Suspensions Notes

Suspensions - Part 1

Learning Outcomes

• Discuss reasons for formulating a drug in a suspension formulation

• Discuss desirable properties of a suspension

• Discuss solid particle-liquid vehicle interactions and DLVO theory

• Discuss sedimentation and factors affecting sedimentation

• Discuss flocculation, de-flocculation and caking

• Describe dispersibility of solids

• Discuss importance of particle size and Ostwald ripening, crystal growth

• Describe how we evaluate suspensions

What are Suspensions?

• Coarse dispersions of finely divided insoluble particles.

• Most have an aqueous dispersion medium, but some use an oily/organic liquid.

• Differ from solutions and colloids in particle size:

  • Solutions: Molecular dispersion.

  • Colloids: $1 nm - 500 nm$

  • Suspensions: Usually have particles > 1\mum

Why Formulate a Suspension?

• External Application:

  • Example: Calamine Lotion.

• Internal Use:

  • Oral suspensions (e.g., antibiotic formulations).

  • Injections: Intramuscular (IM) depot injections.

  • Amoxycillin suspension:

    • Contains amoxicillin trihydrate.

    • The drug is unstable in solution.

    • The drug is poorly soluble in water.

Further Reasons to Formulate as a Suspension

• Flagyl-S Suspension:

  • Contains metronidazole benzoate.

  • The drug is extremely bitter.

  • A less soluble form is used to reduce the bitter taste.

  • It is hydrolyzed before or during absorption into metronidazole.

• Bicillin LA IM Injection:

  • Prolonged release.

  • Penicillin G is used as a benzathine salt.

  • It's poorly soluble.

  • Slowly hydrolyzed and dissolves over 3-4 weeks.

  • Used to prevent certain infections, such as rheumatic fever.

Summary: Why Formulate a Suspension?

• The drug is not sufficiently soluble to make a solution.

• The drug is unstable as a solution (chemical breakdown).

• Offers flexible dosing (0.5, 1, 2, 3 mL, etc.).

• Useful if a patient cannot swallow tablets or capsules (alternative formulation).

• Can disguise the taste of the drug.

• Allows for prolonged release (IM injection).

Desirable Features of a Suspension

• Particles should not settle rapidly.

• If settling occurs, they should re-disperse easily.

• The suspension should flow freely from the bottle.

• Should obtain a uniform dose when the bottle is shaken and remain uniform for a sufficient time.

• The particle size of the suspended solid should remain fairly constant over time.

• Should be acceptable to the patient.

Solid Particle-Liquid Vehicle Interactions

• Interactions between solid particles and the liquid vehicle determine the behavior of the suspension.

• Hydrophobic drugs will not dissolve to any great extent in water.

• Once hydrophobic drugs are dispersed in an aqueous phase, they will acquire a charge.

  • There is an inner fixed layer and an outer diffuse layer.

Factors Affecting the Electrical Double Layer

• Excipients can change the behavior of a solid particle in a suspension.

• Affect either the fixed or diffuse layer, or both.

• Adding material, such as NaCl, increases the number of mobile charges in the system.

• At low concentrations, charges are located only in the diffuse layer, causing thinning of the diffuse layer.

• Higher concentrations will affect both the diffuse and fixed layers (adsorb to the particle surface).

• The charge on the surface will decrease, therefore decreasing the Stern potential and zeta potential.

Impact of Surfactants on Electrical Double Layer

• Surfactants added at concentrations below the Critical Micelle Concentration (CMC) will localize on the particle surface.

• If above the CMC, the drug may be dissolved.

• Surfactant adsorbing to the particle surface will lead to a change in surface charge.

• May also change the sign of the charge.

• Affects the fixed layer, which changes the Stern potential and zeta potential.

DLVO Theory

• Describes the total energy of interaction (VT) between particles as the sum of the energy of attraction (VA) and the energy of repulsion (VR).

  • $VT = VR + VA$

• Energy of attraction (VA):

  • Van der Waals forces.

• Energy of repulsion (VR):

  • Electrical double layer.

• Key concepts within DLVO theory:

  • Primary minimum

  • Primary maximum

  • Secondary minimum

Primary Minimum

• Particles in the primary minimum zone show a higher energy of attraction than repulsion, making them likely to move closer.

• Particles will eventually aggregate irreversibly.

Primary Maximum

• If temperature increases, particles may have sufficient kinetic energy (Brownian motion) to overcome the barrier, become close to each other, enter the primary minimum, and coagulate.

• Formulating a suspension so that particles are in the primary maximum zone is considered risky.

• It has a high energy of repulsion, and particles here will remain separate or deflocculated.

Secondary Minimum

• The particles have an overall limited attraction to each other and behave as floccules - loose aggregates of individual particles.

• Will not collide or coalesce.

Effect of Additives

• Adding ionic or surfactant materials affects how particles behave.

• Change VA and VR.

• Low to medium concentrations of ionizable material lead to a thinner diffuse layer.

  • The secondary minimum will be deeper, and the energy barrier to escape the secondary minimum is higher.

  • Generally considered desirable for suspension (loose floccules).

• Adding surfactant below the CMC will change the surface charge.

  • The magnitude of the effect depends on the chemical characteristics of the surfactant.

Sedimentation

• Downward movement under gravity.

• Observed for particles with a radius > 0.5 \mum.

• A number of factors can influence the rate of sedimentation.

• Governed by Stoke’s Law.

Stoke's Law

• $V = \frac{2r^2( \rho<em>1 - \rho</em>2)g}{9 \eta}$

  • V = terminal velocity (cm/s)

  • r = radius of particles (cm)

  • $\rho_1$ = density of dispersed phase

  • $\rho_2$ = density of dispersion medium

  • g = acceleration due to gravity

  • $\eta$ = viscosity of medium

Factors Affecting Sedimentation Rate

• Reducing particle size has a significant effect; r is squared:

  • Halving the radius reduces the sedimentation rate by ¼.

• Density difference:

  • If the density between suspended particles and the suspension medium is matched, sedimentation could be reduced to zero.

  • Densities approaching 1.3 can be achieved by high sucrose concentrations, which is close to the density of many organic drugs.

  • Changes in temperature change the density of the suspension medium.

More Factors Affecting Sedimentation Rate

• Gravity:

  • Cannot change this.

• Viscosity:

  • Can readily control this.

  • Doubling viscosity will reduce sedimentation by a factor of 2.

  • Achieved by selection of suspending agent and changing the concentration of the suspending agent.

Rheology of Suspensions

• Almost all suspending agents have non-Newtonian flow.

• Cellulose derivatives and soluble polymers have pseudoplastic flow, which is advantageous due to shear thinning.

• Carbomers have plastic flow behavior.

  • Yield value.

  • After the yield value, shear thinning occurs.

  • Care must be taken to ensure the yield value is not too high.

Thixotropy in Suspensions

• Some suspending agents show thixotropy

  • Hysteresis loop in flow curve.

• A thixotropic fluid has a structure that is broken down by shear (as in plastic and pseudoplastic), and the rebuilding of the structure once shear stops takes a finite time.

• This is advantageous in that, as the fluid is shear-thinning, the slower structure build-up allows the fluid to be poured easily after shaking.

Flocculation and Deflocculation

• Flocculation is used to help produce stable suspensions.

• Easy to re-disperse and no caking.

• If the zeta potential is high, repulsive forces > attractive forces.

• Particles remain separated (deflocculated).

• Adding agents to lower the zeta potential lowers repulsive forces, and particles can form loose aggregates called flocs (flocculated system).

Flocculation with Electrolytes

• Adding $KH<em>2PO</em>4$ in increasing concentration reduces the charge on the surface (and hence the zeta potential).

• A point is reached where we have optimal flocculation (middle of the diagram).

• As we continue to add more $KH<em>2PO</em>4$, we see the loss of flocculation, and deflocculation re-appears as the surface charge becomes negative.

• The figure represents what happens with a suspension of bismuth subnitrate.

• When no monobasic phosphate is present, particles have a positive charge on the surface.

Flocculation - Electrolytes

• The addition of a preferentially adsorbed ion with the opposite charge to that on the particle leads to a progressive lowering of the zeta potential.

• At a certain concentration where electrical forces of repulsion are sufficiently lowered and attractive forces dominate, the particles may approach each other more closely and form loose aggregates called floccules.

• If continuously add flocculating agent, increase the zeta potential in the opposite direction and end up back at a deflocculated suspension.

Flocculation - Polymers

• Less sensitive to the addition of other electrolytes.

• More flexibility with other excipients.

• Effectiveness depends on affinity for the surface, charge, size, and orientation.

Flocculation - Surfactants

• Both ionic and non-ionic surfactants can be used.

• Ionic surfactants act similarly to electrolytes.

• Nonionic surfactants also reduce the zeta potential.

• Formation of liquid bridges between particles.

• High concentrations of nonionic surfactants can lead to deflocculation through forming a hydrated layer around particles.

Effect of Flocculation

• Deflocculated systems:

  • Separate particles of different sizes.

  • Settle at different rates.

• Flocculated suspensions:

  • Have particles of similar size.

  • Fall at the same rate, with the initial rate of settling determined by the size of the “flocs.”

Comparison of Deflocculated and Flocculated Systems

Surface Wetting

• Surface wetting of powders is required to make suspensions.

• Often necessary when using hydrophobic drugs.

• Large contact angle (high surface tension) leads to clumping.

• Reduce surface and interfacial tension using a wetting agent.

• Use surfactants at concentrations below the CMC.

Evaluating Suspensions

• Measure sedimentation volume and degree of flocculation.

• Sedimentation volume (F):

  • $F = \frac{Vu}{Vo}$

    • Vu = volume of the sediment

    • Vo = the total volume of the suspension

  • F can range from 0 to 1

Degree of Flocculation

• Degree of flocculation: $\beta$

• Relates the sedimentation volume of the flocculated suspension (F) to the sedimentation volume of a suspension that was deflocculated ($F_\infty$).

• The larger the degree of flocculation, the more flocculated the product.

Importance of Particle Size

• Influences the rate of sedimentation.

• Influences bioavailability, rate of dissolution, and absorption.

• Large particles can give a gritty feel in the mouth or on the skin.

• Affects the flowability of the powder into manufacturing equipment.

• Impacts physical stability (affects the rate of sedimentation and also caking).

• The distribution of particle size can also influence physical stability (desirable to have a narrow distribution).

Ostwald Ripening and Crystal Growth

• While most of the drug is suspended, a small amount will be in solution.

• The concentration in solution changes with temperature.

• Fluctuations in temperature can lead to Ostwald ripening:

  • The drug dissolves and then deposits on larger particles, causing these to grow in size.

  • Changes the size distribution of suspended particles.

• May produce changes in sedimentation, caking, and altered bioavailability.

Crystal Growth - Impact

• Has a negative effect on the physical stability of the suspension.

• When developing formulations, they are usually subjected to temperature cycling (repeated freeze-thaw cycles) to monitor changes in particle diameter and physical stability.

Minimizing Crystal Growth

• Use the most stable crystalline form of the drug.

• Select particles with a narrow range of sizes.

• Use a protective colloid (hydrophilic polymer) to inhibit dissolution.

• Increase viscosity to retard dissolution.

• Avoid temperature extremes during product storage.

A suspension is a coarse dispersion of finely divided insoluble particles. Suspensions usually have particles > 1\mum, while colloids have particles ranging from 1nm−500nm1nm−500nm