(M1530-11-75) Role of Citric Acid in Enhancing Drug Performance: A Double-Edged Sword?

Purpose: Citric acid is commonly used as an excipient in solid oral formulations to improve drug solubility and dissolution rate. In vivo, intimate contact between citric acid and the active pharmaceutical ingredient (API) can create an acidic microenvironment, which may benefit an API with pH-dependent solubility and afford higher supersaturation, ultimately improving drug exposure and performance. Preclinical in vivo studies of weakly basic (pKa= 2.89, 4.68 and 7.71) crystalline API BLU-701 tablet formulation with citric acid have demonstrated pH-independent performance (Figure 1). However, the hygroscopic and deliquescent nature of citric acid in the presence of moisture may contribute to drug product physical instability, leading to changes in physicochemical properties. In this study, we investigated the humidity-induced chemical interaction between BLU-701 API and citric acid in tablet formulations, which we hypothesize to have triggered a solid-state transformation of a weakly basic crystalline drug into a citrate salt form, as a result of the phase transition of citric acid.

Methods: We prepared tablets containing BLU-701 API and citric acid (with other inert excipients) at a ratio of 3:1, and exposed these to different stability conditions [(25°C/60%RH, open condition) and (40°C/75%RH, open and closed condition)] over one month and evaluated changes in their physicochemical properties. Additionally, physical mixtures were prepared by compacting and grinding a blend of BLU-701 and citric acid at a ratio of 3:1, which were then compared to neat BLU-701, citric acid, parent tablet blend, and placebo blend. We used various analytical techniques such as X-ray powder diffraction (XRPD), Dynamic Vapor Sorption (DVS), HPLC (High Performance Liquid Chromatography) and Raman spectroscopy to investigate the solid-state transitions and chemical interactions.

Results: Tablets containing citric acid subjected to 40°C/75%RH for 2 weeks (open) displayed evidence of deliquescence and a change in color from off-white to yellow, and were found to be chemically stable up to one month at this open condition. DVS analysis showed a significant reduction in the critical relative humidity (cRH; %): citric acid (70-80%) > physical mixture (60-70%) > ground tablet blend (40-50%) (Figure 1). This indicates potential risk of moisture uptake even at lower atmospheric %RH during common manufacturing processes and storage over time. XRPD analysis of the tablets displayed the emergence of a new peak at 6.5 – 7.5° 2-theta, which was similarly observed for the post-DVS physical mixture suggesting a change in the thermodynamic properties of the drug. No new peaks were observed under closed conditions, nor were in the placebo blend which likewise exhibited citric acid deliquescence and changes in visual appearance (Figure 1). This evidence suggests that humidity, citric acid, and BLU-701 are required for this transformation, and not the presence of citric acid alone. The BLU-701 polymorph landscape includes a known de-hydrate pattern (low crystallinity), which similarly exhibits a peak in the 6.5 – 7.5° 2-theta region. To investigate whether the new XRPD peak was linked to formation of the metastable de-hydrate pattern, the tablet was subjected to extended drying and humidification. In both experiments no change in the XRPD diffractogram was observed, supporting salt formation over hydrate/dehydrate pattern formation. DSC analysis was inconclusive due to interfering excipient peaks, therefore Raman spectroscopy was used to confirm the physical form. The Raman spectra for the stressed tablet most closely matched that of the citrate salt. It can be inferred from these results that exposure to high humidity conditions in presence of citric acid may have caused citric acid to absorb moisture and deliquesce, and provide more intimate contact to chemically interact with the API. Thus, we hypothesize that the weakly basic crystalline drug transformed into the citrate salt form.

Conclusion: Our study highlights the importance of consideration that excipient moisture uptake ability can affect API solid form during processing or on stability. While citric acid can be advantageous for API with pH-dependent solubility by creating a more acidic microenvironment and thereby enhancing drug performance, it is essential to design robust formulations and packaging that can protect drugs from moisture and prevent solid-state transformations and chemical interactions. Future research should explore alternative excipients that can provide similar benefits without contributing to drug product instability.

Acknowledgements: No conflict of interest was stated in this poster presentation. The study included is solely sponsored by Blueprint Medicines.

Figure 1: Graphical abstract on “Role of Citric Acid in Enhancing Drug Performance: A Double-Edged Sword?” depicting favorable (left; showing pH-independent exposure in preclinical species) and unfavorable performance (right; showing a reduction in the critical relative humidity in the physical mixture and ground tablet blend) of citric acid.

Figure 2: X-ray diffractogram of BLU-701 Free base and citrate form, placebo blend, Tablet blend (T=0, unexposed and T=2 week, tested at 40°C/75%RH open).