Process for preparing spray dried formulations of 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile
View Patent ↗This invention relates to a process for producing a spray-dried powder comprising microcrystalline cellulose in a solid dispersion of the anti-HIV compound etravirine (TMC125) in a water-soluble polymer.
1. A process for producing a solid pharmaceutical powder, comprising the steps of:
(a) providing a feed mixture of microcrystalline cellulose (MCC) and a solution of hydroxypropylmethyl cellulose (HPMC) and 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile (TMC 125), or a pharmaceutically acceptable acid addition salt thereof, in a solvent; wherein the weight ratio of MCC:HPMC:TMC 125 is 0.5:3:1; and
(b) spray-drying the feed mixture from step (a) by introducing the feed mixture as droplets into a spray-drying chamber via an atomizing means to form a solid dispersion of amorphous 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile or a pharmaceutically acceptable acid addition salt thereof, the hydroxypropylmethyl cellulose, and the microcrystalline cellulose;
wherein the solid dispersion has a density of about 0.1 to 0.7 g/ml.
2. The process of claim 1 , wherein 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile base is used.
3. The process of claim 1 , wherein the microcrystalline cellulose has an average particle size of 5-50 μm.
4. The process of claim 1 , wherein the microcrystalline cellulose has an average particle size of 10-30 μm.
5. The process of claim 1 wherein the microcrystalline cellulose has an average particle size of 20 μm.
6. The process of claim 1 , wherein the solvent is selected from the group consisting of acetone, dichloromethane, ethanol, methanol and combinations thereof.
7. The process of claim 1 , wherein the atomizing means comprises a high-pressure nozzle.
8. The process of claim 1 , wherein the 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile, or a pharmaceutically acceptable acid addition salt thereof, in the solid dispersion has a crystallinity of about 10% or less, as characterized by X-ray powder diffraction.
9. The process of claim 1 , wherein the atomizing pressure of the spray drying step is about 40 bar.