Physical pharmacy notes

Osmotic Pressure

• Osmotic pressure ($\pi$) is the pressure required to prevent solvent passage through a semipermeable membrane, stopping osmosis.
• Van't Hoff Equation: \piV = nRT
  • $\pi$: Osmotic pressure
  • V: Volume of solution in liters
  • n: Number of moles of solute
  • R: Gas constant (0.082 L atm/mole deg)
  • T: Absolute temperature

Electrolytes and Colligative Properties

• Electrolytes enhance colligative properties due to dissociation into ions.
  • Example: 0.1m NaCl doubles the freezing point lowering compared to a non-electrolyte.
  • Example: 0.1m CaCl2 triples the boiling point elevation compared to a non-electrolyte.
• Electrolyte solutions exhibit greater osmotic pressure than non-electrolytes of the same molar concentration.
• Increased particle number from dissociation leads to increased osmotic pressure.

Applications of Colligative Properties: Isotonic Solutions

• Non-electrolytes: Solutions containing only molecules; osmotic pressure varies solely with solute concentration.
• Electrolytes: Solutions containing ions; osmotic pressure varies with solute concentration and degree of dissociation.
• Isosmotic solutions: Solutions with the same osmotic pressure.
• Isotonic solution: Solution with the same solute concentration as body fluids.
• Hypotonic solution: Solution with lower solute concentration than intracellular solute concentration.
• Hypertonic solution: Solution with higher solute concentration than intracellular solute concentration.

Classification of Surface Active Agents (SAA)

A. Ionic SAA

1. Anionic SAA

• Polar head: Carboxylate, sulfate, sulfonate, phosphate with counter ion.
• Counter ions:
  • Na, K (monovalent): water-soluble, e.g., Na, K salt of carboxylic acid (soap), unstable due to hydrolysis.
  • Mg, Ca (polyvalent): oil-soluble.
• Non-polar tail: Alkyl chain (12-18 carbons); increased chain length decreases solubility.
• Example: SLS (sodium lauryl sulfate): very water-soluble, preoperative skin cleaner, bacteriostatic against Gram-positive bacteria, used in shampoos.

2. Cationic SAA

• Nitrogen atom as quaternary ammonium (positive, protonated over entire pH range) and amine (pH-dependent; protonated only in acidic medium, not used in alkaline medium).
• Non-polar tail: Alkyl chain (12-18 carbons).
• Examples:
  • Cetrimide: Cleans skin in wounds (external use only due to toxicity), emulsifying agent in O/W creams.
  • Benzalkonium chloride: Preservative in eye drops, cleans wounds, preoperative skin disinfectant.

3. Amphoteric (Ampholytic, Zwitterionic) SAA

• Contain carboxylate or phosphate with amino or quaternary ammonium group.
• Alkyl chain (12-18 carbons).
• Example: Lecithin (phospholipids) - lung surfactant.

B. Non-ionic SAA

• More stable with charged drugs, compatible, safer, not affected by pH.

1. Macrogol Ether (Poly Oxy Ethylene Alkyl Ether)

• Examples: Cetomacrogol, Brij series, Cremophor EL.

2. Sorbitan Ester and Ethoxylated Derivatives

• Span: Ester of sorbitol, insoluble in water, W/O emulsifier, wetting agent.
• Tween: Ethoxylated derivative of Span, soluble in water, wetting agent, O/W emulsifier, solubilizer.

3. Block Copolymer

• Macromolecule with monomer blocks differing in structure, e.g., Poloxamer (Pluronics).
• Triblock copolymer (hydrophilic - hydrophobic polyoxypropylene chain - hydrophilic): water-soluble, O/W emulsifier, wetting, solubilizing agent.

Osmosis & Blood Cells

• Isotonic Solution: Solute concentration is the same inside and outside the blood cell; no net water movement, no change in shape.
• Hypotonic Solution: Solute concentration outside the blood cell is less than inside; net water flow into the cell, causing it to swell and potentially burst.
• Hypertonic Solution: Solute concentration outside the blood cell is greater than inside; net water flow out of the cell, causing dehydration, shrinkage, and potential death.
• Biological fluids (blood, lacrimal fluid) have an osmotic pressure corresponding to 0.9% w/v NaCl solution (physiological saline solution, normal saline solution).
• Normal saline is used in intravenous drips for patients who lost water or are at risk of dehydration.
• Pharmaceutical solutions for delicate membranes should be adjusted to the same osmotic pressure as body fluids.
• Isotonic solutions cause no swelling or contraction of tissues and produce no discomfort when instilled in the eye, nasal tract, blood, or other body tissues.
• Non-isotonic injections should be administered slowly and in small quantities to minimize tissue irritation and pain.
• Hypotonic or hypertonic intravenous infusions can have adverse effects due to large volumes administered.
• Ophthalmic preparations should be isotonic or near isotonic for patient comfort and to reduce eye irritation.
• Aqueous injections and eye drops are isosmotic with blood and lacrimal secretions (tears) when they have a freezing point depression of 0.52 °C.

Measurement of Osmotic Pressure & Molecular Weight Determination

• Osmotic pressure measurement is difficult and time-consuming; freezing point depression is the preferred method.
• Freezing point depression for a solution isosmotic with all body fluids is 0.52°C.
• Molecular weight determination of solute can be found by:
  • Vapor pressure lowering:
    $M2 = \frac{W2 M1 P1}{W1 \Delta p}$
  • Boiling point elevation:
    $M2 = \frac{1000 W2}{W1 \Delta T<em>b} K</em>b$
  • Freezing point depression:
    $M2 = \frac{1000 W2}{W1 \Delta T<em>f} K</em>f$
  • Osmotic pressure:
    $M2 = \frac{C g R T}{\pi}$
    Where C is a constant.
• Boiling point elevation and freezing point depression are less sensitive and limited to polymers with relatively low molecular weights because the changes in boiling and freezing points are small when the number of molecules is small.
• Osmotic pressure measurement is suitable for measuring average molecular weights of large polymers.

Partition Coefficient

• Ratio of solute concentrations in two immiscible liquids.
• $K \text{ or } P = \frac{C<em>1}{C</em>2}$
  • K or P: Partition coefficient (distribution coefficient)
  • $C_1$: Concentration of solute in solvent 1
  • $C_2$: Concentration of solute in solvent 2
• Oil-water partition coefficient (octanol-water) is an indicator for lipophilicity and hydrophilicity of a drug molecule, relevant to drug passage through lipid membranes.
• Applications of the partition coefficient:
  1. Extraction technique
  2. Preservation of oil-water system in emulsion
  3. Absorption and distribution of drugs across the body
• Problem:
  • Calculate the water/hexane partition coefficient for drug x knowing that the concentrations of drug are 2 g% and 5 g % in hexane and water, respectively.
  • Answer: $K = \frac{c \text{ water}}{c \text{ hexane}} = \frac{5}{2} = 2.5$

Diffusion

• A process of mass transfer of individual molecules of a substance by random motion (Brownian motion) driven by a concentration gradient.
• Solute diffuses from side of higher drug concentration to side of lower drug concentration (from donor to receptor).
• Diffusion stops when the concentration of donor equals the concentration of receptor or when the concentration gradient is zero, which is achieved under sink conditions.
• Driving forces for diffusion:
  1. Concentration: Passive diffusion across membranes
  2. Pressure: Osmotic drug release, Pressure-driven jet for drug delivery
  3. Temperature: Lyophilization and microwave-assisted extraction
  4. Electric charge: Iontophoretic dermal drug delivery and electrophoresis
• Notes:
  1. Diffusion mechanism through pores/channels depends on pore size and shape or through non-porous membrane depends on solubility.
  2. Multilayer diffusion: Diffusion through a series of successive barriers.
     • Examples: Drug absorption across biologic barriers, gas passage through container walls and packaging.

Rheology

• Branch of science dealing with deformation and flow of matter under the influence of certain stress.
  • Rheo: flow
  • -ology: study of
• Rheology in pharmaceutical applications:
  1. Injections syringe ability
  2. Liquid dosage form (syrup, suspension, emulsion)
  3. Semisolid dosage forms (creams, gel, ointment spreading)
  4. Release pastes from tubes

Viscosity

• Resistance to flow; reciprocal of viscosity is fluidity ($\frac{1}{\eta}$).
• Gel > honey > water (in viscosity).
• Approach to explain material flow tendency:
  • Honey flows readily and flattens quickly.
  • Mayonnaise resists flow and retains shape.
• Difference in behavior related to their viscosity.

Shear Stress and Rate of Shear

• Shear stress (F): Force per unit area required to flow ($\frac{\text{Dyne}}{\text{cm}^2}$).
• Rate of shear (G): How fast a liquid flows (sec⁻¹).

Newton's Theory

• Higher viscosity requires higher shear stress to cause flow.
• Shear stress is directly proportional to the rate of shearing.
  • $F \propto G$
  • $F = \eta G$
  • $\eta = \frac{F}{G}$
  • $\eta = \frac{F (\frac{\text{Dyne}}{\text{cm}^2})}{G (\text{sec}^{-1})} = \frac{\text{dyne} \cdot \text{Sec}}{\text{Cm}^2} = \text{Poise}$
  • (1 poise = 100 centipoises (CPS))
• Fluidity ($\phi$): Reciprocal of viscosity ($\frac{1}{\eta}$) (unit: poise⁻¹).

Steady State, Lag Time, and Permeability

• Steady State: Uniform concentration gradient (equilibrium) within the membrane separating the donor from the receptor compartment.

• Lag Time: Time required for a solute to establish a uniform concentration gradient within the membrane separating the donor from the receptor compartment.

• Permeability: The degree to which one substance allows another substance to pass through it.

• Resistance and permeability are inversely related.

• P: permeability coefficient.

• $P = \frac{D \cdot K}{h}$
  * (cm/sec)
  * D: diffusion coefficient
  * K: partition coefficient
  * h: thickness of the membrane

• Problem:

  • Calculate the permeability of membrane A to drug X, knowing that the drug's diffusion coefficient is 0.3 mm²/sec, its partition coefficient is 5, and the thickness of the membrane is 1.5 mm.
  • Answer: $P = \frac{D \cdot K}{h} = \frac{0.3 \cdot 5}{1.5} = 1 \frac{\text{mm}}{\text{sec}}$

Fick's First Law of Diffusion

• $J = \frac{dM}{S \cdot dt} = J<em>\text{Flux} = -D \frac{C</em>2 - C_1}{h}$
  • M: amount
  • S: Surface area of membrane.
  • D: Diffusion coefficient
  • h: thickness of the membrane.
  • t: time
  • $(C<em>1 - C</em>2)$: Concentration gradient
  • (-ve sign): Direction of Solute flow to Lower Conc. Compartment

Types of Materials According to Flow

A. Newtonian Fluids

• Obey Newton's law (constant viscosity).
• Rheogram (G against F) shows a straight line passing through the origin; slope of the curve = $\eta$
• Viscosity is not dependent on the rate of shear or time (depends only on temperature).
• Examples: Water, glycerol, ethanol, benzene (simple organic solutions).

B. Non-Newtonian Fluids

• Do not obey Newton's law.
• Viscosity is not constant.
• Rheogram is not a straight line.
• Examples: Colloid, conc suspension, conc emulsion, ointment, gel, cream.

1. Pseudoplastic Flow (Shear Thinning Flow)

• As shear increases, viscosity decreases.
• At rest: Molecules are coiled and bound to solvent, resulting in high resistance to flow (increased viscosity).
• At shearing: Molecules align themselves in the direction of flow; viscosity decreases.
• Curve not linear, start from origin, viscosity can't expressed by one point.
• Examples: Gums tragacanth and sodium alginate, methylcellulose, gelatin.
• Exhibited by polymers in solution.

Factors Affecting Diffusion

• Particle size or molecular weight: Inversely proportional to diffusion (smaller particles need less energy for the Brownian motion).
• Temperature: Directly proportional to diffusion.
• Concentration difference: Directly proportional to diffusion.
• Diffusion distance (h): Inversely proportional to diffusion.
• Surface area: Directly proportional to diffusion.

Pharmaceutical Applications of Diffusion

• Elementary drug release:
  • Drug release is a multistep process that includes disintegration, deaggregation, dissolution, and diffusion.
  • Release from granular matrix depends on leaching drug from pores (porosity and tortuosity).
• Release from Polymer matrix depends on dissolving in polymer matrix, diffuse out from device surface
• Osmosis:
  • Solvent passes through a semipermeable membrane to dilute the solution containing solute and solvent.
  • Osmotic drug release systems use osmotic pressure as a driving force.
  • Osmotic pump consists of osmotic core containing drug with osmotic agent and is coated with a semipermeable membrane.
  • The semipermeable membrane has an orifice for drug release, water diffuse through membrane.
  • Imbibitions of water results in high pressure inside the pump, which causes flow of drug through orifice.
  • Factors affecting osmotic pump: solubility, osmotic pressure, size of orifice, and nature of membrane.

Applications of Pseudoplastic Polymers

• Tear substitute (dry eye syndrome):
  • Low viscosity when blinking, high viscosity at no shear to prevent tear substitute from flowing away.
  • Examples: Dextran, PVA, sodium hyaluronate.
• Syringability of injection:
  • Applying the same force to a smaller area, the system undergoes more shear stress (area is inversely proportional to shear stress).
  • Small area in needle high shear → decrease viscosity so easy to push (more comfortable).

Plastic Flow (Bingham Bodies)

• Curve is linear over most of its length, corresponding to that of a Newtonian fluid.
• Curve does not pass to origin, extrapolated to X-axis at (yield value) (Bingham yield value) (f).
• Bingham bodies do not begin to flow until shear stress exceeds yield value.
• Materials initially (below yield value) resist deformation (act as solid) until yield value is reached.
• Plastic system resembles Newtonian system at shear stress above yield value.
• Yield value used to break Van der Waals forces before flow.

Ultrafiltration & Dialysis

• Ultrafiltration:
  • Used to separate colloidal particles and macromolecules by the use of a membrane using high pressure.
  • Used to purify albumin and enzymes.
• Dialysis:
  • A separation process based on unequal rates of passages of solutes and solvent through a microporous membrane. Example: Hemodialysis.
    • Used in treating kidney malfunction to rid the blood of metabolic waste products (small molecules) while preserving the high molecular weight components of the blood.

Biological Applications of Diffusion

• Diffusion through biological membrane is important for drug absorption, distribution, and elimination (pharmacokinetics).
• Transcellular diffusion: diffusion through the lipid bilayer membrane.
• Paracellular diffusion: diffusion through spaces between adjacent cells.
• Ex: flocculated particles in conc suspension (held by vander waals force) ; yield value is indication for flocculation

Dilatant Flow

• Increase shear, increase viscosity (increase in volume called dilatant).
• At rest: Close packed, small voids in solid, vehicle sufficient to fill voids, low viscosity.
• At shear: Open packed, increase voids, insufficient vehicle to fill voids, increase viscosity.
• When stress is removed, dilatants return to their original state.
• Examples: high conc suspension (> 50 %) as sand, starch susp, deflocculated susp

Drug classification according to Solubility & Permeability per the Biopharmaceutics Classification System (BCS)

• Class I: High Solubility, High Permeability
• Class II: Low Solubility, High Permeability
• Class III: High Solubility, Low Permeability
• Class IV: Low Solubility, Low Permeability

Franz Diffusion Cell

Components:

• Donor Compound
• Donor Chamber
• Membrane
• Receptor Chamber
• Sampling Port
• Stirbar
• Heater/Circulator
• Water Jacket
• Flat Ground Joint
• Molecular Barriers:
  1. Natural membrane
  2. Synthetic polymeric film
  3. Stagnant solvent layer (not moving solvent layer)
• Facilitated diffusion: (transcellular or paracellular): movement of molecules from high conc to low conc across membrane ex: sugars & amino acids(uniporters)

Drawbacks of Dilatant Systems

• Disadvantage in manufacturing as it may damage equipment such as mills or high-speed blenders.
• Injury and pain during injection.

Thixotropy

• Isothermal slow recovery on standing of material when stress is removed (gel-sol-gel transition) produced by (rest - shear- rest) for thinning system like ketchup, yogurt, paint, inks.
  • Mechanism:
    1. During stress: break rigid structure within system
    2. Stop shear: takes time to reform rigid structure, doesn't reform immediately, rebuilds gel structure.
    3. Example application: Viscosity measurement (selection of viscometer)
    4. Single point viscometer
       • Ostwald viscometer
       • Falling sphere viscometer
       • Newtonian flow only
    5. Multiple point viscometer (rotational)
       • Cup and bob viscometer
       • Cone and plate viscometer
       • Newtonian and non newtonian

Pharmaceutical and Biological Applications of Rheology

• Prolongation of drug action:
  • Absorption of ordinary suspension differs from thixotropic suspensions.
  • Suspension is shaken before use to be easily injected, forms compact spherical deposits at the site of injection which resist degradation and prolong effect ex: procaine penicillin G
• Effect on drug absorption:
  • In creams and lotions, as viscosity decreases, drug release increases.
• Thixotropic and good suspension formulation:
  • At rest: high viscosity, increase stability
  • Upon shaking or agitation: viscosity decreases, easy administration
• Thixotropy and drug stability:
  • Vitamins are more stable in thixotropic formulations (solid in rest)

Biorheology

• Study deformation and flow in biological materials or artificially biocompatible materials and effect of drugs and disease.

• Blood:

  • Consists of red blood cells, white blood cells, and platelets suspended in plasma, exhibits pseudoplastic non-Newtonian flow.
  • Low shear: high viscosity due to reversible aggregation of erythrocytes.
  • High shear by heart: low viscosity, moves easily in blood vessels.

• Synovial fluids:

  • Secreted by joints for lubrication.
  • The most important component is hyaluronic acid, which affects rheological properties.
  • Non-Newtonian shear thinning liquids.

• Low shear (standing, slow walking): high viscosity, enable lubrication

• High shear (jumping, running): decrease viscosity allow movement of joints

• Sputum: Secretion of lungs, bronchi, trachea

  • Exhibits non-Newtonian flow (shear thinning systems).
  • Its viscosity is influenced by state of body hydration.
  • Increasing mucus viscosity results in breathing difficulty

Performance Testing

Dissolution Rate Testing

• Drug product: finished dosage from that contain a drug substance associated with other inactive ingredients
• Drug release: process by which drug leaves a drug product.
• Dissolution: rate process by which solid drug molecules are liberated from solid form and dissolved and enter a solution form
  • Dissolution rate testing:
    • Measure of release of active pharmaceutical ingredient (API) from product in controlled laboratory environment (in vitro).
    • Assessment of rate by which drug molecules are dissolved and released from dosage form.
    • Time dependent (kinetic) process, mass transfer process (as diffusion).
    • Only drug in solution form is absorbed.
    • Dissolution is the rate-limiting step for drugs with low solubility.
• Importance:
  1. Evaluating drug performance for any dosage form with drug in solid state.
  2. Assessing difference between brand and generic dosage forms
  3. Predict time of API release modeling in vivo behavior.
  4. Quality control test for batches
  5. Assess long term API release stability.

Noyes-Whitney Equation

• $\frac{dM}{dt} = \frac{D \cdot S (C_s - C)}{V \cdot h}$
  • M: mass dissolved.
  • t: time.
  • $\frac{dM}{dt}$: rate of dissolution.
  • D: diffusion coefficient.
  • S: Surface area of drug.
  • h: thickness of diffusion layer.
  • Cs: Solubility of Solid. (Conc of drug at Saturated Solution).
  • C: Conc of Solute in Bulk solution.
  • V: Volume of Solution.
• Stagnant Liquid film (diffusion layer) Stationary layer of Solvent in which solute conc from Cs to C.

Factors Affecting Drug Dissolution

• Concentration gradient ($C_s - C$) (main driving force for dissolution)
  • As concentration gradient increases, dissolution rate increases.
  • Sink condition: USP specifies that the volume of dissolution medium must be not less than three times that required to form a saturated solution of drug.
  • Decrease (C) by continuous replacement by fresh solvent, using a large volume of medium.
• Thickness of diffusion layer (static diffusion layer) (h):
  • Diffusion layer thickness is altered by force of agitation.
  • Increase agitation-decrease thickness of layer-increase dissolution rate.
  • Decrease agitation increase thickness of layer decrease dissolution rate.
  • Thickness of diffusional layer proportional to particle size
• Surface area of drug particles (S):
  • Surface area is directly proportional to energy and inversely proportional to particle size.
  • Increase particle size decrease surface area decrease in energy decrease in dissolution rate.
  • Decrease particle size increase surface area increase in energy increase in dissolution rate.
  • Decrease particle size after certain limit becomes unstable and tend to aggregate due to high energy so decrease dissolution rate.
• Note: Polymorphism: ability of drug substance to exist in two or more crystalline form that differ in arrangement, conformation and dissolution rate
  • Amorphous structure has higher solubility than crystalline form.

Interfacial Phenomena

• Interface: boundary between two immiscible or insoluble phases.
  • Liquid interface: liquid-liquid (emulsion, lotion), liquid - solid (suspension), liquid gas (aerosol).
  • Solid interface: solid-solid (powder in capsule), solid-liquid (suspension), solid-gas (tablet, capsules).
• Surface: the boundary between two phases, one of them is a gas, so surface is a type of interface, but interface is not surface. Surface tension is a unique property of interfaces containing a gas phase.
• Molecules in bulk (Liquid interfaces):molecules surrounded in all directions by other molecules (cohesive force) (equal attraction).
• At surface: Molecules develop cohesive force with liquid molecules below; develop adhesive force (small) with other phase.
• Net force inward force toward the bulk pull the interface molecules → Surface tension and decrease surface area to decrease energy to achieve minimum free energy state (forming lens) (ex: spherical shape of liquid droplets); Surface tension: the force per unit length that must be applied parallel to the surface to counterbalance the net inward pull.(dyne/cm) (N/m)
• Interfacial tension: the force per unit length that exist at interface between two immiscible liquid phases.
  Interfacial tension: the force per unit length existing at the interface between two immiscible liquid phases (dyne/cm) (N/m) ($\gamma, \gamma<em>{ss}, \gamma</em>{sl}$)
• Measurement of surface and interfacial tension:
  • Drop weight method.
  • Bubble pressure method.
  • Wihelmy plate method.
  • Oscillation drop method.
  • Capillary rise method.
  • Du nouy ring method.
  • pendent drop method
  • sessile drop method

Dissolution Test Methodology

• Subjecting the dosage form to specific conditions to induce drug release (conditions include selection of apparatus and dissolution medium) according to monograph in pharmacopeia

Apparatus

• Apparatus 1: Rotating basket. Dosage form: Suppositories
• Apparatus 2: Paddle. Dosage form: Suspension, disintegrating tablet, chewable tablet, suppositories, liquid filled capsule
• Basket and paddle usually rotate at 50 rpm

Dissolution Medium

• Must ensure sink condition, and stability of drug
• Temperature is 37 for oral formulation, 32 for topical formulations.
  • Biorelevant medium:
    1. Simulated gastric fluid: pH 1.2, NaCl, HCI, deionized water to 1 L
    2. Simulated intestinal fluid: pH 6.8, KH2PO4, NaOH, deionized water to 10 L
    3. Other: 0.1 N HCI, buffer, alcohol, aqueous
• Dissolution test is discriminatory (capable of reflect change in drug release profile related to change in drug product).
• Dissolution test simulate in vivo condition not mimic them.
• In vitro in vivo correlation studies, dissolution medium should be biorelevant.
• Dissolution and Solubility Not interchangeable.

Solute Transfer into Solution

• Maximum amount of solute mass in specific volume.
• Calculate dissolution rate of hydrophobic drug with Surface area 2.5 cm², Saturated Solubility = 0.35 mg/ml, Diffusion Coefficient 1.75 × 10⁻⁵ cm²/sec, thickness of diffusion layer 1.25 μm. Conc of drug in bulk = 2.1X10⁻⁴ mg/ml
• Answer: dm = DS (CS-C)
  • $= \frac{(1.75 \times 10^{-5}) \cdot 2.5 \cdot (0.35 - 2.1 \times 10^{-4})}{1.25 \times 10^{-4}}$
  • Convert μm to cm

Surface Tension Problem

• Surface tension of liquid A is 74 dyne/cm, liquid B is 38 dyne/cm, and interfacial tension between the two liquids is 12 dyne/cm. Which of 2 liquids spread over the other?
• Answer:
  • $S<em>a = \gamma</em>b - (\gamma<em>a + \gamma</em>{ab}) = 38 - (74 + 12) = -48$
  • $S<em>b = \gamma</em>a - (\gamma<em>b + \gamma</em>{ab}) = 74 - (38 + 12) = 24$
  • Liquid B spreads on liquid A
• When a substance like oleic acid is placed on the surface of water, it will spread as a film if the force of adhesion between oleic acid and water is greater than cohesive forces between oleic acid molecules themselves.

Relation Between Molecular Structure & Spreading Coefficient

• As the carbon chain of oleic acid increases, the ratio of polar to non-polar decreases, and the spreading coefficient on water decreases.
• Many non-polar substances, such as liquid petrolatum, fail to spread on water.
• Benzene spreads on water, not due to its polarity, but because cohesive forces between its molecules are much weaker than the adhesion of water.

Wetting (Solid-Liquid Interface)

• It is the process of liquid spreading on a solid surface by displacing the air layer surrounding solid particles.
• $S = \gamma \cdot (\cos \theta - 1)$
• Wetting occurs if S has a (+ve) sign or zero.
• Contact angle $\theta$: Angle between liquid droplet and solid surface (0 to 180).
  • As contact angle decreases, wetting increases
  • As contact angle increases (90 or more), wetting decreases (problem in suspension)
• Example of hydrophobic (non-wetting) drugs: Mg, Al stearates, salicylic acid, phenylbutazone, chloramphenicol palmitate.

Colligative Properties

• Solution = Solute + Solvent
  • Solution Homogenous mixture of two or more Substances.
  • Solute Substance being dissolved.
  • Solvent Substance that solute being dissolved in.
• Physical properties:
  • Note Sugar Solution - Salt Solution with same number of particles. Difference between them is due to Non-Colligative properties.

Colligative Properties

• Colligative properties collected together depend on number rather than the nature of Constituents.
• Non-Colligative properties. taste, Color, Viscosity, Solubility, Surface tension.

Vapor Pressure

• V.P pressure exerted by vapor of liquid at equilibrium State with the liquid at a given temp.
• When there is a lid on the container containing liquid, the gas phase molecules are trapped vapor. Molecules in the vapor phase collide with walls & create pressure vapor pressure.
  • Evaporation rate = condensation rate equilibrium
  • Change in temperature, changes the evaporation rate, thus changes pressure. Thus, vapor pressure is temperature dependent
• Vapor above Solution is provided by Solvent (not Solute)
• Solute block Solvent from escaping into vapor tendency of solvent to exert vapor pressure decrease in up proportional to the number of Particles of Solute
• The vapor pressure of Solution is directly Proportional to the mole fraction of Solvent ($X<em>{solvent}$) $P</em>{solution} = P<em>{solvent} \times X</em>{Solvent}$ *Example:
  • The vapor pressure of an aqueous solution is 24.90 mmHg at 25 °C. what is the mole fraction of solute in this solution. The vapor pressure of water is 25.756 mmHg at 25 °C
  • $P<em>{solution} = P</em>{solute} \times X_{solvent}$
  • $24.9 = 25.756 \times X_{solv}$
  • $X<em>{solv} = 0.967 \rightarrow X</em>{solute} = 0.03$

Effect of Solute Type

*Electrolyte lowering the V.P is higher compared to non-electrolyte (Ex: Nacl – glucose)

• 2Jons(electrolyte) > 1 Particle(non electrolyte)

Pharmaceutical Applications of Surface Active Agents (SAA)

• Solubilization
  • Iodine + non-ionic SAA = iodophore used in instrument sterilization.
  • Non-ionic SAA (polysorbate) increase solubilization of steroids, and oily vitamins .
• Wetting Agent: SAA lowers the contact angle so aiding in displacing the air phase at surface and replace it by a liquid phase EX: formulation of suspensions (sulfur and charcoal), skin sprays, and lotions.
• Emulsifiers (O/W HLB 8-16) (W/O HLB 3-6)
• Lung (Pulmonary) SAA:
  • Mixture of proteins and lipid as phosphatidylcholine decrease surface tension between air and alveoli to zero so prevent collapse of alveoli and decreasing pressure, preventing pulmonary edema, allowing us to breathe.
  • Premature infants have only 1/20 of SAA needed to breathe, so artificial lung SAA must be administered.
• Foaming agent as detergent and shampoo

Relationship Between Molecular Structure, Spreading Coefficient & Carbon Chain Length

• Capillary rise method:
  • A capillary tube is placed in a liquid; liquid rises up to a certain distance because the adhesive force between liquid molecules and the capillary wall is greater than the cohesive force between the liquid, so the liquid wets the wall, spreads on it, and rises upward.
  • By measuring the rise obtain surface tension, not interfacial tension.
• $\gamma = 0.5 \cdot r \cdot h \cdot \rho \cdot g$
  • $\gamma$: surface tension of liquid
  • r: radius of the capillary tube
  • h: liquid height in the capillary
  • $\rho$: density of liquid
  • g: gravity due to acceleration
    Example:
• Calculate surface tension of chloroform by capillary rise method, a sample of chloroform raised to height of 3.67 cm at 20 c in the capillary having inside radium 0.01 cm. what is the surface tension of chloroform at this temperature. The density of chloroform is 1.476 g/cm³
• answer:
• $$\gamma = 0.5 \cdot 0.01 \cdot 3.67 \cdot