Solubility and Distribution PDF

Solubility & Distribution Menna Magdy  A solution may be defined as a mixture of two or more components that form a single phase which is homogeneous down to the molecular level. The component that determines the phase of the solution is termed the solvent; it usually (but...

Solubility & Distribution Menna Magdy  A solution may be defined as a mixture of two or more components that form a single phase which is homogeneous down to the molecular level. The component that determines the phase of the solution is termed the solvent; it usually (but not necessarily) constitutes the largest proportion of the system. The other components are termed solutes, and these are dispersed as molecules or ions throughout the solvent.  The transfer of molecules or ions from a solid state into solution is known as dissolution. Extent Rate Solubility is defined as the conc. of solute in Dissolution rate is the amount of solute a saturated soln. at a certain temp dissolves per unit of time. One point to emphasize at this stage is that the rate of solution (dissolution rate) and amount which can be dissolved (solubility) are not the same and are not necessarily related. In practice, high drug solubility is usually associated with a high dissolution rate, but there are exceptions; an example is the commonly used film-coating material hydroxypropyl methylcellulose (HPMC) which is very water soluble yet takes many hours to hydrate and dissolve  Solubility and distribution phenomena Solubility is defined in quantitative terms as the conc. of solute in a saturated soln. at a certain temp., and in a qualitative way, it may be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. The solubility of a compound depends upon: a) The physical and chemical properties of the solute and the solvent. b) Temperature. c) Pressure. d) pH of the soln. e) The state of subdivision of the solute. Three types of mixtures: 1. Gases in liquids, 2. Liquids in liquids, and 3. Solids in liquids Types of solutions: Saturated soln: is one in which the solution is in equilibrium with excess un-dissolved solid of the solute.  unsaturated or subsaturated soln is one containing the dissolved solute in a conc below that necessary for complete saturation at a definite temp. Supersaturated soln is one that contains more of the dissolved solute than it would normally contain at a definite temp, where the undissolved solute present. Such supersaturated solns can be converted to stable saturated solns by: 1- Seeding the soln with a crystal of solute. 2- Vigorous agitation. 3- Scratching the walls of the container. a. Quantitative terms : Solubility Expressions:  b. Qualitative terms : Table (1): Terms of Approximate Solubility Term Parts of solvent Required for 1 Part of Solute Very soluble Less than 1 part Freely soluble to 10 parts 1 Soluble to 30 parts 10 Sparingly soluble to 100 parts 30 Slightly soluble to 1000 parts 100 Very slightly soluble to 10,000 parts 1000 Practically insoluble or insoluble More than 10,000 parts  Solvent-Solute Interactions The pharmacist knows that water is a good solvent for salts, sugars, and similar compounds. Mineral oil and benzene are often solvents for substances that are normally only slightly soluble in water. There empirical findings are summarized in the statement: "like dissolves like". Polar Solvents: The solubility of a drug is due to the polarity of the solvent, i.e., to its dipole moment. (solvation-ionization-hydration) Polar solvents dissolve ionic solutes and other polar substances. Hildebrand has shown, that a consideration of dipole moments alone is not adequate to explain the solubility of polar substances in water, because of the ability of the solute to form hydrogen bonds with the solvent has a more effect than the polarity.  There empirical findings are summarized in the statement: "like dissolves like". Dielectric constant It measures the ability of solvent to separate 2 oppositely charged bodies Polar solvent Semi-polar solvent Non-polar solvent DEC > 50 ex water DEC 20-50 ex alcohol DEC 1- 20 ex benzene  Polar solvent Water can dissolve Ionic solutes (e.g. NaCl) Polar compounds (e.g. sugars, Due to the dielectric constant phenols, alcohols, ketones, amines mechanism, Water can oppose the and other O and N containing electrostatic attraction between compounds) due to H bond formation positive and negative ions with water  When ethyl alcohol and water are mixed, the hydrogen bonds between the water molecules are replaced partly by hydrogen bonds between water and alcohol molecules. Also the solubility of a substance also depends on structural features such as the ratio of the polar to non-polar groups of the molecule. As the chain length of an aliphatic alcohol increases, the solubility of the compound in water decreases. Straight chain monohydroxy alcohols, aldehydes, ketones, 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 reduces the non-polar effect and leads to increased water solubility. Tertiary butyl alcohol is miscible in all proportions with water, compared to n-butyl alcohol which has limited solubility in water. Polar solvents such as water act as solvents according to the following mechanisms: a)The high dielectric constant, namely about 80 for water, polar solvents reduce the force of attraction between oppositely charged ions in crystals such as sodium chloride. Chloroform has a dielectric constant of 5 and benzene of 2 hence, ionic compounds are practically insoluble in these solvents. b) Polar solvents break covalent bonds of potentially strong electrolytes since these solvents are amphiprotic. For example, water brings about the ionization of HCl as follows: HCl + H2O →H3O+ + Cl- Weak organic acids are not ionized by water; their partial solubility in water is attributed to the hydrogen bond formation with water. Phenols and carboxylic acids, are readily dissolved in solutions of strong bases. c) Polar solvents are capable of solvating molecules and ions through dipole interaction forces, particularly hydrogen bond formation, which leads to the solubility of the compound.  Non polar Solvents: Non polar solvents are unable to reduce the attraction between the ions of ionic salts and strong electrolytes because the solvents have low dielectric constants. The solvents cannot break covalent bonds to produce ionic compound. Cannot form H bonds so, non polar solvents can not dissolve polar solutes. So, ionic and polar solutes are not soluble or are only slightly soluble in non polar solvents. Non polar compounds can dissolve non polar solutes with similar internal pressures through induced dipole interactions. The solute molecules are kept in soln by the weak van der Waals-London type of forces. Oils and fats dissolve in carbon tetrachloride, benzene, and mineral oil.  Semipolar Solvents: Semipolar compounds may act as intermediate solvents to bring about miscibility of polar and non polar liquids. They are also used as co-solvents. Semipolar solvents, such as ketones and alcohols, can induce a certain degree of polarity in non polar solvent molecules. Acetone increases the solubility of ether in water. Propylene glycol increase the mutual solubility of water and peppermint oil. Alcohol dissolve benzene (non polar solute). Alcohol molecules induced in benzene molecules a temporary dipole and form association complex with alcohol molecules.  In short, solubility depends on chemical, electric, and structural effects that lead to mutual interactions between the solute and solvent. Determination of solubility The importance of determination of solubility is : 1.The preparation and dispensing of medicines. 2.Separation of substances in qualitative and quantitative analysis. 3.The accurate determination of the solubility of a substance is one of the best methods for determining its purity. Determination of solubility we should consider purity of both substance and solvent constant temperature complete saturation complete separation of the sample from undissolved solute accurate method the analysis of the saturated solution  The determination is usually carried out using the analytical method: Principal: excess of the finely divided solid is agitated continuously with the solvent at the required temp until equilibrium is attained. The lower bottle is charged with solute and solvent and agitated in a thermostat for 24 hours. The apparatus is then inverted to allow the soln to filter through A into the empty bottle, the expelled air being returned by tube B. The bend in B prevents the transfer of solid into empty bottle. The apparatus is removed from the thermostat and the filtered saturated soln is analyzed. Fig. (1): Apparatus for solubility determinations  Solubility of Gases in Liquids The solubility of a gas in a liquid is the conc of the dissolved gas when it is in equilibrium with some of the pure gas above the soln. Pharmaceutical solns of gases include hydrochloric acid, ammonia water, and effervescent preparations containing carbon dioxide that are dissolved and maintained in soln under positive pressure. Also aerosol products in which the propellant is either carbon dioxide or nitrogen, some of which is dissolved under pressure The solubility depends primarily on the pressure, temp, presence of salts, and chemical reactions that the gas sometimes undergoes with the solvent. 1.Effect of Pressure: The effect of the pressure on the solubility of a gas is expressed by Henry's Law, which states that at constant temp, the conc of dissolved gas is proportional to the partial pressure of the gas above the soln at equilibrium. If C2 is the conc of the dissolved gas in grams/liter of solvent and p is the partial pressure in mmHg of the undissolved gas above the soln, Henry's relationship may be written as C2 =σp in which σ is a proportionality constant for the soln. It is sometimes referred to as the solubility coefficient. 2. Effect of Temp: As the temp increases, the solubility of most gases decreases, owing to the greater tendency of the gas to expand. 3. Salting Out: Gases are often liberated from solns in which they are dissolved by the introduction of an electrolyte such as sodium chloride and sometimes by a non-electrolyte such as sucrose. This phenomenon is known as salting out. The resultant escape of gas is due to the attraction of the salt ions or the highly polar non-electrolyte for the water molecules. 4. Effect of Chemical Reaction: Gases such as hydrogen chloride, ammonia, and carbon dioxide show deviations as a result of chemical reaction between the gas and solvent, usually with a resultant increase in solubility. Accordingly, hydrogen chloride is about 10,000 times more soluble in water than in oxygen HCl + H2O → H3O+ + Cl-  Solubility of Liquids in Liquids: Frequently two or more liquids are mixed together in the preparation of pharmaceutical solns. examples Alcohol is added to water to form hydroalcoholic solns of various concs. Volatile oils are mixed with water to form dilute solns known as aromatic waters, Volatile oils are added to alcohol to yield spirits and elixirs. Ether and alcohol are combined in collodions. Ideal and Real Solutions: According to Raoult's law, pi = pi0 Xi The partial pressure pi of a component in a liquid mixture at a definite temp is equal to the vapor pressure in the pure state (pi0) multiplied by the mole fraction (Xi) of the component in the soln.  The mixture is said to be ideal when both components of a binary soln obey Raoult's law. If one of the components shows a -ve deviation, the other component must also show -ve deviation. The corresponding statement can also be made for +ve deviations from Raoult's law. Negative deviations (where adhesive forces A-B>> cohesive forces A-A or B-B) lead to increased solubility and are associated with hydrogen bonding between polar compounds. Positive deviations, (where adhesive forces