Quantitative Open-Access HPLC Analysis - Pharmaceutical Technology

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Quantitative Open-Access HPLC Analysis
The authors discuss the approach taken to develop a new calibration approach, its associated protocols, and how it can be used to calculate data.

Pharmaceutical Technology
Volume 34, pp. s6-s11


Following the implementation of the Yieldaliser across chemical development at GSK—including sites within the US, UK, and Italy—a wide range of tasks were performed by chemists and engineers using the approach. Three types of analysis—mass-balance determiniation, crystallization endpoints, and solubility curves—exemplify how data provided by the Yieldaliser can be useful in chemical development.

Mass-balance determinations. These determinations involve identifying where major material losses occur during solubilization. For example, during a recrystallization of an API, it is useful to gain an understanding of the efficiency of the initial crystallization along with the subsequent solvent wash steps.

Crystallization endpoints. The Yiedaliser can be used to determine whether visually determined API crystallization endpoints are sound by analyzing the supernatant. Results can be used to determine whether the input batch and crystallization parameters affect the rate of crystallization.

Solubility curves. To aid in the development of the final API-stage crystallization, accurate solubility curves (concentration versus temperature) are required. Several curves can be generated using Yieldaliser data. These curves represent the solubility at several crucial solvent-mixture ratios. Key points in the process can be identified (e.g., seeding composition, point of supersaturation, and completion of crystallization).

Figure 4: Active pharmaceutical ingredient solubility at various acetone:water ratios, including exponential trendline (–10 to +60 C).
Figure 4 shows solubility curves of an API that is crystallized from acetone after adding water. GSK chemists used several curves, which represented the solubility point at several acetone:water ratios. A saturated slurry was prepared at 0 C and equilibrated for 1 h before sampling and assaying the supernatant. This process was repeated at 10 C intervals, going up to 50 C, and the results were plotted. Four solubility curves were determined to model key points in the process (e.g., starting composition 10:0.5 acetone:water, seeding composition 10:3 acetone:water, isolation composition 10:6 acetone: water). To further extend the temperature range, the exponential trend lines were extrapolated to provide a temperature range of –10 to 60C.

Key points in the crystallization process are shown in Figure 4. For example, the line labeled "post-distillation" represents the concentration and composition of the solution at the end of the atmospheric distillation. The line shows that there is an approximate 7 C window between the solution cooling to the point of supersaturation (dark blue line) and the boiling point. Also marked in Figure 4 is the seeding point at 53 C, which is approximately 5 C inside the saturated solubility curve (pink line) for this composition. The red line represents the isolation composition and shows that very little material (1.2 mg/mL) is left in solution once the slurry has been cooled to –10 C. This same line shows that most of the API has crystallized during the water addition and before the cool-down from 47 to –10 C. Therefore, it is more important to examine changes when water is added. Users were able to define the final process parameters with the help of these solubility curves.


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