Amorphous [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid
Publication Date: 2009-Jul-06
The IP.com Prior Art Database
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
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.
Figure 1. A differential scanning calorimetry thermogram of amorphous BZB.
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
The DSC analysis was carried out under the experimental conditions detailed in Table 1.
Table 1. Differential scanning calorimetry experimental conditions
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
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
Generator PW3040; 45 kV, 40 mA
X-Ray tube PW3373/00; Cu anode LFF
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)
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...