1. Lec. 4
Disperse Systems
Are liquid preparations containing undissolved or immiscible drug (dispersed phase) distributed throughout a vehicle (dispersing phase / dispersion medium). Together, they produce a (dispersed system).
Dispersions containing coarse particles, 10 – 50 µm, are coarse dispersions; e.g. suspensions and emulsions.
Dispersions containing fine particles, 0.5 – 10 µm, are fine dispersions; e.g. magmas and gels.
Dispersion containing colloidal particles, < 0.5 µm, are colloidal dispersions.
Largely because of their greater size, particles in a coarse dispersion have a greater tendency to separate from the dispersion medium than do the particles of a fine dispersion. Most solids in dispersion tend to settle to the bottom of the container because of their greater density than the dispersion medium, whereas most emulsified liquids for oral use are oils, which generally have less density than the aqueous medium in which they are dispersed, so they tend to rise toward the top of the preparation. Complete and uniform redistribution of the dispersed phase is essential to the accurate administration of uniform doses that can be achieved by a moderate agitation.

2. Suspensions: -
Are preparations containing finely divided drug particles distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility.
Ready–to–use Suspensions or Oral Suspension are already distributed through a liquid vehicle with or without stabilizers and other additives, whereas USP designated title of the form “for Oral Suspension” are dry powder mixtures containing the drug and suitable suspending and dispersing agents to be reconstituted and agitated with a specified quantity of vehicle, most often purified water. The reason for the latter is due to drugs that are unstable if maintained for extended periods in the presence of an aqueous vehicle (e.g., many antibiotic drugs).
Reasons for Suspensions:
certain drugs are chemically unstable in solution but stable when suspended, i.e. suspension ensures chemical stability while permitting liquid therapy.
E.g. (instable) oxytetracycline HCL (stable) calcium salt.
solution of a disagreeable taste drug is overcome when administered as undissolved particles of an oral suspension, similarly chemical modifications specifically developed for enhancing the insolubility of a bad – taste drug, e.g. erythromycin estolate used to prepare a palatable liquid dosage form of erythromycin, Erythromycin Estolate Oral Suspension, USP.

3. Features Desired in a Pharmaceutical Suspension:
In addition to therapeutic efficacy, chemical stability of the components of the formulation, a few other features are also required in the pharmaceutical suspension:
A properly prepared pharmaceutical suspension should settle slowly and should be readily re-dispersed upon gentle shaking of the container.
The particle size of the suspended drug should remain fairly constant throughout long periods of undisturbed standing.
The suspension should pour readily and evenly from its container.
Sedimentation Rate of the Particles of a Suspension:
Stokes' equation was derived for an ideal situation in which uniform, perfectly spherical particles in a very dilute suspension settle without producing turbulence, without colliding with other particles of the suspended drug, and without chemical or physical attraction or affinity for the dispersion medium.
….. (Eq. 1)
Where dx/dt – rate of settling, d – diameter of the particles, ρi – density of the particle, ρe – density of the medium, g – gravitational constant, and η – viscosity of the medium. Stokes' equation does not apply precisely to the usual pharmaceutical suspension in which the suspended drug is irregularly shaped and of various particle diameters, fall of the particles does result in both turbulence and collision, and also particles may have some affinity for the suspension medium.

4. -From Stokes' equation, the velocity of fall of a suspended particles is greater for larger particles than it is for smaller particles. Reducing the particle size of the dispersed phase produces a slower rate of descent of the particles. The greater the density of the particles, the greater the rate of descent. -Because aqueous vehicles are used in pharmaceutical oral suspensions, the density of the particles is generally greater. If the particles were less dense than the vehicle, they would tend to float and floating particles would be quite difficult to distribute uniformly in the vehicle. Therefore, the rate of sedimentation may be reduced by increasing the viscosity of the dispersion medium. However, a product having too high viscosity is not generally desirable, because it pours with difficulty and it is equally difficult to redisperse the suspended drug. As a result, if the viscosity of a suspension is increased, it is done so only to a modest extent to avoid these difficulties. The viscosity characteristics of a suspension may be altered not only by the vehicle used, but also by the solids content. As the proportion of solid particles in a suspension increases, so does the viscosity. -The physical stability of a pharmaceutical suspension appears to be most appropriately adjusted by an alteration in the dispersed phase rather than through great changes in the dispersion medium. In most instances, the dispersion medium supports the adjusted dispersed phase. These adjustments are concerned mainly with particle size, uniformity of particle size, and separation of the particles so that they are not likely to form a solid cake upon standing.

5. According to the Stokes' equation, the reduction in the particle size is beneficial to the stability of the suspension because the rate of sedimentation is reduced as the size decreased. However, it is crucial to avoid reducing the particle size too much, because fine particles have a tendency to form a compact cake upon settling. The resulted cake resists breakup with shaking and forms rigid aggregates that are larger and less suspendable than the original suspended particles.
The shape of the suspended particles can also affect caking and product stability. For example, the symmetrical barrel–shaped calcium carbonate particles produced more stable suspensions than its asymmetrical needle–shaped counterpart. The latter forms a tenacious sediment cake on standing that could not be redistributed, whereas the former did not cake upon standing.
To prevent particles agglomeration into dense masses and avoid cake formation it is important to ensure flocs or floccules are formed, because the flocculated particles result in a type of lattice that resists complete settling (although flocs settle more rapidly than fine, individual particles) and thus are less prone to compaction than unflocculated particles. The flocs settle to form a higher sediment volume than unflocculated particles, the loose structure of which permits the aggregates to break up easily and distribute readily with a small amount of agitation.

6. Particle size reduction:
Probably the most important single consideration in a discussion of suspensions is the size of the particles. Generally, particle size reduction is accomplished by dry milling prior to incorporation of the dispersed phase into the dispersion medium.
1- Micro Pulverization is the most rapid, convenient, and inexpensive method of producing fine drug powders of about 10–50µm in diameter. It is suitable for preparing oral and topical suspensions. Micro Pulverizers are high–speed attrition or impact mills.
2- Jet Milling / Micronizing used to obtain a particle size of < 10 µm. The shearing action of sonic and supersonic high–velocity compressed airstreams in a confined space swept the particles into violent turbulence produces the desired ultrafine or micronized particles due to their fragmentation as a result of their collision with one another. The ultrafine particles produced are employed for parenteral and ophthalmic suspensions.
3- Spray Drying for producing an extremely small dimensions a cone– shaped apparatus named spray dryer into which a solution of a drug is sprayed, rapidly dried by a current of warm, dry air circulating in the cone and the resulting dry powder is collected.
A pharmacist can’t achieve the same particle – size reduction degree with the mortar and pestle.

7. Interfacial Properties of Suspensoid:
The particles in a liquid suspension tend to flocculate, i.e.; to form light, fluffy conglomerates that are held together by weak van der Waals forces. Thus, the large surface area of the particles that results from the comminution is associated with a surface free energy that makes the system thermodynamically unstable, i.e.; the particles are highly energetic and tend to regroup in such a way as to decrease the total area and reduce the surface free energy.
-The formation of any type of agglomerate, either floccules or aggregates, is taken as a measure of the system’s tendency to reach a more thermodynamically stable state. An increase in the work, W, or surface free energy, ΔG, brought about by dividing the solid into smaller particles and consequently increasing the total surface area, ΔA, is given by:
ΔG = ƔSL. ΔA ….. (Eq. 2)
where ƔSL is the interfacial tension between the liquid medium and the solid particles.
- The potential energy of two particles is a function of the distance of separation. When the repulsion energy is high, the potential barrier is also high, and collision of the particles is opposed. The system remains deflocculated and when sedimentation is complete the particles form a close–packed arrangement with the smaller particles filling the voids between the larger ones.

8. When the particles are flocculated, the energy barrier is still too large to be surmounted, and so the approaching particle resides in the second energy minimum, which is at a distance of separation of perhaps 1000 – 2000 A°. This distance is sufficient to form the loosely structural flocs.
Sedimentation in different systems:
In flocculated systems:  The flocs tend to fall together (fast sedimentation due to large size)  A distinct boundary between the sediment and the supernatant.  The liquid above the sediment is clear because even the small particles present in the system are associated with the flocs
In deflocculated systems (with a range of particle sizes):  in accordance with Stokes' law, the larger particles sediment more rapidly than the smaller particles.  No clear boundary is formed (unless 1 particle size is present)  the supernatant remains turbid for a longer period of time. Indication of a flocculated or deflocculated system: Whether or not the supernatant liquid is clear or turbid during the initial stages of settling.
In summary, flocculated particles are weakly bonded, settle rapidly, do not form a cake and are easily re suspended; deflocculated particles settle slowly and eventually form sediment in which aggregation occurs with the resultant formation of a hard cake that is difficult to re suspend.

10. Sedimentation Volume (F): is the ratio of the final volume of sediment, Vu, to the original volume of suspension, Vo, before settling. Thus: F = Vu/Vo ….. (Eq. 3) The sedimentation volume range from < 1 to > 1. F is normally < 1, the ultimate volume of sediment is smaller than the original volume of suspension in which F = 0.5. If the volume of sediment in a flocculated suspension equals the original volume of suspension, then F = 1. Such a product is in “flocculation equilibrium” and shows no clear supernatant on standing. It is therefore pharmaceutically acceptable. For F > 1, the final volume of sediment is greater than the original suspension volume, because the network of flocs formed in the suspension is so loose and fluffy that the volume they are able to encompass is greater than the original volume of suspension in which sufficient extra vehicles have been added to contain the sediment, F = 1.5.

11. Dispersion Medium:
-Highly flocculated suspensions, the particles settle too rapidly to be considered as a pharmaceutically elegant preparation, then hinders accurate dosage measurement and an esthetic issue of unsightly a supernatant layer.
Most suspending agents perform two functions i.e. besides acting as a suspending agent they also imparts viscosity to the solution. Suspending agents form film around particle and decrease interparticle attraction.
-Types of suspending agents
NATURAL AGENTS This class consists of those from. a. Animal source eg Gelatine b. Plant source eg. Accacia, Tragacanth, Starch, sea weed (Alginates) c. mineral sources.eg Bentonite, Kaoline
SEMI-SYNTHETIC AGENTS These consist of substituted cellulos (minerals) eg. Hydroxyethylcellulose , Sodium Carboxymethylcellulose , methylcellulose, Microcrystalline cellulose
SYNTHETIC AGENTS. They are synthetic polymers eg carboxypolymethylene (carbopol), Polyvinyl Alcohol, Polyvinyl Pyrolidone iodine complex (PVC)
*When polymeric substances and hydrophilic colloids are used as suspending agents, appropriate tests must be performed to check that they do not interfere with drug availability.

12. The suspending agents can bind certain medicinal agents, rendering them unavailable or only slowly available for therapeutic function. Also, the amount of the suspending agent must not be such to render the suspension too viscous to agitate (to distribute the suspensoid) or to pour.
Type and amount of suspending agent required by the dispersion medium may depend on several factors: the density of the suspensoid, degree of flocculation and the amount of suspended material.
The solid content of a suspension intended for oral administration may vary considerably, depending on the dose of the drug to be administered, the volume of product to be administered and the ability of the dispersion medium to support the concentration of drug while maintaining desirable features of viscosity and flow.
Preparation of Suspensions:
On one hand, the dispersed drug has an affinity for the vehicle to be employed and is readily wetted by it. On the other hand, other drugs are not easily penetrated by the vehicle and have a tendency to clump together or to float on the vehicle. In the latter case, the powder must first be wetted to make it more penetrable by the dispersion medium.
Alcohol, glycerin and propylene glycol are hygroscopic liquids employed as wetting agents. They function by displacing the air in the crevices of the particles, dispersing the particles and allowing penetration of aqueous dispersion medium into the powder.

13. In large – scale preparation of suspensions, wetting agents are mixed with the particles by a colloid mill, whereas on a small – scale in the pharmacy, they are mixed with a mortar and pestle. Once the powder is wetted, the dispersion medium (to colorants, flavorants and preservatives are added) is added in portions to the powder and the mixture is thoroughly blended before subsequent additions of vehicle.
A portion of the vehicle is used to wash the mixing equipment free of suspensoid, and this portion is used to bring the suspension to final volume and ensure that the suspension contains the desired concentration of solid matter. The final product is then passed through a colloid mill, blender or mixing device to ensure uniformity.
Evaluation of Suspensions:
Evaluation techniques permits the formulator to screen the initial preparations made and also to compare commercial products.
1.Sedimentation volume "F"
2.Redispersability: which is determined by the number of upside down inversions of the suspension contained in a measure. The smaller the number, the easier would be the re-dispersability of the sediment. A number greater than 15 inversions indicated caking.
3.Rheological Characteristics: The flow of the acceptable suspension will be either pseudoplastic or plastic & it is desirable that thixotropic character (the property of becoming less viscous when subjected to an applied stress) be associated with these two types of flow