Pharmaceutics 1: Colloidal Stability & Suspensions PDF

Pharmaceutics 1 Pharmaceutics Colloidal stability: suspensions Dr Maria Marlow  Aims of this lecture ▪To understand why physical instability occurs in disperse systems ▪To be able to describe the electrical double layer that surround particles in aqueous electrolyte solutions and the forc...

Pharmaceutics 1 Pharmaceutics Colloidal stability: suspensions Dr Maria Marlow  Aims of this lecture ▪To understand why physical instability occurs in disperse systems ▪To be able to describe the electrical double layer that surround particles in aqueous electrolyte solutions and the forces between particles that govern physical instability ▪To be able to describe how electrolyte concentrations effect the electrical double layer, repulsive forces and physical instability in disperse systems ▪To know the how valency of electrolytes can influence the flocculation of disperse systems 2 References Physiochemical Principles of Pharmacy: In Manufacture, Formulation and Clinical Use: Chapter 6 Florence and Attwood Aulton’s Pharmaceutics: Chapter 2:Scientific principles of dosage form design 3  Disperse systems –colloids (recap from year 1) A colloid is a disperse system in which one phase is in the form of tiny particles or droplets. A liquid-in-liquid colloid is an emulsion system A solid-in-liquid colloid is called a suspension 4  Physical instability- what you observe in practice for suspensions? (recap year 1) Physical signs of instability are sedimentation & caking Cake Uniform Particles fall due Cake: a high suspension to density density sediment of differences. particles. Redisperse by Difficult to 5 shaking redisperse.  Flocculation: what is happening to individual particles? Flocculation Particles/droplets cluster together in a open structure Particles/droplets maintain their individual identity Can be redispersed to single particles/droplets by shaking Flocculation is desirable in a formulation to prevent caking 6 Coagulation: what is happening to individual particles? ▪ Coagulation Small aggregates form Attractive forces between particles/droplets very strong Cannot be redispersed to single particles by shaking Permanent failure of the medicine – “cake” 7  Forces Acting on Particles In Disperse Systems ▪Particles of less than about 2 microns diameter are constantly moving due to Brownian motion ▪The kinetic energy of the particles will be dependent on temperature and external forces (eg shaking) ▪As particles approach they experience ▪Forces of repulsion due to electrostatic interactions ▪Energy of electrostatic repulsive interaction = VR ▪Forces of attraction due to van der Waals forces ▪Energy of attractive interaction due to Van der Waals forces =VA ▪Steric forces if they have a non-ionic surfactant on their surfaces Energy of steric interactions (hinderance) = VS ▪These energies combine to determine the overall potential energy VT VT = VA + VR + VS 8  DVLO Theory The theory of the balance between electrostatic repulsion and attractive forces was proposed by Deryagin Landau Verwey Overbeek Consider the case of charged particles. We can ignore VS and simplify the equation VT = VA + VR 9  Forces Acting on Particles In Disperse Systems VT = VA + VR All of the above forces vary with particle separation distance We need to understand these forces and how they act on particles When the particles are widely separated the forces are weak, but get stronger as the particles get closer. To describe them we use a potential diagram - a graph of the force (V) against particle separation (H) 10  Attractive force VA Particle separation = H Particle Radius = a ▪ VA = -Aa/12H ▪ Note this means VA changes as a function of 1/H ▪ Where A is a constant of proportionality (the Hamaker constant) which depends on the particle material and the suspending fluid 11  Attractive force VA Repulsion Potential Energy V Particle separation = H Note – very sharp increase in attraction at small separations Even at big separations there is a small Attraction attractive force 12  Repulsive Forces VR ▪Consider the distribution of charges around a particle in a colloid ▪Most colloidal particles are charged ▪The source of the charge is one of: ▪Ion Dissolution ▪Ionic substances (eg drugs) acquire charge by uneven dissolution of oppositely charged ions. If more cations dissolve then the surface becomes negatively charged. ▪Ion Adsorption ▪For example surfactants 13  Repulsive forces VR due to charge The distribution of charges around a particle is complex because we must consider the role of electrolytes in the liquid phase around the particle Most colloids will be formed with water as the liquid phase. Most water sources containing electrolytes that provide H+, Na+, K+, Mg2+, Ca2+, OH-. These ions will be attracted to or repelled from the charged surface of the colloid particle These ions will be attracted to or repelled from the charged surface of the particle to form an electrical double layer (Stern layer and Gouy-Chapman layer) Electrostatic repulsive force/energy (VR) as a result of the interactions of the electrical double layer 14 Charge Distribution (1) Normal ion distribution Surface of Shear Stern Plane - - - - - - - - - - - - - - - - - - - Gouy-Chapman Double Layer Charged surface of particle  - Charge Distribution (2) - - - - - - - - - - - - - Surface potential (o) Net Charge or Potential Stern potential (d) Zeta potential (z) = Debye-Huckel Constant Debye-Huckel Length (1/) Distance  Repulsive Forces VR (1) ▪Electrostatic forces are repulsive for particles with the same charge ▪The potential is complex and there are a number different ways to describe it. A useful approximation is: VR = 2a(exp−) Where:  = permittivity of liquid  = Debye-Huckel constant a = particle size 17  Repulsive Forces VR (2) VR = 2a(exp−) Note that VR is proportional to exp(-H) This means the value of VR falls rapidly to zero Note that VR is also proportional to yo – So if we have a high density of ionic surfactant at the surface of our droplet we will create a lot of repulsion between neighbouring droplets 18  Repulsive Forces VR (3) Repulsion Potential Energy V Does not increase sharply at close separations Repulsion force reaches zero Particle separation = H Attraction 19  Total Potential Energy of Interaction Repulsion Primary Maximum Potential Energy V Repulsive barrier to aggregation Secondary Minimum Weak Attraction = Flocculation Particle separation = H Primary Minimum Permanent aggregation of particles= cake 20 Attraction  Effect of Kinetic Energy Kinetic energy = low Repulsion Primary Maximum too great a barrier Kinetic energy =high Particle has insufficient energy to continue Primary Maximum is its path towards neighbouring particle insufficient to stop Particle also has insufficient energy to particle escape the secondary minimum RESULT - RESULT - FLOCCULATION COAGULATION Potential Energy V Particle separation = H Kinetic energy = intermediate Primary Maximum too great a barrier Particle has insufficient energy to continue its path towards neighbouring particle Particle also escapes the secondary minimum (brownian motion) RESULT – STABLE COLLOIDAL FORMULATION 21 Attraction Exercise Draw a particle surface with positive charge & anions (negative ions) attracted to the surface You have 5 mins  Repulsive Forces VR: Now the Complex Bit! VR = 2a(exp−) ▪VR decreases with increasing particle separation (H) but VR also decreases with increasing  ▪Remember that k is the Debye-Huckel Constant and 1/  is the Debye- Huckel Length ▪So if the Debye-Huckel Length decreases, the Debye-Huckel Constant increases and VR decreases. ▪Why would the Debye-Huckel Length change? 23  Changing the Debye-Huckel Length (1) Charge Distribution: Intermediate [electrolytes] - - - - - - - - - - - - - - - - - - - Debye-Huckel Length (1/)  Changing the Debye-Huckel Length (2) Charge Distribution: Low [electrolytes] - - - - - - - - - - - - - - - - - Debye-Huckel Length (1/)  Changing the Debye-Huckel Length (3) Charge Distribution: High [electrolytes] - - - - - - - - - - - - - - - - - - - - - - - - - - Debye-Huckel Length (1/)  Effect of high electrolyte concentration on the electrical double layer Particle Particle Electrical double layer Repulsion experienced when electrical double layers overlap No repulsion until the particles get very close Effect of  on VR High [electrolytes] = Small 1/  = Large   Effect of low electrolyte concentration on the electrical double layer Particle Particle Electrical double layer Repulsion experienced at large particle separations Effect of  on VR Low [electrolytes] = Large 1/  = Small   Effect of electrolyte concentration on VR Repulsion Intermediate electrolyte concentration Potential Energy V Low electrolyte concentration High electrolyte concentration Particle separation = H Attraction  Effect of low electrolyte concentration on VT Repulsion Low [electrolyte] Big primary maximum Potential Energy V No secondary minimum STABLE FORMULATION EVEN AT HIGH KINETIC ENERGY Particle separation = H Attraction  Effect of intermediate electrolyte concentration on V T Repulsion Intermediate [electrolyte] Potential Energy V Primary maximum and secondary minimum STABLE FORMULATION Particle separation = H Attraction  Effect of high electrolyte concentration on VT Repulsion High [electrolyte] Potential Energy V No primary maximum! Attraction at all H values UNSTABLE FORMULATION AT ALL KINETIC ENERGIES Particle separation = H Attraction  The Effect of Multivalent Ions ▪DLVO theory is an over simplification ▪OK for monovalent ions eg Na+ ▪SCHULTZE-HARDY RULE states that the flocculating power of ions is proportional to the sixth power of their charge i.e. monovalent :divalent : trivalent = 1 : 64 : 729 ▪e.g. if 1 Mole of sodium flocculates a particular colloid => only 1.4 millimoles (0.0014 Moles) of trivalent aluminium will be needed ▪Therefore, for many disperse systems the addition of divalent and trivalent ions must be avoided  Lecture summary ▪Forces of attraction and repulsion between particles can explain physical instability of particles/droplets according to the DVLO theory ▪Electrolyte concentrations alter the thickness of the electrical double layer i.e Debye-Huckel Length → forces of repulsion ▪Effect of k on VR High [electrolytes] = Small 1/ k = Large k (Aggregation) Low [electrolytes] = Large 1/ k = Small k (Stable formulation even at high kinetic energy) Many disperse systems the addition of divalent and trivalent ions must be avoided