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Suspension Lecture 7 Definition of suspension A dispersion of finely divided insoluble solid particles (disperse phase) in a fluid (dispersion medium) Dispersion medium: aqueous, oily liquid, and solvent Dispersed phase: insoluble solid Types of suspension according to particle size: Col...

Suspension Lecture 7 Definition of suspension A dispersion of finely divided insoluble solid particles (disperse phase) in a fluid (dispersion medium) Dispersion medium: aqueous, oily liquid, and solvent Dispersed phase: insoluble solid Types of suspension according to particle size: Colloidal dispersion: A disperse phase with a mean particle diameter of up to 1 μ Coarse suspension: A solid in liquid dispersion, in which the particles are above colloidal size  Suspensions are classified according to the route of administration 1.Oral suspensions must contain suitable flavoring and sweetening agents. 2.Topical suspensions meant for external application and therefore should be free from gritty particles. 3.Parenteral suspensions should be sterile and should possess property of syringability. 4.Ophthalmic suspensions should be sterile and should possess very fine particles 1- Oral suspensions Uses: Patients who have problems in swallowing solid dosage forms require drugs to be liquid. Poorly soluble drugs. Drugs with unpleasant taste in solution dosage form like (paracetamol, chloramphenicol palmitate) could be formulated as palatable suspension as they are suitable for administration to pediatric patients. Finely divided solids (kaolin, magnesium carbonate) when administered in the form of suspensions will be available to a higher surface area for adsorptive and neutralizing actions in GIT 2.Topical suspensions Suspensions for external application and should be free from gritty particles. There consistency may range from fluid to paste. Examples 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 3. Parenteral suspensions Sterile Examples Vaccines Should possess property of syringability They are formulated as dispersions of killed They are used to control the rate of absorption microorganisms for example in Cholera vaccine or as toxoid adsorbed on to substrate like aluminium As the absorption rate of the drug is dependent on the hydroxide or phosphate for prolonged antigenic dissolution rate of the solid stimulus. For example adsorbed Diphtheria and Tetanus toxoid. Therefore, by varying the size of the dispersed solid Some X-ray contrast media particles the duration and absorption can be controlled Barium sulphate, for the examination of the alimentary tract, is available as a suspension for either oral or rectal administration, and propyliodone is dispersed in either water or arachis oil for examination of the bronchial tract. 4. Ophthalmic suspensions Sterile very fine particles Drugs, which are unstable in aqueous solution, are formulated as stable suspensions using non-aqueous solvents. Example Fractioned coconut oil is used for dispersing tetracycline hydrochloride for ophthalmic use. Methods used to increase stability of easily degraded drug by using suspension A- It may be possible to synthesize an insoluble derivative and formulate it as a suspension E.g.: (oxytetracycline HCl aqueous solution would hydrolyze rapidly, while its insoluble calcium salt of oxytetracycline in aqueous vehicle is stable. B- Formulate the drug as reconstituted suspension This will decrease the contact between solid drug particles and dispersion medium ( Ampicillin reconstituted its shelf life 7 days at room temperature and 14 days refrigerated). C- Formulate the drug as Suspension in oil A drug that degrades in the presence of water may be suspended in a non-aqueous vehicle (Phenoxmethylpenicillin oral suspension in coconut oil). Properties of good pharmaceutical suspensions Suspensions should possess good pourability leading to ease of removal of dose from container. The viscosity must not be so high that removal of the product from the container is difficult. The particle size distribution should be uniform. There should be ease of redispersion of settled solid particles. They should be physically and chemically stable. NB: Suspensions are more stable than solutions. They should be resistant against microbial contamination. Theories involved in disperse phase (In-soluble powder) Interfacial phenomenon Caking Sedimentation concept 1. 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. ΔF = σ.ΔA In order to achieve a state of stability the system F =surface free energy tend to reduce the surface free energy, which may be accomplished by reduction of interfacial tension σ = interfacial tension that is achieved by use of surfactants ΔA = increase in total surface area 2. Caking Cake is formed by growing and fusing crystals together to form solid aggregate. This cake resists breakup upon shaking and form rigid aggregate of particles that larger and less suspendable. To overcome cake formation, suspension should be formed in the form of less rigid or loose aggregation of particles, that held together by weak bonds. This aggregation of particles is termed floc or floccules. The loose structure makes the aggregate to break easily and redisperse by small amount of agitation. 3.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 Stokes’ law 1- Larger particles exhibit greater velocity of sedimentation. But at the same time, we must avoid too much decrease in particle size because fine particle will form compact cake upon settling. 2- The velocity of sedimentation is inversely proportional to the V= d2g (σ-ρ)/18η viscosity of dispersion medium. However, product having very high v = velocity of sedimentation in cm/sec viscosity is not desirable, because d = the diameter of particles in cm the removal of the product from σ = density of solid particles the container will be difficult and g = acceleration due to gravity ρ = the density of the dispersion phase the re-dispersibility of product will η = the viscosity of the dispersion phase in poise. be difficult. Dilute pharmaceutical suspensions containing less than 2gm per 100 ml of liquid conform roughly to these conditions.  Suspensions are classified according to the route of administration 1.Oral suspensions must contain suitable flavoring and sweetening agents. 2.Topical suspensions meant for external application and therefore should be free from gritty particles. 3.Parenteral suspensions should be sterile and should possess property of syringability. 4.Ophthalmic suspensions should be sterile and should possess very fine particles 2. According to nature of dispersed phase and methods of preparation Dispersed phase: Diffusible solids In-diffusible solids Poorly wettable solids Methods of preparation: Precipitate forming liquids Products of chemical reactions 3. According to nature of sediment Flocculated Suspensions Deflocculated Suspensions The solid particles of dispersed phase The solid particles exist as separate entities in aggregate leading to network like structure of solid particles in dispersion medium. dispersion medium. The sediments form hard cake. The aggregates form no hard cake. The solid drug particles settle slowly as rate of These aggregates settle rapidly due to sedimentation is low. their size as rate of sedimentation is high As sediments are formed eventually there is and sediment formed is loose and easily re- difficulty of redispersion. The suspension is more dispersible. elegant as dispersed phase remain suspended for a Not elegant shape long-time giving uniform appearance. More elegant  Types of suspensions 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. Deflocculated suspension Flocculated suspension The larger particles settle more rapidly than smaller Flocculated particles tend to fall together particles No clear boundary is formed, and the supernatant Distinct boundary between the sediment and the remains turbid for longer time supernatant liquid. The liquid above the sediment is clear Slow rate of sedimentation and the sediment The sediment is in the form of loose aggregated becomes compacted and very difficult to redisperse and easily redispersed by agitation (caking). The final volume of sediment is very small The final volume of sediment is large Approaches for developing stable suspensions 1- The use of structured vehicle (increase viscosity), to maintain flocculated particles in suspension. So that, ideally, no settling occurs. 2- Particle size control 3- Use of wetting agents 4- The application of the principles of flocculation, to produce flocs that, although they settle rapidly, are easily resuspended with a minimum of agitation. 1.Structured vehicle 1-Pseudoplastic and plastic in nature, it is desirable that Thixotropy be associated with these types of flow. Disadvantages of 2-Act by entrapping the deflocculated particles so Solutions that no settling occurs. Practically some degree of sedimentation usually takes place. 3-The shear-thinning property of these vehicles facilitates the reformation of a uniform dispersion when shear is applied. 4-Thus, the product must flow readily from the container and possess a uniform distribution of particles in each dose. 5-Optimum physical stability will be obtained when the suspension is formulated with flocculated particles in a structured vehicle of the hydrophilic colloid. 2. Particle size The advantages of small particle size is: a. Avoid the change in the particle size distribution b. Control the rate of dissolution of the drug c. Enhance bioavailability N.B: The drug to be suspended is subdivided form prior to formulation, as the rate of sedimentation is retarded by a reduction in its size. Large particles, about 5 μm diameter will: a- Impart gritty texture to the product. b- Cause irritation if injected or instilled into the eyes. c- Block hypodermic needle (over 25 μm) diameter particularly if acicular in shape rather than isodiametric. Crystal growth Occurs on storage, particularly if temperature fluctuations occur. It might happen due to the presence of difference in size of particles. This is because the solubility of the drug may increase as the temperature rises, but on cooling, the drug will crystallize out. If the drug is poly-dispersed, then the very small crystals of less than 1μ diameter will exhibit a greater solubility than the larger ones. Over time the small crystals will become even smaller, whereas the diameters of the larger particles will increase. How to prevent crystal growth? 1- Use surfactant The inclusion of surface-active agents or polymeric colloids, which adsorb on to the surface of each particle, may also help to prevent crystal growth. 2- Use the stable polymorphic of the drug Different polymorphic forms of a drug may exhibit different solubilities, the metastable state being the most soluble. 3.Wetting of particles Usually added to decrease this hydrophobicity. They get adsorbed at the solid-liquid interface and promote wetting of the solid particles by the liquid of the dispersion medium. Some insoluble solids may be easily wetted by water and will disperse Types of Powders readily throughout the aqueous phase with minimal agitation. Hydrophilic Powders soluble solids easily wetted by water (talc, ZnO, MgCO3). Most, however, will exhibit varying degrees of hydrophobicity and will not be easily wetted. Some particles will form large porous Hydrophobic Powders clumps within the liquid, whereas others They are not easily wetted by water and show a large remain on the surface and become contact angle such as sulfur and charcoal. attached to the upper part of the container.  a- Surfactants Types of wetting agents b-Hydrophilic colloids c-Solvents a- Surface active agents Mechanism of action: Reduce interfacial tension between solid particles and vehicle Generally, non-ionic Surfactants possessing HLB values between 7 and 9 have been employed as wetting agents in a concentration up to 0.1%. -For oral use, polysorbate (Tweens) and sorbitan esters (Spans). -For parenteral use polysorbates, Pluronics, and lethicin. Disadvantage of surfactants as wetting agents: 1) Excessive foaming. 2) Possible formation of a deflocculated system b- Hydrophilic colloids These act by coating the surface of hydrophobic particles and imparting hydrophilic character to these. Various hydrophilic colloids such as acacia, bentonite, colloidal silicon dioxide and cellulose derivatives have also been employed as wetting agents. Disadvantages may produce a deflocculated system particularly if used at low concentration c-Solvents 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. Hydrophilic liquids such as alcohol, glycerol, propylene glycol, etc. are sometimes employed as wetting agents. 4-Controlled flocculation Formation of a loose aggregation of discrete particles held together in a net work like structure by physical adsorption, bridging or when the van der wall forces of attraction exceed forces of repulsion. The stable flocs contain varying amounts of entrapped liquid medium within the net work like structure. 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 Controlled flocculation is usually achieved by: The zeta potential refers to the electrostatic 1- The use of inorganic electrolytes or ionic charge on the particles, which causes them to move surfactants to control zeta potential (addition in electric field towards a pole of opposite charge. of an adsorbed ion whose charge is opposite to the sign of the particles, so particles approach each other and form loose aggregates or flocs. 2-The addition of polymers to enable crosslinking to occur between particles. 3- Hydrophilic colloids ( Suspending agents) I- Electrolytes Mechanism: 1- Decrease electrical barrier between particles 2- Decrease zeta potential 3-Formation of a bridge between particles to link them in a loosely arranged structure ( flocculation). The Hardy Schulze rule: The ability of an electrolyte to flocculate particles depends on the valency of ions. Thus, divalent ions are ten times more effective than the monovalent ions while trivalent ones are thousand times more effect a- Bismuth subnitrate suspension (possess positive charge and positive zeta potential) Because of the strong force of repulsion between adjacent molecules, the system is deflocculated. After the addition of (KH2PO4), decrease in zeta potential by adsorption of negatively charged phosphate anion. With continues addition of electrolyte, the zeta potential falls into zero. If the concentration increases, charge reversal (deflocculated suspension) b- Sodium salts of acetates, phosphates and citrates (possess negative charge and positive zeta potential. The concentration chosen will be that which produces the desired degree of flocculation. Care must be taken not to add excessive electrolyte charge reversal may occur producing a deflocculated system II-Surfactants Ionic surfactants Such as sodium lauryl sulphate and sodium dioctyl sulfosuccinate They act by neutralizing the surface charge on the particles of the dispersed phase, thereby reducing inter-particulate repulsion and causing aggregation. Non-ionic surfactants Spans and Tweens are believed to function by formation of bridges between the adjacent particles. The concentration necessary to achieve this effect would appear to be critical since these compounds may also act as wetting agents to achieve dispersion. III-Hydrophilic Polymers (Suspending agents) Hydrophilic polymers such as alginates, cellulose derivatives, tragacanth, carbomers, silicates, etc. 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. Uses To increase 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.  Suspending agent types Polysaccharides Water-soluble celluloses Hydrated silicates a- Polysaccharides Gum 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 and may need to be sterilized before use. Gum Tragacanth 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 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. 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. Sodium Alginate is slowly soluble in water. It is normally used in concentrations of between 1% and 5%.  Sodium Carboxymethyl cellulose (Carmellose sodium) B- Water-soluble celluloses Concentrations ranging from 0.25% to 1% for oral, topical and parenteral use. It is soluble in hot as well as cold water. Being anionic, it is incompatible with the cationic compounds. Methyl cellulose It dispersed slowly in cold water to form colloidal solution but is insoluble in hot water. It is employed for internal and external preparations. Being non-ionic, it is compatible with ionic additives. Hydroxyethyl cellulose It is soluble in cold and hot water. Solution display maximum stability in pH range 2 to 10. Hydroxypropyl cellulose It used for oral and topical use. Soluble in water below 40 ℃ and insoluble above this temperature. Maximum stability at pH range 2 to 10. Hydroxypropyl methyl cellulose (Hypermellose) It has properties similar to those of methyl cellulose but produces aqueous solutions with higher gelling points. Microcrystalline cellulose Used either alone or in conjunction with other cellulose derivatives such as Carboxymethyl cellulose sodium. C- Hydrated silicates Aluminium Magnesium Silicate (veegum) Used at a concentration range of 0.5% to 2% for internal and external preparations. Dispersions in water are thixotropic, and at concentration of 10% a firm gel is obtained. The viscosity of dispersions is increased by heating. Bentonite Bentonite is a natural colloidal hydrated aluminium silicate. Although it is insoluble in water, it absorbs large quantities of it and may swells up to 12 times its original volume. It is generally used at a concentration in between 0.5% to 2% for suspending powders in aqueous preparations such as calamine lotion. Hectorite Hectorite is a natural colloidal magnesium silicate having properties similar to bentonite. It is mainly used in suspensions for external use. Carbopols It 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. Electrolytes also reduce the viscosity of carbopol dispersions. For external application and some grades can be taken internally. Colloidal Silicon dioxide (Aerisol) 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. It is used for external use only.  Quality control of suspension Sedimentation parameters Sedimentation Centrifugation Particle size Temperature Quality control and size cycling distribution Rheological studies  1- Sedimentation Redispersibility is the major consideration in assessing the acceptability of a suspension. I- Sedimentation parameters The sedimentation volume, F The degree of flocculation, β Sedimentation volume 1- If F1 This means that the final volume of sediment is greater than the original suspension volume. (Vo) before settling This is due to the networks of the flocs formed in the suspension are loose and fluffy that the volume they are able to encompass is greater than the original F = Vu / Vo (1) volume of suspension. (Suspensions formulated with Polymeric flocculating agents). The degree of flocculation (β) The ratio between sedimentation volume of flocculated suspension and deflocculated suspension. The degree of flocculation is a more fundamental parameter than F since it relates the volume of flocculated sediment to that in a deflocculated system. β = Vu /Vo II- Centrifugation It is a qualitative examination (accelerated test) to test for sedimentation volume. Suitable for increasing the rate of sedimentation of a suspension Disadvantage (1) Not always possible to predict accurately the behavior of a system when stored under normal conditions from data obtained after this type of accelerated testing. (2) It may destroy the structure of a flocculated system that remain intact under normal storage conditions. The sediment formed would become tightly packed difficult to redisperse. But this method may give a useful indication of the relative stabilities of a series of trial products. III-Temperature Cycling Used to: (a) Compare the physical stabilities of a series of suspensions. (b) Specific For the assessment of crystal growth. By the exaggeration of the temperature fluctuations that any product is subjected to under normal storage conditions it may be possible to compare the physical stabilities of a series of suspensions. Methodology (1) Cycles consisting of storage for several hours at a temperature of about 40 °C followed by freezing have been used successfully. (2)Similarly normal temperature fluctuations can be used but at increased frequencies of only a few minutes at each extreme. 2- Particle size and size distribution It is of importance to study the changes for absolute particle size and particle size distribution. It is performed by 1- Optical microscopy 2- Laser diffraction 3- Coulter counter NB: It is important to ensure that the suspension is deflocculated to ensure that each individual particle is measured rather than each floccule. 3- Rheological studies Used for determining the settling behavior of the suspension. Apparent viscosity measurements are used as a tool for the assessment of physical stability. Very low rates of shear, using the Brookfield viscometer, can give an indication of the change in the structure of the system before and after various storage times. A measurement of viscosity can be used as a routine quality control procedure after manufacture. Data obtained on aged and stored suspension reveals whether changes have taken place. Rheological behavior 1- High apparent viscosity at low rates of shear (on storage) An ideal pharmaceutical suspension would exhibit 2- Low viscosity at higher rates of shear (moderate shaking of the product), so that A- The product poured easily from its container. B- For external use, spread easily without excessive dragging (not so fluid that it runs off). C- For injection, the product should pass easily through needle with moderate pressure. 3-The initial high apparent viscosity reformed after a short time of storage to maintain adequate physical stability  Rheology of Flocculated Systems 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. If plastic behaviour, they behave like a solid up to a particular shearing stress, yield value (van der waals forces bet. adjacent particles, and no flow occurs until this value exceeded (broken down before flow can occur). Rheology of Deflocculated Systems They exhibit Newtonian behavior due to the absence of such structures in flocculated systems. Their rheological behavior is determined by the continuous phase. If high concentrations of disperse phase are present, the particles come into contact and the system exhibits Dilatancy (Dilatant flow). Application on suspensions 1- sustained release suspension 2- nanosuspension Sustained release suspensions Gives a longer duration of action compared to aqueous solution when given intramuscularly or subcutaneously. The sustained release effect is achieved by decreasing surface area, diffusion coefficient and solubility. Examples Insulin suspension 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. Penicillin G suspension Penicillin G procaine a sparingly soluble form of penicillin G. Nanosuspension as a novel drug delivery system More than 40% of the drugs are lipophilic or poorly water- soluble compounds with low bioavailability. Many formulations are available to solve the problems as: 1- Micronization 2- Use of fatty solutions 3- Use of penetration enhancer or cosolvents, surfactant dispersion method 4- Salt formation These techniques having limited utility in solubility enhancement for poorly soluble drugs  Additional approaches are vesicular system like liposomes, dispersion of solids, emulsion and microemulsion methods, and inclusion complexes with cyclodextrins, which show beneficial effect as drug delivery system, but major problems of these techniques are lack of universal applicability to all drugs. Nanotechnology can be used to solve the problems associated with various approaches described earlier. Nanotechnology is defined as the science and engineering carried out in the nanoscale that is 10–9 m. Definition of nanosuspension Nanosuspensions are submicron colloidal dispersions of nanosized drug particles stabilized by surfactants. Composition ofnanosuspension: Composition of nanosuspension Nanosuspensions consist of the poorly water-soluble drug without any matrix material suspended in dispersion. These can be used to enhance the solubility of drugs that are poorly soluble in water as well as lipid media. Advantage of nanosuspension 1- As a result of increased solubility, the bioavailability increased. 2- This approach is useful for molecules with poor solubility, poor permeability, or both, which poses a significant challenge for the formulators. 3-The reduced particle size renders the possibility of intravenous administration of poorly soluble drugs without any blockade of the blood capillaries. 4- The suspensions can also be lyophilized and into a solid matrix.