Microspheres dispersed systems

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]. 

Emulsions and suspensions are disperse systems that is, a liquid or solid phase is dispersed in an external liquid phase. While emulsions are sometimes formulated from oily drugs or nutrient oils their main function is to provide vehicles for drug delivery in which the drug is dissolved in the oil or water phase. Suspensions, on the other hand, are usually prepared from water-insoluble drugs for delivery orally or by injection, usually intramuscular injection. An increasing number of modern delivery systems are suspensions - of liposomes or of polymer or protein microspheres, nanospheres or dendrimers, hence the need to understand the formulation and stabilization of these systems. Pharmaceutical emulsions and suspensions are in the colloidal state, that is where the particles range from the nanometre size to visible (or coarse) dispersions of several micrometres. 

Moreover, stearic acid is a common constituent in enteric coating for its plasticity and stability in stomach. Occasionally, it is used as binder agent especially in melt pelletization. In addition to be a traditional biomedical material, which has been used for thousands of years, stearic acid also plays an important role in newly developed drug delivery system, like microparticle dispersion system which is usually used for sustained drug delivery. Stearic acid is a vital ingredient candidate for nanoparticle and microsphere preparation. 

General examples of this system are polymer micelles, microsphere, nanoparticles, liposomes, etc. The microparticle dispersion system has the following advantages ... 

Numerous synthetic or natural polymers have been used as matrices for micro- and nanoparticles or -capsules, most of which are biodegradable or bioerodible. Microparticles (or microspheres) are systems in which the drug is dispersed throughout the particle whereas capsules are vesicular systems in which the drug is contained in a cavity surrounded by the polymeric membrane (Couvreur and Puisieux, 1993). 

Stable particles in sufficient number, all the oligo-radi-cals and nuclei generated in the continuous phase are captured by the mature particles, no more particles form, and the particle formation stage is completed. The primary particles formed by the nucleation process are swollen by the unconverted monomer and/or polymerization medium. The polymerization taking place within the individual particles leads to resultant uniform microspheres in the size range of 0.1-10 jjLvn. Various dispersion polymerization systems are summarized in Table 4. 

Seeded dispersion polymerization was extensively investigated for radical systems [17]. Much less is known about seeded dispersion polymerizations with propagation on ionic and/or pseudoionic active centers. Awan et al. reported seeded ionic polymerization of styrene, which at certain conditions produced particles with narrow diameter size dispersity [18,19]. We presented the first data on the seeded ring-opening polymerization with constant number of microspheres. 

The density of a syntactic foam is determined by the relative proportions (volume fractions) of microspheres, resin matrix, and dispersed air. The theoretical lower limit of the density in a two-phase system (without dispersed air) is determined by the close packing rules for spheres. Various packing possibilities in systems containing uniform-size spheres are summarized below 8> 8S) ... 

Figure 6 is a graphic representation of foam structures in which the microspheres are dispersed randomly (a) and uniformly in close packing (b). In both structures, the two phases fill completely the whole volume (no dispersed air voids) and the density of the product is thus calculated from the relative proportions of the two. Measured density values often differ from the calculated ones, due to the existence of some isolated or interconnected, irregularly shaped voids as shown in Fig. 6c. The voids are usually an incidental part of the composite, as it is not easy to avoid their formation. Nevertheless, voids are often introduced intentionally to reduce the density below the minimum possible in a close-packed two-phase structure. In such three-phase systems the resin matrix is mainly a binding material, holding the structure of the microspheres together.

Emulsions and suspensions are colloidal dispersions of two or more immiscible phases in which one phase (disperse or internal phase) is dispersed as droplets or particles into another phase (continuous or dispersant phase). Therefore, various types of colloidal systems can be obtained. For example, oil/water and water /oil single emulsions can be prepared, as well as so-called multiple emulsions, which involve the preliminary emulsification of two phases (e.g., w/o or o/w), followed by secondary emulsification into a third phase leading to a three-phase mixture, such as w/o/w or o/w/o. Suspensions where a solid phase is dispersed into a liquid phase can also be obtained. In this case, solid particles can be (i) microspheres, for example, spherical particles composed of various natural and synthetic materials with diameters in the micrometer range solid lipid microspheres, albumin microspheres, polymer microspheres and (ii) capsules, for example, small, coated particles loaded with a solid, a liquid, a solid-liquid dispersion or solid-gas dispersion. Aerosols, where the internal phase is constituted by a solid or a liquid phase dispersed in air as a continuous phase, represent another type of colloidal system. 

Use of macromonomers as reactive (copolymerizable) surfactants in heterogeneous systems such as emulsion and dispersion constitutes an increasingly important application in the design of polymeric microspheres, as will be discussed later in Sect. 6. Here the macromonomers copolymerize in situ with some of the substrate comonomers to afford the graft copolymers, the grafts (branches) of which serve as effective steric stabilizers by anchoring their backbone onto the surfaces of the particles. In general, however, the copolymerization reactivities of macromonomers in such systems are not well understood yet. 

Dispersion polymerization has also been applied to the ring opening polymerization of e-caprolactone and lactide in heptane-dioxane (4/1 v/v) with poly(dodecyl methacrylate)-g-poly(e-caprolactone) as stabilizer [97]. Diethyl-aluminium ethoxide and tin(II) 2-ethylhexanoate were used as initiators in these two systems, respectively, to obtain functional microspheres with a narrow particle size distribution and a narrow molecular weight distribution [98]. Table 2 provides an overview of microspheres obtained by living dispersion polymerization. 

A wide variety of polymer microspheres can be made by dispersion polymerization. A key component in all of these systems is the stabilizer (dispersant) both during particle formation and for the stability of the resulting colloidal particles. Functionality can be introduced into colloidal particles in various ways by copolymerization of functional monomers (like HEMA), or incorporation of functional dispersants, initiators, chain transfer agents, or macromonomers. Many different types of macromonomer are prepared and used to prepare functional microspheres. Amphiphilic macromonomers provide a particularly versatile component in these systems, being the source of both stabilizer and functional residue. They act as stabilizer because they are covalently grafted onto the particles surface by copolymerization with main monomers, and form tightly bound hairy shells on the particles surface. 

A stirred cell equipped with a 0.22iuni membrane filter was charged with 30 mL of latex, the dispersion of microsphere. The specific surfrice area was adjusted to 0.19 m per ImL and the ionic strength was calibrated to 0.01. At the constant stirrer speed, buffer solution was introduced into the stirred ceil until steady state flux was attained. Protein solutions were introduced with step of pulse injection. The permeate flux was measured continuously with an electronic balance (Precision plus, Ohaus Co., USA) by a data acquisition system. The electronic balance was connected to a PC through a RS 232C interfece. The surface charge density of microspheres was varied as 0.45, S.94, 9.14 and 10.25, and the stirrer speed was varied as 300,400 and 600rpm. 

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