Amorphous form, dissolution rate

This chapter describes some of the properties of solids that affect transport across phases and membranes, with an emphasis on biological membranes. Four aspects are addressed. They include a comparison of crystalline and amorphous forms of the drug, transitions between phases, polymorphism, and hydration. With respect to transport, the major effect of each of these properties is on the apparent solubility, which then affects dissolution and consequently transport. There is often an opposite effect on the stability of the material. Generally, highly crystalline substances are more stable but have lower free energy, solubility, and dissolution characteristics than less crystalline substances. In some situations, this lower solubility and consequent dissolution rate will result in reduced bioavailability. 

The higher thermodynamic activity, a, of the amorphous form compared to that of the crystalline form explains the higher initial dissolution rate per unit surface area (intrinsic dissolution rate, J) and the higher solubility, s, of the amorphous form compared to that of the crystalline form, according to a simple form of the Noyes-Whitney equation [15],... 

When determining the solubility and dissolution rate of amorphous or partially crystalline solids, the metastability of these phases with respect to the highly crystalline solid must be considered. While the low diffusivity of the molecules in the solid state can kinetically stabilize these metastable forms, contact with the solution, for example during measurements of solubility and dissolution rate, or with the vapor, if the solid has an appreciable vapor pressure, may provide a mechanism for mass transfer and crystallization. Less crystalline material dissolves or sublimes whereas more crystalline material crystallizes out. The equilibrium solubility measured will therefore approach that of the highly crystalline solid. The initial dissolution rate of the metastable form tends to reflect its higher... 

In the calculation results (Fig. 26.6), the initial segment of the path is marked by the disappearance of the amorphous silica as it reacts to form cristobalite. The amorphous silica is almost completely consumed after about 10000 years of reaction. The mineral s mass approaches zero asymptotically because (as can be seen in Equation 26.1) as its surface area As decreases, the dissolution rate slows proportionately. During the initial period, only a small amount of quartz forms. 

The metastable forms are preferred in pharmaceutical preparations due to their higher solubility and dissolution rate e.g. the amorphous form of novobiocin is absorbed readily as compared to its crystalline form. 

The release of cations is interpreted to have resulted chiefly from two processes an initial release caused by rapid exchange of surface cations for hydrogen followed by a slow release due to structural attack and disintegration of the aluminosilicate lattice. Other processes which could complicate the form of the dissolution curves are adsorption of cations released by structural breakdown, ion exchange on interlayer sites of cations released by structural breakdown and surface exchange (shale only), precipitation of amorphous or crystalline material, and dissolution rate differences among the various crystalline phases. 

Water is without effect on the element even at a red heat,3 but the combined action of water and ozone produces telluric acid at the ordinary temperature.4 The action of hydrogen peroxide upon tellurium is influenced considerably by the physical state of the element colloidal tellurium is readily oxidised, but crystalline tellurium is not readily attacked and has first to be dissolved in an aqueous solution of alkali hydroxide, when oxidation becomes possible with formation of tellurate.5 Hydrogen peroxide of 60 per cent, strength reacts very slowly with tellurium at a temperature of 100° C., but with increasing amount of telluric acid formed, the rate of dissolution increases. Amorphous tellurium as ordinarily prepared behaves in a similar manner to the crystalline variety, but if it is dried by treatment with alcohol and ether instead of by heating at 105° C. it will dissolve readily in a concentrated solution of hydrogen peroxide.6... 

Solubility values based on a plateau in the dissolution rate curve, when dissolution of the metastable form is essentially complete and the system reaches a pseudoequilibrium state befori conversion to the stable solid state, are reasonably accurate. Those based on peaks in these curves obtained by Ltting exponential functions to estimate the plateau that might be reached in the absenc< of conversion should only be considered estimates ofthe metastable form solubility. The quantitative gain in these systems may be estimated more accurately by comparing initial dissolution rates for the two forms. In most cases, amorphous form solubilities must be estimated by these techniques due to their rapid crystallization when in contact with solvents. 

While the metastable forms offer higher dissolution rates, many manufacturers use a particular amorphous, crystalline, salt, or ester form of a drug with the solubility needed to be dissolved in the established conditions, for instance, to prepare a chloramphenicol ophthalmic solution [39]. Thus, the selection of amorphous or crystalline form of a drug may be of considerable importance to facilitate the formulation, handling, and stability [37]. 

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