Crystal Growth of Pharmaceuticals from Melt

Abstract

The preparation of crystalline powders and single crystals is an activity of utmost importance in many fields of modern industry. Single crystals are the basis of many daily necessities such as electric heaters, strain gauges, laser controllers and piezoelectric devices (Ropp 2003). In the pharmaceutical field, the search for compounds that have suitable properties to be used in drug formulation is nowadays a big challenge. In an increasingly demanding industry, science is asked to prepare crystalline forms of well defined structural patterns, with the size and shape that is required for a certain purpose. Despite recent advances in molecular modelling, it is not yet possible to accurately predict the molecular structures from our knowledge of the chemical compositions (Gdanitz 1997), which means that the study of crystal growth is still done on an experiment basis. Crystallization is a conventional technique used to prepare solid forms. It can be carried out from solutions by decreasing temperature, solvent evaporation or by the diffusion of a much poorer solvent in solution. Alternatively, the crystalline forms can be obtained from the melt upon cooling. Unlike crystallization from solution, this does not require recovery, storage and disposal of liquids, what this means reduced environmental impact, low cost and time saving industrial processes. It therefore accomplishes the desired “green chemistry requirements”. Since the pioneering work carried out in the early 1960’s (Sekiguchi and Obi 1961), meltextrusion has become an important drug delivery technology (Mollan 2003), and is currently being applied in the manufacture of a variety of dosage forms and formulations (Chokshi and Zia 2004, Breitenbach 2002, Crowley, et al. 2007, Repka, et al. 2007, Repka, et al. 2008). Different crystals of a certain organic compound may be obtained by crystallization. These forms, called polymorphs, differ from one another by the packing and/or conformation of the molecules in a crystal lattice (Hilfiker 2006, Bernstein 2002, Threlfall 1995, Brittain 2009). Thus, polymorphs are solid forms constituted by molecules indistinguishable in gas or liquid state but exhibiting different structures in solid phase. When this difference lies just in the conformation, they are designated as conformational polymorphs (Bernstein 2002). Since the discovery that different polymorphs may have different bioavailabilities as drugs (Aguiar, et al. 1967), polymorphism has been a matter deserving great attention by pharmaceutical technology over the last half-century (Brittain 2009, Hilfiker 2006). For a given compound, only the one having the lowest Gibbs energy form is thermodynamically stable. However, in some cases, as consequence of the height of the energy barrier separating some polymorphs and the most stable one, they remain as metastable forms for a period of time long enough to be used for practical purposes as if they were stable forms (Brittain 2009).