Solid dissolution rate, influence

P Singh, S Desai, D Flanagan, A Simonelli, W Higuchi. Mechanistic study of the influence of micelle solubilization and hydrodynamic factors on the dissolution rate of solid drugs. J Pharm Sci 57 959, 1968. 

Since dosage forms contain more than just active drug, it is of practical interest to understand how the various components from a multicomponent solid influence their own dissolution and release. Nelson [18] was one of the first pharma-ceuticists to ponder this question and perform the initial dissolution studies. Unfortunately, Nelson initially considered the dissolution of interacting solids (benzoic acid + trisodium phosphate), which is a more complicated and more complex situation than simple multicomponent dissolution of noninteracting solids. Nelson did show that for his benzoic acid and trisodium phosphate pellets, there was a maximum increase in benzoic acid dissolution in water at a mole fraction ratio of 2 1 (benzoic acid trisodium phosphate) and that the benzoic acid dissolution rate associated with the maximum rate was some 40 times greater than that of benzoic acid alone. 

EL Parrot, DE Wurster, T Higuchi. Investigation of drug release from solids I. Some factors influencing the dissolution rate. J Am Pharm Assoc 44 269-273, 1955. 

It has been shown that the dissolution rates of solids are determined or influenced by a number of factors, 10 of which have been outlined in the preceding sections. These may be summarized as follows ... 

This section considers aspects and examples of the dissolution behaviour of individual iron oxides. Additional data are listed in Table 12.3 for a range of experimental conditions. As yet, characteristic dissolution rates carmot be assigned to the various iron oxides (Blesa Maroto, 1986). There are, however, some consistent differences between oxides with considerable stability differences, hence a comparison of the oxides is included here. In addition, the reactivity of any particular oxide may vary from sample to sample, depending on its source (natural or synthetic) and the conditions under which it formed. To illustrate this. Table 12.4 summarizes conditions and results from dissolution experiments in which a range of samples of the same oxide was compared. How the properties of the sample influence its dissolution behaviour is still not fully understood. A thorough characterization of the samples by solid state analysis, e. g. by EXAFS, to provide a basis for understanding the dissolution behaviour is, therefore, desirable. 

It is clear that under conditions of decomposition control the rate of dissolution of a solid in a liquid is independent of the thickness of the diffusion boundary layer and hence of the intensity of agitation of the liquid. By contrast, in the case of diffusion control the intensity of agitation of a liquid has a strong effect on the thickness of the diffusion boundary layer, thus influencing the value of the dissolution-rate constant, k. 

If (i) the vapour phase does not influence reactions at the solid/liquid interface and (ii) the diffusion of components of the solid (Al and O) in bulk A1203 is slow compared to the dissolution rate at the interface, the values of Xai and X0 must satisfy the condition ... 

The acidic destruction of montmorillonite results in the release of silicon and aluminum. The initial fast exchange of surface cations by hydrogen ions is followed by the release of aluminum and silicon. The dissolution rate of Si is higher than that of A1 and is influenced by the relative ratios of basal siloxane and edge surfaces. The shift of pH to more basic values by the ion-exchange processes and the hydrolysis of dissolved species induce the formation of secondary amorphous solids, initiating the formation of amorphous aluminosilicates (Sondi et al. 2008). 

It is not the aim of this article to evaluate formulation aspects that may influence dissolution of drugs from dosage forms. However, it suffices to mention that dissolution rates of drug substances or drug release from formulated products may be influenced (increased or decreased) by factors such as assay selection, the presence of surfactants, polymorphic modification, and by the use of water-soluble carriers in solid dispersions. 

The term moisture, usually defined as wetness conferred by an unidentified liquid, is assumed here to be due to water. Thus, the scope of this article is the characterization of and consequences due to relatively small amounts of water associated with solids of pharmaceutical interest. Chemical stability, crystal structure, powder flow, compaction, lubricity, dissolution rate, and polymer film permeability are some properties of pharmaceutical interest that have been demonstrated to be influenced by the presence of moisture. Wet granulation, extrusion, spheronization, tray drying, freeze drying, spray drying, fluid-bed drying, tableting, and aqueous film coating are some unit operations that obviously depend on the amount and state of water present. 

Early on in product development, the potential for the successful development of a solid oral dosage form is assessed, based on the physicochemical properties of the API (1). Prior to solid dosage form development, it is necessary to anticipate the physicochemical properties that can have a major influence on product manufacture and performance. The early development (preformulation and early formulation development) studies should focus on these properties so as to avoid problems at later stages of development. While the molecular properties dictate the intrinsic solubility and the chemical stability of the compound, by controlling the physical form of the compound and by modifying physical properties (e.g., particle size), the dissolution rate can be enhanced with the potential for improving bioavailability. This chapter will focus on physical properties including particle characteristics, and most importantly, the physical form (i.e., solid state) of the API. 

For drugs with low solubility, special efforts must be made to bring the concentration into the therapeutically active range. In this section, some of the common methods to increase solubility will be discussed salt versus free form, inclusion compounds, prodrugs, solid form selection, and dissolution rate. It should be noted that efforts to increase solubility also have an influence (often negative) on the stability of a compound. For this reason, the most soluble form is often not the first choice when formulating the drug. 

It is usually not difficult to determine the solubility of solids which are moderately soluble (greater than 1 mg/mL), but the direct determination of solubilities much less than 1 mg/mL is not straightforward. Problems such as slow equilibrium resulting from a low rate of dissolution, the influence of impurities, and the apparent heterogeneity in the energy content of the crystalline solid (Higuchi et al. 1979), can lead to large discrepancies in reported values. 

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