The present invention provides a method of drying nelfinavir mesylate.
Nelfinavir is chemically [3S-[2(2S*,3S*),3a,4ap,8ap]]-/V-(1,1-
dimethylethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinoline carboxamide. It is commercially available in the form of its mono-methanesulfonate of Formula I.
Nelfinavir mesylate, in combination with other antiretroviral agents, is indicated for the treatment of HIV infection. Nelfinavir is a member of the group of drugs referred to as protease inhibitors (Pis). This class of drug combats viral replication of HIV by blocking HIV protease. This enzyme is used by HIV to break up large viral proteins into smaller particles from which new HIV particles can be formed. Protease inhibitors ensure that these new particles are immature and incapable of infecting new cells, thus inhibiting the HIV replication process.
Nelfinavir mesylate is marketed as a white to off-white amorphous powder. US Patent No 5,484,926 discloses a process for the preparation of amorphous nelfinavir mesylate, wherein the process involves cooling a suspension of nelfinavir mesylate in a freezer, followed by filtration at cold temperature and drying in a vacuum oven.
US Patent No 6,303,786 provides a process for drying nelfinavir mesylate by spray drying, wherein the process involves pumping an alcoholic solution of nelfinavir mesylate into a Nitro Atomizer Portable Spray Dryer, which utilizes vane, co-current
flow or countercurrent flow atomizer, and collecting the spray dried product. The 786 patent discloses another method of drying nelfinavir mesylate, wherein the method involves drying a solid nelfinavir mesylate in rotocone drier under vacuum at 60°-65°C for 12-72 h. The drying process is accelerated in this method by milling the drier contents in a Fitzmill grinder.
The present inventors have developed a novel method for drying nelfinavir mesylate by using agitated thin film dryer (ATFD). The present process provides dry free flowing nelfinavir mesylate in a single pass as a one-step process. The present process also eliminates thermal degradation of the product due to low residence time and indirect contact drying. The ATFD process also consumes comparatively low energy and thus improves process economics. The present process also provides nelfinavir mesylate in amorphous form.
The term "feeding" of the present invention includes loading, dozing, introducing, charging, filling, supplying, passing, pouring or heaping. The term "collecting" of the present invention includes unloading, amassing, gathering, scaling or piling.
A first aspect of the present invention provides a method of drying nelfinavir mesylate, wherein the said method comprises,
a) feeding a solution or a slurry of nelfinavir mesylate into an agitated thin film dryer
(ATFD),
b) drying the fed nelfinavir mesylate by agitated thin film drying, and
c) collecting dry nelfinavir mesylate from the agitated thin film dryer (ATFD).
A solution or slurry of nelfinavir mesylate is prepared by mixing nelfinavir mesylate with water or water miscible organic solvent or mixtures thereof. The water miscible organic solvent is selected from a group comprising of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and acetonitrile. A solution or slurry of nelfinavir mesylate can also be obtained by contacting nelfinavir with methane sulfonic acid in the presence of water or water miscible organic solvent or mixtures thereof.
The solution or slurry of nelfinavir mesylate is fed into an agitated thin film dryer (ATFD). A dozing pump can be used for feeding the solution or slurry. The temperature of the ATFD jacket, feed rate, temperature of the condenser and speed of the ATFD rotor can be adjusted to optimize the output and particle size distribution.
The temperature of the jacket can be controlled by the circulation of hot water, steam or hot oil, and preferably maintained between about 60°C and 120°C. The temperature of the condenser can be controlled by the circulation of cold water or brine solution and preferably maintained between about -20°C and 20°C. The feed rate is set between about 10 ml/minute and 100 ml/minute. The set feed rate is preferably constant for the whole process. The speed of the rotor can be set between about 500 and 2500 revolutions per minute. The drying process is accompanied by the application of vacuum. The drying process is carried out for sufficient time to effect maximum removal of the solvents. The dried nelfinavir mesylate is collected at the powder collection point as an amorphous solid.
Figure 1 depicts XRPD of nelfinavir mesylate prepared by agitated thin film drying.
The drying was carried out using an agitated thin film dryer having the following specifications: Heat transfer area: 0.05 m2; MOC: SS-316; Agitator Type: Fixed clearance agitator; Agitator RPM: 1400; Feed Pump: Multi-flow dosing pump with variable frequency drive (capacity: 0-30 L/h); Vacuum Pump: Oil ring pump (Evacuation capacity: 16 m3/h; Vacuum rating: 1 Torr); Condenser: Single pass shell and tube heat exchanger (MOC: SS).
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
PREPARATION OF NELFINAVIR MESYLATE:
The feed was prepared by dissolving crude nelfinavir mesylate (300 g) in methanol (750 ml) at 25°-30°C. The rotor of the agitated thin film dryer was started and
vacuum was supplied using an oil ring vacuum pump, which was regulated by a
pinchcock. The feed was introduced at uniform rate into the agitated thin film dryer
by means of a dozing pump. The agitated thin film dryer was set with the following
settings:
Temperature of hot water circulating in the ATFD jacket: 85°-90°C
Temperature of cold water circulating in the condenser: 8°-10°C
Feed rate: 40 ml/minute
After feeding the entire solution into the dryer, methanol (50 ml) was introduced into
the dryer. After introducing methanol completely into the dryer, the feed pump was
stopped and the sample feed valve was closed. The vacuum was vented slowly by
using the pinchcock. The ATFD rotor was subsequently stopped and the title
compound was unloaded from the powder collector as an off-white amorphous
powder.
Yield: 114.1 g

WE CLAIM:
1. A method of drying nelfinavir mesylate, wherein the said method comprises,
a) feeding a solution or a slurry of nelfinavir mesylate into an agitated thin film
dryer (ATFD),
b) drying the fed nelfinavir mesylate by agitated thin film drying, and
c) collecting dry nelfinavir mesylate from the agitated thin film dryer.

2. A method as claimed in claim 1, wherein the solution or the slurry of nelfinavir
mesylate is obtained by mixing nelfinavir mesylate with water or water miscible
organic solvents or mixtures thereof.
3. A method as claimed in claim 1, wherein the solution or the slurry of nelfinavir
mesylate is obtained by contacting nelfinavir with methane sulfonic acid in the
presence of water or water miscible organic solvent or mixtures thereof.
4. A method as claimed in claims 2 and 3, wherein the water miscible organic solvent
is selected from a group comprising of methanol, ethanol, isopropanol, acetone,
tetrahydrofuran and acetonitrile.
5. A method as claimed in claim 1, wherein the feed rate is controlled between about
10 ml/minute and 100 ml/minute.
6. A method as claimed in claim 5, wherein the feed rate is maintained constant for
the whole process.
7. A method as claimed in claim 1, wherein the temperature of the ATFD jacket is
maintained between about 60°C and 120°C.
8. A method as claimed in claim 1, wherein the temperature of the ATFD condenser
is maintained between about -20°C and 20°C.

9. A method as claimed in claim 1, wherein the drying is accompanied by the
application of vacuum.
10. A method as claimed in claim 1, wherein the nelfinavir mesylate is collected at
step c) as an amorphous powder.