The importance of metastable forms

Tetracaine hydrochloride was also revisited using thermal methods, revealing a complicated system containing six anhydrous crystalline forms, an amorphous form, a hemihydrate, a monohydrate and a tetrahydrate. As with the purine derivative noted above, the identification and classification of these modifications was considerably aided by the use of temperature resolved X-ray diffraction (Giron et al. 1997). 

The so-called hyphenated techniques , incorporating thermal methods as one of the combined analytical techniques are sure to play an increasing role in the identification and characterization of crystalline forms of pharmaceutical substances. The combination of TGA with FTIR allows the simultaneous quantitative analysis of weight changes during thermal processes with the IR identification of the decomposition products (e.g. solvent) resulting from those processes (Materazzi 1997). For substances with low volatility, the FTIR analysis may be replaced with mass spectroscopy (Materazzi 1998). 

As the energy-temperature phase diagram (Section 2.2.3) indicates, at any particular temperature only one polymorphic form is the thermodynamically stable one (except, of course at the temperature of a transition point). The stable form is also the least soluble form at a given temperature (Bym et al. 1999). All other phases are higher in energy and metastable with respect to the most stable phase. A metastable phase may be fleeting in nature (e.g. benzamide, Bernstein and Davis 1999) or may coexist indefinitely with its more stable counterpart in the absence of any perturbations 

The lower solubility of stable forms may limit their pharmacological utility (e.g. ritonavir (Chemburkar et al. 2000 Bauer et al. 2001)), so that it may be advantageous to selectively obtain and maintain a metastable form in a formulation (e.g. Shah et al. 

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