Pharmaceutical Suspension Lecture Notes PDF

SUSPENSIONS  Sedimentation parameters There are 2 useful parameters 1- Sedimentation volume "F” 2- Degree of flocculation ‘β” 1- Sedimentation volume "F” It is the ratio of final sediment volume Vf to the original volume of suspension Vo. F = Vf / Vo 1- F is no...

SUSPENSIONS  Sedimentation parameters There are 2 useful parameters 1- Sedimentation volume "F” 2- Degree of flocculation ‘β” 1- Sedimentation volume "F” It is the ratio of final sediment volume Vf to the original volume of suspension Vo. F = Vf / Vo 1- F is normally < 1 (final sediment volume < original suspension volume). 2- F = 1 (final sediment volume = original suspension volume). This product is flocculated, shows no clear supernatant and it is acceptable pharmaceutically. 3- F > 1 (final sediment volume > original suspension volume). Because the network of flocks are so loose, fluffy and of greater volume than the original volume.  Vf Vo Vo = Vf Vf F = 0.5 F = 1.0 F = 1.5 N.B: F gives only qualitative account of flocculation since it lacks meaningful reference point. 2- Degree of flocculation ‘β” Degree of flocculation is more fundamental than sedimentation volume since it relates the volume of flocculated sediment to that in a deflocculated system. 1- If we consider a suspension is completely deflocculated → the final sediment volume will be relatively small. Fα = Vα / Vo Where: Fα = Sedimentation volume of deflocculated suspension. Vα = Final sediment volume of deflocculated suspension. 2- If we consider a suspension is completely flocculated F = Sedimentation volume of flocculated suspension. F = Vf / Vo Where: F = Sedimentation volume of flocculated suspension. Vf = Final sediment volume of flocculated suspension. 3- Degree of flocculation is defined as ratio between F to Fα β = F / F α = Vf / Vα Final sediment volume of flocculated suspension β = -------------------------------------------------------------------- Final sediment volume of deflocculated suspension  Preparation of suspensions 1- Particle size control 2- Use of wetting agents 3- Use of flocculating agents 4- Use of viscosity modifiers (suspending agents) 5- Other formulation additives in suspension  1- Particle size control In ophthalmic suspension: Large particles (greater than about 5 μm) → gritty texture to the product and cause irritation of the eyes. In parenteral large particles → blocking of a hypodermic needle. The solubility of the drug may increase as the temperature rises but on cooling the drug will crystallize out → crystal growth → increase in particle size of a drug during storage. If the drug is poly dispersed (wide difference in particle sizes) → very small crystals (less than 1 μm diameter) will exhibit a greater solubility than the larger ones.  2- Use of wetting agents Wetting agents → ↓ interfacial tension between solid particles and liquid medium → displacement of the adsorbed air from the solid surfaces by the liquid → adequate wetting of the particles throughout the liquid. Wetting agent Air Water The most widely used wetting agents: A. Surfactants: Surfactants possessing an HLB value of between 7 and 9 in a concentrations of up to about 0.1%. For Oral use: Tweens and Spans. For External use: Sodium lauryl sulphate, Sodium dioctylsulphosuccinate For Parenteral use: Tweens, Pluronics and Lecithin. Disadvantages of the use of surfactants as wetting agents: The excessive foaming and the possible formation of a deflocculated system which may not be required. B. Hydrophilic Polymers and Hydrocolloids: Examples: acacia, bentonite, tragacanth, alginates and cellulose derivatives. These materials will coat the solid hydrophobic particles with a multimolecular layer → imparting a hydrophilic character to the solid → promote wetting. These materials are also used as suspending agents and deflocculated agents at low concentrations. C. Solvents: Alcohol, glycerol and glycols will reduce the liquid/air interfacial tension enabling wetting to occur by the dispersion medium.  3- Use of flocculating agents If it is necessary for the suspension to be converted from a deflocculated to a flocculated state, this may be achieved by the addition of flocculating agents. A. Electrolytes: The most widely used electrolytes include the sodium salts of acetates, phosphates and citrates. The addition of an inorganic electrolyte to an aqueous suspension → ↓ zeta potential of the dispersed particles → flocculation. The ability of an electrolyte to flocculate hydrophobic particles depends on the valency of its counter ions. Trivalent ions more efficient but less widely used than mono- or divalent electrolytes because of their toxicity. If hydrophilic polymers, which are usually negatively charged, are included in the formulation, they may be precipitated by the presence of trivalent ions. Care must be taken not to add excessive electrolyte or charge reversal may occur on each particle thus forming once again a deflocculated system. B. Surfactants: Ionic surfactants may also cause flocculation by neutralization of the charge on each particle. Non-ionic surfactants have a little effect on the charge density of a particle but may because of their linear configuration adsorb onto more than one particle thus forming a loose flocculated structure. If we disperse particles of bismuth subnitrate in water we find that the system is deflocculated because of the strong force of repulsion between adjacent particles. By preparing series of bismuth subnitrate suspensions containing increasing concentration of monobasic potassium phosphate co-relation between apparent zeta potential and sedimentation volume, caking, and flocculation can be demonstrated. Controlled flocculation of a bismuth subnitrate suspension using dibasic potassium phosphate (KH2PO4) as flocculating agent. The addition of monobasic potassium phosphate to the 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. c. Polymeric flocculating agents: Starch, alginates, cellulose derivatives, tragacanth, carbomers and silicates are used to control the degree of flocculation. By their branched linear chain molecules form a gel-like network within the system and become adsorbed onto the surfaces of the dispersed particles thus holding them in a flocculated state.  4- Use of Viscosity Modifiers (Suspending agents) Viscosity modifiers → (↑ viscosity of dispersed phase) 1- Polysaccharides: a. Acacia gum: Acacia mucilage becomes acidic on storage due to enzyme activity and it also contains an oxidase enzyme which may cause deterioration of active agents which are susceptible to oxidation. b. Tragacanth: It is better thickening agent than acacia for both internal and external products. c. Alginates: Sodium alginate is the most widely used but due to its anionic character, it will be incompatible with cationic materials and with heavy metals. The addition of calcium chloride to a sodium alginate dispersion will cause the calcium salt to be formed with a large increase in viscosity. d. Starch: A derivative of starch (sodium starch glycollate) has been evaluated for its use in the preparation of suspensions. 2. Water- soluble celluloses: Several cellulose derivatives are use as suspending agents. Methyl cellulose - Hydroxyethyl cellulose – Sodium Carboxymethyl cellulos - Microcrystalline cellulose 3. Hydrated silicates: They hydrate readily, absorbing up to 12 times their weight of water particularly at elevated temperatures. The most three important silicates are: a. Bentonite: In concentrations of 2 to 3% in preparations for external use such as calamine lotion. it should be sterilized before to kill pathogenic spores,. b. Magnesium aluminum silicate (Veegum): It can be used both internally and externally. This material is often combined with organic thickening agents such as sodium carboxymethyl cellulose or xanthan gum to improve yield values, degree of thixotropy and to control flocculation. C. Hectorite: Synthetic material similar to bentonite and can be used at concentrations of 1- 2% for external use. 4. Carbapol is a totally synthetic. It is used at concentrations of up to 0.5% mainly for external application although some grades can be taken internally. 5. Colloidal silicone dioxide (Aerosil): When dispersed in water, this finely divided product will aggregate forming a three- dimensional network. It can be used at concentrations of up to 4% for external use.  5- Formulation additives in suspension 1. Buffers: The inclusion of buffers may be necessary in order to maintain chemical stability, control tonicity or to ensure physiological compatibility. 2. Density modifiers: Addition of sucrose, glycerol or propylene glycol make same densities between dispersed and continuous phase → sedimentation would not occur. 3. Flavours, colours and perfumes: To enhance the organoleptic properties of suspensions. 4. Humectants: To prevent the product drying out after application to the skin, glycerol and propylene glycol are used in 5%. 5. Preservatives: To prevent the growth of microorganisms (from raw material and/or introduced into the product during use). Bentonite, for example, may contain spores of Clostridium Tetani but can be sterilized by heating the dry powder at 160°C for 1 hour or by autoclaving the aqueous dispersions. 6. Sweetening agents: High concentrations of sucrose, sorbitol or glycerol, will exhibit Newtonian properties, may adversely affect the rheological properties of the suspension.  Stability Testing of Suspension 1- The physical stability: by determination of: Sedimentation rate, Initial volume (or height of the suspension Vo), Final volume (or height of the sediment V), Flocculation value and Ease of redispersion of the product. 2- Chemical stability by determination of concentration of active ingredients