A solvent free, single step continuous process for the synthesis of paracetamol

Abstract

The present invention provides a continuous single step, solvent free and additive free process for the synthesis of Paracetamol with more than 90% conversion of the solid substrates and at least 94-97% selectivity towards paracetamol as product, and that to without the need of any solvent in a screw reactor.

Description

[0001] A SOLVENT FREE, SINGLE STEP CONTINUOUS PROCESS FOR THE SYNTHESIS OF PARACETAMOL

[0002] FIELD OF THE INVENTION

[0003] The invention relates to a continuous process for the synthesis of Paracetamol. Particularly, the present invention relates to a solvent free continuous process for the synthesis of Paracetamol using screw reactors.

[0004] BACKGROUND AND PRIOR ART OF THE INVENTION

[0005] Paracetamol is one of the most widely used drugs globally to treat fever and pain, following its approval by the US Food and Drug Administration (FDA) in the year of 1951. It has been used since the last nearly 73 years and is still the drug of choice for many patients, either alone or in combination with non-steroidal anti-inflammatory drugs such as Ibuprofen or Diclofenac sodium for the effective clinical management to get relief from savior pain and fever. The number of paracetamol doses sold annually in the USA is reported to be around 23 billion, but this figure includes both over-the-counter and prescription drugs. About 115,000 tons of paracetamol are produced annually by companies in China and India, which accounts for roughly 70% of the world market. This clearly indicates the quantum of Paracetamol bulk drug needed globally.

[0006] There is a commendable body of literature in public domain in the form of patents as well as scientific publications describing the possible routes of synthesis of Paracetamol. Most of these literature dislcosed processes for synthesis of paracetamol are in batch mode as well in recent time some of them disclose continuous process as well. Recently, there have been attempts to improve the synthetic processes of paracetamol to economize the process or to reduce the content of impurities.

[0007] References may be made to patent application WO2021219647 which reports a process for synthesis of Paracetamol by acetylation of p-aminophenol with AC2O or acetic acid; in which the three process steps were carried out continuously. When acetic acid is used as the acylating agent, the acetylation is carried out under microwave irradiation and does not use any additional solvents besides acetic acid. This published document allows preparation of paracetamol by a continuous process around in 3 hrs.

[0008] References may be made to patent application CN 114478293, which discloses a process of preparation of paracetamol by injecting aqueous solution containing p-aminophenol and acetic acid into a micro-channel reactor, and reacting at 65-85°C for 4-9 min. This process covers multiple process steps and multiple work ups such as vacuum distilling, redissolving with water, adding activated carbon, decoloring at 90-95 °C, filtering, cooling filtrate to 0-5°C, crystallizing for more than 8 hrs, and vacuum drying at 60-70°C for more than 5 h to obtain paracetamol crystal powder.

[0009] References may be made to patent application RU2574733A, which reports a method of preparation of well-known drug A-(4-hydroxyphenyl) Acetamide based on catalytic hydrogenation of p-nitroso phenol with Pd / C or Ni-Re catalysts at 20-70°C in a combination with acetylation with acetic anhydride in aqueous ethanol or aqueous isopropanol is developed.

[0010] References may be made to patent application EP2975018, which reports a process for preparation of N-acetyl 4-amino phenol (APAP) via nitrosation of phenol as a key process step. This process comprises nitrosation of phenol by continuous preparation of dinitrogen trioxide in a microreactor.

[0011] However, the above reported literature known methods have some limitations / disadvantages considering production of paracetamol such as requirement of higher temperature, multiple process steps, multiple work ups, solvent or mixture of solvents which arises problem like separation and purification at final step, higher reaction times (goes up to 24 hrs) which are not feasible for industrial scale production, etc.

[0012] Moreover, typically, the conventional process (of WO2021219647) has mole ratio of acetic anhydride to PAP is equal to or more than 1.5, which leads to generation of 3 moles of acetic acid at the end of the reaction per mole of product as side or unwanted product with impurities. Thus, there still exists a dire need in the art to provide simpler and economically more relevant process for the synthesis of valuable chemicals such as paracetamol with greater purity and that to in shorter period of time i.e., in few seconds.

[0013] OBJECTS OF THE INVENTION

[0014] Main objective of the present invention is to provide a continuous process for the synthesis of paracetamol.

[0015] Another objective of the present invention is to provide a continuous one step, solvent free process for the synthesis of paracetamol in simple and economically feasible manner to obtain paracetamol continuously with higher purity (around 90-99%) and nearly full substrate conversion (90-99%).

[0016] SUMMARY OF THE INVENTION

[0017] Accordingly, the present invention provides a continuous process for the synthesis of pure chemicals employing a screw reactor via mechanochemical and solvent free approach.

[0018] In an embodiment, the present invention provides a single step, continuous process of preparation of paracetamol, comprising: a. continuously passing liquid acetic anhydride and solid para-aminophenol in a screw reactor under specific reaction conditions for time period in the range of 10-600 seconds, to obtain pure paracetamol wherein the process is done without the addition of solvent.

[0019] In another embodiment, the present invention provides a single step, continuous process for the synthesis of paracetamol comprising reacting p-Aminophenol and acetic anhydride at a temperature in the range of 25-50 °C for a residence time in the range of 10-600 seconds in a vertical or horizontal screw reactor to obtain crystalline paracetamol with a purity of at least 98% and conversion of at least 97-99%.

[0020] In yet another embodiment, the present invention provides A single step, continuous process of preparation of paracetamol comprising the steps of: i. continuously passing liquid acetic anhydride and solid para-aminophenol in a screw reactor under specific reaction conditions for residence time period in the range of 10-600 seconds, to obtain pure paracetamol wherein the process is done without the addition of solvent; wherein, the specific reaction conditions comprise one or more of: a) the temperature is in the range of 10 to 150 °C, b) mole ratio of para-aminophenol to acetic anhydride at the reactor inlet is in the range of 1:1 to 1:2.

[0021] In yet another embodiment of the present invention, the temperature is in the range of 15 to 125 °C, 15 to 100 °C, 15 to 75 °C, 15 to 50 °C or 15 to 30 °C.

[0022] In still another embodiment of the present invention, the residence time of liquid acetic anhydride and solid para-aminophenol in said reactor is in the range of 10 to 600 seconds, 10 to 500 seconds, 10 to 400 seconds, 10 to 300 seconds, 10 to 200 seconds, 10 to 100 seconds, 10 to 75 seconds, 10 to 50 seconds or 10 to 25 seconds.

[0023] In another embodiment of the present invention, the ratio of amount or concentration of p- aminophenol: acetic anhydride is in range of 1: 1 to 1:2, 1: 1 to 1: 1.95, 1: 1 to 1: 1.90, 1: 1 to 1:1.85, 1: 1 to 1:1.80, 1: 1 to 1: 1.75, 1: 1 to 1:1.70, 1:1 to 1: 1.65, 1: 1 to 1:1.60, 1:1 to 1: 1.55, 1:1 to 1:5, 1: 1 to 1: 1.45, 1:1 to 1:40, 1: 1 to 1: 1.35, 1: 1 to 1:30, 1:1 to 1:1.25, 1:1 to 1:20, 1:1 to 1: 15, 1: 1 to l: 1.10 or 1:1 to 1: 1.05.

[0024] In yet another embodiment of the present invention, the screw reactor is selected from the group consisting of vertical screw reactor, horizontal screw reactor, an inclined single screw reactor and twin-screw reactor or two or more combinations thereof.

[0025] In another embodiment of the present invention, the screw reactor is twin-screw reactor comprising one or more of: i. screw shaft diameter in the range of 1.0 - 50 cm; ii. angle of expansion of the screw shaft in the range of -10 to 10°; iii. rotating or screw speed of said reactor is in range of 0 to 200; iv. outer diameter of the screw threads in the range of 1.05 cm - 51 cm; and v. screw length in the range of 30 cm to 500 cm.

[0026] In yet another embodiment of the present invention, the angle of expansion of the screw shaft in said screw reactor which kept around -10°, -7.5°, -5°, -2.5°, 0°, 2.5°, 5°, 7.5°, or 10°. In still another embodiment of the present invention, the screw reactor is a vertical screw reactor with screw shaft diameter of 1.0 cm, angle of expansion of the screw shaft of -10°, outer diameter of the screw threads is 2 cm, and screw length of 30 cm.

[0027] In another embodiment of the present invention, the conversion of p-aminophenol into paracetamol as product is in range of 95 to 99%, wherein the selectivity of paracetamol is in the range of 85-99%, and wherein the purity of prepared paracetamol as product is in range of 95 to 99.8%.

[0028] In yet another embodiment of the present invention, the total number of screw reactor used in said process is in range of 1 to 20 or 1 to 10 or 1 to 8 or 1 to 5.

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 illustrates the screw reactor, as used in accordance with an implementation of the present invention.

[0031] Figure 2 illustrates1H-NMR data of Paracetamol synthesized as per Example 7.

[0032] Figure 3 illustrates 'H-NMR data of Paracetamol synthesized as per Example 2.

[0033] Figure 4 illustrates HPLC data of the pure and crystallized Paracetamol as obtained in Example 7.

[0034] Example 5 illustrates HPLC data of the pure and crystallized Paracetamol as obtained in Example 2.

[0035] Example 6 shows comparative Powder X-ray diffraction graph for the synthesized paracetamol as per the process of present invention, and the commercially available paracetamol.

[0036] DETAILED DESCRIPTION OF THE INVENTION

[0037] The continuous flow mechanochemical synthesis of paracetamol or any other essential chemical have significantly more uses and applications than the standard and conventional batch approaches. Bulk synthesis of any valuable chemical or drug / API (active pharmaceutical ingredient) or compound in the batch mode demands for more setup space; the most setups are manual, thus there will be a fundamental requirement of highly experienced and additional human resources. Accordingly, the energy consumption increases, and controlling reaction parameters and heat transmission in bulk tank reactors is difficult to handle and it’s cumbersome and tedious as well. As a result, the method is dangerous in some situations. A large number of solvents will be required during the separation and purification procedure.

[0038] Thus, a continuous flow synthesis is best alternative attempt to address all of the challenges encountered in said batch technique. The automated long-lasting device replaces human resources in the continuous flow method. Compact size reactors will replace bulk tank reactors, which automatically reduces land space erosion; most of them are safer, user pleasant and simple to operate; they will save more energy and produce more output, which ultimately affects the pricing and costing.

[0039] Accordingly, the present invention provides a simple and economically viable technique for the one step solvent free mechanochemical continuous synthesis of paracetamol with high purity and nearly full substrate (100%) conversion.

[0040] To achieve the invention's goals, the inventors present a continuous and solvent-free process for the synthesis of chemicals and pharmaceuticals using a screw reactor with novel design and / or novel dimensions.

[0041] The terms “white crystalline solid” and “colorless crystalline solid” are used synonymously throughout the specification.

[0042] The present invention provides a continuous process for the synthesis of pure chemicals employing a screw reactor via mechanochemical and solvent free approach.

[0043] The present invention provides a single step, continuous process of preparation of paracetamol, comprising: continuously passing liquid acetic anhydride and solid para-aminophenol in a screw reactor under specific reaction conditions for time period in the range of 10-600 seconds, to obtain pure paracetamol wherein the process is done without the addition of solvent.

[0044] The flow of liquid acetic anhydride and solid para-aminophenol is kept in said screw reactor till obtaining crystalline paracetamol.

[0045] The process further comprises allowing pure paracetamol to crystallize once the reaction is over without stopping the flow of starting materials i.e., liquid acetic anhydride and solid para-aminophenol.

[0046] The process is single step process. The specific reaction conditions comprise one or more of: a) the temperature is in the range of 10 to 150 °C, b) rotating or screw speed of said reactor is in range of 0 to 200, c) angle of expansion of the screw shaft in said reactor is in range of -10 to 10°, d) residence time of starting materials i.e., liquid acetic anhydride and solid paraaminophenol, is in range of 10 to 600 seconds, and / or e) mole ratio of para- aminophenol to acetic anhydride at the reactor inlet is in the range of 1:1 to 1:2.

[0047] One of the specific reaction conditions is temperature which kept in the range of 15 to 125 °C, 15 to 100 °C, 15 to 75 °C, 15 to 50 °C or 15 to 30 °C.

[0048] One of the specific reaction conditions is angle of expansion of the screw shaft in said screw reactor which kept around -10°, -7.5°, -5°, -2.5°, 0°, 2.5°, 5°, 7.5°, or 10°.

[0049] The residence time of starting materials i.e., liquid acetic anhydride and solid paraaminophenol, in said reactor is in range of 10 to 600 seconds, 10 to 500 seconds, 10 to 400 seconds, 10 to 300 seconds, 10 to 200 seconds, 10 to 100 seconds, 10 to 75 seconds, 10 to 50 seconds or 10 to 25 seconds.

[0050] The ratio of amount or concentration of p-aminophenol: acetic anhydride is in range of 1: 1 to 1:2, 1:1 to 1: 1.95, 1: 1 to 1: 1.90, 1: 1 to 1: 1.85, 1:1 to 1:1.80, 1: 1 to 1: 1.75, 1: 1 to 1: 1.70, 1:1 to 1:1.65, 1:1 to 1:1.60, 1:1 to 1: 1.55, 1: 1 to 1:5, 1: 1 to 1:1.45, 1: 1 to 1:40, 1: 1 to 1: 1.35, 1:1 to 1:30, 1: 1 to 1:1.25, 1:1 to 1:20, 1:1 to 1: 15, 1:1 to 1: 1.10 or 1:1 to 1:1.05.

[0051] The screw reactor is selected from vertical screw reactor, horizontal screw reactor, an inclined single screw reactor and twin screw reactor or two or more combinations thereof. The total number of screw reactor used in said process is in range of 1 to 20 or 1 to 10 or 1 to 8 or 1 to 5.

[0052] If more than one screw reactor is used, then it is connected in series as well as parallel in vertical or horizontal manner or combination thereof.

[0053] Said process is solvent-free and free of additives.

[0054] The screw reactor can be a single screw or a twin screw having an orientation of vertical, horizontal or inclined. The screw reactor comprises a shaft that is straight, expanding or contracting with a constant chamber diameter, where the chamber diameter to the maximum screw diameter ratio is in the range of 1.001 to 1.1.

[0055] The solid p-aminophenol is free flowing dry powder.

[0056] Acetic anhydride is free flowing liquid.

[0057] The twin screw reactor comprises one or more of: i. screw shaft diameter = 1.0 - 50 cm, ii. angle of expansion of the screw shaft = -10 to 10°, iii. outer diameter of the screw threads = 1.05 cm - 51 cm, and iv. screw length = 30 cm to 500 cm.

[0058] The screw reactor comprises a screw orientation either vertical or horizontal or from vertical to horizontal, and that to with single screw or twin-screw. p- Aminophenol and acetic anhydride comprises 0% of moisture, are free of agglomerates, and used without need of any solvent or any additives.

[0059] The purity of prepared paracetamol as product is in range of 95 to 99.8%.

[0060] The conversion of p-aminophenol into paracetamol as product is in range of 95 to 99%.

[0061] The selectivity of paracetamol as product is in range of 85 to 99%.

[0062] The present invention provides a single step, continuous process for the synthesis of paracetamol comprising reacting p-Aminophenol and acetic anhydride at a temperature in the range of 25-50 °C for a residence time in the range of 10-600 seconds in a vertical or horizontal screw reactor to obtain crystalline paracetamol with a purity of at least 98% and conversion of at least 97-99%.

[0063] Present invention disclose a continuous solvent-free process for the synthesis of chemicals and pharmaceuticals using a screw reactor. The process provided by the present disclosure has the advantages of simple and easy operation, high raw material utilization rate, it is totally solvent free synthesis done by using mechanochemical approach so ultimately it will wipe out the cost of solvent from the process as there is full conversion of reactant happen just in the single step reaction and there is control over impurity formation it will increase productivity significantly. Finally, the current invention reduces the synthesis cost and increases productivity with high yield with maximum purity achievement thus the preparation method of the invention is very suitable for industrial production of paracetamol.

[0064] The reactants in powder form are fed using two screw conveyers that help maintain the desired feed rate of individual substrates. The feed is given to another vertically aligned screw with downward flow to avoid any liquid due to shear thinning or melting settling even in the meniscus form or an inclined screw with downward flow direction. It is necessary to mention that having horizontal arrangement of the screw for reaction retains some liquid unless extremely close clearance is kept between the threads and the chamber wall. However, such a situation can create friction in the presence of reaction mass, which can lead to unsafe operations.

[0065] In the present invention, vertical alignment for screw reactor (100) (refer, Figure 1) (having glass or metal jacket) (101) such that the distance between the outer diameter of the screw thread and the inner diameter of the j acket is not more than 0.25 mm is preferred to avoid any liquid to remain accumulated. Any liquid used or generated in the reaction flows downward due to gravity and any gas generated in the reaction will either flow in the form of packets or escape from the top if the material is not very densely packed. The inlet and outlet ports of the jacket (102 and 103), which may be alternated or swapped, are connected to a constant temperature circulation bath or wrapped with an electric heating tape. For the reactions where reactants are in liquid or in slurry form, pumps were used for dosing instead of screw feeding system. This ensures no accumulation of reactants in the feed section to the reactor.

[0066] In the process of the present invention, a solid-liquid reaction is occurring in the screw reactor. The substrates which are liquid-solid flow react together to form a solid product.

[0067] Accordingly, in a specific embodiment, referring to Figure 1, the screw reactor comprises:

[0068] In an embodiment of the present disclosure, there is provided a single step, continuous process for the synthesis of paracetamol, the process comprising: reacting p- Aminophenol and acetic anhydride at a temperature in the range of 0 °C to 150 C for a residence time in the range of 10-500 seconds in a vertical screw reactor to obtain crystalline paracetamol with a purity of at least 98% and conversion of at least 50 % to 100% wherein p- Aminophenol and acetic anhydride is in 1: 1.20 to 1:1.50 equivalent ratio.

[0069] In an embodiment of the present disclosure, there is provided a single step, continuous process for the synthesis of paracetamol, the process comprising: reacting p- Aminophenol and acetic anhydride at a temperature in the range of 10 °C - 65 °C for a residence time in the range of 10 s - 300 s in a vertical expanding screw reactor to obtain crystalline paracetamol with a purity of at least 80% and conversion of at least 70%, wherein said p- Aminophenol and acetic anhydride is in 1:1.25 to 1:1.50 equivalent ratio.

[0070] In another embodiment of the present disclosure, there is provided a single step, continuous process for the synthesis of Paracetamol, the process consisting: reacting p- Aminophenol and Acetic anhydride at a temperature in the range of 10 °C to 65 °C for a residence time in the range of 10 s to 180 s in a vertical contracting screw reactor to obtain crystalline Paracetamol with a purity of at least 95% and conversion of at least 90%.

[0071] In an embodiment of the present disclosure, there is provided a single step, continuous process for the synthesis of Paracetamol, the process comprising: reacting p- Aminophenol and Acetic anhydride at a temperature of 10 °C to 65 °C for a residence time in the range of 10 s to 180 s in a twin-screw reactor to obtain crystalline Paracetamol with a purity of at least 85% and conversion of at least 90%.

[0072] In yet another embodiment of the present disclosure, there is provided a single step, continuous process for the synthesis of Paracetamol, the process comprising: reacting p- aminophenol and acetic anhydride at a temperature in the range of 120-130 °C for a residence time in the range of 5 s to 10 s in a vertical screw reactor to obtain crystalline Paracetamol with a purity of more than 95% and conversion of at least 90%.

[0073] In another embodiment of the present disclosure, there is provided a process as described herein, wherein said Paracetamol has purity of more than 97% if the single screw is tilted by 30° to vertical.

[0074] In another embodiment of the present disclosure, there is provided a process as described herein wherein Paracetamol said has purity of more than 98% if the single screw is tilted by 70° to vertical.

[0075] In another embodiment of the present disclosure, there is provided a process as described herein, where said process results in more than 99% selectivity towards paracetamol for the expanding shaft screw where the expansion ratio was 1: 1.5 from one end to the other.

[0076] In an embodiment of the present disclosure, there is provided a process as described herein, wherein said process results in 100% selectivity towards paracetamol for the expanding shaft screw where the expansion ratio was 1: 1.75 from one end to the other.

[0077] In a further embodiment of the present disclosure, there is provided a single step, continuous process for the synthesis of paracetamol, the process comprising: reacting p- Aminophenol and acetic anhydride at a temperature in the range of 0-50 °C for a residence time in the range of 60- 180 seconds in a vertical contracting shaft screw reactor to obtain crystalline paracetamol with a purity of at least 85% and conversion of at least 90%, wherein said acetic anhydride is in liquid form, and p-Aminophenol is in solid form.

[0078] In another embodiment of the present disclosure, there is provided a process as described herein, wherein said p-Aminophenol is free flowing dry powders and acetic anhydride as free flowing liquid supplied continuously in the reactor at room temperature.

[0079] In an embodiment of the present disclosure, there is provided a continuous solvent free process for the synthesis of paracetamol comprises of reacting a 1:1 to 1: 1.5 equivalent of p-Aminophenol and acetic anhydride at 10 - 15 °C for a period ranging from 10 s to 300 s in a vertical contracting shaft screw reactor with a contraction ratio of 1.5: 1, operated at 95 rpm to obtain off-white, crystalline paracetamol of 98% purity, wherein conversion of the reactants is ranging from 97-100%, selectivity towards paracetamol is 95-97%, and wherein the process is a reaction between solid p-Aminophenol and liquid acetic anhydride; wherein said p- Aminophenol and acetic anhydride contain 0% moisture and are free of agglomerates and without using any solvent or any additives.

[0080] In another embodiment of the present disclosure, there is provided a process as described herein, wherein said p-Aminophenol and acetic anhydride undergo at least 99% conversion, and provide greater than 99% selectivity to desired product. The process of the present disclosure avoids formation of colored by- products or impurities in the desired products.

[0081] It is quite non obvious for a person involved in synthetic chemistry to anticipate the use of screw reactor / conveyor for routine chemical synthesis in a continuous manner, more particularly, a solvent fee synthetic approach for an exothermic reaction.

[0082] EXAMPLES

[0083] Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

[0084] Procurement details

[0085] All the chemicals were procured from Loba Chemie (India) and used without any further purification.

[0086] Below examples is exemplification of the continuous process of present invention done at different reaction conditions (temperature, passing speed flow, pressure, etc.), different concentrations of materials / chemicals / starting materials used therein, different dimensions or types of screw reactor, etc. However, all or some of these alternatives / exemplifications are part of the process of present invention.

[0087] General process for preparation of Paracetamol

[0088] In a continuous flow synthesis of Paracetamol, solid p-Aminophenol (1 equivalent) and liquid Acetic anhydride (1 to 3 equivalent; variation in concentration) were continuously fed into a screw reactor (100) (Specifications: SS316, a vertical screw having shaft diameter = 1.0 cm, angle of variation of the screw shaft from -10° to 10°, outer diameter of the screw threads = 2.0 cm, screw length = 30 cm and screw orientation from vertical to horizontal and with single screw or twin-screw) at 0°C with residence time of 100-300 seconds. The process resulted in the generation of acetic acid at elevated temperature of the reaction, and the reaction mass turned off white in color, due to incomplete conversion due to lower temperature. Reaction mass was characterized by HPLC and NMR.

[0089] In the specific continuous experiments, the solid p- Aminophenol (1 equivalent) and liquid Acetic anhydride ( 1 to 3 equivalent; variation in concentration) were continuously fed into the jacketed vertical PTFE screw reactor (100) at a temperature ranging from 25-30 °C for residence time of 100-150 seconds at rpm in the range of 150-200 to obtain the desired solid product, with at least 84-87% selectivity towards Paracetamol. The conversion of the substrates is at least 67-70%. The product formed included Paracetamol, which was isolated and characterized by the formation of white crystalline product.

[0090] In the experimental embodiment, the solid p-Aminophenol ( 1 equivalent) and liquid Acetic anhydride (1 to 2 equivalent; variation in concentration) were continuously fed into the jacketed vertical PTFE screw reactor (100) at a temperature ranging from 45-55 °C for residence time of 100-150 seconds at rpm in the range of 150-200 to obtain the desired solid product, with at least 94-97% selectivity towards Paracetamol. The conversion of the substrates is at least 89-95%. The product formed is Paracetamol and is characterized by the formation of white crystalline product, with no trace of impurities (Figures 2-5).

[0091] HPLC was used for analyzing the standard, reactant, and experimental samples to ensure selectivity and conversion. The progress of the reaction was monitored at regular intervals using HPLC, where the retention times and peak areas were compared with those of the reactant and product standards. In many instances, complete conversion of the reactant was observed, with the desired product formed free of impurities. The HPLC results (Table 1 and 2, Figure 4 and 5) were further validated by NMR analysis (Figure 2 and 3), confirming both the purity and structure of the product in the corresponding samples.

[0092] The purity, structural integrity, and polymorphic stability of the synthesized paracetamol were thoroughly analyzed using Powder X-ray Diffraction (PXRD) and Single Crystal X- ray Diffraction (SCXRD) techniques. The product were compared with the experimental samples. Our results confirm that the synthesized paracetamol represents the most stable and pure polymorphic form, closely matching the commercially available standard in terms of crystallinity and structural stability. (Figure 6) The solvent-free synthesis of paracetamol was thoroughly evaluated, with X-ray Diffraction (XRD) serving as a key analytical tool, alongside High-Performance Liquid Chromatography (HPLC). XRD successfully validated the purity, crystallinity, and polymorphic form of the product, confirming its structural integrity. The combined use of XRD and HPLC provided comprehensive validation, establishing this solvent-free method as a robust process for producing high-purity paracetamol comparable to commercial standards.

[0093] In a comparative example, reaction temperature of greater than 100-150 °C provided a black colored mass as higher temperature led to higher reaction rate. The outlet composition included byproducts and crude product that was blackish in appearance (further explained in below specific examples).

[0094] Example 1 (Synthesis of Paracetamol where temperature is kept at 0°C)

[0095] In continuous flow synthesis of paracetamol, solid p- Aminophenol (1 equivalent) and liquid Acetic anhydride (3 equivalent) were continuously fed into the vertical screw reactor (screw shaft diameter = 1.0 cm, angle of expansion of the screw shaft = 5°, outer diameter of the screw threads = 2.0 cm, screw length = 30 cm) at 0°C with residence time of 100 seconds. Conversion of p-Aminophenol was 6% and selectivity of paracetamol was 80%. At lower temperature, conversion of p-Aminophenol was lower.

[0096] Example 2 (Synthesis of Paracetamol where temperature is kept at 50°C)

[0097] For the experimental set-up as given in Example 1 , at temperature of 50 °C and residence time of 200 seconds, again generation of acetic acid at elevated temperature was observed and the reaction mass turned light-brown in color mass with desired product. Conversion of p-Aminophenol was 96% and selectivity of paracetamol was 50%. It shows increase in the conversion and selectivity towards paracetamol than example 1. (Table-1, Figure 3 and 5)

[0098] Table-1 HPLC data of the pure and crystallized Paracetamol as obtained in Example 2.

[0099] Example 3 (Synthesis of Paracetamol where temperature is kept at 75°C)

[0100] For the experimental set-up as given in Example 1, at 75°C and with residence time of 100 seconds, light-brown reaction mass was collected showed complete conversion of the substrates with 49% selectivity of paracetamol. It shows increase in the conversion and selectivity towards paracetamol than example 1

[0101] Example 4 (Synthesis of Paracetamol where temperature is kept at 100°C)

[0102] For the experimental set-up as given in Example 1 , at identical conditions and set-up, upon increasing the temperature to 100 °C, black coloured dry mass with 99.9% conversion and 25% selectivity of paracetamol. It shows increase in the conversion and selectivity towards paracetamol than example 1 but lower than examples 2 and 3.

[0103] Example 5 (Synthesis of Paracetamol where temperature is kept at 125°C)

[0104] For the experimental set-up as given in Example 1 , at identical conditions in the same setup at 125°C, upon increasing the temperature residence time decreases and reaction rate increases, blackish solid mass with 99.9% conversion and 10% selectivity of Paracetamol was obtained. It shows increase in the conversion and selectivity towards paracetamol than example 1 but lower than examples 2, 3 and 4.

[0105] Example 6 (Synthesis of Paracetamol where temperature is kept at 150°C)

[0106] At the experimental conditions and in the experimental set-up as given in Example 1 , with vertical screw reactor (screw shaft diameter = 1.0 cm, angle of expansion of the screw shaft = 0°, outer diameter of the screw threads = 2 cm, screw length = 30 cm) at 150 °C and 200 seconds residence time blackish solid mass was observed with 99.9% conversion and 2% selectivity of paracetamol. It shows increase in the conversion and selectivity towards paracetamol than example 1 but lower than examples 2, 3, 4 and 5. Example 7 (Synthesis of Paracetamol where temperature is kept at 30°C, and with 30% excess of starting material)

[0107] At the experimental conditions and in the experimental set-up as given in Example 1 , with 50% excess acetic anhydride at 30° C i.e.at room temperature, at residence time of 500 s, off white solid mass with 70% conversion and 97% selectivity of paracetamol was obtained with white crystalline paracetamol after a wash with the highest purity of 99% (Table 2, Figure 2, 4). It shows foremost best conversion, selectivity with pure paracetamol as white crystalline product.

[0108] Table-2 HPLC data of the pure and crystallized Paracetamol as obtained in Example 7.

[0109] Example 8 (Synthesis of Paracetamol where temperature is kept at 30°C, and with 20% excess of starting material)

[0110] At the experimental conditions and in the experimental set-up as given in Example 1 , the with a vertical screw reactor (screw shaft diameter = 1.0 cm, angle of expansion of the screw shaft = 10°, outer diameter of the screw threads = 2 cm, screw length = 30 cm) with 20% excess of acetic anhydride at 30° C, at residence time of 200 s, off white solid mass with 55% conversion and 97% selectivity of paracetamol was obtained consistently.

[0111] Example 9 (Synthesis of Paracetamol where temperature is kept at 15°C, and with 5% excess of starting material)

[0112] At the experimental conditions and in the experimental set-up as given in Example 1 , the with a vertical screw reactor (screw shaft diameter = 1.0 cm, angle of expansion of the screw shaft = -10°, outer diameter of the screw threads = 2 cm, screw length = 30 cm) with 5% excess of acetic anhydride at 15° C, at residence time of 600 s, off white solid mass with 95% conversion and 97% selectivity of paracetamol was obtained. It also shows foremost best conversion, selectivity with pure paracetamol as white crystalline product. Example 10 (Synthesis of Paracetamol where temperature is kept at 45°C, and with 5% excess of starting material)

[0113] At the experimental conditions and in the experimental set-up as given in Example 1 , the with a vertical screw reactor (screw shaft diameter = 1.0 cm, angle of expansion of the screw shaft = -10°, outer diameter of the screw threads = 2 cm, screw length = 30 cm) with 5% excess of acetic anhydride at 45° C, at residence time of 600 s, off white solid mass with 99.9% conversion and 89% selectivity of paracetamol was obtained.

[0114] Example 11 (Synthesis of Paracetamol where temperature is kept at 30°C, and with 5% excess of starting material and with twin screw reactor)

[0115] At the experimental conditions and in the experimental set-up as given in Example 1 , the with a vertical twin screw reactor (screw shaft diameter = 1.0 cm, outer diameter of the screw threads = 2 cm, screw length = 30 cm, and angle of expansion of the screw shaft = 0°) with 5% excess of acetic anhydride at 45° C, at residence time of 600 s, off white solid mass with 90.1% conversion and 93% selectivity of paracetamol was obtained.

[0116] Example 11 (Synthesis of Paracetamol where temperature is kept at 30°C, and with 5% excess of starting material and with horizontal twin screw reactor)

[0117] At the experimental conditions and in the experimental set-up as given in Example 1 , the with a horizontal twin screw reactor (screw shaft diameter = 1.0 cm, outer diameter of the screw threads = 2 cm, screw length = 30 cm, and angle of expansion of the screw shaft = 0°) with 5% excess of acetic anhydride at 45° C, at residence time of 600 s, off white solid mass with 93.1% conversion and 95% selectivity of paracetamol was obtained.

[0118] The examples explained above proved that the paracetamol with higher purity and yield was achieved only by the process disclosed in the present disclosure. Any deviation in the process parameters such as rotating or screw speed, variation in the angle of expansion of the screw, temperature, residence time resulted in the paracetamol with poor characteristics, in terms of yield, purity, and conversion. Hence, the present disclosure provides a process for producing paracetamol which is economically viable. ADVANTAGES OF THE INVENTION

[0119] • The present disclosure provides a process for the production of Paracetamol, including in industrial scale.

[0120] • The process for the preparation of paracetamol with acetic anhydride / acetic acid and p-aminophenol is exothermic reaction. Any known grinding or milling method is not suitable for carrying out exothermic reactions. The fumes of acetic acid generated during the reaction get trapped in the grinders or mills leading to increase in the pressure inside these devices.

[0121] • The process of the present disclosure avoids the use of solvent and additional additives, which in turn makes the process economically suitable.

[0122] • The crystalline Paracetamol obtained from the process of the present disclosure is highly pure which may be directly used for further processing without additional step of purification.

[0123] • The process also involves the use of stoichiometric quantities.

[0124] • The process of the present disclosure includes other economic advantages, in terms of cost.

Claims

Claims1. A single step, continuous process of preparation of paracetamol comprising the steps of: i. continuously passing liquid acetic anhydride and solid para-aminophenol in a screw reactor (100) under specific reaction conditions for residence time period in the range of 10-600 seconds, to obtain pure paracetamol wherein the process is done without the addition of solvent; wherein, the specific reaction conditions comprise one or more of: a) the temperature is in the range of 10 to 150°C, b) mole ratio of para-aminophenol to acetic anhydride at the reactor inlet is in the range of 1:1 to 1:2.

2. The process as claimed in claim 1 , wherein temperature is in the range of15 to 125 °C, 15 to 100 °C, 15 to 75 °C, 15 to 50 °C, 15 to 30 °C, or 45 to 55 °C.

3. The process as claimed in claim 1 , wherein the time of liquid acetic anhydride and solid para-aminophenol in said reactor is in range of 10 to 600 seconds, 10 to 500 seconds, 10 to 400 seconds, 10 to 300 seconds, 10 to 200 seconds, 10 to 100 seconds, 10 to 75 seconds, 10 to 50 seconds, 10 to 25 seconds, or 100 to 150 seconds.

4. The process as claimed in claim 1 , wherein the ratio of amount or concentration of p- aminophenol: acetic anhydride is in range of 1: 1 to 1:2, 1:1 to 1: 1.95, 1: 1 to 1: 1.90, 1:1 to 1: 1.85, 1: 1 to 1: 1.80, 1: 1 to 1: 1.75, 1: 1 to 1: 1.70, 1: 1 to 1:1.65, 1: 1 to 1:1.60, 1: 1 to 1:1.55, 1:1 to 1:5, 1:1 to 1: 1.45, 1:1 to 1:40, 1: 1 to 1: 1.35, 1:1 to 1:30, 1: 1 to 1:1.25, 1:1 to 1:20, 1: 1 to 1: 15, 1:1 to l:1.10 or 1: 1 to 1:1.05.

5. The process as claimed in claim 1, wherein the screw reactor (100) is selected from the group consisting of a vertical screw reactor, a horizontal screw reactor, an inclined single screw reactor and a twin-screw reactor or two or more combinations thereof.

6. The process as claimed in claim 1 or 5, wherein said screw reactor is twin-screw reactor comprising one or more of: i. screw shaft diameter in the range of 1.0 - 50 cm;ii. angle of expansion of the screw shaft in the range of -10 to 10°; iii. rotating or screw speed of said reactor is in range of 0 to 200; iv. outer diameter of the screw threads in the range of 1.05 cm - 51 cm; and v. screw length in the range of 30 cm to 500 cm.

7. The process as claimed in claim 1 or 6, wherein the angle of expansion of the screw shaft in said screw reactor which kept around -10°, -7.5°, -5°, -2.5°, 0°, 2.5°, 5°, 7.5°, or 10°.

8. The process as claimed in claim 1 or 5, wherein said screw reactor (100) is a vertical screw reactor with screw shaft diameter of 1.0 cm, angle of expansion of the screw shaft of -10°, outer diameter of the screw threads is 2 cm, and screw length of 30 cm.

9. The process as claimed in claim 1, wherein the conversion of p-aminophenol into paracetamol as product is in range of 95 to 99%, wherein the selectivity of paracetamol is in the range of 85-99%, and wherein the purity of prepared paracetamol as product is in range of 95 to 99.8%.

10. The process as claimed in claim 1, wherein a total number of the screw reactor used in said process is in range of_l to 20.

Images