Pharmaceutics I Lecture 7-8 PDF

PHARMACEUTICAL SUSPENSIONS BY: Dr. Mahmoud Soliman Professor of Pharmaceutics and Industrial Pharmacy  Outline of Pharmaceutical Suspensions lectures: Definition Types of suspensions Properties of well formulated suspensions Reasons for preparing pharmaceutical...

PHARMACEUTICAL SUSPENSIONS BY: Dr. Mahmoud Soliman Professor of Pharmaceutics and Industrial Pharmacy  Outline of Pharmaceutical Suspensions lectures: Definition Types of suspensions Properties of well formulated suspensions Reasons for preparing pharmaceutical suspensions Preformulation Phase Formulation of suspensions Formulation additives Rheology of suspensions Methods for preparation Stability Testing of pharmaceutical suspensions Intended Learning Outcomes from the lectures (ILOs) Comprehend the physicochemical principles controlling the formulation and performance of the pharmaceutical suspensions. Formulate independently the pharmaceutical suspensions. Analyze, retrieve & evaluate information from different sources specific to pharmaceutical suspensions..  Liquid Dosage Forms Solutions one homogenous phase, prepared by dissolving one or more solutes in a solvent Suspensions A dispersion system where solid particles are dispersed in liquid phase. Emulsions a dispersion system consisting of two immiscible liquids (Cloudy appearance)  Disperse Systems COARSE SUSPENSIONS A solid in liquid dispersion in which the particles are above colloidal size (1 um). Disperse System Dispersion Dispersed medium phase aqueous, oily insoluble liquid solid  Types of Pharmaceutical Suspensions 1- According to dispersion medium: Aqueous suspensions Oily suspensions 2- According to the stability of the drug: Ready to use Suspensions (stable drugs) or Reconstituted powder (non stable drugs) 3- According to formulation: Flocculated or Deflocculated 4- According to uses: Oral, Parenteral, Topical preparations, Ocular eye drops Physical properties of a well-formulated suspension 1. It must remain homogenous for the period between shaking container and removing the required dose. 2. The sediment produced on storage must be easily resuspended by the use of moderate agitation. 3. The viscosity must not be so high that removal of the product from the container is difficult. 4. The suspended particles should be uniformly sized to give a smooth product free from a gritty texture. 5- Resistance to microbial contamination.  Coarse Suspensions Redispersion Pharmaceutical Applications of Suspensions Reasons for preparing suspensions 1- People having difficulty in swallowing solid dosage forms: If the drug is insoluble (a suspension is required). 2- Drugs with poor solubility: Pharmaceutical Applications of Suspensions 3- Bad taste drugs: The tastes drugs are more noticeable if in solution than if in an insoluble form. Paracetamol suspension is more palatable than solution “Pediatric Paracetamol Elixir”  Pharmaceutical Applications of Suspensions 4- Easily degraded drugs in the presence of water: (suspensions are more stable than solutions) 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: insoluble calcium salt of oxytetracycline in aqueous vehicle (stable) Pharmaceutical Applications of Suspensions 4- Easily degraded drugs in the presence of water: B- Formulate the drug as Reconstituted suspension: decrease the contact between solid drug particles and dispersion medium C- Formulate the drug as Suspension in oil: A drug degrades in the presence of water may be suspended in a non-aqueous vehicle. (Phenoxmethylpenicillin oral suspension in coconut oil). Pharmaceutical Applications of Suspensions 5- Materials which should be present in the GIT in a finely divided form and their formulation, as suspensions will provide the desired high surface area. a- Adsorption of toxins b- Neutralize acidity (antacids) e.g.(kaolin, magnesium carbonate and magnesium trisilicate)  Pharmaceutical Applications of Suspensions 6- Topical application: ** (Lotions) Fluid preparations designed to leave a light deposit of the active agent on the skin after evaporation of the dispersion medium (Calamine Lotion BP). ** (Pastes) Semisolid consistency which contain high concentrations of powders dispersed, in a paraffin base. Pharmaceutical Applications of Suspensions 7- Suspensions formulated for parenteral administration for A- prolongation of action of the drug or B- better stability: Prolongation of Action better stability  Pharmaceutical Applications of Suspensions 7- Suspensions formulated for parenteral administration for prolongation of action of the drug: To control the rate of absorption of the drug and duration of activity (Depot, reservior, Long acting) e.g.: Benzathine Penicillin A- Varying particle size: duration of activity (controlled) B- Use Different vehicles to suspend the drug: *Aqueous vehicle diffusion of the product will occur along muscle fibers after injection. * Use Fixed oils such as arachis or sesame oils In order to prolong activity. Pharmaceutical Applications of Suspensions 7- Suspensions formulated for parenteral administration for prolongation of action of the drug: Betolvex ® 1 mg / ml ( Cyanocobalamin ) 2 intramascular ampoules Betolvex is the highest technology in Vitamin B12 preparations, Providing fast onset and the longest duration of action, ensuring replenishment of Vitamin B12 body stores. Ingredients: 1 ml (one ampoule) contains cyanocobalamin/tannin complex equivalent to I mg cyanocobalamin 20 mg aluminium monostearate sesame oil to make I ml. Pharmaceutical Applications of Suspensions 8- Aerosol suspensions: suspensions of the active agent in a mixture of propellants.  Preformulation of suspensions I- Selection of the suitable particle size. II- Control the Particle size to avoid the Change in the particle size distribution. 1- It is necessary to ensure that the drug to be Small particles, if greater than 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 2- Use a particular particle size range to control the rate of release of drug and the bioavailability. 3- It is advantageous to use a suspended drug of narrow size range Low PDI High PDI Same Viscosity at very high volume fraction  Preformulation of suspensions 4- Use the stable polymorphic form of the drug Different polymorphic forms of a drug may exhibit different solubilities. Conversion of the metastable form in solution (soluble) to the less soluble stable state and its subsequent precipitation will lead to changes in particle size. Stable Precipitation Metastable Less changes in particle Soluble size distribution. Soluble  Preformulation of suspensions 5- Prevent Crystal Growth: *At manufacturing: the particle size of a drug (small ) **on storage: Crystal growth can occurs particularly if temperature fluctuation occurs. because the solubility of the drug increase as the temperature rises but on cooling the drug will crystallize out. (paracetamol) (Change in the particle size distribution)  Crystal growth and change in particle size distribution can be controlled by the following procedures and techniques: 1- Selection of the suitable particle size. (bet. 1-10 microns) 2- Selection of stable crystalline drug form that exhibits lower solubility. 3- Increase the viscosity of the vehicle to retard dissolution and crystal growth. 4- Prevent the temp. fluctuation during product storage.  Formulation of Suspensions Deflocculated systems Flocculated systems CLEAR SUPERNATANT Defloc vs Floc  Formulation of Suspensions Deflocculated systems Flocculated systems  Deflocculated vs Flocculated Suspensions Flocculated Deflocculated Deflocculated  Deflocculated suspensions Flocculated suspensions 1- Particles as separate Loose aggregates of particles entities (network) enclosing liquid medium 2- Low sedimentation rate Fast sedimentation rate (uniform dose) (inaccurate dose) 3- Sediment particles is very Loosely packed sediment closely packed (scaffold- like) 4- Good appearance Inelegant 5- Cloudy supernatant Clear supernatant 6- Low sedimentation volume High sedimentation volume 7- Compact sediment, No cake formation, ease in Caking occurs, difficult in redispersion redispersion Flocculated and Deflocculated Systems Deflocculated systems: have the advantages of slow sedimentation rate thus enabling a uniform dose to be taken from the container, but when settling does occur, the sediment is compact and difficult to redisperse. Flocculated systems: form loose sediments which are easily redispersed but the sedimentation rate is fast and there is a danger of an inaccurate dosage and the product would look inelegant. A compromise is reached in which suspension is partially flocculated and viscosity is controlled so that the sedimentation rate is at a minimum.  Formulation of Suspensions Steps: 1- wetting agent Deflocculated (initial step) suspension 2- Structured vehicle, Suspending 3- Controlled flocculation, agent, increases viscosity using flocculating agent (Deflocculated suspension) (Flocculated suspension) (BY TIME, SEDIMENTATION CAN Optimum (combine 2 OCCUR) XX and 3) (Flocculated particles in structured vehicle to decrease sedimentation rate)  Formulation of suspensions The preparation of physically stable suspensions fall into the following categories: 1- The use of Suspending agent (increase viscosity) to maintain deflocculated particles in suspension. so that, ideally, no settling occurs.  Formulation of suspensions 2- The application of the principles of flocculation (Flocculating Agent) to produce flocs that, although they settle rapidly, are easily resuspended with a minimum of agitation. Optimum physical stability will be obtained when the suspension is formulated with flocculated particles in a structured vehicle of the hydrophilic colloid. Optimum physical stability: (wetting agent, flocculating agent and Suspending agent) Model oral suspension: Tween 80 (W.A.)- Sod. Citrate (F.A.)- Acacia (S.A.)  I. Wetting Agents The initial step is the wetting of powder in a vehicle (difficult to disperse owing to adsorbed layer of air) Some particles form porous clumps within the liquid while others remain on the surface (float on surface). Always (Choose lowest concentrations of wetting agent) Wetting Agents Hydrophilic Surfactants Solvents colloids  1- Surface active agents Mechanism: Reduce interfacial tension between solid particles and vehicle, air is displaced from surface, wetting is promoted. Non ionic Surfactants possessing HLB value (7- 9 ) are suitable for use as wetting agents. 2- Solvents: E.g.: glycerol and propylene glycols which are water miscible Mechanism: Glycerin (humectant) flows into the voids between particles to displace air and it coats and separates the material so that water can penetrate and wet the particles.  3- Hydrophilic Colloids e.g.: acacia, bentonite, tragacanth, alginates, and cellulose derivatives. Mechanism: Behave as protective colloids by coating the solid hydrophobic particles with a multimolecular layer. This will impart a hydrophilic character to the solid and thus promote wetting. N.B.: These materials are also used as suspending agents in larger concentrations. II. Controlled Flocculation 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 Waal`s forces of attraction exceed forces of repulsion. * The stable flocs contain varying amounts of entrapped liquid medium within the network like structure. (Flocculated suspensions)  II. Controlled flocculation Flocculating agents Controlled flocculation is usually achieved by: 1- The use of inorganic electrolytes or ionic surfactants to control zeta potential (addition 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 cross-linking to occur between particles.  1- Electrolytes Mechanism: 1- Decrease electrical barrier between particles 2- Decrease zeta potential 3- Formation of a ionic bridges between particles to link them in a loosely arranged structure ( flocculation). The most commonly used electrolytes include: Sodium salts of acetates, phosphates and citrates 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  CAKING DIAGRAM  deflocculated flocculated deflocculated Bismuth subnitrate suspension (possess positive charge and positive zeta potential (deflocculated). After the addition of KH2PO4), decrease in zeta potential by adsorption of negatively charged phosphate anion (flocculated). If the concentration increases, charge reversal (deflocculated suspension)  2- Polymeric flocculating agents Examples: Starch, alginates, cellulose derivatives, tragacanth, carbomers and silicates. Mechanism: Their linear branched chain molecules form a gel-like network within the system and become adsorbed on to the surfaces of the dispersed particles thus holding them in a flocculated state.  2- Polymeric flocculating agents Warning: Care must be taken during manufacture: 1- Avoid excessive blending: It inhibits the cross-linking between adjacent particles and will inhibit aggregation and deflocculated system may result 2- Avoid high concentration of polymer: The whole surface of each particle is coated. Thus, deflocculated system may result.  III- Viscosity Modifiers (Suspending Agents) Suspending agents is added to retard sedimentation of flocs (modification of suspension viscosity) Suspending Agents 1. Polysaccharides (Acacia gum-Tragacanth- Alginates) 2. Water-soluble celluloses (methyl cellulose- hydroxyethyl cellulose- Sodium carboxymethyl cellulose) 3. Hydrated silicates (bentonite-veegum) 4. Carbopols  III- Viscosity Modifiers 1- Polysaccharides Acacia gum (gum arabic) Combined with other thickeners as in Compound Tragacanth Powder BP (acacia, tragacanth, starch and sucrose= 1:1:1:3 by weight). - Sticky: rarely used in preparations for external use. Tragacanth Better thickening agent than acacia Used for both internal and external products..  2- Water-soluble celluloses Semisynthetic polysaccharide. Several grades are available depending on the chain length. ( Na CMC and HPMC) Swelling of bentonite 3- Hydrated Silicates **They hydrate readily, absorbing up to 12 times their weight of water particularly at elevated temperatures. As with most naturally occurring materials they may be contaminated with spores (sterilization process, preservative).  Hydrated Silicates i- Bentonite (Aluminum Silicate) For external use ii- Veegum (Magnesium Aluminum Silicate) *They can be used both internally and externally iii- Laponites (layered hydrous magnesium silicate) Synthetic clay Do not exhibit the batch variability or microbial contamination associated with natural products Can also be used internally.  4- Carbopol Synthetic copolymer of acrylic acid and allyl sucrose. For external application ,some grades can be taken internally. 5- Colloidal Silicon Dioxide (Aerosil) * For external use Used for thickening of non-aqueous suspensions.  Formulation additives (Wetting agents, Flocculating agents and Suspending agents) + 1. Buffers 2. Density modifiers 3. Flavors, colours and perfumes 4. Humectants 5. Sweetening agents 6. Preservatives  Formulation additives 1. Buffers “Compounds by their presence in solution resist the change in pH upon addition of small amount of acid or alkali”. They are necessary in order to: (a) Maintain chemical stability. (b) Ensure physiological compatibility. NB: The addition of electrolytes may have profound effects on the physical stability of suspensions.  Formulation additives 2. Density modifiers Density modifier may be added to decrease the sedimentation rate of suspensions The dispersed and continuous phases must have the same densities to reduce velocity of sedimentation. **Minor modifications to the aqueous phase can be done to increase the density of continuous phase by incorporating: (sucrose, glycerol or propylene glycol) Formulation additives 3. Flavors, Colours and Perfumes 4.Humectants ** Glycerol and propylene glycol are added into aqueous suspensions for external application (lotions). ** They used to prevent the product from drying out after application to the skin. 5. Sweetening agents sucrose, sorbitol or glycerol  for oral use NB: Synthetic sweeteners may be salts thus, Can affect the degree of flocculation. Saccharine, cyclamate Na Formulation additives 6. Preservatives are used (to prevent the growth of M.O. in the raw material and/or introduced to the product during use. e.g.: methyl and propyl paraben Care must be taken to ascertain the extent of inactivation of the preservative system due to: (1) Interactions with other excipients. (2) Solubilization by wetting agents (entrapped inside micelles). (3) Interaction with polymers (4) Adsorption on to suspended solids, may reduce the availability of preservatives.  Formulation of Suspensions For The following “Metronidazole Oral Suspension” formula, Mention the role of each ingredient Ingredients of the formula Role of each ingredient in the formula Rx Metronidazole Drug Tween 80............................................... Acacia............................................... Sodium citrate............................................... Methyl paraben............................................... Propyl paraben............................................... Sucrose............................................... Glycerol............................................... Water ----------------------------------------  Stability testing of suspensions **Physical stability of suspensions is concerned with keeping particles uniformly distributed. Although it is seldom possible to prevent settling completely over a prolonged period of time. The factors that influence the velocity of sedimentation: (Stokes’ Law): 2 d g(ρs – ρo) V= 18 η o V: is the velocity of sedimentation in cm/sec, d: is the diameter of the particle in cm, ρs and ρo: are the densities of dispersed phase and medium g: is the acceleration due to gravity ηo: is the viscosity of the dispersion medium (poise) V: directly proportional to diameter and diff. in densities and inversely proportional to viscosity of medium. Stability Testing of Suspensions 1- Sedimentation parameters (a) The sedimentation volume, F (b) The degree of flocculation, β 2- Rheological assessment 3- Temperature cycling 4- Particle size assessment  1- Sedimentation parameters (a) The sedimentation volume, F, is defined as the ratio of the final, or ultimate volume of the sediment, Vu, to the original volume of the suspension, Vo, before settling. F = Vu / Vo (1) F= Final volume of sediment original volume of suspension before sedimentation The sedimentation volume 150 100 100 100 50 50 50 F= 0.5 F= 1 F= 1.5 F>1 F1 Flocculation equilibrium loose and fluffy Flocs  (a) The sedimentation volume, F The sedimentation volume gives (Qualitative account on flocculation) 1- If The sedimentation volume less than 1: the ultimate volume of sediment is smaller than the original volume of suspension. 2- If the volume of sediment in a flocculated suspension equals the original volume of suspension, then F = 1 Such a product is said to be in “Flocculation Equilibrium” and shows no clear supernatant on standing. 3- If F values greater than 1, meaning that the final volume of sediment is greater than the original suspension volume. This is due to the fact that: the network of the flocs formed in the suspension are so loose and fluffy that the volume they are able to encompass is greater than the original volume of suspension. (suspensions formulated with Polymeric flocculating agents)  1- Sedimentation parameters (b) The degree of flocculation, β, The degree of relates the volume of flocculated sediment to that in a deflocculated system Ultimate sediment volume of flocculated suspension β= Ultimate sediment volume of deflocculated suspension If a suspension is completely deflocculated, the ultimate volume of the sediment will be small.  2-Rheological assessment Apparent viscosity measurements are used as a tool for the assessment of physical stability using the Brookfield viscometer , can give an indication of the change in the structure of the system before and after various storage times. There is a significant increase in viscosity – with the system starting as a free-flowing liquid at low particle concentrations, and evolving through to a paste and eventually a self-supporting soft solid at higher concentrations. other important physical properties affect viscosity of suspension are:  the average particle size and particle size distribution;  the zeta potential or charge for particles;  the shape of the particles 3- Measurement of particle size Particle size measurements is usually carried out using one of the following methods: 1- microscopically, 2- by Laser Diffraction 3- using a Coulter Counter. It is important to ensure that the suspension is deflocculated to ensure that each individual particle is measured rather than each floccule  4-Temperature Cycling (a) To 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: Cycles consisting of storage for several hours at a temperature of about 40 ˚C in an oven followed by cooling or freezing (-20 ˚C) have been used successfully.  Rheology of Suspensions Viscosity of ideal suspension An ideal pharmaceutical suspension would exhibit: 1- High apparent viscosity at low rates of shear (on storage) 2- Low viscosity at higher rates of shear (moderate shaking of the product) 3- the initial high apparent viscosity reformed after a short time of storage To maintain adequate physical stability. A Flocculated system, fulfills these criteria  I-Rheology of Flocculated Systems They exhibit (pseudoplastic or plastic behaviour) The presence of floccules, reduce the amount of free continuous medium (entrapped within the floccules) so: The viscosity of flocculated suspension is higher >>>than deflocculated suspension The viscosity is high when shearing stress is low, but it decreases as the applied stress increases as the structure progressively breaks down under shear. The product then shows the time-dependent reversibility of this loss of structure, which is termed Thixotropy. If plastic behaviour, they behave like a solid up to a particular shearing stress, yield value (van der waal,s forces bet. adjacent particles, and no flow occurs until this value exceeded  II- Rheology of Deflocculated Systems **They exhibit Newtonian behaviour 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). Amount of vehicle is insufficient to wet the particles- resistance to flow Deflocculated Systems High concentrations of dispersed phase “Explanation of dilatant flow behaviour”  Preparation of suspensions on large scale I- use the Suitable particle size If larger- reduce particle size using (milling equipment). II- Prepare concentrated dispersion of suspending agent with solvent using Suitable mixers. This stage is important as it is necessary to ensure that agglomerates of suspending agent are fully broken up without any agglomerates PRECAUTIONS: Very intense shearing can destroy the polymeric structure of the suspending agent, so it may be better to use milder shearing mixers Preparation of suspensions on large scale III- Wetting of the drug with wetting agent: The drug to be suspended is then added in the same way along with the wetting agent. IV- Other ingredients dissolved in a portion of the vehicle, then added and the whole made up to volume if necessary. V- Finally homogenization (using homogenizers) Preparation of suspensions on large scale STEPS YOU