Metastable polymorphs crystallization

Okamoto, M. Hamano, M. Ooshima, H. Utilization of solvent-mediated transformation for exclusive production of metastable polymorph crystals of AEl-923. J. Chem. Eng. Jap 2004, 57, 95-101. 

Okamoto M, Hamano M, and Ooshima H. Active Utilization of Solvent-Mediated Transformation for Exclusive Production of Metastable Polymorph Crystals of AEl-92 >. ] Chem Eng Jap 2004 37 95-101. 

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-... 

A derived crystal packing model proved to be useful in resolving the crystal structure of a metastable polymorph of racemic modafinil, where details of the solved crystal structure of one polymorph was used as a basis for developing the structure of the other [12]. It was found that the calculated XRPD pattern matched well with the experimental data, indicating the correctness of the analysis. The powder diffraction of two polymorphs of chlorothalonil were solved to obtain... 

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... 

The results of the polymorph screening step in combination with bioavailability studies, provide the information required by the clinical research team to nominate the desired crystal form of the API for long term manufacture and formulation. This form will usually be the most stable polymorph, where a number of forms have been identified, or a salt form if bioavailability is low or when there are formulation concerns regarding polymorph stability. In some cases it may be necessary to select an amorphous form or metastable polymorph because of crystallization difficulties, time constraints or bioavailability requirement. The nomination of a hydrate or solvate is generally avoided because of their relative instability and compositional variability such constraints are less of a concern for the earlier synthetic intermediates. 

Where a metastable polymorph is required the crystallizer should ideally operate below the supersaturation curve for the more stable form, thus preventing any primary nucleation of the more stable form. 

Crystallization, by definition, implies that the initial structure be a glass, followed by the nucleation and growth of a crystalline phase, be it the equilibrium one or a metastable phase. The process is a first-order transformation and involves atomic diffusion, or at least atomic shuttles. Types of crystallization reactions that occur include polymorphous crystallization, which is a composition invariant transformation such as that in Fe-B, and eutectic crystallization, T, in FeNiPB glass, where line lamellae of iron-nickel austenite and mclastable (FeNiJj PB phases grow cooperatively. 

We have searched a compound that shows Preferential Enrichment and possesses a homochiral lD-chain structure in the metastable polymorphic form, because it is very possible that the homochiral molecular assembly structure in solution would be retained in the crystal first-formed by crystallization from the same solvent. Finally, racemic NPMe3 was found to possess the desired y-form crystal structure that is classified as a highly ordered racemic mixed crystal and is composed of alternating alignment of homochiral R and S 1D-chains in an antiparallel direction with a space group P-1 (Z = 2) with the... 

Figure 7. Phase diagram of water s stable crystal polymorphs. Metastable polymorphs such as ice IV or ice XII do not show up. Adapted from Ref. [147].

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. 

A primary concern is polymorphic crystallization in which the Ostwald step rule is very useful (9). This rule predicts that phase changes occur step by step by way of successively more stable phases. For the relative rate of nucleation of polymorphic crystals shown in Figure 2, it follows that nucleation of the metastable forms such as a and p occurs first before the most stable p form, when nucleation occurs under a large supercooling or high supersaturation. When the amount of supercooling or supersaturation is decreased, the law is broken and the most stable form tends to nucleate at a relatively slow rate. 

These authors observed that binaphthyl crystallize in two polymorphs. The one is stable at lower temperature, is centrosymmetric and is not optically active. This polymorph melts at 145 °C. The second polymorph is stable at higher temperature but is metastable at room temperature. It is optically active and melts at 158 °C. Wilson and Pincock show that as one cycles in temperature between room temperature and 150 °C a sample which is initially the optically inactive low temperature polymoiph transforms to an optically active solid. After three or four cycles one achieves the maximum optical resolution which corresponds to 56% ee. The crux of the Wilson and Pincock experiment is that at 150 °C, the reaction physically resembles a solid state reaction in which the low temperature form is melting in the near presence of high temperature polymorph crystals. These chiral crystals are therefore nucleating sites for further chiral crystal growth. As at room temperature binaphthyl retains its chirality, the resultant samples can then be dissolved with retention of stereochemistry. 

The induction times of carbamazepine polymorphs [monoclinic, CBZ(M) and trigonal, CBZ(Trg)] were evaluated by optical microscopy. The polymorphs were identified by their crystal morphology where CBZ(M) crystallizes as prismatic crystals and CBZ(Trg) crystallizes as needles, which were confirmed by X-ray powder diffraction. It was determined that under constant supersaturation concomitant crystallization is favored in solvents that accept and donate hydrogen bonds (ethanol, methanol, isopropanol, etc.). However, the metastable CBZ(Trg) polymorph preferentially crystallized in solvents that primarily accept hydrogen bonds (ethyl acetate, methyl acetate, 2-butanone, etc.) with the stable CBZ(M) polymorph crystallizing at least an hour later. The induction times of CBZ polymorphs did not decrease with increases in solubility, suggesting that nucleation is not controlled by solubility differences. It was determined that CBZ polymorph nucleation was governed by the specific solute-solvent interactions that occurred in solution to... 

The supramolecular assembly process can be controlled so that the precursor nuclei in solution adopt a structure that resembles the structure of the desired crystalline modification. " This concept has been used in the design of nucleation inhibitors to prevent growth of the stable polymorph and enhance the growth of the metastable polymorph. Davey and coworkers have explained the solvent dependent polymorph appearance of sulfathiazole by analyzing the intermolecular interactions in the various polymorphic structures, and comparing them with the supramolecular assemblies that could exist in the different solvents. In this case, however, the solvent dependent selective crystallization of a polymorph was not correlated with solubility. 

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 phenomenon of polymorphism was noted by Martin Heinrich Klaproth °i in 1798, when he proposed that the minerals calcite and aragonite must have the same chemical composition, CaCOa. Calcite forms a rhombohedral uniaxial crystal and is the stable form under normal conditions, with a density of 2.71 g/ml. Its metastable polymorph, aragonite, is an orthorhombic biaxial crystal with a density of 2.94 g/ml. This work was continued by Louis Jacques Thernard, Jean Baptiste Biot, and Eilhard Mitscherlich. Mitscherlich, for example, reported on it in his studies of phosphates and arsenates. The transition from calcite to aragonite has been studied at different pressures. ... 

Early in the characterization and development of processes to prepare a final product, crystallization conditions should be screened on small scale to identify the desired salt form (if appropriate) and to investigate the possibility of forming multiple polymorphs, solvates, and hydrates. The benefits in attempting to prepare new polymorphs can be substantial. First, a new polymorph or solvate with superior formulation or stability characteristics may be isolated. Second, if an undesirable crystalline form is prepared, conditions can be designed to avoid its formation on scale. Third, it may be essential to define conditions to reliably prepare a metastable polymorph if the most stable polymorph has not been chosen for development. 

Q-Quartz, which has a trigonal crystal structure, undergoes a rapid, reversible transition to hexagonal /J-quartz at 573 °C and then slowly changes to hexagonal /3-tridymite at about 870 °C tridymite in turn goes over slowly to cubic /3-cristobalite at 1470 °C, and this melts at 1713 °C. The reversion of cristobalite and tridymite to quartz is slow, so that these forms can exist at room temperature (as a-modifications). In addition, dense modifications with six-coordinate Si are found in shocked rocks associated with meteorite impact craters coesite forms only above 450 °C and 3.8 GPa, and stishovite requires over 1200 °C and 13 GPa. Survival of those metastable polymorphs on the geological timescale is evidence of an extremely slow recrystallization rate. 

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