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Amorphous [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid Disclosure Number: IPCOM000184949D
Publication Date: 2009-Jul-06

Publishing Venue

The Prior Art Database

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  Amorphous [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2- [(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid

[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid ("BZB") of Formula I

Formula I

is an anti-neoplastic proteasome inhibitor.

    BZB is marketed under the name Velcade® by Millenium Pharmaceuticals Inc. It is used for the treatment of multiple myeloma and/or mantle cell lymphoma in patients who have received at least one prior therapy.

    Amorhphous BZB is characterized by differential scanning calorimetry thermogram depicted in Figure 1 and by the X-ray powder diffraction pattern depicted in Figure 2.


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Figure 1. A differential scanning calorimetry thermogram of amorphous BZB.

DSC /(mW/mg)








50.0 100.0 150.0 200.0 Temperature /°C

Figure 2. An X-ray powder diffraction pattern of amorphous BZB.









5 10 15 20 25 30 35

2Theta (°)


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The DSC analysis was carried out under the experimental conditions detailed in Table 1.
Table 1. Differential scanning calorimetry experimental conditions

Sample preparation

Samples (1-3 mg), after being powdered in a

mortar and pestle, are sealed in a 25 μl

aluminum pan with holes in the lid.

Instrument DSC 204 F1 NETZSCH Atmosphere Nitrogen

Range 30/10(°C/min)/320

X-ray powder diffraction analysis was carried out on a Philips X'Pert PRO diffractometer using CuKα1 radiation under the conditions detailed in Table 2. The standard error for peak positions obtained on this system is ±0.2°θ.

     Table 2. X-ray powder diffraction experimental conditions Sample holder


Samples after being powdered in a mortar and

pestle are applied directly on silicon

PW1817/32 "zero background" holder

Instrument Philips X'Pert PRO

Goniometer PW3050/60

Generator PW3040; 45 kV, 40 mA

X-Ray tube PW3373/00; Cu anode LFF

Focus Linear

Sample stage PW3072/60 or PW3064

Scan angle range (2Θ) 3 - 40º

Scan mode Continuous absolute scan

Step size (2Θ) 0.017º

Time per step 100 seconds

X-ray radiation λ(CuKα1) = 1.540598 Å

Primary soller slit 0.04 rad

PDS Fixed, divergence 1/2°

Primary mask 10 mm

Secondary soller slit 0.04 rad

Monochromator Inc. Beam α1 Cu/Co for reflection mode

Detector X'Celerator (2.022º 2Θ)

Control program X'Pert Data Collector

    Amorphous BZB can be prepared according to the following process: (a) drying a solution of BZB in a halocarbon solvent over a drying agent; (b) recovering the dried BZB; (c)


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dissolving the dried BZB in an ester solvent using ultrasound; and (d) precipitating amorphous BZB from the ester solvent by adding a sufficient amount of ether solvent to the ester solvent.

    The halocarbon solvent can be dichloromethane, chloroform, carbontetrachloride...