1. SUSPENSION

2. SUSPENSION
A suspension may be defined as a biphasic system( heterogenous mixture) comprising of a solid phase (the dispersed phase) uniformly dispersed in a liquid phase (the continuous phase or dispersion medium).
Suspensions are generally coarse rather than colloidal dispersions, with particle sizes ranging from approximately µm.

3. SUSPENSION
Suspensions represent a useful method of preparing drugs that are poorly soluble in acceptable solvents.
They are formulated for all the major routes of administration, particularly oral, parenteral and topical routes.

4. Some pharmaceutical preparation of suspension
Antacid suspension
Benzoyl metronidazole suspension
Cotrimoxazole suspension
Paracetamol suspension
Dry granules for suspension

5. PHYSIACAL PROPERTIES OF WELL-FORMULATED SUSPENSION
The suspension must remain sufficiently homogenous for at least the period between shaking the container and removing the required amount.
The sediment produced on storage must be easily re-suspended by the use of moderate agitation of the container.
The suspension may be required to be thickened in order to reduce the rate of setting of particles. The viscosity must not be so high that removal of the product from the container and transfer to the site of application is difficult.

6. PHYSIACAL PROPERTIES OF WELL-FORMULATED SUSPENSION
The suspended particles should be small and uniformly sized in order to give a smooth, elegant product, free from a gritty texture.
The product should have an acceptable odor, color and taste.
The product must not decompose or support microbial growth during storage.
It should be physically and chemically stable.

7. Pharmaceutical applications of suspensions:
Insoluble drug or poorly soluble drugs which are required to be given orally in liquid dosage forms (in case of children, elderly, and patients have difficulty in swallowing solids dosage forms)
To over come the instability of certain drug in aqueous solution
A drug that degraded in the presence of water is suspended in non-aqueous vehicles. Examples are phenoxymethypencillin/ coconut oil and tetracycline HCL/ oil

8. Pharmaceutical applications of suspensions:
To mask the taste:
Example: paracetamol suspension (more palatable) and chloramphenicol palmitate.
Some materials are needed to be present as finely divided forms to increase the surface area. For example, Mg carbonate and Mg trisilcate are used to adsorb some toxins

9. Pharmaceutical applications of suspensions:
5) Suspension can be used for topical applications: calamine lotion BP 6)Can be used for parenteral administration ex: intramuscular (i.m.) to control rate of absorption. 7) In vaccines, for example diptheria and tetanus vaccines. 8) In aerosol : suspension of active agents in mixture of propellants

10. Disadvantages of suspension as dosage form:
uniformity and accuracy of dose - not as good as tablet or capsule
sedimentation, cake formation may occur.
since the product is liquid it is bulky and difficult to transport and carry
formulation of an effective suspension is more difficult than for tablet or capsule

12. FACTORS TO BE CONSIDERED FOR SUSPENSION FORMULATION
Wetting of the particles:

13. FACTORS TO BE CONSIDERED FOR SUSPENSION FORMULATION
It is difficult to disperse solid particles in a liquid vehicle due to the layer of adsorbed air on the surface. Thus, the particles, even high density, float on the surface of the liquid until the layer of air is displaced completely. The use of wetting agent allows removing this air from the surface and easy penetration of the vehicle into the pores.
Alcohol, glycerin, and propylene glycol are frequently used to remove adsorbed air from the surface of particles when aqueous vehicle is used to disperse the solids.

14. FACTORS TO BE CONSIDERED FOR SUSPENSION FORMULATION
When the particles are dispersed in a non-aqueous vehicle, mineral oil is used as wetting agent.
Irrespective of the method of preparation, the solid particles must be wetted using any of the suitable wetting agents before the dispersion in the vehicle.

15. FACTORS TO BE CONSIDERED FOR SUSPENSION FORMULATION
Solid particles that are not easily wetted by aqueous vehicle after the removable of the adsorbed air are referred to as hydrophobic particles.
Inability of wetting reflects the higher interfacial tension between material and liquid. The interfacial tension must be reduced so that air is displaced from the solid surface by liquid. It is necessary to reduce the interfacial tension between the particles and the vehicle by using surface-active agents to improve the wettibility.

16. FACTORS TO BE CONSIDERED FOR SUSPENSION FORMULATION
Sodium lauryl sulfate is one of the most commonly used surface-active agents.
Hydrophilic particles are easy to disperse in the aqueous vehicle once the adsorbed air is removed. Hydrophilic particles do not require the use of surface-active agents.
Examples of wetting agents are tragcanth mucilage, glycerin, glycols, bentonite and polysorbates.

17. FACTORS TO BE CONSIDERED FOR SUSPENSION FORMULATION
Excessive amounts of wetting agents can cause foaming or undesirable taste or odor.
Contact angle can be used to measure wettability, if the angle approximately equals or more than 90 degree, particles are floating well out of fluid.
Contact angle: The angle, the liquid makes with the solid surface is called contact angle.

19. B-Particle size
Particle size of any suspension is critical and must be reduced within the range as determined during the preformulation study.
Too large or too small particles should be avoided. Larger particles will settle faster at the bottom of the container and too fine particles will easily form hard cake at the bottom of the container.
Particles greater than 5μm impart a gritty texture to the product which may cause irritation if injected or instilled into the eye.
Particles greater than 25 μm may block a needle.

20. The particle size can be reduced by using mortar and pestle but in large-scale preparation different milling and pulverization (to grind to powder or dust) equipments are used.
Limitation in particle size reduction (after reaching a certain particle size):
Expensive and time consuming
Movement of small particles due to brownian motion cause particles to aggregate, settle, form hard cake that it is difficult to redisperse

21. C-Sedimentation:
Sedimentation of particles in a suspension is governed by several factors:
particle size,
density of the particles,
density of the vehicle, and
viscosity of the vehicle
The velocity of sedimentation of particles in a suspension can be determined by using the Stoke's law:

22. Stoke’s law Where: v = velocity of sedimentation
d = diameter of the particle
g = acceleration of gravity
p1= density of the particle
p2 = density of the vehicle
h = viscosity of the vehicle

23. Viscosity of the dispersion medium / vehicle can be increased using polyethylene glycol, polyvinylpyrolidone, glycerin etc.

24. D-Electrokinetic Properties
Dispersed solid particles in a suspension may have charge in relation to their surrounding vehicle. These solid particles may become charged through one of two situations.
Selective adsorption of a particular ionic species present in the vehicle. This may be due to the addition of some ionic species in a polar solvent. Consider a solid particle in contact with an electrolyte solution. The particle may become positively or negatively charged by selective adsorption of either cations or anions from the solution.

25. Ionization of functional group of the particle
Ionization of functional group of the particle. In this situation, the total charge is a function of the pH of the surrounding vehicle.

26. In the previous figure, the particle is positively charged and the anions present in the surrounding vehicle are attracted to the positively charged particle by electric forces that also serve to repel the approach of any cations.
The ions that gave the particle its charge, cations in this example, are called potential-determining ions

27. Immediately adjacent to the surface of the particle is a layer of tightly bound solvent molecules, together with some ions oppositely charged to the potential-determining ions, anions in this example.
These ions, oppositely charged to the potential-determining ions, are called counterions.

28. These two layers of ions at the interface constitute a double layer of electric charge.
The intensity of the electric force decreases with distance from the surface of the particle.
Thus, the distribution of ions is uniform at this region and a zone of electrolneutrality is achieved.

29. E-Nernst and zeta potential
The difference in electric potential between the actual surface of the particle and the electroneutral region is referred to as Nernst potential. Thus, Nernst potential is controlled by the electrical potential at the surface of the particle due to the potential determining ions. Nernst potential has little effect in the formulation of stable suspension.

30. The potential difference between the ions in the tightly bound layer and the electroneutral region, referred to as zeta potential (see the figure), has significant effect in the formulation of stable suspension. Zeta potential governs the degree of repulsion between adjacent, similar charged, solid dispersed particles.

31. If the zeta potential is reduced below a critical value, the force of attraction between particles succeed the force of repulsion, and the particles come together. This phenomenon is referred to as flocculation and the loosely packed particles are called floccule.

32. F-Deflocculation and flocculation
Deflocculation of particles is obtained when the zeta potential is higher than the critical value and the repulsive forces supersede the attractive forces.
The addition of a small amount of electrolyte reduces the zeta potential. When this zeta potential goes below the critical value, the attractive forces supersede the repulsive forces and flocculation occurs.

33. Differences between flocculated and deflocculated suspension
Non-flocculated
Particles forms loose aggregates and form a network like structure
Rate of sedimentation is high
Sediment is rapidly formed
Sediment is loosely packed and doesn’t form a hard cake
Sediment is easy to redisperse
Suspension is not pleasing in appearance
The floccules stick to the sides of the bottle
Particles exist as separate entities
Rate of sedimentation is slow
Sediment is slowly formed
Sediment is very closely packed and a hard cake is formed
Sediment is difficult to redisperse
6. Suspension is pleasing in appearance
7. They don’t stick to the sides of the bottle

34. It should be noted that the deflocculated suspensions should be avoided because of the formation of irreversible solid hard cake.
Although flocculated suspensions sediment faster and form a clear supernatant, these are easy to redisperse.

35. Thixotropic suspension
A thixotropic suspension is the one that is viscous during storage but loses consistency and become fluid upon shaking.
A well-formulated thixotropic suspension would remain fluid long enough for the easy dispense of a dose but would slowly regain its original viscosity within a short time.
Thixotropic substances on applying shear stress convert to sol(fluid) and on standing they slowly turn to gel (semisolid).

36. Method of preparation
The preparation of suspension includes three methods:
(1) use of saturated vehicle
(2) use of controlled flocculation
(3)- combination of both of the two previous methods
Fig: 7.15 : alternative approaches to the formulation of suspensions. (Sprowl’s American Pharmacy)

37. Use of Structured vehicle
Also called thickening or suspending agents.
They are aqueous solutions of polymeric materials which are usually negatively charged in aqueous solutions.
These are used to increase the viscosity of the suspension.
Ex: Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, acacia, gelatin and tragacanth .
These are non-toxic, pharmacologically inert, and compatible with a wide range of active and inactive ingredients.

38. These structured vehicles entrapped the particle and reduces the sedimentation of particles. Although, these structured vehicles reduces the sedimentation of particles, not necessarily completely eliminate the particle settling. Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage.
The risk of caking may be eliminated by forming flocculated particles in a structured vehicle.

39. Too high viscosity isn’t desirable and it causes difficulty in pouring and administration.
Also, it may affect drug absorption since they adsorb on the surface of particle and suppress the dissolution rate.
Structured vehicles are pseudoplastic or plastic in their rheological behaviors.

40. Controlled flocculation
Controlled flocculation is the intentional formation of loose agglomerates of particles held together by comparatively weak bonding forces.
This can be achieved by the addition of a preferentially adsorbed ion whose charge is opposite in sign to that of the zeta-potential determining ions.
Thus the apparent active charge of the particles is progressively lowered.

41. At certain concentration of the added ion, the forces of repulsion are sufficiently small that the forces of attraction start to predominate.
Under these circumstances the particles may approach each other closely and form loose aggregates termed ‘flocs’, ‘flocculates’ or ‘floccules’ (‘flocculated system’).
When compared to deflocculated particles, the flocs settle rapidly and form a higher sedimentation volume.

42. The loose structure permits the flocculates to break up easily and distribute uniformly with only a small amount of agitation.
Controlled flocculated systems usually develop a clear supernatant solution above the loose sediment.
Thus they might look less uniform upon standing, even though they provide easy redispersion and better dose uniformity compared to other types of suspensions.

43. Controlled flocculation of particles is obtained by adding flocculating agents, which are
(1)-electrolytes
(2)- surfactants
(3)- polymers.
Typical Flocculation agents
Neutral electrolytes such as KCl, NaCl.
Calcium salts
Alum
Sulfate, citrates, phosphates salts

44. 1-Addition of electrolyte to control flocculation
Most frequently used flocculating agents are electrolytes, which reduce the zeta potential surrounding the solid particles. This leads to decrease in repulsion potential and makes the particle come together to from loosely arranged structure (floccules).
The flocculating power increases with the valency of the ions. As for example, calcium ions are more powerful than sodium ions because the valency of calcium is two whereas sodium has valency of one.
The next figure shows the flocculation of a bismuth subnitrate suspension by means of monobasic potassium phosphate (flocculating agents).

45. The particles of bismuth subnitrate are positively charged originally
The particles of bismuth subnitrate are positively charged originally. By addition of electrolyte (phosphate, -ve) the zeta potential falls down near to zero. At this neutralization value it has been noted that there is absence of caking. Continuing adding of negatively charged electrolyte resulted in changing the overall zeta potential of particles to negative and formation of cake.

46. 2-Addition of surfactant to control flocculation
Both ionic and non-ionic surfactants could be used to control flocculation.
Surfactant adsorbed on the surface of solid particle lead to neutralization or reversing the surface charge.
Optimum concentrations of surfactants bring down the surface free energy by reducing the surface tension between liquid medium and solid particles. This tends to form closely packed agglomerates.

47. Since most of surfactants act as wetting agents and flocculating agents, the amount of surfactant to be added should be calculated based on this fact.
Polysorbate 80 is the most widely used surfactant for both oral and parenteral suspension(at a concentration less than 0.5%)
Sodium lauryl sulfate is mostly used for external preparation.

48. 3- Addition of polymers to control flocculation
Polymers are long-chained, high molecular-weight compounds containing active groups spaced along their length.
These agents promote flocculation through adsorption of part of the chain on the surface of particle and the remaining part project out into the dispersion medium. Formation of bridge between the projected parts leads to formation of floccules.
Ex: Xanthan gum

49. At very low concentrations of polymers, the number of particle-particle bridges is relatively low.
At a little higher concentrations of polymers sufficient binding sites are available on the particles, allowing additional interparticle bridges to form.
It is these intermediate concentrations of polymers that result in optimum flocculation and sedimentation volume.

50. Hence, suspensions formulated with relatively high concentrations of polymer would be deflocculated and therefore tend to have small sedimentation volumes.
Fig: Flocculation by hydrophilic polymers.

51. C - Flocculation in structured vehicles
Suspending agents can be added to flocculated suspension to retard sedimentation.
Examples: Carboxymethylcellulose (CMC), Carbopol 934, Veegum (magnesium aluminium silicate) and bentonite (hydrated aluminium silicate).
It should be noted that physical incompatibility can limit the addition of suspending agent. (next fig)

53. Evaluation of suspensions
Suspensions are evaluated by determining their physical stability.
Two useful parameters for the evaluation of suspensions are
sedimentation volume and
degree of flocculation.

54. Sedimentation volume:
Sedimentation volume of a suspension is expressed by the ratio of the equilibrium volume of the sediment, Vu, to the total volume, Vo of the suspension.
F = Vu/Vo
The value of F normally lies between 0 to 1 for any pharmaceutical suspension.
The value of F provides a qualitative knowledge about the physical stability of the suspension.

55. F= 1
No sedimentation, no clear supernatant
F =0.5
50% of the total volume is occupied by sediment
F > 1
Sediment volume is greater than the original volume due to formation of floccules which are fluffy and loose
As the volume of suspension occupied by the sediment increases, the value of F increases.
In the system where F = 0.75 , where 75% of the total volume in the container is apparently occupied by the loose, porous flocs forming the sediment.

57. When F= 1, no sediment is apparent even though the system is flocculated.
This is the ideal condition for suspension where no sedimentation will occur and there will be no caking and the suspension will be aesthetically pleasing and there will be no visible, clear supernatant.

58. Degree of flocculation:
Degree of flocculation (ß), is the ratio of the sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the deflocculated suspension, F
ß = F / F
(Vu/Vo) flocculated
ß =
(Vu/Vo) deflocculated

59. The degree of flocculation is therefore an expression of the increased sediment volume resulting from flocculation. If for example, ß has a value of 5, this means that the volume of sediment in the flocculated system is five times than in the deflocculated system. If a second formulation has a ß value of 6.5, this suspension is more flocculated and is preferred over the previous suspension.

60. Ingredients of suspension
Active Ingredient – Active drug substance
Wetting agent – They are added to disperse solids in continuous liquid phase. Example : surfactants (e.g Polysorbate 80), hydrophilic colloids (e.g acacia, tragacanth, bentonite, veegum, methylcellulose etc), solvents (e.g alcohol, glycerin, polyethylene glycol).
Flocculating agents - They are added to floc the drug particles. Example : electrolytes (e.g NaCl, KCl, citrates etc).

61. Buffers - They are added to stabilize the suspension to a desired pH range.(pH of the suspensions is usually kept between )
Coloring agents - They are added to impart desired color to suspension and improve elegance.
Preservatives - They are added to prevent microbial growth.

62. Suspending agent - Suspending agents form film around particle and decrease interparticle attraction.
They also increase viscosity of the dispersion medium and are known as thickening agents.
List of Suspending Agents –
Alginates
Methylcellulose
Hydroxyethylcellulose
Carboxymethylcellulose

63. Sodium Carboxymethylcellulose
Microcrystalline cellulose
Acacia, Tragacanth, Xanthan gum
Bentonite
Carbomer
Powdered cellulose
Gelatin

64. Packaging and Storage of Suspensions:
1) Should be packaged in wide mouth containers having adequate air space above the liquid.
2) Should be stored in tight containers protected from: freezing, excessive heat & light
3) Label: "Shake Before Use" to ensure uniform distribution of solid particles and thereby uniform and proper dosage.
4) Stored in room temperature if it is dry powder (25 0C). It should be stored in the refrigerator after opening or reconstitute (freezing should be avoided to prevent aggregation)

65. Stability of suspension
A-Physical stability: The following parameters should be checked to ensure the quality of suspension :
Appearance, color, odor and taste pH
Specific gravity
Sedimentation rate
Sedimentation volume
Zeta potential measurement
Compatibility with container

66. A-Physical stability Compatibility with cap liner
Microscopic examination for checking crystal growth which is undesirable
Determination of particle size
Determination uniform drug distribution
Rheological measurement to determine viscosity of the suspension
Stress test
Temperature - Fluctuations in temperature may cause crystal growth and freezing may result in cake formation. (Allow suspension stored in fridge to come to room temperature before redispersing).

67. Stability of suspension
B-Chemical stability:
Degradation of active ingredient
Viscosity change
antimicrobial activity:
Incompatibility with preservative
Degradation of preservative
Adsorption of preservative onto drug particle