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Brincidofovir Polymorph

IP.com Disclosure Number: IPCOM000249394D
Publication Date: 2017-Feb-23

Publishing Venue

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Abstract

Present disclosure discloses novel Brincidofovir Polymorph and its Pre-mix

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Brincidofovir, (S)-[2-(4-amino-2-oxo-1,2-dihydro-1-pyrimidinyl)-1-(hydroxymethyl) ethoxy]methylphosphonic acid 3-(hexadecyloxy)propyl monoester, having the structure shown in Formula-I, is an antiviral drug.

United States Pat. No.  US 6716825 discloses brincidofovir and process for the preparation of same. US 8569321and US 8962829 discloses crystalline forms of brincidofovir.

The present disclosure provides Brincidofovir polymorphic form M1, and processes for the preparation of same.

The polymorphic form M1 was characterized by X-ray powder diffraction patterns.  Thus, X-ray diffraction pattern of polymorphic form M1 was measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/2θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2θ range of 2.0º-50.0°, 0.030° step size and 50 seconds step time.

The brincidofovir polymorphic form M1 was characterized by a powder X-ray diffraction pattern having significant peaks at 2.39, 4.63 and 21.18 ± 0.2° 2-theta   

                                                                                                                      

The polymorphic form M1 of the brincidofovir was further characterized by differential scanning calorimetry (DSC).  The DSC measurement was carried out on a TA Q1000 of TA Instruments.  The experiment was performed at a heating rate of 10.0 °C/min over a temperature range of 30-250 °C purging with nitrogen at a flow rate of 50 ml/min.  Standard aluminum crucibles covered by lids with pin holes were used. 

The polymorph of the present disclosure can be characterized by thermogravimetric analysis (TGA) or differential thermal analysis (DTA).  TGA/DTA was recorded using a TA Q5000 of TA Instruments.  The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30 °C-300 °C purging with nitrogen at a flow rate of 25 ml/min.  The brincidofovir polymorphic form M1 characterized by a TGA/DTA thermal curve as depicted below in Figure 3.

The present disclosure provides a process for the preparation of brincidofovir polymorphic form M1 comprising the steps of:

a)      dissolving brincidofovir in a solvent, and

b)      removing the solvent to isolate brincidofovir crystalline form M1.

brincidofovir was dissolved in a solvent.  The solvent for dissolving brincidofovir is an alcohol solvent or a chlorinated solvent or ethereal solvent, or mixtures thereof.  Examples of suitable alcohol solvents include methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol, and mixtures thereof. Examples of suitable chlorinated solvents include dichloromethane, dichloroethane, and mixtures thereof. Examples of ethereal solvents include tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, anisole and mixtures thereof.

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