Lecture 6: Physical Pharmacy PDF

Faculty of Pharmacy & Drug Manufacturing PHYSICAL PHARMACY Lecture 6 1  Diffusion and Dissolution Dissolution is the process by which a solid solute enters into a solution when added...

Faculty of Pharmacy & Drug Manufacturing PHYSICAL PHARMACY Lecture 6 1  Diffusion and Dissolution Dissolution is the process by which a solid solute enters into a solution when added to a suitable solvent Dissolution rate: the rate at which the solid dissolves in a solvent. Tablet or capsule Dissolution Disintegration Drug Dissolution in Granules or Drug in blood aggregates Absorption solution and other body Disaggregation fluids Dissolution Fine particles 2 The above diagram shows the steps of disintegration, dissolution and absorption of solid drug form tablet or capsule. The dissolution of a solid drug is the slowest step; hence it is the rate limiting step (RLS) in absorption of such drugs. The dissolution of solids in a liquid is of two stages 1- An interfacial reaction liberation of solute molecules from the solid phase. The solution in contact with the solid will be saturated. 2- Migration of solute molecules through the boundary layers surrounding the crystal to the bulk of the solution via diffusion or convection, which determine the rate of dissolution. 3 * Dissolution will occur if solute and solvent are attractive to a degree that is sufficient to overcome solute-solute and solvent-solvent interaction. Diagrammatic representation of the processes involved in the dissolution of a crystalline solute. The release of a drug from a dosage form involves the processes: 1- Dissolution 2- Diffusion 4 Diffusion: is the process of spontaneous migration of solute molecules from a region of higher concentration to a region of lower concentration till the concentration (chemical potential) is uniform throughout the system. The passage of solute molecules through the barrier occurs either by: A- Simple molecular diffusion (permeation) → it involves dissolution of solute in the bulk membrane. or B- Movement through pores and channels→ it involves the movement of solute molecules through solvent pilling the pores of the membrane. 5 Fick's first law of diffusion States that: "the rate of diffusion of a solute molecule through a barrier is proportional to the concentration gradient" 𝑱∝ 𝒅𝒄/𝒅𝒙 → 𝑱 = −𝑫 𝒅𝒄/𝒅𝒙 Where: J = amount/time → the flux diffused component dc/dx = concentration gradient. D = diffusion coefficient of a solute in certain solvent (constant value for a particular system at a given temperature. (-) sign → diffusion occurs in a direction opposite to high concentration N.B. Fick's first law → gives the amount transported across unit area of barrier per unit time. 6  Principles in biological system Drugs molecules pass through living membrane either by passive transport active transport. 1- Passive transport: simple diffusion from a region of higher concentration to a region of low concentration as in drug transport in G.I.T. 2- Active transport: drug molecules are carried out across the membrane by a biological carrier. N.B: * Active transport can occur against concentration gradient → from a region of low concentration to a region of high concentration. * The net movement of the drug → to the blood. 7 Fick's second law of diffusion: States that: "the change in concentration with respect to time (at a special region) is proportional to the change in concentration gradient at that point in the system“ Fick's second law → give rate of change in concentration with time at a definite location. Steady state: in the figure: Semi-permeable membrane The diffusion process occurs from donner to receptor → diffusant concentration falls in the Donner diffusant Receptor solvent donner and raises in receptor → till the system dissolved in solvent reaches an equilibrium based on the rate of removal from donner to receptor + nature of the barrier. When the system reaches such equilibrium; the rate of change of concentration → zero Time lag: the time required for a diffusant to establish a uniform gradient within a membrane that separate donner and receptor components. 8 Rate of drug transport is affected by: 1. Physicochemical properties of the drug. 2. Nature of membrane 3. Concentration of the drug across the membrane. Drugs are either weakly acidic or weakly basic and exist in solution as ionized fractions. The fraction of drug existing as ionized or non ionized is determined by the dissociation constant of the drug (pka value) and pH of solvent medium according to Henderson Hasselbach equation: For weak acidic drug: 𝒑𝑯=𝒑𝑲𝒂+𝑳𝒐𝒈 [𝒔𝒂𝒍𝒕]/[𝒂𝒄𝒊𝒅] [Acid] = concentration of non ionized weak acidic drug. [Salt] = concentration of its ionized part. pka = dissociation constant for that weakly acidic drug 9 For weak basic drug: 𝒑𝑯=𝒑𝑲𝒂+𝑳𝒐𝒈 [𝒃𝒂𝒔𝒆]/[𝒔𝒂𝒍𝒕] [Base] = concentration of weak basic drug [Salt] = concentration of its ionized part. If equal amount of ionized = non ionized of drug form → pH = pka Percutaneous absorption of topically applied drugs (Ointment, creams......etc). This absorption has 3 steps: 1- Dissolution of drug in the vehicle. 2- Diffusion of dissolved drug from the vehicle to skin surface 3- Penetration of drug molecule through skin layer. The slowest step is the third step and it is the RLS for rate of absorption therefore it controls the diffusion of drug to circulation. Diffusion of drug to the skin depends on the solvent and surfactant hence choice of both items plays on important role in topical bioavailability. 10 Biopharmaceutics classification system: "BCS" It means classification of drugs on bases of solubility and intestinal permeability for four possible classes: Class I: High solubility + High permeability → 90% absorption E.g. deltiazem and propranolol ‫أدوية للقلب والضغط المرتفع‬ Class II: low solubility + High permeability → complete absorption E.g. diclofenac , naproxen , pyroxicam , ketoprofen ‫المسكنات‬ Class III: High solubility + Low permeability → unable to penetrate G.I.T wall quickly. E.g. famotidine , cimitidine, ranitidine ‫أدوية لعالج قرحة المعدة‬ Class IV: low solubility + Low permeability → problem in development and manufacture. E.g. furosemide, chlorthiazede ‫أدوية مدرة للبول‬ 11  Colligative Properties of Solution What are Colligative properties of a solution...'why colligative'? Colligative properties are those properties that depend on the concentration of the solute particles rather than the kind of solute particles. All colligative properties are related to each other by virtue of their common dependency on the concentration of the solute molecules. From Greek word “collected together” They include: 1) Osmotic pressure 2) Vapor pressure lowering 3) Boiling point elevation 4) Freezing point depression 12 1. Osmotic pressure ▪The most important colligative property from a pharmaceutical point of view is referred to as osmotic pressure. The osmotic pressure of a solution is the external pressure that must be applied to the solution in order to prevent it being diluted by the entry of solvent via a process known as osmosis. Osmosis: If two solutions of different concentrations are separated by a semi-permeable membrane (only permeable to the solvent) the solvent will move from the solution of lower solute concentration to that of higher solute concentration. 13 Osmotic pressure of nonelectrolytes: ▪The relationship between osmotic pressure and the concentration of a non-electrolyte is given for dilute solutions, which may be assumed to exhibit ideal behavior, by the van't Hoff equation: P V = n R T where V is the volume of solution, n, is the number of moles of solute, T is the absolute temperature and R is the gas constant. This form of the equation has been derived by realizing that n/V gives the concentration of the solute in units of molarity, M. P=MRT The osmotic pressure of solutions of different nonelectrolytes is proportional to the number of molecules in each solution. The osmotic pressures of two nonelectrolyte solutions of same molar concentration are identical. For example, a solution containing 34.2g of sucrose (mol wt. 342) in 1000 g of water has the same osmotic pressure as a solution containing 18.0 g of anhydrous dextrose (mol wt. 180) in 1000 g water. These solutions are said to be iso-osmotic with each other because they have identical osmotic pressures. But this is not true for electrolytes as they ionize therefore the number of particles increase o.p. ↑ 14 Osmotic pressure of electrolytes: ▪If the solute is an electrolyte, the previous equation must be modified to allow for the effect of ionic dissociation, because this will increase the number of particles in the solution. This modification is achieved by insertion of the Van't Hoff correction factor (i) to give: PV=inRT Although the above equation may be simpler to remember, the following form of the equation is more useful. P=iMRT Where the value of i approaches the number of ions produced by the ionization of the strong electrolytes. For weak electrolytes i represents the total number of particles, ions and molecules together, in the solution. 15 2. Vapor pressure lowering: To understand why that might occur, let's analyze the vaporization process of the pure solvent then do the same for a solution. Liquid molecules at the surface of a liquid can escape to the gas phase when they have a sufficient amount of energy to break free of the liquid's intermolecular forces. That vaporization process is reversible. Gaseous molecules coming into contact with the surface of a liquid can be trapped by intermolecular forces in the liquid. Eventually the rate of escape (vaporization) will equal the rate of capture (condensation) to establish a constant, equilibrium vapor pressure above the pure liquid. 16 ❖ When a non volatile solute is dissolved in a liquid solvent the vapor pressure of the solvent is lowered. WHY? ❖ Some of the surface molecules of the solvent are replaced by solute molecules which do not contribute in the vapor pressure and the surface area available for the escaping solvent molecules is reduced because some of that area is occupied by solute particles. A= Solution B = Pure solvent 17 Lowering of Vapour Pressure: ✓ Vapour pressure P1 of solvent over a dilute solution equal to vapour pressure of pure solvent times the mol fraction of solvent X1 ✓ Because the solute non volatile, so the total pressure = the pressure of the solvent ΔP = Po - P = Vapour pressure lowering 18 3. Boiling point elevation ▪Boiling point elevation is a colligative property related to vapor pressure lowering. The boiling point is defined as the temperature at which the vapor pressure of a liquid equals the atmospheric pressure (760 mmHg). Due to vapor pressure lowering, a solution will require a higher temperature to reach its boiling point than the pure solvent. The boiling point of pure water is 100°C, but that boiling point can be elevated by the adding of a solute such as a salt. A solution typically has a measurably higher boiling point than the pure solvent. Phase Diagram for a Solution and the Pure Solvent Indicating the Boiling Point Elevation 19 Determination of The boiling point elevation: The boiling point elevation ΔTb is a colligative property of the solution, and for dilute solutions is found to be proportional to the molal concentration m of the solution: ΔTb = Kb m Where Kb is called the boiling-point-elevation constant (Ebullioscopic constant). Solutions may be produced for the purpose of raising the boiling point and lowering the freezing point, as in the use of ethylene glycol in automobile cooling systems. The ethylene glycol (antifreeze) protects against freezing by lowering the freezing point and permits a higher operating temperature by raising the boiling point. 20 Kb = 2.53 oC/m 21 m AcOH= 0.8 kg 22 23 4. Freezing point depression The freezing point is depressed due to the vapor pressure lowering phenomenon. Freezing point (or melting point): is defined as the temperature at which the solid and the liquid phases are in equilibrium under a pressure of 1 atm. The freezing point of pure water is 0°C, but that melting point can be depressed by the adding of a solute such as a salt. The use of ordinary salt (sodium chloride, NaCl) on icy roads in the winter helps to melt the ice from the roads by lowering the melting point of the ice. A solution typically has a measurably lower melting point than the pure solvent. A 10% salt solution was said to lower the melting point to -6°C and a 20% salt solution was said to lower it to -16°C. Phase Diagram for a Solution and the Pure Solvent Indicating the Freezing Point Depression 24 Determination of The freezing point depression: The freezing point depression ΔTf is a colligative property of the solution and for dilute solutions is found to be proportional to the molal concentration m of the solution: ΔTf = - Kf m Where Kf is called the freezing-point-depression constant (cryoscopic constant). A pleasant application of the freezing point depression is in the making of homemade ice cream. The ice cream mix is put into a metal container which is surrounded by crushed ice. Then salt is put on the ice to lower its melting point. The melting of the solution tends to lower the equilibrium temperature of the ice/water solution to the melting point of the solution. This gives a temperature gradient across the metal container into the saltwater-ice solution which is lower than 0°C. The heat transfer out of the ice cream mix allows it to freeze. 25 26 27 2 g of non-electrolyte solute dissolved in 100 g benzene lowered the freezing point by 0.4 K. The freezing point depression constant of benzene is 5.12 K Kg /mol. The molar mass of the solute is A- 250 gm/mol B- 252 gm/mol C- 256 gm/mol D- 258 gm/mol A solution of sucrose (molar mass 342 g/mol) has been prepared by dissolving 68.5 g of sucrose in 1000 g of water. Kf of water is 1.86 K kg /mol.The freezing point of the solution will be a- -0.372 b- 0.372 c- -0.572 d- 0.572 28 29  Practical Applications of Colligative Properties 1.Preparation of isotonic intravenous and isotonic lachrymal solutions. 2.Determination of the molecular weight of solutes or in the case of electrolytes, the extent of ionization. 3.They also may be used in experimental physiology as in immersion of tissues in salt solutions which are isotonic with the tissue fluids to prevent changes or injuries of the tissues. 30