PPH407 Lecture Notes Biopharmaceutics & Pharmacokinetics - Spring 2024 PDF

Faculty of Pharmacy PharmD Clinical Program Biopharmaceutics & Basics of Pharmacokinetics Spring 2024 Level 3 Dr. Mohammed Salah Teiama Associate Professor of Pharmaceutics & Industrial Pharmacy  Write the following question ✓ Stomach is the site of absor...

Faculty of Pharmacy PharmD Clinical Program Biopharmaceutics & Basics of Pharmacokinetics Spring 2024 Level 3 Dr. Mohammed Salah Teiama Associate Professor of Pharmaceutics & Industrial Pharmacy  Write the following question ✓ Stomach is the site of absorption for weak acidic drug (T or F & why) ✓ Azithromycin dose & why ????????????? ✓ 1000 mg tablet = 2 * 500 mg tablet (T or F & why) ✓ Absorption from syrup or elixir??????? ✓ Inulin or Insulin ??????????? Factors affecting drug Bioavailability The bioavailability of a drug is dependent on The anatomy and physiology of the drug absorption site (Physiological factors) The physicochemical properties of the drug. (Physicochemical factors) The nature of the drug product. (Formulation factors)  2) Physicochemical factors 1. pH partition theory 2. Drug lipid solubility 3. Drug stability in GIT 4. Drug dissolution  2) Physicochemical factors 1. pH partition theory It explains the influence of GI pH and drug pKa on the extent of drug transfer or drug absorption. When a drug is ionized it will not be able to get through the lipid membrane. But only when it is non - ionized and therefore has a higher lipid solubility. The ratio [Unionized U] / [Ionized I] depends on of the pH of the solution and the pKa of the drug;  2) Physicochemical factors 1. pH partition theory The ratio [Unionized U] / [Ionized I] described with Henderson – Hassel Bach equation  2) Physicochemical factors 1. pH partition theory Therefore, according to these equations: 1. A weakly acidic drug, pKa 3.2 will be predominantly unionized in gastric fluid at pH 1.2 ( 1 / 100 = 99%) and almost totally ionized in intestinal fluid at pH 6.8 (99.9%). 2. A weakly basic drug, pKa 5.2, will be almost entirely ionized (1/10000) at gastric pH of 1.2 and predominantly unionized at intestinal pH of 6.8 (98.4%).  2) Physicochemical factors 1. pH partition theory Therefore, according to these equations: A weakly acidic drug is more likely to be absorbed from the stomach where it is unionized. A weakly basic drug from the intestine where it is predominantly unionized. Limitation  2) Physicochemical factors 1. pH partition theory Limitations of the pH-partition hypothesis ✓ Weak acids are also absorbed from the small intestine due to: 1. The significantly larger surface area that is available for absorption in the small intestine in contrast to stomach 2. The longer small intestinal residence time 3. The microclimate pH, that exists at the surface of the intestinal mucosa and is lower than that of the luminal pH of the small intestine  2) Physicochemical factors 1. pH partition theory Limitations of the pH-partition hypothesis ✓ The pH -partition hypothesis cannot explain the fact that certain drugs (e.g. tetracycline) are readily absorbed despite being ionized over the entire pH range of the gastrointestinal tract. ✓ Such drugs may interact with endogenous organic ions of opposite charge to form ion pair which is capable of partitioning into the lipid GIT barrier and be absorbed via passive diffusion.  2) Physicochemical factors 2. Drug lipid solubility ✓Barbitone and thiopentone, have similar dissociation constants (pKa 7.8 and 7.6 respectively) and therefore similar degrees of ionization at intestinal pH. ✓However, thiopentone is absorbed much more than barbitone. ✓Thiopentone, being more lipid soluble than barbitone, exhibits a greater affinity for the gastrointestinal membrane and is thus far better absorbed. 2) Physicochemical factors 2. Drug lipid solubility Barbital Thiopental 2) Physicochemical factors 2. Drug lipid solubility Tetracycline (Pka 3.3) Doxycycline (Pka 3.09)  2) Physicochemical factors 2. Drug lipid solubility ✓ Doxycycline (Vibramycin) is more lipid soluble than tetracycline ✓ How to be measured? ✓ The drug lipid solubility is measured by its partition coefficient between organic and aqueous phases. ✓ The higher the partition coefficient the more lipid soluble the drug and hence the more absorption is expected given that the drug is capable to dissolve.  2) Physicochemical factors 3. Drug stability in GIT ✓ Drugs may be chemically degraded and metabolized in the GIT and result in decreasing of the bioavailability. ✓ e.g., penicillin, erythromycin, spiramycin and azithromycin undergo acid catalysis hydrolysis in gastric fluid (may need to be enterically coated). ✓ What is the recommended dose of azithromycin ✓ Also some drugs are susceptible to enzymatic hydrolysis by enzymes located in the GIT like chlorpromazine, progesterone and testosterone.  2) Physicochemical factors 4. Drug Dissolution ✓ There are two possible scenarios for drug dissolution: 1. Rapid dissolved drug: absorption will be the rate limiting step. 2. Poorly dissolved drug: dissolution will be the rate limiting step. Therefore, the drug absorption (bioavailability) relies on the dissolution rate. So, drug bioavailability can be improved by increasing the rate of dissolution. Noyes-Whitney Equation and Drug Dissolution:  2) Physicochemical factors 4. Drug Dissolution ✓ In order for absorption to occur, a drug or a therapeutic agent must be present in solution form. ✓ This means that drugs administered orally in solid dosage forms (tablet, capsule, etc.) or as a suspension (in which disintegration but not dissolution has occurred) must dissolve in the gastrointestinal (GI) fluids before absorption can occur.  2) Physicochemical factors 4. Drug Dissolution ✓ When solid particles are in the GI tract, a saturated layer of drug solution builds up very quickly on the surfaces of the particles in the liquid immediately surrounding them (called the diffusion layer or stagnant layer). ✓ The drug molecules then diffuse through GI content to the lipoidal membrane where diffusion across the gastrointestinal membrane and absorption into the circulation takes place. 2) Physicochemical factors 2) Physicochemical factors 4. Drug Dissolution ✓ Noyes-Whitney Equation and Drug Dissolution: ✓ The equation, in many aspects, is similar to Fick’s law of diffusion:  2) Physicochemical factors 4. Drug Dissolution ✓ Factors Affecting the Dissolution Rate: 1. Surface area and particle size. 2. Solubility of drug in the diffusion layer. 3. The crystal form of a drug. The state of hydration. 1. Complexation. 2. Chemical modification. Polymorphism  2) Physicochemical factors 4. Drug Dissolution 1. Surface area and particle size. A drug dissolves more rapidly when its surface area is increased. SA ↑: ↓ particle size of the drug. Poorly soluble and slowly dissolving drugs are marketed in micronized or microcrystalline form (i.e. particle size of 2–10 mm). milling, grinding and solid dispersions. (PS, SA α B) For example decreasing the particle size of digoxin from 102 μM to approximately 10 μM resulted in 100% increase in bioavailability.  2) Physicochemical factors 4. Drug Dissolution 1. Surface area and particle size. ✓ But there is a certain limit ? Suggestions please ✓ Reduction in the particle size alone, however, is not enough to improve the dissolution rate of drug particles, especially, for hydrophobic drugs. ✓ Wetting agent: Tween, Span, SLS. Or lecithin  2) Physicochemical factors 4. Drug Dissolution 2. Solubility of the dug in the Diffusion layer ✓ Solubility could be affected by: 1. Salt formation: salt of weak acid or weak base. Sodium salicylate is 550 folds more soluble than the acid. 2. Crystalline and amorphous: amorphous more soluble. Novobiocin 10 times more soluble. 3. Polymorphism: Solubility, stability, melting point, dissolution rate. Metastable more soluble than stable form (chloramphenicol)  2) Physicochemical factors 4. Drug Dissolution 2. Solubility of the dug in the Diffusion layer ✓ Solubility could be affected by: 4. Hydration state: Anhydrous form is more soluble. Ex: Erythromycin, Ampicillin-trihydrate. 5. Complex formation: excipient may be added to improve drug solubility as cyclodextrins. N.B: some drugs form less soluble complexes inside GIT, for example Tetracycline with calcium ion, Neomycin and kanamycin with bile acid  2) Physicochemical factors 4. Drug Dissolution 2. Solubility of the dug in the Diffusion layer 5. Complex formation: excipient may be added to improve drug solubility as cyclodextrins. cyclodextrin  3) Formulation factors 1. Solution as a dosage form 2. Suspension as a dosage form 3. Capsule as a dosage form 4. Tablet as a dosage form 3) Formulation factors Drug to be absorbed from the dosage form, it should be dissolved inside GIT Therefore, it expected for the formulae to show more rapid rate of absorption and may be different extent (bioavailability) according to the order. Solution>Suspension>Capsule>Tablet>Coated tablet>SR tablet It is just a guideline but not universal and not constant order  3) Formulation factors All the physicochemical properties of drugs (i.e. particle size, pKa, etc.) will contribute to the dosage form design Additives incorporated into the dosage form (e.g. diluents, etc.) often may alter the absorption of a therapeutic agent from a dosage form. Ex: a difference of more than 60-fold has been found in the absorption rate of spironolactone (Aldactone®) from the worst to the best formulae 3) Formulation factors 1. Solution as a dosage form Drug absorbed more rapidly from solution. The rate of drug absorption depends on the GER Some excipients like glycerin and propylene glycol, that may be used in formulation of solution reduce GER, and reduce drug absorption The major concern about the solution of dosage form, the stability of dissolved form of the drug 3) Formulation factors 2. Suspension as a dosage form The rate limiting step in drug absorption is drug dissolution Micronized powder gives more rapid absorption Suspension with lower particle size, better wetting agent, amorphous not crystalline particles, and lower viscous vehicle; will give better absorption 3) Formulation factors 3. Capsule as a dosage form Gelatin shell disrupt to release the content to GIT. The capsule contents are not comprised like tablets, so released directly to the bulk of GIT (Hydrophilic or hydrophobic) Hydrophobic contents show bad dissolution and absorption Dispersing agent (gum solution), or hydrophilic diluent (sorbitol, lactose) usually added to increase powder wettability 3) Formulation factors 4. Tablet as a dosage form SA of tablets that exposed for effect of GIT juice until the tablet have broken down is small (dissolution eq) This small SA affect disintegration, dissolution, and bioavailability Enteric coated tablet and SR formulae showed lower dissolution pattern 3) Formulation factors 4. Tablet as a dosage form Factors responsible for the primary breakdown of tablets into granules and their subsequent breakdown into finer particles include: Hydrophobicity of the drug. Type and concentration of a binder. Disintegrating agent. Diluents. Lubricants. Method of manufacture (wet granulation, dry granulation and direct compression). Coating agents used. 3) Formulation factors 4. Tablet as a dosage form Excipients can influence the drug bioavailability: Diluent: Phenytoin with lactose (toxic level, higher absorption), with calcium sulphate dihydrate (insoluble complex, lower absorption) Diluent: kaolin with vitamins, adsorption. Lower bioavailability Binder: xx amount of gums (acacia, PVP), viscous solution, slower GER, may increase or decrease bioavailability 3) Formulation factors 4. Tablet as a dosage form Excipients can influence the drug bioavailability: Lubricant: Mg stearate, talc, hydrophobic, less wetting, less F. Coating: shellac (resist acidic pH), cross linkers (decrease dissolution rate) Disintegrating agent: type and concentration affects F. Thank You