Pharmaceutics Week 3 Solutions 2 PDF

Solutions 2 PY4030/PY5130 Dr Gianpiero Calabrese Room MB1037, [email protected] Why are solution important? In order to be absorbed and thus exert an action a drug must be in solution Swallow a tablet → Tablet Disintegrates & Dissolves → Drug is absorbed Drug Tablet (SOLID) Dissolutio...

Solutions 2 PY4030/PY5130 Dr Gianpiero Calabrese Room MB1037, [email protected] Why are solution important? In order to be absorbed and thus exert an action a drug must be in solution Swallow a tablet → Tablet Disintegrates & Dissolves → Drug is absorbed Drug Tablet (SOLID) Dissolution Drug in solution in GI tract Absorption Drug in solution in Blood Dissolution of Drug Particle in GI Blood Diffusion through GI content Absorption through membrane Gastric fluid (pH 1-3) HAsol Diffusion Fine HA precipitate Absorption Dissolution can affect bioavailability of the drug Blood Noyes Whitney Dissolution Model It describes dissolution of a solid solute Cs= concentration of drug in diffusion layer C = concentration in gastrointestinal fluids k = rate constant of dissolution D = diffusion coefficient of drug in G.I. fluids A = surface area of drug particles in contact with G.I. fluids h = depth of diffusion layer pH and Physiology pH 1-3.5 Secretion of pepsin Variable transit time pH 5-7 Pancreatic enzymes and bile salts Transit ~ 3 hours pH 6-7.5 Bacterial enzymes Long and variable transit time Solubility of drug in water affects ratelimiting step. Non-water soluble drugs are said to be dissolution-rate limited. Measurement of Dissolution Rate Several methods exist for measuring the dissolution rate of solid drugs and drug products. These are described in the pharmacopoeias. • Beaker Method • Flask Stirrer Method • Rotating Disk Method • Rotating Basket Method • Paddle Method pH and Physiology Drug Tablet (SOLID) Dissolution pH effect on dissolution Drug in solution in GI tract Absorption pH effect on absorption? Drug in solution in Blood pH and Drug Absorption We have seen how the pH of a solution and the use of salts may affect drug solubility. However, there is a problem with this approach to increasing solubility. In order for a drug to be absorbed, the drug must permeate through biological membranes. These membranes are non-polar lipids. Ions do not enter lipid regions, so ions are not easily absorbed. Gastric fluid (pH 1-3) HAsol Diffusion Fine HA precipitate Absorption Blood Partition and Diffusion GI Fluid GI Membrane Water Lipid Blood Water Drug in Drug in solution blood Diffusion Partition Partition Basis of pH Partition Model The GI membrane separates the two solutions The drug is partitioned between the two liquid phases assume the GI membrane is a lipid barrier ionised molecules are hydrophilic and won’t pass through the barrier therefore only unionised molecules can be absorbed Absorption of Weak Acids Example: drug with pKa = 3.0 Stomach pH = 1.2 Mostly UNIONISED (HA) Blood pH = 7.4 Mostly IONISED (A-) Weakly acidic drug is readily absorbed Ionization in the blood prevents drug back across the membrane Summary Weak acids are absorbed easily at low pH since HA predominates Strong acids (pKa < 1.0) not absorbed at low pH since Apredominates Weak bases (pKa > 5) not absorbed at low pH since BH+ predominates) Weak bases can absorb from regions of higher pH –for example the small intestine Partition Coefficient P The ability of a molecule to partition between two phases depends on its solubility and diffusivity in each phase We use standard solvents to define the partitioning of a molecule This gives us the octanol- water partition coefficient, P The more hydrophobic the molecule, the larger the value of P Usually log P is tabulated. Hydrophilic drugs have negative log P values Interpreting log P Log P values tell us how a drug may partition between a cellular membrane and the cellular fluid for example Studies have found: Optimum CNS penetration around Log P = 2 Optimum Oral absorption around Log P = 1.8 Optimum Intestinal absorption Log P =1.35 Optimum Colonic absorption LogP= 1.32 Optimum Sub-lingual absorption Log P = 5.5 Optimum Percutaneous absorption log P = 2.6 Co-solvency The drug must be more soluble in the co-solvent The co-solvent must be completely miscible with water Calculating Solubility in Mixed Solvents It is generally found that the log10 of the solubility (S) of the drug in the mixed solvent is proportional to the volume fraction of co-solvent used. where x is volume fraction of co-solvent The volume fraction (x) of co-solvent is calculated as: x= Volume of co-solvent (Volume of co-solvent + volume of solvent) log S = m x + c ? ! ! Scenario: 40 ml of water (solvent ) + 35 ml of ethanol (co-solvent) x= 35 ml of co-solvent (35 ml of co-solvent + 40 ml of solvent) If water only is used x=0 c ! m = 0.47 If ethanol only is used x=1 You are asked to predict the solubility of a New Drug Entity (NDE) in 40 ml of water (used as solvent ) + 35 ml of ethanol (used as co-solvent). You know that its • solubility in pure water = 1 g in 1000 ml= 0.001 g/ml • solubility in pure ethanol = 1 g in 4 ml= 0.25 g/ml log S = m x + c If water only is used x=0 S = 0.001 g/ml log 0.001 = (m × 0) + c c = log 0.001 = -3.0 c = -3.0 m = 2.40 If ethanol only is used x=1 S = 0.25 g/ml log 0.25 = (m × 1) + c log 0.25 = m + (-3.0) m = (log 0.25) + 3.0 = 2.40 log S = m x + c ? x= Volume of co-solvent (Volume of co-solvent + volume of solvent) log S = m x + c log S = (2.4 × 0.47) + (-3.0) log S = -1.872 hence the value of S = 0.013 g/mL = 0.47 c = -3.0 m = 2.4 Excipients Use of solution? Injectable or for oral use? Co-solvents Future lectures Chelators Anti-oxidants Oxidation of a drug catalysed by free metal ions in solution Note: dots represent a radical RSH is a drug such as captopril Metal ion catalyzed: RSH + M(n+1)+ RS- + M(n+1)+ 2RS. RS. + H+ + Mn+ or RS. + Mn+ RSSR 2Mn+ + O2 M(n+1)+ + O22- O22- + H2O 2OH- + ½ O2 Role of Chelators The most effective catalysts (metal ions) are Cu and Fe (most likely contaminants found in additives, containers, closures or manufacturing equipment) The catalytic effect of metal ions can be prevented by adding disodium edetate, a chelating agent M (in red) represents the metal The structure (in black) the edetate Typical Antioxidants OH OH OH HO OH CH3 OCH3 Butylated hydroxy anisole (BHA) COOC3H7 Butylated hydroxy toluene (BHT) Propyl gallate HO HO Nordihydroguariaretic acid (NDGA) OH OH How Does BHT Work? .O R H O O . O . CH3 CH3 Butylated hydroxy toluene (BHT) R O . t-butyl substituents (highlighted in red) prevent side reactions at the ortho positions as they are bulky CH3 O Note: one BHT molecule scavenges two radicals RO References And Further Reading • Aulton's pharmaceutics : the design and manufacture of medicines, Sixth edition / edited by Kevin M.G. Taylor, Michael Aulton. • Physicochemical Principles of Pharmacy. A. Florence & D. Attwood, 5th edition, Pharmaceutical Press (2011).