1. Suspensions Nahed DM HEGAZY, PhD

2. Suspensions  Suspensions are dispersions of an insoluble drug or other substance in an aqueous or nonaqueous continuous phase.  The USP defines suspensions as “finely divided, undissolved drugs dispersed in liquid vehicles” and can be ready-to-use, or for reconstitution.  Pharmaceutical suspensions tend to be coarse dispersions rather than true colloids, although there are many sub-micrometre polymer dispersions available.

3. Pharmaceutical Applications of Suspensions  Preferred for patients, geriatric and pediatric, who have difficulty in swallowing solid oral dosage forms such a tablets and capsules.  Disagreeable tastes can be often overcome by purposefully limiting the amount of drug in solution and by flavoring the liquid vehicle.

4.  Prolonged action can be achieved, for example, in intramuscular injections as well as in oral suspensions.  Bioavailability is high and generally viewed in the following order for various oral dosage forms: solutions > suspensions > capsules > tablets.  Improved chemical stability compared to solutions.

5. Drugs in suspension are prepared mainly for;  oral,  intramuscular or subcutaneous use,  also used as reservoirs in transdermal patch preparations and  in conventional topical formulations.  Many pharmaceutical aerosols are suspensions of drugs in a volatile propellant.

6.  There has been growing interest in nanoparticles as an approach to formulate poorly soluble drugs.  Besides enhanced dissolution rates, and thereby, improved bioavailability, nanoparticles can also provide targeting capabilities when injected intravenously. The latter property has led to increased research and development activities for intravenous suspensions.  The first intravenously administered nanoparticulate product, Abraxane (a reformulation of paclitaxel), was approved by the FDA in 2006.

7. An acceptable suspension has the following characteristics:  Suspended material should not settle too rapidly.  Particles that settle to the bottom of the container should not form a hard mass (cake) but should be easily redispersed on shaking.  The suspension should not be too viscous to pour freely from a bottle or to flow through a needle.

8. Formulations Typical Ingredients Drug  The drug surface can be either hydrophilic or hydrophobic.  Ionic surfaces such as aluminum hydroxide, are readily wetted and dispersed easily in aqueous vehicles.  Most organic drugs form particles with a hydrophobic surface and are difficult to disperse in an aqueous medium.

9. Wetting Agent  Wetting agents are surfactants that reduce the surface tension of an aqueous medium, coat the surface of suspension particles, and thereby facilitate the wetting of each particle.  The goal is to displace air from the particle surface and to separate each particle from adjacent particles using the minimum concentration necessary.  Since wetting agents are surfactants, they adsorb onto the particle surface and, depending on the concentration, can partially coat the surface or form a complete monolayer.

10.  If the surfactant is charged, the particle surface will, therefore, carry the same charge, whereas if the surfactant is nonionic, the particle surface will be hydrophilic but not charged. Wetting AgentIonic Charge Sodium Lauryl SulfateAnionic Docisate SodiumAnionic Polysorbate 80Nonionic

11. Suspending Agent  Suspending agents are materials added to a suspension to increase viscosity and retard sedimentation.  There are many materials that fall into this classification and include cellulose derivatives, clays, natural gums, synthetic polymers and a few miscellaneous materials.  Most suspending agents are either neutral or negatively charged and generally effective in a concentration range of 1 to 5%.

12.  Being polymeric in nature, most suspending agents have hydrophilic and hydrophobic regions in their molecular structure and, as such, can interact with a suspension particle surface.  Some adsorption of the suspending agent to the particle surface almost always occurs giving the particle surface the solubility characteristics of the suspending agent.  As with adsorption of wetting agents, the particle surface, after adsorption of a suspending agent, will be hydrophilic and either neutral or negatively charged.

13. Suspending AgentIonic Charge Cellulose Derivatives Methylcellulose Pseudoplastic Hydroxypropyl Methylcellulose Sodium Carboxymethylcellulose Microcrystalline Cellulose with Sodium Carboxymethylcellulose Neutral Anionic Polymers Carbomer Povidone Anionic Neutral Gums Xanthan gum Anionic

14. Protective Colloid  A protective colloid is a polymeric suspending agent absorbed on the surface of a hydrophobic suspension particle giving the particle a hydrophilic surface. Flocculating Agent  Flocculating agents enable suspension particles to link together in loose aggregates or flocs. These flocs settle rapidly but form a large fluffy sediment which is easily redispersed.

15.  Materials that function as flocculating agents include electrolytes, surfactants, and polymers; the same materials that serve as wetting and suspending agents.

16. Dynamic Suspension Interactions  Since a suspension is composed of many ingredients, it must be kept in mind that all these ingredients interact with each other.  The below figure is a simple representation of some of the possible interactions that affect suspension behavior. Although the drug in a suspension is described as being insoluble, there is always a finite solubility of a drug in water, i.e., the aqueous vehicle surrounding the suspension particle will be a saturated solution of the drug.

18.  This equilibrium changes with changes in temperature and has an influence on crystal growth, polymorphic changes and chemical degradation.  Surfactants used to wet the suspension particle will exist in an equilibrium between surfactant adsorbed on the particle surface, monomers in solution, and surfactant in micelles.  Changes that promote micelle formation, i.e., surfactant concentration, electrolytes, and solvent polarity, will also promote adsorption of the surfactant onto the particle surface.

19.  Likewise, polymers added as protective colloids and suspending agents will be in equilibrium between molecules adsorbed on the suspension particle surface and molecules in solution in the aqueous vehicle.  Changes that decrease polymer solubility, i.e., electrolytes and solvent polarity, will also promote deposition of the polymer on the particle surface.  Electrolytes that affect the adsorption of surfactants and polymers can themselves be adsorbed onto the suspension particle surface directly affecting the surface charge of the particle.

20. Flocculation  Suspensions can exist in essentially two states, deflocculated or flocculated, depending on how suspension particles interact.  The deflocculated state is defined as the condition where each suspension particle exists independently and behaves as a single particle.  Deflocculation occurs when the particles either repel each other or have no reason to aggregate.

21.  Flocculation is the state where suspension particles attract each other and form loosely bound aggregates or flocs. These flocs behave as a unit but are easily broken up with shear. The below figure depicts an electrostatic model of flocculation

23. In ( Figure A ), each particle carries a positive charge of such magnitude that the particles repel, hence, this condition would be deflocculation. Adding negative ions, from a soluble electrolyte, causes the positive charge of the original suspension particles to be “neutralized” or “shielded” so that the particles no longer repel each other but rather aggregate producing a flocculated state ( Figure B ). Further addition of negative ions can reverse the original particle charge and produce negatively particles and if this negative charge is large enough, the particles will again repel each other and become deflocculated ( Figure C ).

24. A comparison of properties of flocculated and deflocculated suspension particles follows: Deflocculated 1. Particles exist as separate entities. 2. Sedimentation is slow - particles settle separately. 3. Sediment is formed slowly from bottom of container. 4. Sediment eventually becomes caked due to weight of succeeding layers of sediment.

25. 5. Pleasing appearance - suspended material remains suspended for a relatively long time. Supernatant remains cloudy. Flocculated 1. Particles are loose aggregates. 2. Sedimentation is rapid - particles settle as large flocs. 3. Sediment is formed rapidly from top of container. 4. Sediment is loosely packed and easy to redisperse. 5. Somewhat unsightly - obvious, clear supernatant.

26. Sedimentation of; (a) deflocculated and (b) flocculated suspensions.

28. The problems that arise when a drug is dispersed in a liquid include;  sedimentation,  caking (leading to difficulty in resuspension),  flocculation and  particle growth (through dissolution and recrystallisation).

29.  In practice we wish to avoid the problems of aggregation of particles in suspensions and in many lyophilised preparations and to ensure their efficient redispersion on reconstitution with water or other media.  Adhesion of suspension particles to container walls has also been identified as a problem, particularly with low-dose drugs.

30.  Formulation of pharmaceutical suspensions to minimise caking can be achieved by the production of flocculated systems.  A flocculate, or floc, is a cluster of particles held together in a loose open structure; a suspension consisting of particles in this state is termed flocculated.

31. A flocculated suspension which has rapidly settled, clearly identifying the sedimentation layer, from which can be calculated the ratio R as R = h ∞ /h 0

32.  There are various states of flocculation and deflocculation. Unfortunately flocculated systems clear rapidly and the preparation often appears unsightly, so a partially deflocculated formulation is the ideal pharmaceutical. o The viscosity of a suspension is obviously affected by flocculation.

33.  Suspensions of liposomes, microspheres and microcapsules, and nanospheres and nanocapsules formed from a variety of polymers or proteins, form a new class of pharmaceutical suspension in which physical stability is paramount.  It is important that on injection these carrier systems do not aggregate, as this will change the effective size and the fate of the particles.

34. Stability of suspensions  Suspension stability is governed by the same forces as in other disperse systems such as emulsions.  There are differences, however, as coalescence obviously cannot occur in suspensions; the adsorption of stabilising polymers and surfactants may also occur in a different fashion.  Flocculation, unlike coalescence, can be a reversible process and partial or controlled flocculation is attempted in formulation.

35. Flocculation of suspensions  In a completely deflocculated systems the particles are not associated; pressure on the individual particles can lead to close packing of the particles at the bottom of the container to such an extent that the secondary energy barriers are overcome and the particles become irreversibly bound together to form a cake.

36.  Caking of the suspension is usually prevented by including a flocculating agent in the formulation :  it cannot be eliminated by reduction of particle size or by increasing the viscosity of the continuous phase.  In flocculated systems (where the repulsive barriers have been reduced) particles form loosely bonded structures (flocs or flocculates) and the particles therefore settle as flocs and not as individual particles.

37. o Because of the random arrangement of the particles in the flocs, the sediment is not closely packed and caking does not readily occur.  Clearance of the supernatant is, however, too rapid for an acceptable pharmaceutical formulation.  The aim in the formulation of suspensions is, therefore, to achieve partial or controlled flocculation.

38. Suspension stability may be assessed by measurement of: 1. The ratio R of sedimentation layer volume ( V s ) to total suspension volume ( V t ).  A measure of sedimentation may also be obtained from the height of the sedimented layer ( h ∞ ) in relation to the initial height of the suspension ( h 0 ). R = V s /V t ≈ h ∞ /h 0

39. 2. The zeta potential of the suspension particles:  Most suspension particles dispersed in water have a charge acquired by specific adsorption of ions or by ionisation of ionisable surface groups. If the charge arises from ionisation, the charge on the particle will depend on the pH of the environment.  Repulsive forces arise because of the interaction of the electrical double layers on adjacent particles.

40.  The magnitude of the charge can be determined by measurement of the electrophoretic mobility of the particles in an electrical field. The velocity of migration of the particles ( μ E ) under unit- applied potential can be determined microscopically with a timing device and eye-piece graticule.  For non-conducting particles, the Henry equation is used to obtain ζ from μ E. This equation can be written in the form: μ E = ζε / 4 π η ∫( κ a)

41. where ∫( κ a) varies between 1, for small κa, and 1.5, for large κ a ; ε is the dielectric constant of the continuous phase and η is its viscosity.  In systems with low values of κ a the equation can be written in the form: μ E = ζε / 4 πη

42.  The zeta potential ( ζ ) is not the surface potential ( ψ o ) as discussed earlier but is related to it. ζ can be used as a reliable guide to the magnitude of electric repulsive forces between particles. Changes in ζ on the addition of flocculating agents, surfactants and other additives can then be used to predict the stability of the system.

43. Controlling the Properties of a Suspension Sedimentation According to Stokes’ law the rate of sedimentation (or creaming) of a spherical particle, v, in a fluid medium is given by v = 2ga 2 (ρ 1 – ρ 2 )/ 9η where ρ 1 is the density of the particles, ρ 2 is the density of the medium and g is the gravitational constant.

44. Sedimentation of a given suspension can be reduced in several ways:  By forming smaller particles ( a↓ )  By increasing the viscosity of the continuous phase ( η↑ )  By decreasing the density difference between the two phases (ideally ρ 1 ≈ ρ 2 )

45. Controlled flocculation  In suspensions of charged particles the flocculation may be controlled by the addition of electrolyte or ionic surfactants that reduce the zeta potential, and hence V R (electrostatic repulsive energy), to give a satisfactory secondary minimum in which flocs may be formed.  The figure shows the changes in a bismuth subnitrate suspension on addition of dibasic potassium phosphate as flocculating agent.

48.  In water, bismuth subnitrate has a positively charged surface with a zeta potential high enough so that the particles repel each other. At this point the suspension is deflocculated and will eventually produce a caked sediment.  As the electrolyte is added, the HPO 4 2- ion is attracted to the positively charged surface thus shielding and lowering the zeta potential. The surface charge is not sufficient for the particles to repel each other and the suspension flocculates. The sediment produced is loose and fluffy and can be redispersed easily by shaking.

49.  Further addition of electrolyte produces a negative surface charge, the suspension becomes deflocculated, and will eventually produce a caked sediment.  Martin's experiments were carried out in dilute suspensions of bismuth subnitrate in water with added electrolyte.  In a real suspension, concentrations of drug are much higher and the suspension contains many other ingredients that can affect surface charge and characteristics.

50.  In the absence of charge on the particles flocculation may be controlled using non- ionic polymeric material including naturally occurring gums (e.g. tragacanth) and cellulose polymers (e.g. sodium carboxymethylcellose).  These polymers increase the viscosity of the aqueous vehicle, so hindering the movement of the particles, and also may form adsorbed layers on the particles which influence stability through steric stabilisation and, in some cases, bridging between particles.

51. The ideal suspending agent for controlling flocculation should:  be readily and uniformly incorporated in the formulation  be readily dissolved or dispersed in water without resort to special techniques  ensure the formation of a loosely packed system which does not cake  not influence the dissolution rate or absorption rate of the drug  be inert, non-toxic and free from incompatibilities.

52. Non-aqueous suspensions  Many pharmaceutical aerosols consist of solids dispersed in a non- aqueous propellant or propellant mixture.  Low amounts of water adsorb at the particle surface and can lead to aggregation of the particles or to deposition on the walls of the container, which adversely affects the product.

53. Adhesion of suspension particles to containers  When the walls of a container are wetted repeatedly an adhering layer of suspension particles may build up, and this subsequently dries to a hard and thick layer.  Where the suspension is in constant contact with the container wall, immersional wetting occurs, in which particles are pressed up to the wall and may or may not adhere.

54.  Above the liquid line, spreading of the suspension during shaking or pouring may also lead to adhesion of the particles contained in the spreading liquid.  Adhesion increases with increase in suspension concentration, and with the number of contacts the suspension makes with the surfaces.