Disperse systems suspensions

To get an idea of the stability of an extemporaneous preparation the only possibility is to keep a part of the preparation in the pharmacy in order to be able to recall if necessary or to have some information in case of a second prescription. For background information on the instability of disperse systems (suspensions, emulsions) and the ways to overcome those stability problems, see Sect. 18.4. For a useful review about the changes in dissolution rate during shelf life and how to prevent them, reference is made to [4]. 

Many polymers are used for the preparation of disperse systems (suspensions and emulsions) in pharmaceutical formulations. An example of such systems is the A-B-A block copolymer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethyl-ene oxide), PEO-PPO-PEO, commercially available as Poloxamers (ICI), Pluronics (BASF) and Synperonic PE (ICI). On hydrophobic drug particles or oil droplets, the polymer adsorbs with the B hydrophobic chain (PPO) close to the surface, leaving the two hydrophilic A chains dangling in solution. 

Dispersed Systems. Many fluids of commercial and biological importance are dispersed systems, such as soflds suspended in Hquids (dispersions) and Hquid-Hquid suspensions (emulsions). Examples of the former include inks, paints, pigment slurries, and concrete examples of the latter include mayonnaise, butter, margarine, oil-and-vinegar salad dressing, and milk. Blood seems to fall in between as it is a suspension of deformable but not hquid particles, and it does not behave like either a dispersion or an emulsion (69) it thus has an interesting rheology (70). 

Detailed treatments of the rheology of various dispersed systems are available (71—73), as are reviews of the viscous and elastic behavior of dispersions (74,75), of the flow properties of concentrated suspensions (75—82), and of viscoelastic properties (83—85). References are also available that deal with blood red ceU suspensions (69,70,86). 

This chapter describes the basic principles involved in the development of disperse systems. Emphasis is laid on systems that are of particular pharmaceutical interest, namely, suspensions, emulsions, and colloids. Theoretical concepts, preparation techniques, and methods used to characterize and stabilize disperse systems are presented. The term particle is used in its broadest sense, including gases, liquids, solids, molecules, and aggregates. The reader may find it useful to read this chapter in conjuction with Chapters 8, 12, and 14, since they include some of the most important applications of disperse systems as pharmaceutical dosage forms [1]. 

Disperse systems can be classified in various ways. Classification based on the physical state of the two constituent phases is presented in Table 1. The dispersed phase and the dispersion medium can be either solids, liquids, or gases. Pharmaceutically most important are suspensions, emulsions, and aerosols. (Suspensions and emulsions are described in detail in Secs. IV and V pharmaceutical aerosols are treated in Chapter 14.) A suspension is a solid/liquid dispersion, e.g., a solid drug that is dispersed within a liquid that is a poor solvent for the drug. An emulsion is a li-quid/liquid dispersion in which the two phases are either completely immiscible or saturated with each other. In the case of aerosols, either a liquid (e.g., drug solution) or a solid (e.g., fine drug particles) is dispersed within a gaseous phase. There is no disperse system in which both phases are gases. 

The number of the constituent phases of a disperse system can be higher than two. Many commercial multiphase pharmaceutical products cannot be categorized easily and should be classified as complex disperse systems. Examples include various types of multiple emulsions and suspensions in which solid particles are dispersed within an emulsion base. These complexities influence the physicochemical properties of the system, which, in turn, determine the overall characteristics of the dosage forms with which the formulators are concerned. 

Content uniformity and long-term stability of a pharmaceutical product are required for a consistent and accurate dosing. Aggregation of dispersed particles and resulting instabilities such as flocculation, sedimentation (in suspensions), or creaming and coalescence (in emulsions) often represent major problems in formulating pharmaceutical disperse systems. 

For suspensions primarily stabilized by a polymeric material, it is important to carefully consider the optimal pH value of the product since certain polymer properties, especially the rheological behavior, can strongly depend on the pH of the system. For example, the viscosity of hydrophilic colloids, such as xanthan gums and colloidal microcrystalline cellulose, is known to be somewhat pH- dependent. Most disperse systems are stable over a pH range of 4-10 but may flocculate under extreme pH conditions. Therefore, each dispersion should be examined for pH stability over an adequate storage period. Any... 

Substances that have been used as preservatives for disperse systems include chlorocresol, chlorobutanol, benzoates, phenylmercuric nitrate, parabens, and others [76,77]. The use of cationic antimicrobial agents such as quaternary ammonium compounds (e.g., benzalkonium chloride) is contraindicated in many cases because they may be inactivated by other formulation components and/or they may alter the charge of the dispersed phase. Clay suspensions and gels should be adequately preserved with nonionic antimicrobial preservatives. The use of preservatives is generally limited to products that are not intended for parenteral use. Intravenous injectable... 

The determination of the zeta potential of particles in a disperse system provides useful information concerning the sign and magnitude of the charge and its effect on the stability of the system (see Sec. II.B) [56, 206 208], It can be of value in the development of pharmaceutical suspensions, particularly if the... 

RA Nash. Pharmaceutical suspensions. In HA Lieberman, MM Rieger, GS Banker, eds. Pharmaceutical Dosage Forms Disperse Systems, Vol. 1. New York Marcel Dekker, 1988, pp 151-198. 

Investigations of the rheological properties of disperse systems are very important both from the fundamental and applied points of view (1-5). For example, the non-Newtonian and viscoelastic behaviour of concentrated dispersions may be related to the interaction forces between the dispersed particles (6-9). On the other hand, such studies are of vital practical importance, as, for example, in the assessment and prediction of the longterm physical stability of suspensions (5). 

Many drugs are administered as parenterals for speed of action because the patient is unable to take oral medication or because the drug is a macromolecule such as a protein that is unable to be orally absorbed intact due to stability and permeability issues. The U.S. Pharmacopoeia defines parenteral articles as preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal. They include intravenous, intramuscular, or subcutaneous injections. Intravenous injections are classified as small volume (<100 mL per container) or large volume (>100 mL per container) injections. The majority of parenteral dosage forms are supplied as ready-to-use solutions or reconstituted into solutions prior to administration. Suspension formulations may also be used,101 although their use is more limited to a subcutaneous (i.e., Novolin Penfill NOVO Nordisk) or intramuscular (i.e., Sandostatin LAR Depot Novartis) injection. Intravenous use of disperse systems is possible but limited (i.e., Doxil Injection Ortho Biotec). 

Sustained release from disperse systems such as emulsions and suspensions can be achieved by the adsorption of appropriate mesogenic molecules at the interface. The drug substance, which forms the inner phase or is included in the dispersed phase, cannot pass the liquid ciystals at the interface easily and thus diffuses slowly into the continuous phase and from there into the organism via the site of application. This sustained drug release is especially pronounced in the case of multilamellar liquid crystals at the interface. 

Mixing processes involved in the manufacture of disperse systems, whether suspensions or emulsions, are far more problematic than those employed in the blending of low-viscosity miscible liquids due to the multi-phasic character of the systems and deviations from Newtonian flow behavior. It is not uncommon for both laminar and turbulent flow to occur simultaneously in different regions of the system. In some regions, the flow regime may be in transition, i.e., neither laminar nor turbulent but somewhere in between. The implications of these flow regime variations for scale-up are considerable. Nonetheless, it should be noted that the mixing process is only completed when Brownian motion occurs sufficiently to achieve uniformity on a molecular scale. 

Disperse systems often necessitate particle size reduction, whether it is an integral part of product processing, as in the process of liquid-liquid emulsification, or an additional requirement insofar as solid particle suspensions are concerned. (It should be noted that solid particles suspended in liquids often tend to agglomerate. Although milling of such suspensions tends to disrupt such agglomerates and produce a more homogeneous suspension. 

Liquid dosage forms which are disperse systems (colloidal, i.e., microspheres, nanoparticles, and micelles suspensions and emulsions) often contain preservatives which are methyl, ethyl, propyl, and butyl esters of para-hydroxybenzoic acid in various combinations. A typical example is the antacid suspensions which have high pH values which make the esters of the preservatives susceptible to hydrolysis. One way to circumvent this problem is to use several preservatives in combination with the hope that some quantities of the preservatives will remain to prevent the suspension from microbial attack. A report showing the assay of the four esters and the parent acid (one of the decomposition products) in drug products in which all the preservatives were used has been given [13]. 

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