(T1430-08-53) Development of Rifaximin Soluble Solid Dispersion (SSD). III XRPD Method Development to Evaluate % Crystallinity and Amorphousness

Purpose: Rifaximin is a non-aminoglycoside, semi-synthetic, non-systemic antibiotic of the rifamycin class. It is a BCS class IV molecule with poor solubility and poor oral absorption. Currently Rifaximin is available as Xifaxan® - 200 mg and 550 mg tablets. Rifaximin in Xifaxan is present in its native crystalline form. In order to overcome the dissolution limiting local bioavailability of Rifaximin, amorphous rifaximin in form of a soluble solid dispersion (SSD) was developed. The purpose of the current study is to develop and validate a sensitive and differentiating Powder X-ray Diffraction (XRPD) method to characterize crystalline conversion of amorphous Rifaximin SSD.

Methods: To evaluate the % crystallinity and the amorphousness of the Rifaximin soluble solid dispersion (SSD), a PXRD method was developed using Rigaku X-ray diffractometer (XRD), Model MiniFlex, 6^th Generation equipped with SmartLab Studio II. Final PXRD conditions were set at: 40 kV 15 mA, 2θ up to 40°, step angle 0.02, scan speed 0.7, spin 10 rpm using Aluminum, 2 mm depth sample holder. Rifaximin SSD samples spiked with crystalline Rifaximin α form 2.5-20% were prepared and evaluated in this study. These sample blends were transferred into sample holder using a glass slide to flatten the sample onto the holder and were analyzed using parameters mentioned above. Each sample along with 100% crystalline Rifaximin powder were quantified for intensity and a linearity curve was established. The method was further validated as per ICH Q2 guideline (1) and USP general chapter < 941 > (2) for monitoring crystallization during shelf life of SSD powder.

Results: PXRD is in general a semi-quantitative method due to inherent technological limitations. In this study, we report a systematic approach to increase the sensitivity of the method including change in voltage and current along with changing sample preparation and scan speed change to optimize a sensitive and reproducible method. PXRD diffractograms of powder with different level of % crystallinity is presented in Figure 1. To evaluate the sensitivity of the method, intensity at θ/2θ° of each blend at different % crystallinity was plotted, and linear regression analysis was performed (Figure 2). As observed in Figure 2, using optimized XRPD method, detectable limits of % crystallinity in Rifaximin SSD powder was estimated to go as low as 2.5% w/w.

Conclusion: A sensitive PXRD method was developed to detect and quantify crystalline Rifaximin in amorphous Rifaximin SSD powder.. PXRD method was further validated as per ICH guideline ICH Q2 and USP general chapter USP < 941 > to evaluate percent crystalline Rifaximin in the SSD during stability. The method was found to be robust, linear with R² more than 0.99.

References: 1. ICH G2 Guideline
2. USP General Chapter

Acknowledgements: SR, SMM, SK, TW are employed by Bausch Health USA.

Figure 1: PXRD diffractograms of Rifaximin SSD powder with different levels of crystallinity (spiked samples).

Figure 2: Linearity of Rifaximin crystalline alpha form (Spiked into Rifaximin SSD powder)