Ultra high performance liquid chromatography method development for separation of omeprazole and related substances on core-shell columns using a Quality by Design approach.

An updated and improved method for analysis of omeprazole/esomeprazole and related substances on core-shell columns was developed using Fusion LC Method Development™. The method was optimized with respect to column type, column temperature, mobile phase pH level, and gradient time. Four different core-shell columns were examined to develop a method suitable for both high performance- and ultra-high performance liquid chromatography using a Quality by Design approach. The final method offers two alternative columns: Poroshell EC C18 (3.0 × 100 mm, 2.7 µm) or Poroshell HPH (3.0 × 100 mm, 2.7 µm) with the same gradient elution condition and mobile phase composition. Total run time is 18 min with 12 min of gradient elution. Phosphate buffer (15 mM, pH 7.8) is selected as the aqueous mobile phase and acetonitrile as the organic mobile phase. Column temperature is set at 40°C and ultraviolet detection at 302 nm. Furthermore, by studying parameters in a systematic way, an understanding of the effect of the input parameters enhances the method robustness and should allow for regulatory flexibility in terms of post-approval changes. Compared to the current United States Pharmacopeia method, the updated method is faster, more efficient and performs well above acceptance criteria.

Degradation caused by incompatibility between sodium stearyl fumarate (PRUV) and AZD7986 in the drug product.

During compatibility study of the AZD7986 project, a peak of 3 area% at the tail (RRT 1.03) of the active pharmaceutical ingredient (API) was discovered for all tablets containing sodium stearyl fumarate (PRUV) under humid condition (e.g. 50 °C/75% RH), regardless of choice of disintegrant or filler combination. The degradant was needed to be identified to understand the corresponding reaction mechanism and help the final formulation design. Structure elucidation was therefore done by analysis using high resolution mass spectrometry. The degradant was found to be a Michael addition product of the API and fumaric acid. Reaction between deuterated fumaric acid and the API was carried to confirm the proposed structure and reaction mechanism. Fumaric acid was a degradant product of PRUV in the presence of other excipients, revealed by the stability study. The Michael addition reaction needs facilitation by water and basic conditions. The result from this study should serve as a precaution note for projects using PRUV as one of excipients where the API could act as a nucleophile. In such cases the microenvironment should be optimised to minimize the reaction, such as pH adjustment and incorporating protection from moisture.

Core-shell column Tanaka characterization and additional tests using active pharmaceutical ingredients.

In the last decade, core-shell particles have gained more and more attention in fast liquid chromatography separations due to their comparable performance with fully porous sub-2 µm particles and their significantly lower back pressure. Core-shell particles are made of a solid core surrounded by a shell of classic fully porous material. To embrace the developed core-shell column market and use these columns in pharmaceutical analytical applications, 17 core-shell C18 columns purchased from various vendors with various dimensions (50 mm × 2.1 mm to 100 mm × 3 mm) and particle sizes (1.6-2.7 µm) were characterized using Tanaka test protocols. Furthermore, four selected active pharmaceutical ingredients were chosen as test probes to investigate the batch to batch reproducibility for core-shell columns of particle size 2.6-2.7 µm, with dimension of 100 × 3 mm and columns of particle size 1.6 µm, with dimension 100 × 2.1 mm under isocratic elution. Columns of particle size 2.6-2.7 µm were also tested under gradient elution conditions. To confirm the claimed comparable efficiency of 2.6 µm core-shell particles as sub-2 µm fully porous particles, column performances of the selected core-shell columns were compared with BEH C18 , 1.7 µm, a fully porous column material as well.