DDS Lecture 3 Content

Colloid

• mixture in which one substance consisting of microscopically dispersed insoluble particles is suspended throughout another substance.

• derived from Greek word for glue

• ex. smoke from fire, gem stones, milk

Pharmaceutical examples of colloids

• hydrogels

• micro-particles

• emulsions

• suspensions

• liposomes

• nanoparticles

• nanocrystals

Blood as a complex dispersion

• dispersion medium: plasma (90% water)

• dispersed phase: peptides, cells, proteins

Attractive forces

cause molecule to cohere

repulsive forces

prevent molecular interpenetration

Molecular Dispersions

• particles less than 1nm

• invisible in EM

• pass through ultra filter and semipermeable membrane

• rapid diffusion

• ex. Oxygen molecules, ordinary ions, glucose in water

Colloidal dispersions

• particles 1nm-0.5 mcm

• detected by ultra EM

• pass through filter paper

• do not pass semipermeable membrane

• diffuse very slowly

• ex. colloidal silver solutions, polymers, jelly, milk, paint, shaving cream

Coarse dispersions

• particles greater than 1 mcm

• visible under microscope

• do no dialyze through semipermeable membrane

• do not diffuse

• ex. most pharmaceutical emulsions/suspensions

• red blood cells

Dialysis

• uses semi-permeable membrane to separate and obtain sub-colloidal material and free from colloidal contamination

• when kidneys fail, dialysis removes colloidal material from blood

  • keeps body in balance by removing waste, salt, and extra water from building up in body

  • keeps safe level of potassium, sodium, and bicarbonate in blood

  • help control blood pressure

Ultrafiltration

• separate and purify colloidal material

• pressure-driven barrier for suspended solids, bacteria, viruses, endotoxins, and other pathogens

• produces water with high purity and low silt density

• variety of membrane filters in which hydrostatic pressure forces liquid against semi-permeable membrane

Electrodialysis

• movement of ions is aided by electric field applied across semi-permeable membrane

• driving force: electrical potential (positive charge attracted to negative charge)

Reverse Electrodialysis

• driving force: concentration difference

• movement of ions based on concentration gradient

Shapes of Colloidal Particles

• spheres and globules

• short rods and prolate ellipsoids

• oblate ellipsoids and flakes

• long rods and threads

• loosely coiled threads

• branched threads

Colloidal particle behavior

• in friendly environment, unrolls and exposes maximum surface area

• under adverse conditions, rolls up and reduces exposed area

Properties of colloidal particles affect

1. flow

2. sedimentation

3. osmotic pressure

4. pharmacological action

Environment of colloidal particle dictates the shape and form of the colloidal particle. This physical property is important for the stability of the pharamaceutical drug. However, the efficacy of pharmacological activity is not directly dependent on the physical nature. (T/F)

Flase

Solid sol

solid in solid colloid

ex. pearls, opals

Solid emulsion

liquid in solid colloid

ex. cheese, butter

solid foam

gas in solid colloid

ex. pumice, marshmallow

sol, gel

solid in liquid colloid

ex. jelly, paint

emulsion

liquid in liquid colloid

ex. milk, mayonnaise

foam

gas in liquid colloid

ex. whipped cream, shaving cream

solid aerosols

solid in gas colloid

ex. smoke, dust

liquid aerosols

liquid in gas colloid

ex. clouds, mist, fog

Can gas in gas form colloid?

No, gas-in-gas always produces solution

Lyophilic Collloids

• systems containing particles that interact to an appreciable extent with the dispersion medium

• solvent loving

• ex. dissolution of acacia or gelatin in water = sol formation

• dispersed phase consists of large organic molecules lying within colloidal size range

• molecules of dispersed phase are solvated

• molecules disperse spontaneously to form colloidal systems

• viscosity of the dispersion medium is increased greatly by presence of dispersed phase

• dispersion is stable in presence of electrolytes

• may be salted out by high concentration of soluble electrolytes

Solvation

attachment of solvent molecules to the molecules of dispersed phase

Lyophobic colloids

• materials have no attraction for dispersed medium

• solvent-hating colloids

• ex. inorganic particles in water (silver, gold, sulfur

• preparation methods:

  • coarse particles reduced in size

  • aggregates into particles of colloidal range (condensation)

• dispersed phase consists of inorganic particles

• little interaction between particles and dispersion medium

• material does not disperse spontaneously

• viscosity of dispersion medium is not greatly increased by the presence of lyophoic colloidal particles

• unstable in presence of electrolytes

Amphiphilic

• association colloids

• amphiphiles/surface active agents have 2 distict regions of opposing solution affinities

• can be anionic, cationic, nonionic, or ampholytic

• dispersed phase consists of aggregates (micelles) of small organic molecule (below colloidal range)

• colloidal aggregates formed spontaneously when concentration of amphiphile excess critical micelle conc

• viscosity of system increases as conc of amphiphile increases as micelles increase in number and become asymmetric

• in aqueous system, critical micelle con reduced by addition of salt (salting out)

Faraday Tyndall Effect

• when strong beam of light is passed through a colloidal solution, a visible cone, rsesulting from the scattering of light by colloidal particles, is formed

• optical property of light depends on:

  • size, shape, and molecular weight of colloids

Kinetic Properties of Colloids

• brownian motion

• diffusion

• osmotic pressure

• sedimentation

• viscosity

Brownian Motion

• random movement of colloidal particles

• velocity of particle decreases with particle size

• increase in viscosity of medium decreases Brownian movement

Diffusion

• Fick’s law of diffusion

• particles diffuse from region of higher concentration to lower concentration until system is uniform

• direct result of Brownian motion

Osmotic Pressure (pi)

Osmotic pressure of dilute colloidal solution is described by van’t Hoff equation

pi=cRT

c= molar concentration of solute

R=gas constant

T=temperature

Sedimentation

• velocity of sedimentation of spherical particle having density p in medium p0 and viscosity no is given my stoke’s law

• g= acceleration due to gravity

Donnan Membrane Equilibrium

• equilibrium that exists between two solutions that are separated by a membrane

• membrane constructed so that it allows passage of certain charged components of solution

• the presence of a charged impermeant ion (for example, a protein) on one side of a membrane will result in an asymmetric distribution of permeant charged ions.

Pharmaceutical Applications of Colloids

• extensively used for modifying properties of pharmaceutical agents

• most commonly affect solubility of drug

• colloidal forms exhibit different properties than traditional forms

• used as drug deliversy systems

Advantages of Colloidal formulations/State

• some medications found to possess unusual or increased therapeutic property

  • colloidal silver chloride, silver iodide, silver protein are effective germicides without irritation

  • colloidal copper used for cancer tratment

  • colloidal gold as diagnostic agent

  • colloidal sulfur has higher potency than coarse powder

Hydrogels

• colloid

• dispersion medium=water

• dispersed phase= solid

• natural and synthetic gels used for wound healing, scaffolds for tissue engineering, sustained release delivery systems

Disadvantages of Hydrogels

• designing useful environmentally sensitive hydrogels

• slow repsonse time

• limited biocompatibility

• biodegradability

Microparticles

• 0.2-5 mcm loaded microspheres of natural of synthetic polymers

• developed as carriers for vaccines and anticancer drugs

• increase efficacy and release profiles, drug targeting

• non-traditional routes of drug administration

• can be used to use mucosal route of administrationg for immunzation

Emulsions/Micro-emulsions

• excellent potential drug delivery systems

• improved drug solubilization

• long shelf life

• easy to prepare and administer

• 3 distinct types: oil external, water external, middle phase used for drug delivery depending on drug and site of action

• Microemulsion: used for controlled release and targeted delivery

  • ex. oligonucleotides

Liposomes

• easily utilized by cells

• hydrophilic head and lipophilic tail

• liquid compartment inside bilayer

• uses:

  • antibodies, proteins, sugars (drug targeting)

  • chelation therapy for heavy metal poisoning

  • enzyme replacement

  • diagnostic imaging (tumors)

  • cosmetics

Micelles

• biocompatible

• delivers poorly soluble hydrophobic drugs

• similar to liposomes but without liquid core (no bilayer)

• uses:

  • low molecular mass drugs

  • polypeptides

  • DNA

  • polycation based gene drug delivery (polyplexes)

Nanoparticles

• submicroscopic colloidal drug carrier systems

• composed of oily or aquaeous core surrounded by thine polymer membrane

• used for non-viral gene delivery systems

Nano-crystals

• inorganic nanostructures

• size <10nm

• use of semiconductor quantum dots as fluorescent labeling

• targeted delivery to blood vessels and lung tissues

The major difference between liposomal drug delivery and Micelles is that one form contains liquid core and the other does not (T/F)

True, Liposomes have liquid core

Interfacial tension

the force causing each liquid to resist breaking up into smaller particles when the liquid is in contact with a second liquid in which it is insoluble and immiscible

Gibbs Free Energy

W=ΔG=ΔAγ

Δ is the size of change in G and A

A is the total surface area of dispersed particles

 γ is the surface interfacial tension

Dimensions of Surface Tension

γ=ΔG/ΔA = erg/cm2 = dyne/cm

Affect of agitation on liquid-liquid systems

• distributes dispersed phase throughout dispersion medium

• when agitation is stopped, the drive to reduce interfacial free energy results in dispersed phase forming spheres which coalesce

Molecular forces in interface

• molecules in bulk exposed to symmetrical force field

• molecules in interface pulled into bulk to minimize interfacial area

To stabilize emulsions…

reduce free energy by reducing interfacial tension

Cohesion

The attraction between molecules or atoms of the same substance.

W_C=γ_L+γ_L=2γ_L

Adhesion

The attraction between molecules of different chemical substances

For solid-liquid systems:

W_A=γ_L+γ_S-γ_LS

Spreading of a liquid on a solid

occurs when work of adhesion exceeds work of cohesion

S= spreading coefficient

S= WA-WC

S=γ_S-γ_L-γ_LS

Molecular Forces in the Liquid/Vapor Interface

• dispersion force interactions across interface are possible

• low density of gas means few molecules are close enough to interact

Molecular Forces in liquid/liquid interface

• dispersion force interactions across interface possible

• higher density of liquids means molecules are close enough to interact

• diminished pull of interfacial molecules into bulk of each phase

Why does surfactant lower surface tension?

• amphiphilic

• locate preferentially at interface, decreasing difference between two phases

• less tension because polar heads interact with polar phase, nonpolar region interact with nonpolar phase

Wetting

• when surface tension (cohesion) is greater than attractive forces on surface, liquid will not wet surface

• when attractive forces to surface (adhesion) exceed surface tension, liquid wets surface

Rheology

• study of mechanical properties of condensed matter (in particular, complex fluids)

• derives from greek “to flow”

• concerned with deformation of matter under stress

Newtonian liquid

• linear relationship between shear rate and stress

• constant viscosity

• velocity gradient/rate of shear (dv/dr) is difference of velocity dv between two planes of liquid separated by distance dr

• force (F’/A) applied to top layer that is required to result in flow (rate of shear, G) is called shearing stress (F)

• plot of F vs G = rheogram

• newtonion fluid rheogram will be straight line with slope of line being viscosity

Non-Newtonian liquid

• nonlinear relationship between shear rate and stress

• change in viscosity with increasing shear rates

• plastic, pseudoplastic, dilatant flow

• colloidal solutions, emulsions, liquid suspensions, ointments

Viscosity

• expression of resistance of a fluid to flow

• higher viscosity=higher resistance

• η

• unit = poise

  • most convinient unit = centipoise (cP)

  • 1 cP = 1 mPa*s

  • PA=kg*m/s²=N/m²

Plastic Flow

• substances that exhibit plastic flow are called Bingham bodies

• flow does not begin until shearing stress corresponding to certain yield value is exceeded

• Materials are elastic below yield value

• η_P= (F-f)/G

  • f= yield point

Pseudoplastic flow

• begin flow when shearing stress is applied

• rate of shear increases with increasing shearing stress

• shear-thinning systems

• viscosity decreases with added force

• polymers align along long axis with additional force

Dilatant Flow

• increase in volume when sheared

• viscosity increases with increasing shear rate

• shear-thickening systems

• high percentage of solids in formulation

• particles must expand to get past each other

Thixotropic flow

• used in some pharmaceutical formulations

• reversible gel-sol transformation

• upon setting, network gel forms and provides rigid matrix that will stabilize suspensions and gels

• when stressed (shook), the matrix relaxes and forms a sol with the characteristics of a liquid dosage form for ease of use

Anti-Thixotropic

• Rheopectic

• liquids or gases whose viscosity increases with stress over time

• increases upon increasing shear stress

• ex. some gypsum pastes, lubricants

Viscosity and Formulation

• higher viscosity = higher stability

  • slower settling

• higher viscosity = more difficult to dispense

Importance of viscosity in fluids

• mixing

• particle size reduction of disperse systems with shear

• passage through orifices

• fluid transfer

• physical stability

Important of viscosity in semi-solids

• emulsions, pastes, suppositories, tablet coatings can flow/deform

• spreading and adherence on skin

• removal from jars or extrusion from tubes

• capacity of solids to mix with immiscible liquids

• release of the drug from the base

Importance of viscosity in processing

• production capacity and power requirements of equipment

• manufacturing equipment fitted with strain gauges to permit monitoring of torque measurements

Viscosity measurements

• cone and plate for semisolids

• viscometer for liquids