Lecture 3 & 4 Suspensions PDF

Lecture 3 1- Pharmaceutical Coarse Dispersion Suspensions Classifications of suspensions: 1- Based on the dispersion medium: i) Aqueous ii) Non-aqueous Dispersion medium is water Non-aqueous vehicle 2-...

Lecture 3 1- Pharmaceutical Coarse Dispersion Suspensions Classifications of suspensions: 1- Based on the dispersion medium: i) Aqueous ii) Non-aqueous Dispersion medium is water Non-aqueous vehicle 2- Based on route of administration: i) Oral: Pediatric antibiotics Antacids ii) Topical: Dermatological Cosmetic ii) Parenteral: Long-acting (DEPOT) I.M. injections. 4 SC. Injections (e.g. Insulin ). 3- Based on proportion of solid particles: i) Dilute ii) Concentrated # 2-10% w/v solid # 50% w/v solid e.g. Predinisolone acetate e.g. Zinc oxide suspension 4- Based on electro-kinetic nature of solid particles (Physical stability of susp): ii) Deflocculated i) Flocculated - Particles exist as separate entities Particles form a network - They settle slowly They settle rapidly - Supernatant is turbid Supernatant is clear - Sediment forms a hard cake Sediment not hard cake (fluffy) - Difficult to be resuspended Easy to be resuspended 5 Advantages of suspensions: 1- Formulation of liquid dosage forms for drugs insoluble in the delivery vehicle. e.g. corticosteroids suspension. 2- Mask the bitter taste of drugs. e.g. chloramphenicol palmitate. 3- Increases drug stability. e.g. procaine penicillin G. 4- Achieves controlled/sustained drug release. e.g. protamine zinc-insulin. 5- Higher bioavailability and faster onset of action compared to other dosage forms. 6 ( Generally, solution>suspension>capsule>tablet). e.g. Antacid suspension. Disadvantages of suspensions: 1- Sedimentation of solids occasionally gives poor form of product (caking). 2- Microbial contamination takes place if preservative not added in accurate proportion. 3- Dose precision cannot be achieved unless suspensions are packed in unit dosage forms. 4- Bulky and need sufficient care during transportation and handling. 7 Characteristics of an acceptable suspension: General Safe, effective and stable (chemically and physically). Pharmaceutically elegant Particles should not settle rapidly Must be easily resuspended It should be physically, chemically and microbiologically stable Parenteral Good syringeability Sterilizable Topical Easily spreadable over the affected area 8 Not too watery that it runs off the surface Non- gritty Types of suspensions Flocculated Deflocculated Physical stability Rapid rate of Cake formation sedimentation Inaccurate dosing Difficult to redisperse Particles Form network Particles are separate entities They settle rapidly They settle slowly Supernatant is clear Supernatant is turbid Sediment is fluffy Sediment is hard cake 9 Easy to be resuspended Difficult to be resuspended Controlled flocculation The most acceptable product. 1- 2- 3- Sedimentation in suspensions: suspension 4- Brownian movement can be observed If particle size is about 2 to 5mm. When the density of particle & viscosity of medium are favorable. Brownian motion is given by equation Where, R = gas constant T = temp. in degree Kelvin N = Avogadro’s number η = viscosity of medium t = time 5- 6- Controlled flocculation The most acceptable product.  1- Wetting of particles: Wetting phenomena Formulation of a stable suspension: Wetting is the ability of a liquid to maintain contact with a solid surface, Wetting of when the two are brought together. particles When a drop of liquid is placed on a solid Controlled surface , it may adhere to it or no. flocculation When the forces of adhesion are greater Structured vehicle than the forces of cohesion, the liquid tends to wet the surface and vice versa.  Wettability is the degree of wetting and is determined by the balance between adhesive and cohesive forces. An important parameter reflecting the wettability is the contact angle (θ); It is the angle made by the liquid with the solid surface at the point of contact  The contact angle quantifies the wettability of a solid surface by a liquid. - Contact angle = 0° → complete wetting. - Contact angle ˂ 90° → wetting. - Contact angle = 90° → incomplete wetting. - Contact angle ˃ 90°→ no wetting.  Some insoluble solids may be easily wetted by water and will disperse readily throughout the aqueous phase with only minimal agitation. Other solids exhibit varying degrees of hydrophobicity and will not be easily wetted. Some particles will form large porous clumps within the liquid, whereas others remain on the surface and become attached to the upper part of the container. To ensure adequate wetting, the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air is displaced from the solid surfaces by the liquid.  Based on these concepts a wetting agent is a substance that; 1- When dissolved in water → ↓contact angle. 2- Replaces the air at the solid surface with a liquid phase. 3- Reduces the surface tension of the liquid. Air microbubbles Removal of air from at the interface the surface Wetting agent Lower surface tension 30 Particles float on Penetration of the the surface vehicle into the pores 1- Surfactants possessing an HLB value between about 7-9 would be suitable for use as wetting agents. Hydrocarbon chains would be adsorbed by the hydrophobic particle surfaces whereas the polar groups project into the aqueous medium and become hydrated. Most surfactants are used at concentrations of up to about 0.1%. 1. For oral use, the polysorbates (Tweens) and sorbitan esters (Spans). 2. For external application, sodium lauryl sulphate, sodium dioctyl sulphosuccinate and quillaia extract can also be used. 3. For parenteral use polysorbates, some of the poloxamers (polyoxyethylene/polyoxypropylene copolymers) and lecithin.  Disadvantages in the use of this type of wetting agent include excessive foaming and the possible formation of a deflocculated system which may not be required. 2.Hydrophilic colloids include acacia, bentonite, tragacanth, alginates, xanthan gum and cellulose derivatives. They behave as protective colloids by coating the solid hydrophobic particles with a multimolecular layer. This will impart a hydrophilic character to the solid and so promote wetting. These materials are also used as suspending agents and may, like surfactants, produce a deflocculated system, particularly if used at low concentrations. 3. Solvents such as alcohol, glycerol and glycols, which are water miscible, will reduce the liquid/air interfacial tension. The solvent will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles, so enabling wetting to occur by the dispersion medium Wetting agents: Lower the surface tension, decrease the contact angle HLB value between 7 and 9 Surfactants Concentration up to 0.1% Polysorbates (Tween 80), sodium lauryl sulfate (SLS). Form a hydrophilic coating around the solid particles Hydrophilic Acacia, tragacanth, xanthan gum, bentonite, colloidal silica, polymers and cellulose derivatives, such as sodium carboxymethyl cellulose Lower the liquid surface tension, helping solvent penetration into the loose agglomerates of powder Solvents (Levigating agents) Hygroscopic solvents, such as alcohol, glycerol, and glycols, especially, propylene glycol 34 2- Controlled flocculation: Controlled flocculation The most acceptable product. Flocculating agent Electrolytes Reduce surface charge bringing particles together to form loosely arranged structures. Flocculating power increases with the valence of the ions. NaCl, sulphates, citrates and phosphates. Surfactants Both ionic and nonionic surfactants can be used. Ionic surfactants cause flocculation by neutralizing the charge on particles Nonionic SAA adsorbed onto more than one particle, thereby bridge adjacent particles forming a loose flocculated structure. Polymers Linear and branched chain polymers form a gel-like network that adsorbs onto the surface of dispersed particles, holding them in a flocculated state Alginates, starch and cellulose derivatives 35 Electrolytes act as flocculating agents by reducing the electric barrier between the particles, as evidenced by a decrease in the 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 possess a large positive charge (zeta potential). Because of the strong forces of repulsion between adjacent particles, the system is deflocculated The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles causes the positive zeta potential to decrease owing to the adsorption of the negatively charged phosphate anion.  With the continued addition of the electrolyte, the zeta potential eventually falls to zero and then increases in the negative direction. At a certain positive zeta potential, maximum flocculation occurs and will persist until the zeta potential has become sufficiently negative for deflocculation to occur once again. The onset of flocculation coincides with the maximum sedimentation volume determined F remains reasonably constant while flocculation persists, and only when the zeta potential becomes sufficiently negative does the sedimentation volume start to fall. 3- Structured vehicles (Suspending agents): ▪ Aqueous solutions of natural or synthetic polymers which are pseudoplastic or plastic in nature; e.g. methylcellulose, sodium carboxymethylcellulose and carbopol 934. ▪ They are viscosity-imparting agents to reduce the rate of sedimentation in dispersed systems. ▪ They form a three dimensional gel network structure which entrap the particles so that no sedimentation occurs. ▪ Some degree of thixotropy (gel-sol-gel transformation) is desirable (viscous on the shelf to prevent sedimentation and fluid when shaken due to destruction of the gel structure to facilitate administration). 39  Too high viscosity is not desirable as: a) It causes difficulty in pouring and administration. b) It may affect drug absorption since they adsorb on the surface of particle and suppress the dissolution rate. Structured vehicle is not useful for Parenteral suspension because they may create problem in syringeability due to high viscosity. Effect of the charge of particles on the stability of suspensions Incompatibilities may occur as the systems contain charged particles, flocculating agent and suspending agent. Interaction depends on charge on each of the suspension components. In case of; Positively charged + Flocculating agent + Suspending agent Negatively charged particle Negatively charged In case of; No Incompatibility occurs Negatively charged + Flocculating agent + Suspending agent Negatively charged particle Positively charged Incompatibility occurs 41 How to avoid this incompatibility? Addition of a protective colloid avoids any probable incompatibility. Protective colloid as gelatin carry a positive charge, it will form a sheath on the suspended particles whatever their charges ( +ve, -ve or even neutral) converting them to positively charged particles. The flocculating agent for such system must be anionic. No incompatibility in such system as the floccules is -ve and the suspending agent is -ve too. Protective Positively Form a sheath Independent of the Particles become colloid charged around particles suspended particle positively Gelatin charge charged 42 Effect of gelatin as protective colloid 43 Other Formulation Aspects……. A perfect suspension provides content uniformity. The formulator must control particle size distribution, crystal growth and polymorphic changes. The formulator must ensure storage stability. pH, particle size, viscosity, flocculation, taste, color and odor are some of the most important factors that must be controlled. Perfect suspension provides Content uniformity and storage stability 44  Components of suspension formulations Component Function API Active pharmaceutical ingredient Wetting agents Disperse solids in continuous aqueous phase Flocculating agents For controlled flocculation of a deflocculated suspension Thickeners Increase viscosity of the suspension Buffers Stabilize the suspension to a desired pH range Coloring and flavoring Give desired color and flavor to the suspension agents Preservatives Prevent microbial growth External vehicle Construct the structure of the final suspension 45 Non aqueous suspensions: Most pharmaceutical suspensions have aqueous continuous phase. Formulation of a drug in a non aqueous continuous phase is occasionally required to prepare a liquid formulation with enhanced stability for a drug having poor stability in aqueous medium. Dispersions of drugs in oleaginous vehicles can provide a sustained drug release as observed with certain depot IM injections and topical products. Aerosols represent another important class of non aqueous suspensions. Physical stability of suspended drugs in non aqueous propellants for aerosol products can have a significant impact on the uniformity of dose and operation of the aerosol system. Caking of the suspended particles can cause clogging of the valve of the aerosol system. 46 Packaging of suspensions: 1.Wide mouth container for ease of pouring. 2.Adequate airspace above the liquid to allow for shaking. 3.Protected from freezing, heat and light. 4.Carry the label: “Shake well before use”. 5.In case of dry suspensions powder the specified amount of vehicle to be is indicated clearly on label. 47 Quality control tests of suspensions: 1. Appearance, color, odor and taste. 2. Physical characteristics: particle size determination and microscopical examination for crystal growth. 3. Sedimentation volume and degree of flocculation. 4. Zeta potential measurement. 6. Rheological measurements. 7. Compatibility with container and cap liner.