1. Chapter 2 States of Matter

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

3. Binding forces between molecules
Intramolecular forces
Intermolecular forces

4. Binding forces 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. Repulsive & attractive energies
Fig. 2-1

6. Chemical bonds
Ionic bonds
Covalent bonds
Polar covalent bonds

7. Van der Waals forces Neutral Molecule Dipole Induced-Dipole Dipole
Debye
Dipole
Induced-Dipole
Keesome
Dipole
Dipole
London
Induced-Dipole
Induced-Dipole

8. Ion-dipole & ion-induced dipole forces
Na+
Dipole
Cl-
Dipole
Na+
Induced-Dipole

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

10. Hydrogen bonds 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. States of matter
The liquid state

12. The liquid state 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) H2O (647 K, 218 atm)
He (5.2 K, 2.26 atm)

13. Aerosols
1 atm
1 - 6 atm
Drug + Propellant

14. Vapor pressure of liquids
V.P. vs. Temp.
Fig. 2-5

15. Clausius-Clapeyron equation
The relationship between the vapor pressure and the absolute temperature of a liquid
Eqn 2-15
ln 𝑃 =− ∆ 𝐻 𝑣 𝑅 1 𝑇 +𝑐𝑜𝑛𝑠𝑡𝑎𝑛𝑡
Eqn 2-16a

16. Boiling point & Melting point
Van der Waals forces
Hydrogen bonds

17. Solids & the crystalline state
States of matter
Solids & the crystalline state

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

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

20. X-ray diffraction Laue or Transmission method
Bragg or Reflection method

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

22. Polymorphism Theobroma oil (cacao butter)
4 polymorphism forms (Polymorphs)
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
α - form
β - form
γ - form
β' - form

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

24. Polymorphism
Form I
Losartan
Form II

25. Polymorphism Enantiotropic polymorphism Monotropic 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. Amorphous solids
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.
Isotropic – exhibit similar properties in all directions
Amorphous solids (+ cubic crystals)
Anisotropic – show different characteristics in
various directions along the crystal
Crystals (except cubic crystals)

27. Amorphous solids Differ from crystalline solids Ex) Novobiocin acid
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
States of matter
The liquid crystalline state

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

30. Thermotropic liquid crystals
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 4th edition
Alexander T Florence and David Attwood

31. Thermotropic liquid crystals
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 4th edition
Alexander T Florence and David Attwood

32. Thermotropic liquid crystals
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 4th edition
Alexander T Florence and David Attwood

33. Lyotropic liquid crystals
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 4th edition
Alexander T Florence and David Attwood

34. The supercritical fluid state
States of matter
The supercritical fluid state

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

36. Supercritical fluid
Fig. 2-16

37. Supercritical fluid Advantages over traditional methodologies
Low temperature extractions
Purification of compounds
Solvent volatility under ambient conditions
Selectivity of the extracted compounds
Fig. 2-17
The effect of pressure on the selectivity of extraction

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

39. Example Decaffeination of coffee
Traditionally, solvents like methylene chloride have been used.
 Expensive, toxic
Utilization of supercritical CO2
 Reduced cost and toxicity
Adding water to supercritical CO2  Reduced the loss of the flavor

40. Phase equilibria & the phase rule
States of matter
Phase equilibria & the phase rule

41. The phase rule
F is the number of degrees of freedom in the system
C is the number of components
P is the number of phases present
𝐹=𝐶−𝑃+2

42. Phase diagram for water
Fig. 2-22

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

44. Two component systems containing liquid phases I
Water vs Phenol
Upper Consolute
Temperature
Fig. 2-23

45. Two component systems containing liquid phases II
Water vs Triethylamine
Fig. 2-24
Fig. 2-25
Water vs Nicotine

46. Two component systems containing solid & liquid phases: Eutectic mixtures
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. Eutectic mixtures
Eutectic system of salol-thymol
Fig. 2-26

48. Eutectic mixtures 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. Solid dispersion 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 II
Amorphous precipitations in crystalline matrix A
III
Solid solutions M IV
Glass suspension V VI
Glass solution
* 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. Solid dispersion Solid solution Mixed amorphous or glass solutions
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. Solid dispersion 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. Phase equilibria in three-component systems
Condensed system & constant temperature 
𝐹=𝐶−𝑃+2
𝐹=3−1+2=4
𝑭=𝟐

53. Triangular diagrams
Fig. 2-27

54. Triangular diagram of microemulsion

55. Triangular diagram
A system of three liquids, one part of which is partially miscible
Fig. 2-28

56. Effect of Temp. on Binodal Curves
Fig. 2-29

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

58. Effect of Temp. on Binodal Curves
Fig Temperature effects on a system of three pairs of partially
miscible liquids.

59. Homework
다음을 자세히 설명하고 그 약학적 응용의 의미(중요성)와 관련 사례들을 제시하고 설명하시오. (Due Date: )
Polymorphism
Solid dispersions
Supercritical fluids
Eutectic mixture
Liquid crystals
Van der Waals forces