Crystallization solvent, metastable form

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. 

Many drugs can exist in more than one crystalline form, for example chloramphenicol palmitate, cortisone acetate, tetracyclines and sulphathiazole, depending on the conditions (temperature, solvent, time) under which crystallization occurs. This property is referred to as polymorphism and each crystalline form is known as a polymorph. At a given temperature and pressure only one of the crystalline forms is stable and the others are known as metastable forms. A metastable polymorph usually exhibits a greater aqueous solubility and dissolution rate, and thus greater absorption, than the stable polymorph. 

In an example from the pharmaceutical industry Sudo et a/. (1991) studied the relative nucleation properties of forms A and B of cimetidine, which is reported to have four polymorphic non-solvated forms and three polymorphic monohydrates. Modification A is preferred for pharmaceutical formulations. The waiting time method was used to study the primary nucleation process (Harano and Oota 1978), mainly for competitive crystallization of the A and B modifications. A is a thermodynamically metastable form and is more soluble than B in any solvent. At high supersaturation... 

The influence of methanol proportions in solvents, and temperature, on the solubility and the transformation behavior of 2-(3-cyano-4-isobutyloxyphenyl) -methylthiazole-5-carboxylic acid (BPT) was investigated. The transformation behavior was explained by the chemical potential difference between the stable and metastable forms. It was shown that a specific solute-solvent interaction contributes to the preferential nucleation and growth of the stable or metastable forms and influences the transformation behaviors, and the solubility of the solvated crystals is much more influenced by the solvent compositions than the true polymorphs. The solubility ratio of the solvated crystals depends on the solvent composition, whereas the solubility ratio of the true polymorphs is considered to be independent of the solvents. The crystallization behavior was also investigated. The transformation rate after crystallization appeared to depend on the initial concentration of BPT and the addition rate of the antisolvent. The cause of this phenomenon was presumed to be a slight inclusion of the stable form in the metastable form <2005PAC581>. 

Because of kinetic factors, metastable forms are encountered in temperature ranges outside the thermodynamic range. Crystallization processes generally imply the cooling of concentrated solutions or precipitation by addition of cosolvent. Depending on the relative positions of the solubility curves of the metastable polymorphic forms and the metastable curve of supersaturation, the first nucleous can be a metastable form. Transformation to the stable crystalline form may or may not occur, depending on kinetic factor. Furthermore solvates exist at lower temperatures and their presence should be considered and finally due to the humidity of the air or from water activity of the solvents, hydrates may be formed. Polymorphism of solvates and hydrates is not uncommon. This phenomenon of concomittant polymorphs has been recently reviewed. ... 

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. 

According to McCrone [27], in a poor solvent the rate of transformation of a metastable to a more stable polymorph is slower. Hence a metastable form once crystallized can be isolated and dried before it is converted to a more stable phase by solution phase mediated transformation. In some systems the metastable form is extremely unstable and may be prepared only with more extreme supercooling. This is usually performed on a very small scale with high boiling liquids so that a saturated solution at a high temperature that is suddenly cooled to room temperature will achieve a high degree of supersaturation [28]. 

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