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.
Monday, November 1, 2010
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.
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
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.
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