Dabigatran etexilate mesylate is polymorphic and can exist in different crystalline forms. Two polymorphs have been encountered during the development of this drug substance, namely anhydrous form I and anhydrous form II. Additionally, a hemihydrate was observed, if larger amounts of water were present during crystallization in the salt formation step. Finally, a high temperature form III can be obtained by heating anhydrous form I above 150 °C. All three at room-temperature accessible forms were characterized by means of microscopy, X-ray powder diffraction, thermal analysis, IR- and Raman spectroscopy. In addition, solubility parameters (equilibrium solubility and intrinsic dissolution rate, heat of solution) were collected on all three forms. The crystal structure of all three at room-temperature accessible forms could be obtained using electron diffraction. Anhydrous form I has a monoclinic crystal lattice (C2/c), anhydrous form II a triclinic one (P1¯), and the hemihydrate crystallizes also in a monoclinic space group (P2/c). From the obtained data there is clear evidence that anhydrous form II is thermodynamically more stable than anhydrous form I. Form I and form II are monotropically related to each other indicating that they may coexist over a wide temperature range. The hemihydrate is a completely independent crystalline modification of dabigatran etexilate mesylate. It is another thermodynamically stable form and structurally not related to the two anhydrous forms. The hemihydrate melts at ca. 125 °C, there is no conversion to either anhydrous form I or form II upon dehydration. The high temperature form III is enantiotropically related to form I and only stable above the phase transition temperature at ca. 150 °C and its melting point at ca. 183 °C. The energy difference between anhydrous form I and form II was found to be only 2.5 - 3.0 J/g. Both forms have very similar aqueous solubility characteristics. Although anhydrous form II is the thermodynamically more stable form, anhydrous form I was chosen for development. The selection of form I for development was mainly based on the superior bulk processing properties of anhydrous form I in drug substance synthesis and further drug product processing as well as its slightly better chemically stability in pivotal long term stability studies. Anhydrous form I, although meta stable, is still stable enough that conversion to the more stable form II can occur only to a limited extent during drug substance synthesis and drug product manufacturing. From long term stability data on both bulk drug substance as well as drug product, there is no indication that form I transforms to form II during storage. Even under stress conditions where form I was stored up to 4 weeks at 70 °C, no conversion to form II was observed.
Keywords: Crystal structure analysis; Electron diffraction; Metastable form; Physicochemical properties; Polymorphism; Solubility; Stability.
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