solubility

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In General In general, SOLUBILITY is an ability of a substance to dissolve. In the process of dissolving, the substance which is being dissolved is called a solute and the substance in which the solute is dissolved is called a solvent . A mixture of solute and solvent is called a solution . SOLUBILITY is understood as a maximum amount of solute that dissolves in a solvent at so called equilibrium . In chemistry an equilibrium is a state where reactants and products reach a balance - no more solute can be dissolved in the solvent in the set conditions ( temerature , pressure). Such a solution is called a saturated solution .

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Key word If the solvent is volatile there will be a vapour pressure above the solution which depends on the solvent’s properties, the presence of solute and the temperature. When a solution contains a solute at the limit of its solubility at any given temperature and pressure it is said to be saturated. If the solubility limit is exceeded,solid particles of solute may be present and the solution phase will be in equilibrium with the solid, although under certain circumstances supersaturated solutions may be prepared, where the drug exists in solution above its normal solubility limit. The maximum equilibrium solubility of a drug dictates the rate of solution (dissolution) of the drug; the higher the solubility, the more rapid is the rate of solution

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Factors influencing solubility The solution process can be considered in three stages 1. A solute (drug) molecule is ‘removed’ from its crystal. 2. A cavity for the molecule is created in the solvent. 3. The solute molecule is inserted into this cavity.

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The surface area of the drug molecule affects solubility because placing the solute molecule in the solvent cavity (step 3) requires a number of solute–solvent contacts; the larger the solute molecule, the larger the cavity required (step 2) and the greater the number of contacts created. For simple molecules solubility decreases with increase of molecular surface area. Conti….. The boiling point of liquids and the melting point of solids both reflect the strengths of interactions between the molecules in the pure liquid or the solid state (step 1). In general, aqueous solubility decreases with increasing boiling point and melting point.

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The influence of substituents on the solubility of molecules in water can be due to their effect on the properties of the solid or liquid (for example, on its molecular cohesion, step 1) or to the effect of the substituent on its interaction with water molecules (step 3). Substituents can be classified as either hydrophobic or hydrophilic, depending on their polarity: Polar groups such as –OH capable of hydrogen bonding with water molecules impart high solubility . Non-polar groups such as –CH3 and – Cl are hydrophobic and impart low solubility . Ionisation of the substituent increases solubility, e.g. –COOH and –NH2 are slightly hydrophilic whereas –COO– and –NH3+ are very hydrophilic. Conti…..

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The position of the substituent on the molecule can influence its effect on solubility, for example the aqueous solubilities of o-, m- and p- dihydroxybenzenes are 4, 9 and 0.6 mol dm–3, respectively. Conti….. The solubility of inorganic electrolytes is influenced by their crystal properties and the interaction of their ions with water (hydration). Additives may either increase or decrease the solubility of a solute in a given solvent; their effect on the solubility of sparingly soluble solutes may be evaluated using the solubility product. Salts that increase solubility are said to salt in the solute and those that decrease solubility salt out the solute .

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pH Acidic drugs , such as the non-steroidal anti-inflammatory agents, are less soluble in acidic solutions than in alkaline solutions because the predominant undissociated species cannot interact with water molecules to the same extent as the ionised form which is readily hydrated. The equation relating the solubility, S, of an acidic drug to the pH of the solution is: where So is the solubility of the undissociated form of the drug .

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Basic drugs such as ranitidine are more soluble in acidic solutions where the ionised form of the drug is predominant. The equation relating the solubility, S, of a basic drug to the pH of the solution is:

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Amphoteric drugs such as the sulfonamides and tetracyclines display both basic and acidic characteristics. The zwitterion has the lowest solubility, So, and the variation of solubility with pH is given by: at pH values below the isoelectric point at pH values above the isoelectric point

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IONISATION OF DRUGS IN SOLUTION Ionisation of weakly acidic drugs and their salts If the weak acid is represented by HA, its ionisation in water may be represented by the equilibrium: The equilibrium constant, Ka, is referred to as the ionisation constant, dissociation constant or acidity constant and is given by:

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Conti….. The percentage ionisation at a given pH can be calculated from: Weakly acidic drugs are virtually completely unionised at pH up to 2 units below their pKa and virtually completely ionised at pHs greater than 2 units above their pKa . They are exactly 50% ionised at their pKa values. for example when sodium salicylate (salt of the weak acid, salicylic acid, and the strong base NaOH )

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IONISATION OF WEAKLY BASIC DRUGS AND THEIR SALTS If the weak acid is represented by B, its ionisation in water may be represented by the equilibrium: The equilibrium constant, Kb, is referred to as the ionisation constant, dissociation constant or basicity constant and is given by: The percentage ionisation at a given pH can be calculated from: Conti…..

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Conti….. Weakly basic drugs are virtually completely ionised at pHs up to 2 units below their pKa and virtually completely unionised at pHs greater than 2 units above their pKa . They are exactly 50% ionised at pHs equal to their pKa values. for example, ephedrine hydrochloride (salt of the weak base, ephedrine, and the strong acid HCl ) Ionisation of polyprotic drugs Several acids, for example citric, phosphoric and tartaric acid, are capable of donating more than one proton and these compounds are referred to as polyprotic or polybasic acids. Similarly, polyprotic bases are capable of accepting two or more protons. Examples of polyprotic drugs include the polybasic acids amoxicillin and fluorouracil, and the polyacidic bases pilocarpine , doxorubicin and aciclovir .

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pH OF DRUG SOLUTIONS The pH of a strong acid such as HCl is given by pH = –log[H+]. This is because strong acids are completely ionised in solution. However, as seen above, weak acids and bases are only slightly ionised in solution and the extent of their ionisation changes with pH and so therefore does their pH. The pH at any particular concentration, c, can be calculated from the pKa value: (note that there is no concentration term in this equation, meaning that the pH does not vary with concentration).

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Buffers Buffers are usually mixtures of a weak acid and its salt (that is, a conjugate base), or a weak base and its conjugate acid. A mixture of a weak acid HA and its ionised salt (for example, Na A) acts as a buffer because the A– ions from the salt combine with the added H+ ions, removing them from solution as undissociated weak acid: Added OH– ions are removed by combination with the weak acid to form undissociated water molecules:

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A mixture of a weak base and its salt acts as a buffer because added H+ ions are removed by the base B to form the salt and OH– ions are removed by the salt to form undissociated water: The concentration of buffer components required to maintain a solution at the required pH may be calculated from the Henderson– Hasselbalch equations:

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The effectiveness of a buffer in minimising pH change is expressed as the buffer capacity, β, calculated from: where c0 is the total initial buffer concentration. A plot of β against pH (Figure) shows that: – The buffer capacity is maximum when pH = p Ka . – Maximum buffer capacity, βmax , = 0.576 co.