Chapter 2 States of Matter

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

Binding forces between molecules Intramolecular forces Intermolecular forces

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

Repulsive & attractive energies Fig. 2-1

Chemical bonds Ionic bonds Covalent bonds Polar covalent bonds

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

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

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

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) 162-168

States of matter The liquid state

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)

Aerosols 1 atm 1 - 6 atm Drug + Propellant

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

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

Boiling point & Melting point Van der Waals forces Hydrogen bonds

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

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

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

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

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

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

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

Polymorphism Form I Losartan Form II

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

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)

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

The liquid crystalline state States of matter The liquid crystalline state

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

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

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

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

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

The supercritical fluid state States of matter The supercritical fluid state

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

Supercritical fluid Fig. 2-16

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

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

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

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

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

Phase diagram for water Fig. 2-22

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

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

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

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

Eutectic mixtures Eutectic system of salol-thymol Fig. 2-26

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

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

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

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

Phase equilibria in three-component systems Condensed system & constant temperature  𝐹=𝐶−𝑃+2 𝐹=3−1+2=4 𝑭=𝟐

Triangular diagrams Fig. 2-27

Triangular diagram of microemulsion

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

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

Effect of Temp. on Binodal Curves Fig. 2-30. Effect of temperature changes on the binodal curves representing a system of two pairs of partially miscible liquids.

Effect of Temp. on Binodal Curves Fig. 2-31. Temperature effects on a system of three pairs of partially miscible liquids.

Homework 다음을 자세히 설명하고 그 약학적 응용의 의미(중요성)와 관련 사례들을 제시하고 설명하시오. (Due Date: 2016. 9. 19) Polymorphism Solid dispersions Supercritical fluids Eutectic mixture Liquid crystals Van der Waals forces