Metastable solubility

Aluminum trifluoride trihydrate [15098-87-0], AIF. -3H20, appears to exist in a soluble metastable a-form as well as a less soluble P-form (3). The a-form can be obtained only when the heat of the reaction between alumina and hydrofluoric acid is controlled and the temperature of the reaction is kept below 25°C. Upon warming the a-form changes into a irreversible P-form which is insoluble in water and is much more stable. The P-form is commercially available. 

Solution characteristics eomposition, equilibrium relationships (solubility), metastable zone width, purity, partition eoeffieient, liquid density, viseosity, and their temperature dependenee (Chapter 3). 

A classic example of metastability is surface-seawater supersaturation with respect to calcite and other carbonate minerals (Morse and Mackenzie 1990 Millero and Sohl 1992). The degree of calcite supersaturation in surface seawater varies from 2.8- to 6.5-fold between 0 and 25 °C (Morse and Mackenzie 1990). In Fig. 3.18, experimental calcite solubility (metastable state) is approaching model calcite solubility (stable state) at subzero temperatures. In Table 5.1, the difference in seawater pH, assuring saturation or allowing supersaturation with respect to calcite, is 0.38 units. Moreover, in running these calculations, it was necessary to remove magnesite and dolomite from the minerals database (Table 3.1) because the latter minerals are more stable than calcite in seawater. But calcite is clearly the form that precipitates... 

Utilizing an amorphous form of an API is not, however, universally desirable. Amorphous compounds are often metastable. As a result, there is a real risk that they will transform to crystalline materials in the final dosage form. Novobiocin again provides a case in point. The amorphous form, in aqueous suspension, will transform on standing into the inactive crystalline form.10 Similarly, the highly soluble metastable crystals of riboflavin revert to less soluble forms if they are washed with water above 10°C.9... 

The various crystal modifications of a substance will possess different melting points and thereby have different solubilities (Brittain, 2002). Only one solid phase is thermodynamically stable for a given set of environmental conditions. The most stable form has the lowest free energy and therefore the lowest solubility. Metastable forms can theoretically be used to improve solubility, but the kinetics of the transformation back to the stable crystal modification must then be taken into account. In suspension, solvent-mediated transition is generally too rapid to give a product with an acceptable shelf-life. In solid dosage forms, it may be possible, however, to utilize a less stable crystal modification. Due to the decreased molecular mobility in the solid state the transition rate can be low. 

Smodls, M., Livk, I., Pohar. C. Measurements of solubility, metastable zone width and conductivity of aqueous SPB solutions for the precipitation design purpose. In CMSA 93, F2.46,3196, Praha 1993... 

Fig. 1. Solubility system of (—) Na2S04-H20 where R and M refer to rhombic and monoclinic Na2S04, respectively, ia H2O and represent Glauber s salt and sodium sulfate hemihydrate, Na2S04-7H20, respectively, at saturation ia H2O and (—) Na2S04-NaCl-H2 0 where and G represent the rhombic form and Glauber s salt, both saturated with NaCl. The dashed line represents a metastable form.

The shape of the equilibrium line, or solubility curve, is important in determining the mode of crystallization to be employed in order to crystallize a particular substance. If the curve is steep, i.e. the substance exhibits a strong temperature dependence of solubility (e.g. many salts and organic substances), then a cooling crystallization might be suitable. But if the metastable zone is wide (e.g. sucrose solutions), addition of seed crystal might be necessary. This can be desirable, particularly if a uniformly sized product is required. If on the other hand, the equilibrium line is relatively flat (e.g. for aqueous common salt... 

Certainly a thermodynamically stable oxide layer is more likely to generate passivity. However, the existence of the metastable passive state implies that an oxide him may (and in many cases does) still form in solutions in which the oxides are very soluble. This occurs for example, on nickel, aluminium and stainless steel, although the passive corrosion rate in some systems can be quite high. What is required for passivity is the rapid formation of the oxide him and its slow dissolution, or at least the slow dissolution of metal ions through the him. The potential must, of course be high enough for oxide formation to be thermodynamically possible. With these criteria, it is easily understood that a low passive current density requires a low conductivity of ions (but not necessarily of electrons) within the oxide. 

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi-... 

Fig. 5 Dissolution profiles obtained from the solubility determination of two polymorphic forms of the same drug substance. A is the stable form with solubility 31 mg/mL. B is the profile of the metastable form with solubility 46 mg/mL. This solubility (circles) is not achieved in many instances, and precipitation of the stable form occurs at a point beyond the solubility of A, and the trace becomes B. C is the hypothetical profile of the metastable form. 

In such cases, the Nogami method can be applied to the early points curve (Fig. 6) and the solubility, S, of the polymorph can be assessed. One of the important aspects of metastable polymorphs in pharmacy is exactly their higher solubility, since the dissolution rate will also be higher [Eq. (7)]. Hence the bioavailability will be increased where this is dissolution rate limited [21]. 

Knowledge of polymorphic forms is of importance in preformulation because suspension systems should never be made with a metastable form (i.e., a form other than the stable crystal form). Conversely, a metastable form is more soluble than a stable modification, and this can be of advantage in dissolution [Eq. (9)]. There are two types of polymorphism, a fact illustrated in the following discussion. 

There are numerous experimental complications in the measurement of solubility. Solid phases, formed incipiently, are often metastable with respect to a... 

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... 

Also, hydrates are more soluble in water-miscible solvents than are the corresponding anhydrous forms. For example, the solubility of caffeine hydrate is lower than that of anhydrous caffeine in water but higher in ethanol. The maximum concentration seen may be due to the solubility of the anhydrous crystalline phase or due to a temporary steady state in which the rate of dissolution of the metastable anhydrous form and the rate of crystallization of the stable hydrate are equal. The decreasing concentration represents crystallization of the stable hydrate from a solution supersaturated with respect to it. If the maximum concentration of the solute in the dissolution experiment corresponds to the solubility, then the initial increase in concentration follows the Noyes-Whitney equation [15]. Van t Hoff plots of log solubility versus the reciprocal of temperature give linear relationships (Fig. 16). 

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