Biopharmaceutics 4th year

Biopharmaceutics: is defined as the study of factors influencing the rate and amount of drug that reaches the systemic circulation. Absorption is the process of movement of drug from its site of administration to systemic circulation. Bioavailability is defined as the rate and amount of drug that reach systemic circulations

Drug Absorption and Bioavailability The oral route of drug administration is the most common for systemically acting drugs. To achieve the desired therapeutic objective, the drug product must deliver the active drug at an optimal rate and amount.

Drug absorption and Bioavailability After oral administration of solid dosage form the drug undergo the following steps

Drug absorption and Bioavailability After oral administration of solid dosage form the drug undergo the following steps: Disintegration of drug product Deaggregation and release Dissolution Movement of the dissolved drug to systemic circulation  

Factors affecting GI absorption of drug Physicochemical factors Dosage form factors Patient related factors

Factors affecting GI absorption of drug Physicochemical Factors

1) Drug solubility and dissolution rate Events that occur after oral administration of solid dosage form

1) Drug solubility and dissolution rate The two rate determining process in orally administered drug are   Rate of dissolution Rate of permeation

1) Drug solubility and dissolution rate -Dissolution is RDS in hydrophobic drug - If drug is hydrophilic dissolution is rapid but permeation through biomembrane is said to be RDS.

2)Particle size and effective surface area -Particle size and effective surface area are inversely related to each other. -Effective surface area?? -According to Noyes-Whitney equation - Greater the effective surface area, more the contact between the solid surface and the aqueous solvent and faster dissolution.

2)Particle size and effective surface area -Reduce in particle size can be done by micronization. -Particle size reduction is not always advisable especially when the drugs are unstable and degrade in solution form (penicillin G and erythromycin) or produce undesirable effect like gastric irritation (nitrofurantoin).

3) Polymorphism and Amorphous Depending on internal structure , solid can exist as crystalline or amorphous when a substance exist in more than one crystalline form is known as polymorph and the phenomena known as polymorphism

3) Polymorphism and Amorphous Polymorphs differ in their physical properties: Solubility Melting point Density Hardness Compression characteristics

3) Polymorphism and Amorphous Depending on stability: Stable polymorph : Lowest energy state High melting point Least aqueous solubility Metastable polymorph: higher energy state lower melting point High aqueous solubility

3) Polymorphism and Amorphous -Since metastable have greater aqueous solubility show better bioavailability and are more preferred in formulations -Metastable on aging convert to less soluble stable -This conversion can be inhibited by dehydration of the environment or adding viscosity building agent such as PVP , gelatin….

3) Polymorphism and Amorphous Amorphous have higher aqueous solubility than crystalline form Order of dissolution of solids Amorphous > metastable> stable

4) Hydrate/Solvate -the anhydrous form of the drug has greater aqueous solubility than the hydrates . -The hydrate is already in interaction with water so has less energy to break up than the anhydrates The anhydrous form of theophylline and ampicillin have greater aqueous solubilities Dissolve at faster rate Show better bioavailability In comparison to monohydrate and trihydrate form respectively.

Most of drug are either weak acid or weak base 5) Salt form of drug Most of drug are either weak acid or weak base To enhance their solubility and dissolution rate they converted to their salt form

5) Salt form of drug With weak acidic drug a strong base salt is prepared e.g. sodium or potassium salt With weak basic drug a strong acid salt is prepared e.g. HCL salt or sulfate salt

5) Salt form of drug -In the case of salt of weak acid the pH of the diffusion layer will be higher than that of free acid -Due to high pH of the diffusion layer solubility and dissolution of weak acid occur

5) Salt form of drug -In the case of salt of weak base the pH of the diffusion layer will be lower than that of free base -Due to low pH of the diffusion layer solubility and dissolution of weak base is enhanced

5) Salt form of drug

6) Drug pKa and Gastrointestinal pH - Most drugs are weak acid or weak base - undergo ionization at pH of biological fluid Only unionized drug if its lipid soluble can permeate the membrane Amount of unionized drug depend on pKa and pH of biological fluid

6) Drug pKa and Gastrointestinal pH -the amount of ionized and unionized drug can be determined by Henderson-Hasselblach equation For weak acids

6) Drug pKa and Gastrointestinal pH Henderson-Hasselblach equation For weak bases

6) Drug pKa and Gastrointestinal pH

6) Drug pKa and Gastrointestinal pH

7) Lipophilicity and drug absorption - if the drug exists in unionized form it will be poorly absorbed if it has poor lipid solubility ideally, the drug should have sufficient aqueous solubility to dissolve in the fluids at the site of absorption and High lipid solubility to facilitate the partitioning of drug through biomembranes to systemic circulations