슬라이드 1

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2 Binding forces between molecules Intramolecular forces Intermolecular forces States of matter Liquid state Solids and the crystalline state Liquid crystalline state Supercriticial fluid state Phase equilibria & phase rule 2

3 Intramolecular forces Intermolecular forces

4 4 Inter(Intra-)molecular forces Van der Waals forces Ion-dipole & Ion-induced dipole Forces Hydrogen bonds Ionic bonds Covalent bonds Polar covalent bonds Cohesion Adhesion

5 5 Fig. 2-1

6 6 Ionic bonds Covalent bonds Polar covalent bonds

7 7 Neutral Molecule Dipole Dipole Induced-Dipole Induced-Dipole Dipole Induced-Dipole Debye Keesome London

8 8 Na + Dipole Cl - Dipole Na + Induced-Dipole

9 9 The attractive interaction of a hydrogen atom with an electronegative atom Fig. 2-4

10 10 Ibuprofen Ibuprofen Poloxamer Schematic representation of (a) hydrogen bonding within the ibuprofen dimer and (b) proposed ibuprofen:poloxamer interaction * W. Alt et al., International Journal of Pharmaceutics 391 (2010)

11 The liquid state

12 12 Liquefaction of gases Critical Temperature Above this temperature, a liquid can no longer exist. Critical Pressure The pressure required to liquefy a gas at its critical temperature Ex) H 2 O (647 K, 218 atm) He (5.2 K, 2.26 atm)

13 13 1 atm 1-6 atm Drug + Propellant

14 14 V.P. vs. Temp. Fig. 2-5

15 15 The relationship between the vapor pressure and the absolute temperature of a liquid ( ) log P H T T = v P 2.303RTT Eqn 2-15 H v : Molar heat of vaporization ln P = H v R 1 T + constant Eqn 2-16a

16 16 Van der Waals forces Hydrogen bonds Fig. 2-14

17 Solids & the crystalline state

18 18 Cubic (NaCl) 입 ( 등 ) 방정계 Tetragonal (Urea) 정방정계 Hexagonal (Iodoform) 육방정계 Rhombic (Iodine) 사방정계 Monoclinic (Sucrose) 단사정계 Triclinic (Boric acid) 삼사정계 * Fast track SKKU Physical Physical Pharmacy Laboratory Alexander 성균관대학교 T Florence and 물리약학연구실 David Attwood

19 19 Ionic & atomic crystal Hard, brittle and high m.p. Molecular crystal Ionic Crystal Soft and low m.p. Metallic crystal

20 20 Laue or Transmission method Bragg or Reflection method

21 Polymorphic Some elemental substances exist in more

Nature of solvent Temperature Rate of cooling Heating

of physicochemical properties Crystal shape Optical

21 21 Polymorphic Some elemental substances exist in more than one crystalline form Formulation of polymorphs Nature of solvent Temperature Rate of cooling Heating Boiling Van der Waals forces Hydrogen bonds Difference of physicochemical properties Crystal shape Optical property Solubility Dissolution rate Solid state stability

22 22 Theobroma oil (cacao butter) 4 polymorphism forms (Polymorphs) α - form β - form γ - form β' - form Melting point, ºC γ - form melting at 18 ºC, unstable α - form melting at 22 ºC, unstable β' - form melting at 28 ºC, unstable β - form melting at 34.5 ºC, stable Used for stable suppository

23 23 Spiperone 2 polymorphs Dimer (molecules in pairs) Nondimerized molecules

24 24 Form I Form II Losartan

25 25 Enantiotropic polymorphism The change from one form to another is reversible. Metastable form Stable form Monotropic polymorphism The transition takes place in one direction only. Metastable form Stable form

26 26 Def) Amorphous solids may be considered as supercooled liquids in which the molecules are arranged in a random manner somewhat as in the liquid state. Crystals (except cubic crystals) Anisotropic show different characteristics in various directions along the crystal Amorphous solids (+ cubic crystals) Isotropic exhibit similar properties in all directions

27 27 Differ from crystalline solids Tend to flow when subjected to sufficient pressure Do not have definite melting point Ex) Novobiocin acid Crystalline form : poorly absorbed No activity Amorphous form : readily absorbed Therapeutically active Amorphous form: prompt action Crystalline form: long action Insulin zinc suspension(lente) AF:CF=30:70 24h effect Insulin formulation

28 The liquid crystalline state

29 State of matter that have properties between those of a conventional liquid and those of a solid crystal Thermotropic liquid crystal Phase transition

29 29 State of matter that have properties between those of a conventional liquid and those of a solid crystal Thermotropic liquid crystal Phase transition into liquid crystal phase as temperature is changed. Lyotropic liquid crystal Phase transition as a function of both temperature and concentration (solvent)

30 Produced when certain substances are heated Three types of thermotropic liquid crystals Nematic (thread-like) liquid crystals Orientate with long axes parallel, but

30 30 Produced when certain substances are heated Three types of thermotropic liquid crystals Nematic (thread-like) liquid crystals Orientate with long axes parallel, but not ordered into layers Mobile and orientated by electric or magnetic fields * Physiochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood

31 31 2. Smectic (soap-like) liquid crystals Arrange with long axes parallel, also arranged into layers Viscous and not oriented by magnetic fields * Physiochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood

32 32 3. Cholesteric (chiral nematic) liquid crystals Formed by several cholesteryl esters Stack of very thin two-dimensional nematic-like layers Nematic-like layer * Physiochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood

33 The liquid crystalline phases that occur on increasing the

concentration of surfactant Spherical micelle elongated or rod

some surfactants) neat phase (lamellar phase) * Physiochemical

33 33 The liquid crystalline phases that occur on increasing the concentration of surfactant solutions As increase of concentration of surfactant Spherical micelle elongated or rod like micelle hexagonal phase (middle phase) cubic phase (with some surfactants) neat phase (lamellar phase) * Physiochemical Principles of Pharmacy 4 th edition Alexander T Florence and David Attwood

34 The supercritical fluid state

35 35 Intermediate between those of liquids and gases Gas-like property Better ability to permeate solid substances Liquid-like property High densities that can be regulated by pressure Pressure Density of the gas, Ability to dissolve compounds

36 36 Fig. 2-17

37 37 Advantages over traditional methodologies Low temperature extractions Purification of compounds Solvent volatility under ambient conditions Selectivity of the extracted compounds Fig The effect of pressure on the selectivity of extraction

38 38 Pharmaceutical applications Extraction Crystallization Preparation of formulations Preparation of polymer mixtures Formulation of micro- and nanoparticles

39 39 Decaffeination of coffee Traditionally, solvents like methylene chloride have been used. Expensive, toxic Utilization of supercritical CO 2 Reduced cost and toxicity Adding water to supercritical CO 2 Reduced the loss of the flavor

40 Phase equilibria & the phase rule

41 41 F = C P + 2 F is the number of degrees of freedom in the system C is the number of components P is the number of phases present

42 42 Fig. 2-23

43 43 Systems in which the vapor phase is ignored and only solid and/or liquid phases are considered are termed condensed systems

44 44 Water vs Phenol Upper Consolute Temperature Fig. 2-24

45 45 Water vs Triethylamine Water vs Nicotine Fig Fig. 2-26

46 46 Eutectic mixture A mixture of chemical compounds has a single chemical composition that solidifies at a lower temperature than any other composition. Eutectic point The component ratio that exhibits the lowest observed melting point Typical phase diagram of eutectic mixture

47 47 Eutectic system of salol-thymol Fig. 2-27

48 48 Eutectic Mixture of Local Anesthetics (EMLA) The eutectic system of Lidocaine / Prilocaine Eutectic point 1:1 mixture Eutectic temperature 18 ºC A mixed local anesthetic that can be used for topical application EMLA Cream (AstraZeneca) Menthol + Testosterone

49 Definition The dispersion of one or more active ingredients in an inert carrier or

precipitations in crystalline matrix III Solid solutions C M IV Glass suspension A C V

matrix in the crystalline state ** A: drug dispersed as amorphous clusters in the matrix,

49 49 Definition The dispersion of one or more active ingredients in an inert carrier or matrix at solid state Solid dispersion type Matrix * Drug ** I Eutectics C C II Amorphous precipitations in crystalline matrix III Solid solutions C M IV Glass suspension A C V Glass suspension A A VI Glass solution A M C A * A: matrix in the amorphous state, C: matrix in the crystalline state ** A: drug dispersed as amorphous clusters in the matrix, C: drug dispersed as crystalline particles in the matrix, M : drug molecularly dispersed throughout the matrix

50 50 Solid solution Each solid phase contains both components A solid solute is dissolved in a solid solvent Higher, lower, or unchanged melting behavior depending upon the degree of interaction between components Mixed amorphous or glass solutions Molecular dispersion of one component in another where the overall solid is amorphous Exhibit an intermediate glass transition temperature

51 51 Advantages Reduction of particle size Increased wettability of the material Reduced aggregation and agglomeration Increase in solubility of the drug Facilitating the dissolution and the bioavailability of poorly soluble drugs Rate of solution of griseofulvin solid solutions, eutectic and crystalline material

52 52 F = C P + 2 F = = 4 Condensed system & constant temperature F = 2 F 계를완전히설명하기위하여고정하여야하는강도인자의수

53 53 Fig. 2-28

54 54

55 55 A system of three liquids, one part of which is partially miscible A Water B Alcohol C Benzene Fig. 2-29

56 56 Fig. 2-30

57 57 Fig Effect of temperature changes on the binodal curves representing a system of two pairs of partially miscible liquids.

58 58 Fig Temperature effects on a system of three pairs of partially miscible liquids.

59 59 다음을자세히설명하고그약학적응용의의미 ( 중요성 ) 와관련사례들을제시하시오. 1. Hydrogen bonding 2. Polymorphism 3. Solid dispersions 4. Supercritical fluids 5. Liquid crystals 6. Phase equilibria 7. Thermal analysis (DSC, TGA, Karl Fisher methods only) 1. 과제는 team 별로준비하고평가를받게됨. 2. 관련내용에대한보고서 ( 손글씨요약본 & full version report) 와함께발표용 ppt 를작성하여제출함. 3. 보고서는 10 페이지이내, ppt 는 7 분발표분량으로축약하여작성함. ( 제공되는 templet 에작성할것 ) 4. Due Date: ( 금요일 ) 오후 5 시

60 60 다음을자세히설명하고그약학적응용의의미 ( 중요성 ) 와관련사례들을제시하시오. 1. Van der Waals forces 2. Solvates 3. Eutectic mixture 4. Amorphous solids 5. Triangular (phase) diagrams 6. Lyophilization 7. (Powder) X-ray diffraction 1. 과제는 team 별로준비하고평가를받게됨. 2. 관련내용에대한보고서 ( 손글씨요약본 & full version report) 와함께발표용 ppt 를작성하여제출함. 3. 보고서는 10 페이지이내, ppt 는 7 분발표분량으로축약하여작성함. ( 제공되는 templet 에작성할것 ) 4. Due Date: ( 월요일 ) 오후 5 시

슬라이드 1

슬라이드 1 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