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Physicochemical drug

interaction

Cation and anion interactions

(2)

Applications of Cation and anion interactions

Cation and anion interactions

(2)

Dilution of mixed solvent system.

(2)

Ion-pair formation :

What is cation and anion ?

In several cases the special nature of a formulation will preclude dilution by an aqueous infusion fluid.

- The interaction between a large organic anion and organic cation may result in formation of relatively insoluble precipitate or phase separation.

the process of an atom an ion is called "ionization".

is Neutral species formed by electrostatic attraction between oppositely charged ion in solution, which are often sufficiently lipophilic to dissolve in nonaqueous solvent.

* Injectable products containing phenytoin , digoxin and diazepam may come into this category if they are formulated in a nonaqueous but water – miscible solvent ( e.g. an alcohol-water mixture ) or as a solubilize (e.g. Micelle ) preparation.

2-Colloid

1-Micelles

Positive ion (cation):

atom loses an electron .

The formation of an ion pair result in :

burying of charges and alteration to

the physical properties.

Negative ion (anion):

-The interaction are not always visible the formation of visible precipitate depends to

large extent on the insolubility of the two

combining species in the particular

mixture and the size to which the

precipitate particular grow.

* Addition of the formulation to water may result in precipitation of the drug depending on the final concentration of the drug and solvent .

atom gains an electron

3- Flocculating

(2)

p in vivo

(in the body)

(3)

(2)

pH in vivo

(in the body)

(3)

pH in vitro

(in an artificial environment)

pH in vivo and vitro

Dilution of mixed solvent system.

(2)

pH in vitro

(in an artificial environment)

(2)

Sensitivity of drugs to changes in the pH of their environments means that:-

*The aim of graphical method is to plot diluion curves and solubility curves on the same graph .

-Chemical and physical stability may result

in the changes of pH, buffering capacity, salt formation or complexation.

*A graphical technique has been described to predict whether solubilised drug system will become supersaturated and thus have the potential to percipitate

The pH in a medium, whether

in a formation or in the body can be a primary determent of a drug behavior.

hydrogen ion will be an important determinant of solubility, crystallization and partitioning

**Advantages:

avoids the need to teach the antibody producer tissue culture method.

* When a drug dissolved in a cosolvent system is diluted with water, both drug and cosolvent are diluted.

*This is achieved in, where the dilution curve have been potted semilogarithmically for thee systems containing initially 1,2 and 3 mg.cm of drug substance ( plot l,ll,and lll, respectively).

**Advantages:

avoids and decrease for the laboratory personal experienced in subject handling(like animals).

-when there’s chemical instability it may give

rise to the formation of inactive or toxic products.

ex: -Gastric pH is 1-3 normal in the human stomach.

-The stomach PH changes by ingesting

antacids ,food ,weak electrolytes.

* Addition of this formulation to normal saline result in the formation of the precipitate .

-Gastric secretion can be inhibited by

some drugs.

* With solution lll, dilution below about 30% cosolvent cause the system to be supersaturated.

*With solution ll, below 20% codolvent the solubility line and the

dilution line touch only eith solution containing 1 mg cm can

there be dilution whithout preciptation.

-some additives may change the pH of a

solution or solvent.

* The logarithm of the solubility of a drug in a cosolvent system

generally increase lineary with percentage of cosolvent present

**Disadvantages:

can cause significant pain or distress on

subject.

**Disadvantages:

methods more expensive.

* On dilution, the drug concentration falls linearly whith

a fall in the percentage of cosolvent .

Ex: 500mg of ampicillin sodium can

raise the pH of 500cm3 of some

fluids to over 8.

(6)

(5)

Complexation

Solubility & dissolution

(in vivo)

(2)

(4)

(2)

Lipid solubility

Importance complexation:

Lipid solubility

What is Complexation?

Drug complexes:

How dissolution of the drug affects its absorption ?

How dissolution of the drug affects its absorption ?

6-Lipid solubility

Relative Solubility of drug:

How dissolution of the drug affects its absorption ?

presence of both lipophilic and hydrophilic features within structure,

logP < 0.5

water soluble drug

Eg: gentamicin , heparin , streptokinase

Poorly absorption after oral so it given by injection

1-Drug complexation can lead to beneficial properties such as enhanced aqueous solubility

(e.g. theophylline complexation with ethylenediamine to from aminophylline) and stability

(e.g. inclusion complexes of labile drugs with cyclodextrins).

Caffeine + organic acid anions – more water soluble; example complex with xanthine .

Drugs need to dissolve before they can be absorbed ..

A coordination complex is the product of a Lewis

acid-base reaction in which neutral molecules or anions (called ligands ) bond to a central metal atom (or ion) by coordinate covalent bonds.

Laboratory Estimation of Relative Solubility:

• drugs’ molecules which possess balanced solubility is much better absorption.

Noyes-whitney equation:

2- Complexes can alter the pharmacologic activity of the agent by inhibiting interactions with receptors.

logP > 0.5

lipid soluble drug

Absorbed after oral administration

-Measure of lipophilicity .

-Determined by the ratio of the solubility of drug in an organic solvent to the solubility of the same drug in an aqueous solvent

-Which called partition coefficient (P).

Factor affecting in complexation :

Used to discribe dissolution of drug ..

Dm\dt = DA (Cs - C) \ h

1- Surface area and particle size

 Eg: antifungal drug griseofulvin

2- pH

Eg: antifungal drug ketoconazole

3- salt

Eg: anti-inflamatory drug & osteoarthritis naproxen

4- crystal form

Eg: antibiotic novobiocin

5- surfactant

Eg: aqueous suspention phenacetin for pain relieving and fever reducing

6- Lipid solubility

Caffeine + organic acids – less soluble but masks the bitter taste of caffeine.

Ex – complex w/ gentisic acid formulated in extended release chewable tablet.

Because there is a need for drugs’ molecules to move through both

-aqueous (plasma,extracellular fluid, cytoplasm, etc.) .

-lipid media (biologic membranes) .

3- In some instances, complexation also can lead to poor solubility or decreased absorption of drugs in the body

- Ionic strength

- Temperature

- pH

- Competing ions

logP > 3

Very lipid soluble drug

- Absorbed but more susceptible metabolizm &

biliary clearance.

-Drugs with LogP value close to 2

able to enter the CNS.

• n-Octanol (lipid phase) have similar properties for

biological membrane

• Phosphate buffer of pH 7.4 (aqueous phase).

• P is often expressed as a log value

Complexation of benzocaine with salicylates will decrease the boavailability of benzocaine while its comlexation with PEG will increase its absorption

4- Complexation also can aid in the optimization of delivery

systems (e.g. ion-exchange resins) and affect the

distribution in the body after systemic administration as

a result of protein binding

Eg: thiopen

(7)

Protein binding of Drug

(7)

Protein binding of Drug

1- Drug related factor

Types of protein drug binding

2- Drug interaction

Factor affecting protein binding of drugs:

Fate of Bound and Unbound Drug:

A)-Displacement interactions

competition between Drugs for the binding sites.

A)-Physiochemical characteristics of the drug

Increase in lipophilicity increases the extent of binding

-Acidic drugs bind to HSA

-Basic drug to AAG

-Neutral drug to lipoproteins

1- Reversible

Hydrogen bonds

Hydrophobic bonds

Ionic bonds

Van der waal’s forces

The bound drug is kept in the blood stream While the unbound component may be metabolized or excreted ( making it the active part)

2- Irreversible

Irreversible drug binding, though rare, arises as result of covalent binding and often a reason for carcinogenicity or tissue toxicity of the drug

B)- Competition between drug and normal body constituents

The free fatty acids are known to interact with a number of drugs that bind primarily to HSA.

-Factors relating to the drug

-Factors relating to the protein and other binding component

- Drug interaction

-Patient related factors

B)- concentration of drug in the body

Alternation in the concentration of drug substance as well as protein subsequently brings alternation in the bindin

C)- Allosteric changes in protein molecule

The process involves alteration of the protein structure by the drug or it’s metabolic thereby modifying its

binding capacity

C)- Affinity of a drug for a particular binding component

e.g: Digoxin has more affinity to cardiac muscles

protein as compared to skeletal muscles.

(1)

Physicochemical factors:

(1)

Physicochemical factors:

Physicochemical Interaction

(1)

Physicochemical Interaction is

known as :

- changes in pH which lead to precipitation of the drug .

- Ion exchange interaction where ionised drugs interact with oppositely charged resins .

* Drug-drug interactions are modifications of the effects of one drug when used in conjunction with another drug .

- Change f solvent characteristics on dilution, which may also cause precipitation

- Adsorption to excipients and containers causing

loss of drug .

- Cation-anion interactions in which complexes are formed .

*Drug –drug interaction can take place before administration of a drug. These may result in precipitation of the drug from solution, loss of potency or instability .

- The influence of salt on decreasing or increasing solubility, respectively salting-out and salting-in .

- Protein binding to plasma proteins through which the free plasma concentration of drugs’s reduced .

* These interactions, which can result in either an augmentation or diminution of pharmacologic

activity, may account for a significant proportion

of all adverse drug reactions.

- Interaction with plastics and loss of drug .

Physicochemical Drug Interaction

Learning objectives:

1-Describe the effect of ionization on drug interaction.

2-undersatd the effects of solvent dilution on drug interaction.

3-diffrenate between PH in vivo and vitro.

4-understand factors that affecting the solubility and dissolution in vivo.

5- summaries the factors affecting protein binding and complexation.

Cation is:

log value OF partition coefficient (P) > 0.5 , means :

The drug complexation can lead to enhanced :

A- more electron than proton.

B-negative ion.

C- more proton than electron.

D-atom gain electron.

A- lipid soluble drug

B- water soluble drug

C- Very lipid soluble drug

D- Not lipid or water soluble

A- solubility

B- stability

C- temperature

D- A & B

1- Physical Pharmacy; by Alexander T. Florence (Author), David Attwood (Author). (2007), pharmaceutical Press. ch:8,p125 .

solubility of weakly acidic drugs increase with :

From the following what's factor affecting protein binding of drug:

2- physicochemical principles of pharmacy-6th edition; By alexander taylor florence d. attwood. (2012), pharmaceutical Press, london.

ch:11, p:451

ch:11, p:450

ch:11, p: 444

ch:4, p:153

3- National Research Council (US) Committee on Methods of Producing Monoclonal Antibodies, (Summary of Advantages and Disadvantages of In Vitro and In Vivo Methods) -1999, National Academy of Sciences

a) Drug interaction

b) Factor relating to solubility

c) Factor relating to the drug

d) A-C

A- pH increase ( base media )

B- pH decrease ( acid media )

C- increase lipid solubility of drug

D- decrease lipid solubility of drug

4- Aulton's Pharmaceutics-4th edition; By Michael E. Aulton, Kevin M.G. Taylor. (2013), Churchill Livingstone. ch:20, p:314.

5- artical https://www.corrosionpedia.com/definition/305/complexation

6- http://www.slideshare.net/eckotanglao/complexation-and-protein-binding

7- Handbook of essential pharmacokinetics, pharmacodynamics

and drug metabolism for industrial scientists by; younggil kwon,

2002, kluwer academic. Ch:7, p114

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