Metastable form

Transformations in the Solid State. From a practical standpoint, the most important soHd-state transformation of PB involves the irreversible conversion of its metastable form II developed during melt crystallization into the stable form I. This transformation is affected by the polymer molecular weight and tacticity as well as by temperature, pressure, mechanical stress, and the presence of impurities and additives (38,39). At room temperature, half-times of the transformation range between 4 and 45 h with an average half-time of 22—25 h (39). The process can be significantly accelerated by annealing articles made of PB at temperatures below 90°C, by ultrasonic or y-ray irradiation, and by utilizing various additives. Conversion of... 

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.

Zirconia prepared by the thermal decomposition of zirconium salts is often metastable tetragonal, or metastable cubic, and reverts to the stable monoclinic form upon heating to 800°C. These metastable forms apparently occur because of the presence of other ions during the hydrolysis of the zirconium their stabiUty has been ascribed both to crystaUite size and surface energy (152—153) as well as strain energy and the formation of domains (154). 

For (Z)-cinnamic acid [102-94-3], three distinct polymorphic forms have been characteri2ed. The most stable form, referred to as aHocinnamic acid, has a melting point of 68°C, and the two metastable forms, isocinnamic acids, have melting points of 58°C and 42°C, respectively. (E)-Cinnamic acid can be converted to the (Z)-isomer photochemicaHy through kradiation of a solution with ultraviolet light. 

Let us consider, for instance, the case of i-PB. By crystallization on cooling from the melt, the metastable form II is obtained, which spontaneously and gradually in a few days at room temperature is transformed into the crystalline form I, which is the most thermodynamically stable [65],... 

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. 

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. 

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... 

A highly reactive form of titanocene could be obtained when a suspension of the gray-green hydride 14 was stirred in ethyl ether for 2 hours at room temperature. The solid gradually disappeared concurrent with the evolution of 0.5 equivalent of H2 per equivalent of Ti. Molecular weight measurements showed this metastable form of titanocene (15) to be dimeric. Treatment of a cold ethereal solution of (Cp2Ti)2 (15) with CO resulted in a quantitative yield of Cp2Ti(CO)2 (1) (24,36). 

Crystallization conditions can often be manipulated to favor the nucleation of alternate crystal forms. A metastable polymorph of metformin hydrochloride has been isolated using capillary crystallization techniques, and subsequently studied using thermal microscopy [24]. Calculations based on classical nucleation theory indicated that a metastable form could be obtained using high degrees of... 

Since it was known that theophylline monohydrate can be thermally dehydrated to form either the stable Form I or the metastable Form I, the effect of different drying methods on the phase composition was studied [89], Using either a multichamber microscale fluid bed dryer or the hot stage of a variable-temperature XRPD diffractometer, Form I was produced when the drying was conducted at 40-50°C. Drying at 60°C in the VT-XRPD unit yielded only Form I, while mixtures of products were produced in the microscale fluid bed dryer even at temperatures as high as 90 °C. 

Secondary processing does not always lead to phase transformations, as was shown during studies of the polymorphs of ranitidine hydrochloride [92]. No solid-solid transformation could be detected during either the grinding or compression of metastable Form I, stable Form II, or of a 1 1 mixture of these forms. The dissolution rates of both forms were found to be equivalent, and the solution-mediated transformation of Form I to Form II was observed to be slow. 

Conformational disorder and kink-bands structures have recently been found also in random copolymers of syndiotactic polypropylene with small amounts of ethylene.192 193 The ethylene units are included in the crystalline regions193 and induce the crystallization of the metastable form II of sPP with conformationally disordered chains characterized by kink bands. Portions of chains containing the ethylene units tend, indeed, to assume a trans planar conformation, producing the kink-band defects in chains in the prevailing twofold helical conformation.192193... 

In another experiment, the newly melted material from the second rescan (bottom trace, Fig. 4.14) was slowly allowed to cool from 120 to 20°C over a two-day time period. As shown in Fig. 4.16, the DSC thermogram of this sample showed the same three-part pattern, but the ratio of lower melting metastable form to the higher melting stable form was greatly shifted in favor of the thermodynamically stable form. 

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