Pharmaceutical Suspensions Notes

Pharmaceutical Suspensions

Classification of Suspensions

• Based on the proportion of solids, suspensions are empirically classified as:

  • Dilute suspensions: Solid content 2 - 10 %
    • e.g., Cortisone acetate and prednisolone acetate suspension.
  • Concentrated suspensions: Solid content 10 - 50 %
    • e.g., Zinc oxide suspension for external use, Procaine penicillin G injection, Antacid suspension, etc.

• Depending on the nature and behavior of solids, suspensions are classified as:

  • Flocculated
  • Deflocculated

Deflocculated Suspension

• In this system, solids are present as individual particles.

Flocculated Suspension

• In this system, particles aggregate themselves by physical bridging.
• These flocs are light, fluffy conglomerate which are held together by weak van der Waal’s forces of attraction.
• If the aggregate is an open network it is called floccule.
  • They are fibrous, fluffy, open network of particles.
  • It is loosely packed after sedimentation.
• If the aggregate is a closed one - it is called coagule.
  • They are tightly packed, produced by surface film bonding.

Comparison Between Deflocculated and Flocculated System

Factors Affecting the Stability of a Suspension

Settling in Suspensions - Brownian Movement

• Brownian movement of particles prevents sedimentation.
• In general, particles are not in a state of Brownian motion in pharmaceutical suspensions due to:
  • Larger particle size (Brownian movement is seen in particles having a diameter of about 2 to 5 $µm$ depending on the density of the particles and the viscosity and density of the suspending medium.
  • Higher viscosity of the medium.

Sedimentation

• The rate of sedimentation of particles can be expressed by Stoke’s Law using the following formula:

  • $Sedimentation rate = \frac{d^2 (ρ<em>s - ρ</em>l)g}{18η}$
    • Where:
      • $d$ is the particle diameter
      • $ρ_s$ is the density of the particle
      • $ρ_l$ is the density of the liquid
      • $g$ is the acceleration of gravity
      • $η$ is the viscosity of the medium

• Stock’s law is applicable if:

  • Particles are spherical; but particles in the suspension are largely irregular.
  • Particles settle freely and independently.

• In suspensions containing 0.5 - 2 % (w/v) solid, the particles do not interfere with each other during sedimentation - hence free settling occurs.

• Most pharmaceutical suspensions contain 5 - 10 % or higher percentages of solid. In these cases, particles interfere with one another as they fall - hence hindered settling occurs and Stoke’s law no longer applies.

• Stoke’s law is applicable to deflocculated systems because particles settle independently.

• However, this law is useful in a qualitative manner in fixing factors which can be utilized in the formulation of suspensions.

Stoke’s Law Interpretation

1. Particle Size

• Rate of sedimentation $∝$ (diameter of particle)$^2$
• So smaller the particle size more stable the suspension.
• The particle-particle interaction results in the formation of floccules or coagules where the sedimentation rate increases.
• The particles are made fine either by dry milling prior to suspension or wet- milling of the final suspension in a colloid mill or a homogenizer.

2. Viscosity of the Medium

• According to Stoke’s law: Rate of sedimentation $∝$ 1 / (viscosity of the medium)
• The viscosity of suspension should be optimum.
• Viscosity can be increased by adding suspending agents or thickening agents.
• Selection of high viscosity have both advantages and disadvantages.

Advantages

• Sedimentation rate is retarded, hence enhances the physical stability of the suspension.
• Inhibits crystal growth because movement of particles is diminished.
• Prevents the transformation of metastable crystals to stable crystals.

Disadvantages

• Redispersibility of the suspension on shaking is difficult.
• Pouring out of the suspension from the container may be difficult.
• Creates problems in the handling of materials during manufacture.
• May retard absorption of drugs from the suspension.

3. Density

• Rate of sedimentation $∝$ (density of solid - density of liquid medium)
• Lesser the difference between the densities of solid particles and liquid medium slower is the rate of sedimentation.
• Since it is very difficult to change the absolute density of the solid particles so the density of the liquid medium can be manipulated by changing the composition of the medium.
• The addition of nonionic substances such as sorbitol, polyvinylpyrrolidone (PVP), glycerin, sugar, or one of the polyethyleneglycols or combination of these may be helpful in the manipulation.
• If the density of the particles is greater than the continuous medium the particles will settle downwards, the phenomenon is known as sedimentation.
• If the density of the particle is lesser than that of the liquid medium then the particles will move upward - the phenomenon is known as creaming.

Formulation of Suspensions

General Requirements

• The product must:
  1. Flow readily from the container
  2. Possess a uniform distribution of particles in each dose.

Approaches

• Two approaches are commonly employed to secure the two requirements:
  1. The use of structured vehicle to maintain deflocculated particles in suspension.
     • Structured vehicles are pseudoplastic and plastic in nature.
     • It is frequently desirable that thixotropy be associated with these two types of flow.
     • Structured vehicles act by entrapping the particles so that, ideally, no settling occurs.
     • In reality, some degree of sedimentation will usually take place.
     • The shear thinning property of these vehicles does however facilitate the redispersion when shear is applied.
  2. The application of the principles of flocculation to produce flocs that, although they settle rapidly are easily redispersed with a minimum of agitation.

Wetting of Particles

• The initial dispersion of an insoluble powder in a vehicle is an important step in the manufacturing process.
• Powders sometimes are added to the vehicle, particularly in large scale operations, by dusting on the surface of the liquid.
• It is frequently difficult to disperse the powder owing to an adsorbed layer of air, minute quantity of grease and other contaminants.
• Powders those are not easily wetted by water and accordingly show a large contact angle, such as sulfur, charcoal and magnesium stearate are said to be hydrophobic.
• Powders those are readily wetted by water when free of adsorbed contaminants are called hydrophilic.
  • e.g. zinc oxide, talc, magnesium carbonate etc. belong to this category.
• When a strong affinity exists between a liquid and a solid, the liquid easily forms a film over the surface of the solid.
• When this affinity is non-existent or weak, the liquid faces difficulty in displacing the air or other substances surrounding the solid.
• Hydrophilic solids usually can be incorporated into suspensions without the use of a wetting agent, but hydrophobic materials are extremely difficult to disperse and frequently float on the surface of the fluid owing to poor wetting of the particles or the presence of tiny air pockets on the surface of the solid particles.
• To reduce the contact angle between solid and liquid (i.e. increase the wettability) the following agents can be used:
  1. Surfactants
     • Solid-liquid interfacial tension is reduced by incorporating a surfactant with a HLB value between 7 to 9.
     • These are employed to allow the displacement of air from hydrophobic material and permit the liquid to surround the particles and provide a proper dispersion.
     • The surfactant is mixed with the solid particles if required by shearing.
     • The hydrocarbon chain is preferentially adsorbed to the hydrophobic surface, with the polar part of the surfactant being directed towards the aqueous phase.
  2. Hydrophilic polymers such as sodium carboxymethyl cellulose, certain water-insoluble hydrophilic material such as bentonite, aluminum- magnesium silicates, and colloidal silica, either alone or in combination can be incorporated in desired concentration.
     • These materials are also used as suspending agents and may produce a deflocculated system particularly if used at low concentration.
  3. Solvents such as alcohol, glycerol and glycols which are water miscible will reduce the liquid / air interfacial tension.
     • The solvent will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles thus enabling wetting by dispersion medium.

Method of selection of a suitable wetting agent

• In order to select a suitable wetting agent Heistand has used a narrow trough, several inches long and made of a hydrophobic material, such as Teflon, or coated with paraffin wax.
• At one end of the trough is placed the powder and the other end the solution of the wetting agent.
• The rate of penetration of the wetting agent solution into the powder can then be observed directly.
• Greater the rate of penetration of the solution into the powder better is the wetting property of the solution.

Rheologic Considerations

• Rheologic consideration are important in:
  • (i) the viscosity of a suspension as it affects the settling of particles. As viscosity increases rate of sedimentation of the particles reduces.
  • (ii) the change in flow properties of the suspension when the container is shaken and when the product is poured out off the bottle.
  • (iii) the spreading quality of the lotion when applied to the affected area.
  • (iv) during the manufacture of the suspensions.

Importance of Suspending Agents

• The particles in a suspensions are experiencing bombardment constantly with each other owing to the Brownian movement.
• During this type of inter-particular interaction the particles may circumvent the repulsive force between them and form larger particles which will then settle rapidly.
• Suspending agents reduce this movement of the particles by increasing the viscosity of the medium.
• According to Stoke’s law rate of sedimentation is inversely proportional to the viscosity of medium. So the settling of the particles , either in flocculated or deflocculated system, can be slowed down by increasing the drag force on the moving particles by increasing the viscosity of the medium.
• Hydrophilic polymers such as sodium carboxymethyl cellulose, certain water-insoluble hydrophilic material such as bentonite, aluminum-magnesium silicates, and colloidal silica, either alone or in combination can be incorporated in low concentration as wetting agent.
• Hydrophilic polymers also acts as protective colloids and particles coated in this manner are less prone to cake than are uncoated particles.
• Cellulose polymers e.g. sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose.
• Proteins e.g. gelatin.
• Synthetic polymer e.g. Polyacrylic acid (Carbopol)
• Clays essentially hydrated aluminum and/or magnesium silicates are also useful in suspension formulation.

Characteristics of Ideal Suspending Agent

• (i) An ideal suspending agent should have a high viscosity at negligible shear; i.e. during shelf storage; and it should have a low viscosity at high shear rates, i.e. it should be free flowing during agitation, pouring and spreading on the skin.
• (ii) Suspending agents should coat the particles which will be less prone to caking than the uncoated particles.
• Pseudoplastic substances e.g. tragacanth, sodium alginate and sodium carboxymethylcellulose show these desirable qualities. It is a shear thinning system, i.e. when this type of system is shaken or agitated the viscosity diminishes.
• A suspending agent that is thixotropic as well as pseudoplastic should prove to be useful since it forms gel on standing and becomes fluid when disturbed. e.g. Bentonite - Carboxymethylcellulose has both pseudoplastic and thixotropic behavior.

Controlled Flocculation

• Assuming that the powder is properly wetted and dispersed, attention may now be given to the various means by which controlled flocculation may be produced so as to prevent compact sediment which is difficult to redisperse.
• Controlled flocculation can be described in terms of the materials used to produce flocculation suspensions, namely,
  • (i) electrolytes,
  • (ii) surfactants, and
  • (iii) polymers.

(i) Electrolytes

• Electrolytes act as flocculating agents by reducing the electric barrier between the particles, as evidenced by a decrease in the zeta-potential and formation of a bridge between adjacent particles so as to link them together in a loosely arranged structure.
• Example:
  • When bismuth subnitrate is suspended in water it has been found (by electrophoretic studies) that they possess a large positive charge, or zeta potential.
  • Because of the strong forces of repulsion between adjacent particles, the system remains in deflocculated state.
  • The addition of monobasic potassium phosphate (KH2PO4) to the suspension causes the positive zeta- potential to decrease owing to the adsorption of the negatively charged phosphate anion. The particles then can come closer to form aggregates.

Zeta Potential

• The zeta potential is defined as the difference in potential between the surface of the tightly bound layer (shear plane) and electro-neutral region of the solution.

(ii) Surfactants

• Surfactants both ionic and nonionic, have been used to bring about flocculation of suspended particles. The concentration necessary to achieve this effect would appear to be critical since these compounds may also act as wetting agents to achieve dispersion.

(iii) Polymers

• Polymers are long chain, high molecular weight compounds containing active groups spaced along their length. These agents act as flocculating agents because part of the chain is adsorbed on the particle surface, with the remaining parts projecting out into the dispersion medium. Bridging between these latter portions leads to the formation of flocs.
• hydrophilic polymers also acts as protective colloids and particles coated in this manner are less prone to cake than are uncoated particles.

Flocculation in Structured Vehicle

• Although the controlled flocculation approach is capable of fulfilling the desired physical chemical requisites of a pharmaceutical suspension, the product can look unsightly if F, the sedimentation volume, is not close to or equal to 1. So a suspending agent is added to retard sedimentation of the flocs.
• Such agents as carboxymethylcellulose (CMC), Carbopol 934, Veegum, tragacanth or bentonite have been employed, either alone or in combination.
• These may lead to incompatibilities, depending on
  • (i) the initial particle charge
  • (ii) the charge carried by flocculating agent and
  • (iii) the charge carried by suspending agent.