Forms of bendamustine free base

#This invention pertains to bendamustine free base-containing compositions, pharmaceutical compositions comprising bendamustine free base, processes to reproducibly make them, and methods of treating patients using them.

#Active pharmaceutical ingredients (APIs) can be prepared in a variety of different forms, for example, chemical derivatives, solvates, hydrates, co-crystals, or salts. APIs may also be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states. By varying the form of an API, it is possible to vary the physical properties thereof. For instance, crystalline polymorphs typically have different solubilities such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical and pharmacological properties thereof.

#Bendamustine, 4-{5-[Bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid:

#FIG. 1 is an X-Ray Powder Diffractogram (XRPD) spectrum of bendamustine free base Form 1.

#FIG. 1A Differential Scanning Calorimetry/Thermogravimetric Analysis (DSC/TGA) Overlay Data for Form 1.

#FIG. 2 is an XRPD spectrum of bendamustine free base Form 2.

#Stable forms of bendamustine free base have now been discovered. Six polymorphic forms of anhydrous bendamustine free base are described herein (Form 1, Form 2, Form 4, Form 6, Form 7, Form 10), as well as four hydrate forms (Form 3, Form 5, Form 13, Form 14) and four solvate forms of bendamustine free base (Form 8, Form 9, Form 11, Form 12, Form 15). Amorphous bendamustine free base is also within the scope of the present invention.

#In preferred embodiments are crystalline forms of bendamustine free base that are Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, Form 12, Form 13, Form 14, Form 15, or mixtures thereof. These polymorphs may be identified by X-ray powder diffraction and characterized by one, two, three, four, five or more reflection peaks that are characteristic of each polymorphic form. The 15 crystalline polymorphs (Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, Form 12, Form 13, Form 14, Form 15) can also be identified by reference to their X-ray powder diffractograms (XRPD), Differential Scanning Calorimetry (DSC) thermograms, Thermogravimetric Analysis (TGA) thermograms, and/or Gravimetric Vapor Sorption (GVS) traces, which are set forth in FIGS. 1-29. Methods of making each polymorph, or a mixture of polymorphs, can be preformed using the techniques described herein.

#In another embodiment of the invention are pharmaceutical compositions comprising Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, Form 12, Form 13, Form 14, Form 15, or mixtures thereof, of bendamustine free base. In other embodiments of the invention are pharmaceutical compositions comprising one or more of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, Form 12, Form 13, Form 14, or Form 15 with amorphous (i.e., non-crystalline) bendamustine.