Suspensions in Pharmaceutical Science

Suspensions

• Dispersed systems consist of particulate matter (dispersed phase) distributed throughout a continuous medium.
• Dispersed material ranges in size from atomic/molecular dimensions to millimeters.
• "Disperse System" describes a system where one substance (dispersed phase) is distributed in discrete units throughout a second substance (dispersed medium).
• Pharmaceutical suspensions are coarse dispersions (heterogeneous systems) where the internal phase (active ingredient) is evenly dispersed throughout the external phase.
• Suspensions contain insoluble solid particles (0.5-5 microns) dispersed with a suspending agent.
• The external phase (suspending medium) is usually aqueous, but can be organic/oily for non-oral use.
• Finer particles may self-suspend if Brownian motion energy exceeds gravitational force, leading to low viscosity.
• Suspensions are used as drug products and in-process materials.

Types of Suspensions

• Colloidal Dispersion: Particle size <1 nm, visible with electron microscope; diffuse slowly (e.g., colloidal silver, cheese, milk).
• Coarse Dispersion: Particle size 0.1-0.2 µm or >0.2 µm, visible with microscope; do not diffuse (e.g., sand, pharmaceutical emulsions, red blood cells).
• Nano suspensions: Biphasic colloidal dispersions of nanosized drug particles stabilized by surfactants; particle diameter typically 10-50 nanometers.

Classification of Suspensions

• Administration:
  • Oral (e.g., paracetamol, antacid).
  • Topical (e.g., calamine lotion).
  • Ophthalmic (e.g., prednisolone).
  • Otic (e.g., hydrocortisone-neomycin-polymyxin).
  • Rectal (e.g., barium sulfate).
  • Aerosols (e.g., tolnaftate).
  • Parenteral (e.g., vaccines, insulin zinc).
• Physical State: Suspensions, Aerosols, Gels, Foams
• Proportion of solid particles: Dilute (2-10% w/v solid), Concentrated (50% w/v solid).
• Electro-kinetic nature of solid particles: Flocculated, Deflocculated

Advantages and Disadvantages of Suspensions

• Advantages*
• Improved chemical stability of certain drugs (e.g., procaine penicillin G).
• Higher bioavailability compared to other dosage forms (solution > suspension > capsule > compressed tablet > coated tablet).
• Controlled duration and onset of action (e.g., protamine zinc-insulin suspension).
• Masking of unpleasant/bitter taste (e.g., chloramphenicol).
• Disadvantages*
• Physical stability problems (sedimentation, compaction).
• Bulky nature requiring careful handling and transport.
• Formulation difficulty.
• Inaccurate dosage unless packed in unit form.

Qualities of a Good Suspension

• Uniform content.
• Low settling volume.
• Absence of API crystal growth.
• Palatability.
• Resuspendability.
• Absence of caking.
• Deliverability.
• Flow.
• Lack of microbial growth.
• Physical integrity.
• Physical stability.
• Particle adhesion to the package.
• Polymorphic integrity.
• Chemical stability.
• Drug release.

Desired Features in a Pharmaceutical Suspension

• Particles settle slowly and are readily redispersed.
• Viscosity allows easy pouring.
• Chemically and physically stable.
• Palatable (if oral).
• Free from gritting particles.
• Consistent particle size.

Reasons for Formulating a Pharmaceutical Suspension

• When the drug is insoluble in the delivery vehicle, e.g., prednisolone suspension.
• To mask the bitter taste of the drug, e.g., chloramphenicol palmitate suspension.
• To increase drug stability, e.g., oxytetracycline suspension.
• To achieve controlled/sustained drug release, e.g., penicillin procaine.

Dry Powders for Oral Suspension

• Commercial preparations consist of dry powder mixtures or granules to be suspended in water, or another oral vehicle.
• Most prepared products used for oral suspensions are antibiotics.
• These products contain the antibiotic drug, colorants, flavorings, sweeteners, stabilizing agents, suspending agents, and preservatives.

Flocculated and Deflocculated Systems

• Flocculated Suspension:

  • Weak particle bonds form flocs.
  • Rapid settling and easy re-dispersion.
  • Less prone to compaction.
  • Flocculated particles form agglomerations that resist complete settling.

• Deflocculated Suspension:

  • Strong particle bonds form a hard cake.
  • Slow settling and difficult re-dispersion.
  • Prone to compaction.

Theoretical Considerations for Suspensions

• Settling in suspensions is important to physical stability.
• Factors influencing sedimentation velocity include:
  • Theory of Sedimentation.
  • Particle size.
  • Brownian movement.
  • Interfacial properties.
  • Electrokinetic properties.
  • Sedimentation of flocculated particles.
  • Sedimentation parameters.

Theory of Sedimentation

• Sedimentation is particle or floc settling under gravity in liquid.
• Brownian motion counteracts this settling.
• Related to particle size, density, and dispersion medium viscosity.
• Stokes Equation describes sedimentation velocity.

Stoke Law

• Not applicable to irregular particles or those with hindered settling, or high concentration.
• Sedimentation velocity is proportional to d² (density difference).

Particle Size

• Critical for suspension stability.
• Reduced particle size enhances re-dispersibility and prevents caking.
• Symmetrical particles tend to be stable.
• Asymmetrical particles form hard cakes.

Density of the Vehicle

• Increasing vehicle density can reduce sedimentation velocity.
• Adding substances (polyethylene glycol, polyvinyl pyrrolidone, glycerin, sorbitol, sugar) to the vehicle increase its density.
• If the density of the dispersed phase and dispersion medium are equal, the rate of settling is zero.

Viscosity of Dispersion Medium

• High viscosity reduces settling due to increased particles' suspending time.
• Lower viscosity may pose problems with pouring, syringeability and re-dispersibility.

Viscosity of Suspensions

• Viscosity plays a key role in suspension stability and pourability.
• Increasing viscosity decreases settling rate, hence increasing stability.

Interfacial Properties of Suspended Particles

• The large surface area of solid particles results in high surface free energy thus instability.
• Flocculation (formation of flocs, light and fluffy, aggregates) occurs to reduce surface energy.
• Wetting of particles by a vehicle is crucial to disperse the solid particles.

Wetting of Particles

• Wetting agents decrease interfacial tension, allowing vehicle penetration into pores.
• Alcohol, glycerin, propylene glycol are common agents for aqueous vehicles. Mineral oil is used for non-aqueous vehicles.
• Hydrophobic particles require more effort to wet.

DLVO Theory

• Describes the stability of colloidal systems based on attractive and repulsive forces between particles.

Electrical Properties of Interfaces

• Particles often have surface charges, so surrounding ions (cations) are attracted to create the electric double layer.
• The adsorbed ions (anions) determine the surface potential.
• Adhesion / clumping of these particles is minimized with an electric double layer.

Electro-thermodynamic (Nernst) Potential

• The difference in electric potential between a particle's surface and the electroneutral region.
• Controlled by the electrical potential determined by the ions on the particle's surface.

Electrokinetic or Zeta Potential

• Potential difference between the tightly bound layer (shear plane) and the electroneutral region of the solution.
• Governs the degree of repulsion between similarly charged particles.
• A high zeta potential reduces attraction forces, preventing aggregation and enhancing stability.

Deflocculation and Flocculation

• Deflocculation: Higher zeta potential; strong repulsive forces; particles dispersed.
• Flocculation: Lower zeta potential; attractive forces surpass repulsive forces; particles form aggregates.

Potential Energy Curves

• Shows attractive and repulsive forces, and net energy, as a function of the distance of separation between particles for better understanding of flocculation or deflocculation phenomena.

Kinetic Stability of Dispersed Systems

• Brownian movement counteracts sedimentation by keeping particles in random motion.
• Brownian motion depends on particle size, density of dispersed phase and dispersion medium viscosity.
• Particle size below a critical radius is key.

Effect of Brownian Movement

• Brownian motion counteracts particle settling.
• Significant for small particles, but the effect is reduced in concentrated suspensions (large volume).

Methods for Stabilizing Suspension

• Controlling particle charges (like charges repel, preventing agglomeration), and using a solvent sheath around the particle to prevent coming close.

Sedimentation in Different Systems

• Flocculated systems: Particles tend to fall together, with a clear boundary between sediment and supernatant liquid.
• Deflocculated systems: Larger particles settle faster, without a clear boundary, depending on Stokes' law.

Sedimentation Parameters

• Sedimentation volume (F): ratio of final sediment volume (V_u) to the initial suspension (V_o) volume.
• F < 1 implies less sediment volume.
• F > 1 indicates fluffy aggregates.

The Sedimentation Behavior of Flocculated and Deflocculated Suspensions

• Diagrams show the different settling behavior of flocculated and deflocculated suspensions.

Methods for Formulation of Suspensions

• Controlled flocculation using electrolytes, surfactants, polymers
• Structured vehicles to increase viscosity
• Combining both methods

Addition of Electrolytes

• Electrolytes reduce repulsive surface charges, leading to flocculation.
• The flocculating power is strongly dependant on the valency of the ions.

Addition of Surfactants

• Surfactants reduce the interfacial tension between solid and liquid phases leading to enhanced wetting; can also control flocculation by changing the surface charge.

Addition of Polymers

• Polymers adsorb onto particles, forming a gel-like network and increasing viscosity and suspension stability through bridge formation .

Use of Structured Vehicles

• Aqueous solutions of natural or synthetic gums to increase viscosity and inhibit settling.
• This is especially useful for topical suspensions.

General Procedure for Suspension Formulation

• Reduce particle size of insoluble drug - Levigate/grind to a smooth paste in a vehicle containing a wetting agent. - Dissolve all soluble ingredients in a portion of the vehicle and add. - Gradually add more portion of vehicle to obtain a finished suspension.

Formulation of Suspension

• Some dispersed phases have high affinity with the vehicle, thus readily wetted. - Other drugs or particles require initial wetting before suspension, to prevent clumping or floating. - Liquids may be mixed in phases before or after wettability.

Flow Chart for Formulation of Suspension

• A step-by-step process demonstrating the steps in formulating and creating a suspension

Ingredients of Suspensions

• Insoluble drug.
• Vehicle (suspending medium).
• Wetting agents.
• Compounds that control stability and sedimentation (flocculating/suspending agents).
• Additives for flow (e.g. viscosity modifiers). Other additives (e.g. flavour, color, sweeteners, preservatives).

Formulation Components

• Drug: Should be uniform particle size (1-50µm), water insoluble, surface charge characteristics must be considered.
• Vehicle: Mostly distilled water, deionized water, alcohol, glycerol solution, non-aqueous vehicles (for topical use), structured vehicles (pseudoplastic or plastic).
• Wetting Agents: Surfaces must be easily wetted by the vehicle, can include surfactants, hydrophilic colloids, certain solvents.

Wetting Agents

• Hydrophilic materials are wetted by water; hydrophobic materials require non-polar liquids.
• Wetting agents (surfactants) are used to reduce interfacial tension between particles and liquid to facilitate wetting.
• Examples: sodium lauryl sulfate, polysorbate 80.

Hydrophilic Colloids

• Examples: acacia, bentonite, tragacanth, alginates, xanthan gum.
• Coat hydrophobic particles which imparts a hydrophilic character, improves wetting, and increases viscosity of water.
• Act as protecting colloids, increasing stability.

Solvents

• Materials like alcohol, glycerol, glycols, are miscible with water to reduce interfacial tension, permitting penetration into the pores of the particles and enabling wetting.
• Common used in conjunction with aqueous vehicles and for hydrophobic particles.

Flocculating Agents

• Electrolytes, surfactants, polymers.
• Electrolytes reduce particle repulsion and induce aggregation.
• Surfactants affect surface charges and induce aggregation.
• Polymers bind particles to form aggregated flocs, leading to rapid settling.

Flocculating Agents

• Suspended particles with high charge density tend to deflocculate then cake.
• Neutralizing the charged particles results in flocculation (aggregation in loose clusters).
• Flocculated aggregates settle rapidly but are easily redispersed.

Zeta Potential

• Zeta potential is a function of a particle’s surface charge.
• High zeta potential = increased repulsion between particles, better stability.
• Low zeta potential = increased attraction between particles, leading to instability.

Flocculating Agents

• Electrolytes
• Surfactants
• Polymers
• pH adjustment

Viscosity Modifiers (Suspending Agents)

• Typically hydrophilic polymers used to increase viscosity and retard sedimentation.
• Hydrophilic regions interact with suspension particle surface and gel-like network is created.

Suspending Agents

• Polysaccharides (e.g., acacia, tragacanth, alginates, and xanthan gum).
• Water-soluble celluloses (e.g., methylcellulose and hydroxypropylcellulose).
• Hydrated silicates (e.g., bentonite).
• Carbomers (e.g., carboxymethylcellulose).
• Colloidal silicon dioxide (Aerosil).

Other Additives

• Buffers: Materials that resist pH change (e.g., carbonates, citrates, gluconates, phosphates). Ideal range 7.4-8.4 for suspensions
• Preservatives: Prevent microbial growth (e.g., propylene glycol, disodium EDTA, benzalkonium chloride).
• Sweeteners/Flavors/Colorants: Enhance palatability and appearance.

Preparation of Suspensions

• Precipitation Method: Insoluble drugs are dissolved in a water-miscible organic solvent, which then gets precipitated when added to water.
• Dispersion Method: Solid particle dispersion (often using particle reduction methods) into the vehicle (which may incorporate a wetting agent).

Evaluation of Suspensions

• Sedimentation Method: Measures sedimentation volume (F) and degree of flocculation (β) to determine stability.
• Rheological Method: Evaluates viscosity changes in response to shearing forces for thixotropic properties.
• Electrokinetic Method: Measures zeta potential to assess particle stability.
• Micromeritic Method: Measures particle size changes to determine stability.

Rheology of Suspensions

• Flocculated: Plastic or pseudoplastic flow, dependent on concentration.
• Deflocculated: Dilatant flow; apparent viscosity increases with shearing stress.

Thixotropic Properties of Suspensions

• Thixotropic suspensions are viscous when stored but become fluid when shaken. They are beneficial to topical and certain oral medications, as well as certain parenteral injections.

Packaging and Storage of Suspensions

• Wide-mouth containers with adequate headspace to allow thorough mixing; tightly sealed to protect from light heat and freezing.

Other Suspensions

• Topical: Often semisolid, high concentrations of dispersed powder in a paraffin base; examples include lotions and pastes.
• Parenteral: Formulated to control drug absorption rate based on size of dispensed particles; examples include, but are not limited to, eye drops, ear drops, and even some injections.

Innovations in Suspensions

• Nano suspensions: very fine, solid drug particles suspended for oral, topical, or parenteral administrations.
• Taste-masked suspensions: Uses various ingredients that cover up the bitter taste, increasing patient palatability.
• Sustained release suspensions: Coating with polymers that slow the absorption rate of the drug.