Method of Flocculated suspensions:

There are three general methods of producing colloidally stable dispersions:
Adsorption of a smaller hydrophilic and lypophilic colloid on larger suspended particles: When a strongly hydrated hydrophilic protective colloid (e.g. -gelatin) is adsorbed on the surface of the suspended particles, the affinity for water exceeds the mutual attraction of adjacent particles for each other. Essentially the protective colloid and hydrogen-bonded water molecules form a protective hydration layer around each suspended particle.
Stearic hindrance due to adsorption of an oriented nonionic surfactant or polyelectrolyte: Adsorption of nonionic polymer (gum or cellulosic) or surfactant (polysorbate-80) of sufficient chain length creates stearic hindrance and prevents adjacent suspended particles from coming close enough to join. Stearic stabilization is relatively insensitive than electrostatic stabilization to the presence of added electrolyte.

Flocculated suspensions:

Flocculation: It refers to the formation of a loose aggregation of discrete particles held together in a net-work like structure either by physical adsorption of macromolecules, bridging during chemical interaction or when the longer range Van-der Waal’s forces of attraction exceed the shorter range forces of repulsion.

Agglomeration: Here a large number of particles, a mass, are closely bound together as aggregates either in a dry or liquid state.

Coagulation (severe over flocculation): It refers to massing of particles in a liquid state alone and sometimes in the form of a fluid gel structure. The solubility rate of unprotected, nucleated particles is greater than that of the large crystals, dissolution of smaller particles creates a temporary or metastable state of saturation, which causes eventual growth from solution onto the proper crystal edge of large particles until a new, more thermodynamically stable distribution of particle sizes is achieved. This phenomenon tends to promote ‘caking or cementing’ together of particles. The creation of a protective coat or boundary layer with a hydrophilic colloid about such particles offers the best protection to crystal growth.
According to the above figure, the flocculated stable state (C) may be reached either directly by wetting and dispersing hydrophobic particles (A) with a suitable flocculating surfactant or indirectly by first wetting and dispersing to produce a dispersed or peptized particle (B) with a suitable surfactant and then flocculating with a suitable agent such as a hydrophilic colloid or polyelectrolyte. Good pharmaceutical suspensions are best achieved through the formation of a stable floc, which resists the tendency toward either deflocculation or agglomeration.

The chief advantages of the stable floc are as follows –
The aggregates tend to break up easily under the application of small amounts of shear stress, such as gentle agitation of a bottle or vial or by the flow through a small orifice and reform an extended network of particles after the force is removed.
The stable floc will settle rapidly, usually to a high sediment volume, and may be easily resuspended even after standing for prolonged periods of storage.
The stable floc can be produced by employing aseptic techniques that are safe for intramuscular injection.

There are several methods of producing flocculated pharmaceutical suspensions. The choice of method depends on the properties of the drug and the class of suspension desired. The following example illustrates how suspensions may be prepared by controlled flocculation procedures.
The weting agent, polysorbate (not more than 0.1-0.2%w/v of the final conc) is dissolved thoroughly in approximately half the final volume of aqueous vehicle. An anionic surfactant such as docusate Na USP may also be used as a wetting agent. In case of hydrophilic solids, a wetting agent is usually not required.
Ultrafine [articles of the drug at the desired final concentration are uniformly and carefully spread over the surface of the vehicle ad the drug is permitted to wet undistributed for as much as 16hr.
The wetted slurry is passed a very fine wir mesh screen (120mesh of larger) to remove poorly wetted powder. Alternatevly a colloid mill can be used to achieve the same result.

The slurry concentrate of the drug is agitated gently using an impeller type mixer.
Small amounts of a 10% w/v solution of aluminum chloride hexahydrate are then added drop-wise to the drug slurry from a burette or dropping pipette until the flocculation end point is reached.
After the flocculation end point has been established and verified, the rest of the suspension components dissolved in the liquid vehicle are added and the slurry is brought to final volume with liquid vehicle.

Structured vehicle:

The vehicle is said to behave like a “false body” which is able to maintain the suspended particle in a state of more or less permanent suspension. Structured vehicles are not normally considered for the preparation of parenteral suspensions since, because of their high viscosity, such systems lack sufficient syringeability for ease of use.

Bingham-type plastic flow:

Vehicles that exhibit the unusual property of Bingham-type plastic rheological flow are distinguished by the need to overcome a finite yield stress before flow is initiated. Bingham-type plastic flow is rarely produced by solutions of most pharmaceutical gums and hydrophilic colloids. Permanent suspension of most pharmaceutical systems requires yield-stress values of at least 20 to 50 dynes cm-2.

Thixotropic flow:

Thixotropic flow is defined as a reversible, time dependent, isothermal gel-sol transition. Thixotropic systems exhibit easy flow at relatively high shear rates, but when the shear stress is removed the system is slowly reformed into a structured vehicle. Procaine pen-G parenteral suspension, in conc. above 40% exhibits Thixotropic flow. Thixotropic suspensions have been prepared for oral or topical use with bentonite, colloidal Mg-Al silicate, trihydroxy stearain, and calcium and Mg ion tragacanth combinations.

Formulation of suspensions:

During the preparation of physically stable pharmaceutical suspensions, a number of formulation components are employed to help keep the solid particles in a state of suspension, whereas other components are merely part of the liquid vehicle itself. These formulation components are classified as follows -

Components of the suspending system:
à Wetting agents
à Dispersant or deflocculation agents
à Flocculating agents
à Thickeners

Components of the suspending vehicle or external phase:
à pH control agents and buffers
à Osmotic agents
à Coloring agents, favors and fragrances
à Preservatives to control microbial growth
à Liquid vehicles

Wetting agents:

The degree of wettability depends on the affinity of drugs for water and whether the solids are hydrophilic of hydrophobic. Hydrophilic solids are easily wetted by water and can increase the viscosity of aqueous suspensions. Hydrophobic solids repel water but can be wetted by non-polar liquids. Hydrophilic solids usually can be incorporated into suspensions without the use of wetting agent. The majority of drugs in aqueous suspension are, however, hydrophobic. These are extremely difficult to suspend and frequently float on the surface of water and polar liquid due to entrapped air and poor wetting. Wetting agents are surfactants that lower the interfacial tension and contact angle solid particles and liquid vehicle. The usual concentration of surfactant varies from 0.05 to 0.5% and depends on the solids content intended for suspension. The use of surfactants as wetting agents will also retard crystal growth. On the other hand, employing surfactants at conc. less than 0.05% can result incomplete wetting and greater than 0.5% may solubilize ultra-fine particles and lead eventually to changes in particle size distribution and crystal growth. The high HLB surfactants are also foaming agents; however, foaming is an undesirable property during wetting of suspension for formulation. Polysorbate-80 is still the most widely used surfactant for suspension formulation because of its lack of toxicity and compatibility with most formulation ingredients. The rate of wetting is often determined by placing measured amount of powder on the undisturbed surface of water containing a given conc. of surfactant and measuring the time required to completely wet and sink the powder.

Dispersant or deflocculation agents:

Theses are polymerized organic salts of sulfonic acid of both alkyl-aryl or aryl-alkyl types that can alter the surface charge of particles through physical adsorption. Their mechanism of action is not clear, but they appear to function by producing as negatively charged particle or increasing the negative charge already present in order to aid dispensability.Unlike surfactants, these agents do not appreciably lower surface and interfacial tension; hence they have little or no tendency to create foam or wet particles

Flocculating agents:

Simple neutral electrolytes in solution that are capable of reducing the zeta potential of suspended charged particles to zero are considered to be primary flocculating agents. Small conc. (0.01-1.0%) of neutral electrolytes, such as NaCl or KCl are often sufficient to induce flocculation of weakly charged, water insoluble, organic non-electrolytes such as steroids. In case of more highly charged, insoluble polymers and polyelectrolyte species, such as Ca-salts and alums or sulphates, citrates and phosphates are usually required to achieve floc formation depending on particle charge, positive or negative.

Thickeners:

These are protective or hydrophilic colloids, they increase the strength of the hydration layer formed around suspended particles through H-bonding and molecular interaction. Since these agents do not reduce surface and interfacial tension greatly, they function best in the presence of a surfactant. Many of these agents are protective colloids in low conc. (<0.1%)>0.1%).

pH control agents and buffers:

If a specific pH value is found necessary to provide for optimum stability and / or to minimize solubility in the suspending vehicle, the system can be maintained at this desired pH value (as pharmaceutically acceptable buffer). This is especially important for drugs that possess ionizable acidic or basic groups; then the pH of the vehicle often influences drug stability and / or solubility. However, the use of salts and buffers should be avoided; science small changes in electrolyte concentration will often alter the surface charge of suspended particles. Such effects can influence the nature and stability of flocculated suspensions. This is especially noticeable when polyvalent ions, such as citrates and phosphates are used in buffering systems. Suspensions of stable neutral drugs, which possess no charge such as corticosteroids, are usually insensitive to pH change.

Osmotic agents:

Substituting organic non-electrolytes, such as dextrose, mannitol or sorbitol are used as osmotic agents and stabilizer.

Coloring agents, favors and fragrances:

Organoleptic agents, such as colorants, flavors or fragrances should not normally affect the physical stability of topical or oral suspensions. On the other hand, since many flavoring agents and fragrances are water-insoluble, oily liquids that are usually added to the batch in the final phase after the primary physical stability of the suspension has been established and thereby influence the physical stability of the final suspension.

Preservatives to control microbial growth:

Preservatives to control microbial growth is an important duration not only on the chemical stability of ingredients but also on the physical integrity of the system. Orally accepted preservatives such as parabens, benzoates and sorbates. The use of cationic antimicrobial agents such as benzalkonium chloride, is usually contraindicated, because cationic agents may be inactivated by formulation components or they may alter the charge of the suspended particles. A well preserved oral or topical suspension does not have to be sterile to prevent microbial growth. The sue of small amounts of propylene glycol (5-15%) disodium edtate (about 0.1%) or decrease of pH all have been used to increase the efficiency of preservative systems without adversely affecting physical stability of pharmaceutical suspensions.

External phase:

The suspending vehicle chosen also governs the selection of the suspending agents to be employed. For example, in the case of non-polar liquids, such as aliphatic or halogenated hydrocarbons, fatty esters and oils, the best suspending agents are low HLB surfactants, water insoluble resins, and water-insoluble film formers. Polar liquids such as water, alcohols, polyols and glycols the higher HLB surfactants, clays silicates, gums and cellulose derivatives are usually preferred. Liquid vehicles are selected based on safety, density, viscosity, taste and stability considerations.

Sterile suspensions

Sterility, syringeability ease of re-suspension, slow settling after shaking and drainage as well as absence of pyrogens and foreign particulate matter. Preparation of a sterile paraenteral suspension is a very difficult procedure. It requires complete attention to detail during the following broad phases of manufacture.
o Final re-crystallization of the drug
o Size reduction of the drug
o Sterilization of the drug
o Sterilization of the vehicle
o Aseptic wetting of the powder with a portion of the sterile vehicle
o Aseptic dispersion and milling of the bulk suspension
o Aseptic filling of the finished suspension into sterile containers

Selection of milling equipments:

Some types of mechanical dispersion equipment is often required to break up agglomerates of poorly wetted, hydrophobic particles though the use of a colloidal mill that can be sterilized with ethylene oxide or live steam prior to use. The principle advantage of the particular mill is that the head are relatively inexpensive and therefore, several units can be purchased to provide continuous trouble free operation.

Syringeability:

It is the ability of a parenteral solution or suspension to pass easily through a hypodermic needle, especially during the transfer of product from vial to hypodermic syringe prior to injection. ↑ syringeability → ↓ flowing characteristics, thus make material transfer through the needle more difficult:
o The viscosity of the vehicle
o The density of the vehicle
o The size of suspended particulate matter
o The concentration of suspended drug

Drainage:

The ability of the suspension to break cleanly away from the inner walls of the primary containe4r closure system is another important characteristic of well formulated parenteral suspension. Completely peptized to flocculated systems show this property, while over flocculated systems exhibit some degree of poor drainage. The process of silicone coating of containers, vials and plugs with dimethicone makes good suspensions drain better and helps reverse the tendency toward poor drainage by slightly over flocculated systems.

Resuspendability:

The ability to resuspended settle particles with a minimum amount of shaking after a suspension has stood for some time. Preparation of a stable floc offers the formulator a convenient method of overcoming this problem. Stable, flocculated parenteral suspensions that have stood undisturbed for prolonged periods of storage are therefore the easiest systems to resuspend