Topologically directed confocal Raman imaging (TD-CRI): Advanced Raman imaging towards compositional and micromeritic profiling of a commercial tablet components.

Particle size distribution (PSD), spatial location and particle cluster size of ingredients, polymorphism, compositional distribution of a pharmaceutical product are few of the most important attributes in establishing the drug release-controlling microstructural and solid state properties that would be used to (re)design or reproduce similar products. There are numerous solid-state techniques available for PSD analysis. Laser diffraction (LD) is mostly used to study PSD of raw materials. However, a constraint of LD is the interference between the active pharmaceutical ingredients (API) and excipients, where it is very challenging to measure API size in a tablet. X-ray powder diffraction (XRPD) is widely employed in establishing the polymorphism of API and excipients. This research examined a commercial osmotic tablet in terms of extracting solid state properties of API and functional excipient by Raman Imaging. Establishing repeatability, reproducibility, and sample representativeness when the samples are non-uniform and inhomogeneous necessitates multiple measurements. In such scenarios, when employing imaging-based techniques, it can be time-consuming and tedious. Advanced statistical methodologies are used to overcome these disadvantages and expedite the characterization process. Overall, this study demonstrates that Raman imaging can be employed as a non-invasive and effective offline method for assessing the solid-state characteristics of API and functional excipients in complex dosage forms like osmotic tablets.

QBD-driven HPLC method of eltrombopag olamine: Degradation pathway proposal, structure elucidation, and in silico toxicity prediction.

Eltrombopag olamine is prescribed for chronic immune (idiopathic) thrombocytopenic purpura (ITP). This work aims to investigate the formation of potential degradants of the drug and determine their toxicity in silico. A stability-indicating high performance liquid chromatography (HPLC) method was developed to separate six oxidative degradation impurities and three thermal degradation impurities employing the quality by design (QBD) approach. The degradation impurities were resolved with minimum resolution of 1.5 using a phenyl column with 0.1 % trifluoroacetic acid (TFA) and acetonitrile as the mobile phase and quantified at 245 nm. The structure and degradation pathway for the degradants was proposed by employing liquid chromatography with tandem mass spectrometry (LC-MS/MS), among the identified degradation pathways demethylation and decarboxylation are common reactions observed during oxidation resulted in majority of degradation products. All the degradation products are characterized with help of the daughter ions and product ion obtained upon LC-MS/MS analysis. The HPLC method parameters such as column temperature, flow rate, TFA concentration and organic concentration are identified as critical method attributes (CMA), a design of experiments (DOE) mediated design space was established through use of design experts. The resolution between sets of adjacent peaks was identified as a critical quality attribute; among the investigated CMAs, column temperature and flow rate significantly affected the resolution. Furthermore, the toxicology of the degradation products was predicted with the help of in silico TOPKAT analysis, the carcinogenicity of the impurities was discussed.