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INTERMOLECULAR FORCES AND STATES OF MATTERPHAR 1313
Prepared by:
Wan Rosalina Wan Rosli, PhD
03-83137080
Learning objectives1.Describe the types of intermolecular forces2.Detail the physical characteristics of each state of matter3.Describe the mechanism involved in phase changes4.Describe the use of eutectics5.Relate and apply the use of the knowledge of intermolecular forces
and states of matter in current pharmaceutical practice
Intermolecular bond• Occur between molecules.• Weaker than covalent bonds.• Affect the physical and chemical properties of molecules.• Most important:
• Van der Waals forces• Hydrogen bonding
• A knowledge of intermolecular forces is important for understanding:• Stabilization of emulsions• Compaction of powders and granules in tablets• Drug action• Protein binding• Protein formulation and activity.
Van der Waal forces• There are 3 van der Waal forces of attraction:
1. Dipole-dipole forces (Keesom forces)2. Dipole-induced dipole (Debye forces)3. Induced dipole-induced dipole (Dispersion forces, London
forces)• Van der Waal forces are involved in solubility,
complexation, and numerous other physical bonding phenomena.
Dipoles• Dipole: a pair of equal positive and negative charges
separated by a small distance.
• If a molecule have separate regions of positive and negative charge, its dipole moment is permanent.
Dipole-dipole forces
• Molecules with permanent dipoles are polar.
• These molecules align themselves so that the negative pole of one molecule points to the positive pole of another.
• Example: water, HCl, acetone, phenol.
Dipole-induced dipole• A polar molecule can produce a temporary electric dipole
in nonpolar molecules that are easily polarizable.• Easily polarized molecules include ethylacetate,
methylene chloride and ether.
Induced dipole-induced dipole• A.k.a: London force, dispersion force.• Forces of attraction in nonpolar molecules originate from
the interaction between momentary dipoles.• Momentary electric dipoles arises from the asymmetry of
the electron distribution surrounding the nucleus of an atom.
• Nonpolar molecules exhibiting induced dipole-induced forces of attraction include organic compounds such as carbon disulfide, carbon tetrachloride, and hexane.
Visualization of the induced dipole- induced dipole
• Size of the induced dipole determines the strength of the dispersion interaction: the larger this dipole, the stronger the interaction.
• The size of the induced dipole depends on its polarizability (how much a given electric field will distort the electron distribution).
Example• Fluorine atoms (high ionization energy the electrons are
tightly held).• Thus, compounds containing many fluorine atoms tend to
have low polarizabilities, and so the dispersion interaction is weak. • Many fluoro compounds occur as gases at RT.
• Which one is stronger, interaction between permanent dipoles or induced dipoles?• Induced dipoles
• Why?• The key point is that induced dipoles are always oriented so that
their interaction is favorable; this is not true for permanent dipoles.
Hydrogen bond• It is the attraction of a H atom for a strongly
electronegative atom such as oxygen, nitrogen, fluoride and sulfur.
• Since any other atom will bind the electron from H atom more tightly, the electron will spend more time with the other atom. • This creates a permanent dipole (a partially exposed proton) that
can interact with other dipoles nearby.
• Hydrogen bonding in water molecules account for properties of water:• Form aggregates: Liquid at RT• High Tm and Tb
• Hydrogen bonding is also responsible for:• The conformation of proteins and DNA double helix structure.• Protein-ligand interaction• Solubility
STATES OF MATTER
What is matter?• Everything that take up space and have mass are
“Matter”.• It normally exist in one of the 3 states: solid, liquid or gas.
States of Matter
Solid Liquid Gas
Definite mass & volume
Yes Yes No
Shape Fixed Take the shape of container
Fill all available space in container
Density High High Very low
Compressibility Relatively incompressible
Only slightly compressible
Compressible
Kinetic energy Low Medium High
Solids• There are 3 types of solids:
1. Crystalline
2. Amorphous
3. Polymers
1. Crystalline• The atoms/molecules/ions are arranged in large
repetitious 3D units.• Have definite melting points (±1 or 2 degrees).• There are definite geometric form with 7 common
structures.
7 crystal systems
Sodium chloride Urea Fluorapatite Calcite
ArgoniteSucroseCopper sulfate
Polymorphism• Some substance exist in >1 crystalline form
• The different forms are called “polymorphs” and the property is called “polymorphism”
• Two types of polymorphs:• Enantiotropic : Exist in MULTIPLE stable forms• Monotropic : Exist in only ONE stable form while other polymorphs
are unstable
• Any pharmaceutical property of a solid will be influenced by its polymorphic form. Example:• Density • Melting temperature• Solubility• Dissolution rate• Chemical stability• Shelf-life
• Example of polymorphic drugs
Drug No. of polymorphsChloramphenicol palmitate
4
Progesteron 2Caffeine 2Phenytoin 2
Pharmaceutical importance of polymorphism
• Exploitation of the polymorphic properties to design drug formulations.
• Example: use of cocoa butter as suppositories• Cocoa butter most stable polymorph is firm enough at
25°C but melts at 35°C.• If it is overheated (>40°C) and cooled quickly, it melts at
lower temperatures (15- 28°C)• Careful, slow heating produces suppositories that don’t
melt in hands but melt at body temperature.
• Polymorphism has direct impact upon drug processability and drug quality/performance, (i.e stability, dissolution, and bioavailability). • May result in product development delay and commercial
production disruption
Effect of polymorphism
• Taken from http://www.chemistry-blog.com/2010/06/07/puzzling-polymorphs/ . Pictures from Org. Process Res. Dev., 2010, 14 (4), pp 878–882
Issues• Ritonavir (Norvir; Abbott) is a drug for treating patients
infected with HIV-1. • When it was first discovered in late 1992, ritonavir
crystallized as Form I. Ritonavir was marketed in 1996.• Early in 1998, some lots of ritonavir capsules failed the
dissolution test.
• Investigations revealed a stable new form :Form II. • Accidental seeding
• The adverse effect on the bioavailability led to withdrawal of the products.
• A new formulation of ritonavir has to be developed.
2. Amorphous
• Noncrystalline materials• No definite order or structure.• No definite melting point.• More soluble• Higher bioavailability than crystals
• Some exist in both crystalline and amorphous forms. Example: petrolatum, insulin.
• Amorphous form used for prompt action and crystalline forms for long actions.
3. Polymers
• Most are carbon based.• Example of pharmaceutical applications
• use as binders in tablets. • used as film coatings.• Modifies drug release characteristics
• Example: Methylcellulose, polyethylene, polypropylene, polyvinyl alcohol, carbomer.
Liquids
• Surface tension is a physical property of pure liquids and solutions:
a) A molecule in the bulk liquid experiences cohesive forces with other molecules in all directions.
b) A molecule at the surface of a liquid experiences only net inward cohesive forces.
• Surface tension ↓ when temperature ↑• Example of application:
• Solubility of powders in water is affected by high surface tension• Transdermal delivery of drugs can be optimized by controlling the
surface tension
Gases• The physical behavior of gases is independent of
the chemical nature of molecules• Therefore almost all gases respond in a similar way to
variations in pressure, temperature and volume.
• Properties of gases can be described using the various gas laws.• Boyle’s law• Charles’ law• Gay-Lussac’s law• Avogadro’s law• Ideal gas law
Combined gas law
Henry’s law• Henry’s law of gas solubility states that:
• the mass of gas dissolved in a given volume of solvent at constant temperature is proportional to the partial pressure of gas in the equilibrium with the solution.
• Partial pressure: • the pressure a gas would exert if it alone occupied the whole
volume of the mixture
• Example: carbonated drinks
Partial pressure
Application• Blood gases
• Gas plasma concentrations are related to atmospheric conditions and to biological and catalytic metabolic activity.
• Values are given as PO2, and PCO2.
• The partial pressure of O2 in the blood is on average about 80 mmHg and the partial pressure of CO2 is on average 35-45 mmHg.
• PCO2 is influenced by respiratory function.
• Reflect expiratory efficiency• If PCO2 ↑ : poor ventilation.
• If PCO2 ↓ : excessive ventilation/ hyperventilation.
*If patient have ↑PCO2 :respiratory acidosis (↓pH). If the reverse, patient may have respiratory alkalosis.
• Why?
CHANGES IN THE STATE OF MATTER
Changes in the state of matter
Parameters involved in phase change
1) Vapour pressure• The pressure exerted by the liquid’s vapour when
the vapour is in equilibrium with the substance• Measures tendency of a material to change into the
gaseous state• Increases with temperature
Parameters involved in phase change
2) Boiling points• a liquid boils when the vapor pressure of the gas
escaping from the liquid is equal to the pressure exerted on the liquid by its surroundings
Parameters involved in phase change
3) Melting point and freezing point• Melting point a solid becomes a liquid• Freezing point a liquid becomes a solid• Theoretically both are the same temperature points but in
reality small differences can be observed.
Phase diagram• Phase diagrams is a type of graph that show the
equilibrium conditions between the distinct phases• It shows what phases are present in the material system
at various temperature, pressure, and compositions• Phase diagrams are used to illustrate phase changes.
Phase diagram
• Field: 1 phase, Line: 2 phase co-exist• The triple point: all three phases co-exist.• Critical Point is is the condition where it is no longer possible to
distinguish between the gas and liquid phases.
Gibbs Phase Rule• The rule describes the possible number of degrees of
freedom (F) in a closed system at equilibrium, in terms of the number of separate phases (P) and the number of chemical components (C) in the system
• Given by:
• Phase, P, is a homogeneous portion of a system that has uniform physical and chemical characteristics.
• A phase can refer to a chemical or physical difference.• Two immiscible liquids separated by a distinct boundary
are counted as two different phases, as are two immiscible solids.
• Degree of freedom, F, is the number of variables that can be changed independently without causing the appearance of a new phase or disappearance of an existing phase.• The variables must be parameters that are independent
of the amount of material in the system (eg. temperature, pressure, concentration and density)
• Component, C, is the minimum number of chemical constituents necessary to define the composition of each phase present at system equilibrium
• The number of components is not always easy to determine at first glance, and it may have to be determined experimentally.
Why is phase rule useful?• Helps to characterize state of the system• Predict equilibrium relations of phases• Helps to construct phase diagrams• To standardize the system so that it will produce standard
products• Standard production of medicine
Example• In the reaction of heat decomposition of calcium carbonate:
• There are three phases.• There are also 3 different chemical constituents, but the number of components is 2 because any two constituents completely define the system in equilibrium. • Any third constituent may be determined if the
concentration of the other two is known.
• Substituting into the phase rule we can see that the system is univariant
F = C – P + 2 = 2 – 3 + 2 = 1. • Therefore only one variable, either temperature or
pressure, can be changed independently.
Example 2
How many intensive variables can be independently specified at the triple point of water ?
• Number of chemical species present, C= 1 • Number of phases present at equilibrium, P= 3
F = 1 - 3 + 2= 0
NO variables can be independently specified at the triple point! This means that there is just one triple point and ALL of the properties of all of the phases are fixed. The triple point is unique.
Eutectics• A eutectic system is a mixture of chemical compounds or
elements that has a single chemical composition that solidifies at a lower temperature than any other composition made up of the same ingredients. • This composition is the eutectic composition and the temperature is
the eutectic temperature.• Intersection of both is the eutectic point.
Example
• In addition of A to B or B to A, melting points are reduced.
• At a particular composition: eutectic point is reached have the lowest melting point than A or B.
• Used to increase drug solubility
Application• The mixture, AB is made at eutectic composition: A low
soluble drug (A%) + inert soluble carrier (B%)• B% is more than A• Solid AB prepared by rapid cooling of A+B in order to
obtain a physical mixture of very fine crystals of the two components.
• When this mixture is dissolved in an aqueous medium, the carrier will dissolve rapidly, releasing very fine crystals of the drug.
• The large surface area of the resulting suspension should result in an enhanced dissolution rate• Improved bioavailability.
Example• An eutectic mixture of drug and soluble carrier.• The carrier dissolves and leaves the drug in a fine state of
solution in vivo, usually in a state which predisposes to rapid solution.
• Eg: griseofulvin the eutectic solid of griseofulvin-succinic acid dissolves 6-7 times faster than pure griseofulvin
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