Study_Material_Attachment_22.pdf

Suspensions INTRODUCTION A pharmaceutical suspension is a coarse dispersion in which insoluble particles, generally greater than 1 µm in diameter, are dispersed in a liquid medium, usually aqueous. A pharmaceutical suspension is also a liquid system. However, in...

Suspensions INTRODUCTION A pharmaceutical suspension is a coarse dispersion in which insoluble particles, generally greater than 1 µm in diameter, are dispersed in a liquid medium, usually aqueous. A pharmaceutical suspension is also a liquid system. However, in this case, the solid material (usually the drug) does not dissolve in the vehicle to any appreciable extent but remains as solid particles which are distributed throughout the vehicle. Technically, the term suspension describes a dispersion of a solid material (the dispersed phase) in a liquid (the continuous phase) without reference to the particle size of the solid material. However, the particle size of the solid material can affect both its physical and chemical behaviour, so a distinction is usually made between a colloid or colloidal suspension with a particle size range of up to about 1 µm and a ‘coarse dispersion’ with larger particles. Unfortunately, pharmaceutical suspensions fall across the borderline between colloidal and coarse dispersions, with solid particles generally in the range of 0.1 to 10 µm. Suspensions are not optically clear and will appear cloudy unless the size of the particles is within the colloidal range. Some suspensions are available in ready-to-use form, that is, already distributed through a liquid vehicle with or without stabilizers and other additives. Other preparations are available as dry powders intended for suspension in liquid vehicles. Generally, this type of product is a powder mixture containing the drug and suitable suspending and dispersing agents to be diluted and agitated with a specified quantity of vehicle, most often purified water. Drugs that are unstable if maintained for extended periods in the presence of an aqueous vehicle (e.g., many antibiotic drugs) are most frequently supplied as dry powder mixtures for reconstitution at the time of dispensing. This type of preparation is designated in the USP by a title of the form “for Oral Suspension.” Prepared suspensions not requiring reconstitution at the time of dispensing are simply designated as “Oral Suspension.” Reasons for Suspensions There are several reasons for preparing suspensions. For example, certain drugs are chemically unstable in solution but stable when suspended. In this instance, the suspension ensures chemical stability while permitting liquid therapy. For many patients, the liquid form is preferred to the solid form of the same drug because of the ease of swallowing liquids and the flexibility in administration of a range of doses. This is particularly advantageous for infants, children, and the elderly. The disadvantage of a disagreeable taste of certain drugs in solution form is overcome when the drug is administered as undissolved particles of an oral suspension. In fact, chemical forms of certain poor-tasting drugs have been specifically developed for their insolubility in a desired vehicle for the sole purpose of preparing a palatable liquid dosage form. For example, erythromycin estolate is a less water-soluble ester form of erythromycin and is used to prepare a palatable liquid dosage form of erythromycin, the result being Erythromycin Estolate Oral Suspension, USP. Use of insoluble forms of drugs in suspensions greatly reduces the difficult taste-masking problems of developmental pharmacists, and selection of the flavorants to be used in each suspension may be based on taste preference rather than on a particular flavorant’s ability to mask an unpleasant taste. For the most part, oral suspensions are aqueous preparations with the vehicle flavored and sweetened to suit the anticipated taste preferences of the intended patient. Features Desired in a Pharmaceutical Suspension There are many considerations in the development and preparation of a pharmaceutically elegant suspension. In addition to therapeutic efficacy, chemical stability of the components of the formulation, permanency of the preparation, and aesthetic appeal of the preparation— desirable qualities in all pharmaceutical preparations—a few other features apply more specifically to the pharmaceutical suspension: 1. A properly prepared pharmaceutical suspension should settle slowly and should be readily redispersed upon gentle shaking of the container. 2. The particle size of the suspensoid should remain constant throughout long periods of undisturbed standing. 3. The suspension should pour readily and evenly from its container. TYPES OF SUSPENSIONS Based on Route of Administration 1. Oral suspension e.g.: Paracetamol suspension, antacids, Tetracycline HCl. 2. Externally applied suspension e.g.: Calamine lotion. 3. Parenteral suspension e.g.: Procaine, penicillin G, Insulin, Zinc Suspension Based on Proportion of Solid Particles 1. Dilute suspension (2 to10% w/v solid) E.g.: cortisone acetate, prednisolone acetate 2. Concentrated suspension (50% w/v solid) E.g.: zinc oxide suspension Based on Electro kinetic Nature of Solid Particles 1. Flocculated suspension 2. Deflocculated suspension Based on Size of Solid Particles 1. Colloidal suspensions (< 1 micron) Suspensions having particle sizes of suspended solid less than about 1micron in size are called as colloidal suspensions. 2. Coarse suspensions (>1 micron) Suspensions having particle sizes of greater than about 1micron in diameter are called as coarse suspensions. 3. Nano suspensions (10 ng) Suspensions are the biphasic colloidal dispersions of nanosized drug particles stabilized by surfactants. Size of the drug particles is less than 1mm. METHODS OF SUSPENSION PREPARATION In the preparation of a suspension, the pharmacist must be acquainted with the characteristics of both the intended dispersed phase and the dispersion medium. In some instances, the dispersed phase has an affinity for the vehicle to be employed and is readily wetted by it. Other drugs are not penetrated easily by the vehicle and tend to clump together or to float on the vehicle. In the latter case, the powder must first be wetted to make it more penetrable by the dispersion medium. Alcohol, glycerin, propylene glycol, and other hygroscopic liquids are employed as wetting agents when an aqueous vehicle is to be used as the dispersion phase. They function by displacing the air in the crevices of the particles, dispersing the particles, and allowing penetration of dispersion medium into the powder. In large-scale preparation of suspensions, wetting agents are mixed with the particles by an apparatus such as a colloid mill; on a small scale in the pharmacy, they are mixed with a mortar and pestle. Once the powder is wetted, the dispersion medium (to which have been added all the formulation’s soluble components, such as colorants, flavorants, and preservatives) is added in portions to the powder, and the mixture is thoroughly blended before subsequent additions of vehicle. A portion of the vehicle is used to wash the mixing equipment free of suspensoid, and this portion is used to bring the suspension to final volume and ensure that the suspension contains the desired concentration of solid matter. The final product is then passed through a colloid mill or other blender or mixing device to ensure uniformity. Whenever appropriate, suitable preservatives should be included in the formulation of suspensions to preserve against bacterial and mold contamination. The formulation of a suspension depends on whether the suspension is flocculated or deflocculated. Three approaches are commonly involved 1. Use of structured vehicle 2. Use of controlled flocculation 3. Combination of both methods Structured Vehicle Structured vehicles called also thickening or suspending agents. They are aqueous solutions of natural and synthetic gums. These are used to increase the viscosity of the suspension. It is applicable only to deflocculated suspensions. E.g. methyl cellulose, sodium carboxy methyl cellulose, acacia, gelatin and tragacanth. These structured vehicles entrapped the particle and reduces the sedimentation of particles. Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage. 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 syringe filling and administration due to high viscosity. Controlled Flocculation Controlled flocculation of particles is obtained by adding flocculating agents, which are: 1. Electrolytes 2. Surfactants 3. Polymers Flocculation in structured vehicles Sometimes suspending agents can be added to flocculated suspension to retard sedimentation Examples of these agents are: Carboxymethylcellulose (CMC), Carbopol 934, Veegum, and bentonite PROPERTIES OF SUSPENSIONS 1. Sedimentation Sedimentation means settling of particle or floccules occur under gravitational force in liquid dosage form. Velocity of sedimentation 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 limitations of Stoke’s Law: 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. Sedimentation in Flocculated Suspension In flocculated suspension, formed flocs (loose aggregates) will cause increase in sedimentation rate due to increase in size of sedimenting particles. Hence, flocculated suspensions sediment more rapidly. Sedimentation in Deflocculated Suspension In deflocculated suspension, individual particles are settling, so rate of sedimentation is slow which prevents entrapping of liquid medium which makes it difficult to re-disperse by agitation. This phenomenon also called ‘cracking’ or ‘claying’. In deflocculated suspension larger particles settle fast and smaller remain in supernatant liquid so supernatant appears cloudy whereby in flocculated suspension, even the smallest particles are involved in flocs, so the supernatant does not appear cloudy.  2. Electrokinetic Properties Zeta Potential The zeta potential is defined as the difference in potential between the surface of the tightly bound layer (shear plane) and electro-neutral region of the solution. As shown in figure 2.3, the potential drops off rapidly at first, followed by more gradual decrease as the distance from the surface increases. This is because the counter ions close to the surface acts as a screen that reduce the electrostatic attraction between the charged surface and those counter ions further away from the surface. Zeta potential has practical application in stability of systems containing dispersed particles since this potential, rather than the Nernst potential, governs the degree of repulsion between the adjacent, similarly charged, dispersed particles. If the zeta potential is reduced below a certain value (which depends on the system being used), the attractive forces exceed the repulsive forces, and the particles come together. This phenomenon is known as flocculation. The flocculated suspension is one in which zeta potential of particle is -20 to +20 mV. Thus, the phenomenon of flocculation and deflocculation depends on zeta potential carried by particles. Particles carry charge may acquire it from adjuvants as well as during process like crystallization, grinding processing, adsorption of ions from solution e.g. ionic surfactants. 3. Rheological Behavior Rheology is defined as the study of flow and deformation of matter. The deformation of any pharmaceutical system can be arbitrarily divided into two types: 1) The spontaneous reversible deformation, called elasticity; and 2) Irreversible deformation, called flow. The second one is of great importance in any liquid dosage forms like suspensions, solutions, emulsions etc. Generally, viscosity is measured as a part of rheological studies because it is easy to measure practically. Viscosity is the proportionality constant between the shear rate and shear stress, it is denoted by η. η = S/D Where, S = Shear stress D = Shear rate Viscosity has units: dynes-sec/cm 2 or g/cm-sec or poise in CGS system SI unit of Viscosity is N-sec/m2 1 N-sec/m2 = 10 poise Kinematic Viscosity: It is defined as the ratio of viscosity (η) and the density (ρ) of the liquid. Kinematic viscosity = η/ ρ Unit of Kinematic viscosity is stokes and centistokes. Relative Viscosity: The relative viscosity denoted by ηr. It is defined as the ratio of viscosity of the dispersion (ηd) to that of the vehicle, ηv. Mathematically expressed as, ηr = ηd/ηv Types of Flow Flow pattern of liquid s can be divided mainly in two types: a) Newtonian Flow Newton was the first scientist to observe the flow properties of liquids in quantitative terms. Liquids that obey Newton ’s law of flow are called Newtonian liquids, E.g., simple liquids. Newton’s equation for the flow of a liquid is S=ηD Where, S = Shear stress D =Shear rate Here, the shear stress and shear rate are directly proportional, and the proportionality constant is the Co-efficient of viscosity. If we plot graph of shear stress verses shear rate, the slope gives the viscosity. The curve always passes through the origin. b) Non-Newtonian Flow Emulsions, suspensions and semisolids have complex rheological behavior and thus do not obey Newton ’s law of flow and thus they are called non-Newtonian liquids. They are further classified as under Plastic flow Pseudo-plastic flow Dilatant flow A) Plastic flow The substance initially behaves like an elastic body and fails to flow when less amount of stress is applied. Further increase in the stress leads to a nonlinear increase in the shear rate which then turns to linearity. Extrapolations of the linear plot gives ‘x’ intersect which is called yield value. This curve does not pass through the origin. As the curve above yield value tends to be straight, the plastic flow is similar to the Newtonian flow above yield value. Normally flocculated suspensions are associated with the plastic flow, where yield value represents the stress required to break the inter-particular contacts so that particles behave individually. Thus, yield value is indicative of the forces of flocculation. B) Pseudo-plastic Flow Here the relationship between shear stress and the shear rate is not linear and the curve starts from origin. Thus the viscosity of these liquids cannot be expressed by a single value. Normally, pseudo plastic flow is exhibited by polymer dispersions like: Tragacanth water Sodium alginate in water Methyl cellulose in water Sodium carboxy methyl cellulose in water C) Dilatant Flow In this type of liquids resistance to flow (viscosity) increases with increase in shear rate. When shear stress is applied their volume increases and hence, they are called Dilatant. This property is also known as shear thickening. Dilatant flow is observed in suspensions containing more than 50% v/v of solids. Thixotropy: Thixotropy is defined as the isothermal slow reversible conversion of gel to sol. Thixotropic substances on applying shear stress convert to sol(fluid) and on standing they slowly turn to gel (semisolid). SUSPENDING AGENTS Suspending agents are substances that are used to keep finely divided insoluble materials suspended in a liquid media by preventing their agglomeration (coming together) and by imparting viscosity to the dispersion media so that the particles settle more slowly. Care must be taken when selecting a suspending agent for oral preparations as the acid environment of the stomach may alter the physical characteristics of the suspension and therefore the rate of release of the drug from suspension. Most suspending agents perform two functions i.e. besides acting as a suspending agent they also impart 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 enough 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. Classification of Suspending Agents 1. Natural Animal origin – Gelatin Plant origin - Accacia, Tragacanth, Starch, sea weed (Alginates) Mineral sources - e.g., Bentonite, Kaoline 2. Semi-synthetic These consist of substituted cellulos (minerals) e.g., Hydroxyethyl cellulose, Sodium Carboxymethylcellulose, methylcellulose, Microcrystalline cellulose. 3. Synthetic They are synthetic polymers. E.g., carboxypolymethylene (Carbopol), Polyvinyl Alcohol, Polyvinyl Pyrrolidone iodine complex (PVC). SUSPENSION STABILITY General chemical stability considerations apply to suspensions as much as to any other formulation. The drug must remain chemically stable over the intended shelf-life of the product (and allowing some time as a ‘margin of error’ afterwards) and specifications will be in place for the maximum permitted levels of specified degradation products (these will be determined for each drug independently, based on safety considerations). If the chemical degradation pathway of the drug is determined, then the appropriate chemical preservative(s) can be added to the suspension. Similarly, the effect of temperature on the chemical stability of the drug needs to be established, to assess whether any temperature restrictions are necessary during storage or transport. However, physical stability is equally important for suspension formulations. Sedimentation should ideally be kept to a minimum as discussed previously, and where sedimentation is permitted or unavoidable, easy redispersion of the sediment is necessary. The patient or care taker should be able to re-disperse the sediment by inversion and gentle shaking of the bottle only; the bottle should carry an appropriate instruction. The redispersion pattern should be established, testing at suitable time intervals and under various storage conditions, and used as a measure during shelf-life determinations. Visual assessment of sediment redispersion on shaking is useful but can only provide a general indication of whether there is a problem or not. A more quantitative approach is taken by assessing the particle size distribution and drug content of representative samples taken from the top, middle and bottom of the container. Ideally, these should be consistent across depth and over time, meeting the pre-set product specifications.