Solubility and Factors Affecting Solubility PDF

Solubility Factors Affecting Solubility LECTURE NO. 4 Factors affecting solubility; expression of dissolution; dissolution rate versus solubility; preparation of solutions containing non- volatile materials.  Solubility : o It is the con...

Solubility Factors Affecting Solubility LECTURE NO. 4 Factors affecting solubility; expression of dissolution; dissolution rate versus solubility; preparation of solutions containing non- volatile materials.  Solubility : o It is the concentration of solute in a saturated solution at a certain temperature. Solubility Expressions: The solubility of drugs may be expressed in number of ways 1. The USP and National Formulary : o Solubility is expressed as the number of ml of solvent in which 1 g of solute will dissolve. e.g., the solubility of boric acid: 1 g of boric acid dissolves in 18 ml of water or alcohol and in and in 4 ml of glycerine. The solubility of boric acid is --------------in water or alcohol than in glycerine. 2. Solubility in Qualitative terms:- o The official pharmaceutical compendia use general terms to describe the solubility of substances whose solubilities are not definitely known.  Factors (Parameters) that affect total solubility I. The nature and strength of solute-solvent attractions (intermolecular interaction):- o We assume that the drug is present as a crystalline structure. o Dissolution (solubility) is opposite to crystallization. o The attraction of the solvent for solute molecules (adhesive forces) OPPOSES the attraction of the solute molecules (cohesive forces). o If the solvent sufficiently interacts with the solute particles , reduce their crystalline structure converting it to molecules, and ions. ❖ Solute-Solvent Interactions Affect Solubility:-. o Strong solute-solvent attractions equate to greater solubility while weak solute-solvent attractions equate to lesser solubility o The extent of the solute to dissolve in a solvent is dependent on the intermolecular interactions, which leads to cohesive and adhesive forces between the similar molecules and the different molecules respectively of the solutes and the solvent. o Adhesion > cohesive forces increase solubility o In turn, polar solutes tend to dissolve best in polar solvents. o non-polar solutes tend to dissolve best in non-polar solvents. o A general rule to remember is, "Like dissolves like." Solubility capacity:- o It is the resting point for the equilibrium between undissolved solute and the solubilized solute. o Once the capacity of the solvent to dissolve any further solute is reached, further addition of solute will result in settling of the solute in the bottom of the container. o Solutions can be made into supersaturated solution by altering the temperature of the solvent. o Supersaturated solutions are unstable and easily precipitate out excess solute to reach the solubility capacity at a given temperature. ❖ Common-ion effect on solubility:- o It is a term that describes the decrease in solubility of an ionic compound when another salt that contains common ion is added to the mixture. o This effect best be explained by Le Chatelier's principle. o The net ionic equation for the resulting chemical equilibrium is: o Imagine if the slightly soluble ionic compound calcium sulfate, Ca SO​4, is added to water. Ca SO4 ⇌ Ca+2 aq) + SO-2 (aq) o Suppose the soluble ionic compound copper sulphate (Cu SO4) were added to the solution. o Copper sulphate is soluble; therefore, its only important effect on the net ionic equation is the addition of more sulphate (SO42-) CuSO4(s) ⇌ Cu2+ (aq)+SO2− (aq) o The sulphate ions dissociated from copper sulphate are already present (common to) in the mixture from the slight dissociation of calcium sulphate. o Thus, this addition of sulphate ions places stress on the previously established equilibrium. o Le Chatelier's principle dictates that the additional stress on this product side of the equilibrium results in the shift of equilibrium towards the reactants side in order to alleviate this new stress. o Because of the shift toward the reactant side, the solubility of the slightly soluble calcium sulphate is reduced even further. ❖ Polarity of the solvent and the solute:- o The concept is that Polar solutes are more soluble in polar solvents. o Nonpolar solutes are more soluble in nonpolar solvents. LIKE DISSOLVES LIKE ❖Temperature:- Effect of temperature on solids solubility The effects of temperature on the solubility of solids differ depending on whether the reaction is endothermic or exothermic. o When heat is absorbed in the dissolution process (endothermic) the solubility of the compound increases with heat. o When heat is evolved in the dissolution process (exothermic) the solubility of the compound decreases with heat. o Most solids belong to the class of compounds that absorb heat (endothermic) when they dissolve. o Sodium sulphate exists in the hydrated form Na2SO4.10H2O. o up to a temperature of about 32°C, the solution process is endothermic, and solubility increases with temperature. o Above this point, the compound exists as the anhydrous salt, Na2SO4 the dissolution is exothermic, and solubility decreases with an increase of temperature. o 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 Effect of temperature on Gas solubility:- o note that the process of dissolving gas in liquid is usually exothermic. o increasing temperatures result in stress on the product side (because heat is on the product side). o Consequently, the equilibrium concentration of the gas particles in gaseous phase increases, resulting in lowered solubility. o Conversely, decreasing temperatures result in stress on the reactant side (because heat is on the product side). o Consequently, the equilibrium concentration of the gas particles in gaseous phase would decrease, resulting in greater solubility. Pressure Affects on Solubility of Gases:- o Effect of pressure is only significant on gases in liquids solubility. Solids & Liquids: The effects of pressure changes on the solubility of solids and liquids are negligible. Gases & Liquids: The effects of pressure on the solubility of gases in liquids can best be described through a combination of Henry's law and Le Chatelier principle. Henry's law dictates that, the solubility of the gas corresponds to it's partial pressure at fixed temperature. P = kh c (3) where: P = is the partial pressure of the gas above the liquid, Kh = is Henry's law constant, depend on the nature of the gas, and c = the concentrate of the gas in the liquid Example:- Consider the following exothermic reaction that is in equilibrium CO2(g) + H2O(l) ⇌ H2CO3(aq) What will happen to the solubility of the carbon dioxide if: 1.Temperature is increased? 2.Pressure and temperature are increased? 3.Pressure is increased but temperature is decreased? 4.Pressure is increased? ❖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. Example:- 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) 9/27/2024 16 The reduction in aqueous solubility esterification:- Such a reduction in solubility may provide a suitable method for: o 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 o protecting the parent drug from excessive degradation in the gut, e.g., Erythromycin propionate is less soluble and, consequently, less readily degraded than erythromycin. o increasing the ease of absorption of drugs from the gastrointestinal tract, e.g., erythromycin propionate is also more readily absorbed than erythromycin. ❖Nature of solvent /cosolvents:- 'like dissolves like’ o Using cosolvents such as ethanol or propylene glycol, which are miscible with water and which" act as better solvents for the solute in question. Example:- o The aqueous solubility of metronidazole is about 100 mg in 10 ml; o 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 ❖Effect of molecular size on solubility:- o Solubility decreases as the molecular size increases. o The larger the size of molecules in a solute, the more difficult it is for solvent molecules to wrap around them in order to dissolve them. o On the other hand, solvent molecules wrap around molecules of smaller size more easily, increasing the solubility of the substance. o In general, under the same temperature and pressure conditions, solutes with smaller particles are more soluble than solutes with larger particles. o Changing the temperature and pressure can change the solubility of the substance. ❖Crystal characteristics: polymorphism & solvation Polymorphism:- o Some substances have different crystalline forms, which are known as polymorphs. ❖ Polymorphism is the presence of a substance in more than one crystalline forms that having different physical characteristic but having same chemical properties, ▪ The polymorphic form with the lowest free energy will be the' most stable and possess the highest melting point and lowest solubility. ▪ Other less stable (metastable) form is the most soluble one and will tend to transform into the most stable on storage. ▪ The absence of crystalline structure that is 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., novobiocin. ❖Solvation:- ▪ The incorporation of molecules of the solvent from which crystallization occurred. ▪ If water is the solvating molecule, i.e.,(hydrates), 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. Example:- calcium gluceptate, which is very water soluble, has a sparingly soluble crystalline hydrate. o In contrast to the effect of hydrate formation, the aqueous solubilities of other non-aqueous solvates are often greater than those of the un-solvated forms. In conclusion:- o Metastable polymorph is more soluble than the stable form. o Amorphous drugs are more soluble than their crystals. o The hydrates are less soluble in water than anhydrous form. ❖Effect of pH:- o weakly acidic drug or its salt:- If the pH of a solution unionized acid molecules and solubility decreased (PPT). o weakly basic drug or its salt If the pH of a solution unionized basic molecules and solubility decreased (PPT). o The relationship between pH & the solubility & pKa value of an acidic drug is given by a modified Henderson-Hasselbalch eq  𝑆0 pH = p Ka + log 𝑆 −𝑆0 S is the overall solubility of the drug (ionized and unionized) So is the solubility of its unionized form S = So + solubility of ionized form From the 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 must be maintained in order" to prevent precipitation from a solution of known concentration. ❖ Effect of electrolytes on the solubility of nonelectrolytes 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. In the presence of a very soluble electrolyte, the ions of which have a marked affinity for water, will reduce the solubility of a non- electrolyte by competing for the aqueous solvent and breaking the intermolecular bonds between the non-electrolyte and water. (Salting Out). This effect is important in the precipitation of proteins. Solubilizing agents:-. These agents are capable of forming large aggregates or micelles in solution when their concentrations exceed certain values (CMC) In aqueous solution the centre of these aggregates resembles a separate organic phase, thus 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. o 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. o If polar solutes are taken up into these regions their apparent solubilities in the organic solvents are increased. 9/27/2024 26 ❖Complex formation:-. Example:- o The complexation of non-ionic surfactants, such as Polysorbate 80, with Preservative (Parabens) resulting in the inactivation of the preservatives. o Certain Polyols (e.g., sorbitol) have been shown to inhibit this complexation, thus maintaining Paraben antimicrobial activity. 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) mercuric iodide (HgI2) 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) o When complex formation occurs, the total solubility is equal to. the inherent solubility of the un-complexed drug plus the concentration of drug complex in solution. Solubility of Slightly soluble Electrolyte Solubility product Ksp When slightly soluble electrolytes are dissolved to form saturated solutions, the solubility is described by a special constant, known as the solubility product Ksp of that compound. The equation is only approximate for sparingly soluble salts. It does not hold for freely soluble salts such as sodium chloride.  Silver chloride (slightly soluble. salt). The excess solid in equilibrium with the ions in saturated solution at a specific temperature is represented by the equation. Ag Cl solid Ag+ + Cl – [Ag+ ][CI- ] = Ksp o The concentrations of each ion is raised to a power equal to the number of ions appearing in the formula. o Thus, for Al (OH)3 Al(OH)3 solid Al+++ + 3 OH- [Al+++][OH- ] 3 = Ksp. ❖Effect of common ion:- If an ion in common with AgCl that is Ag+ or Cl - , is added to a solution of AgCl. The equilibrium is altered. E.g., addition of strong electrolyte as Na+ Cl- [Ag+ ][CI - ] > Ksp and some of the AgCl precipitates from the solution until the equilibrium [Ag + ] [Cl - ] = Ksp is reestablished. The addition of common ion reduces the solubility of a slightly soluble electrolyte Salts having no ion in common with the slightly soluble electrolyte produce an effect opposite to that of a common ion at moderate concentration they increase rather than decrease the solubility. E.g., addition of Na2 SO4. THE 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 - pressure, - temperature and - presence of salts. o Effect of Temperature: As the temperature is increased the solubility of most gases decreases, owing to the greater tendency of the gas to expand. (solubility of gas is exothermic) Salting Out: Gases are often liberated from solutions in which they are dissolved by the introduction of an electrolyte such as NaCl and sometimes by a nonelectrolyte such as sucrose. This is due to the attraction of the salt ions or the highly polar non-electrolyte for the water molecules. 9/27/2024 32 Effect of Chemical Reaction:. Henry's law applies strictly to gases which are only slightly soluble in solution, and which do not react in any way in the solvent. The effect of the pressure on the solubility of a gas is expressed by Henry’s Law. C=kpC C = is the concentration of the dissolved gas in g/ liter of solvent P = is the partial pressure in mm Hg of the undissolved gas above the solution, K = is a proportionality constant for the solution. Gases such as hydrogen chloride, ammonia and CO2 show deviations as a result of chemical reaction between the gas and solvent result in increasing the solubility. Accordingly, hydrogen chloride (H Cl) is about 10,000 times more soluble in water than is oxygen.  expression of. dissolution dissolution rate versus solubility o Solubility and dissolution are different concepts but are Related o Dissolution rate is a kinetic process. o In contrast to solubility, when we speak of dissolution, it is understood that rate is a major consideration. Solubility is an endpoint. o A solute may have poor solubility in a solvent, yet its dissolution rate may be rapid. o Conversely, a solute can be very soluble yet require longer time to arrive at the final saturation concentration. Rate of Solution (Dissolution rate). :- The rate at which the solute goes into solution. A solid particle dispersed in a solvent is surrounded by a thin layer of solvent having a definite thickness L (cm) = stagnant layer. The stagnant layer remains a part of the solid regard-less of how fast the solution may be stirred. It will move wherever the particle moves. The thickness of this layer may get smaller by stirring, but it will always have a definite thickness.  The rate of solution may be explained using Fick’s First Low of Diffusion: It is the rate at which a dissolved solute particle diffuses through the stagnant layer to the bulk solution 9/27/2024 36. o The driving force behind the movement. of the solute molecule through the stagnant layer is the difference in concentration between: C1 the conc. of the solute, in the stagnant layer at the surface of the solid and C2 the conc. of the solute on the farthest side of the stagnant layer. o The greater this difference (C1 - C2 ), the faster the rate of Dissolution Thus, according to Fick’s low the Dissolution rate is: Directly proportional to C1 - C2 & surface area of the solid A in cm2 Inversely proportional to the length L of the pass the molecule must diffuse. Rate of Dissolution = D (Diffusion coefficient cm2 /sec- (proportionality constant) C2 is too small compared to C1 thus neglected C1 is most often the saturation solubility of the solute Cs Rate of solution = Q/t = D A Cs/ L 9/27/2024 39 From the equation, how to enhance. the Dissolution rate? 1. the surface area how? Decrease particle size 2. the thickness of the stagnant layer how? Stirring rate 3. the saturation solubility how? If the drug has different polymorphs, the metastable polymorph usually has higher solubility. 4. viscosity why? 5. Diffusion coefficient. D is inversely proportional to the viscosity. TERMS:- o The solubility of a solute is the concentration of the saturated solution. o A saturated solution a solution in which the maximum amount of solute has dissolved in the solvent at a given temperature. o An unsaturated solution a solution in which the solute has completely dissolved in the solvent. o A supersaturated solution is a solution in which the amount of solute dissolved under given conditions exceeds it's supposed upper limit. o Le Châtelier's principle states that when a system in chemical equilibrium is stressed, the system will shift in a way that alleviates the stress. o Endothermic reaction: a reaction in which heat is absorbed (ΔH>0) o Exothermic reaction: a reaction in which heat is released (ΔH < 0)