FORM 2
THE PATENTS ACT, 1970
(Act 3 9 of 1970)
COMPLETE SPECIFICATION
{See Section 10)
Title. "An improved process for manufacturing cold water soluble Hydroxy Propyl Methyl Cellulose"
Name: M/s. Gujarat Alkalies and Chemicals Limited.
Address: P.O. Petrochemicals - 391 346,
Dist: Vadodara, Gujarat - India.
Nationality: Indian
The following specification particularly describes the invention and the manner in which it is to be performed.

Title of the Present Invention
An improved process for manufacturing cold water soluble Hydroxy Propyl Methyl Cellulose.
Field of the Present Invention
This invention relates to an improved & economical, industrial process for manufacturing low viscosity cold water soluble Hydroxy Propyl Methyl Cellulose suitable for Pharmaceutical applications..
Background of the Present Invention
Hydroxy Propyl Methyl Cellulose is a valuable product. The preparation of alkali cellulose is very important to the overall process of manufacturing of Hydroxy Propyl Methyl Cellulose and the quality of the final product. The uniformity in the alkalization is one of the controlling factor for achieving a uniformly substituted water soluble Hydroxy Propyl Methyl Cellulose. The presence of excess alkali with alkali cellulose mass give rise to the undesirable side products during the etherification eventually affecting the rate of etherification.
There are several ways reported in the literature to prepare Alkali Cellulose. It has been reported in patent US 1,999,043 that the cellulose sheets are steeped, in alkali liquor followed by pressing of the same to expel the excess liquid. US 2,145,862 has disclosed the preparation of Alkali Cellulose at 55 - 144°C using 60 - 80% Caustic solution. Drawback of such method is that the use of large quantity of caustic lye during alkali cellulose formation may result in to the partial hydrolysis of methyl chloride leading to slow rate of reaction and formation of more side products during etherification.
The complexity in the alkali cellulose formation, partial hydrolysis of methyl chlonde primarily responsible for the formation of side products and formation of non -uniform product are more pronounced at the higher scale of operation. There are several controlling factors whose proper matching is required at the higher scale of operation in order to minimize the process related obstacles / problems so as to make the process economical.
The process of manufacturing Hydroxy Propyl Methyl Cellulose in accordance with the present invention discloses a method of preparing the alkali cellulose which is simple, easy to operate at industrial scale and the alkali cellulose thereof prepared is

suitable for etherification. The process does not use caustic bath, any solvents, catalyst and the reaction is performed at moderate temperature conditions.
IN 189587 reported the low viscosity cold water soluble Hydroxy Propyl Methyl Cellulose conforming to all laid down pharmacopoeia specifications and suitable for tablet coating purpose, which can be prepared by reaction of cellulose powder with Caustic Lye with stirring under Nitrogen atmosphere followed by reactions with Propylene Oxide and Methyl Chloride, washing of Crude product with hot water and finally drying the product.
Hydroxy Propyl Methyl Cellulose has been reported in as early as 1930. Initially, the reaction was conducted in the presence of NH3 or aqueous solution of Hydroxy Alkylamine as catalysts. The various substitution types of Hydroxy Propyl Methyl Cellulose has been reported and prepared by changing the ratio of alkylating agent and temperature. The use of different solvents has been reported by several workers during the etherification steps. Solvents like Isopropanol, mixed solvent system like toluene and isoporpanol, etc have been used.
There are drawbacks in the known processes like alkali cellulose formation, reaction conditions, reactant ratios & the formation of final product with desired viscosity and conforming to the pharmacopeia specifications.
In the absence of proper reactant ratio and reaction temperature both vapor and liquid phase etherification gives non-uniformly substituted product, not meeting the pharmacopoeia specification with respect to 2 % solution clarity. The Dimethyl ether is formed as a side product.
Summary of the Present Invention
The present invention discloses an improved industrial process for manufacturing cold water soluble Hydroxy Propyl Methyl Cellulose comprising of the step of Alkali Cellulose formation by reacting Cellulose powder with Caustic Lye under inert atmosphere and efficient stirring; the step of gradual charging of propylene oxide in a pre cooled reactor, and the step of reacting the alkali cellulose mass with charged propylene oxide; the step of charging liquid Methyl Chloride in apre-cooled reactor; the step of reacting the contents with the charged liquid Methyl Chloride; the step of recovering excess liquid Methyl Chloride for recycling the same in the subsequent batches; the step of slurring the crude product in hot water having minimum 90°C temperature; the step of centrifuging the slurry with simultaneous washings with hot water having minimum 90°C temperature; the step of drying, pulverizing and sieving the dry Hydroxy Propyl Methyl Cellulose.

The process of manufacturing Hydroxy Propyl Methyl Cellulose in accordance with the present invention neither requires large quantity of caustic lye nor any solvent during the methylation and reactions are performed at very low temperature to give high yield with minimum formation of undesirable side products. The product so obtained has been found to be suitable for tablet coating purpose.
The process of manufacturing Hydroxy Propyl Methyl Cellulose in accordance with the present invention involves two etherification reactions. The first etherification reaction is carried out with Propylene Oxide followed by the reaction with Methyl Chloride. The reaction of alkali cellulose with Propylene Oxide & Methyl Chloride requires precision in the reaction conditions otherwise the final product will not meet the criterion of 2% solution clarity.
The process of manufacturing Hydroxy Propyl Methyl Cellulose in accordance with the present invention exclusively utilizes Methyl chloride both as reaction media & reactant, restricts the formation of Dimethyl ether - a side product to < 3% per cycle of Methyl Chloride used in the methylation and effectively utilizes the recovered Methyl Chloride in the process. The process of manufacturing Hydroxy Propyl Methyl Cellulose in accordance with the present invention does not use any solvent in the reaction. The recovered Methyl Chloride may be recycled as such or as a blend with fresh /pure Methyl Chloride. The recovered Methyl Chloride also contains 0.5 -1.0 % Propylene Oxide. In the prior art such recycling of Methyl Chloride does not find any specific attention.
In the process of manufacturing Hydroxy Propyl Methyl Cellulose in accordance with the present invention, the temperature gradient standardized for both the etherification reactions has been such that the uniformly substituted product is obtained. The process does not use any solvent at any stage. The recovery and recycling of the Methyl Chloride makes the process more economical. The quantity of liquid Methyl Chloride taken also plays a very important role in the reaction & the quality of final product.
Over & above, the process of manufacturing Hydroxy Propyl Methyl Cellulose in accordance with the present invention provides an easy process to operate at this scale since all of the process steps are carried out in the same reactor system. The present invention solves the problems faced in earlier processes to a great extent.

Detailed Description of the Present Invention
The process of manufacturing Hydroxy Propyl Methyl Cellulose in accordance with the present invention is successfully modified / improved than the earlier reported process at small scale and has provided an economical Industrial process for preparing low viscosity, cold water soluble Hydroxy Propyl Methyl Cellulose conforming to all the laid down pharmacopoeia specifications and suitable for tablet coating. The various parameters like the reactant ratios, temperature, pressure and down stream processing have been modified / improved in a such a way that the process in very easy to operate at the semi - commercial / commercial scale with the desired specifications of the final product obtained in > 90% of the theoretical value.
The whole process of the present invention consists of several controlling factors whose proper matching is required at the higher scale of operation in order to minimize the process related obstacles/problems so as to make the process more economical.
The complexity in the alkali cellulose formation, partial hydrolysis of methyl chloride primarily responsible for the formation of side products & formation of non -uniform product are more pronounced at the higher scale of operation. Hence, proper care should be taken while carrying out each step.
Stepl:
In the first stage the alkali cellulose is prepared by charging 5 kg. cellulose powder in the 250 ltr. capacity S S - 316 L pressure reactor provided with mechanical seal, agitator, heating & cooling system, solid charging port, sampling point, addition vessel, liquid Methyl Chloride charging line, pressure gauge, digital temperature indicator, distillation system with storage tanks etc. The cellulose powder is reacted with 50% Caustic Lye (prepared separately by dissolving 6 kg. Caustic Flakes in 6 ltr. D M Water).The 50% Caustic Lye is added at 15 - 25°C under Nitrogen atmosphere & efficient stirring for 2 - 4 hrs. The quantities used should be used in certain ratio. The weight ratio of Cellulose: Caustic .-water should be 1:1.2:1.2.

Step 2:
The contents are cooled up to 7 - 10°C & the required quantity of Propylene Oxide is slowly added preferably at the same temperature under the stirring. The reaction is further continued at 10 - 50 °C for 4 - 8 hrs under the Nitrogen atmosphere with reactor pressure of 0.5-1 kg/cm . The weight ratio of propylene oxide taken should be 0.50-0.35 times of the cellulose powder.
Step 3:
The reactor is again cooled to 7 - 10°C & liquid Methyl Chloride (fresh / recovered /
blend of both) is charged at 4 - 5 kg. / cm2 pressure. The temperature of the reactor
is gradually increased to 45 - 55°C under the stirring. The methylation is continued
for 16 - 20 hrs. at 10 -14 kg. / cm2 pressure. The weight ratio of liquid Methyl
Chloride taken should be 15-20times of the cellulose powder taken.
Step 4:
After the completion of methylation, the excess of the Methyl Chloride is recovered by carrying out the distillation under pressure. The recovered Methyl Chlonde is stored at room temperature in 200 ltr. S S 316 L storage vessel. The process enables to recover the unreacted Methyl Chloride, which can be used / recycled in the subsequent batches, making the process more attractive and economical.
Step 5:
The Crude product is slurried in hot water (> 90°C) & centrifuged using SS - 316 basket type centrifuge. The washings are also given simultaneously using the hot water ( > 90 °C) in order to remove the Sodium Chloride. Thus, the final product does not contain more than 0.5 % Chloride content, which is the requirement of the pharmaceutical grade product
Step 6:
The wet cake is taken out and dried at 90 - 105°C using the air circulating dryer / oven.

Step 7:
The dried product is finally Pulverized & sieved.
Hydroxy Propyl Methyl Cellulose manufactured has the following properties: Methoxy substitution 27-30%, 5-12 % Hydroxy Propoxy substitution, cold water solubility 99±1%, Chloride content less than 0.5 %, 2% aqueous solution viscosity 4-8cps, Solution clarity 10-15 NTU and suitable for tablet coating. The final product prepared by this process shows excellent consistency with respect to the viscosity in the given range .
The above mentioned process efficiently utilizes the recovered Methyl chloride in each cycle. The process will form a by-product Dimethyl ether but this particular process restricts the formation of Dimethyl ether to not more than 3% per cycle of the Methyl Chloride used in the methylation. The recovered Methyl Chloride in each cycle contains 0.5%-l .0% of Propylene Oxide.
Over & above, the present invention provides an easy process to operate at this scale since most of the process steps are carried out in the same reactor system. The examples described herein will substantiate our claims regarding the advantages of our process.
Example -1
5.0 kgs cellulose powder is reacted with 6.0 kgs Caustic dissolved in 6.0 litres DM water at 20 ± 2° C under nitrogen atmosphere and efficient stirring, The total reaction time including the addition of Caustic solution is kept in between 2-4 hrs. Now the temperature of the reactor is brought down to 7 - 10° C and 2.0 kgs of Propylene Oxide is gradually added in 1 hr. The reaction is continued for 8 hrs at 10 - 50° C. After the completion of the reaction, the reactor is again cooled down to 7-10° C and 75 kg liquid Methyl Chloride is transferred at 4 - 5 kg / cm2 pressure and Methylation is carried out for 20 hrs at 50° C and 12.5 kg / cm" pressure. The excess Methyl Chloride is recovered by carrying out the distillation under pressure and stored for the recycling / reuse in the process. The recovered Methyl Chloride contains less than 3% Dimethyl ether & less than 1% Propylene Oxide. The crude product is slurned in 80 -100 litres hot water (> 90° C) and immediately centrifiiged under the hot conditions including the washings. The wet product is dried in the air circulating oven at 90 -105° C followed by pulverization and sieving of the product.

Example - 2
5.0 kgs cellulose powder is reacted with 6.0 kgs Caustic dissolved in 6.0 litres DM water at 23 ± 2° C under nitrogen atmosphere and efficient stirring. The total reaction time including the addition of Caustic solution is kept in between 2-4 hrs. The reactor is cooled to 7 -10° C and 1.7 kgs of Propylene oxide is gradually added in 1 hr. The reaction is further continued for 4 hrs at 20 - 50° C. After the completion of the reaction, the reactor is again cooled down to 7 - 10° C and 100 kg liquid Methyl Chloride is transferred at 4 - 5 kg / cm2pressure and Methylation is earned out for 16 hrs at 55° C and 14.0 kg / cm2 pressure. The excess Methyl Chloride is recovered by carrying out the distillation under pressure and stored for the recycling / reuse in the process. The recovered Methyl Chloride contains less than 3% Dimethyl ether & less than 1.0% Propylene Oxide. The crude product is slurried in 80 - 100 litres hot water (> 90° C) and immediately centrifuged under the hot conditions including the washings. The wet product is dried in the air circulating oven at 90 -105° C followed by pulverization and sieving of the product.
Example - 3
5.0 kgs cellulose powder is reacted with 6.0 kgs Caustic dissolved in 6.0 litres DM water at 17 ± 2° C under nitrogen atmosphere and efficient stirring. The total reaction time including the addition of Caustic solution is kept in between 2-4 hrs. The reactor is cooled to 7 -10° C and 2.5 kgs of Propylene oxide is gradually added in 1 hr. The reaction is further continued for 6 hrs at 30 - 50° C. After the completion of the reaction, the reactor is again cooled down to 7 - 10° C and 80 kgs recovered liquid Methyl Chloride is transferred at 4 - 5 kg / cm2 pressure and Methylation is carried out for 20 hrs at 40 - 50° C and 10 - 12 kg / cm2 pressure. The excess Methyl Chloride is recovered by carrying out the distillation under pressure and stored for the recycling / reuse the process. The recovered Methyl Chloride contains less than 5.0% Dimethyl ether & less than 1.0% Propylene Oxide. The crude product is slurried m 80 - 100 litres hot water (> 90° C) and immediately centrifuged under the hot conditions including the washings. The wet product is dried in the air circulating oven at 90 -105° C followed by pulverization and sieving of the product.
The product obtained in all the examples shows Methoxy substitution 27 - 30%, Hydroxy Propoxy content 5 - 12% Chloride content < 0.5%, 99 ± 1% cold water solubility, viscosity of 2.0%, solution 4-8 cps and solution clarity 10-15 NTU.

We Claim:
1. An improved process for manufacturing cold water soluble Hydroxy Propyl Methyl Cellulose comprising:
- the step of Alkali Cellulose formation by reacting Cellulose powder with Caustic Lye under inert atmosphere and efficient stirring;
- the step of gradual charging of propylene oxide in a pre cooled reactor;
- the step of reacting the alkali cellulose mass with charged propylene oxide;
- the step of charging liquid Methyl Chloride in apre-cooled reactor;
- the step of reacting the contents with the charged liquid Methyl Chloride;
- the step of recovering excess liquid Methyl Chloride for recycling the same in the process;
- the step of slurring the crude product in hot water having minimum 90°C temperature;
- the step of centrifugmg the slurry with simultaneous washings with hot water having minimum 90°C temperature;
- the step of drying the wet cake; and
- the steps of pulverization and sieving the dry Hydroxy Propyl Methyl Cellulose.

2. A process as per claim 1 wherein the weight ratio of Cellulose: Caustic: Water is 1:1.2:1.2.
3. A process as per claim 1 wherein the Alkali Cellulose by the reaction of Cellulose powder and Caustic Lye at 15-25°C under inert atmosphere using Nitrogen.
4. A process as per claim 1 wherein the Propylene oxide is gradually charged in a pre cooled reactor at 7-10°C for one hour.
5. A process as per claim 4 wherem the weight of Propylene oxide charged per cycle in the pre-cooled reactor is 0.50-0.35 times of that of the Cellulose powder used in each cycle.
6. A process as per claim 1 wherein the Hydroxy Propylation is carried out at 10-50°C for 4-8 hours with reactor pressure 0.5-1 kg/cm2
7. A process as per claim 1 wherein the charging of liquid Methyl Chloride is carried out in the pre-cooled reactor below 10°C at pressure 4-5 kg/cm2.
8. A process as per claim 7 wherein the weight of liquid Methyl Chloride charged per cycle in the pre-cooled reactor is 15-20 times of that of the Cellulose powder used in a given batch . .
9. A process as per claim 1 wherem the methylation is carried out at 50 ± 5 °C for 16-20 hours with reactor pressure 9-14 kg/cm2.
10. A process as per claim 1 wherein the wet cake is dned in air-circulating dryer at 90-105°C followed by the operations of pulverization and sieving.

11. A process as per claim 1 wherein the Hydroxy Propyl Methyl Cellulose
manufactured has the following properties:
Methoxy substitution 27-30%, 5-12 % Hydroxy Propoxy substitution, cold water solubility 99±1%, Chloride content less than 0.5 %, 2% aqueous solution viscosity 4- 8cps, Solution clarity 10-15 NTU and suitable for tablet coating.
12. A process as per claim 1 wherein Dimethyl Ether formation as a side product is restricted to <3% per cycle of liquid Methyl Chloride used in the process.
13. A process as per claim 1 wherein the recovered Methyl Chloride contains 0.5-1 % of Propylene Oxide.