Critical Aspects of pH Measurement for Bacteriostatic Water for Injection.

Bacteriostatic water for injection (bWFI) is a common diluent for parenteral pharmaceutical products. bWFI is sterile water for injection containing one or more suitable antimicrobial agents to suppress the growth of microbial contaminants. United States Pharmacopeia (USP) monograph describes bWFI with pH ranging from pH 4.5 to 7.0. Lacking buffering reagents, bWFI has very low ionic strength, no buffering capacity and is prone to sample contamination. These characteristics pose a challenge for accurate bWFI pH measurements which are characterized by long response times and noisy signals, resulting in inconsistent results. The challenging nature of bWFI pH measurement, however, is not fully recognized as pH is generally considered a routine analytical technique. Even with the addition of KCl to increase ionic strength as recommended by the USP bWFI monograph, variability in pH results is still observed without careful consideration of other critical measurement factors. To bring awareness to the challenges associated with bWFI pH measurement, we present a comprehensive characterization of the bWFI pH measurement process that includes an evaluation of probe suitability, measurement stabilization time, and pH meter settings. While these factors may be non-critical and sometimes overlooked when developing pH methods for buffered samples, they can have a significant impact on bWFI pH measurement. We present recommendations that can help reliable bWFI pH measurements for routine execution in a controlled environment. These recommendations also apply to other pharmaceutical solutions or water samples with low ionic strength.

Atroposelective Brønsted Acid-Catalyzed Photocyclization to Access Chiral N-Aryl Quinolones with Low Rotational Barriers.

Herein, a novel route to atropisomeric N-aryl quinolones with low rotational barriers is demonstrated, leveraging a dual photochemical/organocatalytic approach to the required ring closure in up to 94% yield and up to >99% ee. The use of a continuous flow system allows for impurity suppression and enables rapid scale-up to a decagram scale.

Enhancing and sustaining AMG 009 dissolution from a bilayer oral solid dosage form via microenvironmental pH modulation and supersaturation.

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier (e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement.

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation.

The objective of this study was to investigate the combined effect of pH modifiers and nucleation inhibitors on enhancing and sustaining the dissolution of AMG 009 tablet via supersaturation. Several bases and polymers were added as pH modifiers and nucleation inhibitors, respectively, to evaluate their impact on the dissolution of AMG 009 tablets. The results indicate that sodium carbonate, among the bases investigated, enhanced AMG 009 dissolution the most. HPMC E5 LV, among the nucleation inhibitors tested, was the most effective in sustaining AMG 009 supersaturation. The release of AMG 009 went from 4% for tablets which did not contain both sodium carbonate and HPMC E5 LV to 70% for the ones that did, resulting in a 17.5-fold increase in the extent of dissolution. The effect of compression force and disintegrant on the dissolution of tablets were also evaluated. The results indicate that compression force had no effect on AMG 009 release. The addition of disintegrating agents, on the other hand, decreased the dissolution of AMG 009.

Development and Validation of a HPLC-UV Method for Urea and Related Impurities.

Urea is used in biopharmaceutical manufacturing processes for the purification of therapeutic proteins, for cleaning columns, and for refolding proteins after purification. The urea used for such purposes is typically USP grade material obtained from commercial sources and further characterization is required prior to use, such as determination of purity and identity. For this purpose, a robust analytical method is needed that can characterize the known organic impurities of urea. However, the existing methods show high assay variability and are not able to resolve all known organic impurities as desired for accurate quantification. In the present manuscript we developed a new high-performance liquid chromatography method with UV detection for the separation of urea and its impurities (biuret, cyanuric acid, and triuret). The method performance characteristics evaluated for urea and biuret were specificity, linearity, accuracy, identity, precision, and robustness and the newly developed method met all predefined performance acceptance criteria.