Seminars at UMET
From the fundamental point of view, the shape of molecules, their masses, and interaction potential determine the thermodynamics, dynamics and structural properties of any kinds of the real substances. Consequently, the forces occurring between molecules also decide on the crystallization tendency and the glass forming ability of a given material. At first glance, the increase in the attractive intermolecular interactions should cause the decrease in glass forming ability and makes that system should crystalize easier. However, our very last experimental and theoretical studies reveal completely contrary behavior. Our results indicate that the strength of the attractive forces affects the location of the nucleation and crystal growth rate maxima with respect to each other and the melting point. Nevertheless, the system characterized by weaker attractive forces occurring between molecules are more sensitive to the pressure changes, which is due to significant pressure influence on their interfacial free energy.
The vast majority of Active Pharmaceutical Ingredients (APIs) used to produce solid forms of drugs are in a crystalline state because it is the most thermodynamically stable solid state. It means that their physicochemical properties do not change even during a long-term storage. Unfortunately, many crystalline APIs are not sufficiently soluble in water and, consequently, their bioavailability is strongly limited.The scale of this problem is quite enormous, because more than 75% of drug candidates and 40% of the marketed drugs are poorly soluble in water.
One of the efficient way to solve the problem is to convert crystalline API to the amorphous form. It arises from the fact the logarithm of the ratio of crystal solubility to amorphous solubility is proportional to difference between the Gibbs free energy of crystal and amorphous state, respectively. Since the Gibbs free energy of amorphous state is always higher than crystal, thus drugs prepared in amorphous form should exhibit a better water solubility than their crystalline counterparts. However, this solution is not free from difficulty. It is well known that the amorphous drugs are, in general, physically unstable systems and they may simply re-crystalize during storage losing their original advantages. Consequently, a lot of efforts is made to determine the key factors governing recrystallization process of amorphous drugs to benefit from their better solubility. It is widely believed that structural dynamics becomes one of the most relevant factors which should be studied to reliably predict the tendency of amorphous drugs to recrystallization. This belief can be partially rationalized by the fact that molecules need to rearrange in order to incorporate into crystal lattice. In this presentation we will critically review and discuss correlations between properties of molecular dynamics and crystallization tendency of amorphous APIs. For this purpose we will show and analyse a numerous experimental data obtained from broadband dielectric spectroscopy measurements which is one of the most powerful technique to probe molecular dynamics of glass-forming materials. Finally, a number of important conclusions will be formulated.