Dabigatran Formulation for Oral Administration – an Evaluation

Dabigatran etexilate mesylate is a pro-drug of Dabigatran – a BSC Class II drug used as anti-coagulant in deep vein thrombosis as a direct thrombin inhibitor. Due to increasing solubility in the acidic regime, tartaric acid pellets (TAP) are used as starter beads. A processed formulation is compared with the existing formulation from the innovator Boehringer Ingelheim Pharmaceuticals (Pradaxa, 150 mg). Experimental findings in this note have been first conducted and published by Balaji et al..

Motivation for Dabigatran
The apparent partition coefficient of the neutral form (free base) of Dabigatran etexilate mesylate is log­ P = 3.8, and the dissociation constants are pKa1 = 4.0 ± 0.1 (Benzimidazole moiety) pKa2 = 6.7 ± 0.1 (Carbamic Acid Hexyl Ester moiety). The solubility of the API is a critical factor in pharmaceutical formulations and in case of Dabigatran depends strongly on the pH value. Thereby, the solubility is increasing at lower pH values: In pure water, the solubility of a saturated solution of the API is at 1.8 mg/ml. Additionally with the high intrinsic passive permeability of the API, Dabigatran etexilate mesylate is classified as a BCS class II drug substance according to the Biopharmaceutical Classification System [2-6]. Obviously, an increase of local solubility is strongly requested and fulfilled by the use of Tartaric acid pellets in size from 600 µm to 800 µm.

Materials
Dabigatran etexilate mesylate (CAS number 593282-20-3 is used as active. TAP 500 and TAP 700 are used as functional starter beads. Further excipients are Povidone K-30, Hydroxypropyl cellulose (HPC), PEG 400, Isopropyl alcohol (IPA), Opadry white, Sodium laurilsulfate (SLS), Talc. Acetone and methanol are solvents for spray drying or dissolution tests. Layering and coating of pellets is performed by fluidized bed technology.

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