Interfacial phenomena.pdf

WHY IS SURFACE CHEMISTRY IMPORTANT IN PHARMACEUTICAL SCIENCES? Surface chemistry deals with chemical processes at the interface between two phases 1. Solid dosage forms (eg. tablets) 2. Colloidal and dispersed systems (eg. emulsions) 3. Suspensions 4. Suppositories 5. Eye drops 6. Topical and transd...

WHY IS SURFACE CHEMISTRY IMPORTANT IN PHARMACEUTICAL SCIENCES? Surface chemistry deals with chemical processes at the interface between two phases 1. Solid dosage forms (eg. tablets) 2. Colloidal and dispersed systems (eg. emulsions) 3. Suspensions 4. Suppositories 5. Eye drops 6. Topical and transdermal drug delivery systems 7. Nasal aerosols 3 DEFINITION OF A DISPERSED SYSTEM In a pharmaceutical liquid preparation, the particle distributed (e.g. an undissolved or immiscible drug) is referred to as the dispersed phase, and the vehicle is termed the dispersing phase or dispersing medium. Together they produce a dispersed system. 1. Coarse dispersion: particles range in size from 10 to 50 µm (e.g. suspensions, emulsions). 2. Fine dispersion: particles range from 0.5 to 10 µm (e.g. gels) 3. Colloidal dispersion: particles in the nanometer range (e.g. liposomes, micelles) 4 General types of pharmaceutical mixtures 1. Solutions • • • Molecularly dispersed Spatially homogeneous Thermodynamically stable (ΔG = 0) 2. Particle dispersions (powder blends) • Particles dispersed within other particles • Not spatially homogeneous • Thermodynamically unstable (e.g. sifting) 3. Liquid dispersions (particles in liquid) • Particles dispersed within a liquid (e.g. suspensions, emulsions) • Not spatially homogeneous • Thermodynamically unstable 5 Examples of liquid dispersions in pharmaceutical applications: Suspensions: solid-in-liquid Emulsions: liquid-in-liquid Foams: vapor-in-liquid Administration routes: • • • Suspensions: parenteral, oral, topical, otic Emulsions: primarily topical Foams: topical, rectal, vaginal 6 Advantages of liquid dispersions relative to solutions Solutions: a homogeneous, one-phase system that has two or more components; no solids or immiscible liquids present (e.g. syrup) Suspensions: dispersion of insoluble particles in a liquid. • • • Prolongs chemical stability of the drug • The dispersion phase can be used to mask poor tasting drugs Ease of swallowing over a pill Useful for administering less soluble drugs in convenient volumes (e.g. antibiotics administered orally, erythromycin ethylsuccinate 200 mg/5mL) 7 Disadvantages of liquid dispersions relative to solutions • Particles often will not mix uniformly with the liquid (we say that they are not “wetted”) • Float on the surface • Agglomerate • Stick to the container 8 For liquid dispersions: Three general physical instability problems 1. Non-wetting. Solid particles don’t disperse uniformly when placed into the liquid. 2. Aggregation/Coalescence. Particles aggregate to form larger agglomerates or, if liquid-liquid or vapor-liquid, they coalesce. 3. Sedimentation/Creaming. Particles (liquid, vapor, solid) sediment or cream due to gravitational effects and density differences. All of these phenomena lead to non-uniformity of particle dispersion within the liquid. 9 H-bonding of water molecules at the surface vs. the bulk Vapor phase A water molecule B Liquid phase 10 Surface tension can be illustrated by a three-sided wire frame • • Soap film is stretched by applying force f to the movable bar of length L. Surface tension γ is the force that must be applied to break the film over the length of the bar in contact with the film C L D L Soap film B f A dx What causes this inward force opposing f ? Surface tension or γ 11 Definition of Surface Tension (γ) L • • • • • f dx Force (f) is needed to expand the surface a distance dx across a length of surface (L). This requires work or an increase in free energy: • dW = dG = force × distance = f∙dx By definition, surface tension (γ) = f/L and hence f = γ ∙L ∴ dG = γ ∙(L∙dx) Since the surface area change, dA = (L∙dx) thus dG = γ ∙dA Therefore, γ = dG/dA or the increase in surface free energy per unit area (when increasing the surface area). 12 Surface tension (L-V interface) correlates with strength of intermolecular forces glycerin Liquid Surface Tension (γ) (ergs/cm2) Water 72 Glycerin 63 Ethylene Glycol 48 Oleic Acid 33 Benzene 29 Hexane 18 Ethanol 22 Ethylene glycol Oleic acid ethanol 13 Interfacial tension (L-L or L-S interface) of water against immiscible liquids Liquid Interfacial Tension (γ) (ergs/cm2) Hydrocarbons ~ 50 Fluorocarbons ~ 50 CCl4 45 CHCl3 33 Oleic Acid 15 n-Octanol 9 Ethanol 0 14 Impact of surface tension on wettability of solids (in general) Solids and liquids with sufficiently similar surface tensions will be compatible even if they do not dissolve: “good wetting” (e.g., silica, SiO2, in water) Solids and liquids with very different surface tensions will not wet very well (e.g., Teflon in water, certain hydrophobic drugs and excipients) 15 Different extents of wetting #1 θ = 180° #2 θ > 90° #3 θ < 90° #4 θ = 0° By convention the angle produced at the point of liquid-solid-vapor contact is known as the contact angle, θ. The greater the angle past 90º, the lower the wettability of the liquid on the solid θ 16 Factors affecting contact angle • Young’s Equation cos θ = (γSV - γSL)/γLV • Teflon - Water θ cos θ = (20 - 50)/72 = -0.417 θ = 115° • Glass - Water cos θ = (80 - 10)/72 = +0.972 θ = 13.5° 17 For wetting to occur certain changes in interfacial area must occur L vapor vapor L solid solid ΔG = γSL∙ΔA • ΔASL must increase • ΔALV must increase • ΔASV must decrease 18 Whenever a new surface is created, there must be an increase in overall free energy ΔG =γΔA = dW The higher γ and ΔA, the greater the work (more positive the free energy change) 19 What is the total free energy change (ΔGT) upon wetting? ΔGT = ΔGSL + ΔGLV + ΔGSV The smaller ΔGT, the better the extent of wetting... •Upon Spreading: • ΔGLV = γLV∙ΔALV • ΔGSL = γSL∙ΔASL • ΔGSV = γSV∙ΔASV : must increase : must increase : must decrease To promote wetting we must: • lower γSL ; lower γLV ; or raise γSV 20 What strategies can we use to improve wetting? • Raise γ • Lower γ • Lower γ SV of the solid LV of the water SL of water/solid HOW DO WE DO THIS? • Coat the solid with other polar solids to raise γ • Use surface active agents to lower γ and γ . LV SV. SL 21 Contact angles of water with various pharmaceutical solids Material θ (deg) Aspirin 74 Ampicillin 35 Caffeine 43 Indomethacin 90 Lactose 30 Magnesium stearate 112 Prednisone 63 Salicylic acid 103 Theophylline 48 lactose caffeine salicyclic acid magnesium stearate 22 • What would happen to the surface tension if we dissolved some ethanol in water? We would expect ethanol molecules, when replacing some water molecules at the surface, to lower the value of γLV of water to somewhere between 24 and 72 ergs/cm2? CH3CH2 OH H O HO CH2CH3 O H O H H H H 23 Surface tension of ethanol-water mixtures At low concentrations, ethanol molecules added to water will immediately rise up to the water-vapor interface and disrupt the surface layer of tightly bonded water molecules. 24 Accumulation of molecules at an interface is described as Adsorption HO Polar head group CH2 Nonpolar tail CH3 can be depicted pictorially as: Polar head group Nonpolar tail Concentrations of molecules at interfaces (L-V, L-S) is greater than in the bulk liquid. 25 The number of carbons in the alkyl chain is important • The more nonpolar the chain (i.e. the longer the alkyl chain), the more efficient the alcohol in lowering the γLV of water at a given concentration c (every carbon → 3-fold change). 72 (ergs/cm2) γLV = 23 erg/cm2 Adsorption is driven by the “hydrophobic effect” γLV = 24 ergs/cm2 γLV = 24 ergs/cm2 c 26 Surfactants: surface-active • • molecules Molecules that adsorb at water surfaces or interfaces at very low concentrations to form an oriented monomolecular area. Typically, they have a long alkyl chain at one end and a water-soluble polar group at the other end. Carbon # Fatty Acid Chain 12 lauric dodecyl 14 myristic tetradecyl 16 palmitic hexadecyl 18 stearic octadecyl 18Δ9cis oleic Polar head group Nonpolar tail oleic acid 27 Examples of polar head groups Ionic head groups: Soaps O O R O C X R S O Sulfates O R O S O CH3 O X R N CH3 Sulfonates X O Quaternary ammonium salts CH3 X 28 Nonionic surfactants have a polar but uncharged head group • Two major types • poly(hydroxy-) O H R C H2C HC HO sorbitan CH H C OH OH • poly(oxy-) OH CH2 CH2 HO CH2 CH2 O OH ethylene glycol CH2 CH2 O CH2 CH2 OH n poly(ethylene glycol) = PEG 29 Nonionic surfactants Polysorbates (Tweens) : R-Sorbitan-PEO Polysorbate 20: R = laurate (12) Polysorbate 40: R = myristate (14) Longer R Polysorbate 60: R = palmitate (16) Polysorbate 80: R = oleate (18) • A “longer” R is more hydrophobic and thus more surface active • A “longer” PEO chain is more hydrophilic and less surface active -Spans (e.g. sorbitan monopalmitate): sorbitan fatty acid esters oil-soluble emulsifiers that promote W/O emulsions (no PEG) -Tweens (e.g. PEG-200-sorbitan monostearate, polysorbate 60) polyethylene glycol sorbitan fatty acid ester 30 O O-(CH2-CH2-O)x O HO O-(CH2-CH2-O)y HO O-(CH2-CH2-O)z OH Cremophor PEG Fatty Acid Ester (PEG-400 stearate) O Spans Sorbitan Ester of Fatty Acids (sorbitan monopalmitate) Tweens, Polysorbates PEG-Sorbitan Fatty Acid Esters (PEG-200-sorbitan monostearate, Polysorbate 60) 31 Typical pharmaceutical anionic surfactants Anionic hydrophilic head/Hydrophobic tail Sodium Laurate O Na O Sodium Lauryl Sulfate O O S O OH Sodium Cholate CH3 H OH H O H3C CH3 O Na ONa H H OH 32 Typical pharmaceutical cationic surfactants • Generally used as antimicrobial agents Cl N C12H25 NH R Benzalkonium Chloride Br Dodecylpyridinium Bromide 33 Classification of surfactants based upon their polarity The “Hydrophile-Lipophile Balance” (HLB system) • • HLB = (molecular weight fraction of hydrophile/5) × 100 For example • CH3(CH2)15-(OCH2CH2)7OH Mtotal HLB = f(mole fraction of hydrophile) 34 Typical HLB values of pharmaceutically useful surfactants Surfactant HLB Sorbitan trioleate (Span 85) 1.8 Sorbitan monooleate (Span 80) 4.3 Sorbitan monolaurate (Span 20) 8.6 Polysorbate 80 (Tween 80)* 15.0 Polysorbate 40 (Tween 40)* 15.6 Polysorbate 20 (Tween 20)* 16.7 *The length of the PEG group is the same for all Tweens. 35 General rules • For water-soluble surfactants, the lower the HLB, the more hydrophobic. • At a given concentration, the lower the HLB the greater the adsorption to surfaces from water. • At a given concentration, the lower the HLB the greater the lowering of surface and interfacial tension. • At a given concentration, the lower the HLB the lower the contact angle of the solution against a given solid (better wetting). 36 Adsorption to solid surfaces generally leads to monolayers Monolayer adsorption on the solid 37 Amount of solute adsorbed on a solid surface wrt concentration At some concentration c, the solid surface saturates with a monolayer of solute c 38 Possible surfactant orientations during adsorption to solid surfaces Non-polar or polar surfaces non-polar surface (i.e. hydrophobic) monolayer polar surface (i.e. hydrophilic) I, II, III, or IV depending on surfactant concentration, properties of the surface and liquid 39 Adsorption as a monomolecular layer saturates at a given concentration Gibbs equation (for dilute solutions): c  dγ  Γ=−   RT  dc  Γ = surface excess (concentration) of surfactant c = concentration of surfactant in the bulk R = gas constant (units: J/(mole⋅K) T = absolute temperature (K) dγ/dc = change in surface tension of the solution wrt change in bulk concentration of the surfactant described by Langmuir isotherm equation (for dilute solutions) (won’t discuss) 40 Surface tension lowering ceases at the critical micelle concentration 41 What can cause such changes? • Monomers begin to self-associate into aggregates called micelles at the “critical micelle concentration” (CMC) Factors affecting micelle formation:  Structure of head and tail e.g. long tails promote micelle formation and lower CMC Branched tails increase CMC  Counter ion used (divalent vs univalent) Amount (e.g. more ions decreases CMC for ionic surfactants)  Temperature 42 Effect of adding surfactants on the surface tension (summarized) Fig 15-13 in Physical Pharmacy Region BC corresponds to Γmax Point C corresponds to the CMC Note that between Points B and C, there aren’t enough surfactant molecules yet to form micelles 43 The Gibbs adsorption equation for monolayer formation at the L-V interface: B γ (mN/m) Γ max c  dγ  1  dγ  =−  =−   RT  dc  RT  d ln c  C Ln c (or Log c) CMC 44 Sample calculation: If the slope dγ/d(ln c) was -5.2937 dynes/cm at 23ºC, calculate the surface excess and area occupied per molecule for this surfactant. Γ max 1 = RT  dγ  −   d ln c  1 erg = (dyne * cm) 1 2 5.2937 erg / cm = ⋅ − ( ) 7 8.3143 ×10 ergs / ( K ⋅ mol )  ⋅ 296.15 K = 2.15 ×10−10 mole/cm 2 molecules / cm 2 = Γ max ⋅ Avogadro ' s number 2.15 × 10−10 mole  6.0221× 1023 molecules  = ×  cm 2 mole   1.29 × 1014 molecules = cm 2 1 1.29 ×1014 molecules cm 2 7.75 × 10−15 cm 2 = molecule Area / molecule = 45 Other properties of surfactants change at the CMC osmotic pressure solubility surface tension light scattering conductivity see Fig 16-3 in Physical Pharmacy 46 Note the effect of nonpolar surfactants on the CMC in water At low conc, B is a more effective surfactant for decreasing surface tension of water With only a 2-carbon difference in the fatty acid chain, the CMC of B is at least 1 order of magnitude or more lower than A cmc cmc y = bx means that x = logb(y) Octyl glucoside 47 CONCEPTS TO REVIEW 1. What is a dispersed system? 2. How are liquid dispersions different from solutions? 3. What is surface tension? What is interfacial tension? 4. How can you calculate the extent of wetting of a liquid on solid? 5. What is the total free energy change (∆GT) upon wetting? 6. What strategies can we use to improve wetting? 48 7. The lower the HLB of the surfactant, the lower the contact angle of the solution against a solid (better wetting) – T or F? 8. The Gibbs equation describes maximum adsorption of surfactants as a monomolecular layer at the L-V interface (i.e., called surface excess concentration or point B on graph) 9. At concentrations between regions (B) and the CMC (C), the surface tension decreases sharply but Γmax is assumed to be constant (ie. slope) thus allowing for a single unique area occupied per surfactant molecule to be calculated 10. The CMC is the minimum conc for maximum surface tension reduction SAMPLE PROBLEMS Given this structure, where w = x = y = z = 5 (sum of 20) calculate the HLB. (OCH2CH2)xOH HO(CH2CH2O)w (OCH2CH2)yOH O O (OCH2CH2)z O C17H33 Compare the two surfactants given below in the ways requested. Check the correct answer. [ ] [ ] Y CH3(CH2)14-CH2-O— CH2-CH2-O— 8CH2OH Z CH3(CH2)14-CH2-O— CH2-CH2-O— 6CH2OH 1. Which one in water should be the better wetting agent? Y Z _____ _____ 2. Which one in water should have the higher HLB? _____ _____ 3. Which one in water will have the lower cmc? _____ _____ 4. Which one in water will better prevent particles suspended in water from aggregation when both are used at the same aqueous concentration below their cmc values? _____ _____ 5. Which one will require a higher concentration to solubilize a very water-insoluble drug to the same extent? _____ _____ The slope of the 15ºC line on the low concentration side of the CMC is about -13.3 mN/m (see below). Calculate the molecule per area for the range of concentrations shown. Plot of γ versus log10 c for the dodecyl ether of hexaethylene oxide at three temperatures: (1) 15ºC, (2) 25ºC, and (3) 35ºC. (a) 1.45 x 1014 molecules/cm2 (b) 1.45 x 1016 molecules/cm2 (c) 1.45 x 1018 molecules/cm2 (d) 2.41 x 10-6 molecules/cm2 (e) 2.41 x 10-8 molecules/cm2 53 Compare the two surfactants given below in the ways requested. Check the correct answer. [ ] [ ] Y CH3(CH2)14-CH2-O— CH2-CH2-O— 8CH2OH Z CH3(CH2)14-CH2-O— CH2-CH2-O— 6CH2OH Lower HLB 1. Which one in water should be the better wetting agent? Y Z _____ _____ 2. Which one in water should have the higher HLB? _____ _____ 3. Which one in water will have the lower cmc? _____ _____ 4. Which one in water will better prevent particles suspended in water from aggregation when both are used at the same aqueous concentration below their cmc values? _____ _____ 5. Which one will require a higher concentration to solubilize a very water-insoluble drug to the same extent? _____ _____ The slope of the 15ºC line on the low concentration side of the CMC is about -13.3 mN/m (see below). Calculate the molecule per area for the range of concentrations shown. Plot of γ versus log10 c for the dodecyl ether of hexaethylene oxide at three temperatures: (1) 15ºC, (2) 25ºC, and (3) 35ºC. (a) 1.45 x 1014 molecules/cm2 (b) 1.45 x 1016 molecules/cm2 (c) 1.45 x 1018 molecules/cm2 (d) 2.41 x 10-6 molecules/cm2 (e) 2.41 x 10-8 molecules/cm2 1J=N·m R = 8.314 J/(K · mol) = 8.314 N·m/(K·mol) Slope = -13.3 mN/m = -13.3 x 10-3 N/m = -0.0133 N/m