(M1330-09-59) Development of Rifaximin Soluble Solid Dispersion (SSD): I. Solubility and Dissolution Advantage Over Commercially Available Xifaxan 550 mg Tablet

Purpose: Rifaximin is a non-aminoglycoside, semi-synthetic, non-systemic antibiotic of the rifamycin class. It is a BCS class IV molecules with poor solubility and poor absorption. Currently Rifaximin is available as Xifaxan® - 200 mg and 550 mg tablet and approved for the treatment of traveler's diarrhea caused by noninvasive strains of E. Coli, irritable bowel syndrome and/or reduction in risk of overt hepatic encephalopathy. Rifaximin in Xifaxan is present in its native crystalline form. To overcome the dissolution limiting local bioavailability of Rifaximin, amorphous rifaximin in form of soluble solid dispersion (SSD) was developed. Preliminary screening was conducted by spray drying Rifaximin with different commonly used carrier polymers at different ratios. Rifaximin SSD powder with better ability to maintain supersaturation for longer period of time was selected as the most optimum formulation. The purpose of the current study is to evaluate the solubility and dissolution advantage of amorphous rifaximin SSD over crystalline Rifaximin.

Methods: A comparative evaluation of equilibrium solubility for 24 hours of optimized Rifaximin SSD powder was made with crystalline Rifaximin in 250 mL of different pH media (pH 1.2, 4.5, 6.8, 7.4, FeSSIF V2) using shake flask method (1). To evaluate differentiation in dissolution profile, comparative dissolution study of Xifaxan 550 mg and Rifaximin SSD IR Tablets, 40 mg was performed in 4 different dissolution media (pH 1.2, pH 4.5, FeSSIF V2 (pH 5.8) and pH 7.4; 500 mL, 37°C, USP Apparatus II, 75 RPM). To simulate transition of dosage form from stomach to small intestine and to colon and their residence time, three stage dissolution (1 hour in pH 1.2, 6 hours in pH 5.8 and up to 24 hours in pH 7.4) was conducted. For each dissolution run, six tablets (N=6) of both the formulations were evaluated and % drug release along with concentration of Rifaximin released in µg/mL were reported.

Results: From equilibrium solubility study it was found that Rifaximin SSD powder was able to maintain supersaturation for at least 24 hours. Rifaximin SSD powder showed 2 to 94-fold higher solubility compared to crystalline Rifaximin in the pH range of 1.2 to 7.4. Moreover, the solubility of Rifaximin SSD powder was found to be at least 465-fold over crystalline Rifaximin in FeSSIF V2 media (pH 5.8). Rifaximin SSD IR tablet, 40 mg showed 3 to 19-fold higher dissolution/Rifaximin released compared to Xifaxan 550 mg tablet despite significantly smaller dose of 40 mg (Figure 1). Further, three stage dissolution study mimicking transition of dosage form from stomach-intestine-colon also confirmed a significantly higher dissolution (3 to 7-fold in stage II and III) of Rifaximin from SSD IR tablet 40 mg, when compared to Xifaxan 550 mg tablet (Figure 2).

Conclusion: The present study confirms distinct solubility and dissolution advantage of Rifaximin SSD over crystalline form. The dissolution advantage of Rifaximin SSD IR tablet was further confirmed using three stage dissolution which mimics the residence time and pH changed likely to be encountered during GI transit of the dosage from stomach to colon. Thus, despite significantly lower dose, by virtue of Rifaximin in amorphous form, Rifaximin SSD IR tablet 40 mg is expected to provide higher local bioavailability compared to Xifaxan 550 mg tablet.

References: Biopharmaceutics Classification System-Based Biowaivers M9, ICH guidelines 2019

Acknowledgements: SMM, SK, EP and AA are employed by Bausch Health USA.

Figure 1: Comparative dissolution profile of Xifaxan 550 mg tablet vs. Rifaximin SSD IR tablet 40 mg in pH 1.2, 4.5, FeSSIF V2 (pH 5.8) and pH 7.4.

Figure 2: Three stage dissolution study of Xifaxan 550 mg tablet vs. Rifaximin SSD IR tablet 40 mg. Stage I dissolution was conducted with 250 mL of pH 1.2 media for 1 hour followed by adjusting the pH to 5.8 for 6 hours (stage II) and pH 7.4 (Stage III) for next 24 hours. For pH 5.8 and pH 7.4, 900 mL volume of media was used.