Polymorphs disappearing

Much of chemistry deals with controlling the reactions and interactions between molecules. Although this chapter deals with the principles behind controlling the polymorph obtained—that is in a sense controlling the interactions among molecules in the formation of crystals—in polymorphic systems that control is not always easy 

Many other difficult questions arise when a situation described as a disappearing polymorph is encountered. Among them are Why did the new polymorph appear at all (often after years of no hint of its existence) Why does a previously robust process no longer yield the crystal form that had been obtained prior to the appearance of the new one What crystallization parameters must be modified to obtain either the old or the new form exclusively and robustly  

As we have noted repeatedly in this chapter, there is a vast variety of conditions that can affect a crystallization, and for any polymorphic system it is indeed difficult to single out a particular factor that might dominate. However, it is certain that seeding can and often does play an important role in determining the fate of a crystallization, especially one in which competitive processes can lead to individual polymorphs, or a mixture of them. 

Intentional seeding is a common practice among chemists who wish to coax the crystallization of a compound from solution or from the melt small crystals or crystallites of the desired material (seeds) are added to the system (e.g. Pavia et al. 1988 Shriner et al. 1997). In this way, the rate-limiting nucleation step, which may be extremely slow, can be accelerated. For this method to be applied, it is of course necessary that a sample of the desired crystalline material is available that is, the compound must have been already crystallized in a previous experiment. When polymorphic forms of a substance are known to occur, intentional seeding with one of the polymorphs is a useful and often the most successful way of preferentially producing it rather than the other form(s). 

Unintentional seeding may also occur even if small amounts of the undesired polymorph are present as contaminants—in fact, in principle just one such seed is 

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As introduced above, different forms of the same molecule can be observed in the solid state. The phenomenon is known as polymorphism, i.e., the concurrent presence of more crystal forms, only one of which is thermodynamically stable at a given pressure and temperature. However, more polymorphs can be observed simultaneously when kinetic conditions allow formation of metastable phases together with (or even in the absence of) the thermodynamically stable one. It might even occur that metastable phases are not recognized as such, simply because the most stable polymorph is (as yet) unknown. This might produce the extraordinary phenomenon of disappearing polymorphs [97]. 

It is important that the solid-state chemists keep a watchful eye on the possibility of disappearing polymorphs [92] and also of the well-known phenomenon of concomitant polymorphs which has been discussed recently [93], The generation of new polymophs via the addition of a meaningful choice of impurities in controlled amounts [93,94] is worthy of experimentation. 

The exchanges with Roald Hoffmann of Cornell University on disappearing polymorphs in song and story were particularly memorable, and I am grateful for his... 

It is essential to determine the range of crystalline forms that are accessible to a potential drug substance and to determine which of the various forms will be the one used in products used in pivotal trials. To answer this question, investigators must conduct whatever studies might be required to evaluate the full range of possible polymorphs and solvatomorphs. The situation can be further complicated by the phenomenon of disappearing polymorphs, where metastable crystal forms become impossible to produce once more stable forms are uncovered. " ... 

Blagden N, Davey ly, Rowe R, and Roberts R. Disappearing Polymorphs and the Role of Reaction By-Products The Case of Sulphathiazole. Int JPharm 1998 172 169-177. 

A major consideration for a polymorph screen needs to be addressed at this stage. A polymorph screen, no matter how extensive, cannot guarantee that a new polymorphic form will not appear in the future. Stories of appearing and disappearing polymorphs are plentiful (48). Such occurrences are likely related to seeding. The first step in crystallization is formation of a seed, which involves collection of disordered molecules into an ordered array. Seed formation is the rate-determining step in a crystallization process. Now consider Ostwald s rule, which states that in passing from a less stable state (disordered) to a more stable... 

JD Dunitz, J Bernstein. Disappearing polymorphs. Accts Chem Res 28 193, 1995. 

Whilst examples of disappearing polymorphs exist, perhaps more common is the crystallization of mixtures of polymorphs. Many analytical techniques have been used to quantitate mixtures of polymorphs, e.g., XRPD has been used to quantitate the amount of cefepime 2HC1 dihydrate in cefepime 2HC1 monohydrate (Bugay et al. 1996). As noted by these workers, a crucial factor in developing an assay based on a solid-state technique is the production of pure calibration and validation samples. Moreover, whilst the production... 

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