Monday, November 1, 2010

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

Compatibility with diluents and other injectable products:

Dilution of parenteral suspensions prior to use is often necessary, especially if only small conc. of drug are required. If it is diluted with water or normal saline it causes the system to deflocculation thus produce the more serious incompatibility.

Cosmetic suspensions:

Basically two types of cosmetic suspensions are used at present –
First type (Pigmented products): e.g. – liquid make-ups, eyeliners, mascaras etc. particles are suspended in aqueous vehicle. Features-high solid content, high density and pigments permanently suspended in either a primary oil-in-water emulsion type of base or a complex system of hydrophilic cellulosic derivatives, lays and /or polymeric film formers.
Second type: consists of pigment containing nail enamels. The coloring tints, pigments, pearls and lakes in the latter system are suspended with the aid of organophilic, Thixotropic gallant etc.

Test methods for pharmaceutical suspensions:

The procedures outlined were designed to determine whether as given formula is flocculated. Since there is more than one method of preparing stable suspensions, the following tests were found useful for determining the stability of both flocculated and dispersed systems.

Photo-microscopic techniques:
The microscope can be used the estimate and detect changes in particle size distribution and crystal form. Its usefulness can be enhanced through the use of a Polaroid camera attached to the eyepiece of a monocular microscope to permit the rapid processing of photo-micrographs. This method is helpful to distinguish between flocculated and non- flocculated particles and to determine changes ion the physical stability of such systems conveniently with time.
Particle Coulter Counter:
It is an electronic particle counter and sizer that measure the change of resistance caused by the presence of a particle in an electrolyte. Particles pass through the aperture substantially one at a time. The size range of the counter is 0.2 to 300μm. It is helpful to determine the particle size distribution of hydrophobic particles such as steroids and some antibiotics. As the suspensions must be diluted with electrolytes and surfactants, the stability of the suspensions may be hampered so this method is not used to determine the physical stability and properties of particles aggregates.

Cylindrical Graduates:
Cylindrical Graduates (100-1000ml) are quite useful for determine the physical stability of suspension. It may be used to determine the settling rates of flocculated and non-flocculated suspension, by making periodic measurement of sedimentation height without disturbing the system.

Bookfield Viscometer with Hellpath Attachment:
Bookfield Viscometer is a valuable rheological equipment for measuring the settling behavior and structure of pharmaceutical suspensions. The instrument consists of a slowly rotating T-bar spindle, which while descending slowly into suspensions encounters new, essentially undisturbed material as it rotates. The dial reading of the viscometer measures resistance to flow that the spindle encounters form the structure at various levels in the sediment. Taking rheograms a various time intervals, under standard conditions of sample preparation, gives a description is most useful suspension and its physical stability. It mostly used in viscous suspensions containing high solid particles, that develop sufficient shear stress. It is also excellent for characterizing flocculated systems.

Specific gravity measurement with Hygrometers:
Specific gravity is ratio of the density (mass of a unit volume) of a substance to the density (mass of the same unit volume) of a reference substance. Apparent specific gravity is the ratio of the weight of a volume of the substance to the weight of an equal volume of the reference substance. The reference substance is nearly always water. Temperature and pressure must be specified for both the sample and the reference. Specific gravity or density of pharmaceutical suspension is measured to provide the qualitative information on the amount of air entrapped by a suspension during manufacture.
Measurement of specific gravity: A hydrometer is an instrument used to measure the specific gravity (or relative density) of liquids; that is, the ratio of the density of the liquid to the density of water. A hydrometer is usually made of glass and consists of a cylindrical stem and a bulb weighted with mercury or lead shot to make it float upright. The liquid to be tested is poured into a tall jar, and the hydrometer is gently lowered into the liquid until it floats freely. The point at which the surface of the liquid touches the stem of the hydrometer is noted. Hydrometers usually contain a paper scale inside the stem, so that the specific gravity can be read directly.

Aging tests:
This is performed by subjecting suspensions to cyclic temperatures of repeated freezing and thawing or exposed them to elevated temp (>400c) for short periods of storage to test for physical stability. At elevated temp causes significant amounts of drug to go into solution and subsequent cooling indices excess drug in solution to re-precipitate. If suspension is able to withstand exposure to extremes in temp, it is claimed as physically stable suspension but if it fails to meet the test for significance then it must not be considered a bar to father testing.

Zeta potential:
Zeta potential is electric potential in the interfacial double layer (DL) at the location of the slipping plane versus a point in the bulk fluid away from the interface. In other words, zeta potential is the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle. It has practical application in the stability of systems containing dispersed particles. If the zeta potential is reduced below a certain value, the attractive forces exceed the repulsive forces and particles come together. This phenomenon is known as flocculation.
The significance of zeta potential is that its value can be related to the stability of colloidal dispersions (e.g. a multivitamin syrup). The zeta potential indicates the degree of repulsion between adjacent, similarly charged particles (the vitamins) in a dispersion. For molecules and particles that are small enough, a high zeta potential will confer stability, i.e. the solution or dispersion will resist aggregation. When the potential is low, attraction exceeds repulsion and the dispersion will break and flocculate. So, colloids with high zeta potential (negative or positive) are electrically stabilized while colloids with low zeta potentials tend to coagulate or flocculate.

Sedimentation:

Sedimentation: Factors governing the physical stability of a suspension are due to unequal gravitational pull on the suspended particles and the medium, and are depicted by Stocke’s equation:

v = d2 (ρ – ρ0) g/18η
Where,
V = sedimentation velocity
d = particle diameter
ρ = particle density
ρ0 = medium density
g = gravitational constant
η = viscosity of continuous external phase

Form the above equation it is clear that the reduction of (ρ – ρ0) value causes decreases the rate of sedimentation significantly. Physical stability of a suspension can be improved by increasing the viscosity of the external phase. In case of non-Newtonian suspending medium, too high viscosity is undesirable because it is difficult to re-disperse the settled material. By using the polyols (e.g. – glycerin or sorbitol) we may increase viscosity but it is rarely used to stabilize pharmaceutical suspensions.

Rheology:

The rheological behavior of a pharmaceutical suspension furnishes the greatest control over sedimentation and optimization of the physical stability of the system. The choice of the rheology is depends on the type of bodying agent and its intended application.
For more viscous medium → a bodying agent is not necessary to increase the viscosity.
For less viscous medium → a bodying agent is necessary to increase the viscosity.

For example - for a topical suspension:
It should be fluid enough to permit proper shaking and pourability
Should not flow readily form the skin
Should provide sufficient resistance against gravitational settling while in the container

Pseudoplasticity:

Pseudoplastic flow of a system is inversely proportional to the shear rate. As shear stress is increased, the resistance to flow decreases and the system becomes more fluid. This shear thinning behavior is called pseudoplasticity. Many colloidal systems especially polymer solutions exhibits this type of flow. The apparent viscosity of such system therefore cannot be defined I terms of on e value

Plasticity:

Plastic behavior is characterized by the presence of a yield value. Some materials like semisolids do not flow at low shear stress. A Bingham body dose not flow until shearing stress equals or exceeds the yield value. When the shear stress equals or exceeds the yield value, the composition begins to flow. This system exhibits solid like behavior under quiescent conditions. Agitation temporarily disrupts the rigid network of solids making it possible to poor or apply the suspensions to the skin.

Thixotropy:

Thixotropy is characterized by they fact that the rate of shear at any given shearing stress can vary depending on weather the rate of shear is increasing or decreasing. It is a measure of the breakdown and rebuilding of the structure of the system. This system contains a structural network of colloidal particles. At rest, it may produce the rigidity of the system, but when disrupted shear, the system beings to flow. Upon removal of shear stress, the structure begins to reform.

Dilatancy:

This system is the reverse of a pseudoplastic system and is a shear thickening system. An increase in the resistance to flow when stress is exerted the system returns to its original state of fluidity when the stress is removed. Pharmaceutical suspensions that exhibit plastic or thixotropic rheological behavior generally exhibit good physical stability. Such a suspension may prevent sedimentation, aggregation and caking by virtue of its high-yield value at rest.

Injectable suspensions:

Injectable suspensions are heterogeneous systems consisting of a solid phase dispersed within a liquid phase. They must be sterile, pyrogen free and maintain suitable physical and chemical stability over the intended shelf-life. They are limited to s.c and i.m routes of administration i.v administration may result in vasoocclusion. They may usually contain between 0.5-5.0% solids and should have the particle size less than 5μm but certain antibiotic preparations may contain up to 0% solids.

Advantages of Injectable suspensions
Therapeutic use of drugs those are insoluble in conventional solvents (i.e. – aqueous, water miscible and water immiscible).
Increase chemical stability when compared to solution preparations
Possible for depot preparation
Elimination of first-pass effects..
Disadvantages of Injectable suspensions
Difficulty in formulation and manufacturing
Discomfort to patient
Difficulty in maintaining of uniformity of dose
Difficulty in maintenance of physical stability

Formulation considerations:

It is difficult to formulate a stable suspension in the inherent thermodynamic aspect. In order to prepare a thermodynamically stable suspension, the interfacial tension is minimized by the use of surface active agents. Let consider the following equation –

∆G = Ys/1. ∆A …………………….. (i)
Where,
∆G = change in surface free energy
Ys/1 = interfacial tension
∆A = change in surface area
Eq (i) illustrate that as the interfacial tension and /or surface area approaches zero, the surface free energy is minimized. Further -

d2 (ρ – ρ0) g
s = …………………. (ii)
18η




Where,
s = sedimentation rate
d = particle diameter
ρ = density of the dispersed phase (solid phase)
ρ0 = density of the dispersion phase (liquid phase)
g = acceleration due to gravity
η = viscosity of dispersion phase

According to the Eq (ii) sedimentation are will decreases with the decreasing of particle size. It also indicates that an increase in the viscosity of the liquid phase and / or minimal difference between the densities of the solid / liquid phases will minimize the sedimentation rate enhance physical stability.

As it is difficult to formulate an injectable suspension, the pre-formulation data is useful in developing a suspension and should include various physical and chemical properties and interactions between the active ingredient (s), excipients and packaging components.

Suspensions ingredients

a.Active ingredients
b.Excipients; The excipients used in the case of injectable suspensions, must have –
ü Non-pyrogenic
ü Non-toxic and
ü Non-irritating
Typical excipients used in parenteral suspensions are -
a. Preservatives
b. Antioxidants
c. Chelating agents
d. Flocculating agents
e. Buffering agents
f. Tonicity modifiers
g. Solvents systems
a. Preservatives:
Formulation containing active ingredient (s) devoid of any antimicrobial activity must require one or more preservatives. A growth promotion study should be conducted in order to determine the microbiological power of the preservative free formulation. One procedure is to inoculate the preservative free formulation with approximately 1000 organisms and incubate at 30-320c for 7days. At the end of the incubation period, the sample should be examined quantitatively and qualitatively.
No growth upon qualitative examination → sample should streaked onto Tryptic Soya Agar-plate and incubate at 3days at specified temp. → no growth/growth → the formulation is bacteriocidal / bacteriostatic in nature.
The most commonly used preservatives are either benzyl alcohol or a combination of propyl and methyl parabens. But benzyl alcohol can cause convulsions in neonates and should be avoided in certain drug products with neonatal indications.

b. Antioxidants / chelating agents:
Oxidation (which is catalyzed by metals, heat, light, H+ or OH-) can lead to unacceptable discoloration of the drug product without necessarily causing potency loss. Antioxidants are used to increase stability of the drug product by inhibiting oxidation of the active ingredient(s). Some substances containing the functional groups e.g. – aldehydes, ketones, amines, alcohols and unsaturated fats and oils suffers oxidative degradation (auto-oxidation).
The antioxidants act by either – (i) preferential oxidation of the antioxidant due to a lower oxidation potential or (ii) termination of the propagation step by the antioxidant in the free radical oxidation mechanism.
Chelating agents are used to sequester heavy metals in a preparation, thus preventing the catalysis of oxidation reactions.
For auto-oxidation manner, the exposure of active ingredients to oxygen during the manufacturing processes we must follow the underline processes –
Boiling the WFI USP during manufacturing to displace the solubilized oxygen
Purging the solvent system with filtered (0.22μm) nitrogen during the manufacturing process
Blanketing the bulk drug product with filtered (0.22μm) nitrogen during the filling operation
Displacing oxygen form the headspace of the filled container with filtered (0.22μm) nitrogen

c. Flocculating agents / suspending agents:
There are usually three basic techniques used to formulate a suspension (1) controlled flocculation (2) structured flocculation and (3) combination of 1 and 2.

Types of flocculating agents –
Electrolytes: alter the electrical barrier between particles and allow the flocs to form e.g. -
KCl / NaCl
K-citrate / Na-citrate
K-acetate / Na-acetate
Surfactants: function same as electrolytes e.g. -
Lecithin
Tween (polyoxyethylene sorbitan monooleate)-20, 40, 80
Pluronic F-68
Sorbitan Trioleate(Span-85)

Hydrophilic colloids: provide a mechanical barrier to the particles and also affect the repulsive forces e.g. -
Na-CMC
Acacia
Gelatin
Methylcellulose
PVP




d. Wetting agents:
These are the most important for the injectable suspensions since the hydrophobic powders are often suspended in aqueous solvent systems e.g. – glycerin, alcohols and propylene glycol are the commonly used wetting agents in pharmaceutical field.
YS = YS / 1 + Y1 cosӨ


Where,
YS = surface tension of solid
YS / 1 = solid / liquid interfacial tension
Y1 = surface tension of liquid
e. Buffering agents:
These agents are used to maintain a specific pH of the drug product. pH profiles obtained during pre-formulation studies determine the most suitable pH at which the drug product should be formulate. Examples-
Na/K- acetate → acetic acid
Na/K-citrate → citric acid
Na/K-phosphate → Phosphoric acid
f. Tonicity modifiers:
Parenteral suspensions must be isotonic in nature to reduce paion at the injection site but they are less crucial for i.v administration than the s.c or i.m administration. Example- NaCl.

g. Solvent system:
The solvent system for injectable preparations provides a medium for incorporation of both the ingredients and excipients necessary to provide a stable, safe, and efficacious dosage form.

The type of solvent co-solvents used in parenteral preparations are-
(i) Aqueous vehicle: safest and most widely used e.g. - WFI
(ii) Non-aqueous vehicle:
Water miscible: these are widely used as co-solvents with WFI to promote solubility and stability e.g. – ethanol, benzyl alcohol, glycerin, propylene glycol and N-lactamide.
Water immiscible: e.g. – fixed oil in nature ethyl oleates, isopropyl myristate and benzyl benzoate. Examples of some fixed oils are sesame oil, peanut oil, cottonseed oil and corn oil.

Manufacturing considerations:

Manufacturing of a sterile suspension is a complicated process that typically requires –
The sterilization and milling of the active ingredient (s)
Sterilization of the vehicle system
Aseptic wetting and dispersion of the active ingredient (s)
Milling the bulk suspension
Aseptic filling of the bulk suspension into suitable sterile containers

Basic methods which are applied to sterilize the solids for injectable suspensions are –
Re-crystallization
Spray drying
Lyophilization
Ethelyne oxide gas
Dry heat and
Gamma radiation



1. Re-crystallization
The hydrophobic active ingredient (s) is dissolved in an organic solvent. Then the drug solution is sterilized by filtration. A sterile ‘counter’ solvent is aseptically added to the sterile drug solution to generate the sterile crystalline material. The crystals are aseptically collected, washed, dried to remove residual solents and milled to the appropriate particle size.
Advantage: The method is weconomical.
Disadvantage: aseptic amanipulation is required and the choice of solvents is limited.
Commonly used solvents are – acetone, CHCl3 and CH2Cl2.

2. Spray drying:
The active ingredient (s) is dissolved in a solvent, filtered through a sterilizing filter, sprayed into a spray drying chamber and exposed to extremely high heat for a very short interval to yield a sterile dry powder. It forms hollow spheres of uniform size.
Advantages: Milling is not required here. It is applicable for heat liable materials.

3. Lyophilization (freeze drying):
It is a technique for removing a solvent from solution of heat liable materials. The process yields solid material with high surface area that is readily reconstituted upon addition of solvent. A sterile solution containing the active ingredient is frozen by lowering the temperature of the solution below its characteristic eutectic temperature. The solvent is then removed by sublimation (by using controlled application of vacuum and temperature), thus leaving a dry powder or cake.

Advantages:
To maintain accurate dose of high surface area solid
To increase stability
To prepare pharmaceutically elegant product
To reduce transportation cost
To minimize interaction between product and packaging ingredient and
To minimize potential for particulate development

Disadvantages:
Time consuming for processing
Milling results possible formation of light friable or dense hard materials
Costly set-up is required
Labor cost

4. Sterilization:
(a) Gaseous sterilization (by ethylene oxide): for previously milled materials, it requires 2-4 hrs exposure time depending on the gas composition, temperature ranging form 50-600c and the RH approximately is 70%.
Precaution: after sterilization by it the level of ethylene oxide, ethylene glycol and chlorohydrine residues should be monitored. The occupational health and safety administration has changed personal Eto exposure limits from 50-0.5ppm.

(b) Dry heat sterilization: previously milled material is generally exposed to heat above 1400c for various time periods depending on temperature.
Advantages: easiest and safest method for sterilization.
Disadvantages: not suitable for volatile and heat sensitive materials.

(c) Sterilization by radiation therapy: e.g. – gamma radiation, the primary source used for gamma irradiation is cobalt 60. For stability conformance, the preliminary experiment should be conducted.
Advantages:
to sterilize the bulk drugs and/or and finished products
relatively low temperature is required
no residual mater is deposited in the product
maximum sterility assurance is achieved
Disadvantages: it can cause physical and chemical degradation of product and /or packaging materials.

Processing of preparing injectable suspensions:

Processing of preparing injectable suspensions:

Aseptically dispensing the sterile, milled active ingredient (s) into a sterile vehicle system, milling the resulting suspension as necessary and filling the milled suspension into suitable sterile containers.
Solubilizing the active ingredient (s) in a suitable solvent system, adding a sterile vehicle system or counter solvent system that causes the active ingredient (s) to crystallize, aseptically removing the organic solvent; milling the resulting suspension as necessary and the milled suspension into suitable containers.
If the suspensions requires milling, then it is reticulated for a period of time through the colloid mill to ensure complete dispersion.