Effect of Cryogrinding on Chemical Stability dients (APIs) belonging to the last category (i.e. IV class) are likely to exhibit low bioavailability and are still the most challenging molecules for the modern pharmaceutical industry. One of the most promising ways to tackle the problem of insufficient dissolution rate of poorly water- soluble drugs is particle size reduction. As shown in the literature, micronization generally leads to improvement of dissolution properties of drugs through increase in surface area of micro- or nano-substances (2). A variety of methods are used for producing drugs with reduced particle size. However, micronization of drugs is frequently attempted through extended mechanical milling. Mechanical treatment of crystalline solids in a mill (known also as grinding) is a very popular technique applied in many fields of industry to reduce particle size. The large amount of mechanical perturbations generated during milling may result in significant changes in the structure of the grinded material, including polymorphic transformations, crystal defects and partial or complete amorphization (3,4). In the latter case, complete transfor- mation from crystal to amorphous state occurs only if the grinding process takes place at a temperature much lower than the glass transition temperature, Tg, of an equivalent supercooled liquid. Amorphous drugs offer a very interesting perspective for pharmacy, basically because they are markedly more soluble and dissolve faster as compared to their crystalline counterparts (5). Nevertheless, one should still remember that an amorphous solid is in the state of non-equilibrium and sooner or later will revert to a more stable crystalline state (6). Moreover, many studies have revealed that enhanced chemical reactivity of amorphous pharmaceut- icals related to molecular mobility speeds up their chemical degradation (7). Solid state amorphization via grinding has extensively been studied for a long time. This research is concerned mainly with metallic systems and inorganic compounds (8). However, in recent years a lot of effort has been taken by the Decamps group to put some insight into crystal-glass transformation induced by milling in organic materials, especially in the food and pharmaceuticals areas (9–11). It is generally claimed that physical stability of amor- phous drugs prepared by grinding of crystalline solids is reduced as compared to that obtained by quenching of liquid. For instance, glassy state of indomethacin obtained by very slow cooling of the liquid is stable against crystallization for over 2 years (12), but amorphous state of IMC obtained by grinding is less stable and recrystallizes to 90% after approximately 13–15 h (13). Certainly, the changes which appear during grinding can affect the stability and other physical properties of outcome material. Thus, a better understanding of the nature of the crystal-to- amorphous transformation seems to be fundamental. 3221 In the literature there are several concepts for elucida- tion of the crystalline-amorphous state transformation induced by milling. For example, it has been suggested that during mechanical impact, a certain amount of mechanical energy is liberated. This can cause a local heating effect resulting in local melting of the sample followed by fast quenching. However, as demonstrated a few years ago, no significant increase in temperature upon milling occurred (10,11). The next scenario is based on the Lindemann melting criterion stating that the crystalline- amorphous solid transformation can simply be explained in terms of melting of critically disordered crystals at temper- atures below the glass transition point where the super- cooled liquid exists in a configurationally-frozen state (glassy state) (14). On the other hand, some researchers have suggested that the solid-state amorphization occurs as the result of softening of the crystalline lattice vibrations, leading in a consequence to its collapse, while others claim that during milling progressive lattice defects give rise to the energy of the system. This provides essential thermody- namic-driven force to begin transformation (15). It is also worth keeping in mind that in the Martin and Bellon’s ‘driven material concept’ approach, the whole transforma- tion involves competition between thermally independent disordering process induced by milling and thermally depending restoration process (16). Grinding, as a non-conventional way of amorphization, is a great alternative for the commonly used supercooling of the molten crystal. This method is especially important with compounds undergoing thermal degradation at the melting point. It is thus impossible to prepare amorphous state by quenching a liquid. It is also very suitable when a material has a strong sensitivity to solvents and consequently there is a big problem associated with selection of the solvent for the freeze- and spray-drying technique, or when it is necessary to prepare a pure amorphous API without additional excipients, not dispersed molecularly in any polymeric matrix. Grinding of various types of crystalline materials can be carried out using two options: 1) at room temperature in a traditional ball mill or 2) in a cryogenic impact mill immersed in liquid nitrogen (so-called cryogrinding, cry- omilling). Recently, cryogrinding of pharmaceuticals has attracted much attention (13,17,18). As it turns out, this method is more efficient to prepare the glassy drugs than the ball milling, since the material is completely frozen during grinding. It is also believed that chemical degrada- tion does not occur in this case, because the liquid nitrogen temperature should prevent local temperature warm-up. It is worth noting that until now there have been no precise studies concerning drug decomposition upon cryomilling. A few years ago, Graeser et al. reported on a lowered chemical stability of simvastatin during cryomilling; however, the