Physical & Chemical Factors that Affect’s

Drug’s Biological Performance

Roselyn Aperocho-NaranjoPharmacy Instructor

USPF, College of Pharmacy

Particle Size

How does Particle size How does Particle size affects drug affects drug absorption?absorption?

The decreasing size of drug particles will increase the surface area of the drug & will cause a rapid dissolution rate in a dissolution media.

Particle Size

However, the solubility does not significantly affect the particle size reduction or micronization in the manufacture of pharmaceutical agents.

Drug’s therapeutic effect depends on its particle size: Amphotericin, aspirin, bishydroxycoumarin,

chloramphenicol, griseofulvin, digoxin, fluocinolone acetonide, meprobamate, nitrofurantoin, phenobarbital, phenothiazine, phenylbutazone, prednisolone, penicillin, sulfadiazine, and tolbutamide.

Co-Solute & Complex Formation

The co-solute formation is concerned only with drugs having low solubility.

Processes of forming co-solutecompounds:1. Salting-out

Organic nonelectrolyte

dissolved

water

NaClNa

Cl

Precipitated organic nonelectrolye

Hydrated ions

Co-Solute & Complex Formation

The co-solute formation is concerned only with drug’s having low solubility.

Processes of forming co-solutecompounds:1. Salting-In

Undissolved organic electrolyte

water

Organic salt/AcidOr Salt of Ammonium

compounds

RCOOH

dissolved organic electrolyte

3. Clathrate FormationClathrate forming substances are: Gallic acid, urea, thiourea, amylose and zeolite

Drugs used in dissolving clathrates are:- Vitamin A, Sulfathiazole, chloramphenicol & reserpine.

Co-Solute & Complex Formation

Co-Solute & Complex Formation

4. Solid-in Solid Solution Complex

- is formed when a melted solid substance is mixed with another solid such as mannitol dissolved in succinic acid. These substances are rapidly dissolved in water.

Chemical Variation

Made for two reasons:1. change the strucutre of the active compound to increase pharmacologic response

2. maintain basic structure but the solubility is changed by the formation of either salts, ester, ether or other complex compounds.

Chemical Variation

Salt formation Electrolytes have higher solubility More rapidly dissolved/faster dissolution

rate than free acids & free bases In acidic drugs, dissolution rate increases

with increasing pH (salt formation)

• Esters- drugs dissolves at higher pH in the

small intestines- possess different rate of hydrolysis

Amorphous Crystalline Solids

Is more stable and have higher dissolution rate than the crystalline form

Example: PenG should not be used in amorphous form because it is more rapidly dissolved in the stomach fluid the crystalline form.

Anhydrous Form, Hydrates & Solvates

HydratesHydrates – are additon compounds of drugs with water

- dissolves more rapidly than the crystalline form

SolvatesSolvates – are addition compounds of drug and organic solvent

- dissolves faster than the non-solvated form

Polymorphism

Drug exist in different forms Exist only in a solid state Highest form of stability but lowest

dissolution rate When dissolution rate is high, stability

is low Can be stabilized by adding viscosity

increasing agents

Viscosity

Prolongs the diffusion time of solvent molecules

Disintegration & dissolution of drugs in tablet form is decreased with increasing viscosity

Food increases the viscosity of GIT content

Delay the absorption of drugs such as ethanol, salicylic acid, sulfonamides

Solubilizing Agents

Refers to Surface Active Agents (surfactants) The drug possess a hydrophilic and a

lipophilic ends, these will associate with the solvent molecule forming a colloidal solution

The associate ,molecules formed are called micelles or aggregates

Critical Micelle Concentration contains 50 to 150 molecules

If drug concentration is below the CMC, released rapidly

Solubilizing Agents

If drug concentration is below the CMC, released rapidly

If the CMC of the drug is high, drug release is affected

Examples are drug that are not diluted upon administration such as those given topically, rectally, intramuscularly and subcutaneous route

Solubilizing Agents

Drugs may have an increased bioavailability due to the surface active agents added

Include vitamin A, riboflavin, spironolactone and sulfisoxazole

Adsorption

Is the tendency of the substance to accumulate at a surface due to the unbalanced forces that causes the attraction of molecules on any surface.

Occur when the valence requirement of the molecule is bonded to adjacent molecules.

Adsorption

These attraction between adjacent molecules is called Van der waals force.

Adsorption & desorption occur rapidly Chemisorption occur when the valence

requirements of surface molecule are not fully met by the adjacent molecules.

Usually require heating to activate electron transfer

Example: Charcoal is used as antidote due to its adsorptive property.

Manufacturing Factors

Increased tablet compression and Increased amount of binders forced increased hardness of tablets and may prolong disintegration and dissolution time.

Increased amount of lubricants decrease hydrophilicity and wetting of tablets, also prolong disintegration and dissolution time

Manufacturing Factors

Increased amount of heat will cause suppositories to dissolve in the base which when cooled down,, it will form crystals and large needles thus prolonging the drug release

Summary

Different factors alter biological performance of drugs such as the rate and extent of drug release from the dosage form upon administration

Drugs should be in aquoues form except for rare cases of pinocytosis

Drug release can be determined in vitro by dissolution rate test for peroral and oral dosage forms and by dialysis for rectal and topical preparations

Summary

Drugs having different release characteristic reslts in different blood level curves in vivo

The difference in drug release is caused by the rates of drug release rather than the absorption pattern

Absorption rate is encountered in drugs with low solubility

Prepare on whole sheet of paper

Answer the following questions:How does the following factors affect the

release of drug from its original dosage form and solubility?

A. ClathratesB. Solid Amorphous FormsC. Chemical VariationD.