Predicting the Physical Stability of Amorphous Tenapanor Hydrochloride Using Local Molecular Structure Analysis, Relaxation Time Constants, and Molecular Modeling.

The conformational flexibility of organic molecules introduces more structural options for crystallization to occur but has potential complications, such as, reduced crystallization tendency and conformational polymorphism. Although a variety of energetically similar conformers could be anticipated, it is extremely difficult to predict the crystal conformation for conformationally flexible molecules. The present study investigates differences in thermodynamic parameters for the free base, c-FB, and an amorphous dihydrochloride salt, a-Di-HCl, of a conformationally flexible drug substance, tenapanor (RDX5791). A variety of complementary techniques such as, thermal analysis, powder X-ray diffraction (PXRD), and molecular modeling were used to assess the thermodynamic properties and the propensity of crystallization for a-FB and a-Di-HCl, tenapanor. Molecular modeling and total scattering measurements suggested that the a-Di-HCl salt exists in an open elongated state with local 1D stacking, which extends only to the first nearest neighbor, while the a-FB shows local stacking extending to the third nearest neighbor. The overall relaxation behavior, which typically is an indicator for physical stability, as measured by modulated temperature differential scanning calorimetry and PXRD suggested a nontypical dual relaxation process for the dihydrochloride salt form. The first relaxation was fast and occurred on warming from the quench conditions without any thermal annealing, while the second relaxation step followed a more traditional glass relaxation model, exhibiting an infinite relaxation time. Similar analysis for the a-FB suggested a comparatively shorter relaxation time (about 19 days) that results in its rapid crystallization. This observation is further validated with the extensive amount of physical stability data collected for the a-Di-HCl salt form of tenapanor under accelerated and stress stability conditions, as well as long-term storage for more than 3 years that show no change in its amorphous state.

Investigation of Metformin HCl lot-to-lot variation on flowability differences exhibited during drug product processing.

The purpose of this study was to determine the cause for flowability difference observed during drug product processing when different Metformin HCl drug substance batches of varying age were used. It was found that the lead time (age) between the final step (milling) in the manufacturing process of the Metformin HCl drug substance could be a factor. The lead time had an impact on flowability of Metformin/excipient blends during drug product processing even though these batches had no apparent differences in their release specifications. To study and understand the aging effect, two batches of Metformin HCl manufactured at different periods of time were selected. The surface energy values obtained by the density functional theory (DFT) method together with X-ray diffraction patterns, thermally stimulated current measurements, and dynamic vapor sorption isotherms indicated that the freshly manufactured Metformin HCl material contains detectable amounts of surface crystal defects, but are absent in aged sample, which could be the cause of flowability differences of Metformin/excipient blends observed during the drug product processing. Having identified the cause for different flow behavior, a method to destroy these defects was designed and the issue was resolved by rapid aging of Metformin HCl under humidity at room temperature.

Application of surface area measurement for identifying the source of batch-to-batch variation in processability.

The primary goal of this study was to evaluate the use of specific surface area as a measurable physical property of materials for understanding the batch-to-batch variation in the flow behavior. The specific surface area measurements provide information about the nature of the surface making up the solid, which may include defects or void space on the surface. These void spaces are often present in the crystalline material due to varying degrees of disorderness and can be considered as amorphous regions. In the present work, the specific surface area for 10 batches of the same active pharmaceutical ingredient (compound 1) with varying quantity of amorphous content was investigated. Some of these batches showed different flow behavior when processed using roller compaction. The surface area value was found to increase in the presence of low amorphous content, and decrease with high amorphous content as compared to crystalline material. To complement the information obtained from the above study, physical blends of another crystalline active pharmaceutical ingredient (compound 2) and its amorphous form were prepared in known proportions. Similar trend in specific surface area value was found. Tablets prepared from known formulation with varying amorphous content of the active ingredient (compound 3) also exhibited the same trend. A hypothesis to explain the correlation between the amorphous content and specific surface area has been proposed. The results strongly support the use of specific surface area as a measurable tool for investigation of source of batch to batch variation in processability.