Physical Pharmacy Part 1 PDF

Dr/ Heba Barakat CONTENT: I- Solubility and Solutions - Definitions of solubility (Qualitative & Quantitative). - Definition and types of solutions. - Methods of expression of solubility (Qualitative & Quantitative). - Types of solubility (gas in liquid, solid in liq...

Dr/ Heba Barakat CONTENT: I- Solubility and Solutions - Definitions of solubility (Qualitative & Quantitative). - Definition and types of solutions. - Methods of expression of solubility (Qualitative & Quantitative). - Types of solubility (gas in liquid, solid in liquid &liquid in liquid). II- Partition coefficient III- Diffusion. IV- Osmosis. V- Surface phenomena. - Surface &interfacial tension. - Wetting Phenomena. - Adsorption at liquid interfaces (surface active agents). - Adsorption at solid interfaces.  I- SOLUTIONS AND SOLUBILITY Dispersed systems: Heterogeneous systems consist of one component, the disperse phase distributed throughout another component , the dispersion medium/ continuous phase. Based on the size of dispersed phase, three types of dispersed systems are considered;  Solution: Mixture of two or more components forming a homogenous molecular dispersion. These components are referred to as the solvent (constitutes the largest proportion of the system) and the solute(s); (dispersed as molecules or ions throughout the solvent). The transfer of the molecules or ions from a solid state into solution is known as dissolution. DISSOLUTION 𝑺𝒐𝒍𝒖𝒕𝒆 + 𝑺𝒐𝒍𝒗𝒆𝒏𝒕 𝑺𝒐𝒍𝒖𝒕𝒊𝒐𝒏 Diagrammatic representation of the process of dissolution QUALITATIVE definition of solubility: Spontaneous interaction of two or more substances to form a homogenous molecular dispersion. 𝑪𝒐𝒎𝒑𝒐𝒏𝒆𝒏𝒕 𝒙 + 𝑪𝒐𝒎𝒑𝒐𝒏𝒆𝒏𝒕 𝒚 Spontaneous Interaction 𝑯𝒐𝒎𝒐𝒈𝒆𝒏𝒐𝒖𝒔 𝑴𝒐𝒍𝒆𝒄𝒖𝒍𝒂𝒓 𝑫𝒊𝒔𝒑𝒆𝒓𝒔𝒊𝒐𝒏 (SOLUBILITY) Solubility of a solute in a solvent is enhanced when the adhesion forces between solute-solvent molecules exceed the cohesion forces between solute-solute or solvent-solvent molecules.  Equilibrium: 1- When excess solute is placed in a solvent, many particles leave the solid surface and go into solution. 2- As the number of solute particles in solution increases, some of the dissolved particles return to the solid surface of the solute. 3- When the number of particles leaving the solute surface into solution equals the number returning to the surface; this point is called solution equilibrium. QUANTITATIVE definition of solubility: The amount of solute that passes into solution when equilibrium is established between the solute in solution and the excess undissolved solute at constant temperature. For any given solute; the solubility has a constant value at a given constant temperature. TYPES OF SOLUTIONS:- 1- Saturated solution: - Solution in which the dissolved solute is in equilibrium with the undissolved solute at a definite temperature. 2- Unsaturated solution: - Solution in which the concentration of dissolved solute is less than that necessary for complete saturation at a definite temperature. 3- Supersaturated solution: - Solution in which the concentration of dissolved solute is more than that necessary for complete saturation at a definite temperature.  eg: Some salts such as sodium acetate can be dissolved in large amounts at an elevated temperature, and on cooling, fail to crystallize from the solution. Such unstable supersaturated solution can be converted to a stable saturated one by seeding with crystals of the solute, vigorous agitation or by scratching the walls of the container.  METHODS OF EXPRESSING SOLUBILITY:- A. Qualitative description: (descriptive terms); Descriptive term Solvent parts (ml)/ 1 part of solute (gm) Very soluble Less than 1 part Freely soluble 1-10 Soluble 10-30 Sparingly soluble 30-100 Slightly soluble 100-1000 Very slightly soluble 1000-10 000 Practically insoluble More than 10 000 parts Very > freely > soluble> sparingly > slightly > very slightly > insol. B. Quantitative description: ( concentration terms) 1. Molarity (M): moles solute / Liter solution. 2. Percent weight in volume (%w/v): (mass of solute /volume of solution)* 100 “No of grams of solute per 100 ml of solution.“ 3. Volume percent (%v/v): (volume of solute / volume of solution) *100 "No of ml of solute in 100 ml of solution“ TYPES OF SOLUBILITY:- The concept of solubility can be applied to any of the three states of matter (gas, liquid, solid). 1. Solubility of gases in liquids. e.g. CO2 in H2O (carbonated beverages). 2. Solubility of solids in liquids. e.g. NaCl in H2O 3. Solubility of liquids in liquids. e.g. Methanol in H2O However, in case of solubility of liquids in liquids, it is more usual to say miscibility rather than solubility. 1. Solubility of gas in liquid: It is the concentration of the dissolved gas when it is in equilibrium with some of the pure gas above the solution. Examples: CO2 in H2O (carbonated beverages). Hydrogen sulphide (H2S) in H2O. Hydrochloric acid. Ammonia. Factors affecting solubility of gas in liquid: 1) Pressure (Henry’s law) At constant temperature, the concentration of the dissolved gas is proportional to the partial pressure of the gas above the solution. ↑𝑷 ↑ 𝒔𝒐𝒍𝒖𝒃𝒊𝒍𝒊𝒕𝒐𝒇 𝒈𝒂𝒔 𝒊𝒏 𝒍𝒊𝒒𝒖𝒊𝒅 𝑪𝟏 𝑪𝟐 = 𝑷𝟏 𝑷𝟐 As the pressure increases, more gas molecules strike the surface of the liquid to enter solution. THEREFORE; ✓ Gas tanks should be opened slowly. ✓ Effervescent solutions should be kept sealed 2) Temperature: Solubility of gases DECREASES at higher temp. The ↑ temperature → ↑ KE of gas molecules → → Gas molecules escape easily from solution. THEREFORE; ✓ CO2 free water for injection may be prepared by boiling water and preventing air access during cooling. ✓ Bottles containing strong ammonia solution should be cooled before opening. ✓ Gas solutions are potentially dangerous when exposed to warm temp. because of the liberation of the dissolved gas, which may cause the container to burst. 3) Electrolytes (Salting out): Electrolytes e.g. NaCl; DECREASE Solubility of gas in liquid. Electrolytes react with water more than the gas molecules → consumption of water adjacent to the gas molecules → liberation of free gas. 2. Solubility of solid in liquid: Solid in liquid solutions are the most common type of pharmaceutical solutions. Generally, it is based on "LIKE DISSOLVES LIKE" principle. Polar solutes (NaCl, KCl, sugars , amines …etc) best dissolve in polar solvents (water, glycerol, methanol …… etc). Non-polar solutes (oils, fats, fatty acids… etc) dissolve in non-polar solvents (mineral oil, carbon tetrachloride & benzene). MECHANISM OF SOLUTE-SOLVENT INTERACTIONS: Solvents are classified into two types:- A- Polar solvents B - Non-polar solvents A- Polar solvents: e.g. water, ethanol, glycerol. They are strong dipolar molecules having high dielectric constant (DEC). Dielectric constant is the ability of solvent to reduce the attraction between the opposite ions in the crystal of the solute.  Polar solvents dissolve molecules and ions through dipole interaction and hydrogen- bond formation. Note: The very high DEC and strong H.b. forming ability make water a universal solvent for ionic substances especially monovalent ions. The solubility in water in called hydration.  e.g1 ion-dipole interaction between the sodium salt of oleic acid and water e.g2 Water dissolves oxygen and nitrogen- containing compounds (e.g. phenols, alcohols, aldehydes, ketones, amines) through H.B. formation. B- Non-polar solvents: e.g. benzene, vegetable oil or mineral oil. They are molecules having no dipolar character & don't form hydrogen bonds. They dissolve non-polar solutes by: weak Van der Waals forces. e.g. Oils and fats dissolve in benzene & mineral oil (liquid paraffin). Factors affecting solubility of solid in liquid: 1) Temperature: Plots of solubility versus temperature are called solubility curves. They are used to describe the effect of T on solubility of a given system. 1. When the process is endothermic i.e. Heat is absorbed (+ΔH). Increase in T → Increase in solubility. e.g. Sodium sulphate pentahydrate. 2. When the process is exothermic (i.e. heat energy is evolved (-ΔH). increase in T → Decrease in solubility e.g. Calcium acetate. 3. When the process is isothermic i.e. No heat is absorbed nor given off. Solubility is not affected by the variation of T e.g. NaCl.  Solubility of sodium sulphate decahydrate in water increases with the rise in T until 32.4°C, above which solubility decreases, comment?  Solubility of Sodium sulphate decahydrate; (Na2SO4.10H2O), in water is endothermic up to 32.4°C Therefore, solubility increases with rise in T until 32.4°C. Above 32.4°C , the solid is converted into the anhydrous form (Na2SO4). Solubility of this compound is exothermic Therefore, solubility decreases as the Temp. exceeds this transition value. 2) pH: Most drugs are weak acids or weak bases. Acids ionize in alkaline medium, while bases ionize in acidic medium. Ionized drugs are more soluble in water, while neutral (unionized) drugs are more soluble in organic solvents e.g., alcohol, chloroform, acetone. Basic drugs are slightly soluble in water, but if the pH of the medium is reduced (i.e. acidic medium) the solubility is increased.  This is due to the conversion of the base into salt which is relatively soluble in water. e.g. Procaine (basic drug): Decreased pH → ↑ ionization → ↑ water solubility. HCl Procaine Procaine HCl More ionizable. More water sol.  Acidic drugs are slightly soluble in water, but if the pH of the medium is increased (i.e. basic medium) the solubility is increased. e.g. Phenobarbital (acidic drug): Increased pH → ↑ ionization → ↑ water solubility. NaOH Phenobarbitl Phenobarbitone Na More ionizable. More water sol. 3) Particle size: Decrease in P.S. → ↑ surface area → ↑ solubility (up to 1 μ) HOWEVER Decrease in P.S. < < 1 μ → ↑ surface free energy → → formation of agglomerate → ↓ surface area → → ↓ solubility. 4) Crystal structure: Amorphous form of drugs is more soluble than crystalline form. Molecules in the amorphous form are in a random arrangement → more spaces → higher S.A. → higher solubility. Molecules in crystalline structure are packed in a regularly ordered, repeating pattern → lower spaces → lower S.A. → lower solubility. 5) Molecular structure: Change in the molecular structure affects solubility of compound: Examples: SALT FORMATION 1) Salicylic acid Sodium salicylate → greater ionization → ↑ water solubility. Compound Salicylic acid Sodium salicylate Solubility in water 1 in 550 1 in 1 2) ESTRIFICATION Chloramphenicol chloramphenicol palmitate → ↓aqueous solubility → # Mask its bitter taste. ESTRIFICATION 3) Erythromycin erythromycin propionate → ↓aqueous solubility → # ↑ Stability in the GIT. → # ↑Drug absorption. 4) Additional polar groups (OH, CH2OH, COOH….etc ) → ↑ water solubility. e.g. Pyrogallol is more water soluble than Phenol. 6. Nature of solvent: Like dissolves like (as discussed earlier). 7. Effect of electrolytes: a) Common ion effect Decrease in solubility of an ionic compound in presence of a salt containing an ion in common. e.g. Solubility of (AgCl) is lowered in presence of (NaCl), a source of the common ion chloride. b) Salting out : Solubility of macromolecules (e.g. proteins) depends on the formation of weak hydrogen bonds with water molecules. Presence of a very soluble electrolyte (e.g. NaCl), having higher affinity for water, will reduce the solubility of the macromolecules by competing for the aqueous solvent and breaking their intermolecular bonds with the macromolecules. This effect is important during mixing of protein drugs (e.g. insulin) with saline infusion prior to injection, the drug may be precipitated in the infusion. Methods to improve solubility of drugs: 1) Use of co-solvents: A co-solvent is a water miscible organic solvent e.g. ethanol, glycerol, propylene glycol. This strategy is based on the fact that poor solubility of drugs in water results from great difference in polarity of the two components. Co-solvents reduce the difference between polarity of the drug & water/co-solvent system, thereby improving solubility. e.g. Digoxin injection contains 40% propylene glycol and 10% ethanol. 2) Complexation: It is a reversible association between 2 or more molecules to form a non-bonded product with a well defined stoichiometry (ratio between reactants and products). It relies on relatively weak bonds such as Van der Waals forces, H-bonding and hydrophobic interactions Solubility of a solute in a particular liquid can be increased by the addition of complexing agent which forms a water soluble complex with the solute. e.g1 : Improving the aqueous solubility of mercuric iodide (HgI2) by the addition of potassium iodide (KI), leading to the formation of water soluble complex K2HgI4 known as Nessler reagent (tetraiodomercurate).  Nessler reagent, very water soluble, pale yellow, used to test for the presence of ammonia where it turns into deep yellow. e.g2. Cyclodextrin complexes Cyclodextrins are a group of cyclic structurally related natural oligosaccharides formed during bacterial digestion of cellulose. Their molecular structure resembles a bucket with a hydrophilic exterior surface and a nonpolar interior cavity.  CDs can interact with appropriately sized drug molecules to yield an inclusion complex. Used to enhance aqueous solubility, physical chemical stability, and bioavailability of drugs. 3) Water soluble prodrugs Prodrugs are pharmacologically inactive derivatives of active drugs. They can maximize the amount of active drug reaching site of action, through manipulation of physicochemical, and pharmacokinetic properties of the drug. They are converted into active drug within the body through enzymatic or non-enzymatic reactions. Usually an ionisable group (phosphate) is added to the parent compound or a dicarboxylic acid hemiester is formed to produce the prodrug. Examples: Phosphate esters: Fosphenytoin a phenytoin prodrug Chloramphenicol sodium succinate 4) Solubilisation using SAA DISSOLUTION VS. DISSOLUTION RATE: Solubility: Saturation process independent from time. (physical property, constant at constant conditions). Dissolution: The process by which a solid goes into solution. Dissolution rate: The rate at which a solute goes into solution (i.e. amount per unit time). 41  Dissolution theory: When a solid particle is dispersed in a solvent, it is surrounded by a thin layer of solvent having a finite thickness "l" in cm. this layer is an integral part of the solid, & thus is referred as the (stagnant layer). Regardless of how fast the bulk solution is stirred, the stagnant layer remains a part of the solid surface moving wherever the particles move. The thickness of this layer may get smaller as the stirring of the bulk solution increases. 42  Stagnant layer is saturated with the dissolved solute. (i.e. conc. of the solute represents the solubility; Cs). Solute molecules then migrate gradually by diffusion through the stagnant layer to the bulk of solution where the conc.; C. Migration of the solute is driven by conc. gradient; change in conc. with distance; (Cs – C)/l. Like any multistep process, the overall rate is dependent on the slowest step (the rate-limiting/ rate determining step), which is; the diffusion of the dissolved solute through the stagnant layer. 43  Mathematically, dissolution rate of a solid is given by Noyes- Whitney equation; Dissolution Rate (dm/dt) = DA (Cs − C)/L D: proportionality constant called " diffusion coefficient" in cm2/sec. A: surface area of solid. Cs: conc. in the stagnant layer, saturated solubility. C: conc. In the bulk solution. L: thickness of the stagnant layer in cm. 44 Sink Conditions: C must be