Biphasic Suspensions PDF

Biphasic liquids Two phases: Dispersed phase & dispersion medium Internal phase & external phase Need for biphasic DF: ? Medicaments are poorly soluble in solvent systems Medicament form dispersed phase (solid or liquid)  Suspensions  Emulsions  Biphasic liqu...

Biphasic liquids Two phases: Dispersed phase & dispersion medium Internal phase & external phase Need for biphasic DF: ? Medicaments are poorly soluble in solvent systems Medicament form dispersed phase (solid or liquid)  Suspensions  Emulsions  Biphasic liquids  Suspensions Definition Advantages and Disadvantages Classifications Flocculated and Deflocculated suspension Preparation of suspensions Stability problems and methods to overcome Emulsions  Suspensions “Biphasic system consisting of finely divided solid particles dispersed in a liquid vehicle” The insoluble solid drugs is uniformly suspended throughout the suspending vehicle by the aid of a single of a combination of suspending agents. Suspensions - unstable Substance distributed is referred as dispersed phase Vehicle – is dispersion medium or continuous phase  Classification 1. Based on proportion of solids: Dilute suspensions: 2-10%w/v eg. Cortisone acetate & Prednisolone acetate suspension Concentrated suspensions: Upto 50%w/v eg. Zinc oxide & Procaine penicillin G suspension 2. Based on routes of administration Oral, parenteral (i.m/s.c), intranasal, topical, ophthalmic, rectal Eg. ?  3. Based on size of the solid particles Coarse dispersion: 10-50 m Fine dispersions: 0.5 – 10 m (Mixtures & Magmas) Colloidal dispersion: 1 nm - 0.5 m 4. Based on nature & behavior of solids: Deflocculated suspensions Flocculated suspensions  Advantages of suspensions 1. Easy to adjust the dose to meet patient’s requirements 2. Suspensions may be beneficial for patients having difficulty to swallow solid dosage forms 3. Water insoluble medicaments can be formulated in to suspension 4. Provide stability to the drugs which are unstable in aqueous medium:  Different form of the drug, such as ester or insoluble salt that does not dissolve in water may be used eg. Procaine penicillin G suspension  Can be supplied as powders for reconstitution at the time of dispensing – designated as “for oral suspension” eg. Amoxycillin, Erythromycin, Ampicillin for oral suspension Granular powders Labeling instructions: Add specified amount of water to dissolve. Shake well to form homogenous solution Time within which the preparation should be consumed 7 8  Advantages of suspensions… 5. Mask the taste: 1. Chloramphenicol (water soluble) Chloramphenicol palmitate (water insoluble), hence improved palatability 2. Quinine tannate 6. Prolonged action dosage forms: To control the release of the drug eg. Protamine zinc insulin and procaine pencillin G 7. Drugs in suspension exhibit higher rate of bioavailability compared to tablet or capsule: eg Antacid suspensions solutions > suspensions > powders > capsules > tablets > coated tablets  Limitations of suspensions 1. Sedimentation of dispersed particles – can be minimized but not completely 2. Caking: Sedimented particles form ‘cake’ that can not be re-dispersed on shaking Physical instability, sedimentation & compaction of sediment causes problems Requirement of suspending agents 3. Suspending agents are hydrocolloids - supports Microbial growth 4. Liable to undergo oxidation and hydrolysis 5. Relatively bulky, handling and transportation issues 6. Wetting agents may be required for drugs having poor wettability  Ideal properties/qualities Particles should not settle rapidly Should not form a hard cake Redisperse immediately Should have optimum viscosity Should be chemically stable Have an acceptable taste/palatable Free from gritty particles Spread evenly when applied topically Resist microbial attack Flocculated suspension & Deflocculated suspension Flocculated suspension: Particles form loose networks of flocks that settle rapidly, do not form cakes and are easy to redisperse flock Deflocculated suspension: Individual particles are settling, so rate of sedimentation is slow - form cakes that is difficult to redisperse cake  Flocculated suspension Sedimentation depends not only on the size of the flocs but also on the porosity of flocs. Loose structure of the rapidly sedimenting flocs tends to preserve in the sediment, which contains an appreciable amount of entrapped liquid. The volume of final sediment is thus relatively large and is easily redispersed by agitation. flock  Flocculated suspension… Properties of flocculated suspension: 1. Particles in the suspension are in form of loose agglomerates. 2. Flocs are collection of particles, so rate of sedimentation is high. 3. The sediment is loosely packed. Hard cake is not formed. 4. The sediment is easily redispersed 5. The suspension is somewhat unpleasant, due to rapid sedimentation and presence of an obvious clear supernatant region. Aggregates tend to adhere to the sides of the container.  Deflocculated suspension Larger particles settle fast and smaller remain in supernatant liquid so supernatant appears cloudy whereas in flocculated suspension, even the smallest particles are involved in flocs, so the supernatant does not appear cloudy cake  Deflocculated suspension… Properties of deflocculated 1. Particles exhibit as separate entities. 2.Particle size is less as compared to flocculated particles. Particles settle separately and hence, rate of settling is very low. 3. Form closely packed sediment, difficult to resuspend 4. Has a pleasing appearance, since the particles are suspended relatively longer period of time. 5. The supernatant liquid is cloudy, no clear boundary exists between sediment and supernatant Flocculated suspension Deflocculated suspension Loose aggregates Separate entities High rate of sedimentation Rate of sedimentation is slow Loosely packed network Cake - Closely packed Easy to redisperse Redispersion of cake is difficult Suspension not pleasing in Pleasing in appearance appearance Floccules stick to the sides of Do not stick the bottle  Properties of Suspension 1. Interfacial properties of suspended partilcles When particle size reduced – surface area increased Results in thermodynamically unstable system – development of high surface free energy (ΔF) Δ F = γSL. ΔA Particles become highly energetic & tend to regroup - Form floccules or aggregate (cake) Stability can be achieved by– 1. Reducing total surface area but its not practical – leads to sedimentation 2. Reduce interfacial tension between solid & liquid  Properties of Suspension 2. Electrokinetics of the system (Zeta Potential) Particles may become charged by – adsorption of ionic species present in solution or preferential adsorption of OH- – Dissociation of ionizable groups at the surface (-COOH or -NH2) Ionic atmosphere of opposite charged ions is developed surrounding the particle – electrical double layer is established  Properties of Suspension Bulk solution Zeta Potential … aaI - Potential determining Solid ions (positive) bbI - Counter ions / gegenions (negative) Considered as shear plane or true surface bbI & ccI - Excess negative ions, but potential at bbI is aaI & bbI - tightly bound positive  Properties of Suspension Zeta Potential … Potential at bbI is still positive Solid There are less anions in the tightly bound layer than cations adsorbed onto the surface of the solid These anions start aaI & bbI - tightly bound - attracting the cations from bulk  aaI & bbI - tightly bound bbI & ccI - diffused aaI - potential is Nernst potential bbI - potential is Zeta potential Zeta potential potential difference between the surface of the tightly bound layer and the electro-neutral region of solution (bulk) governs electrostatic force of repulsion between adjacent, similarly dispersed particles Zeta potential Governs stability of the dispersed systems. If the zeta potential is reduced below a certain value, the attractive forces exceed the repulsive forces, and the particles come together - known as flocculation. Flocculated: attractive forces > repulsive forces Deflocculated: repulsive > attractive forces [affected by electrolytes]  3. Sedimentation Velocity of sedimentation (V) expressed by Stoke’s equation  Sedimentation velocity (V) is directly proportional to the square of diameter of particle 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. Sedimentation velocity is inversely proportional to viscosity of dispersion medium. So, increase in viscosity of medium, decreases settling, so the particles remain dispersed for longer time yielding higher stability to the suspension, but greater increase in viscosity gives rise to problems like pourability, syringeability and re-dispersibility of suspension  4. Brownian Movement Prevents sedimentation by keeping the dispersed material in random motion Brownian motion depends on density of dispersed phase & dispersion medium Brownian motion is observed with smaller particles < 2 microns  Formulation of suspension 1. Flocculating agents Flocculating agents decreases zeta potential of the suspended charged particle and thus cause aggregation (floc formation) of the particles. Electrolytes such as KCl, NaCl: Electrolytes decrease electrical barrier between the particles and bring them together to form floccules. Sulfate, citrates, phosphates salts pH change: alters the electrical barrier between the particles and forming a bridge to link them together 2. Suspending/thickening 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 interparticulate attraction. Called as structured vehicles Natural gums: acacia, tragacanth Cellulose derivatives: sodium CMC, methyl cellulose Clays: bentonite, veegum, hydrated aluminium silicate, magnesium silicate Nonionic substances: PEG, sorbitol, glycerin  3. Wetting agent Light & hydrophobic particles have tendency to float over the surface Wetting agent causes replacement of air from the solid liquid interface 1. Surface active agents: reduce the angle of contact and make the particles wettable and dispersible. eg. Tweens, macrogols 2. Hydrocolloids: coat hydrophobic drug particles in one or more than one layer eg: tragacanth, NaCMC, Colloidal silica, Bentonite 4. Dispersing agents Increase zeta potential Keep particles separate 5. Preservatives Benzoic acid Sodium benzoate Parabens 6. Organoleptic additives Colour: ferric oxide, amaranth, titanium dioxide Sweetening: sucrose, saccharine, aspartame Favors  Preparation of suspensions First step is to reduce particle size of the medicament Reasons for smaller size dispersed phase: Topical preparations should not feel gritty Topical preparations should feel smooth to the touch Injectables should not produce tissue irritation To increase bioavailability Increased rate of release Can influence rate of sedimentation, flocculation  Preparation of suspensions General Procedure First the particle size of all materials is reduced to a desired size with the help of mill or other equipments. Insoluble materials are levigated or grinded to a smooth paste with a vehicle containing the wetting agent. All soluble ingredients are dissolved in same portion of the vehicle and added to the smooth paste to get slurry. If preparing on small scale, the slurry is then transferred to a graduated cylinder and mortar is rinsed with successive portion of vehicle.  If preparing on industrial scale, then slurry is transferred to a colloid mill / fluid energy mill / ball mill or a disperser or any other equipment to completely wet the particles. Then a deflocculated suspension is obtained. Decide whether the solids are: Suspended in a structured vehicle Flocculated Flocculated and then suspended Add the vehicle containing the suspending agent or flocculating agent. Make up the dispersion to the final volume to get suspension Dispersers Colloid mill Ball mill Fluid Energy Mill  Evaluation of suspension 1. Sedimentation Volume Vo Rate of sedimentation / Sedimentation volume (F) or height (H) = is a ratio of the ultimate volume of sediment (Vu) to the Vu original volume of sediment (VO) before settling. F = Vu / VO F=0.5 F can be less than 1 or greater than 1 When F < 1 then Vu 1, Ultimate volume Vu is greater than original volume Vo Vo - Network of flocs are so loose & fluffy, & sediment volume may exceed than original volume F>1  Evaluation of suspension 1. Sedimentation Volume… when F =1 then Vu = VO The system is in equilibrium and shows no sedimentation on standing. Slower the rate of sedimentation, greater is the stability of the suspension 2. Degree of Flocculation (β) It is the ratio of the sedimentation volume of the flocculated suspension (F), to the sedimentation volume of the deflocculated suspension, (F∞) ß = F / F∞ ß is 1, when flocculated suspension sedimentation volume is equal to the sedimentation volume of deflocculated suspension. Gives only a qualitative account of flocculation. 3. Ease of redispersibility Number of inversions necessary to restore the suspension are determined. If homogeneity is achieved with one inversion – ease of redispersibility is 100% 4. Viscosity determination – using viscometer 5. Particle size distribution – Microscopy / particle size analyzer 6. Electrokinetic method – determining the zeta potential by Zeta sizer  Stability problems and methods to overcome Effect of storage conditions (temperature)s - Caking & flocculation - Crystal growth - Settling/sedimentation - Stability can be improved by the addition of surfactants, structured vehicles General considerations for suspenions Suspensions should not be frozen freezing causes coarsening of dispersed particle and looses the consistency If available as freeze-dried powders they are reconstituted upon use and should be kept in the refrigerator, not at freezer Must be shaken before use