슬라이드 1

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2 Solution : a liquid in which a solid substance has been dissolved. Solute : a solid substance that is dissolved in a liquid. Solvent : a liquid that can dissolve other substances. Solubility : the concentration of solute in a saturated solution at equilibrium at a given temperature given as per weight or volume of solvent g (solute) / 100g (solvent) 1g (solute) / volume (ml) of solvent

3 Solubility (continue) Unbuffered solubility Water solubility Buffered solubility Intrinsic solubility (cf. dissolution - extrinsic property) solubility of an ionizable compound in its neutral form (the molar solubility of the undissociated acid S 0 ) Thermodynamic solubility

4 Saturated Solution the solute is in equilibrium with the solid phase Unsaturated or Subsaturated Solution one containing the dissolved solute in a concentration that necessary for complete saturation at a definite temperature Supersaturated Solution one that contains more of the dissolved solute than it would normally contain at a definite temperature

5 Miscible when a solute is a liquid and will form a solution with a solvent over any concentration range The Phase Rule F = C P + 2

6 Description Forms (Solubility Definition) Parts of Solvent Required for One Part of Solute Solubility Range (mg/ml) Solubility Assigned (mg/ml) Very soluble(vs) <1 >1,000 1,000 Freely soluble(fs) From 1 to Soluble From 10 to Sparingly soluble(sps) From 30 to Slightly soluble(ss) From 100 to 1, Very slightly soluble(vss) From 1,000 to 10, Practically insoluble(pi) >10,000 <

7 USP Chart of Descriptive terms 대한약전제 11 개정 Term Parts solvent to 1 part solute 용어 Very soluble Less than 1 썩잘녹는다 Freely soluble 1-10 (3-10%) 잘녹는다 Soluble 녹는다 Sparingly soluble 조금녹는다 Slightly soluble 녹이어렵다 Very slightly soluble ,000 매우녹기어렵다 Practically insoluble, insoluble More than 10,000 거의녹지않는다

8 Temperature Pressure ph Common Ion Effects Chemical Structures - Dipole moment - Dielectric properties - Hydrogen bonding

9 Like Dissolves Like

10 Hydrogen bonding capability Polar Solvents Nonpolar Solvents Semipolar Solvents Yes No No Dielectric constant High Low Interaction Dipole interaction Induced dipole interaction (London type) Induce polarity in non-polar solvent Example Water Hydrocarbons Amphiprotic Ketones, alcohols Cosolvents

11 (dissolve ionic solutes and other polar substances) Influential Factors Dipole moment Hydrogen bonds Acidic and basic character of constituents Structural features Mechanism High dielectric constant Amphiprotic Dipole interaction force Water

12 (dissolve nonpolar solutes) Influential Factors Induced dipole interactions Weak van der Waals-London type forces Low dielectric constant, No hydrogen bond Hydrocarbons

13 (Intermediate solvents) Influential Factors Induce a certain degree of polarity in non-polar solvent molecules No hydrogen bond Cosolvent Ketones and alcohols

14 Solubility of Gases in Liquids

15 Henry s Law C 2 = σp C 2 = concentration of the dissolve gas (g/l) p = partial pressure (mm of the undissolved gas) σ = inverse of the Henry s law constant, K in a dilute solution at constant temperature, the concentration of dissolved gas is proportional to the partial pressure of the gas above the solution at equilibrium

16 As the temperature increases, the solubility of most gases decreases, owing to the greater tendency of the gas to expand

17 Gases are often liberated from solutions in which they are dissolved by the introduction of an electrolytes and sometimes by a nonelectrolyte NaCl or sucrose gases carbonated solution

18 Gases (HCl, NH 3, CO 2 ) + Solvent Chemical reaction Increase solubility

19 Inverse Henry s law constant, C 2 = P Bunsen absorption coefficient, V gas. STP V soln. = P : 일정온도, gas 의 partial pressure 1 기압하에 solvent 1L 에녹는 gas 의 volume (L) Saturated condition : 0, 760mmHg

20 Solubility of Liquids in Liquids

21 Complete Miscibility Solvents are said to be completely miscible when they are mix in all proportions Partial Miscibility When certain amounts of two liquids are mixed, two liquid layers are formed, each containing some of the other liquid in the dissolved state

22 Mixture of polar and semipolar solvents Water-Alcohol Glycerin-Alcohol Mixture of nonpolar solvents Benzene-Carbon tetrachloride Completely miscible liquid mixtures in general create no solubility problems

23 Phenol-Water System Triethylamine-Water System Nicotine-Water System Consolute temperature mixture of water-ether mixture no consolute temp.

24 The solubility of peppermint oil in various portions of water and polyethylene glycol. Triangular phase diagram for the threecomponent system.

Binary Added material Ternary If the added material is soluble in only one of the two

solubility of the liquid pair is decreased When the third substance is soluble in both of

Blending The increase in mutual solubility of two partially miscible solvents by another

25 Binary Added material Ternary If the added material is soluble in only one of the two components / if the solubilities in the two liquids are markedly different The mutual solubility of the liquid pair is decreased When the third substance is soluble in both of the liquids roughly the same extent The mutual solubility of the liquid pair is increased Blending The increase in mutual solubility of two partially miscible solvents by another agent Micellar Solubilization Solubility in water of a non-polar liquid is increased by a micelle-forming surfactant

26 Solubility of Solids in Liquids

29 Acidic Indomethacin Basic Chlorpromazine Amphoteric Oxytetracycline Figure 25. Alexander T. Florence and David Attwood. Physicochemical Principles of Pharmacy, Pharmaceutical Press(2016) p.165

30 Weak Acids + HA + H 2O = H 3O + A S = HA + A 분자형이온형 K a + [ H 3 O ] = [ HA][A ] [ HA] S = [ HA] + K a = [ HA](1 [ H 3O ] K a S = S (1 + 0 [ H O + ] + + 약전해질포화용해도 S 0 [HA] ) K = logk log[ H O ] = log 10 a + + a 3 = 3 ] [ H O 3 K a ) + [ H O ] 3 ph pk a S = S 0 ( ph pk a) S 0, pk a 를알면주어진 ph 에서의 S 계산

31 Weak Acids S = S + S K a [ H 3 O ] S S = S K a [ H 3 O ] + log( S S0) = logk a + logs0 log[ H 3O ] ph p = pk a + log S S 0 S 0

32 Weak Bases B BH + + OH K b = [ BH ] [ OH [ B] + + ] S = S 0 ( pk a ph ) ph p = pk a + log S S 0 S 0

33 Strong Electrolytes : strong acids and bases and all salts are soluble in water Weak Electrolytes : weak acids and bases with high molecular weight are not soluble in water Nonelectrolytes : high-molecular-weight organic drugs that do not dissociate or associate in water are generally soluble in organic solvents and have little or no solubility in water Cosolvency : a solute is more soluble in a mixture of solvents than in one solvent alone

34 Cosolvency a solute is more soluble in a mixture of solvents than in one solvent alone cosolvents The solubility of phenobarbital in a mixture of water, alcohol, and glycerin at 25

35 Weak electrolyte buffered aqueous solution + Alcohol increases the solubility of the un ionized species S 0 decreases the dissociation of a weak electrolyte K a ( pk a ) The influence of alcohol concentration on the dissociation constant (k a ) of phenobarbital. Example 9-3.

39 Solubility product, : K sp the real solution solubility of poorly soluble strong electrolytes in water is calculated by using the solubility product constant obtained from thermodynamics Common ion : adding a common ion is to reduce the solubility of a slightly soluble electrolyte

40 Solubility determination: 1. Drug is added in a specific amount of solvent. 2. After equilibrium is achieved, excess drug is removed (usually by filtering). 3. The concentration of the dissolved drug is measured using standard analysis techniques such as HPLC. Saturation Shake Flask Method Limitations (p.196)

41 F = C P + 2 temperature, pressure and concentration, etc. F = 1 (concentration) F = 0 (temp., pressure, conc. are constant) solid state drug, P=2 saturate concentration valid only for pure drug substance

42 System having one impurity solution saturated with two components solution saturated with the first component

43 measure a precipitation rate rather than solubility Using highthroughput kinetic measurement of antisolvent precipitation commonly referred to kinetic solubility Use of Dimethyl sulfoxide(dmso) stock solutions small amount of stock solution is added to the aqueous buffer incrementally until the limit of solubility is achieved. Advantages but limitations Speed up the process, limit compound consumption, reduce the occurrence of manual errors, and increase data consistency.

44 Solubility product, : K sp the real solution solubility of poorly soluble strong electrolytes in water is calculated by using the solubility product constant obtained from thermodynamics Common ion : adding a common ion is to reduce the solubility of a slightly soluble electrolyte

45 Partition Phenomena

46 The partition law : a solute will distribute itself between two immiscible solvents so that the ratio of its conc. in each solvent is equal to the ratio of its solubility in each one C 0 K d = Cw C o = molar conc. in organic layer C w = molar conc. in aqueous layer K d = partition coefficient or distribution constant

47 Strong Electrolyte Nonelectrolyte Strong electrolytes are completely dissociated in aqueous solution cations & anions in aqueous layer water soluble Without ion pairing, do not partition into the organic layer K d O C 0 K d = Cw

48 The partition law : depends on ph ph different from pk a (ph < pk a for weak acid ; ph > pk a for weak base) For a weak organic acid, C 0 K d = Cw For a weak organic base, C 0 K d = Cw K K d d [ HA] 0 = [ HA] w [ B] 0 = [ B] w

49 Effect of Ionic Dissociation and Molecular Association on Partitioning

50 Schematic representation of the distribution of benzoic acid between water and an oil phase.

51 51

52 Benzoic acid Peanut Butter Oil & Water Solution

53 In Peanut Butter Oil In Water K true distribution coefficient K apparent distribution coefficient [HA] 0 : concentration of benzoic acid in oil [HA] w : concentration of benzoic acid in water C o : total concentration of benzoic acid in oil C w : total concentration of benzoic acid in water

54 In Peanut Butter Oil In Water K true distribution coefficient C o : total concentration of benzoic acid in oil C w : total concentration of benzoic acid in water C: concentration of benzoic acid in water before distribution

55 Benzoic acid Benzene & Acidic Water Solution

56 In Water In Oil (Benzene) K true distribution coefficient K d : dissociation constant [HA] o : concentration of benzoic acid in oil [HA] w : concentration of benzoic acid in water C o : total concentration of benzoic acid in oil C w : total concentration of benzoic acid in water

57 Distribution of Solutes between Immiscible Solvents

58 K = Concentration of solute in original solvent Concentration of solute in extracting solvent = w 1 /v 1 (w w 1 )/v 2 w 1 wt. of the solute remaining in the original solvent after extracting with the first portion of the other solvent Example 9-7

59 K: distribution coefficient The most efficient extraction results when a larger number (n) of extractions are carried out with small portions (v) of extracting liquid v 2 n w 1 Amount extracted E E E Total vol. of extracting liq. is fixed.

60 Total Preservative added = C = C o + C w C = HA] + [ HA] + [ A ] K K C d a = [ 0 HA] [ HA] w w [ 0 = [ HA ] = K [ HA] 0 d w + [ H3O ][ A = [ HA] K d [ HA] = [ HA] w w ( K w ] + [ HA] d w w w [ A + K Ka + 1+ [ H O 3 a + ] w [ HA] [ H O ) ] 3 w + = ] Ka[ HA] + [ H O ] 3 [ HA] w Conc. of undissociated acid in the aqueous phase w = K d C Ka + 1+ [ H O 3 + ]

2 폐기물실험실

2 폐기물실험실 II. Basic Water Chemistry 1. Governing Concepts - Stoichiometry ( 화학양론식 ): - Chemical Equilibrium ( 화학적평형 ): - Reaction Kinetics ( 반응동역학 ): 1.1 Stoichiometry b R + c R m P + n P 1 2 1 2 where R 1 and R