Polymorphism Precipitate

The mixture of diastereomers has been separated into its two principal components by Izatt, Haymore, Bradshaw and Christensen who had previously identified the two principal diastereomers as the cis-syn-cis and cis-anti-cis isomers. Their previous separation technique involved a protracted chromatography on alumina but the new method relied upon the difference in water solubility between the lead perchlorate and hydroniur perchlorate complexes. The lead perchlorate complex is essentially insoluble in aqueous solution and precipitates from it. Using this method, one may obtain 39% of the high-melting polymorph (mp 83—84°) and 44% of the low-melting compound (mp 62—63°). Note that the former also exists in a second crystalline form, mp 69—70°. 

During precipitate ageing, a gradual transformation of an initially precipitated metastable phase into a final crystalline form often occurs. The metastable phase may be an amorphous precipitate, a polymorph of the final material, a hydrated species or some system-contaminated substance (Mullin, 2001). In 1896, Ostwald promulgated his rule of stages which states that an unstable... 

Chakraborty, D. and Bhatia, S.K., 1996a. Fomiation and aggregation of polymorphs in continuous precipitation. 1. Mathematical modelling. Industrial and Engineering Chemistry Research, 35, 1985-1994. 

Tai, C.Y. and Chen, F.-B., 1998. Polymorphism of CaC03 precipitated in a constant-composition environment. American Institution of Chemical Engineers Journal, 44, 1790-1798. 

HgS is polymorphic. The red a-form is the mineral cinnabar, or vermilion, which has a distorted rock-salt structure and can be prepared from the elements. )3-HgS is the rare, black, mineral metacinnabar which has the zinc-blende structure and is converted by heat to the stable a-form. In the laboratory the most familiar form is the highly insoluble black precipitate obtained by the action of HzS on aqueous solutions of Hg. HgS is an unreactive substance, being attacked only by cone HBr, HI or aqua regia. HgSe and... 

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. 

They made several assumptions about which minerals could precipitate from the fluid. The alkaline lakes tend to be supersaturated with respect to each of the silica polymorphs (quartz, tridymite, and so on) except amorphous silica, so they suppressed each of the other silica minerals. They assumed that... 

Once the amorphous silica has nearly disappeared, the cristobalite that formed early in the calculation begins to redissolve to form quartz. The cristobalite dissolves, however, much more slowly than it formed, reflecting the slow rate of quartz precipitation. After about 300 000 years of reaction, nearly all of the cristobalite has been transformed into quartz, the most stable silica polymorph, and the reaction has virtually ceased. 

The rate of nucleation is dependent on the degree of supersaturation as described in section 2.4.1, and because this will always be larger for Form 1 it may be incorrectly assumed that Form I will always precipitate first. The true situation is somewhat more complicated because the critical size, activation energy and nucleation rate also depend on the solid state that is being formed [6]. It is quite feasible and a regular occurrence, that a less stable polymorph will have a higher rate of nucleation than a more stable form, as illustrated in figure 6. 

Ritonavir is a product of Abbott Laboratories Ltd. for the treatment of HIV and is marketed as Norvir , in liquid and semisolid capsule formulations. It received FDA approval for market launch in march 1996, at which time only one polymorphic form of Ritonavir (Form I) was known. Two years later in early 1998 a laboratory responsible for testing the formulated product in the US reported dissolution test failures of the semisolid capsules, and noted that drug product had precipitated out of solution. A new polymorphic form had been discovered that was thermodynamically more stable than the existing form and approximately 5 times less soluble in the formulation. Figure 7. 

At a high degree of supersaturation, the nucleation rate is so high that the precipitate formed consists mostly of extremely small crystallites. Incipiently formed crystallites might be of a different polymorphous form than the final crystals. If the nucleus is smaller than a one-unit cell, the growing crystallite produced initially is most likely to be amorphous substances with a large unit cell tend to precipitate initially as an amorphous phase ("gels"). 

Metastable crystalline phases frequently crystallise to a more stable phase in accordance with Ostwald s rule of stages, and the more common types of phase transformation that occur in crystallising and precipitating systems include those between polymorphs and solvates. Transformations can occur in the solid state, particularly at temperatures near the melting point of the crystalline solid, and because of the intervention of a solvent. A stable phase has a lower solubility than a metastable phase, as indicated by the solubility curves in Figures 15.7a and 15.7/ for enantiotropic and monotropic systems respectively and,... 

Typical methods for generation of polymorphs include sublimation, crystallization from different solvents, vapor diffusion, thermal treatment, melt crystallization, and rapid precipitation. High-throughput screening methods have been reported for polymorph screening.50... 

Oral Solutions and Suspensions Formation of precipitate, clarity for solutions, pH, viscosity, microbial bioburden, extractables, and polymorphic conversion when applicable. Additional tests for suspensions include redispersability, rheological properties, mean size, and distribution of particles. 

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