Physical & Chemical Factors that Affect’s Drug’s Biological Performance

1. Physical & Chemical Factors that Affect’s Drug’s Biological Performance Roselyn Aperocho-Naranjo Pharmacy Instructor USPF, College of Pharmacy

2. Particle Size How does Particle size affects drug 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.

3. Particle Size • However, the solubilitydoes 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.

4. Na Cl Co-Solute & Complex Formation • The co-solute formation is concerned only with drugs having low solubility. Processes of forming co-solute compounds: • Salting-out Hydrated ions water NaCl Organic nonelectrolyte dissolved Precipitated organic nonelectrolye

5. RCOOH Co-Solute & Complex Formation • The co-solute formation is concerned only with drug’s having low solubility. Processes of forming co-solute compounds: • Salting-In water Organic salt/Acid Or Salt of Ammonium compounds dissolved organic electrolyte Undissolved organic electrolyte

6. Co-Solute & Complex Formation 3. Clathrate Formation Clathrate forming substances are: • Gallic acid, urea, thiourea, amylose and zeolite Drugs used in dissolving clathrates are: • Vitamin A, Sulfathiazole, chloramphenicol & reserpine.

7. 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.

8. 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.

9. 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

10. 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.

11. Anhydrous Form, Hydrates & Solvates Hydrates – are additon compounds of drugs with water - dissolves more rapidly than the crystalline form Solvates – are addition compounds of drug and organic solvent - dissolves faster than the non-solvated form

12. 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

13. 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

14. 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

15. 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

16. Solubilizing Agents • Drugs may have an increased bioavailability due to the surface active agents added • Include vitamin A, riboflavin, spironolactone and sulfisoxazole

17. 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.

18. 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.

19. 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

20. 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

21. 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

22. 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

23. 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. Clathrates B. Solid Amorphous Forms C. Chemical Variation D.