 11 58 41 61 54

LIPOPHILICITY AND DRUG ABSORPTION:

• The gastro intestinal cell membrane are essentially lipoidal. Highly lipid soluble drugs are generally absorbed while decidedly lipid insoluble drugs are in general poorly absorbed.
• Certain drugs are poorly absorbed after oral administration even though they are largely unionized in the small intestine, low lipid solubility of the uncharged molecule may be the reason.
• A guide to the lipophilic nature of a drug is its partition coefficient between a fat like solvent and water or an aqueous buffer.