Solubility and Distribution Phenomena PDF

Distribution Phenomena Dr Manal N AL Soub Distribution and Partitioning Qualitative Description When two immiscible liquids are added to each other they form two separate and distinct phases. Systems of water and ether or amyl alcohol, octanol or peanut oil are examples of such...

Distribution Phenomena Dr Manal N AL Soub Distribution and Partitioning Qualitative Description When two immiscible liquids are added to each other they form two separate and distinct phases. Systems of water and ether or amyl alcohol, octanol or peanut oil are examples of such liquid systems. If an excess solid or liquid is added to such a system, it will distribute itself between the two phases so that each become saturated. Solubility and Distribution Phenomena  Solubility definitions Solubility is: the concentration of solute in a saturated solution at a certain temperature, the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. Solubility is an intrinsic material property that can be altered only by chemical modification of the molecule.  the solubility of a compound depends on: 1. the physical and chemical properties of the solute and the solvent 2. temperature, pressure, the pH of the solution, The term miscibility refers to the mutual solubility of the components in liquid–liquid systems.  Solubility Expressions The United States Pharmacopeia (USP): describes the solubility of drugs as parts of solvent required for one part solute. Solubility is also quantitatively expressed in terms of molality, molarity, and percentage. For exact solubilities of many substances: official compendia (e.g., USP) and the  Solvent–Solute Interactions “like dissolves like.” 1. Polar Solvents 2. Nonpolar Solvents 3. Semipolar Solvents  Polar Solvents dissolve ionic solutes and other polar substances. reduce the attraction between the ions of strong and weak electrolytes because of the solvents' high dielectric constants. Water dissolves sugars, phenols, alcohols, aldehydes, ketones, amines, and other oxygen- and nitrogen-containing compounds that can form hydrogen bonds with water:  As the length of a nonpolar chain of an aliphatic alcohol increases, the solubility of the compound in water decreases. Straight- monohydroxy chain aldehydes, ketones,alcohols, and acids with more than four or five carbons cannot enter into the hydrogen-bonded structure of water and hence are only slightly soluble.  When additional polar groups are present in the molecule, as found in propylene glycol, glycerin, and tartaric acid, water solubility increases greatly. Branching of the carbon chain increase the polar effect and leads to increased water solubility. Tertiary butyl alcohol is miscible in all proportions with water, whereas n-butyl alcohol dissolves to the extent of about This is due8 g/100 to the reasonmL of water at 20°C. that as branching increase, surface area of non-polar hydrocarbon part decreases and solubility increases  Nonpolar Solvents such as the hydrocarbons, a carbon tetrachloride, benzene, and s mineral oil Nonpolar solvents are unable to reduce the attraction between the ions of strong and weak electrolytes because of the solvents' low dielectric constants. they cannot form hydrogen bridges with nonelectrolytes. Hence, ionic and polar solutes are not soluble or are only slightly soluble in nonpolar solvents.  can dissolve nonpolar solutes through induced dipole interactions. The solute molecules are kept in solution by the weak van der Waals–London type of forces. Thus, oils and fats dissolve in carbon tetrachloride, benzene, and mineral oil. Alkaloidal bases and fatty acids also dissolve in nonpolar solvents  Semipolar Solvents such ketones and alcohols, Propylene glycol as , glycerin can induce a certain degree of polarity in nonpolar solvent molecules, so that, for example, benzene, which is readily polarizable, becomes soluble in alcohol. act as intermediate solvents to bring about miscibility of polar and nonpolar liquids. ( cosolvents ) Acetone increases the solubility of ether in water. Propylene glycol increases the solubility of water and peppermint oil.  Solubility of Liquids in Liquids Complete Miscibility: Polar and semipolar solvents, such as water and alcohol, glycerin and alcohol, and alcohol and acetone, are completely miscible because they mix in all proportions. Nonpolar solvents such as benzene and carbon tetrachloride are also completely miscible.  Partial Miscibility: Binary and ternary phase diagrams The Phase Rule and Solubility Single phase and two components F = 2-1+2 = 3 Pressure is fixed so temperature and composition must be  Solubility of Solids in Liquids The influence of Temperature When heat is absorbed in the dissolution process (endothermic) the solubility of the compound increases with heat When heat is evolved in the dissolution process (exothermic) the solubility of the compound decreases with heat Most solids belong to the class of compounds that absorb heat when they dissolve.  100 KNO3 Solubility (g/100g H2O Na2SO4 50 NaCl (CH3COO)2Ca.2H2O Na2SO4.10H2O 0 50 0 Sodium sulfate exists in 100 the hydrated form Na2SO4.10H2O up Temperature to a temperature of about 32°C, (°C) process is endothermic, the solution and solubility increases with temperature. Above this point, the compound exists as the anhydrous salt, Na2SO4 the dissolution is exothermic, and solubility decreases with an increase of temperature NaCl does not absorb or evolve an appreciable amount of heat when it dissolves in water thus, its solubility is not altered much by a change of temperature, and the heat of solution is approximately zero  Solubility of Solids in Liquids The influence of PH weakly acidic drug or its salt weakly basic drug & its salt If the If the pH of a solution  pH of a solution  unionized acid molecules unionized base molecules  A weak acid is more WATER-soluble in an alkaline solution - A weak base is more WATER-soluble in an acidic solution. Precipitation may occur because the solubility of the unionized species is less than that of the ionized form (chemical incompatibility) The relationship between pH & the solubility & pKa value of an acidic drug is given by a modified Henderson-Hasselbalch equation. From equation we can calculate: minimum pH that must be maintained in order" to prevent precipitation from a solution of known concentration.  the equation for the solubility of a weak acid as a function of the pH of a solution: pHp is the pH below which the drug separates from solution as the undissociated acid. So is the solubility of the acid in water S is the molar concentration of salt initially added.  the equation for the solubility of a weak base as a function of the pH of a solution. pHp is the pH above which the drug begins to precipitate from solution as the free base. So is the molar solubility of the free base in water. S is the molar concentration of salt initially added.  Example Below what pH will free phenobarbital begin to separate from a solution having an initial concentration of 1 g of sodium phenobarbital per 100 mL at 25°C? The molar solubility, So, of phenobarbital is 0.0050 and the pKa is 7.41 at 25°C. The molecular weight of sodium phenobarbital is 254. The molar concentration of salt initially added is  Nature of solvent: cosolvents 'like dissolves like‘ using cosolvents such as ethanol or propylene glycol, which are miscible wi water and which" act as better solvents for the solute in question. e.g. The aqueous solubility of metronidazole is about 100 mg in 10 ml; the solu of this drug can be increased exponentially by the incorporation of one or m water-miscible cosolvents so that the solubility is increased up to 500mg in ml  The Influence of Solvents on the Solubility of Drugs Weak electrolytes can behave like strong electrolytes or like nonelectrolytes in solution. When the solution is of such a pH that the drug is entirely in the ionic form, it behaves as a solution of a strong electrolyte, and solubility does not constitute a serious problem. when the pH is adjusted to a value at which un-ionized molecules are produced in  a solute is more soluble in a mixture of solvents than in one solvent alone. This phenomenon is known as cosolvency, and the solvents that, in combination, increase the solubility of the solute are called cosolvents. The solubility of phenobarbital in a mixture of water, alcohol, and glycerin Solid refers to the state of matter in which the particles are locked into place without much freedom of movement. They can be locked into crystal lattices or just kind of stuck together with intermolecular forces so tightly that they can’t really move around. Solids differ from liquids in that the particles in liquids, while still stuck together, do have some freedom of motion. Solids differ from gases in that gas molecules really don’t interact with each other much, flying all over the place Classification of Solids Amorphous Crystalline Polymorphism Solvate and hydrates Co-crystal 64  Crystalline Solids E.g. diamond, graphite Regular shape i.e. fixed geometric patterns Incompressible Definite /specific boiling points Diffract X-rays 65 Crystal Structure Crystals contain highly ordered molecules or atoms held together by non-covalent interactions E.g. NaCl has the cubic structure 66 Can be defined on the basis of variations on the themes of 7 systems Types of Crystal Structure 4. Rhombic 1. Cubic - iodine - sodium 5. Monoclinic chloride - sucrose 2. Tetragonal 6. Triclinic - urea - boric acid 3. Hexagonal 7. Trigonal 67 - iodoform Angles & lengths that describe crystal habit α = between length & breadth β = between breadth & height γ = between length & height Crystal Angle of axes Length of axes Examples Cubic (regular) α = β = γ = 90º x =y =z NaCl Tetragonal α = β = γ = 90º x =y ≠z NiSO4 Orthorhombic α = β = γ = 90º x ≠y ≠z K2MNO4 Monoclinic α = β = γ ≠ 90º x ≠y ≠z Sucrose Triclinic (asymmetric) α ≠β ≠ γ ≠ 90º x ≠y ≠z CuSO4 Trigonal (rhombohedral) α = β = γ ≠90º x =y =z NaNO3 Hexagonal Z at 90º to base - AgNO3 68 Triclinic 69 Monoclinic simple centered monoclinic monoclinic 70 Tetragonal body-centered simple tetragonal tetragonal 71 Orthorhombic xtals base- simple centered body-centered face-centered orthorhombic orthorh orthorhombic orthorhombic ombic 72 Bravais Lattices 1. End-centred Total of 14 possible i. Monoclinic types of unit cells ii. orthorombic 2. Face-centred For drugs, only 3 types: i. Cubic (NaCl) ii. Orthorombic 1. Triclinic 3. Body-centred 2. Monoclinic i. Cubic tetragonal ii. Orthorombic 3. Orthorombic 73 FCC Structure of NaCl Small spheres represent Na+ ions, large spheres represent Cl- ions. Each sodium ion is octahedrally surrounded by 74 Crystallisation Crystallisation steps from solution:- 1. Supersaturation of the solution e.g. cooling, evaporation, addition of precipitant or chemical reaction 2. Formation of crystal nuclei e.g. collision of molecules, deliberate seeding 3. Crystal growth around the nuclei 75 Crystal Growth Steps involved: 1. Transport of molecules to the surface 2. Arrangement in the lattice  Degree of agitation in the system affects the diffusion coefficient, thus affects crystal growth. 76 Precipitation 1. Induced by altering pH of solution to reach saturation solubility. 2. By chemical reaction to produce precipitate from a homogeneous solution.  The rate of reaction is important in determining habit. 77 Crystallization from Supersaturated Solutions of Sodium Acetate Description: A supersaturated solution of sodium acetate is crystallized by pouring it onto a seed crystal, forming a stalagmite- like solid. Heat is radiated from the solid. 78 Polymorphisms When compounds crystallise as different polymorphs, properties change. Molecules arrange in two or more ways in the crystal: packed differently in crystal lattice, different orientation, different in conformation of molecules at lattice site. X-ray diffraction patterns change. 79 Polymorphism of Spironolactone A diuretic (no potassium loss) 2 polymorphic forms and 4 solvated crystalline Form 1: spironolactone powder is dissolved in acetone at a temperature near boiling point and cooled to 0 deg. C within a few hours – needle-like Form 2: powder dissolved in acetone or dioxane or chloroform and acetone allowed to evaporate for several weeks – prism 80 Polymorphs of spironolactone 1 PHM1213 Physical Pharmacy 1 2008/9 81 Amorphous Solids E.g. silica gel, synthetic plastics/polymers Irregular shape - molecules are arranged in a random manner No definite melting point - no crystal lattice to break Exhibit characteristic glass transition temperature, Tg Flow when subject to pressure over time Isotropic i.e. same properties in all direction Affect therapeutic activity e.g. amorphous 82 antibiotic novobiocin is readily absorbed