SUSPENSIONS.
Suspensions are important pharmaceutical dosage forms that are still widely in use today. Owing to their versatility they are often used in situations where an ‘emergency’ formulation is required.
Common pharmaceutical products that are suspensions include:
_ ear drops
_ enemas
_ inhalations
_ lotions
_ mixtures for oral use.
British Pharmacopoeia (BP) defi nition (oral suspensions)
Oral suspensions are oral liquids containing one or more active ingredients suspended in a suitable vehicle. Suspended solids may slowly separate on standing but are easily redispersed.
A pharmaceutical suspension is a preparation where at least one of the active ingredients is suspended throughout the vehicle. In contrast to solutions (see Chapter 2), in a suspension at least one of the ingredients is not dissolved in the vehicle and so the preparation will require shaking before a dose is administered.
Diffusible and indiffusible suspensions
Diffusible suspensions
These are suspensions containing light powders which are insoluble, or only very slightly soluble in the vehicle, but which on shaking disperse evenly throughout the vehicle for long enough to allow an accurate dose to be poured.
Indiffusible suspensions
These are suspensions containing heavy powders which are insoluble in the vehicle and which on shaking do not disperse evenly throughout the vehicle long enough to allow an accurate dose to be poured. In the preparation of indiffusible suspensions, the main difference when compared to diffusible suspensions is that the vehicle must be thickened to slow down the rate at which the powder settles. This is achieved by the addition of a suspending agent.
Choice of suspending agent
The amount of suspending agent used in any given formulation depends on the volume of vehicle being thickened. It does not vary with the amount of powder in the preparation. A suspending agent is intended to increase the viscosity of the vehicle and therefore slow down sedimentation rates. This outcome could also be achieved by decreasing the particle size of the powder in suspension. The most common suspending agents used in extemporaneous dispensing are Tragacanth BP (internal or external suspensions), Compound Tragacanth Powder BP (containing: 15% Tragacanth BP, 20% Acacia BP, 20% Starch BP and 45% Sucrose BP) (internal suspensions) and Bentonite BP (external suspensions). Details on the appropriate quantities to use can be found below.
General method
General method for the preparation of a suspension containing a diffusible solid
1. Check the solubility in the vehicle of all solids in the mixture.
2. Calculate the quantities of vehicle required to dissolve any soluble solids.
3. Prepare any Double Strength Chloroform Water BP required.
4. Weigh all solids on a Class II or electronic balance.
5. Dissolve all soluble solids in the vehicle in a small glass beaker using the same procedures as outlined in Chapter 2.
6. Mix any insoluble diffusible powders in a porcelain mortar using the ‘doubling-up’ technique to ensure complete mixing (see key point below).
7. Add a small quantity of the vehicle (which may or may not be a solution of the soluble ingredients) to the solids in the mortar and mix using a pestle to form a smooth paste.
8. Add further vehicle in small quantities, and continue mixing until the mixture in the mortar is of a pourable consistency.
9. Transfer the contents of the mortar to a conical measure of suitable size.
10. Rinse out the mortar with more vehicle and add any rinsings to the conical measure.
11. Add remaining liquid ingredients to the mixture in the conical measure. (These are added now, as some may be volatile and therefore exposure whilst mixing needs to be reduced to prevent loss of the ingredient by evaporation.)
12. Make up to fi nal volume with vehicle.
13. Stir gently, transfer to a suitable container, ensuring that all the solid is transferred from the conical measure to the bottle, and label ready to be dispensed to the patient.
General method for the preparation of a suspension containing an indiffusible solid
Oral indiffusible suspensions are prepared using the same basic principles as for oral diffusible suspensions. The main difference is that the preparation will require the addition of a suspending agent. The suspending agent of choice will normally be combined with the indiffusible solid using the ‘doublingup’ technique before incorporation into the product.
1. Check the solubility in the vehicle of all solids in the mixture.
2. Calculate the quantities of vehicle required to dissolve any soluble solids.
3. Prepare any Double Strength Chloroform Water BP required.
4. Weigh all solids on a Class II or electronic balance.
5. Dissolve all soluble solids in the vehicle in a small glass beaker.
6. Mix any insoluble indiffusible powders and the suspending agent in a porcelain mortar using the ‘doubling-up’ technique to ensure complete mixing.
7. Add a small quantity of the vehicle (which may or may not be a solution of the soluble ingredients) to the solids in the mortar and mix using a pestle to form a smooth paste.
8. Add further vehicle in small quantities, and continue mixing until the mixture in the mortar is a pourable consistency.
9. Transfer the contents of the mortar to a conical measure of suitable size.
10. Rinse out the mortar with more vehicle and add any rinsings to the conical measure.
11. Add remaining liquid ingredients to the mixture in the conical measure. (These are added now, as some may be volatile and therefore exposure whilst mixing needs to be reduced to prevent loss of the ingredient by evaporation.)
12. Make up to fi nal volume with vehicle.
13. Stir gently, transfer to a suitable container, ensuring that all the solid is transferred from the conical measure to the bottle, and label ready to be dispensed to the patient.
Advantages and disadvantages of suspensions as dosage forms
Advantages
1. Insoluble drugs may be more palatable.
2. Insoluble drugs may be more stable.
3. Suspended insoluble powders are easy to swallow.
4. The suspension format enables easy administration of bulk insoluble powders.
5. Absorption will be quicker than solid dosage forms.
6. Lotions will leave a cooling layer of medicament on the skin.
7. It is theoretically possible to formulate sustained-release preparations.
Disadvantages
1. Preparation requires shaking before use.
2. Accuracy of dose is likely to be less than with equivalent solution.
3. Storage conditions can affect disperse system.
4. Suspensions are bulky, difficult to transport and prone to container breakages.
Suspension
A pharmaceutical suspension may be defined as a coarse dispersion containing finely divided insoluble material suspended in a liquid medium.
The physical chemist defines the word “suspension” as two-phase system consisting of an undissloved or immiscible material dispersed in a vehicle (solid, liquid, or gas).
Generally pharmaceutical suspensions contain aqueous dispersion phase however in some cases they may be an oily or organic phase. The suspensions have dispersed particles above the colloidal size that is mean particle diameter above 1µm.
Routes of administration of suspension
Suspensions are used to administer insoluble and distasteful substances in a form that is pleasant to taste by providing a suitable form, for the application of dermatological materials to the skin and mucous membrane and for parenteral usage. Thus suspensions can be administered by oral, topical, parenteral and ophthalmic application
Oral suspensions
Patients who have problems in swallowing solid dosage forms require drugs to be dispersed in a liquid. Oral suspensions permit the formulation of poorly soluble drugs in the form of liquid dosage form. As these suspensions are to be taken by oral route therefore they must contain suitable flavoring and sweetening agents. Drugs, which possess unpleasant taste in solution dosage form like paracetamol, chloramphenicol palmitate etc. can be formulated as palatable suspension as they are suitable for administration to peadiatric patients. Finely divided solids like kaolin, magnesium carbonate etc., when administered in the form of suspensions will be available to a higher surface area for adsorptive and neutralizing actions in the gastrointestinal tract.
Topical suspensions
These suspensions are meant for external application and therefore should be free from gritty particles. There consistency may range from fluid to paste. Example of fluid suspension includes calamine lotion, which leave a deposit of calamine on the skin after evaporation of the aqueous dispersion phase. Zinc cream has a consistency of semisolid. Zinc cream consists of high percentage of powders dispersed in an oily (paraffin) phase.
Parenteral suspensions
These suspensions should be sterile and should possess property of syringability. Parenteral suspensions are also used to control the rate of absorption. As the absorption rate of the drug is dependent on the dissolution rate of the solid. Therefore by varying the size of the dispersed solid particles the duration and absorption can be controlled. Vaccines are also formulated as dispersions of killed microorganisms for example in Cholera vaccine or as toxoid adsorbed on to substrate like aluminium hydroxide or phosphate for prolonged antigenic stimulus. For example adsorbed Diphtheria and Tetanus toxoid.
Ophthalmic suspensions
These should also be sterile and should possess very fine particles. Drugs, which are unstable in aqueous solution, are formulated as stable suspensions using non-aqueous solvents. For example fractioned coconut oil is used for dispersing tetracycline hydrochloride for ophthalmic use.
Properties of Suspensions
Desirable properties of suspensions
Suspensions should possess good pourability leading to ease of removal of dose from container.
They should have good organoleptic properties.
The particle size distribution should be uniform.
There should be ease of redispersion of settled solid particles.
They should be physically and chemically stable.
They should be resistant against microbial contamination.
Theories involved in disperse phase
Interfacial phenomenon
Smaller solid particles are used to disperse in a continuous medium. Smaller particle size and large surface area is associated with a surface free energy making it thermodynamically unstable. Thus the particles possess high energy which leads to grouping together to reduce surface free energy thus leading to formation of floccules. These floccules are held together among themselves and within by weak van der waals forces. However in cases where particles are adhered by stronger forces to form aggregates forming hard cake. These phenomena occur in order to make system more thermodynamically stable. In order to achieve a state of stability the system tend to reduce the surface free energy, which may be accomplished by reduction of interfacial tension that is achieved by use of surfactants.
Electrical Double layer and Zeta potential
Most surfaces acquire a surface electric charge when they come in contact with aqueous surface. A solid charged surface when in contact with an aqueous medium possesses positive and negative ions. The counter ions are attracted towards the surface co-ions that ions of like charge are repelled away from the surface. This results in the formation of an electrical double layer, made up of the charged particles. The charges influence the distribution of ions resulting in the formation of an electrical double layer, made up of the charged surface and a neutralizing excess of counter-ions over co-ions distributed in a diffuse manner in the aqueous medium resulting into electric potentials. The zeta potential refers to the electrostatic charge on the particles, which causes them to move in electric field towards a pole of opposite charge. Its magnitude may be measured using microelectrophoresis or any other of the electrokinetic phenomena. The two parts of the double layer are separated by a plane, the stern plane. The stern plane, which occur at a hydrated ion radius from the particle surface. The ions or molecules to be strongly adsorbed at the surface-termed specific adsorption rather than by electrostatic attraction. The specifically adsorbed ion or molecule may be uncharged e.g., with non-ionic surfactant. Surfactants specifically adsorb by the hydrophobic effect and impart effect on the stern potential. Thus the zeta potential is reduced by additives to the aqueous system in either (or both) of two different ways.
Sedimentation Concept
In dispersions the dispersed particles encounters between themselves as a result of Brownian movement. Depending upon the forces of interactions-electrical forces of repulsion, forces of attraction and forces arising due to solvation, the particles aggregate to form collection of particles. The collisions result in permanent contact of particles known as coagulation leading to the formation of larger aggregates, which sediment out known to exhibit flocculation or if the particles rebound they remain freely suspended and form stable system. These particles sediment according to stokes’ law.
According to Stokes’ law
v = 2a2g (σ-ρ)/9η
Where v is velocity of sedimentation, a is the radius of particles, σ density of solid particles, g is acceleration due to gravity and ρ is the density and η is the viscosity of the dispersion phase.
The equation of stokes’ law reflects that larger particles exhibit greater velocity of sedimentation. The velocity of sedimentation is inversely proportional to the viscosity of dispersion medium.
DLVO Theory
According to DLVO (Derjaguin Landau Verwey and overbeek) theory, in a dispersed system the interactions involved between particles are electrical repulsion and van der Walls attraction. The total potential energy of interaction is addition of these parameters. Fig.1. the curve between total energy of interactions versus distance between particles. In the curve the attraction predominates at small distances hence a very deep primary minimum. The attraction at large interparticle distance that produces the secondary minimum as the fall-off in repulsive energy with distance is more rapid than that of attractive energy. At intermediate distances double-layer repulsion is larger giving a primary maximum in the curve. If this maximum is large as compared to thermal energy of the particles the system would be stable. Otherwise the interacting particles will reach the energy depth of the primary minimum and irreversible aggregation. If the secondary minimum is smaller than thermal energy the particles will not aggregate but will always repel one another leading a de-flocculated system, but if it is significantly larger than thermal energy. A loose aggregate will form with the ease of redispersibility by shaking i.e., flocculation occurs. The depth of secondary minimum depends on particle size and particles should be of radius greater than 1 m. The particles possessing particle size less than 1 m exhibit great attractive forces for flocculation to occur. The height of the primary maximum energy barrier to coagulation depends on the zeta potential. The addition of electrolyte compresses the double layer and reduces the zeta potential, this has the effect of lowering the primary maximum and deepening the secondary minimum and is the principle of the controlled flocculation approach to pharmaceutical suspension. The primary maximum can also be lowered (and the secondary minimum deepened) by adding substances, such as ionic surfactants, which are adsorbed within the Stern Layer.
Types of suspensions
Suspensions are classified as:
1. According to the route of administration
Oral suspensions should be taken by oral route and therefore must contain suitable flavoring and sweetening agents.
Topical suspensions meant for external application and therefore should be free from gritty particles.
Parenteral suspensions should be sterile and should possess property of syringability.
Ophthalmic suspensions should be sterile and should possess very fine particles
2. According to nature of dispersed phase and methods of preparation
The suspensions are classified as suspensions containing diffusible solids, indiffusible solids, poorly wettable solids, precipitate forming liquids and products of chemical reactions.
3. According to nature of sediment
Flocculated Suspensions, in this type the solid particles of dispersed phase aggregate leading to network like structure of solid particles in dispersion medium. The aggregates form no hard cake. These aggregates settle rapidly due to their size as rate of sedimentation is high and sediment formed is loose and easily redispersible. The suspension is not elegant, as dispersed phase tends to separate out from the dispersion medium. Therefore it is desired that flocculation should be carried out in a controlled manner so that a balance exists between the rate of sedimentation and nature of sediment formed and pourability of the suspension.
Non-flocculated Suspensions, in this type the solid particles exist as separate entities in dispersion medium. The sediments form hard cake. The solid drug particles settle slowly as rate of sedimentation is low. As sediments are formed eventually there is difficulty of redispersion. The suspension is more elegant as dispersed phase remain suspended for a long time giving uniform appearance.
Various approaches for developing suspensions
Structured Vehicles
The approach employed in the preparation of physically stable suspensions involve the use of structured vehicle so that particles remain deflocculated and applying the principles of flocculation to produce floccules that settle rapidly with ease of dispersibility with a minimum agitation. Structured vehicles act by entrapping the deflocculated particles so that no settling occurs. Practically some degree of sedimentation usually takes place. The shear-thinning property of these vehicles facilitates the reformation of a uniform dispersion when shear is applied. Thus the product must flow readily from the container and possess a uniform distribution of particles in each dose. Controlled Flocculation From stability point of view a suspension in which all the particles remain discrete are regarded to be stable. However in pharmaceutical suspension solid particles are coarser and sedimentation is due to size of the particles. The electrical repulsive forces between the particles allow to form a closely packed sediment at the bottom, whereas the smaller particles fills within the voids of larger particles leaving a cloudy supernatant liquid due to colloidal particles. The particles, which form the lowest layer in the pack, are pressed by the weights of the particles above them thus overcoming the repulsive barrier. Whereas in the case of particles in the secondary minimum, which is a desirable state for a pharmaceutical suspension, the particles form a loose aggregates known as floccules. The sedimentation of floccules is rapid leading to loosely packed high volume sediment which are easily redispersible. The supernatant liquid is clear as colloidal particles get entrapped within the floccules and sediment with them. Particles with size greater than 1 m should posses high charge to show a deep secondary minimum for flocculation to occur as the attractive force depend on particle size, shape and concentration. It is essential with highly charged particles to control the depth of the secondary minimum to induce a desired flocculation state, which is achieved by the addition of electrolytes or ionic surfactants with reduction of zeta potential. This results in production of desired secondary minimum leading to floccules, which is termed as controlled flocculation (Fig.2).
Rheological Behaviour
Plastic or pseudoplastic flow is exhibited by flocculated suspension depending upon concentration. The apparent viscosity of flocculated suspensions is high when applied shearing stress is low but decreases as the applied stress increases and the attractive forces resulting in flocculation are overcome. The dialant flow is exhibited by the concentrated deflocculated suspensions. The apparent viscosity is low at low shearing stress however it increases as the applied stress increases. The rheological consideration are of interest to investigate the viscosity of a suspension as it affects the settling of dispersed particles, transformation of flow properties while a suspension is shaken and product is poured out of bottle and the spreading qualities of the lotion when it is applied to effected area.
Formulation of Suspensions
Suspensions containing diffusible solids consist of solids insoluble in water but easily wettable. On shaking with water solid particles diffuse readily through out the liquid and remain suspended for a long time. The suspensions containing diffusible solids are prepared by triturating the solids in a mortar with sufficient quantity of vehicle to form a smooth cream. Any soluble nonvolatile substance is then added by separately dissolving them in a small quantity of vehicle. More vehicles are then added and any foreign particle is strained through a muslin cloth. Any volatile component is added at this stage and adding the required quantity of vehicle makes up the final volume.
Example: Magnesium Trisilicate Mixture
Magnesium Trisilicate
Light Magnesium Carbonate
Sodium bicarbonate
Concentrated Peppermint water 2.5 ml
Chloroform water 50.0 ml
Purified water qs to 100 ml
Suspensions containing indiffusible solids consist of substances, which do not remain distributed in the dispersion medium when shaken for long time to ensure uniformity of dose. They are prepared by adding a suitable thickening agent to the vehicle, which increases the viscosity of the vehicle and delays the separation or sedimentation of indiffusible particles.
Example: Calamine Lotion
Calamine
Zinc Oxide
Bentoite
Sodium Citrate
Liquified Phenol 0.5 ml
Glycerine 5 ml
Purified water qs to 100ml
Suspensions containing poorly wettable solids consist of substances, which are poorly soluble, and at the same time poorly wetted by the dispersion medium, and clump together with the difficulty to disperse. They are prepared by including suitable wetting agent in the formulation. These agents get adsorbed at the solid/liquid interface and promote wetting of the solid particles by the liquid of the dispersion medium.
Example: Sulphur Lotion
Precipitated Sulphur
Quillia Tincture 0.5 ml
Glycerin 2.0 ml
Alcohol (95%) 6 ml
Calcium hydroxide solution qs to 100ml
Suspensions of precipitate forming liquids consist of liquid tinctures which are alcoholic or hydroalcoholic extract of vegetable drugs which contain resinous material. When tinctures are added to water they precipitate. Precipitates are indiffusible and stick to the walls of the container. They are prepared by adding a suitable thickening agent prior to the addition of the precipitate forming liquid.
Example: Lobelia and Stramonium Mixture
Lobelia Ethereal Tincture 16 ml
Tragacanth mucilage 40 ml
Potassium Iodide
Chloroform water qs to 180 ml
Suspensions produced by chemical reactions are prepared by mixing two dilute solutions of reactants to form a fine precipitate. Generally precipitates so formed are diffusible and no suspending agent is required. If precipitate is indiffusible a suitable thickening or suspending agent may be added. They are prepared by dissolving the reactants separately in approximately half volumes of the vehicle and the two portions are then mixed together.
Example: Zinc Sulphide Lotion
Zinc Sulphate
Sulphurated Potash
Purified water qs to 100 ml
Stability of Suspensions
The physical stability of a pharmaceutical suspension is the condition in which the particles do not aggregate and in which they remain uniformly distributed throughout the dispersions. In order to achieve this ideal situation the suspension should have additive, which are added to achieve ease in resuspension by a moderate amount of agitation. Taking a case example: In case of dispersion of positively charged particles that is flocculated by addition of an aninonic electrolyte like monobasic potassium phosphate. The physical stability of the system is enhanced by addition of carboxymethylcellulose, Carbopol 934, veegum, tragacanth or bentonite either alone or in combination. No physical incompatibility is recorded as majority of hydrophilic colloids are negatively charged and are compatible with anionic flocculating agents. When a flocculated suspension of negatively charged particles with a cationic electrolyte is prepared (aluminum chloride) the addition of hydrocolloid may result in an incompatible product resulting in stingy mass, which has no suspending action, and settle rapidly. In such a condition protective agent is added to change the sign on the particles from the negative to positive is employed which can also be achieved by the adsorption onto the particle surface by fatty acid amine or gelatin. Thus an anionic electrolyte is used to produce floccules that are compatible with negatively charged suspending agent.
Quality control tests for suspensions
Sedimentation volume
Redispersibility is the major consideration in assessing the acceptability of a suspension. The measurement of the sedimentation volume and its ease of redispersion form two of the most common basic evaluative procedures. The sedimentation volume is the simple ratio of the height of sediment to initial height of the initial suspension. The larger the value better is the suspendability.
Particle size and size distribution
The freeze-thaw cycling technique used to assess suspension for stress testing for stability testing result in increase of particle growth and may indicate future state after long storage. It is of importance to study the changes for absolute particle size and particle size distribution. It is performed by optical microscopy, sedimentation by using Andreasen apparatus and Coulter counter apparatus. None of these methods are direct methods. However microscopic method allows the observer to view the actual particles. The sedimentation method yields a particle size relative to the rate at which particles settle through a suspending medium.
Rheological studies
Rheologic methods can help in determining the settling behaviour of the suspension. Brookefield viscometer with variable shear stress control can be used for evaluating viscosity of suspensions. It consist of T-bar spindle which is lowered into the suspension and the dial reading is noted which is a measure of resistance the spindle meets at various levels in the suspension. This technique also indicates in which level of the suspension the structure is greater due to particles aggregates. Data obtained on aged and stored suspension reveals whether changes have taken place.
Stability testing
It is not possible to conduct accelerated temperature studies as it can be done in solutions. The formulation exhibiting thixotropic properties a rise in temperature would change the properties. In this physical form, the preparation would exhibit parameters that could not be extrapolated to those that would exist in the normal system. The valid temperature data could be obtained that will be useful in the estimation of the physical stability of a product at normal storage conditions. The extended aging tests must be employed under various conditions to obtain the desired information.
Sustained release suspensions
A suspension usually gives a longer duration of action as compared to an aqueous solution when given intramuscularly or subcutaneously. The drug is continuously dissolved to replenish what is being lost. The constraints are imposed by stability, syringeability, pain upon injection and minimum effective concentration. The sustained release by suspensions is achieved by decreasing surface area, diffusion coefficient and solubility. An example of sustained release suspension is that of insulin. Insulin is normally administered subcutaneously and it precipitates as an insoluble complex in the presence of zinc chloride and depending on the pH either an amorphous or crystalline form results. The crystalline form is less soluble than the amorphous form and result in longer duration of action. Extended insulin zinc suspension USP consist of crystalline zinc complex. Another example includes Penicillin G procaine a sparingly soluble form of penicillin G. Others include medroxyprogestrone acetate (Depo-provera), triamcinolone hexacetonide (Aristopan ) etc.
Formulation Additives
In addition to vehicle, stabilizer, sweetening and flavouring agents, which are common in liquid dosage forms, the following additives are required to prepare suspensions which include:
1. Suspending and Thickening agents
They are added with the objective to increase apparent viscosity of the continuous, phase thus preventing rapid sedimentation of the dispersed particles. The selection of the type and concentration of a suspending agent depends on sedimentation rate of dispersed particles, pourability and spreadibility. The ideal suspending agent should have a high viscosity at negligible shear i.e., during shelf storage and it should have a low viscosity at high shearing rates i.e., it should be free flowing during agitation, pouring and spreadibility. A suspending agent that is thixotropic as well as pseudoplastic should prove to be useful as it forms a gel on standing and becomes fluid when shaken. They include natural polysaccharides (Gum Acacia, Gum Tragacanth, Guar Gum, Sodiun Alginate, Xanthan Gum and Carrageenan), Semi-synthetic polysaccharides (Sodium Carboxymethylcellulose, Methyl Cellulose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, Hydroxypropyl Methyl Cellulose and Microcrystalline Cellulose), Clays (Aluminium Magnesium Silicate, Bentonite and Hectorite) and synthetic agents (Carbomer, Colloidal silicon dioxide). Pseudoplastic substances like tragacanth, sodium alginate and sodium carboxymethyl cellulose show these desirable qualities. In cases of combination use of suspending agents like bentonite and CMC dispersions are both pseudoplastic and thixotropic.
A. Natural Polysaccharides
Gum Acacia :It is the dry exudates obtained from stems and branches of various species of Acacia. It has low thickening properties but it is a good protective colloid. It is used in combination with tragacanth and starch for internal preparations but is too sticky to be being a natural product, acacia may be frequently contaminated with microorganism such as Escherichia coli and Salmonella species and may need to be sterilized before use. Preservative such as chloroform water, benzoic acid or hydroxybenzoates should be included in formulations containing Gum Acacia.
Gum Tragacanth: Gum Tragacanth is dried exudates obtained from Astragalus gummifer or other species of Astragalus. It is widely used as suspending agent in form of tragacanth mucilage or compound tragacanth powder which consists of a mixture of acacia (20%), tragacanth (15%), starch (20%) and sucrose (45%). Tragacanth forms viscous solution or gels with water, depending on the concentration usually the powdered tragacanth is first dispersed in a wetting agent, such as alcohol, to prevent agglomeration on the addition of water. Tragacanth gels are non thixotropic and most stable at pH values between 4 and 7.5. Tragacanth is non-toxic and almost tasteless and is widely used in suspensions for internal use. Being less sticky, it may also be used for external applications.
Guar Gum: It consists of gum obtained from the ground endosperms of the seeds of Cyamopsis tetragonolobus belonging to family Leguminosae. Guar Gum disperses in hot and cold water to form a colloidal solution. A 1% aqueous dispersion has same viscosity to acacia mucilage, while 3% dispersion has similar viscosity to tragacanth mucilage. Guar Gum is a poor suspending agent for insoluble powders. It is employed as a thickener in lotions in concentrations up to 2.5%. Maximum stability is achieved at pH values between 3 and 9. Dispersions can be preserved with benzoic acid 0.2%.
Sodium Alginate: Sodium Alginate consists of purified carbohydrate product extracted from brown seaweeds by use of dilute alkali. It chiefly consists of sodium salt of alginic acid. Various grades are usually available commercially for different applications and yield solutions of various viscosities. Sodium Alginate is slowly soluble in water. It is normally used in concentrations of between 1% and 5%. A 1% solution has suspending properties similar to those of tragacanth mucilage. Maximum stability is achieved at pH values between 4 and 10. It is generally dispersed in a wetting agent, such as alcohol, glycerol or propylene glycol before addition to water to prevent lump formation.
Xanthan Gum: Xanthan Gum consists of the purified polysaccharide gum obtained by fermentation of a carbohydrate by bacteria of genus Xanthomonas chiefly Xanthomonas campestris. It is soluble in hot and cold water and produces a viscous product that is stable over a wide range of temperature and pH. A 1% solution has a viscosity of about 1000 centipoise. Xanthan Gum has been used as an alternative to tragacanth in the preparation of suspensions. In comparison to tragacanth, it is easier to use and is capable of preparing suspensions of better quality and improved consistency.
Carrageenan: Carrageenan consists of hydrocolloidal material extracted from certain red seaweeds of class Rhodophyceae. It is soluble in 30 parts of water at 80o forming a viscous clear or slightly opalescent solution. Dispersions of Carrageenan are stable at pH values between 4 and 10. Carrageenan is used in pharmacy and the food industry as a suspending and gelling agent.
B. Semi-Synthetic Polysaccharides:
The Semi-Synthetic polysaccharides used as suspending and thickening agents mainly consists of derivatives of the natural polysaccharide, cellulose.
Sodium Carboxymethyl cellulose: It is also known as Carmellose Sodium, it consists of the sodium salt of Carboxymethyl ether derivative of cellulose. Different viscosity grades are available which yield 1% aqueous solutions with viscosities in the range of 6 to 4000 centipoise. It is used in the concentrations ranging from 0.25% to 1% in suspensions meant for oral, topical and parenteral use. It is soluble in hot as well as cold water forming stable mucilage within the range of 5 and 10. Being anionic, it is incompatible with the cationic compounds. Aqueous preparations that is unlikely to be stored for long periods should contain an antimicrobial preservative.
Methyl cellulose: It consists of the ethyl ether derivative of cellulose. It dispersed slowly in cold water to form colloidal solution but is insoluble in hot water. It is mainly employed as a suspending and viscosity increasing agent for both internal and external preparations. Various grades are available and are classified according to the viscosity of a 2% solution at 20o. The use of the lower viscosity grades is preferred at concentrations up to 5% while higher viscosity grades are used at concentration of 0.5% to 2%. An aqueous dispersion may be prepared by adding the methyl cellulose to about one third the required amount of boiling water and when the powder is thoroughly hydrated, adding the remainder of the water preferably in form of ice and stirring until homogeneous. Methyl cellulose is nonionic and is stable over a wide range of pH values. Heating an aqueous dispersion first causes a decrease in viscosity followed by dehydration and gelling at 50o C. On cooling, however viscosity returns to normal.
Hydroxyethyl cellulose: It consists of the hydroxyethyl ether derivative of cellulose and is mainly used as viscosity increasing agent. It is soluble in cold as well as hot water and produces a clear solution that is stable even at higher temperatures. Various grades are available that differs in their aqueous viscosities. Solution display maximum stability in pH range 2 to 10.
Hydroxypropyl cellulose: It consists of hydroxypropyl ether derivative of cellulose and is mainly used as a viscosity enhancing agent for oral and topical use. It is soluble in water below 40o C and insoluble above this temperature. A wide range of grades are available that differs in their aqueous solution viscosities. Maximum stability is demonstrated at pH range 2 to 10.
Hydroxypropyl methyl cellulose: It is also known as Hypermellose, it consists of the hydroxypropyl derivative of methyl cellulose. It has properties similar to those of methyl cellulose but produces aqueous solutions with higher gelling points. Various grades are available that differs in their aqueous solution viscosities.
Microcrystalline cellulose: Microcrystalline cellulose is widely used as suspending agent, either alone or in conjunction with other cellulose derivatives such as Carboxymethyl cellulose sodium or hypermellose or with clays such as bentonite.
C. Clays:
Clays are inorganic materials, mainly hydrated silicates derived from natural sources. They form highly thixotropic gels. The gels must be preserved with suitable antimicrobial agents as clays are liable to heavy contamination with microbial spores.
Aluminium Magnesium Silicate: Also known as Veegum, Aluminium Magnesium Silicate is mainly used at a concentration range of 0.5% to 2% as a suspending agent for both internal and external preparations. A number of different grades are available; which are distinguished by the degree of alkalinity and the viscosity of an aqueous dispersion. Dispersions in water are thixotropic, and at concentration of 10% a firm gel is obtained. The viscosity of dispersions is increased by heating, by addition of electrolytes and at higher concentration by ageing.
Bentonite: Bentonite is a natural colloidal hydrated aluminium silicate found in the midwest of USA and Canada. Although it is insoluble in water, it absorbs large quantities of it and may swells up to 12 times its original volume. Bentonite in contact with water forms either sols or gels depending on its concentration. It is generally used at a concentration in between 0.5% to 2% for suspending powders in aqueous preparations such as calamine lotion. Dispersion shows maximum stability at pH values between 3 and 10.
Hectorite: Hectorite is a natural colloidal magnesium silicate having properties similar to bentonite. It swells up to 36 times its original volume and forms highly thixotropic gels at concentration of 1 to 2%. It may contain traces of lithium and fluorine and is mainly used in suspensions for external use.
D. Synthetic Agents:
The quality of synthetic agents tends to be less variable than that of suspending agents derived from natural sources.
Carbomer: Carbomer is a high molecular weight polymer of acrylic acid crosslinked with allyl sucrose. It dispersed in water to form an acidic colloidal solution of low viscosity, which produces a high viscous gel oeutralization with inorganic or organic bases like sodium hydroxide, triethanolamine, etc. several viscosity grades are available and the usual concentration used varies from 0.1% to 4% as suspending agent. Carbomer gels are most viscous between pH 6 and 11. The viscosity is reduced on lowering the pH to below 3 or rising above 12. Electrolytes also reduce the viscosity of carbopol dispersions. Carbomer is susceptible to oxidation especially on exposure to light and hence formulations should be stabilized by addition of appropriate antioxidants and chelating agents. Aqueous dispersion of Carbomer should also contain an antimicrobial preservative.
Colloidal Silicon dioxide: This is a form of Silicon dioxide having colloidal dimensions. It acts as a suspending agent by forming aggregates which associates to form three dimensional networks, thus preventing sedimentation. In a concentration between 1.5 to 4%, it acts as a suspending stabilizer while at higher concentrations, it forms a soft gel. Aqueous dispersions generally have a pH of 4 and neutralization does not affect the binding capacity.
2. WETTING AGENTS:
Although some insoluble solids get easily wetted by water, most of them exhibits hydrophobicity and does not get easily wetted by it. Wetting agents are additives which are usually added to decrease this hydrophobicity. These agents generally get adsorbed at the solid-liquid interface and promote wetting of the solid particles by the liquid of the dispersion medium. A variety of substances including the following have been employed as wetting agents.
Surfactants: Generally, Surfactants possessing HLB values between 7 and 9 have been employed as wetting agents. These orient themselves at solid-liquid interface and decrease the interfacial tension between the particles of the dispersed phase and the dispersed medium. Most surfactants are used at concentration of 0.1 to 0.2%. The minimum concentration that is sufficient to cause wetting should generally be employed since an excess of these agents may cause foaming in the preparation. Examples of surfactants employed for oral preparation includes polysorbates, sorbitan, esters, etc. for external preparations, sodium lauryl sulfate, sodium dioctyl sulfosuccinate and quillia extracts can also be used.
Hydrophilic Polymers: Various hydrophilic colloids such as acacia, bentonite, colloidal silicon dioxide and cellulose derivatives have also been employed as wetting agents. These act by coating the surface of hydrophobic particles and imparting hydrophilic character to these.
Hydrophilic Liquids: Hydrophilic liquids such as alcohol, glycerol, propylene glycol, etc. are sometimes employed as wetting agents. These penetrate the loose aggregates of solid particles and displace the air from the pores thus facilitating wetting of the particles by the dispersion medium.
3. DISPERSING AGENT
These additives are generally added as an aid to uniform distribution and dispersion of solid particles of the dispersed phase. Such agents are generally used during the preparation of deflocculated suspensions where they get adsorbed at the solid-liquid interface. Wetting agents such as surfactants are often employed as dispersing agents. Other agents used for this purpose include agents such as Darvans, Daxads, etc. which carry a good surface charge and get absorbed on the particles of the dispersed phase thus preventing their agglomeration.
4. FLOCCULATING AGENTS:
These are substances added to cause controlled aggregation of the particles of the dispersed phase in a suspension. Examples of such agents include surfactants, electrolytes and hydrophilic polymers.
Surfactants: Ionic as well as non-ionic surfactants may be employed as flocculation agent. The ionic surfactants such as sodium lauryl sulphate and sodium dioctyl sulfosuccinate act by neutralizing the surface charge on the particles of the dispersed phase, thereby reducing inter-particulate repulsion and causing aggregation. Non-ionic ones such as Spans and Tweens are believed to function by formation of bridges between the adjacent particles.
Electrolytes: Electrolytes such as sodium salt of acetates, phosphates and citrates have been commonly employed as flocculating agents. These acts by neutralizing the surface charge on the particles of the dispersed phase thereby reducing the electrical barrier between them. The effectiveness of the electrolytes as flocculating agents depends on the valance of the ions of these electrolytes. Thus, divalent ions are ten times more effective then the monovalent ions while trivalent ones are thousand times more effective. The concentration of the electrolytes used should be minimum that is required to cause flocculation since an excess may cause reversal of this phenomenon.
Hydrophilic Polymers: Hydrophilic polymers such as alginates, cellulose derivatives, tragacanth, carbomers, silicates, etc. have also been know to cause flocculation of particles of the dispersed phase. These polymers have a linear branched chain structure and form a gel like network within the system. They get adsorbed on to the surface of the dispersed particles and hold them in a flocculated state.
Suspensions of medicinal substances are prepared by two methods:
Dispersion
1. The method of obtaining the certain degree of dispersion by powdering dry medicinal substances
2. The method of “making muddy” for hydrophilic substances with a high density
(basic bismuth nitrate)
Condensation
1. The method of formation of large particles from molecules – aggregates, due to the chemical interaction or replacement of a solvent (Thin suspensions)
2. Аs a result of the chemical interaction;
3. Аs a result of the solvent’s replacement
Formulation of suspensions by the dispersion method
Formulation of suspensions with hydrophobic substances
Stage I Triturate a dry medicinal substance in the mortar
Stage II Triturate (according to the Deryagin rule) with 50% amount of the liquid (add 0.4-0.6 ml of a liquid (40-60%) per 1.0 g of the powdered substance)
Stage III Mix and dissolve in water (add water gradually) and transfer into the bottle for dispensing
Rp.: Zinci oxydi 10.0
Aquae purificatae 100 ml
Misce. Da. Signa. For washes.
WCP (front side)
Date № Pr.
Zinci oxydi 10.0
Aquae purificatae 100 ml
m total = 110.0
Prepared by: (Signature)
Checked by: (Signature)
Weigh
Stick the labels «External», «Shake well before use» and «Keep out of the reach of children».
Formulation of suspensions by the dispersion method
Method of “making muddy” (“shaking”) is applied for preparing suspensions with hydrophilic substances characterized by a great density.
Stage I Triturate a dry medicinal substance in the mortar
Stage II Triturate (according to the Deryagin rule) with 50% amount of the liquid calculated by the amount of a dry substance (add 0.4-0.6 ml of a liquid (40-60%) per 1.0 g of the powdered substance)
Stage III Add 5-10 % of the liquid to the mixture obtained, triturate, allow to stand for 1-2 minutes
Stage VI When the liquid is settled (the big particles settle at the bottom and the thin particles are on the top of the surface), transfer it into the bottle for dispensing.
The stages III-IV are repeated until all precipitate is transferred into a thin dispersed state.
Rp.: Bismuthi subnitratis 2.0
Aquae Menthae 200 ml
Misce. Da. Signa. 1 tablespoon
3 times a day.
Formulation of suspensions by the dispersion method
Rp.: Therpini hydrati 2.0
Natrii hydrocarbonatis 2.0
Aquae purificatae 100 ml
Misce. Da. Signa. 1 tablespoon
3 times a day.
The mixture is a suspension with terpin hydrate, a substance with poor expressed hydrophobic properties. Therefore, the suspension with terpin hydrate differs by the tendency to flocculation and, as a result, the tendency to fast sedimentation.
Measure 80 ml of the purified water and 20 ml of the 5 % sodium hydrocarbonate solution into the bottle for dispensing. Triturate
WCP (front side)
Date № Pr.
Aquae purificatae 80 ml
Solutionis Natrii hydrocarbonatis 5 % 20 ml
Therpini hydrati 2.0
Gelatosae 1.0
Vtotal = 100 ml
Prepared by: (signature)
Checked by: (signature)
Formulation of suspensions with hydrophobic substances
Rp.: Mentholi 0.5
Natrii hydrocarbonatis
Natrii tetraboratis aa 1.5
Aquae purificatae 100 ml
Misce. Da. Signa. Rinsing.
It is a suspension for external application with a hydrophobic odorous and volatile substance called menthol with distinctly expressed hydrophobic properties.
Measure 100 ml of the purified water into the bottle and dissolve sodium hydrocarbonate and sodium tetraborate (or take 30 ml of sodium hydrocarbonate as the 5% concentrated solution). Place
Rp.: Sulphuris praecipitati 2.0
Glycerini 5.0
Aquae purificatae 100 ml
Misce. Da. Signa. Rub into the head’s skin.
Potassium or green soap is used as a stabilizer of sulphur suspensions for external application in the ratio
Triturate sulphur with the part of glycerol of 0.8 –
Formulation of suspensions by the condension method
Rp.: Calcii chloridi 10.0
Natrii hydrocarbonatis 4.0
Aquae purificatae 200 ml
Misce. Da. Signa. 1 tablespoon 3 times a day.
СаCl2 + 2NaHCO3 = CaCO3↓ + H2O + 2NaCl
WCP (reverse side)
Sol. Calcium chloride 50 % (1:2): 10.0 ´ 2 = 20 ml
Sol. Sodium hydrocarbonate 5 % (1:20): 4.0 ´ 20 = 80 ml
Purified water: 200 – (20+80) = 100 ml
At first two solutions – calcium chloride solution and sodium hydrocarbonate solution – should be prepared and then mix these solutions. Measure 100 ml of the purified water into the bottle for dispensing, add 20 ml of 50 % calcium chloride solution and 80 ml of 5 % sodium hydrocarbonate solution.
Rp.: Plumbi acetatis
Zinci sulfatis ana 1.5
Aquae purificatae 100 ml
Misce. Da. Signa. For urethral injections.
Pb (CH3COO)2 + ZnSO4 = PbSO4 ↓ + Zn (CH3COO)2
It is impossible to use separate dissolution of substances in this case, as in the previous example, because the crystals of lead sulphate with the sharp edges will precipitate. At first powder dry solid ingredients in the mortar, then add water in half of the amount of the weight of dry substances, triturate until a pulp is obtained, add the remaining amount of water, mix and pour into the bottle for dispensing.
Opalescence and muddy mixtures are formed after adding tinctures, liquid extracts, aromatic liquids (ammonium anise drops) to aqueous solutions
STABILIZATION OF SUSPENSIONS
To increase of the aggregation stability of suspensions with hydrophobic substances, which do not form protective hydrate layers on the surface, it is necessary to lyophilize them, i.e. to add hydrophilic colloidal substances (stabilizers). Natural or synthetic high-molecular compounds (HMC): proteins, gelatosa, vegetative slime, natural polysaccharide complexes, methylcellulose, sodium – carboxymethylcellulose, polyvinylpyrrolidon, polyglycine, tweens, spens, bentonites, etc. are applied as stabilizers.
The stabilization of these substances consists of formation of hydrate layers on the surface of the suspension’s particles, as well as in spanning of these particles by long macromolecules.
The ratio between the suspension’s solid phase and protective HMC depends on a degree of the hydrophobic properties of solid substances and hydrophilic properties of protective substances. These data were scientifically proven by experiments
The amount of a stabilizer per
|
The name of a stabilizer |
The amount of a stabilizer per
|
|
|
with distinctly expressed hydrophobic properties: camphor, menthol |
with poor expressed hydrophobic properties: terpin hydrate, phenylsalicylate, etc. |
|
|
Gelatose |
1.0 |
0.5 |
|
5 % methylcellulose solution |
2.0 |
1.0 |
|
Tween-80 |
0.2 |
0.1 |
The rule of Deryagin
for thinner dispersion of powdered substances it is
necessary to add the liquid in half the amount
of its weight
The maximum effect of dispersion in the liquid medium is observed when adding 0.4-0.6 ml of a liquid
per
