Polymorph metastable

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-... 

Polymorphism is an important aspect of the physical properties of a drug substance. One of the characteristics of a metastable polymorph (to be discussed in some detail at a later point) is that it is more soluble than its stable counterpart. The solubility profile of the polymorph will be as shown in Fig. 5 A is the stable form, with solubility of 31 mg/mL. B is the profile of the metastable form, with solubility of 46 mg/mL. This solubility (circles) is usually not achieved, and precipitation of the stable form occurs at a point beyond the solubility of A, and the trace becomes B. 

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]. 

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. 

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 organic chemicals exist in two or more crystalline forms, which are referred to as polymorphs. The preferred crystalline form depends on temperature and pressure however, multiple polymorphic forms can exist under identical temperature and pressure conditions. Generally, there is one stable form at any particular temperature and pressure, but one or more metastable forms may be produced under different experimental conditions. Typically, the conditions leading to different polymorphs include solvents, seeding, and external influences during precipitation. Often a desired polymorph can be produced from solution by initiating the nucleation with seeds of the desired polymorph. A metastable polymorph may convert to the stable form, but external influences may be required to increase the rate of the conversion. 

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. 

Mitra, A. K., Ghosh, L. K. and Gupta, B. K. (1993). Development of methods for the preparation and evaluation of chloramphenicol palmitate ester and its biophar-maceutically effective metastable polymorph. Drag Dev. Ind. Pharm., 19, 971-80. [246]... 

Consequently, it can be concluded for the mixtures of LLL-MMM, LLL-PPP, LLL-SSS, MMM-PPP, and PPP-SSS that the TAG binary mixtures are miscible in metastable polymorphs of a and p forms when the difference in the number of carbon atoms of the fatty acid moieties. An, equals 2, whereas immiscible mixtures are found in all polymorphic forms when An is larger than 2. Results obtained for these mixture systems may indicate a relationship between polymorphism and phase behavior of the binary mixtures of the saturated-acid TAGs in such a way that rotational freedom of hydrocarbon chains and entropy of methyl-end stacking are crucial factors determining the polymorph-dependent phase behavior. 

Shah, J.C. Chen, J.R. Chow, D. Metastable polymorph of etoposide with higher dissolution rate. Drug Dev. Ind. Pharm. 1999, 25 (1), 63-67. 

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. 

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. 

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. ... 

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