2.Solubility and distribution phenomena.pdf

Solubility and distribution phenomena 1 Importance of studying the phenomenon of solubility : Understanding the phenomenon of solubility helps the pharmacist to: - Select the best solvent for a drug or a mixture of drugs. Overcome problems arising dur...

Solubility and distribution phenomena 1 Importance of studying the phenomenon of solubility : Understanding the phenomenon of solubility helps the pharmacist to: - Select the best solvent for a drug or a mixture of drugs. Overcome problems arising during preparation of pharmaceutical solutions. Serve as a standard or test of purity Have information about the structure and intermolecular forces of the drug 2 Terminology True solution: is a mixture of two or more components that form a homogenous molecular dispersion. The components are referred to the solute & the solvent Solute: is the dissolved agent (less abundant part of the solution). Solvent: is the component in which the solute is dissolved (more abundant part of the solution). A saturated solution: is one in which an equilibrium is established between dissolved and un-dissolved solute at a definite temperature. 3  An unsaturated solution: is one containing the dissolved solute in a conc. below that necessary for complete saturation at a definite temperature. A supersaturated solution: contains more of the dissolved solute than it would normally contain in a saturated state at a definite temperature. Some salts (e.g.. sod. thiosulfate) can be dissolved in large amounts at an elevated temperature and, upon cooling fail to crystallize from the solution; these super saturated solutions can be converted to saturated ones by seeding the solution. Solubility (in a quantitative way) : it is the concentration - solute in a saturated solution at a certain temperature. (in a qualitative way) : it is the spontaneous interaction of two or more substances (solute & solvent) to form a homogeneous molecular dispersion 4 Solubility expressions : 1) The solubility of a drug can be expressed in terms of:  Molarity  Normality  Molality  Mole fraction  percentage (% w/w, % w/v, % v/v). 2) The USP lists the solubility of drugs as the number of ml of solvent in which 1 g of solute will dissolve. E.g. 1g of boric acid dissolves in 18 mL of water, and in 4 mL of glycerine. 3) Substances whose solubility values are not known are described by the following terms: 5  Term Parts of solvent required for 1 part of solute Very soluble Less than 1 part Freely soluble 1 to 10 parts Soluble 10 to 30 parts Sparingly soluble 30 to 100 parts Slightly soluble 100 to 1000 parts Very slightly soluble 1000 to 10 000 parts Practically insoluble More than 10 000 parts 6  Concentration expression Concentration of solution can be expressed either in terms of the quantity of solute in a definite volume of solution or as the quantity of solute in a definite mass of solution. This various expression can be summarised as 7 Expression symbol definition molarity M, c Moles (gram molecular weight)of solute in 1 litre of solution normality N Gram equivalent weights of solute in 1 litre of solution Molality m Moles of solute in 1000 g of solvent Mole fraction X,N Ratio of the moles of one constituent(solute) of a solution to the total moles of all constituents(solute + solution) Mole percent Moles of one constituents in 100 moles of the solution , it is obtained by multiplying mole fraction by 100 Percent by %w/w Grams of solute in 100 g of solution weight Percent by %v/v Millilitres of solute in 100 ml of solution volume Percent %w/v Grams of solute in 100 ml of solution weight in volume Milligram Milligrams of solute in 100 ml of solution percent 8 Molarity We need two information to calculate the molarity of a solute in a solution: The moles of solute present in the solution. The volume of solution (in litres) containing the solute. To calculate molarity we use the equation: Molarity=moles of solute/volume of solution in litre 9 Molality We need two of information to calculate the molality of a solute in a solution: The moles of solute present in the solution. The mass of solvent (in kilograms) in the solution. To calculate molality we use the equation: Molality=moles of solute/mass of solvent in kilograms 10  Mole Fraction To calculate mole fraction, we need to know: The number of moles of each component present in the solution. The mole fraction of A, XA, in a solution consisting of A, B, C,... is calculated using the equation: Xa= moles of A/(moles of A+ moles of B+ moles of C+....) 11  Practice problem An aqueous solution of exsiccated ferrous sulfate was prepared by adding 41.5 g of FeSO4 to enough water to make 1000 ml of solution at 18⁰ C. The density of the solution is 1.0375 and the molecular weight of FeSO4 is 151.9 Calculate: a. The Molarity b. The Molality c. The mole fraction of FeSO4 d. The mole fraction of water e. The percentage by weight of FeSO4 12 Answer: Moles of feso4=g of feso4/Mwt =41.5/151.9=0.2732 Molarity=moles of feso4/lit of solution=0.2732/1 lit=0.2732M Molality= grams of solvent = gram of solu-graams of feso4=1037.5- 41.5=996.0g Molality=moles of Feso4/kg of solvent=0.2743/0.996=0.2743m Mole fraction of feso4=x2=moles of feso4/(moles of water+moles of feso4)=0.2732/(55.27+0.2732)=0.0049 Mole fraction of wate=55.27/(55.27+0.2732)=0.9951 Mole percent of feso4=0.0049x100=0.49% Mole percent of water=0.9951x100=99.51% Percentage by weight of feso4=g of feso4/g of solution x 100 =41.5/1037.5 x 100 = 4% 13 Solute-Solvent interactions Solubility depends on chemical, electrical & structural effects that lead to mutual interactions between the solute and the solvent. In pre-or early formulation, selection of the most suitable solvent is based on the principle of “like dissolves like”. That is, a solute dissolves best in a solvent with similar chemical properties. i.e.  Polar solutes dissolve in polar solvents. E.g salts & sugar dissolve in water.  Non polar solutes dissolve in non polar solvents. Eg. naphtalene dissolves in benzene. To explain the above rule, consider the forces of attraction between solute and solvent molecules 14 Types of solutions 15 Solutions of pharmaceutical importance include: Gases in liquids Liquids in liquids Solids in liquids 16 Solubility of gases in liquids: The solubility of a gas in a liquid is the concentration of the dissolved gas when it is in equilibrium with some of the pure gas above the solution. The solubility depends on the pressure, temperature, presence of salts & the chemical reactions that sometimes the gas undergoes with the solvent. 17  Factors affect solubility of gases i n liquids: Pressure: the pressure of a gas above a liquid is an important consideration in gaseous solutions because it changes the solubility of the dissolved gas in equilibrium with it. 18 The effect of the pressure on the solubility of the dissolved gas is expressed by Henry's law Which states that in a very dilute solution at constant temperature , the concentration of the dissolved gas is proportional to the partial pressure of the gas above the solution at equilibrium. Henry’s law: C2= σ p C=conc of the dissolved gas in grams/lit of the solvent p= partial pressure of the undissolved gas above the solution, σ=constant or solubility coefficient. 19 Effect of temperature: Temperature has a marked influence on the solubility of a gas in a liquid. As the temperature increase the, solubility of most gases decrease. The property of expansion couples with the pressure , requires the pharmacist to exercise caution in opening containers of gaseous solutions in warm climate and under condition of elevated temperature. 20 21 Salting out: Gases are often librated from solutions in which they are dissolved by the introduction of an electrolyte such as sodium chloride and some times by nonelectrolyte such as sucrose. This phenomenon is known as salting out. The salting out effect can be demonstrated by adding a small amount of salt to a carbonated solution. The resultant escape of gas is due to the attraction of the salt ions or the highly polar non electrolyte for the water molecules , which reduces the density of the aqueous environment adjacent to the gas molecules.. 22 Salting out can also occur in solutions of liquid in liquid and solids in liquids Effect of chemical reaction Gases such as hydrogen chloride, ammonia, and carbon dioxide, show chemical reaction between the gas and the solvent, usually with resultant increase in the solubility. 23 Solubility of liquids in liquids Preparation of pharmaceutical solutions involves mixing of 2 or more liquids (alcohol & water to form hydro alcoholic solutions, volatile oils & water to form aromatic waters, volatile oils & alcohols to form spirits. Liquid-liquid systems may be divided into 2 categories: 1) Systems showing complete miscibility such as alcohol & water, glycerine & alcohol, benzene & carbon tetrachloride.. 2) Systems showing Partial miscibility as phenol and water; two liquid layers are formed each containing some of the other liquid in the dissolved state. The term miscibility refers to the mutual solubility of the components in liquid-liquid systems. 24 25 Solubility of Solids in Liquids Factors affecting solubility of solid in liquid 1. 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. 26  2. Molecular structure of solute Even a small change in the molecular structure of a compound can have a marked effect on its solubility in a given liquid e.g. The introduction of a hydrophilic hydroxyl group can produce a large improvement in water solubility: solubility of phenol is more than100-fold greater than that of benzene. The conversion of a weak acid to its sodium salt leads to a much greater degree of ionic dissociation of the compound when it dissolves in water: aqueous solubility of salicylic acid (1: 550) and its Na salt (1:1) 27  The reduction in aqueous solubility of a parent drug by its esterification. Such a reduction in solubility may provide a suitable method for:  masking the taste of a parent drug, e.g. Chloramphenicol palmitate is used in paediatric suspensions rather than the more soluble and very bitter chloramphenicol base  protecting the parent drug from excessive degradation in the gut, e.g. erythromycin propionate is less soluble and, consequently, less readily degraded than erythromycin.  increasing the ease of absorption of drugs from the gastrointestinal tract, e.g. erythromycin propionate is also more readily absorbed than erythromycin 28 3. Nature of solvent: cosolvents 'like dissolves like‘ using cosolvents such as ethanol or propylene glycol, which are miscible with 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 solubility of this drug can be increased exponentially by the incorporation of one or more water-miscible cosolvents so that the solubility is increased up to 500mg in 10 ml 29 4. Crystal characteristics: polymorphism & solvation a) Polymorphism Some substances produce crystals in which the constituent molecules are aligned in different ways with respect to one another in lattice structure. These different crystalline forms of the same substance, which are known as polymorphs, consequently possess different lattice energies which is reflected by changes in other properties. 30  the polymorphic form with the lowest free energy will be the most stable and possess the highest melting point. Other less stable (metastable) form is the most soluble one and will tend to transform into the most stable on storage Many drugs exhibit polymorphism,' e.g. steroids, barbiturates and sulphonamides. The absence of crystalline structure that is usually associated with a so-called amorphous powder may also lead to an increase in the solubility of a drug when compared with that of its crystalline form e.g the antibiotic novobiocin 31 b) Solvation The incorporation of molecules of the solvent from which crystallization occurred. If water is the solvating molecule( i.e. if a hydrate is formed), then the interaction between the substance and water that occurs in the crystal phase reduces the amount of energy liberated when the solid hydrate dissolves in water. Consequently hydrated crystals tend to exhibit a lower aqueous solubility than their un-hydrated forms. This decrease in solubility can lead to precipitation from solutions of drugs. 32 e.g. calcium gluceptate, which is used in the treatment of calcium deficiency and which is very water soluble, has a sparingly soluble crystalline hydrate. In contrast to the effect of hydrate formation, the aqueous solubilities of other ( i.e. Non- aqueous solvates ) are often greater than those of the un solvated forms 33 5. Particle size of the solid The changes in interfacial free energy that accompany the dissolution of particles of varying sizes cause the solubility of a substance to increase with decreasing particle size This effect may be significant in the storage of pharmaceutical suspensions. Since the smaller particles in such a suspension will be more soluble than the larger ones. As the small particles disappear, the overall solubility of the suspended drug will decrease, and growth of the larger particles will occur. The occurrence of crystal growth by this mechanism is of particular importance in the storage of suspensions intended for injection. 34  The increase in solubility with decrease in particle size ceases when the particles have a very small radius, and any further decrease in size causes a decrease in solubility. This change arises from the presence of an electrical charge on the particles and that the effect of this charge becomes more important as the size of the particles decreases 35 6. pH If the pH of a solution of either a weakly acidic drug or its salt is reduced then the proportion of unionized acid molecules in the solution increases (viseversa in case of weakly basic drug & its salt) 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 36 pH = pKa + log S0/S-S0 S is the overall solubility of the drug So is the solubility of its unionized form S = So + solubility of ionized form. From equation we can calculate: If the pH of the solution is known then we can calculate the solubility of an acidic drug at that pH. minimum pH that must be maintained in order to prevent precipitation from a solution of known concentration. 37 7. Effect of electrolytes on the solubility of non-electrolytes Non-electrolytes do not dissociate into ions in aqueous solution In dilute solution the dissolved species therefore consists of single molecules. Their solubility in water depends on the formation of weak intermolecular bonds (hydrogen bonds) between their molecules and those of water. The presence of a very soluble electrolyte the ions of which have a marked affinity for water, will reduce the solubility of a nonelectrolyte by competing for the aqueous solvent and breaking the intermolecular bonds between the non- electrolyte and water. This effect is important in the precipitation of proteins 38 8. Solubilizing agents These agents are capable of forming large aggregates or micelles in solution when their concentrations exceed certain values. In aqueous solution the centre of these aggregates resembles a, separate organic phase and organic solutes may be taken up by the aggregates thus producing an apparent increase in their solubilities in water, this phenomenon is known as solubilization. A, similar phenomenon occurs in organic solvents containing dissolved solubilizing agents because the centre of the aggregates in these systems constitutes a more polar region than the bulk of the organic solvent. If polar solutes are taken up into these regions their apparent solubilities in the organic solvents are increased. 39 9. Complex formation The apparent solubility of a solute in a particular liquid may be increased or decreased by the addition of a third substance which forms an intermolecular complex with the solute. The solubility of the complex will determine the apparent change in the solubility of the original solute i.e. solubility may increase or decrease due to complex formation. Example for a complex formation as an aid to solubility is the preparation of solution of mercuric iodide (HgI2). It is not very soluble in water but it is soluble in aqueous solutions of potassium iodide because of the formation of a water soluble complex, K2(Hgl4). 40 COLLIGATIVE PROPERTIES 41  Colligative Properties Dissolving solute in pure liquid will change all physical properties of liquid, Density, Vapor Pressure, Boiling Point, Freezing Point, Osmotic Pressure Colligative Properties are properties of a liquid that change when a solute is added. The magnitude of the change depends on the number of solute particles in the solution, NOT on the identity of the solute particles. 42  Colligative properties include: Vapour pressure lowering Freezing point depression, Boiling point elevation, Osmotic pressure 43  Lowering of the vapor pressure The escaping tendency of a solvent is measured by its vapor pressure. Vapor pressure measures the concentration of solvent molecules in the gas phase. Adding a nonvolatile solute lowers the vapor pressure of the solvent since a smaller proportion of the molecules at the surface of the solution are solvent molecules, fewer solvent molecules can escape from the solution compared to the pure solvent. The quantitative relationship between vapor pressure lowering and concentration in an ideal solution is stated in Raoult's Law 44 “ for an ideal solution the partial vapor pressure of a component in solution is equal to the mole fraction of that component times its vapor pressure when pure” Pa = XaPao Pa = vapor pressure of the solution Pao = vapor pressure of pure solvent Xa = mole fraction of the solvent only the solvent (a) contributes to the vapour pressure of the solution 45 46  Mixtures of Volatile Liquids Both liquids evaporate & contribute to the vapor pressure 47  Since BOTH liquids are volatile and contribute to the vapour, the total vapor pressure can be represented using Dalton’s Law: PT = PA + PB The vapor pressure from each component follows Raoult’s Law: PT = cAP°A + cBP°B 48 1. What is the vapor pressure of water above a sucrose (MW=342.3 g/mol) solution prepared by dissolving 158.0 g of sucrose in 641.6 g of water at 25 ºC? The vapor pressure of pure water at 25 ºC is 23.76 mmHg 49 mol sucrose = (158.0 g)/(342.3 g/mol) = 0.462 mol mol water = (641.6 g)/(18 g/mol) = 35.6 mol Xwater= mole water/(mol water+mol sucrose)=35.6/35.6+23.76 =0.987 Psol’n = Xwater Pwater = (0.987)(23.76 mm Hg) = 23.5 mm Hg 50  Elevation of the boiling point The presence of a nonvolatile solute lowers the vapor pressure of a solution so it is necessary to heat the solution to a higher temperature in order for it to boil. The amount by which the boiling point is raised is known as the boiling point elevation. The boiling-point elevation is proportional to the concentration of solute particles expressed as moles of solute per kilogram of solvent. 51 52  The elevation of the BP is T-Tₒ=∆ Tb The expression for the boiling point elevation ΔTb is: Δ Tb = kb m where kb is the boiling point elevation constant for the liquid and m is the molality of the solute. 53  Depression of freezing point The difference in temperature between the freezing point of a solution and the freezing point of the pure solvent The freezing point of a solution is lower than the freezing point of the pure solvent. The expression for the freezing point depression ΔTf is: Δ Tf = kf m where kf is the freezing point depression constant for the liquid and m is the molality of the solute. 54 Osmotic pressure 55  When a solvent passes through a semipermeable membrane from dilute solution(or pure solvent) into a concentrated one, with the result that the concentrations become equalized, this phenomenon is known as osmosis. 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 the solvent via osmosis. 56  Since only solvent molecules can pass through the semi-permeable membrane, the driving force for osmosis arises from the inequality of the chemical potentials of solvent on opposing sides of the membrane. Thus the direction of osmotic flow is from dilute solution where the chemical potential of the solvent is highest because of the higher concentration of solvent molecules, into the concentrated solution 57  The pressure required to stop osmosis, known as osmotic pressure, , is  V = n RT * Where  is the osmotic pressure in atm, V is the volume of solution in liter, n is the number of moles in solute , R is the gas constant, and T is the absolute temp. * van’t Hoff and Morse equation for osmotic pressure 58 59  Osmosis and Blood Cells (a) A cell placed in an isotonic solution. The net movement of water in and out of the cell is zero because the concentration of solutes inside and outside the cell is the same. (b) In a hypertonic solution, the concentration of solutes outside the cell is greater than that inside. There is a net flow of water out of the cell, causing the cell to dehydrate, shrink, and perhaps die. (c) In a hypotonic solution, the concentration of solutes outside of the cell is less than that inside. There is a net flow of water into the cell, causing the cell to swell and perhaps to burst. 60