Physical Stability of Amorphous Drug with Structurally Related Impurities Evaluated Using Thermal Analysis

摘要

APIs usually contain some minor component referred to as an "impurity". The amounts of impurities, such as heavy metals, moisture, residual organic solvents and organic substances, are rigorously evaluated in the manufacturing process of an API and the drug product. However, these impurity profiles can vary depending on the manufacturer or the process scheme. The synthetic procedure in the stage of research and development is usually immature, so we commonly experience handling various APIs with different impurity profiles. Especially, organic substances, such as process intermediates, byproducts and degradation products, are structurally related to the API compound, but their physicochemical properties are thought to show quite a great diversity, which is dependent upon each impurity compound. It is possible for the content of organic impurities to be around as much as several percent of API. It may be possible that this affects the physical properties of the API. For instance, we often experience variations in the behavior of the crystallization process of an API depending on the material used. The reason for such variation is also considered to existence of active impurity compound to inhibit the crystallization and that the deference in their impurity profiles was suspected. As described, the behavior of crystallization and amorphization may be affected by the existence of structurally related impurities. In this study, sulfanilamide (SNA), sulfamerazine (SMR), and sulfadimethoxine were used as virtual impurities of sulfamethazine. The crystallinity of sulfamethazine was not decreased when it was ground alone. However, when structurally related impurities with sulfonamide derivatives were blended, the crystallinity of sulfamethazine was decreased by grinding. Other materials without a sulfonamide moiety showed no such effect. The Raman spectra of sulfamethazine demonstrated that there was a difference between its crystalline and amorphous states within its sulfonamide structure. It was suggested that the sulfonamide structure of the impurities was important in causing the inhibition of recrystallization of sulfamethazine during grinding. The effects of structurally related organic impurities on the molecular dynamics of amorphous sulfamethazine were evaluated using thermal analysis. An amorphous state was prepared in situ in differential scanning calorimetry by quenching the melted physical mixtures of sulfamethazine and each impurity compound in the differential scanning calorimetry pan. In the following heating process, the glass transition temperatures (Tg) of each were measured. The fragility parameters were estimated from the width of Tg. The Tg of amorphous sulfamethazine with those impurities changed in accordance with the manner set forth in the Gordon-Taylor equation. The fragility parameter slightly increased when a small amount of SNA or SMR was incorporated. Moreover, the probability of a measurement in which crystallization of sulfamethazine was observed above its Tg, increased at a low concentration range of SNA, SMR, or sulfadimethoxine. It was considered that the existence of a small amount of impurity would induce heterogeneity in the molecular density of the amorphous state, which would be associated with the local fluctuation. It was suggested that the change in the molecular dynamics would be related to the probability of crystallization of sulfamethazine. [1,2].