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Formulation and Delivery - Chemical

Category: Poster Abstract

(T0930-01-04) High Throughput Excipient Compatibility Screen Visualization and Analysis Using Spotfire

Tuesday, October 24, 2023
9:30 AM – 10:30 AM ET


Purpose: Excipients are formulated with an active pharmaceutical ingredient (API) to protect API from environmental factors, and to enhance its pharmaceutical activity, such as increasing solubility or improving absorption. API-excipient compatibility screening is a critical part of the formulation development workflow, which is utilized to predict the chemical compatibility of the excipient ingredients with APIs in formulations. The Excipient Compatibility Screen is conducted by monitoring solid API/Excipient blend compacts for chemical and physical instability. Over the years, our internal preformulation group has generated a large amount of data from the High Throughput Excipient Compatibility Screen (HTECS). However, in the past, this data was only analyzed within individual formulation development project teams. It would be beneficial to understand what key attributes contribute to incompatibility between the API and excipient components. Therefore, a number of hypotheses have been formed regarding what physicochemical factors may impact compatibility. To achieve this goal, high throughput excipient compatibility data were collected from project teams and the internal database, then compiled together for analysis. By examining this data, we can gain valuable insights into the factors that contribute to API-excipient incompatibility, and ultimately improve our formulation development process.

Methods: This study focused on the datasets of oral dosage form excipient compatibility screening results, excluding all sterile formulations. Only small molecule APIs were selected for the dataset, and only conventional formulation APIs were used to simplify the case, excluding all enabled formulations. The excipients analyzed included only the most common oral formulation excipients, a total of 57 excipients for this analysis. The Excipient Compatibility Screen is conducted by monitoring solid API/Excipient blend compacts for chemical and physical instability. Blend samples are compacted in 96-well plates to mimic intimate excipient and API contact in a tablet. The plates are then stored under accelerated conditions at 40°C/75% R.H for 2 and 4 weeks. A peak in a chromatogram showing growth over time is reported as a degradant and expressed as a ratio of area of degradant to area of parent. To simplify the data comparison, the chemical stability risk was classified into three levels based on the amount of total degradation in UPLC chromatograms after 4 weeks under 40°C/75% R.H: Low risk (total degradation < 1%), Medium risk (total degradation 1.0-3.5%), and High risk (total degradation >3.5%). Data regarding the API physicochemical properties were calculated via ACD Labs Percepta software. For APIs, properties in consideration included molecular weight, logD, number of hydrogen bond donors and acceptors, number of rotational bonds, number of aromatic rings, polar surface area, the counts of halogens and nitrogen. The data were then cross-referenced between the datasets and visualized in TIBCO Spotfire software to determine if there is a correlation between the identified properties and chemical stability from the API and excipients.

Results: Our analysis of 22 APIs and 57 excipients reveals that solid-state forms of an API affect its chemical stability and that grades of excipients may also influence the risk level. We identified a few critical properties that contribute to excipient compatibility, as well as factors that do not affect stability. Not surprisingly, we found that strongly acidic or basic APIs tend to have higher risk, and caution should be taken in handling these APIs. In commonly used excipients, we found that ATAB, citric acid, crospovidone, HPMC, poloxamer 407, and Soluplus exhibited higher than average chemical stability risk. Another interesting finding was that the presence of peroxide in excipients increases the risk level in compatibility tests.

Conclusion: To facilitate excipient compatibility analysis and support formulation development, we generated an expandable data table as a template and suggested low-risk excipients by function as a reference for High Throughput Excipient Compatibility Screen (HTECS). Furthermore, we plan to expand the Spotfire dashboards to illustrate the effect of parameters with more compatibility screening datasets. These efforts can provide researchers with useful tools for developing stable and effective pharmaceutical formulations. In summary, this study provides valuable insights into the physicochemical factors that contribute to API-excipient incompatibility, which can inform the development of more stable and effective oral dosage forms. The findings of this study can help advance the field of pharmaceutical formulation and improve the quality and efficacy of medications.

Overview for excipients: some excipients are riskier than the others