STABLE AMOURPHOUS VALGANCICLOVIR HYDROCHLORIDE
Field of the Invention
The present invention relates to stable amorphous valganciclovir hydrochloride and process for the preparation of the same.
Background of the Invention
The L-valinate ester of 2- (2-amino-1, 6-dihydro-6-oxo-purin-9-yl) -methoxy-3-hydroxy-1-propanyl hydrochloride salt commonly known as Valganciclovir hydrochloride of Formula I, is the mono-L-valyl ester prodrug of the antiviral compound ganciclovir.
(Formula Removed)
NH
Ganciclovir is disclosed in U. S. Patent No. 4,355,032. Ganciclovir inhibits replication of human cytomegalovirus in vitro and in vivo, and is effective against viruses of the herpes family, for example, against herpes simplex and cytomegalovirus.
Ganciclovir is mostly used as an intravenous infusion, as it has a very low rate of absorption when administered orally.
Various mono and diacyl esters of ganciclovir are disclosed in J. Pharm. Sci. 76 (2),p. 180-184 (1987). The preparation of these esters is also mentioned in this article..
European Patent No. 375329 discloses diester prodrugs of ganciclovir and physiologically acceptable salts thereof having improved bioavailability when administered by an oral route.

U. S. Patent Nos. 5,856,481; 5,840,890; 6,103,901; 5,700,936; 5,756,736 and 6,040,446 describe processes for the preparation of mono L-valyl ester of ganciclovir (valganciclovir) and pharmaceutical compositions containing it. These references
T
provide various protecting groups and a methodology to prepare selectively mono L-valyl ester of ganciclovir. These processes provide crystalline valganciclovir hydrochloride.
U. S. Patent No. 6,083,953 provides a process for preparing crystalline valganciclovir hydrochloride.
Our co-pending application PCT/IB/2004/002789 published as WO2005/021549 discloses amorphous valganciclovir hydrochloride. Also disclosed is the process for the preparation of valganciclovir hydrochloride from ganciclovir in which valganciclovir hydrochloride is recovered in amorphous form from the reaction mixture itself. Amorphous valganciclovir hydrochloride has also been prepared from its crystalline form by spray drying. For the purpose of spray drying, mini-spray dryer system utilizing pressure nozzle atomizer has been used. However, later it was found that the amorphous valganciclovir hydrochloride as obtained by spray dryer fitted with a pressure nozzle spray showed conversion to crystalline form over the time on storage as well as when present in the dosage form. Such a conversion is undesirable as bioavailability would be influenced by differences in the solubility of the amorphous and crystalline valganciclovir hydrochloride. Also, differences in the bulk density and particle size of the amorphous and crystalline valganciclovir hydrochloride in the bulk may cause problems like content uniformity in dosage forms.
Thus, it would be advantageous to prepare stable amorphous valganciclovir hydrochloride, which is does not convert into its crystalline form when stored at ambient conditions of temperature and stability or formulated into a dosage form.
As mentioned earlier, WO 2005/021549 discloses spray drying an aqueous solution of valganciclovir hydrochloride using pressure nozzle type of atomizer to obtain

valganciclovir hydrochloride in amorphous form. However, it does not suggest or disclose that using a rotary type of atomizer would give stable amorphous valganciclovir hydrochloride.
Summary of the Invention
In one general aspect it relates to amorphous valganciclovir hydrochloride free of crystalline valganciclovir hydrochloride.
In another general aspect, it relates to stable amorphous valganciclovir hydrochloride wherein the amorphous valganciclovir hydrochloride does not convert to crystalline form when stored for one month at 40 °C and 75% relative humidity.
In another general aspect, it relates to a pharmaceutical composition comprising stable amorphous valganciclovir hydrochloride free of crystalline valganciclovir hydrochloride and a pharmaceutically acceptable carrier.
In one general aspect, it relates to a process for the preparation of amorphous valganciclovir hydrochloride wherein the process comprises spray drying a solution of valganciclovir hydrochloride in a spray drying system fitted with a rotary atomizer.
In another general aspect, it relates to a process for the preparation of amorphous valganciclovir hydrochloride wherein the process comprises spray drying a solution of valganciclovir hydrochloride in a spray drying system fitted with a rotary atomizer and the rotary atomizer speed is between 45 Hertz to 75 Hertz.
In another general aspect, it relates to a process for the preparation of amorphous valganciclovir hydrochloride wherein the process comprises spray drying a solution of valganciclovir hydrochloride in a spray drying system fitted with a rotary atomizer and drying gas inlet temperature is between 135°C to 160°C and drying gas outlet temperature is between 80°C to110°C.

In another general aspect, it relates to a process for the preparation of amorphous valganciclovir hydrochloride wherein the process comprises spray drying a solution of valganciclovir hydrochloride in a spray drying system fitted with a rotary atomizer and the rotary atomizer speed is between 45 Hertz to 75 Hertz and drying gas inlet temperature is between 135°C to 160°C and drying gas outlet temperature is between 80°Cto110°C.
In another general aspect, it relates to a process for the preparation of amorphous valganciclovir hydrochloride wherein the process comprises spray drying a solution of valganciclovir hydrochloride in a spray drying system fitted with a rotary atomizer and the rotary atomizer speed is between 45 Hertz to 75Hertz and drying gas inlet temperature is between 135°C to 160°C and drying gas outlet temperature is between 80°C to110°C and the spray drying system is an open spray drying system.
In another general aspect, it relates to a process for the preparation of amorphous valganciclovir hydrochloride wherein the process comprises spray drying a solution of valganciclovir hydrochloride in a spray drying system fitted with a rotary atomizer and the rotary atomizer speed is between 45 Hertz to 75Hertz and drying gas inlet temperature is between 135°C to 160°C and drying gas outlet temperature is between 80°C to110°C and the spray drying system is a closed spray drying system.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Brief Description of the Drawings
Figure 1 is an X-ray diffraction pattern of valganciclovir hydrochloride prepared as per the process of example 1.

Figure 2 is an X-ray diffraction pattern of valganciclovir hydrochloride prepared as per the process of example 2.
Figure 3 is an X-ray diffraction pattern of valganciclovir hydrochloride prepared as per the process of example 3.
Figure 4 is an X-ray diffraction pattern of valganciclovir hydrochloride prepared as per the process of example 4.
Figure 5 is an X-ray diffraction pattern of valganciclovir hydrochloride prepared as per the process of example 5.
Detailed description of the Invention
The term "stable" means that the amorphous valganciclovir hydrochloride as obtained by the processes described herein does not convert to a crystalline form detectable by XRD investigations having a limit of detection of 0.5% when stored under controlled conditions of temperature and humidity.
The term "free of crystalline valganciclovir hydrochloride" means that the amorphous valganciclovir hydrochloride described herein does not have any detectable crystalline valganciclovir hydrochloride present, based on XRD investigations having a limit of detection of 0.5%.
Spray drying is a commonly used technique in the preparation of amorphous materials. Spray drying of a solid dissolved in a solvent generally involves three basic steps, the atomization of solution into a spray of fine droplets which are contacted with a heated gas stream which removes the solvent and solid is obtained in essentially the same size as atomized fine droplet. Finally, the dried powder is separated from the gas stream and collected. The nature of the spray dried material i.e. the shape of the particles, bulk

density is influenced by parameters like the type of atomizer, the temperature of the heated gas stream and the time of contact between the fine droplets and gas stream.
The atomizer plays an important part in the spray drying process as it increases the surface area of the solution by breaking it into fine droplets from which rapid evaporation of the solvent takes place. There are three types of atomizers commonly used in the spray drying technology, namely, rotary atomizer, pressure-nozzle atomizer and two fluid pneumatic atomizer. In a pressure nozzle atomizer a spray is created by forcing the solvent feed through an orifice while the two-fluid nozzle atomization produces spray by contacting two fluids, the solvent feed and a compressed gas, usually air. The atomization energy is provided by the compressed gas and the contact between the two can be internal or external to the nozzle. The present invention uses rotary atomizer.
A rotary atomizer uses a rotating wheel on which the solution containing the solid is spread as a thin film, which is sheared into fine droplets under the influence of centrifugal forces. A spray drying system fitted with a rotary atomizer uses a drying chamber with a large diameter such that particles dry completely before hitting the drying chamber walls. The dried particle size can be varied by changing the speed of the atomizer. A large diameter wheel running at fixed speed would give finer particles and at same speed a smaller diameter wheel would give larger particles. Generally particles of less than 100um are obtained with rotary atomizer. The rotating speed of the rotary atomizer may be between 45 Hertz to 75 Hertz; particularly between 45 Hertz to 60 Hertz. The rotary atomizers are available from, for example from Niro Inc., USA and APVAnhydro, Denmark.
A typical spray drying procedure would involve preparing a solution of the valganciclovir hydrochloride in a suitable solvent, filtering and charging the filtered solution in a charging vessel from which the filtered solution is forced through the rotary atomizer to make fine droplets, which are dried in the drying chamber with circulating, heated drying

gas. The amorphous valganciclovir hydrochloride is collected as fine powder in the cyclone separator.
The solvent may be water and organic solvents like methanol, ethanol, isopropanol, n-butanol, acetone, isopropanol, tetrahydrofuran, cyclohexane, n-hexane, ethyl acetate, diethyl ether and diisopropyl ether and mixtures thereof. Generally the concentration of valganciclovir hydrochloride in the solution may vary from about 5% to about 50%, particularly from about 5% to about 40%.
The drying gas can be air or inert gases such as nitrogen, argon or carbon dioxide. Nitrogen has been used in some examples. The drying gas inlet temperature may be between 135°C to 160 °C; particularly it may be between 140°C to 150°C. The drying gas outlet temperature may be between 80°C to 110°C; particularly it may be between 80°C to 100°C. The flow rate of the solution from the atomizer may vary from 1.0 litres/hour to about 20 litres/hour.
There are various types of spray drying systems available such as open spray drying system, closed spray drying system and semi-closed spray drying system. In an open spray drying system the air is allowed to escape into atmosphere once the dried product is separated. The closed spray drying system features drying in an inert gas atmosphere such as nitrogen or carbon dioxide, which recycles within the dryer, and the semi-closed spray drying system featuring either the partial recycle mode (recycle of upto 60% of the exhaust air as inlet air to the dryer). These spray dryers are available from, for example, Alfa Laval India Ltd and Niro Inc. USA.
In one embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with a rotary atomizer and isolating the amorphous valganciclovir hydrochloride.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with a rotary

atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with a rotary atomizer and isolating the amorphous valganciclovir hydrochloride wherein the spray drying system is an open spray drying system.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with a rotary atomizer and isolating the amorphous valganciclovir hydrochloride wherein the spray drying system is a closed spray drying system.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with a rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the spray drying system is an open spray drying system.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in deionised water to form solvent feed; drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the spray drying system is a closed spray drying system.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the drying gas inlet temperature is between 140°C to 150°C and drying gas outlet temperature is between 80°C to100°C and the spray drying system is an open spray drying system.

In another embodiment, crystalline valganciclovir hydrochloride is dissolved in deionised water to form solvent feed, drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the drying gas inlet temperature is between 140°C to 150°C and drying gas outlet temperature is between 80°C to100°C and the spray drying system is an open spray drying system.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the drying gas inlet temperature is between 140°C to 150°C and drying gas outlet temperature is between 80°C to100°C and the spray drying system is a closed spray drying system.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in deionised water to form solvent feed, drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the drying gas inlet temperature is between 140°C to 150°C and drying gas outlet temperature is between 80°C to100°C and the spray drying system is a closed spray drying system.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the drying gas inlet temperature is between 144°C to 147°C and drying gas outlet temperature is between 88°C to 92°C and the spray drying system is an open spray drying system and the drying gas is air.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in deionised water to form solvent feed, drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous

valganciclovir hydrochloride wherein the drying gas inlet temperature is between 144°C to 147°C and drying gas outlet temperature is between 88°C to 92°C and the spray drying system is an open spray drying system and the drying gas is air.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in a solvent to form solvent feed, drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the drying gas inlet temperature is between 142°C to 147°C and drying gas outlet temperature is between 88°C to 92°C and the spray drying system is a closed spray drying system and the drying gas is nitrogen.
In another embodiment, crystalline valganciclovir hydrochloride is dissolved in deionised water to form solvent feed, drying the solvent feed in a spray drying system fitted with rotary atomizer rotating at speed of about 50 Hertz and isolating the amorphous valganciclovir hydrochloride wherein the drying gas inlet temperature is between 142°C to 147°C and drying gas outlet temperature is between 88°C to 92°C and the spray drying system is a closed spray drying system and the drying gas is nitrogen.
In one aspect of the invention, the amorphous valganciclovir hydrochloride prepared according to the embodiments given above may be used in the formulation of pharmaceutical dosage forms. Solid dosage forms include tablets, capsules and granules while liquid dosage forms include solutions and suspensions. The solid dosage forms may be prepared with customary pharmaceutically acceptable carriers like fillers, binders, disintegrants lubricant and glidants. The liquid dosage forms include solutions and suspensions. The liquid dosage forms may be prepared with customary pharmaceutically acceptable carriers like water, alcohols, sweeteners, preservatives and other substances known to the skilled in the art.
The following examples are illustrative of the invention, and are not intended to be construed as limiting the invention.

EXAMPLE 1
The spray drying system was open spray drying system supplied by Alfa Laval (I) Ltd.
The following parameters were maintained:
Inlet air temperature: 144-147 °C;
Outlet air temperature: 88-91 °C
Atomizer: Rotary type rotated at speed of 50 Hertz
Flow rate: 13-15 litres/hour
Crystalline valganciclovir hydrochloride (2.0 kg) was dissolved in deionised water (6 litres) and the solution was filtered through hyflo supercel bed in a sparkler filter. The hyflo supercel bed was washed with 2 litres of deionised water and the washing combined with the previously filtered solution. The solution was loaded into the charging vessel and then into spray chamber with peristaltic pump. The solution was atomized using rotary atomizer in the spray drying chamber and dried in presence of circulating hot air. The dried amorphous valganciclovir hydrochloride was collected in a receiver at cyclone separator. The yield was 1.72 kg (86%). The X-ray diffraction pattern did not show any crystallinity.
EXAMPLE 2
The spray drying system was open spray drying system supplied by Alfa Laval (I) Ltd.
The following parameters were maintained:
Inlet air temperature: 143-146 °C;
Outlet air temperature: 90-92°C
Atomizer: Rotary type rotated at speed of 50 Hertz
Flow rate: 13-15 litres/hour
Crystalline valganciclovir hydrochloride (2.0 kg) was dissolved in deionised water (6 litres) and the solution was filtered through hyflo supercel bed in a sparkler filer. The hyflo supercel bed was washed with 2 litres of deionised water and the washing combined with the previously filtered solution. The solution was loaded into the charging vessel and then into spray chamber with peristaltic pump. The solution was atomized

using rotary atomizer in the spray drying chamber and dried in presence of circulating hot air. The dried amorphous valganciclovir hydrochloride was collected in a receiver at cyclone separator. The yield was 1.65 kg (82.5%). The X-ray diffraction pattern did not show any crystallinity.
EXAMPLE 3
The spray drying system was open spray drying system supplied by Alfa Laval (I) Ltd.
The following parameters were maintained:
Inlet air temperature: 144-145 °C;
Outlet air temperature: 88-90°C
Atomizer: Rotary type rotated at speed of 50 Hertz
Flow rate: 13-15 litres/hour
Crystalline valganciclovir hydrochloride (3.5 kg) was dissolved in deionised water (10.5 litres) and the solution was filtered through hyflo supercel bed in a sparkler filer. The hyflo supercel bed was washed with 3.5 litres of deionised water and the washing combined with the previously filtered solution. The solution was loaded into the charging vessel and then into spray chamber with peristaltic pump. The solution was atomized using rotary atomizer in the spray drying chamber and dried in presence of circulating hot air. The dried amorphous valganciclovir hydrochloride was collected in a receiver at cyclone separator. The yield was 2.72 kg (77.7%). The X-ray diffraction pattern did not show any crystallinity.
EXAMPLE 4
The spray drying system was closed spray drying system supplied by Alfa Laval (I) Ltd.
The following parameters were maintained:
Inlet nitrogen temperature: 142-147 °C;
Outlet nitrogen temperature: 89-91 °C
Atomizer: Rotary type rotated at speed of 50 Hertz
Flow rate: litres/hour

Crystalline valganciclovir hydrochloride (3.0 kg) was dissolved in deionised water (9 litres) and the solution was filtered through hyflo supercel bed in a sparkler filer. The hyflo supercel bed was washed with 3.0 litres of deionised water and the washing combined with the previously filtered solution. The solution was loaded into the charging vessel and then into spray chamber with peristaltic pump. The solution was atomized using rotary atomizer in the spray drying chamber and dried in presence of circulating hot nitrogen gas. The dried amorphous valganciclovir hydrochloride was collected in a receiver at cyclone separator. The yield was 2.58 kg (86%). The X-ray diffraction pattern did not show any crystallinity.
EXAMPLE 5
The spray drying system was closed spray drying system supplied by Alfa Laval (I) Ltd.
The following parameters were maintained:
Inlet nitrogen temperature: 142-147 °C;
Outlet nitrogen temperature: 89-91 °C
Atomizer: Rotary type rotated at speed of 50 Hertz
Flow rate: jjjjg^jj^ |jtres/hour
Crystalline valganciclovir hydrochloride (9.0 kg) was dissolved in deionised water (27 litres) and the solution was filtered through hyflo supercel bed in a sparkler filer. The hyflo supercel bed was washed with 9.0 litres of deionised water and the washing combined with the previously filtered solution. The solution was loaded into the charging vessel and then into spray chamber with peristaltic pump. The solution was atomized using rotary atomizer in the spray drying chamber and dried in presence of circulating hot nitrogen gas. The dried amorphous valganciclovir hydrochloride was collected in a receiver at cyclone separator. The yield was 8.20 kg (91.1%). The X-ray diffraction pattern did not show any crystallinity.
The amorphous valganciclovir hydrochloride obtained form example 3 was stored under controlled conditions of temperature and humidity and was found to be stable. The results are given in Tables 1 and 2 below:

Table 1: Stability data of valganciclovir hydrochloride of example 3 stored at 25 ± 2°C and 92 ± 5% relative humidity for 20 days.
(Table Removed)

Table 2: Stability data of valganciclovir hydrochloride of example 3 stored at 40 ± 2°C and 75 ± 5% relative humidity for one month.
(Table Removed)

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 included within the scope of the present invention. Further, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention and be so described as a negative limitation. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

WE CLAIM:
1. Amorphous valganciclovir hydrochloride free of crystalline valganciclovir
hydrochloride.
2. Stable amorphous valganciclovir hydrochloride wherein the amorphous
valganciclovir hydrochloride does not convert to crystalline form when stored
for one month at 40 °C and 75% relative humidity.
3. A pharmaceutical composition comprising amorphous valganciclovir
hydrochloride according to claim 1 or 2 and a pharmaceutically acceptable
carrier.
4. A process for the preparation of amorphous valganciclovir hydrochloride
wherein the process comprises spray drying a solution of valganciclovir
hydrochloride in a spray drying system fitted with a rotary atomizer.
5. The process according to claim 4 wherein the rotating atomizer speed is
between 45 Hertz to 75 Hertz.
6. The process according to claims 4 or 5 wherein the spray drying system is
selected from an open spray drying system or closed spray drying system.
7. The process according to claim 6 wherein the spray drying system uses air or
inert gas as the drying gas.
8. The process according to claim 7 wherein the drying gas inlet temperature is
between 135°C to 160°C and drying gas outlet temperature is between 80°C
to110°C.
9. The process according to claim 7 wherein the drying gas is inert gas selected
from nitrogen, argon and carbon dioxide.
10. The process according to claim 4 wherein the solution of valganciclovir is
prepared in a solvent selected from the group consisting of water methanol,
ethanol, iso-propanol, n-butanol, acetone, isopropanol, tetrahydrofuran,
cyclohexane, n-hexane, ethyl acetate, diethyl ether and diisopropyl ether and
mixtures thereof.

11. A process for the preparation of amorphous valganciclovir hydrochloride
wherein the process comprises spray drying a solution of valganciclovir
hydrochloride in a spray drying system fitted with a rotary atomizer rotating at
speed of about 50 Hertz and isolating the amorphous valganciclovir
hydrochloride wherein the drying gas inlet temperature is between 140°C to
150°C and drying gas outlet temperature is between 80°C to100°C and the
spray drying system is an open spray drying system.
12. A process for the preparation of amorphous valganciclovir hydrochloride
wherein the process comprises spray drying a solution of valganciclovir
hydrochloride in a spray drying system fitted with a rotary atomizer rotating at
speed of about 50 Hertz and isolating the amorphous valganciclovir
hydrochloride wherein the drying gas inlet temperature is between 140°C to
150°C and drying gas outlet temperature is between 80°C to100°C and the
spray drying system is a closed spray drying system.
13. A process fro the preparation of amorphous valganciclovir hydrochloride
substantially described and exemplified herein.