RU2840649C1 - Method and apparatus for continuous purification of paracetamol by recrystallisation - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to chemical engineering, particularly to a novel method for continuous purification of paracetamol by recrystallisation, as well as to an apparatus for realizing said method. Method for continuous purification of paracetamol by recrystallisation is implemented in several main successive steps: preparing a saturated solution of contaminated paracetamol; purification from insoluble impurities of saturated solution of contaminated paracetamol; cooling the saturated solution of purified paracetamol and creating crystal nuclei; growing crystals in a suspended layer and separating crystals of a given size. Disclosed method is based on using several circulation loops, which enable to simultaneously carry out several process operations in continuous mode without detriment to quality for each of the steps. Furthermore, use of the nucleation step in circulation conditions through an ultrasonic disintegrator enables accurate control of the required size and type of the obtained crystals depending on the given end characteristics of the product. Method enables to carry out recrystallisation of paracetamol in a continuous mode without the need for external inoculum for crystallisation of the product to obtain purified paracetamol of high purity (not less than 99.9 %) and homogeneity on the polymorphic shape of the crystals, and also enables to control a given particle size distribution, having a narrow distribution of crystals by size.

EFFECT: unit provides trouble-free loading of solid contaminated paracetamol eliminating lumping and sticking of paracetamol powder as a result of solvent vapours penetration.

18 cl, 5 dwg, 2 ex

Description

The present invention relates to the field of chemical technology, in particular to a new method for the continuous purification of paracetamol by recrystallization, as well as to an installation for implementing this method.

para- Acetylaminophenol (acetaminophen, paracetamol) is a medicinal product, analgesic and antipyretic from the anilide group, which has an antipyretic effect. According to the mechanism of action, paracetamol blocks cyclooxygenase 1 and cyclooxygenase 2 mainly in the central nervous system, affecting the pain and thermoregulation centers. In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on cyclooxygenase, which explains the almost complete absence of an anti-inflammatory effect. The absence of a blocking effect on the synthesis of prostaglandins in peripheral tissues determines the absence of a negative effect on water-salt metabolism and the mucous membrane of the gastrointestinal tract.

Paracetamol is included in the World Health Organization's list of essential drugs, as well as in the list of vital and essential drugs of the Russian Federation. Therefore, there is still significant interest in the development and implementation of new effective methods of synthesis in research and production areas and cleaning paracetamol, which meet the modern realities of ever-increasing raw material prices and increasingly stringent requirements for ensuring environmentally friendly production.

In order to meet the ever-increasing demands on production efficiency and the quality of the resulting product, pharmaceutical companies are trying to place correspondingly high demands on pharmaceutical substances used in the production of medicines, not only with regard to their purity, but also to the granulometric composition of the crystalline product and the presence of various polymorphic modifications in it.

Polymorphic forms of the same compound may have a noticeable difference in physicochemical properties, such as solubility and melting point. Also, different polymorphs are capable of exhibiting different mechanical properties. In addition, changes in the morphology of the crystal, its shape and size, can affect the process of manufacturing the dosage form and its subsequent stability. For this reason, when manufacturing drugs, the resulting active pharmaceutical substance should be in the most stable state and be characterized by the greatest possible homogeneity of the required polymorphic modification.

It is known (Crystal Growth & Design 2006, 6, 6, 1407-1414) that paracetamol exists in three polymorphic forms: monoclinic (form I, stable), orthorhombic (form II, metastable) and form III (unstable, cannot be clearly characterized).

To obtain the required polymorphic form by crystallization of the substance, it is necessary to observe certain strictly controlled conditions (concentration, temperature of the solution, cooling rate, presence of a seed) with the correct selection of the solvent. Going beyond the limits of at least one of the defined parameters will lead to heterogeneity of the polymorphic form.

The simplest method of purification is recrystallization from various solvents or mixtures, with sorbents and clarifying additives usually used additionally. The process consists of the following main stages: dissolution of the substance, addition of the sorbent and additives, processing with stirring, hot filtration, cooling of the filtrate, crystallization of the purified product, separation of pure crystals.

For example, European patent EP 0 320 484 A2 discloses a method for purifying contaminated N-acetylaminophenol by crystallizing it from a solvent medium, followed by treating the resulting solvent medium (the so-called mother liquor) with an ion-exchange resin to remove chromogenic impurities contained therein, then recirculating the said mother liquor for use as a solvent medium for the crystallization (recrystallization) of subsequent batches of contaminated N-acetylaminophenol. The patent notes that the proposed method for purifying N-acetylaminophenols can be easily adapted for both periodic and semi-continuous and continuous processes, but no examples of implementing this method in a continuous mode are given. There is also no information on the crystalline modification of the obtained paracetamol and data on the granulometric distribution.

In the Chinese patentCN 101624352 AA method for treating purified acetaminophen (paracetamol) mother liquor is disclosed, according to which the purified aqueous acetaminophen mother liquor is treated with electrodialysis or an ion exchange resin and the electrical conductivity of the mother liquor is reduced to below 300 μS/cm; then the aqueous mother liquor purified from paracetamol is recirculated to re-purify the unrefined paracetamol. According to a specific example of implementation contaminated paracetamol and activated carbon are added to the purified mother liquor of paracetamol processed by the claimed method, heated to boiling with stirring, then filtered from activated carbon, cooled the filtrate, then filtered after cooling, washed the sediment on the filter with a small amount of purified water, dried and then dried in a drying cabinet until dry, obtaining white crystals of paracetamol. The process is carried out in a periodic mode.

US Patent No. 5,981,799 A discloses a method for purifying crude N-acetyl-para-aminophenol by preparing a hot aqueous solution of said crude paracetamol and then contacting it with an acid-washed carbon adsorbent that has been pre-treated with an aqueous solution of reducing sulfite. According to the disclosed method: contaminated paracetamol is mixed with water, followed by heating the mixture (preferably from about 70°C to the boiling point of the solution) to dissolve the paracetamol and thereby prepare a hot aqueous solution of crude paracetamol; said hot aqueous solution of crude paracetamol is then contacted with the sorbent using a reflux condenser, wherein the preferred weight ratio of paracetamol to carbon is from about 2:1 to about 200:1; the solution is then filtered and cooled to crystallize the paracetamol, followed by drying the crystals.

Russian patent RU 2668500 C2 discloses a method for producing paracetamol of pharmacopoeial quality by purifying technical paracetamol by recrystallization from an aqueous solution, according to which technical paracetamol and water are loaded into a reactor, the reaction mixture is heated to a temperature of 85±5°C, held for 10-20 minutes, filtered through a pressure filter into a crystallizer, then the reaction mass is self-cooled for 2.5 hours, after which it is additionally cooled to a temperature of 15±5°C and held for 1.5-3.0 hours, then the reaction mixture is filtered, washed with water and dried at a temperature of 90±5°C until the moisture content is no more than 0.5%. The method provides, if necessary, for adding clarifying activated carbon to the reaction mass.

All the presented methods are implemented using large batch reactors, in which the processes of mass and heat transfer are complicated, which inevitably affects the quality of the product. In the case of obtaining significant quantities of the product in these methods, the raw material must be divided into separate batches, as a result of which it is difficult to maintain the same conditions for recrystallization for each batch, the heterogeneity of the properties of the obtained product increases, both in terms of polymorphic form and granulometric composition.

Thus, at present, there still remains a significant need to develop new methods for purifying paracetamol by recrystallization that eliminate or at least minimize the previously mentioned disadvantages of the prior art and make it possible to produce a popular pharmacological product on an industrial scale with reduced consumption of chemical reagents and the ability to maintain high homogeneity of properties throughout the entire continuous purification cycle.

Therefore, the objective of the present invention was to provide a new method for purifying paracetamol by recrystallization, implemented in a continuous mode, and characterized by obtaining purified paracetamol of a high degree of purity and homogeneity in the polymorphic form of crystals, as well as with a given granulometric composition, having a narrow crystal size distribution, which would at the same time ensure economically advantageous recycling of the resulting liquid waste.

The stated problem was solved by means of a new method of continuous purification of paracetamol by means of recrystallization, which includes the following stages:

a) loading solid contaminated paracetamol into the feed line of the recrystallization unit;

b) feeding contaminated paracetamol from the feed line into a recirculation loop of the apparatus for preparing a saturated solution of contaminated paracetamol, through which a portion of the saturated solution of contaminated paracetamol in a suitable solvent continuously circulates as a recirculation flow from the middle section of the apparatus for preparing a saturated solution of contaminated paracetamol, and moving the resulting suspension of contaminated paracetamol along the recirculation loop through a heating heat exchanger to the apparatus for preparing a saturated solution of contaminated paracetamol;

c) introducing a heated suspension of contaminated paracetamol through a dip tube into an apparatus for preparing a saturated solution of contaminated paracetamol to create a suspended layer;

d) taking a portion of the prepared saturated solution of contaminated paracetamol from the upper part of the apparatus for preparing a saturated solution of contaminated paracetamol and directing it to the purification filter system;

e) filtering the saturated solution of contaminated paracetamol through a purification filter system to obtain a saturated solution of purified paracetamol;

f) pre-cooling a saturated solution of purified paracetamol in a flow-through refrigerator and creating crystal nuclei in the pre-cooled saturated solution of purified paracetamol using an ultrasonic disintegrator;

g) directing the suspension enriched with purified paracetamol seed crystals through a cooling circulation circuit to the crystallizer;

h) introducing a cooled suspension enriched with purified paracetamol seed crystals through a dip tube into a crystallizer at a given flow rate to create a suspended layer and grow purified paracetamol crystals;

i) removing part of the purified paracetamol solution enriched with paracetamol crystals from the bottom of the crystallizer into a separating device for separating paracetamol crystals and the mother liquor;

j) directing the crystals of purified paracetamol from the separating device to a drying apparatus to obtain the final product, and the mother liquor to a storage tank;

wherein at step b) the introduction of a portion of the saturated solution of contaminated paracetamol from the middle part of the apparatus for preparing a saturated solution of contaminated paracetamol into the recirculation circuit is carried out through at least two lines located at different heights of the apparatus for preparing a saturated solution of contaminated paracetamol,

wherein part of the purified paracetamol solution is continuously removed at a given flow rate from the middle part of the crystallizer into the cooling circulation circuit, and

whereby part of the mother solution of purified paracetamol is removed from the upper part of the crystallizer into a storage tank, from where, as needed, the mother solution is sent to an apparatus for preparing a saturated solution of contaminated paracetamol.

The presented method according to the invention allows for the recrystallization of paracetamol in a continuous mode without the need for external introduction of a seed for crystallization of the product with the production of purified paracetamol of a high degree of purity (not less than 99.9%) and homogeneity in the polymorphic form of crystals, and also by regulating the rate of circulation of flows through the suspended layer and varying the power of the ultrasonic disintegrator allows for the control of a given granulometric composition having a narrow distribution of crystals by size, while the method according to the invention ensures environmentally and economically advantageous recirculation of waste liquid flows, which significantly reduces the amount of liquid waste.

In addition, by using several streams of saturated solution of contaminated paracetamol to feed the suspension into the apparatus for preparing the solution of contaminated paracetamol, the authors solved the problem of trouble-free loading of solid contaminated paracetamol, eliminating clumping and sticking of paracetamol powder as a result of penetration of solvent vapors, which is extremely important when implementing a continuous recrystallization mode.

Another object of the present invention is a recrystallization unit for carrying out the method for continuously purifying paracetamol according to the invention, comprising

• solid contaminated paracetamol dispenser;

• solid contaminated paracetamol supply line;

• recirculation circuit of a saturated solution of contaminated paracetamol, equipped with a pump and a heat exchanger;

• an apparatus for preparing a saturated solution of contaminated paracetamol, which is a container with a conical narrowing in the lower part, equipped with a heating jacket, a dip tube for introducing a suspension of contaminated paracetamol, a liquid level sensor and a temperature sensor, and also having in the middle part at least two outlets for a saturated solution of contaminated paracetamol into a recirculation circuit of a saturated solution of contaminated paracetamol, located at different heights, and in the upper part an outlet for a saturated solution of contaminated paracetamol;

• a purification filter system fluidly connected to the outlet for the saturated solution of contaminated paracetamol at the top of the apparatus for preparing the saturated solution of contaminated paracetamol;

• flow-through pre-cooling refrigerator, fluidly connected to the cleaning filter system;

• ultrasonic disintegrator for creating crystal nuclei, connected via a fluid medium to a flow-through condenser;

• a circulation cooling circuit equipped with a pump and a refrigerator, connected by fluid medium through a T-shaped tee to a flow-through refrigerator;

• a crystallizer, which is a cylindrical container equipped with a dip tube for introducing a cooled suspension enriched with crystal nuclei of purified paracetamol from a circulation cooling circuit, a liquid level sensor and a temperature sensor, and also having in the middle part an outlet for a solution of purified paracetamol into the circulation cooling circuit, in the lower part an outlet for a solution of purified paracetamol enriched with crystals of paracetamol, and in the upper part an outlet for a mother solution of purified paracetamol;

• a separating device for separating crystals of purified paracetamol, connected via a fluid medium to an outlet for a solution of purified paracetamol enriched with paracetamol crystals, at the bottom of the crystallizer;

• apparatus for drying purified crystalline paracetamol;

• a storage tank for the mother liquor, connected by fluid medium to the outlet for the mother liquor of purified paracetamol at the top of the crystallizer and to the outlet for the mother liquor from the separating device,

wherein the storage tank for the mother solution has an inlet for fresh solvent and an outlet for the mother solution, connected via a fluid medium to the apparatus for preparing a saturated solution of contaminated paracetamol.

The said unit operates in a fully continuous mode, in this mode of operation it is much easier to control the necessary conditions of recrystallization, which allows for the stable production of purified paracetamol of high purity and homogeneity in the polymorphic form of crystals, as well as with a given granulometric composition having a narrow distribution of crystals by size. The fully continuous mode of operation ensures high productivity and allows for easy scaling of the process. In addition, the unit developed by the authors of the invention ensures trouble-free loading of solid contaminated paracetamol, eliminating lumping and sticking of paracetamol powder as a result of penetration of solvent vapors.

The suspended layer technology used in the installation, according to the invention, eliminates the need for mechanical stirrers, which affects the almost complete absence of mechanical destruction of the resulting crystals, which also has a positive effect on the distribution of crystals by size.

In another aspect of the present invention, the object is a method for continuously purifying paracetamol in a recrystallization plant according to the invention.

Detailed description of the essence of the technical solution

Figure 1 shows one of the embodiments of the process flow diagram of a recrystallization unit for the continuous purification of paracetamol.

The detailed description of the method presented below is given for clarity with reference to the installation variant shown in Fig. 1, but does not impose any restrictions on the hardware implementation of the method proposed in the invention.

The developed method is based on the use of several circulation circuits allowing several technological operations to be carried out simultaneously in continuous mode without any loss of quality for each of the stages. In addition, the use of the nucleation stage under circulation conditions using an ultrasonic disintegrator allows for precise regulation of the required size and type of crystals obtained depending on the specified final characteristics of the product.

The method is implemented in several main successive stages: preparation of a saturated solution of contaminated paracetamol; purification of the saturated solution of contaminated paracetamol from insoluble impurities; cooling of the saturated solution of purified paracetamol and creation of crystal nuclei; implementation of crystal growth in a suspended layer and isolation of crystals of a given size.

At the first technological stage a) solid contaminated paracetamol is continuously loaded into the feed line L-5.1 using a feeding device.

The specific type of the feeder is selected based on the characteristics of the raw material used (its moisture, flowability, etc.), for example, the feeder can be selected from a cellular feeder or a screw with a hopper. In the preferred embodiment, the feeder is a cellular feeder with a silo tank P-5.1.

Step b) of the method according to the invention includes feeding contaminated paracetamol from feed line L-5.1 into the recirculation loop of the apparatus for preparing a saturated solution of contaminated paracetamol, through which a portion of the saturated solution of contaminated paracetamol in the corresponding solvent continuously circulates as a recirculation flow from the middle part of the apparatus for preparing a saturated solution of contaminated paracetamol, and moving the resulting suspension of contaminated paracetamol along the recirculation loop through a heating heat exchanger to the apparatus for preparing a saturated solution of contaminated paracetamol D-5.1 .

In this case, the introduction of a portion of the saturated solution of contaminated paracetamol from the middle section of the apparatus for preparing a saturated solution of contaminated paracetamol into the recirculation circuit is carried out through at least two lines located at different heights of the middle section of the apparatus for preparing a saturated solution of contaminated paracetamol D-5.1 .

Recirculation loop of saturated solution of contaminated paracetamol formed by external linesL-5.2/L-5.3 → L-5.4/L-5.6 → L-5.7/L-5.8, which receive contaminated paracetamol from the supply lineL-5.1. Recirculation is maintained by means of a circulation pump.H-5.1. The recirculation circuit also includes a heat exchanger.TO-5.1, the task of which is to heat and maintain the temperature of the recirculating flow with a suspension of contaminated paracetamol.

As a result of continuous circulation of a saturated solution of contaminated paracetamol through the recirculation circuit, a certain vacuum is created in the L-5.1 feed line, which allows for the effective removal of hot solvent vapors and eliminates the soaking and clumping of solid raw materials in the feed device.

The creation of a vacuum in the feed line L-5.1 is affected by the introduction of a saturated solution of contaminated paracetamol through at least two lines located at different heights of the middle part of the apparatus for preparing a saturated solution of contaminated paracetamol. Moreover, the height of the location of these lines is determined by the "established" level of the suspended layer, the first line should be above the boundary of the suspended layer, in the zone of low solids content, and the second line - below the boundary of the suspended layer, in the zone of high solids content. This ensures different flow densities in these lines due to different solid fraction content.

On at least two lines feeding the contaminated paracetamol solution, there are valves with adjustable dampers, for example, K-5.1 (on line L-5.2 ) and K-5.2 (on line L-5.3 ). Since solutions with different solid fraction contents are fed through these lines, flow control using valves on each line allows regulating the density of the suspension created in the recirculation loop and the resulting vacuum in the feed line L-5.1 . However, the density of the resulting suspension still has its limit values, since it also determines the throughput of the recirculation flow through the recirculation loop.

Undoubtedly, according to the invention, more than two lines can be used for introducing a saturated solution of contaminated paracetamol into the recirculation loop, all of them must be located at different heights of the middle part of the apparatus for preparing a saturated solution of contaminated paracetamol in order to have a different content of solid matter and thus provide a finer adjustment of the final density of the suspension in the recirculation loop, and accordingly the necessary vacuum in the feed line L-5.1 and the feed device P-5.1 .

The H-5.1 circulating centrifugal pump additionally ensures wet grinding of solid paracetamol when pumping the suspension, which facilitates its dissolution.

In the method according to the invention, the appropriate solvent for the contaminated paracetamol solution is selected from water-miscible aliphatic alcohols, in particular methanol, ethanol, isopropanol and n-propanol, as well as mixtures thereof with each other and mixtures thereof with water.

Preferably, water-isopropanol mixtures in volume ratios of 1:2 to 6:1, more preferably from 1:1 to 4:1, and particularly preferably in a volume ratio of 4:1 are used as a solvent in the method according to the invention.

It should be separately noted that the said method is described in this document as continuous and already in operation, however, at the initial start-up, a preliminary stage pre-a) of providing a starting amount of a saturated solution of contaminated paracetamol is used once to start the method, wherein at this stage either the corresponding solvent and the calculated amount of solid paracetamol, or the circulating mother solution of paracetamol from another installation are loaded into the apparatus for preparing the saturated solution of contaminated paracetamol, and recirculation and heating are initiated. After reaching the operating temperature of the recirculation stream, the implementation of the method according to the invention itself is started. The operating temperature of the recirculation stream depends on the choice of the corresponding solvent and is generally in the range of 50 to 100°C, preferably in the range of 60 to 80°C, more preferably from 65 to 70°C.

In a preferred embodiment, to bring the installation into operation and balance the flows in the lower part of the D-5.1 apparatus, a bypass K-5.3 is provided, which can also be used in the operating mode to regulate the suction force of hot solvent vapors and air from the P-5.1 cell feeder.

In the next step c) of the method according to the invention, the heated suspension of contaminated paracetamol from the recirculation circuit is introduced through a dip tube into an apparatus for preparing a saturated solution of contaminated paracetamol, creating a suspended layer.

There is always some excess of solid paracetamol in the machine during the dissolution process, resulting in a saturated solution of contaminated paracetamol.

The apparatus for preparing a saturated solution of contaminated paracetamol (also briefly referred to in this document as a "dissolver") is a container with a conical narrowing at the bottom and a heating jacket. This shape facilitates the creation of a suspended layer in the apparatus and the effective separation of crystals from the liquid. The control and management systems in the apparatus include a liquid level sensor LE-5.1 and a temperature sensor TIR-5.1 .

The heated suspension of contaminated paracetamol is introduced into the D-5.1 apparatus through a vertical submersible pipe. The diameter and distance from the bottom of this inlet line are selected in such a way that, at a given pump capacity of H-5.1 , a stable suspended layer of paracetamol crystals is created in the D-5.1 apparatus, a dense sediment layer is not allowed to accumulate at the bottom, and the liquid is separated from undissolved paracetamol crystals in the upper part of the D-5.1 apparatus.

In a preferred embodiment, the apparatus for preparing a saturated solution of contaminated paracetamol is provided with a dip tube, the outlet of which is located in the lower part of the apparatus for preparing a saturated solution of contaminated paracetamol.

Within the framework of the present invention, the "lower part of the apparatus" is located in the region virtually limited by the bottom of the apparatus and the plane running parallel to the horizon at the point of the beginning of the lower third of the height of the corresponding apparatus. The height of the apparatus is determined inside the apparatus from the lowest point on the bottom of the apparatus to the highest point on the cover of the apparatus.

The heating jacket in the apparatus maintains the required temperature of the solution to ensure the required degree of dissolution of the solid paracetamol and, accordingly, the required degree of supersaturation of the solution. Preferably, the solution in the apparatus is heated to a temperature in the range of 60 to 80°C, more preferably from 65 to 70°C.

The prepared hot saturated solution of paracetamol must be treated with a clarifying sorbent and filtered to remove possible microimpurities. For this purpose, at the next technological stage d), a portion of the prepared saturated solution of contaminated paracetamol is collected from the upper part of the apparatus for preparing a saturated solution of contaminated paracetamol and sent to the purification filter system.

The use of a suspended layer in the D-5.1 apparatus significantly reduces the content of solid paracetamol in the upper zone of the solution. In addition, for additional protection against the entrainment of crystals, a cut-off device is provided inside the apparatus. In the preferred embodiment, the cut-off device is an internal separator shelf.

The outlet for the saturated solution of contaminated paracetamol in the upper part of the apparatus for preparing the saturated solution of contaminated paracetamol D-5.1 is connected via a fluid medium to the purification filter system.

In the next step of the method e) the saturated solution of contaminated paracetamol is filtered through a system of purification filters to obtain a saturated solution of purified paracetamol.

The hot solution is fed into the purification filter system using a pump, for example, a membrane or plunger pump, preferably a membrane pump H-5.2 .

The purification filter system may include a different set of filtering equipment that provides the level of purification required within the framework of the present invention.

The prepared hot saturated solution of paracetamol must be treated with a clarifying sorbent and filtered to remove possible microimpurities. For this purpose, at the next technological stage d), a portion of the prepared saturated solution of contaminated paracetamol is collected from the upper part of the apparatus for preparing a saturated solution of contaminated paracetamol and sent to the purification filter system.

The use of a suspended layer in the D-5.1 apparatus significantly reduces the content of solid paracetamol in the upper zone of the solution. In addition, for additional protection against the entrainment of crystals, at least one cut-off device is provided inside the apparatus. In a preferred embodiment, the cut-off device is an internal separator shelf.

The outlet for the saturated solution of contaminated paracetamol in the upper part of the apparatus for preparing the saturated solution of contaminated paracetamol D-5.1 is connected via a fluid medium to the purification filter system.

In the next step of the method e) the saturated solution of contaminated paracetamol is filtered through a system of purification filters to obtain a saturated solution of purified paracetamol.

The hot solution is fed into the purification filter system using a pump, for example, a membrane or plunger pump, preferably a membrane pump H-5.2.

The purification filter system may include a different set of filtering equipment that provides the level of purification required within the framework of the present invention.

In a preferred embodiment, the purification filter system includes a heated bag filter PF-5.1, followed by a heated cartridge filter PF-5.2.

According to the invention, the heated bag filter PF-5.1 is filled with a suitable clarifying sorbent intended for purifying a paracetamol solution from colored impurities. Activated carbon suitable for use in the pharmaceutical industry is preferably used as a clarifying sorbent, for example, NORIT® A SUPRA EUR/USP, NORIT C EXTRA USP and any suitable analogs.

After filtration in a bag filter, the purified solution passes through a heated cartridge filter PF-5.2, where the filter membrane prevents sorbent particles from entering the purified solution and retains all undissolved microimpurities.

In the preferred embodiment, to bring the installation into operation and regulate the flows after the PF-5.1 and PF-5.2 filters, a reverse bypass L-5.12/L-5.13 with a regulating valve K-5.4 is provided.

At the next stage f), crystallization of paracetamol from the purified solution is initiated by pre-cooling the saturated solution of purified paracetamol in a TO-5.2 flow-through condenser and creating crystal nuclei in the pre-cooled saturated solution of purified paracetamol using an UZDN-5.1 ultrasonic disintegrator.

To do this, the solution leaving the purification filter system is directed by pump H-5.3 into the nucleation circulation circuit, which includes a flow-through pre-cooling refrigerator, an ultrasonic disintegrator and the lines connecting them (L-5.14 → L-5.15 → L-5.16), and the nucleation circulation circuit is connected to the purification filter system via a fluid medium through the inlet of the flow-through pre-cooling refrigerator TO-5.2 .

In the flow-through pre-cooling refrigerator TO-5.2, the saturated solution of purified paracetamol is cooled to a temperature in the range from 40 to 50°C. Since the flow-through pre-cooling refrigerator is included in the nucleation circulation circuit, the portion of the saturated solution of purified paracetamol coming from the purification filter system is constantly mixed with the circulating solution, thereby providing the necessary cooling in a short period of time.

Further downstream in the specified nucleation circulation circuit, there is an ultrasonic disintegrator UZDN-5.1 for creating paracetamol crystal nuclei, which is accordingly connected via a fluid medium to a flow-through condenser via line L-5.15 .

The ultrasonic disintegrator UZDN-5.1 is designed to create crystal nuclei as a result of the action of ultrasonic waves with a frequency of 20-150 kHz of a given power on the circulating solution of purified paracetamol. Due to cavitation and mechanical mixing of the solution, ultrasonic waves contribute to the emergence of a large number of crystallization centers in the solution, which leads to the formation of homogeneous crystal nuclei. In addition, ultrasonic waves prevent the emergence of larger agglomerates in the solution, which contributes to a more uniform distribution of the substance and improves the conditions for nucleation and crystal growth.

According to the present invention, flow-type devices equipped with a special waveguide for ultrasonic treatment of liquids can be used as an ultrasonic disintegrator.

When exposed to an ultrasonic disintegrator, significant heating occurs in the liquid, so the disintegrator is equipped with an additional cooling jacket, which also maintains the temperature inside the disintegrator in the range from 40 to 50 ° C. Temperature control is carried out using a TIR-5.2 temperature sensor located inside the disintegrator. The use of ultrasound and flow mode allows you to obtain a large number of high-quality embryonic crystals uniform in their properties (size, polymorphic form).

From the ultrasonic disintegrator, the purified paracetamol solution with the formed crystal nuclei is fed back into the flow-through pre-cooling refrigerator together with a new portion sent from the purification filter system, thus closing the nucleation circulation circuit.

To remove the suspension enriched with crystal nuclei of purified paracetamol, a T-shaped tee is installed at the outlet of the flow-through pre-cooling refrigerator TO-5.2 , with the help of which the excess of the circulating suspension leaves the nucleation circulation circuit.

Accordingly, in the next step of the method g), the suspension enriched with crystal nuclei of purified paracetamol is directed through a circulation cooling circuit to the crystallizer.

In particular, the excess of pre-cooled suspension from the T-shaped tee enters the external circulation cooling circuit of the crystallizer via line L-5.17 . The suspension is circulated in the cooling circuit L-5.18 → L-5.19 using pump H-5.4 through refrigerator TO-5.3 , which maintains the temperature in the circuit in the range from 20 to 30°C.

Next, at stage h), the suspension, cooled to the required temperature and enriched with crystal nuclei of purified paracetamol, is introduced at a given flow rate through a dip tube into the crystallizer to create a suspended layer and grow crystals of purified paracetamol.

The KR-5.1 crystallizer is a cylindrical high container in which the growth of purified paracetamol crystals, separation of crystals by size using a suspended layer and continuous product collection occur. To monitor the process and facilitate the adjustment of input-output flows, the KR-5.1 crystallizer is equipped with a LE-5.2 level sensor. Temperature control in the KR-5.1 crystallizer is performed by a TIR-5.3 sensor.

In a preferred embodiment, for emergency draining and maintenance, the crystallizer is equipped with a drain line L-5.22 with a shut-off valve K-5.7.

The suspended layer of purified paracetamol crystals in KR-5.1 is created in a similar way to that used in the D-5.1 apparatus.

The introduction from the cooling circuit into the crystallizer KR-5.1 occurs through a vertical immersion pipe. The diameter and distance from the bottom of this vertical immersion pipe L-5.19 are selected in such a way that, with a given capacity of the pump H-5.4, a given stable suspended layer of purified paracetamol crystals is created, a dense sediment layer is not allowed to accumulate on the bottom, and the necessary growth and separation of crystals by size is ensured.

In a preferred embodiment, the crystallizer is provided with a dip tube, the outlet of which is located in the lower part of the crystallizer.

Within the framework of the present invention, the "lower part of the crystallizer" is in the region virtually limited by the bottom of the crystallizer and a plane running parallel to the horizon at the point of the beginning of the lower third of the height of the crystallizer. The height of the crystallizer is determined inside the crystallizer from the lowest point on the bottom of the crystallizer to the highest point on the cover of the crystallizer.

In this case, in order to maintain circulation, a portion of the purified paracetamol solution is continuously removed at a given flow rate through the outlet for the purified paracetamol solution from the middle part of the crystallizer into the circulation cooling circuit. This is accomplished using the previously mentioned pump H-5.4 of the circulation cooling circuit. Thus, due to the given suspended layer and the continuous circulation of the fraction from the middle part of the crystallizer, having a certain crystal size, uniform growth of the crystals to the given sizes is ensured, and the stable crystallization conditions (temperature, concentration, etc.) maintained in continuous mode guarantee the formation of crystals of the required modification. Within the framework of the present invention, the "middle part of the crystallizer" is located in the region virtually limited by a plane running parallel to the horizon at the point of the beginning of the middle third of the crystallizer height and a plane running parallel to the horizon at the point of the end of the middle third of the crystallizer height. The height of the crystallizer is determined inside the crystallizer from the lowest point on the bottom of the crystallizer to the highest point on the cover of the crystallizer.

Under the action of the suspended layer in the crystallizer, the crystals are constantly separated by size, due to which the crystals that have reached the required size are concentrated in the lower part of the crystallizer, the crystals that require further growth are concentrated in the middle part, and the mother liquor, practically free of paracetamol crystals, accumulates in the upper part.

Therefore, at stage i) of the method, a portion of the purified paracetamol solution, enriched with paracetamol crystals of a given size, is removed from the lower part of the crystallizer into a separating device, in which the paracetamol crystals are separated from the mother liquor.

In particular, the removal is carried out through the outlet for the solution of purified paracetamol enriched with paracetamol crystals in the lower part of the crystallizer along the lineL-5.21at the entrance separation device, while the intensity of the discharge can be adjusted using a tapK-5.6.

According to the present invention, the separating device is any device that allows for the efficient separation of a solid crystalline precipitate and a liquid mother liquor. In a preferred embodiment, the separating device is selected from a centrifuge or a Nutsche filter.

In a specific embodiment, in the method according to the invention, a Nutsche filter NF-5.1 is used as a separating device.

In the separation device, the crystalline precipitate of paracetamol is squeezed out to a moisture content of 30-50% and, as it accumulates, is sent for drying.

At stage j), the crystals of purified paracetamol from the separating device are sent to a drying apparatus (not shown in the diagram) for final drying and obtaining the final product - purified pharmaceutical grade paracetamol.

Any device capable of gentle drying, such as a vacuum oven, vibration dryer, drum dryer, suspended bed dryer in a gas stream, etc., may be used as a suitable drying apparatus for purified paracetamol. Drying is carried out at a temperature not exceeding 50°C and preferably in an inert atmosphere and/or under reduced pressure to prevent the appearance of color.

Also at stage j), the separated filtrate (mother solution) from the separation device is sent via line L-5.23 to the storage tank for mother solution E-5.1 for storage and reuse.

In addition, excess mother liquor from the upper part of the KR-5.1 crystallizer enters the E-5.1 storage tank. Excess mother liquor is removed naturally through the overflow. As was previously indicated, the use of a suspended layer in the KR-5.1 crystallizer allows achieving a fairly complete separation of the suspension by density, but for additional protection against the entrainment of crystals into the L-5.20 overflow, a cut-off device can be installed inside the KR-5.1 ; in the preferred embodiment, the cut-off device is an internal separator shelf.

Within the framework of the present invention, the "upper part of the crystallizer" is in the region virtually limited by a plane running parallel to the horizon at the highest point of the crystallizer cover and a plane running parallel to the horizon at the end point of the upper third of the crystallizer height. The height of the crystallizer is determined inside the crystallizer from the lowest point on the bottom of the crystallizer to the highest point on the crystallizer cover.

The storage tank for the mother solution also has an inlet for fresh solvent and an outlet for the mother solution, which is connected by fluid to the apparatus for preparing a saturated solution of contaminated paracetamol.

In order to minimize liquid waste in the installation, according to the invention, the recycled mother liquor is repeatedly used. For this purpose, the mother liquor from the storage tank for the mother liquor is directed along lines L-5.24/L-5.25 to the contaminated paracetamol feed line before the heat exchanger TO-5.1 , from which the mother liquor enters the apparatus for preparing a saturated solution of contaminated paracetamol. The intensity of the mother liquor feed from the tank E-5.1 is regulated using the pump H-5.5 and the tap K-5.9 .

Thus, as can be seen from the detailed description provided, the method according to the invention is implemented in a continuous mode and is characterized by obtaining purified paracetamol of a high degree of purity and homogeneity in the polymorphic form of crystals, as well as with a given granulometric composition, having a narrow distribution of crystals by size, and also ensures economically advantageous recirculation of the resulting liquid waste.

The figures show:

Fig. 1 shows a flow chart of one of the embodiments of the installation according to the invention.

Fig. 2 shows a diagram of the crystal size distribution of the original technical grade paracetamol.

Fig. 3 shows a diagram of the crystal size distribution of recrystallized paracetamol according to Example 1.

Fig. 4 shows a diagram of the crystal size distribution of recrystallized paracetamol according to Example 2.

Fig. 5 shows a diagram of the change in the polymorphic composition of paracetamol during recrystallization.

Legend:

D-5.1 Apparatus for the preparation of a saturated solution of contaminated paracetamol (dissolver)

P-5.1 Cellular feeder with silo capacity

PF-5.1 Bag filter with sorbent

PF-5.2 Fine cartridge filter

UZDN-5.1 Ultrasonic disintegrator

KR-5.1 Crystallizer

NF-5.1 Nutsche filter

H-5.1 Recirculation circuit circulation pump

H-5.2 Diaphragm pump for feeding paracetamol solution

H-5.3 Nucleation circuit circulation pump

H-5.4 Cooling circuit circulation pump

H-5.5 Pump for feeding solutions from tank E-5.1 to tank D-5.1

E-5.1 Storage tank for mother solution

TO-5.1 Heat exchanger for heating the recirculation flow

TO-5.2 Flow-through pre-cooling refrigerator

TO-5.3 Cooling circuit refrigerator

LE-5.1 Tank level sensor D-5.1

TIR-5.1 Temperature sensor

TIR-5.2 Temperature sensor

TIR-5.3 Temperature sensor

K-5.1 Crane, operating position - open, adjustment of the upper solvent supply from D-5.1 for adjustment of the suspension density in the circulation circuit (initial position - closed)

K-5.2 Crane, operating position - open, adjustment of the lower solvent feed from D5.1 for adjusting the density of the suspension in the circulation circuit (initial position - closed)

K-5.3 Crane, operating position - closed, adjustment of the solvent supply bypass to bring the unit to mode D5.1 (initial position - open)

K-5.4 Crane, operating position - closed, adjustment of the solvent supply bypass to bring the unit into operation (initial position - open)

K-5.5 Crane, working position - open, shut-off valve of the nucleation circuit (initial position - closed)

K-5.6 Tap, working position - open, tap for feeding paracetamol suspension for filtration (initial position - closed)

K-5.7 Crane, working position - closed, used for emergency draining and washing (initial position - closed)

K-5.8 Crane, working position - open, shut-off valve for returning mother solution and fresh solvent (initial position - closed)

K-5.9 Crane, working position - open, adjustment valve for returning mother solution and fresh solvent (initial position - closed)

L-5.1 Solid contaminated paracetamol feed line into the recirculation loop

L-5.2 Line for removing saturated solution with reduced solid fraction content from dissolver D-5.1

L-5.3 Line for removing saturated solution with increased content of solid fraction from dissolver D-5.1

L-5.4 Contaminated paracetamol suspension supply line

L-5.5 Drain line from dissolver D-5.1 to recirculation circuit

L-5.6 Line for feeding contaminated paracetamol suspension to a centrifugal pump H-5.1

L-5.7 Output line from centrifugal pump H-5.1 for removing mixed suspension after wet grinding into heat exchanger TO-5.1 for heating it

L-5.8 Line for feeding heated suspension of contaminated paracetamol from heat exchanger TO-5.1 to dissolver D-5.1 through a dip tube to create a suspended layer of solid particles in D-5.1

L-5.9 Line for the discharge of hot saturated solution of contaminated paracetamol without solid fraction from dissolver D-5.1

L-5.10 Line for feeding hot saturated solution of contaminated paracetamol to pump H-5.2

L-5.11 Line for pumping a saturated hot solution of paracetamol through two sequentially located filters PF-5.1 and PF-5.2 and feeding the purified solution into the nucleation circuit

L-5.12 Bypass line for feeding part of the solution after the PF-5.1 and PF-5.2 filter block to the K-5.4 tap to adjust the pressure in the system and bring the unit into operation

L-5.13 Bypass line for feeding part of the solution after the K-5.4 adjustment valve back to line L-5.9 to adjust the pressure in the system and bring the unit into operation

L-5.14 Input line for circulation of purified solution into pump H-5.3 in the nucleation circuit

L-5.15 Output line from pump H-5.3 for circulation of purified solution and its supply to refrigerator TO-5.2 in the nucleation circuit

L-5.16 Feeding part of the cooled purified paracetamol solution from the TO-5.2 refrigerator through a T-shaped tee into the UZDN-5.1 ultrasonic disintegrator for generating seed crystals

L-5.17 Feeding part of the cooled purified paracetamol solution from the TO-5.2 refrigerator through a T-shaped tee into the external cooling circuit of the purified paracetamol suspension

L-5.18 Output line from crystallizer KR-5.1 to external cooling circuit of purified paracetamol suspension

L-5.19 Output line from the TO-5.3 refrigerator of the external cooling circuit of the purified paracetamol suspension to the KR-5.1 crystallizer through a dip tube to create a suspended layer of purified paracetamol crystals in the KR-5.1

L-5.20 Overflow line from crystallizer KR-5.1 for natural removal of excess mother liquor into tank E-5.1

L-5.21 Line for sampling a solution of purified paracetamol enriched with paracetamol crystals from a suspended layer in the KR-5.1 crystallizer into the NF-5.1 Nutsche filter

L-5.22 Drain line of crystallizer KR-5.1

L-5.23 Line for removing mother liquor after filtration from the NF-5.1 filter into the E-5.1 tank

L-5.24 Line for feeding depleted mother liquor from tank E-5.1 for recycling using pump H-5.5

L-5.25 Output line from pump H-5.5 for feeding depleted mother liquor for recycling

L-5.26 Feeding pure solvent into tank E-5.1

L-5.27 Line for unloading squeezed purified paracetamol for drying.

The invention is further explained in more detail using embodiment examples, which, however, do not limit the scope of the claims of this invention.

EXAMPLES

Example 1. Recrystallization of paracetamol in continuous mode to obtain crystals with the main crystal fraction of 42-75 µm

The initial technical paracetamol for recrystallization was preliminarily prepared on the unit according to patent RU2802285C1. The main part of technical paracetamol crystals in the initial raw material was a fraction of 60-300 μm, with a purity of 97% (Fig. 2). Insoluble impurities in the initial raw material were ~1.5%, mainly: elemental sulfur, ammonium sulfate, polymers, mechanical impurities. The raw material was characterized by a wide range of crystal sizes and a high content of unstable polymorphic form II (Fig. 5).

A continuous recrystallization setup was constructed according to the scheme shown in Figure 1.

The entire setup was filled with a depleted paracetamol mother liquor in an isopropanol-water (1:4) system with a residual paracetamol content of 54 g/kg of solution. In a 50-liter conical dissolver with a D-5.1 jacket and a recirculation loop of the prepared solution L-5.2/L-5.3 → L-5.4/L-5.6 → L-5.7/L-5.8, the temperature was brought to 65°C using a D-5.1 jacket and a TO-5.1 heat exchanger. The solution pumping rate by the H-5.1 pump along the external loop was selected in such a way as to create a suspended layer of crystals in D-5.1 reaching the level of the L-5.3 line (pumping rate 30-35 l/min). After reaching the temperature regime, solid technical paracetamol was fed through the P-5.1 cellular feeder at a rate of 19.7 g/min. The outlet recirculation flows were regulated by the K-5.1 and K-5.2 valves in such a way that due to the resulting air suction, there was no release of hot solvent vapors into the P-5.1 cellular feeder, and so that the suspension of technical paracetamol in the L-5.4 line did not thicken and moved freely in the circuit.

The prepared hot solution of technical paracetamol without a solid phase was discharged from the D-5.1 dissolver via the L-5.9 line at a rate of 150 g/min. The hot solution was pumped via the L-5.10 line using a membrane pump H-5.2 through a heated bag filter PF-5.1 (70°C, heated using an external electric cuff) at a rate of 150 g/min. In the filter, the solution passed through a layer of carbon sorbent (NORIT® A SUPRA EUR USP, 1 kg). Then the purified solution entered a heated fine cartridge filter PF-5.2 (70°C, heated using an external electric cuff) with a 0.5 micron filter membrane.

After the filter system, the purified solution entered the nucleation circulation circuit L-5.14 → L-5.15 → L-5.16 , where a temperature of 45°C was maintained using a TO-5.2 flow-through refrigerator. The pre-cooled purified paracetamol solution continuously passed through the UZDN-5.1 flow-through ultrasonic cell using an H-5.3 pump at a speed such that the residence time of 90% of the selected portion of the solution in it was 30 seconds (300-350 g/min). The frequency of ultrasonic oscillations of the cell waveguide was 30 kHz ±5%, the maximum power was 1 kW, the power used during the operation of the unit was 300 watts (30% of the power). Mass generation of nuclei of highly homogeneous purified paracetamol crystals took place in the cell.

The excess of purified paracetamol crystal suspension was removed from the nucleation circuit through a T-shaped tee along line L-5.17 into the cooling circuit and then into the isohydric crystallizer KR-5.1 with a volume of 50 l. In the cooling circuit L-5.18 → L-5.19 → KR-5.1, a temperature of 25°C was maintained using a TO-5.3 refrigerator. The speed of pumping the solution by pump H-5.4 in the external circuit was set so as to maintain a stable suspended layer of paracetamol crystals in KR-5.1 (30 l/min). In this case, only the very top layer of small crystals rose to the outlet line L-5.18 , and the solid fraction did not rise to the overflow line L-5.20 . The bulk of the purified paracetamol crystals was located in the lower third of the KR-5.1 crystallizer, at the level of the L-5.21 outlet line.

Through the outlet line L-5.21 , part of the solution with crystals of a given size was removed from the KR-5.1 crystallizer into the NF-5.1 Nutsche filter. The crystalline paracetamol removed from the crystallizer was squeezed out on the filter and washed with distilled water at a flow rate of 12 ml/min. The filtrate from the Nutsche filter entered the E-5.1 tank through the line L-5.23 , and the wet sediment of pure paracetamol with a moisture content of ~40% was discharged into the Stegler VAC-52 vacuum drying oven as it accumulated for final drying at 45°C and a pressure of 20 mbar.

In addition, the excess pure mother liquor was removed from the KR-5.1 crystallizer by gravity through line L-5.20 into the E-5.1 storage tank. A fresh isopropanol-water solution (1:4) was also fed into tank E-5.1 through line L-5.26 at a rate of 720 g/hour to compensate for the loss of the working solution during product isolation. Using pump H-5.5 , the recycled mother liquor was fed from tank E-5.1 at a rate of 130.3 g/min through line L-5.24/L-5.25 into the recirculation loop for preparing the contaminated paracetamol solution.

The setup operated continuously for 48 hours with a capacity of 1.09 kg/hour of purified paracetamol (yield 94.9% of theoretical, purity 99.9%). The obtained paracetamol fully complies with the pharmacopoeial article FS.2.1.0154.18. The main fraction of crystals was 42-75 μm (Fig. 3) with a content of polymorphic form II of ~1.25% (Fig. 5).

Example 2. Recrystallization of paracetamol in continuous mode to obtain crystals with a main fraction of crystals of 30-55 µm

The initial technical paracetamol for recrystallization was preliminarily prepared on the unit according to patent RU2802285C1. The main part of technical paracetamol crystals in the initial raw material was a fraction of 60-300 μm, with a purity of 97% (Fig. 2). Insoluble impurities in the initial raw material were ~1.5%, mainly: elemental sulfur, ammonium sulfate, polymers, mechanical impurities. The raw material was characterized by a wide range of crystal sizes and a high content of unstable polymorphic form II (Fig. 5).

A continuous recrystallization setup was constructed according to the scheme shown in Figure 1.

The process was carried out similarly to the method from Example 1, but with an increased power of the ultrasonic module to 50% and a decrease in the flow rate to 20 l/min in the cooling circuit L-5.18 → L-5.19 → KR-5.1 . This made it possible to obtain smaller crystals of purified paracetamol. Increasing the power of ultrasonic treatment of the solution allows generating more crystal nuclei. Reducing the mass flow rate of the suspension in the cooling circuit reduces the force of the ascending flow in the crystallizer, which is created using a submersible pipe. As a result, the upper boundary of the suspended layer of crystals drops lower and a fraction of smaller crystals appears in the zone of product collection from the crystallizer along line L-5.21 .

The setup operated continuously for 48 hours with a capacity of 1.07 kg/hour of purified paracetamol (yield 93.2% of theoretical, purity 99.9%). The obtained paracetamol fully complies with the pharmacopoeial article FS.2.1.0154.18. The main fraction of crystals was 30-55 μm (Fig. 4) with a content of polymorphic form II of ~2.1% (Fig. 5).

The results obtained in the presented examples 1-2 demonstrate that the method according to the invention allows for the recrystallization of paracetamol in a continuous mode without the need for external introduction of a seed for crystallization of the product with the production of purified paracetamol of a high degree of purity (more than 99.9%) and homogeneity in the polymorphic form of crystals, and also by regulating the rate of circulation of flows through the suspended layer and varying the power of the ultrasonic disintegrator allows for the control of a given granulometric composition having a narrow distribution of crystals by size.

Claims (44)

1. A method for the continuous purification of paracetamol by recrystallization, comprising the following steps: a) loading solid contaminated paracetamol into the feed line of the recrystallization unit; b) feeding contaminated paracetamol from the feed line into the recirculation loop of the apparatus for preparing a saturated solution of contaminated paracetamol, through which part of the saturated solution of contaminated paracetamol in the appropriate solvent continuously circulates as a recirculation flow from the middle part of the apparatus for preparing a saturated solution of contaminated paracetamol, and moving the resulting suspension of contaminated paracetamol along the recirculation loop through the heating heat exchanger to the apparatus for preparing a saturated solution of contaminated paracetamol; c) introducing a heated suspension of contaminated paracetamol through a dip tube into an apparatus for preparing a saturated solution of contaminated paracetamol, creating a suspended layer; d) taking a portion of the prepared saturated solution of contaminated paracetamol from the upper part of the apparatus for preparing a saturated solution of contaminated paracetamol and directing it to the purification filter system; e) filtering the saturated solution of contaminated paracetamol through a purification filter system to obtain a saturated solution of purified paracetamol; f) pre-cooling a saturated solution of purified paracetamol in a flow-through refrigerator and creating crystal nuclei in the pre-cooled saturated solution of purified paracetamol using an ultrasonic disintegrator; g) directing the suspension enriched with purified paracetamol seed crystals through a cooling circulation circuit to the crystallizer; h) introducing a cooled suspension enriched with purified paracetamol seed crystals through a dip tube into a crystallizer at a given flow rate to create a suspended layer and grow purified paracetamol crystals; i) removing part of the purified paracetamol solution enriched with paracetamol crystals from the bottom of the crystallizer into a separating device for separating paracetamol crystals and the mother liquor; j) directing the crystals of purified paracetamol from the separating device to a drying apparatus to obtain the final product, and the mother liquor to a storage tank; wherein at step b) the introduction into the recirculation circuit of a portion of the saturated solution of contaminated paracetamol from the middle part of the apparatus for preparing a saturated solution of contaminated paracetamol is carried out through at least two lines located at different heights of the apparatus for preparing a saturated solution of contaminated paracetamol, and wherein part of the purified paracetamol solution is continuously removed at a given flow rate from the middle part of the crystallizer into the cooling circulation circuit, and whereby part of the mother solution of purified paracetamol is removed from the upper part of the crystallizer into a storage tank, from where, as needed, the mother solution is sent to an apparatus for preparing a saturated solution of contaminated paracetamol. 2. The method according to claim 1, characterized in that the corresponding solvent for the contaminated paracetamol solution is selected from water-miscible aliphatic alcohols, in particular methanol, ethanol, isopropanol and n-propanol, as well as mixtures thereof with each other and mixtures thereof with water. 3. The method according to claim 2, characterized in that the corresponding solvent for the contaminated paracetamol solution is a water-isopropanol mixture in a volume ratio of 1:2 to 6:1. 4. The method according to claim 1, characterized in that the temperature of the heated suspension of contaminated paracetamol in step c) is in the range from 50 to 100°C, preferably in the range from 60 to 80°C. 5. The method according to claim 1, characterized in that the preliminary cooling of the saturated solution of purified paracetamol in a flow-through refrigerator at stage f) is carried out to a temperature in the range from 40 to 50°C. 6. The method according to claim 1, characterized in that in the cooling circulation circuit at stage g) the temperature is maintained in the range from 20 to 30°C. 7. A recrystallization unit for carrying out the method for continuous purification of paracetamol according to any one of claims 1-6, comprising • solid contaminated paracetamol dispenser; • solid contaminated paracetamol supply line; • recirculation circuit of a saturated solution of contaminated paracetamol, equipped with a pump and a heat exchanger; • an apparatus for preparing a saturated solution of contaminated paracetamol, which is a container with a conical narrowing in the lower part, equipped with a heating jacket, a dip tube for introducing a suspension of contaminated paracetamol, a liquid level sensor and a temperature sensor, and also having in the middle part at least two outlets for a saturated solution of contaminated paracetamol into a recirculation circuit of a saturated solution of contaminated paracetamol, located at different heights, and in the upper part an outlet for a saturated solution of contaminated paracetamol; • a purification filter system fluidly connected to the outlet for the saturated solution of contaminated paracetamol at the top of the apparatus for preparing the saturated solution of contaminated paracetamol; • flow-through pre-cooling refrigerator, fluidly connected to the cleaning filter system; • ultrasonic disintegrator for creating crystal nuclei, connected via a fluid medium to a flow-through condenser; • a circulation cooling circuit equipped with a pump and a refrigerator, connected by fluid medium through a T-shaped tee with a flow-through refrigerator; • a crystallizer, which is a cylindrical container equipped with a dip tube for introducing a cooled suspension enriched with crystal nuclei of purified paracetamol from a circulation cooling circuit, a liquid level sensor and a temperature sensor, and also having in the middle part an outlet for a solution of purified paracetamol into the circulation cooling circuit, in the lower part an outlet for a solution of purified paracetamol enriched with crystals of paracetamol, and in the upper part an outlet for the mother solution of purified paracetamol; • a separating device for separating crystals of purified paracetamol, connected via a fluid medium to an outlet for a solution of purified paracetamol enriched with paracetamol crystals, at the bottom of the crystallizer; • apparatus for drying purified crystalline paracetamol; • a storage tank for the mother liquor, connected by fluid medium to the outlet for the mother liquor of purified paracetamol at the top of the crystallizer and to the outlet for the mother liquor from the separating device, wherein the storage tank for the mother solution has an inlet for fresh solvent and an outlet for the mother solution, connected via a fluid medium to the apparatus for preparing a saturated solution of contaminated paracetamol. 8. The installation according to item 7, characterized in that the separating device is any device that allows for the effective separation of the solid fine-crystalline sediment and the liquid mother liquor, preferably the separating device is selected from a centrifuge or a Nutsche filter. 9. The installation according to item 7, characterized in that the apparatus for preparing a saturated solution of contaminated paracetamol is additionally equipped in the upper part with at least one cut-off device to protect against the entrainment of crystals. 10. The installation according to item 9, characterized in that the shut-off device is an internal separator shelf. 11. The installation according to item 7, characterized in that the crystallizer in the upper part is additionally equipped with at least one cut-off device to protect against the entrainment of crystals. 12. The installation according to item 11, characterized in that the shut-off device is an internal separator shelf. 13. The installation according to item 7, characterized in that the apparatus for preparing a saturated solution of contaminated paracetamol is equipped with a submersible pipe, the outlet of which is located in the lower part of the apparatus for preparing a saturated solution of contaminated paracetamol. 14. The installation according to item 7, characterized in that the crystallizer is equipped with a submersible pipe, the outlet of which is located in the lower part of the crystallizer. 15. The installation according to item 7, characterized in that the cleaning filter system includes a heated bag filter and a heated cartridge filter following it. 16. The installation according to item 15, characterized in that the bag filter contains a clarifying sorbent, which is selected from grades of activated carbon suitable for use in pharmaceutical production. 17. The installation according to item 7, characterized in that the ultrasonic disintegrator is a flow-type device equipped with a waveguide for ultrasonic treatment of liquids. 18. The installation according to item 7, characterized in that the flow-through pre-cooling refrigerator, the ultrasonic disintegrator and the lines connecting them are combined into a nucleation circulation circuit.