Pharmaceutical Suspensions 3_compressed_compressed.pdf

Pharmaceutical suspensions  SUSPENSIONS Definition A Pharmaceutical suspension is a dispersion in which internal phase is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles having a specific range of size which is mai...

Pharmaceutical suspensions  SUSPENSIONS Definition A Pharmaceutical suspension is a dispersion in which internal phase is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles having a specific range of size which is maintained uniformly throughout the suspending vehicle with aid of single or combination of suspending agent. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.  Classification of Suspensions Based On General Classes Oral suspension Externally applied suspension Parenteral suspension Based On Proportion Of Solid Particles Dilute suspension (2 to10 % w/v solid) Concentrated suspension (50 % w/v solid) Based On Electrokinetic Nature Of Solid Particles Flocculated suspension Deflocculated suspension Based On Size Of Solid Particles Colloidal suspension (< 1 micron) Coarse suspension (>1 micron) Nano suspension (10 ng) Advantages of Suspensions  To administer an insoluble compound as a liquid.  Suspension can improve chemical stability of certain drug by reducing the fraction of drug in solution. E.g. Procaine penicillin G  Drug in suspension exhibits higher rate of bioavailability than other dosage forms. Bioavailability is in following order, Solution > Suspension > Capsule > Compressed Tablet > Coated tablet  Suspension can mask the unpleasant/ bitter taste of drug by E.g. Chloramphenicol formulating a vehicle in which the drug is not soluble using an insoluble form of the drug (ie. salt form or prodrug) adsorbing the drug onto an insoluble carrier Disadvantages  Physical instability, sedimentation and compaction can causes problems.  It is bulky, sufficient care must be taken during handling and transport.  It is difficult to formulate.  Uniform and accurate dose can not be achieved unless suspension are packed in unit dosage form. Features Desired In Pharmaceutical Suspensions  The suspended particles should not settle rapidly and sediment produced must be easily re-suspended by the use of moderate amount of shaking.  It should be easy to pour yet not watery and no grittiness.  It should have pleasing odour, colour and palatability (oral).  Good syringeability (parenteral).  It should be physically, chemically and microbiologically stable during its shelf life.  Parenteral/Ophthalmic suspension should be sterilizable. Pharmaceutical Applications of Suspensions  Suspension is usually applicable for drug which is insoluble or poorly soluble. E.g. Prednisolone suspension  To prevent degradation of drug or to improve stability of drug. E.g. Oxytetracycline suspension  To mask the taste of bitter of unpleasant drug. E.g. Chloramphenicol palmitate suspension  Suspension of drug can be formulated for topical application e.g. Calamine lotion.  Suspension can be formulated for parenteral application in order to control rate of drug absorption.  Vaccines as a immunizing agent are often formulated as suspension. E.g. Cholera vaccine  X-ray contrast agent are also formulated as suspension. E.g. Barium sulphate for examination of alimentary tract  Examples of Pharmaceutical Suspensions: 1. Antacid oral suspensions 2. Antibacterial oral suspension 3. Dry powders for oral suspension (antibiotic) 4. Analgesic oral suspension 5. Anthelmintic oral suspension 6. Anticonvulsant oral suspension 7. Antifungal oral suspension Routes of Administration Oral Ocular Otic Rectal Parenteral Topical Theory Of Suspensions Sedimentation Behaviour Sedimentation means settling of particle or floccules occur under gravitational force in liquid dosage form. Theory of Sedimentation Velocity of sedimentation is expressed by Stoke’s equation Where, vsed.= sedimentation velocity in cm / sec d = Diameter of particle r = radius of particle ρ s= density of disperse phase ρ o= density of disperse media g = acceleration due to gravity η o = viscosity of disperse medium in poise Limitation Of Stoke’s Equation Stoke’s equation applies only to:  Spherical particles in a very dilute suspension (0.5 to 2 gm per 100 ml).  Particles which freely settle without interference with one another (without collision).  Particles with no physical or chemical attraction or affinity with the dispersion medium. But most of pharmaceutical suspension formulation has conc. 5%, 10%, or higher percentage, so there occurs hindrance in particle settling. Factors Affecting Sedimentation Particle size diameter (d) : V α d 2 Sedimentation velocity (v) is directly proportional to the square of diameter of particle. Density difference between dispersed phase and dispersion media (ρs - ρo) : V α (ρ s - ρo) Generally, particle density is greater than dispersion medium but, in certain cases particle density is less than dispersed phase, so suspended particle floats & is difficult to distribute uniformly in the vehicle. If density of the dispersed phase and dispersion medium are equal, the rate of settling becomes zero. Viscosity of dispersion medium (η ): V α 1/ ηo Sedimentation velocity is inversely proportional to viscosity of dispersion medium. So increase in viscosity of medium, decreases settling, so the particles achieve good dispersion system but greater increase in viscosity gives rise to problems like pouring, syringibility and redispersibility. Sedimentation Parameters I) Sedimentation volume (F) or height (H) for flocculated suspensions F = V u / VO Where, Vu = final or ultimate volume of sediment VO = original volume of suspension before settling. Sedimentation volume is a ratio of the final or ultimate volume of sediment (Vu) to the original volume of sediment (VO) before settling. when a measuring cylinder is used to measure the volume F= H u/ HO Where, Hu= final or ultimate height of sediment H O = original height of suspension before settling  Sediment Volume Sediment Volume (F) =(volume of sediment Vu)/(original volume Vo) Sedimentation volume can have values ranging from less than 1 to greater than 1; F is normally less than 1. F=1, such product is said to be in flocculation equilibrium. And show no clear Supernatant on standing. The sedimentation volume gives only a qualitative account of flocculation. II) Degree of flocculation (β) Suspensions quantified by sedimentation volume (f) It is a very useful parameter for flocculation II) Degree of flocculation (β) Degree of flocculation- ß = Ffloc/Fdefloc (Vsed/Vtot)floc =------------------- (Vsed/Vtot)defloc When the total volume of both the flocculated and the deflocculated suspensions are same, the degree of flocculation, ß = (Vsed)floc/(Vsed)defloc  Flocculated and Deflocculated suspensions: I- Flocculated suspensions II-Deflocculated suspensions 1. Particles form a loose 1. Particles exit separately aggregates 2. Rate of sedimentation is 2.Rate of sedimentation is fast low because particles are because particles settle as small and light in weight. aggregates 3. A turbid supernatant is 3. A clear supernatant is formed as sedimentation is formed as sedimentation is slow. fast. 4. A closely packed sediment 4.A loosely packed sediment is formed (hard cake) which is is formed that can be easily difficult to re-dispersed. re-dispersed. Sedimentation behavior of flocculated and deflocculated suspensions II) Flocculating Agents Flocculating agents cause aggregation (floc formation) of the particles in a loosely arranged structure. Careful control of flocculation is required to ensure that the product is easy to administer. Such control is usually is achieved by using optimum concentration of electrolytes, surface-active agents or polymers. Change in these concentrations may change suspension from flocculated to deflocculated state. Method of Floccules Formation: 1-Electrolytes Electrolytes act as flocculating agents by reducing the electric barrier between the particles, as evidenced by a decrease in zeta potential and the formation of a bridge between adjacent particles so as to link them together in a loosely arranged structure. If we disperse particles of bismuth subnitrate in water we find that they possesses a large positive charge or zeta potential that causes strong repulsion force between adjacent particles, the system is peptized or deflocculated. By addition of monobasic potassium phosphate to suspended bismuth subnitrate particles causes the positive zeta potential to decrease owing to the adsorption of negatively charged phosphate anion. With continued addition of the electrolyte, the zeta potential eventually falls to zero and then increases in negative directions. Only when zeta potential becomes sufficiently negative to affect potential does the sedimentation volume start to fall. Finally, the absence of caking in the suspensions correlates with the maximum sedimentation volume, which, as stated previously, reflects the amount of flocculation. Caking diagram, showing the flocculation of a bismuth subnitrate suspension by means of the flocculating agent.  Caking diagram, showing the flocculation of a bismuth subnitrate suspension by means of the flocculating agent. Flocculating agent changes zeta-potential of the particles (it can be electrolyte, charged surfactant or charged polymer adsorbing on a surface). If the absolute value of the zeta-potential is too high the system deflocculates because of increased repulsion and the dispersion cakes. 2-Surfactants Both ionic and non-ionic surfactants can be used to bring about flocculation of suspended particles. Optimum concentration is necessary because these compounds also act as wetting agents to achieve dispersion. Optimum concentrations of surfactants bring down the surface free energy by reducing the surface tension between liquid medium and solid particles. This tends to form closely packed agglomerates. The particles possessing less surface free energy are attracted towards to each other by van der waals forces and forms loose agglomerates. 3-Polymers Polymers possess long chain in their structures. The part of the long chain is adsorbed on the surface of the particles and remaining part projecting out into the dispersed medium. Bridging between these later portions, also leads to the formation of flocs. Characteristics Of Flocculated Suspensions Particles in the suspension are in form of loose agglomerates. Flocs are collection of particles, so rate of sedimentation is high. The sediment is formed rapidly. The sediment is loosely packed. Particles are not bounded tightly to each other. Hard cake is not formed. The sediment is easily redispersed by small amount of agitation. The flocculated suspensions exhibit plastic or pseudo plastic behavior. After rapid sedimentation, there is an obvious clear supernatant region. The pressure distribution in this type of suspension is uniform at all places, i.e. the pressure at the top and bottom of the suspension is same. In this type of suspension, the viscosity is nearly same at different depth level. The purpose of uniform dose distribution is fulfilled by flocculated suspension. Characteristics Of Deflocculated Suspensions In this suspension particles exhibit as separate entities. Particle size is less as compared to flocculated particles. Particles settle separately and hence, rate of settling is very low. The sediment after some period of time becomes very closely packed, due to weight of upper layers of sedimenting materials. After sediment becomes closely packed, the repulsive forces between particles are overcomed resulting in a non-dispersible cake. more concentrated deflocculated systems may exhibit dilatant behavior. This type of suspension has a pleasing appearance, since the particles are suspended relatively longer period of time. The supernatant liquid is cloudy even though majority of particles have been settled. As the formation of compact cake in deflocculated suspension, Brookfield viscometer shows increase in viscosity when the spindle moves to the bottom of the suspension. There is no clear-cut boundary between sediment and supernatant. Advantages and Disadvantages due to viscosity of medium Advantages High viscosity inhibits the crystal growth. High viscosity prevents the transformation of metastable crystal to stable crystal. High viscosity the sedimentation rate decreases, thus physical stability increases enhances the physical stability. Disadvantages High viscosity hinders the re-dispersibility of the sediments. High viscosity retards the absorption of the drug. High viscosity creates problems in handling of the material during manufacturing. Different Approaches To Increase The Viscosity Of Suspensions : Various approaches have been suggested to enhance the viscosity of suspensions. Few of them are as follows: 1. Viscosity Enhancers: The following materials are the most widely used to modify suspension viscosity. Some natural occuring polyysaccarides (acacia, tragacanth, alginates, starch), water soluble cellulose derivatives (sodium CMC, methyl cellulose, microcrystalline cellulose), hydrated silicates (bentonite, magnesium aluminium silicate), and synthetic polymers (carboxypolymethylene). 2. Co-solvents: Some solvents which themselves have high viscosity are used as co-solvents to enhance the viscosity of dispersion medium. 3. Structured vehicles: Formulation of Pharmaceutical Suspensions Structured Vehicle Structured vehicle should posses some degree of Thixotropic behaviour viz., the property of GEL-SOL-GEL transformation. Because during storage it should remain in the form of GEL to overcome the shear stress and to prevent or reduce the formation of hard cake at the bottom which to some extent is beneficial for pourability and uniform dose at the time of administration. A thixotropic suspension is the one which is viscous during storage but loses consistency and become fluid upon shaking. A well-formulated thixotropic suspension would remain fluid long enough for the easy dispense of a dose but would slowly regain its original viscosity within a short time. Suspension Syringeability Parenteral suspensions are generally deflocculated suspensions and many times supplied as dry suspensions, i.e. in one bottle freeze dried powder is supplied and in another bottle the vehicle is supplied and the suspension is to be reconstituted at the time of injection. If the parenteral suspensions are flocculated one, their syringeability will be less i.e. difficult to inject for the doctor or nurse and painful to patient due to larger floccule size. Parenteral suspensions are generally given by intra muscular route. Now a days intravenous suspension are also available with particle size less than 1 micron, termed as nano-suspension. Optimum suspensions viscosity should be used to ensure easy syringeability and less pain to patient. Formulation Components All or combinations of the following components are used in suspension formulation. Components Function API (Active Pharmaceutical Ingredient ) Active drug substances Wetting agents They are added to disperse solids in continuous liquid phase. Flocculating agents They are added to floc the drug particles Thickeners They are added to increase the viscosity of suspension. Buffers & pH adjusting agents They are added to stabilize the suspension to a desired pH range. Osmotic agents They are added to adjust osmotic pressure comparable to biological fluid. Coloring agents They are added to impart desired color to suspension and improve elegance. Preservatives They are added to prevent microbial growth. External liquid vehicle They are added to construct structure of the final suspension. Suspending Agents :  Most suspending agents perform two functions i.e. besides acting as a suspending agent they also imparts viscosity to the solution. Suspending agents form film around particle and decrease interparticle attraction.  A good suspension should have well developed thixotropy. At rest the solution is sufficient viscous to prevent sedimentation and thus aggregation or caking of the particles. When agitation is applied the viscosity is reduced and provide good flow characteristic from the mouth of bottle.  Suspending agents also act as thickening agents. They increase in viscosity of the solution, which is necessary to prevent sedimentation of the suspended particles as per Stoke’s law.  Preferred suspending agents are those that give thixotropy to the media such as Xanthan gum, Carageenan, Na CMC/MCC mixers, Microcrystalline cellulose (Avicel ) Cellulose derivatives Several cellulose derivatives can be used suspending agents. They easily disperse in water to produce viscous colloidal solutions suitable for use  Methylcellulose  Hydroxyethylcellulose  Microcrystalline cellulose Wetting Agents  Hydrophilic materials are easily wetted by water while hydrophobic materials are not. However, hydrophobic materials are easily wetted by non-polar liquids.  The extent of wetting by water is dependent on the hydrophilicity of the materials. If the material is more hydrophilic it finds less difficulty in wetting by water. Inability of wetting reflects the higher interfacial tension between material and liquid.  The interfacial tension must be reduced so that air is displaced from the solid surface by liquid.  Wetting can be achieved by: I) Surfactants II) Hydrophilic Colloids III) Solvents Wetting is achieved by: I) Surfactants Polar Surfactants decrease the interfacial tension Hydrophilc head between drug particles and liquid and thus liquid is penetrated in the pores of drug particle displacing air from them and thus ensures wetting. Surfactants in optimum concentration facilitate dispersion of particles. Generally, we use non-ionic surfactants but ionic surfactants can also be used depending upon certain conditions. Disadvantages of surfactants are that they have foaming tendencies, bitter in taste, and some surfactants interact with preservatives and reduce Hydrophobic antimicrobial activity. tail II) Hydrophilic Colloids Hydrophilic colloids coat hydrophobic drug particles in one or more layers. This will provide hydrophilicity to drug particles and facilitate wetting. They cause deflocculation of suspension because force of attraction is declined. e.g., acacia, tragacanth, alginates, guar gum, pectin, gelatin, wool fat, egg yolk, bentonite, Veegum, Methylcellulose etc. III) Solvents The most commonly used solvents used are alcohol, glycerin, polyethylene glycol and polypropylene glycol. The mechanism by which they provide wetting is that they are miscible with water and reduce liquid air interfacial tension. Liquid penetrates in individual particle and facilitates wetting. Buffers To encounter stability problems, all liquid formulation should be formulated to an optimum pH. Rheology, viscosity and other property are dependent on the pH of the system. Most commonly used buffers are salts of weak acids such as carbonates, citrates, gluconates, phosphate and tartarates. Prevent decomposition of API by change in pH. Control of tonicity Physiological stability is maintained Maintain physical stability Osmotic Agents: They are added to produce osmotic pressure comparable to biological fluids when suspension is to be intended for ophthalmic or injectable preparation. Most commonly used osmotic agents for ophthalmic suspensions are dextrose, mannitol and sorbitol. The tonicity-adjusting agents used in parenteral suspension are sodium chloride, sodium sulfate, dextrose, mannitol and glycerol. Preservatives The naturally occurring suspending agents such as tragacanth, acacia, xanthan gum are susceptible to microbial contamination that may cause problem such as loss in suspending activity of suspending agents, loss of color, flavor and odor, change in elegance etc. Most common incidents, which cause loss in preservative action, are:  Solubility in oil  Interaction with suspending agents  Interaction with container  The use of cationic antimicrobial agents is limited because as they contain positive charge they alter surface charge of drug particles. Secondly, they are incompatible with many adjuvants. Flavoring And Coloring Agents They are added to increase patients acceptance. The choice of color should be associated with flavor used to improve the attractiveness by the patient. The flavoring agents are added to aid the sweetening agent to complete taste masking of unpleasant drugs. Because of the high surface area of the dispersed powders in this type of formulation, adsorption of these materials (flavoring and coloring) may occur thus reducing their effective concentration in solution. E,g. the finer the degree of subdivision of the disperse phase the paler may appear the color of the product for a given concentration of dye. Grape-Flavored Orange-Flavored Cough -suppressant suspension Cough -suppressant suspension Sweetening Agents They are usually present in oral suspensions for taste masking of bitter drug particles. High concentration of sweetening agents like sucrose, sorbitol, glycerol which exhibit Newtonian properties may adversely affect the rheological properties of suspensions. Synthetic sweeteners (Sodium cyclamate, Na saccharin) may be salts and affect the degree of flocculation. Humectants Humectants absorb moisture and are used to prevent the product from drying out after application to the skin. Examples of humectants most commonly used in suspensions are propylene glycol and glycerol used at concentration of 4-5 % w/w in aqueous suspensions for external application. Quality Control tests of Suspensions Appearance Color, odor and taste Physical characteristics such as particle size determination and microscopic photography for crystal growth Sedimentation rate and Zeta Potential measurement Sedimentation volume Redispersibility and Centrifugation tests Rheological measurement Compatibility with container and cap liner Ideal Requirements of Packaging Material It should be inert. It should effectively preserve the product from light, air, and other contamination through shelf life. It should be cheap. It should effectively deliver the product without any difficulty. Label: "Shake Before Use" to ensure uniform distribution of solid particles and thereby uniform and proper dosage. Shake Before Use