بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. PHARMACEUTICS SOLUBILITY AND DISTRIBUTION PHENOMENA

3. SOLUBILITY AND DISTRIBUTION PHENOMENA • The solubility of a compound depends upon: a) the physical and chemical properties of the solute and the solvent, b) temp, c) pressure, d) pH of the soln, and e) the state of subdivision of the solute. • Definitions: • 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.

4. Solubility Expressions: • The solubility of a drug may be expressed in a number of ways: • The U.S. Pharmacopoeia and National Formulary list the solubility of drugs as the number of milliliters of solvent in which 1 gram of solute will dissolve. • For example, the solubility of boric acid is 1 g of boric acid dissolves in 18 ml of water, in 18 ml of alcohol, and in 4 ml of glycerin. • Solubility is also quantitatively expressed in terms of molality, molarity, and percentage. • For substances whose solubilities are not definitely known, the values are described in pharmaceutics by the use of certain general terms, as given in Table (1).

5. Table (1): Terms of Approximate Solubility

6. 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. • Polar solvents dissolve ionic solutes and other polar substances. • Accordingly, water mixes in all proportions with alcohol and dissolves sugars and other polyhydroxy compounds.

7. Water dissolves phenols, alcohols, aldehydes, ketones, amines, and other oxygen and nitrogen-containing compounds that can form hydrogen bonds 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. • the solubility of a substance also depends on the ratio of the polar to non-polar groups of the molecule. • As the length of a non-polar chain of an aliphatic alcohol increases, the solubility of the compound in water decreases. • When propylene glycol, glycerin, and tartaric acid present, water solubility increases greatly.

8. Non polar Solvents: • ionic and polar solutes are not soluble or are only slightly soluble in non polar solvents. • Non polar compounds can dissolve non polar solutes • Oils and fats dissolve in carbon tetrachloride, benzene, and mineral oil. • Alkaloidal bases and fatty acids also dissolve in non polar solvents.

9. Semipolar Solvents: • Semipolar solvents, such as ketones and alcohols, can induce a certain degree of polarity in non polar solvent molecules. • Semipolar compounds may act as intermediate solvents to bring about miscibility of polar and non polar liquids. (definition) • Benzene, becomes soluble in alcohol. • Acetone increases the solubility of ether in water. • Propylene glycol increase the mutual solubility of water and peppermint oil and of water and benzyl benzoate.

10. Solubility of Gases in Liquids • 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. • 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. (definition) • The solubility depends primarily on the pressure, temp, presence of salts, and chemical reactions that the gas sometimes undergoes with the solvent.

11. 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.

12. Importance of Henry's law in pharmacy: Solubility of a gas increases directly as the pressure of the gas in the soln is increased and conversely, that the solubility of the gas decreases so that sometimes the gas escapes with violence when the pressure above the soln is released. • This phenomenon is commonly recognized in effervescent solutions when the stopper of the container is removed. • Effect of Temp: • As the temp increases, the solubility of most gases decreases, owing to the greater tendency of the gas to expand.

13. 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 salting out effect may be demonstrated by adding a small amount of salt to a carbonated soln. • 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.

14. 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-

15. 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.

16. Liquid-liquid systems may be divided into two categories according to the solubility of the substances in one another: • (1) complete miscibility and • (2) partial miscibility. • The term miscibiltiy refers to the mutual solubilities of the components in liquid-liquid systems. • Complete Miscibility: • Polar and semi-polar solvents, such as water and alcohol, glycerin and alcohol, and alcohol and acetone, are said to be completely miscible since they mix in all proportions. • Non-polar solvents such as benzene and carbon tetrachloride are also completely miscible.

17. Partial Miscibility: • When certain amounts of water and ether or water and phenol are mixed, two liquid layers are formed, each containing some of the other liquid in the dissolved state. • The mutual solubilities of partially miscible liquids are influenced by temperature. • In a system such as phenol and water, the mutual solubilities of the two phases increasewith temp. until, the critical soln temp. (or upper consolute temp.), the compositions become identical. • At this temp., a homogeneous or single phase system is formed.

18. In the case of some liquid pairs, (ex. Triethyl amine in water) the solubility can increase as the temp. is lowered, and the system will exhibit a lower consolute temp., below which the two members are soluble in all proportions and above which two separate layers form. • Another type, involving a few mixtures such as nicotine and water shows both an upper and a lower consolute temp. with an intermediate temp. region in which the two liquids are only partially miscible. • A final type exhibits no critical soln temp, the pair, ethyl ether and water, has neither an upper nor a lower consolute temp. and shows partial miscibility over the entire temp. range at which the mixture exists.

19. Influence of Foreign Substances: • The addition of a substance to a binary liquid system produces a ternary system, i.e., one having three components. • 1- If the added material is soluble in only one of the two components, the mutual solubility of the liquid pair is decreased. • 2- If the original binary mixture has an upper critical solution temp., the temperature is raised by addition of of the third component 3- if it has a lower consolute temp., it is lowered by the addition of the third component. • For example, if naphthalene is added to a mixture of phenol and water, it dissolves only in the phenol and raises the consolute temp.

20. If potassium chloride is added to a phenol-watermixture, it dissolves only in water and raises the consolute temp. • When the third substance is soluble in both of the liquids to roughly the same extent, the mutual solubility of the liquid pair is increased, an upper critical solution temp. is lowered and a lower critical solution temp. is raised. • Ex. The addition of succinic acid or sodium oleate to a phenol-water system.

21. Solubility of Solids in Liquids: • Factors affecting the solubility of solid in liquid: • 1- Effect of temp: • The effect of temp. on the solubility of some salts in water is shown in (Fig. 2). • A rise in temp. increases the solubility of a solid that absorbs heat (endothermic process) when it dissolves. • Conversely, if the soln process is exothermic, i.e., if heat is evolved, the temp. of the soln when rises the solubility decreases with an elevation of the temp. • Most solids belong to the class of compounds that absorb heat when they dissolve.

22. Sodium sulfate exists in the hydrate form, Na2SO4. 10 H2O, up to a temp. of about 32°C, the soln process (dissolution) is endothermic, and solubility increases with temp. • Above this point, the compound exists as the anhydrous salt, Na2SO4, the dissolution is exothermic, and solubility decreases with an increase of temp. • Sodium chloride 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 temp., and the heat of solution is approximately zero.

23. Temperature (˚C) Fig. (2): The influence of temperature on the solubility of various salts.

24. 2- Effect of complex formation: • The solubility of a solute in 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. • Mercuric iodide , not very soluble, so we need the complex formation as an aid to the solubility in the preparation of solution of mercuric iodide (HgI2) by potassium iodide. Hg I2+ KI→K2(HgI4).

25. 3- The Influence of Solvents on the Solubility of Drugs: • Frequently 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 undissociatedphenobarbital in various solvents.

26. Approximately 1 g of phenobarbital is soluble in 1000 ml of water, in 10 ml of alcohol, in 40 ml of chloroform, and in 15 ml of ether. • Solubility increase as increase in percent of glycerin. • The solubility of phenobarbital in water-alcohol-glycerin mixtures is plotted on a semilogarithm grid in (Fig. 3). • For example, at 22% alcohol, 40% glycerin, and the remainder water (38%), 1.5% w/v of Phenobarbital is dissolved.

27. Phenobarbital (%w/v) Solubility of Phenobarbital in water 0 20 40 60 80 100 Alcohol in solvent (%by volume) Fig. (3): The solubility of Phenobarbital in a mixture of water, alcohol, and glycerin. The vertical axis is a logarithmic scale representing the solubility of Phenobarbital in g/100 ml

28. The Distribution of Solutes Between Immiscible Liquids: • Principal: • If a substance, which is soluble in both components of a mixture of immiscible liquids, is dissolved in such a mixture then, when equilibrium is attained at constant temp., it is found that the solute is distributed between the two liquids in such a way that the ratio of the activities of the substance in each liquid is a constant. • This is known as the Nernst distribution law, which can be expressed by equation: aA/aB= constant (6) • where aA and aBare the activities of the solute in solvent A and B, respectively. • When the solns are dilute or when the solute behaves ideally, the activities may be replaced by concs (CA and CB) CA/CB = K (7) • Where the constant K is known as the distribution or partition coefficient.

29. For example, a partition coefficient of 2 for a solute distributed between oil and water may also be expressed as a partition coefficient between water and oils of 0.5.

30. The partition coefficient of the drug is important : 1- Release of drug from dosage form. 2- Transport and distribution of drugs throughout the body; e.g. the absorption of drugs from the gastrointestinal tract, 3- Distribution of drugs between various tissues, and 4- Penetration of drugs to the sites where they can exert their pharmacological activity.