Formulation process aqueous systems

For a number of years, economic and safety considerations have driven the substitution of solvent-based formulations with aqueous systems in all industrial sectors, and the process has recently received a further impetus from the regulatory activity of the European Union to limit the release of volatile organic compounds in the environment. 

Water Uptake. There is evidence to suggest that water uptake caused by capillary forces is the crucial factor in the disintegration process of many formulations. In such systems the pore structure of the tablet is of prime importance and any inherent hydrophobicity of the tablet mass will adversely affect it. Therefore, disintegrants in this group must be able to maintain a porous structure in the compressed tablet and show a low interfacial tension towards aqueous fluids. Rapid penetration by water throughout the entire tablet matrix to facilitate its breakup is thus achieved. Concentrations of disintegrant that ensure a continuous matrix of disintegrant are desirable and levels of between 5 and 20% are common. 

Surfactants are produced on very large or medium technical scales. Their analysis by manufacturers in products and their formulations sometimes may be complicated because of the great variety of surfactants [5]. After use as directed in aqueous systems they were discharged mainly with wastewaters. Their analysis in environmental samples then becomes quite difficult because analysis must be performed at trace concentrations with limited sample amounts after essential matrix-dependent pre-concentrations steps. In addition, homologues and isomers that exist for many surfactants, besides metabolites which are generated in biochemical processes, complicate their specific determination [6]. 

Despite the apparent variety expressed by these options, aqueous systems hold a dominant position in the pharmaceutical industry at this time. As a consequence, serious constraints are often imposed on the products being coated, the coating formulations used, and the coating processes that are adopted, with the result that scaling up the coating process can present serious challenges. 

A preferred location of the solubilizate molecule within the micelle is largely dictated by chemical structure. However, solubilized systems are dynamic and the location of molecules within the micelle changes rapidly with time. Solubilization in surfactant aqueous systems above the critical micelle concentration offers one pathway for the formulation of poorly soluble drugs. From a quantitative point of view, the solubilization process above the CMC may be considered to involve a simple partition phenomenon between an aqueous and a micellar phase. Thus the relationship between surfactant concentration Cm and drug solubility Ctot is given by Eq. (3). 

Simethicone as supplied is not generally compatible with aqueous systems and will float like an oil on a formulation unless it is first emulsified. It should not be used in formulations or processing conditions that are very acidic (below pH 3) or highly alkaline (above pH 10), since these conditions may have some tendency to break the polydimethylsiloxane polymer. Simethicone cannot normally be mixed with polar solvents of any kind because it is very minimally soluble. Simethicone is incompatible with oxidizing agents. 

This chapter reviews a) the characterization of proteins and peptides in a variety of non-aqueous or co-solvent conditions, both acceptable and unacceptable for pharmaceutical applications, b) the applicability of non-aqueous conditions for increasing solubility, stability and activity, and c) novel drug delivery and formulation process technology applications. This review focuses on non-aqueous solutions, suspensions and co-solvent systems that result in miscible conditions. 

Alternatively, TbrlonAI-30 and AI-50 are amenable to aqueous systems when formulated with a tertiary amine Table 12.4 [27]. Due to the very low degree of imidization compared to AI-10 or polyamide-imides produced in the isocyanate process, these polymers can form stable, low-viscosity solutions in water at low to moderate polymer sohds. Generally the polymer sohds are 5 to 15%, depending on the polyamide-imide used, and provide solutions with a viscosity in the range of 50 to 2000 cP. 

Recently, Tsakala et al. (90) formulated pyrimethamine systems based on several lactide/glycolide polymers. These studies were conducted with both microspheres (solvent evaporation process) and implants (melt extrusion process). In vitro studies indicated that pyrimethamine-loaded implants exhibited apparent zero-order release kinetics in aqueous buffer whereas the microspheres showed an initial high burst and considerably more rapid drug release. In vivo studies in berghi infected mice confirmed that the microspheres did not have adequate duration of release for practical application. However, the implants offer promise for future clinical work as more than 3 months protection was observed in animals. 

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