Controlled flocculation suspensions

Usually, suspensions are flocculated so that the particles form large aggregates that are easy to disperse—normally this is achieved using potassium or sodium chloride (Akers et al. 1987). However, for controlled flocculation suspensions, sonication maybe required to determine the size of the primary particles (Bommireddi et al. 1998). 

Flocculating agents can be simple electrolytes that are capable of reducing the zeta potential of suspended charged particles. Examples include small concentrations (0.01-1%) of monovalent ions (e.g., sodium chloride, potassium chloride) and di- or trivalent ions (e.g., calcium salts, alums, sulfates, citrates or phosphates) [80-83], These salts are often used jointly in the formulations as pH buffers and flocculating agents. Controlled flocculation of suspensions can also be achieved by the addition of polymeric colloids or alteration of the pH of the preparation. 

The controlled flocculation method may be used in conjunction with the addition of a polymeric material to form a structured vehicle. After the formation of the floes, an aqueous solution of polymeric material, usually negatively charged, such as carboxy-methylcellulose or carbopol, is added. The concentration employed depends on the consistency desired for the suspension, which also relates to the size and density of the dispersed phase. Care must be taken to ensure the absence of any incompatibility between the flocculating agent and the polymer used for the formation of the structured vehicle. 

When suspensions are formulated to provide a stable system, the particle size becomes critical. Flocculated suspensions also require careful particle size control either in the process of manufacturing or in the starting material. Equally important is the crystal habit — the outward appearance of an agglomeration of crystals. Crystal structure can be altered during the manufacturing process, particularly if the product is subject to temperature cycling, and this can alter the stability of suspensions. 

Ranucci, J. A., Dixit, S., Bray, R. N., Goldman, D. Controlled flocculation in metered-dose aerosol suspensions. Pharm Tech 14(4) 68, 70-72, 74 (1990). 

Light-scattering experiments on flocculating suspensions of silica colloids provided the data in the following table. (R is the average cluster radius.) Estimate the fractal dimension of the clusters formed and indicate whether the flocculation process is transport or reaction controlled. Hint Apply Eq. 6.1 and the concepts in Section 6.1.)... 

Direct particle counting of an initially monodisperse suspension was used to measure the time dependence of the q-moment M0, as given in the following table. Examine these data for conformity to either transport- or reaction-controlled flocculation kinetics and estimate the characteristic time scale, 2/kn p0, wherekn = kmn for m n 1. (Answer k n= 3.05 x 10 22 m3 s"1 = 2KD/Wmn, corresponding to Wmn = 4.07 X 104 for all m, n.)... 

Although the production of highly deflocculated suspensions is a primary objective for formulation of suspension concentrates, these systems tend to settle under gravity forming dilatant sediments (clays). The latter must be prevented either by controlled flocculation or by the addition of a second disperse phase to the continuous medium (1). One method which may be applied to sterlcally stabilised dispersions, is to add a free (ie. non-adsorbing) polymer to the continuous medium. 

Controlled flocculation In metered-dose aerosol suspensions... 

Controlled flocculation is a widely used technique for stabilizing suspended systems. The aim is to alter particle surface charge or to achieve particle separation via steric hindrance with the help of appropriate stabilizing excipients. However this is particularly difficult to achieve in non-polar systems such as suspensions in CFC (or HFA) propellants. Controlled flocculation to optimise the stabilisation of MDIs has been recommended by Ranucci et al. but disputed by Hickey, Dalby, and Byron. ... 

Ranucci, J.A. Dixit, S. Bray, R., Jr. Goldman, D. Application of controlled flocculation to metered dose aerosols suspensions. Pharm. Res. 1987, 4 (2 suppl.), S-25. 

Flocculated pharmaceutical suspensions are prepared using several methods. The choice depends on the properties of the drug and the class of suspension desired. The following examples illustrate how suspensions may be prepared by controlled flocculation procedures ... 

Figure 7.30 Caking diagram showing controlled flocculation of a bismuth subnitrate suspension employing dibasic potassium phosphate as the flocculating agent.

Figure 7.31 Diagrammatic drawing of flocculation and controlled flocculation in a sulfamerazine suspension the effect of the addition of sodium dioctyl sulfosuccinate (docusate sodium) and aluminium chloride is shown and two interpretations of the results are outlined.

Somasundaran P, Xiang Y, Krishnakumar S. Role of conformation and orientation of surfactants and polymers in controlling flocculation and dispersion of aqueous and nonaqueous suspensions. Colloids Surf A 1998, 133, 125-133. 

Suspension formulations are prepared to achieve a controlled flocculation (DLVO theory, ref), which will allow ease of redispersion upon shaking. A number of physicochemical phenomena may occur to disrupt the stability of the product. Moisture ingress to the container (and association with the drug particles) will lead to hydrolysis for molecules that are susceptible to this mechanism of degradation. Because of the inert hydrophobic nature of propellant, this can be controlled to some extent. The presence of moisture will also give rise to interactions between particles, which may result in irreversible aggregation. Related forms of aggregation may result... 

For a structured suspension, obtained by controlled flocculation or the addition of thickeners (such polysaccharides, clays or oxides), the floes sediment at a rate depending on their size and porosity of the aggregated mass. After this... 

During extended storage, the particles in (pharmaceutical) suspensions often form agglomerates that can be no longer destroyed by shaking the preparation. This is of particular concern in, for example, eye drops. The problem can be avoided by controlled flocculation of the solids. After the addition of an electrolyte, the fine particles aggregate to loose floes that can be easily redispersed by shaking the dispenser prior to application. 

H Schott. Controlled flocculation of coarse suspensions by colloidally dispersed solids. I Interaction of bismuth subnitraie with bentonite. J. Pharm. Sci. 65 865-871. 1976,... 

This is governed by the same forces as those described for other dispersion systems such as emulsions. There are differences, however, as coalescence obviously cannot occur in suspensions and the adsorption of polymers and surfactants also occurs in a different fashion. Flocculation, unlike coalescence, can be a reversible process and partial or controlled flocculation is attempted in formulation. 

Figure 6.5.2 shows a flocculated suspension with a yield stress as well. The yield stress is best measured with a stress-controlled rotational rheometer but may be confirmed by rate-controlled and capillary measurements. In Chapter 8 we discuss... 

Schott, H., 1976, Controlled Flocculation of Coarse Suspensions by CoUoidally Dispersed Solids I Interaction of Bismuth Subnitrate with Bentonite , Journal of Pharmaceutical Sciences, 65(6), pp 855-861. 

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