4.1 Solubility and Distribution Phenomena 2011 aa-1.pptx

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1. Solubility and Distribution Phenomena

2. Content of presentation Objectives Introduction Introduction to intermolecular force of interaction Solute-solvent interactions (polar, nonpolar and semipolar solvents) Solubility expressions Solubility of gases in liquids Factors affecting solubility of gases, Solubility of liquids in liquids Ideal and real solutions, complete and partial miscibility, factors affecting solubility of liquids

3. Objectives After completion of this lecture, the student should be able to: Define saturated solution, solubility, and unsaturated solution. Describe the various intermolecular force of interaction Describe and give examples of polar, nonpolar , and semipolar solvents Describe the various factors that affect the solubility of gases in liquids Explain the ideal solution and real solution Describe complete & partial miscibility . Understand the factors controlling the solubility liquids in liquids

4. Introduction 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. Have information about the structure & intermolecular forces of the drug

5. Introduction…. Solubility is defined in quantitative terms as the concentration of solute in a saturated solution at a certain temperature, and in a qualitative way, it can be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. Solubility is an intrinsic material property that can be altered only by chemical modification of the molecule. In contrast to this, dissolution is an extrinsic material property that can be influenced by various chemical, physical, or crystallographic means such as complexation , particle size, surface properties, solid-state modification, or solubilization enhancing formulation strategies.

6. Introduction…. A solution can be defined as a system in which molecules of a solute are dissolved in a solvent vehicle When a solution contains a solute at the limit of its solubility at any given temperature and pressure, it is said to be saturated. An unsaturated solution is one containing the dissolved solute in a concentration below that necessary for complete saturation at a definite temperature. A supersaturated solution is one that contains more of the dissolved solute than it would normally contain at a definite temperature, were the undissolved solute present.

7. 1. Introduction to intermolecular force of interaction Intermolecular forces Forces of attraction or repulsion which act between neighboring particles: atoms, molecules or ions. They are weak compared to the intramolecular forces Manifested by aggregations of molecules in gases, liquids & solids Cohesion or the attraction of like molecules and adhesion or the attraction of unlike molecules b/n molecules The knowledge is important for understanding: The properties of gases, liquids, and solids The properties of interfacial phenomena Flocculation in suspensions & stabilization of emulsion Compaction of powders in capsules, and The compression or granules to form tablets. 1/26/2020 7

8. Types of attractive intermolecular forces 1. Van der waals forces 2. Ion-dipole and ion-induced dipole force 3. Hydrogen bonds Van der waals forces The weak intermolecular bonds in liquids and solids are often called van der Waals forces . These forces can be divided into three categories: (1) dipole-dipole ( Keesom forces) (2) dipole-induced dipole ( Debye force ) and (3) induced dipole-induced dipole London dispersion forces 1/26/2020 8

9. A. Dipole-Dipole Forces ( Keesom forces) A dipole- if a molecule acts as if it has a positive and negative pole (polar molecules) Due to the difference b/n the electronegativities of the atoms Example The dipole-dipole interaction in HCl is only 3.3 kJ/mol (The covalent bonds in HCl are 130 times as strong.) The force of attraction between HCl molecules is so small that hydrogen chloride boils at -85.0 o C. 1/26/2020 9

10. B. Dipole-Induced Dipole Forces or Debye force Permanent dipoles are capable of inducing an electric dipole in nonpolar molecules For instance, what would happen if we mixed HCl with argon, which has no dipole moment? By distorting the distribution of electrons around the argon atom, the polar HCl molecule induces a small dipole moment This force is very weak, with a bond energy of about 1 kJ/mol 1/26/2020 10

11. C. Induced Dipole-Induced Dipole Forces or London dispersion forces Movement of the electrons around the nuclei of a pair of neighboring atoms can become synchronized so that each atom simultaneously obtains an induced dipole moment. These fluctuations in electron density occur constantly, creating an attraction between pairs of atoms The weak electrostatic force of attraction is common in nonpolar molecules such as hydrogen gas, carbon tetrachloride, & benzene helium -- only 0.076 kJ/mol 1/26/2020 11

12. 2. Ion-dipole and ion-induced dipole force An ion-dipole force consists of an ion and a polar molecule interacting. An ion-induced dipole force consists of an ion and a non-polar molecule interacting. Like a dipole-induced dipole force, the charge of the ion causes a distortion of the electron cloud on the non-polar molecule. Because the charge of any ion is much greater than the charge of a dipole moment , these forces are stronger than other IMF Ion-induced dipole forces are presumably involved in the formation of the iodide complex, I 2 + K + I - K + I 3 - 1/26/2020 12

13. 3. Hydrogen bonds The interaction b/n a molecule containing a H-atom & a strongly electronegative atom such as fluorine, oxygen, or nitrogen Because of small size of a hydrogen atom and its large electrostatic field , it can move in close to the electronegative atom and form an electrostatic type of union- hydrogen bridge. 1/26/2020 13

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15. Solubility Expressions The solubility of a drug may be expressed in a number of ways. The United States Pharmacopeia (USP) describes the solubility of drugs as parts of solvent required for one part solute. Solubility is also expressed quantitatively in terms of percentage, molarity and molality . In pharmaceutical field, three concentration terms are often used. These are: Percent wt by wt (%w/w) which is the number of grams of solute dissolved in 100 grams of solution. Percent volume by volume (%v/v) which is the number of ml of solute dissolved in 100ml of solution. Percent weight by volume (%w/v) which is the number of grams of solute dissolved in 100ml of solution. The USP describes solubility using the seven groups listed in Table 5-1

16. Methods of expressing solubility Table: General terms used to approximate solubility Terms Parts of solvent required to dissolve 1 part of solute Very soluble Less than 1 part Freely soluble Between 1 and 10 Soluble Between 10 and 30 Sparingly soluble Between 30 and 100 Slightly soluble Between 100 and 1000 Very slightly soluble Between 1000 and 10 000 Practically insoluble > 10 000 1/26/2020 16 phase rule

17. Solvent–Solute Interactions Solubility depends on chemical, electrical & structural effects that lead to mutual interactions between the solute and the solvent As a general rule: like dissolves like i.e., 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

18. Solvent–Solute Interactions..... If the solvent is A & the solute is B, and the forces of attraction are represented by A-A, B-B and A-B, one of the following conditions will occur: If A-A >> A-B , The solvent molecules will be attracted to each other & the solute will be excluded. Example: Benzene & water If B-B >> A-A The solvent will not be able to break the binding forces between solute molecules. Example: NaCl in benzene If A-B >> A-A or B-B, or the three forces are equal…The solute will disperse & form a solution. Example: NaCl in water .

19. Classification of solvents & their mechanism of action Polar solvents Polar solvents (water, glycols, methyl & ethyl alcohol), dissolve ionic solutes & other polar substances. Solubility of substances in polar solvents depends on hydrogen bonding, dipole moment & structural features.

20. Solubility of substances in polar solvents depends on structural features: Straight-chain monohydroxy alcohols, aldehydes , ketones , and acids with more than 4 or 5C are only slightly soluble Because cannot enter into the hydrogen-bonded structure of water Branching of the carbon chain in aliphatic alcohols increases water solubility. Tertiary butyl alcohol » soluble than n-butyl alcohol Polyhydroxy compounds as glycerin, tartaric acid, PEG are water soluble.

21. Polar solvents acts as a solvent according to the following mechanisms: Dielectric constant: due to their high dielectric constant, polar solvents reduce the force of attraction b/n oppositely charged ions in crystals . Example: water possessing a high dielectric constant (80) can dissolve NaCl , while chloroform (5) & benzene (2) cannot.

22. Hydrogen bond formation: Water dissolves phenols, alcohols, aldehydes , ketones , amines and other oxygen- and nitrogen-containing compounds that can form hydrogen bonds with water. Hydrogen force is more influential than dipole moment. nitrobenzene & phenol have dipole moment of 4.2x10 -18 & 1.7x10 -18 , respectively. Solubility 0.0155 & 0.95mole/kg in water at 20 o C.

23. Solvation through dipole interaction: Polar solvents are capable of solvating molecules & ions through dipole interaction forces. The solute must be polar to compete for the bonds of the already associated solvent molecules. Example: Ion-dipole interaction between sodium salt of oleic acid & water

24. Polar solvents break covalent bonds of potentially strong electrolytes by acid-base reactions since these solvents are amphiprotic . For example, water brings about the ionization of HCl as follows HCl + H 2 O = H 3 O + + Cl -

25. Non polar solvents Non polar solvents are unable to reduce the attraction between the ions due to their low dielectric constants. They are unable to form hydrogen bonds with non electrolytes. and also the solvents can not break covalent bonds and ionize weak electrolytes Hence, ionic and polar solutes are not soluble or are only slightly soluble in nonpolar solvents Non polar solvents can dissolve non polar solutes through weak van der Waals forces Example: solutions of oils & fats in carbon tetrachloride or benzene.

26. Semipolar solvents Semipolar solvents, such as ketones & alcohols can induce a certain degree of polarity in non polar solvent molecules. They can act as intermediate solvents to bring about miscibility of polar & non polar liquids. Example: acetone increases solubility of ether in water. Alcohol increases the mutual solubility of water and castor oil. Propylene glycol increases the mutual solubility of water and peppermint oil and water and benzyl benzoate.

27. Solubility of gas in liquids Examples of pharmaceutical solutions of gases include: Effervescent preparations containing dissolved carbon dioxide, Ammonia water and hydrochloric acid ( HCl gas in water). Pharmaceutical aerosols containing nitrogen or carbon dioxide as the propellant The solubility of a gas in a liquid is the concentration of 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 & chemical reactions that sometimes the gas undergoes with the solvent

28. Factors affecting solubility of gases in liquids Effect of pressure Solubility of gas depends on the pressure of a gas above the solution & the effect is indicated by Henry's law According to Henry’s law: In a very dilute solution at constant T, the concentration (C2) of dissolved gas is proportional to the partial pressure ( p) of the gas above the solution at Equilibrium. C2= σ p C2 is concentration of dissolved gas P is partial pressure ( p) of the gas above the solution at Equilibrium σ is solubility coefficient Caution: When the pressure above the solution is released (decreases), the solubility of the gas decreases, and the gas may escape from the container with violence. E.g. effervescent solns .

29. B. Effect of temperature As the temperature increases the solubility of gases decreases, owing to the great tendency of the gas to expand. Pharmaceutical application: The pharmacist should be cautious in opening containers of gaseous solutions in warm climates. A container filled with a gaseous solution or a liquid with high vapor pressure, such as ethyl nitrite, should be immersed in ice or cold water, before opening the container

30. C. Effect of Salting out Adding electrolytes ( NaCl ) & sometimes non electrolytes (sucrose) to gaseous solutions ( eg . carbonated solutions) induces liberation of gases from the solutions. Why? Due to the attraction of the salt ions or the highly polar electrolyte for the water molecules and reduction of the aqueous environment adjacent to the gas molecules.

31. E. Effect of chemical reaction Henry’s law generally applies to gases that are only slightly soluble in solvent and that do not react in any way with the solvent. Chemical reaction if any between a gas and a solvent greatly increases the solubility of the gas in the solvent. For example hydrogen chloride gas reacts with water by hydrogen bonding when it dissolves in water. HCl is about 10,000 times more soluble in water than is oxygen

32. Solubility of liquids in liquids Pharmaceutical solution containing a liquid dissolved in another liquid include Hydro-alcoholic solutions Aromatic water such as chloroform water and Peppermint water Volatile oil in alcohol such as spirits. Liquid–liquid systems can be divided into two categories according to the solubility of the substances in one another: ( a) complete miscibility and (b) partial miscibility. The term miscibility refers to the mutual solubilities of the components in liquid–liquid systems.

33. A. Ideal and real solutions Ideal solutions No change in the properties of the components, solution. No heat is evolved & absorbed during the mixing process The final volume of the soln is additive That is, no shrinking or expansion occurs when mixed. The constitutive properties, are the weighted averages of the properties of the pure individual constituents. for example, the vapor pressure, and viscosity of the solution,

34. Ideal solutions are formed by mixing substances with similar properties. methanol is mixed with ethanol sulfuric acid is mixed with water, solution is said to be nonideal , or real. Ideality in a gas implies the complete absence of attraction forces Ideality in a solution means complete uniformity of attraction forces. The force b/n A and A, B and B, A and B are all in the same order

35. Ideal solutions and Raoult’s law In 1887, Raoult recognized that, in an ideal solution the partial pressure (P A ) of a component (A) in a liquid mixture is equal to vapour pressure in the pure state ( P o A ) multiplied by the mole fraction of the component (X A ) in solution. Raoult’s law for ideal solution is expressed as P A = P o A X A P B = P o B X B where P A and P B are the partial pressure of the component A and B in the mixture (in the solution), respectively. P o A and P o B are the vapor pressure of the pure component A and B X A and X B are the mole fraction of the component A and B in the mixture (in the solution)

36. Once the components in the solution have reached equilibrium, the total vapor pressure p of the solution is:

37. Example What is the partial vapor pressure of benzene and of ethylene chloride in a solution at a molar fraction of benzene of 0.6? The vapor pressure of pure benzene at 50 o C is 268mm, and the corresponding P o A of ethylene chloride is 236mm. Answer: P A = 236x0.4= 94.4mm P B =268x0.6=160.8mm

38. Real solution In practice, there are deviations from Raoult’s law. Many pairs of liquids are present in which there is no uniformity of attractive forces the adhesive and cohesive forces of attraction are not uniform between the two liquids The deviations may be negative leading to increased solubility because of hydrogen bonding b/n components. If the deviation is positive, it leads to a decreased solubility because of the association of the molecules of one the components to form dimmers or polymers of high order.

39. Negative deviation When adhesive forces b/n molecules of A and B are greater than the cohesive force between A and A, or B and B, then the vapor pressure of the solution is less than the expected vapor pressure from Raoult's law. Chloroform and benzene

40. Positive deviation When the cohesive forces > adhesive forces , the dissimilarities of polarity or internal pressure will lead both components to escape solution more easily. the vapor pressure will be greater than the expected from the Raoult's law e.g. benzene and ethyl alcohol, carbon disulfide and acetone, chloroform and ethanol.

41. B. Complete and partial miscibility Complete miscibility Polar and semipolar solvents such as Water & alcohol, Glycerol & alcohol, and Alcohol & acetone Complete miscibility because they mix in all proportions Non polar solvents such as Benzene and carbon tetrachloride Complete miscibility occurs when: (A-B) >> A-A or B-B Partial miscibility Partial miscibility results when: Cohesive forces of the constituents of a mixture are quite different, e.g. water (A) and hexane (B), Dependent on temperature phenol and water

42. Two Component (Binary) systems phase rule 42 In two component systems, the max. F is 3 (P is 1) T, P and C the 3 variables affecting the equilibrium A. binary systems containing liquid phases Two liquids could be: Miscible in all proportions. eg . Water and ethanol Practically immiscible. eg . Water & fixed oils. Partially miscible. eg . Phenol and water, water and ether, water and acetone, water and benzene. Solubility of partially miscible liquids depend on intensive variables

43. Phase diagram of phenol-water system phase rule 43

44. bimodal curve/bimodal/ or phase boundary phase rule 44 Starting at point a (pure water) at 50 O C, the addition of phenol to fixed weight of water results in one phase up to point b At point b minute amount of 2 nd phase appears at bottom, at conc. of 11% by wt. of phenol in water. The analysis of this 2 nd phase ( phenol-rich phase ) shows that it contains 63% by wt. phenol in water (denoted by point c ) . The 1 st phase is known as water-rich phase and contains 11% by wt. of phenol (denoted by point b ) Once the conc. of phenol exceeds 63%, a single phenol-rich liquid phase is formed

45. The tie line phase rule 45 The parallel line drawn across the region containing the two conjugates phases (at a given T) All systems prepared on a tie line, will separate into two conjugate phases of : constant composition but the relative amount (proportion) is not constant. For example: any system represented by a point on the line bc , at 50 o C, gives a pair of conjugate phases whose composition is b and c If we prepare a system containing 24% by wt of phenol &76% by wt of water (point d), we get 2 phases Upper phase (A) has a composition of 11% phenol in water (point b) Lower layer (B) contains 63% phenol (point c)

46. phase rule 46 The tile line can be used to calculate: The relative proportions (weights) of the two phases The amount of each phase and amount of each component in each phase Let the water-rich phase and phenol-rich phase be phase A and phase B, respectively. At point d, Wt. Of phase A = length dc Wt. of phase B length bd It is possible measure lenght dc & bd using ruler (cm). It is more convenient to take % by wt. of phenol from x-axis

47. phase rule 47 For example: Since point b =11%, point c = 63% & pt d= 24%, The ration dc/bd= (63-24)/(24-11)= 3/1 Therefore, for every 10 gm of a liquid system in equilibrium at pt d, one finds 7.5gm of phase A & 2.5gm of phase B It should be apparent that system containing 37% of phenol gives Phase A= Phase B

48. Example: 2 A mixture of phenol and water at 20 o C has a total composition of 50% phenol. The tie line at this temperature cuts the binodal at points equivalent to 8.4 and 72.2% w/w phenol. What is the weight of the aqueous layer and of the phenol layer in 500g of the mixture and how many grams of phenol are present in each of the two layers? Let z be the weight in grams of the aqueous layer. Therefore, 500-z is the weight in grams of phenol layer, and the sum of the percentages of phenol in the two layers must be equal to the overall composition 50% (250g). 250= Zx8.4% + (500-z)x72.2% Z= 174, the weight of aqueous layer 500-z= 500-174= 326g is weight of phenol rich layer The weight of phenol in the aqueous layer is 8.4% x 174= 15g The weight of phenol in the phenol rich layer= 72.2%x326= 235g

49. Upper critical solution temperature phase rule 49 Is, the upper consolute T, max. T at which the two conjugate phases exist It is 66.8 O C for phenol water system Above this T, they are miscible (only one phase exists) As the temperature decreases, the positive deviation from Raoult's law occurs and result in a decrease in miscibility sufficient to cause the separation of the mixture into two phases.

50. Systems showing a decrease in miscibility with rise in temperature phase rule 50 A few mixtures, which probably involve compound formation, exhibit a lower critical solution temperature (CST) e.g. triethylamine plus water (20 O C) , paraldehyde plus water The formation of a compound produces a negative deviation from Raoult's law, & miscibility therefore increases as the temperature falls

51. phase rule 51 Some mixtures have both upper & lower critical solution T Nicotine-water system (208 O C & 60.8 O C, respectively)

52. The effects of additives on critical solution temperature (CST) phase rule 52 Type of CST Solubility of additive in each component Effect on CST Effect on miscibility Upper Approx. equally soluble in both components Lowered Increased Upper Readily soluble in one component but not in other Raised Decreased Lower Approx. equally soluble in both components Raised Increased Lower Readily soluble in one component but not in other Lowered Decreased

53. C. Influence of foreign substances Salt out effect : If the added material is soluble in only one of the two components or if the solubilities in the two components liquids are markedly different, The mutual solubility of the liquid pair is decreased. If the original binary mixture has an upper critical solution temperature, the temperature is raised; For example, if 0.1M naphthalene is added to a mixture of phenol and water it dissolves only in the phenol and raises the consolute temperature by 20 o C; if 0.1M potassium chloride is added to a mixture of phenol and water, it dissolves only in the water and raises the consolute temperature approximately by 8 o C.

54. 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; blending . propylene glycol in volatile oils and water An upper consolute temperature is lowered and the lower critical solution temperature is raised. The addition of succinic acid or sodium oleate to a phenol-water system When the solubility in water of a nonpolar liquid is increased by a micelle forming surface active agent, the phenomenon is called micellar solubilization .

55. Three component (ternary systems) liquid systems phase rule 55 For a three component system the maximum degree of freedom (when p =1) is 4 T, P and C of the two components should be defined to describe the system completely. Considering condensed phases and keeping T constant, the effect of conc. on the phase equilibria can be presented using triangular coordinate system .

56. phase rule 56

57. phase rule 57

58. Rules related to triangular diagrams phase rule 58 Each of the three corners (apexes of the triangle) represent 100% by wt of one component and 0% of the other two components The three lines joining the corner points represent two-component mixtures of the three possible combinations AB, BC and AC represent two component system mixtures of A & B, B &C and A & C , respectively The area with in the triangle represents all the possible combinations of the three components. Point X represents 15% B, 55% A and 30% C 4. Any line drawn parallel to one side represents ternary systems in which the proportion (%) of one component is constant Line HI contains 20% C and varying proportions of A & B

59. phase rule 59 Ternary systems with one pair of partially miscible liquids. Example benzene-water-ethanol system Benzene and water are partially miscible

60. phase rule 60 A, B and C represent water, alcohol & benzene respectively. Two conjugate phases or single phase will appear depending on the proportion of the two and conc. of ethanol. a and c are limits of solubility of C in A and A in C respectively. The curve afdeic is the binodal curve. It represents the extent of the two phase region. The tie lines with in the bimodal are not necessarily parallel to each other and to the base line.

61. phase rule 61 The effect of ethanol is similar to the effect of temperature in phenol water system. It increases the solubility of benzene in water Mixture of water & intermediately polar organic solvents increases solubility of poorly water soluble drugs. Such solvents are known as consolvents Examples water-ethnaol, water-glycerol, water-propylene glycol,Water-sorbitol, etc. Effect of temperature It increases solubility For most ternary systems, the bimodal region (two phase region) is reduced as temperature increases

62. Ternary systems with 2 pairs of partially miscible liquids phase rule 63 There are two binodal curves The tie line still exists in the two phase region and rule of tie lines still apply Number of degrees of F(under constant T & P): 1 in two phase region (Only conc. of one of the 3 components needs to be specified to describe the system completely). 2 in one phase region (only conc. of two of the 3 components needs to be specified to describe the system completely).

63. Ternary systems with 3 pairs of partially miscible liquids phase rule 65 There are three binodal curves The tie line still exists in the two phase region and rule of tie lines still apply At low temperature (low miscibility) three conjugate phases will exsit at the centre of the triangle. Number of degrees of freedom(under constant T & P: 0 in three phase region (invariant) 1 in two phase region (Only conc. of one of the 3 components needs to be specified to describe the system completely). 2 in one phase region (only conc. of two of the 3 components needs to be specified to describe the system completely).