Mladen Ladika

Ab initio calculations of conformational effects in saturated cyclic amines

Abstract In order to study the conformational equilibria of substituents at nitrogen in six-membered rings, the energies of three azacyclohexanes and their N-methylated derivatives were calculated using the 6-31G∗ basis set. The results obtained were compared with experimental data and with previous calculations for those molecules. All our results are in agreement with experimental data. When molecular mechanics or ab initio calculations using smaller basis sets were applied in energy calculations of these polyazines, some discrepancies with the experimental results were observed. This work indicates that ab initio methods which include larger basis sets give better agreement with experimental data, and also give more reliable predictions in cases where no experimental data exist.

High-Throughput Raman Spectroscopy Screening of Excipients for the Stabilization of Amorphous Drugs.

Low aqueous solubility of active pharmaceutical ingredients (APIs) is an enduring problem in pharmaceutical development, and it is becoming increasingly prevalent among new drug candidates. It is estimated that about 40% of drugs in the development pipeline and approximately 60% of the drugs coming directly from discovery suffer from poor aqueous solubility and slow dissolution, thereby reducing their bioavailability and efficacy and thus preventing their commercialization. It is well known that utilizing the amorphous form of a drug can be a useful approach to improve the dissolution rate and solubility of poorly water-soluble APIs. Amorphous compounds are thermodynamically unstable, but they can be stabilized by combining them with a carrier polymer (excipient) to form a solid dispersion. High-throughput Raman spectroscopy was used in this study to identify excipients that promote formation and stabilization of the amorphous drug form in solid dispersions. Four model APIs were used as poorly soluble drug candidates: ketoprofen, danazol, griseofulvin, and probucol. The Raman signals of excipients were generally negligible, and therefore Raman bands from the drugs were used with minimal spectral pre-processing. By comparing Raman spectra collected from the APIs in the crystalline and molten state, appropriate spectral features and regions were identified for the development of semi-quantitative methods to determine the amorphous content for each API. It is demonstrated that methods based on peak intensity ratio, peak width, peak distance, and classical least squares can all be effective methods for the screening of excipients. Interesting excipient-dependent phase transformation behavior was also observed for probucol.