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INTERMOLECULAR FORCES AND STATES OF MATTER PHAR 1313 Prepared by: Wan Rosalina Wan Rosli, PhD...

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  • INTERMOLECULAR FORCES AND STATES OF MATTER PHAR 1313 Prepared by: Wan Rosalina Wan Rosli, PhD [email protected] 03-83137080
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  • Learning objectives 1. Describe the types of intermolecular forces 2. Detail the physical characteristics of each state of matter 3. Describe the mechanism involved in phase changes 4. Describe the use of eutectics 5. Relate and apply the use of the knowledge of intermolecular forces and states of matter in current pharmaceutical practice
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  • 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
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  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • Nonpolar molecules exhibiting induced dipole-induced forces of attraction include organic compounds such as carbon disulfide, carbon tetrachloride, and hexane.
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  • Visualization of the induced dipole- induced dipole
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  • 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).
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  • 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.
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  • 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.
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  • Hydrogen bond It is the attraction of a H atom for a strongly electronegative atom such as oxygen, nitrogen, fluoride and sulfur.
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  • 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.
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  • Hydrogen bonding in water molecules account for properties of water: Form aggregates: Liquid at RT High T m and T b
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  • Hydrogen bonding is also responsible for: The conformation of proteins and DNA double helix structure. Protein-ligand interaction Solubility
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  • STATES OF MATTER
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  • 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.
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  • States of Matter SolidLiquidGas Definite mass & volume Yes No ShapeFixedTake the shape of container Fill all available space in container DensityHigh Very low CompressibilityRelatively incompressible Only slightly compressible Compressible Kinetic energyLowMediumHigh
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  • Solids There are 3 types of solids: 1. Crystalline Crystalline 2. Amorphous Amorphous 3. Polymers Polymers
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  • 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.
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  • 7 crystal systems Sodium chlorideUrea Fluorapatite Calcite Argonite Sucrose Copper sulfate
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  • 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
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  • Any pharmaceutical property of a solid will be influenced by its polymorphic form. Example: Density Melting temperature Solubility Dissolution rate Chemical stability Shelf-life
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  • Example of polymorphic drugs DrugNo. of polymorphs Chloramphenicol palmitate 4 Progesteron2 Caffeine2 Phenytoin2
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  • 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 25C but melts at 35C. If it is overheated (>40C) and cooled quickly, it melts at lower temperatures (15- 28C) Careful, slow heating produces suppositories that dont melt in hands but melt at body temperature.
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  • 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
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  • 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 878882 http://www.chemistry-blog.com/2010/06/07/puzzling- polymorphs/
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  • 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.
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  • 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.
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  • 2.Amorphous Noncrystalline materials No definite order or structure. No definite melting point. More soluble Higher bioavailability than crystals
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  • Some exist in both crystalline and amorphous forms. Example: petrolatum, insulin. Amorphous form used for prompt action and crystalline forms for long actions.
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  • 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.
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  • 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.
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  • 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
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  • 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. Boyles law Charles law Gay-Lussacs law Avogadros law Ideal gas law Combined gas law
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  • Primary gas laws Boyles law states that the volume of a gas varies inversely with its pressure, if the temperature is held constant: P 1 V 1 = P 2 V 2 *Subscript 1 is for initial volume (V) and pressure (P) and subscript 2 is for the volume and pressure after the change. Charless law states that the volume of a gas varies in proportion to its temperature, if the pressure is held constant: V 1 /T 1 = V 2 /T 2 *Subscript 1 is for initial volume and temperature (T, expressed in Kelvin) and subscript 2 is for the volume and temperature (in Kelvin) after the change.
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  • Gay-Lussac's Law states that if the volume of gas is constant, the pressure is directly proportional to its temperature in Kelvin: P 1 T 1 = P 2 T 2 *Subscript 1 is for initial pressure and temperature and subscript 2 is for the pressure and temperature after the change. Avogadros law states that that equal volumes of all gases at the same temperature and pressure contain the same number of molecules. V A n A = V B n B *Subscript 1 is for gas A volume and number of moles (n) and subscript 2 is for the volume and number of moles of gas B.
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  • Combined gas law This equation combines Boyles, Charles and Guy- Lussacs law to get: (P 1 V 1 )/T 1 = (P 2 V 2 )/T 2 *Subscript 1 is for initial pressure, volume and temperature and subscript 2 is for the pressure, volume and temperature after the change. *You can just remember this one equation, if any of the values are constant then they will cancel out. Therefore, when using this equation and a parameter is not mentioned, just ignore it entirely. You will get one of the primary laws
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  • Ideal gas law This law combines Boyles, Charles and Avogadros law to find the properties of gases without changing the parameters: PV = nRT Where P is the pressure of the gas (atm or kPa), V is the volume (L), n is the number of moles, R is the ideal gas constant, and T is the temperature (in Kelvin). There are two common values for the ideal gas constant. 0.08206 L.atm / K.mol and 8.314 L.kPa / K.mol
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  • Henrys law Henrys 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
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  • Partial pressure
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  • Application Blood gases Gas plasma concentrations are related to atmospheric conditions and to biological and catalytic metabolic activity. Values are given as PO 2, and PCO 2. The partial pressure of O 2 in the blood is on average about 80 mmHg and the partial pressure of CO 2 is on average 35-45 mmHg.
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  • PCO 2 is influenced by respiratory function. Reflect expiratory efficiency If PCO 2 : poor ventilation. If PCO 2 : excessive ventilation/ hyperventilation. *If patient have PCO 2 :respiratory acidosis (pH). If the reverse, patient may have respiratory alkalosis. Why?
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  • CHANGES IN THE STATE OF MATTER
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  • Changes in the state of matter
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  • Parameters involved in phase change 1) Vapour pressure The pressure exerted by the liquids vapour when the vapour is in equilibrium with the substance Measures tendency of a material to change into the gaseous state Increases with temperature
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  • 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
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  • 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.
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  • 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.
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  • 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.
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  • 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:
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  • 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.
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  • 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)
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  • 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.
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  • 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
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  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • 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
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  • 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.
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  • 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 ratedissolution Improved bioavailability.
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  • 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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  • THANK YOU
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