Pharmaceutical Suspensions: Lec 6 PDF

1 Coarse dispersion, suspension 10/30/2024  Excipients used in the formulation of suspensions for oral administration There is a direct similarity between the types of excipients used for the formulation of suspensions and solutions for oral...

1 Coarse dispersion, suspension 10/30/2024  Excipients used in the formulation of suspensions for oral administration There is a direct similarity between the types of excipients used for the formulation of suspensions and solutions for oral administration. The major difference between these two categories of formulations is the inclusion of excipients to physically stabilize suspensions. Many of the categories (and examples) of excipients used for suspensions are the same for suspensions as for solutions. 2 10/30/2024  Excipients used in the formulation of suspensions for oral administration Vehicle The most common vehicle is purified water. It may also contain buffer to control pH, citric acid/Na citrate is the most common buffer used. Excipients to enhance the physical stability of suspensions As detailed previously, pharmaceutical suspensions may be stabilized by controlled flocculation and by the control of the rate of particle/floccule sedimentation. Addition of electrolytes Surface-active agents (Effect on wetting, Effect on flocculation) 3 10/30/2024  Excipients used in the formulation of suspensions for oral administration Hydrophilic polymers Hydrophilic polymers are commonly used to enhance the physical stability and to affect the flow properties of oral suspensions. These two aspects are detailed below. Effects on the physical stability of suspensions Hydrophilic polymers may adsorb on to the surface of suspended drug particles in pharmaceutical suspensions. Due to their large molecular weight, one section of the polymer chain will adsorb on to the particles, leaving the remainder of the chain to extend into the aqueous vehicle. As the concentration of polymer in the formulation increases, the thickness of the adsorbed layer of polymer increases. As two (polymer- coated) particles approach each other, there will be stearic repulsion due to an overlap of the adsorbed polymer chains. This will prevent the particles coming into close contact. 4 10/30/2024  Excipients used in the formulation of suspensions for oral administration It is important to note that the ability of hydrophilic polymers to stabilize suspensions sterically is dependent on several features, e.g. (1)the concentration of polymer; and (2)the type of polymer. The concentration of polymer The concentration of polymer affects the density of the adsorbed polymer layer on the surface of the particles. The required concentration of polymer should be that which enhances repulsion but does not prevent the interaction of the particles (flocculation). Generally flocculation occurs at a distance which is approximately twice the thickness of the adsorbed polymer layer. 5 10/30/2024  Excipients used in the formulation of suspensions for oral administration The type of polymer The type (and hence the chemistry) of polymer influences the stabilization properties of hydrophilic polymers in two ways. Firstly, the chemical structure of the polymer will influence the nature of the adsorption on the surface of the drug particles which, in turn, influences the thickness and integrity of the adsorbed layer. Secondly, as the interaction between specific groups on adjacent polymer chains is responsible for the stearic stabilization, the nature of the interacting groups on each chain is important. This ability to interact may effectively maintain the polymer-coated particles at a distance, resulting in the production of a structured floccule. 6 10/30/2024  Excipients used in the formulation of suspensions for oral administration Finally if ionic (e.g. anionic) polymers are added to the formulation in the presence of divalent ions (e.g. Mg2+, Ca 2+),or trivalent Al3+ the ions may act as a bridge by interacting both with the surface of the particle and with the charged moieties on the polymer. In this way the polymer is ‘connected’ to two particles and prevents the interaction of the particles. Secondarily, the addition of hydrophilic polymers to the aqueous vehicle will increase the viscosity of the formulation so act as suspending agent. According to Stokes’ equation, increasing the viscosity of an aqueous vehicle will reduce the rate of sedimentation, thereby increasing the physical stability of the formulation. 7 10/30/2024  Excipients used in the formulation of suspensions for oral administration Effect of hydrophilic polymer on the rheological properties of oral suspension As detailed in the previous paragraph, increasing the concentration of a hydrophilic polymer within an aqueous vehicle will alter the viscosity of the system. At very low polymer concentrations (frequently 0.01% for branched polymers), aqueous vehicles will behave as Newtonian systems, in which the shearing stress and rate of shear are proportional. However at higher polymer concentrations, typically of those used in oral suspensions, the flow properties are pseudoplastic (shear thinning). This is a useful property for suspensions as the apparent viscosity will be high under conditions of low shear stress (e.g. storage in the bottle) but under high shearing stress (e.g. those exerted whenever the contents of the bottle are shaken) the apparent viscosity will be low, thereby facilitating administration to the patient. In addition, pseudoplastic formulations may also exhibit thixotropy, a time-dependent recovery of the flow properties. It is important to understand this property in particular, as this should ideally be minimized to enable the rapid recovery of the rheological properties of the formulation. 8 10/30/2024  Alginates 9  Alginate salts have about same suspending action to that of Tragacanth.  Alginate solution looses its viscosity when heated above 60ºC due to polymerization.  Maximum viscosity is observed at a pH range of 5-9.  Chemically alginates are polymers composed of mannuronic acid and glucuronic acid monomers.  In practice, alginate is used at concentration less than 10 % w/w, particularly at 5 % w/w. 10/30/2024  Methylcellulose 10  Methylcellulose is available in several viscosity grades.  The difference in viscosity is due to difference in methylation and polymer chain length.  Methylcellulose is more soluble in cold water than hot water.  Methylcellulose is stable at pH range of 3-11.  Methyl cellulose On Heating Gel form On Cooling Solution form 10/30/2024  Hydroxy ethylcellulose: 11  In HEC hydroxyethyl group is attached to cellulose chain.  Hydroxyethylcellulose (HEC) is another good suspending agent having somewhat similar characteristics to methylcellulose.  Unlike methylcellulose, HEC is soluble in both hot and cold water and do not form gel on heating. 10/30/2024  Carboxy methylcellulose (CMC) 12  Carboxy methylcellulose is available at different viscosity grades.  Low, medium and high viscosity grades are commercially available.  In case of HV-CMC, the viscosity significantly decreases when temperature rises to 40 ºC from 25 ºC.  Therefore, to improve viscosity and stability of suspension MV-CMC is widely accepted. 10/30/2024 Microcrystalline Cellulose (MCC; Tradename-Avicel) 13  Microcrystalline Cellulose is not soluble in water, but it readily disperses in water to give thixotropic gels.  It is used in combination with Na-CMC, MC or HPMC, because they facilitate dispersion of MCC.  The advantages of MCC:  Alginate complex compositions are that they provide excellent stability.  Formulation of dry powder suspensions with MCC;  Produce an excellent dry readily hydratable and dispersible formulation for reconstitution. 10/30/2024  Excipients used in the formulation of suspensions for oral administration Preservatives Oral suspensions are non-sterile; however there are restrictions on the number and type of microorganisms present in this type of dosage form. Whilst the presence of microorganisms within oral suspensions is allowed, it is essential that highly pathogenic microorganisms, e.g. Escherichia coli, are absent. Oral suspensions are multidose formulations and therefore inhibition of the growth/elimination of less pathogenic bacteria and fungi (the latter primarily causing spoilage) is required. Specifications are defined in the various pharmacopoeias regarding the number and type of microorganisms in oral products (solutions and suspensions). For example, the European Pharmacopoeia states that in oral products E. coli must be absent and, in addition, there should be not more than 1000 aerobic bacteria and 14 not more than 100 fungi per gram or millilitre. 10/30/2024  Excipients used in the formulation of suspensions for oral administration Examples of preservatives that are employed in oral suspensions include: Parabens (i.e. esters of parahydroxybenzoic acid, e.g. methyl and propyl parahydroxybenzoic acid are often used in combination in a ratio of 9:1 or 10:1. The concentration is usually 0.22% w/v (i.e. 0.2% w/v methylhydroxy benzoate and 0.02% w/v propylhydroxy benzoate). Organic acids, e.g. benzoic acid (circa 0.9% w/v). 15 10/30/2024  Excipients used in the formulation of suspensions for oral administration When selecting the type and concentration of preservative for inclusion in an oral suspension formulation, the following points should be considered: To exert the antimicrobial effect, preservative must exist in solution within the formulation. Certain preservatives, e.g. the parahydroxybenzoate esters, will interact with hydrophilic polymers, e.g. polyvinylpyrrolidone, cellulose ethers and surface- active agents (e.g. polysorbate 80), thereby reducing the concentration of ‘free’ preservative in the formulation. As a result the antimicrobial efficacy of the preservative is decreased. To overcome this problem it is customary to increase the initial concentration of preservative to ensure that, after adsorption to the dissolved polymer, the required free concentration of preservative is available. The selected preservative must not adversely affect the chemical and physical 16 stability of the suspension product. 10/30/2024  Excipients used in the formulation of suspensions for oral administration Sweetening agents/flavors As is the case for oral solutions, sweetening agents (e.g. sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium and aspartame) and flavors are used for taste- masking purposes. The type (particularly in the case of flavors) and the concentrations of these are selected, as before, to provide the necessary aesthetic properties. 17 10/30/2024  Excipients used in the formulation of suspensions for oral administration Antioxidants Antioxidants are required in certain pharmaceutical suspensions for oral usage to enhance the chemical stability of the therapeutic agent, where this may be compromised by oxidation. The chosen antioxidants are compounds that are redox systems which exhibit higher oxidative potential than the therapeutic agent or, alternatively, are compounds that inhibit free radical-induced drug decomposition. Commonly used examples for incorporation into oral suspensions (usually at concentrations less than 0.1% w/w) include: sodium sulphite, sodium metabisulphite, sodium formaldehyde sulphoxylate, ascorbic acid. As for solutions, chelating agents, e.g. ethylenediamine tetraacetic acid, citric acid, that form complexes with heavy metal ions which are normally involved in 18 oxidative degradation of therapeutic agents, may be included. 10/30/2024  Manufacture of suspensions for oral administration Direct incorporation In this method the soluble components are normally dissolved in the appropriate volume of diluent (vehicle). The solid therapeutic agent is then dispersed into the vehicle with the aid of mixing, prior to correction for volume. The mixing rate employed during the addition is an important determinant in the manufacture of the formulation. If the suspension is flocculated, high-speed mixing may be employed as the flow properties of the system are pseudoplastic (shear thinning). However, if the formulation has been poorly designed and has poor flocculation properties, high-speed mixing will result in an increase in the viscosity of the product (termed dilatant flow). Ultimately this leads to issues regarding the quality of mixing as the increased viscosity 19 may render the product difficult to mix homogeneously. 10/30/2024  Manufacture of suspensions for oral administration The particle size of the suspended drug within the formulation may then be reduced using a ball mill. Alternatively, the particle size of the active ingredient may be optimized (by particle size reduction techniques) prior to incorporation into the vehicle. 20 10/30/2024  Manufacture of suspensions for oral administration 21 Precipitation method: Three precipitation methods are used: Organic solvent precipitation: Water insoluble drugs can be precipitated by dissolving them in water- miscible organic solvent and then adding organic phase to distilled water under standard conditions Organic solvents used are ethanol, propylene glycol and polyethylene glycol. Precipitation by pH: The method of changing the pH of medium is more readily accomplished and does not present the same difficulties associated with organic solvent precipitation. This method is applicable only to those drugs in which solubility is dependent on pH value. Examples include Estradiol Suspension and Insulin Suspension. Double Decomposition: This method involves simple chemistry. 10/30/2024 Example includes White Lotion (NF XIII).  Manufacture of suspensions for oral administration Precipitation method In this method the drug is dissolved in the vehicle (or a portion of the available volume), prior to precipitation following the addition of a counterion; the salt formed is insoluble. Such systems are frequently deflocculated and are therefore mixed at low shear rates. The excipients are then dissolved in the vehicle, or dissolved in a portion of the vehicle, which is then added to the suspension of drug. At this stage the formulation may be exposed to high shearing rates to ensure homogeneity. The volume of the formulation is then corrected by adding the required mass of diluent. One potential problem with this technique is the production of ionic byproducts from the precipitation interaction. If the concentration of these is too high, then the precipitated therapeutic agent requires to be washed with an aqueous solvent. 22 10/30/2024