UA57045C2 - A process for the crystallization of losartan - Google Patents

Abstract

Losartan potassium is an angiotensin II antagonist useful in the treatment of hypertension and congestive heart failure. This invention relates to the process for the controlled crystallization of losartan potassium utilizing anti-solvent addition combined with massive seeding in order to obtain the desired crystal morphology and bulk physical properties necessary for successful formulation.

Description

Description of the invention

Losartan potassium, also known as 2-butyl-4-chloro-1-((2-(tetrazol-5-yl)-biphenyl-4-yl)umethyl|-5-hydroxymethyl)imidazole potassium salt, is approved for the treatment hypertension.

It is known that losartan inhibits the action of the octapeptide hormone angiotensin I! (AII) and, as a result, is suitable for alleviating the state of hypertension caused by angiotensin. The renin enzyme acts on o-2-globulin of the blood plasma, angiotensinogen, with the formation of angiotensin!, which is then transformed into AI under the action of the angiotensin-converting enzyme. This substance is a potent vasoconstrictor agent that is a blood pressure-increasing agent in various mammalian species such as rats, dogs, and humans. Losartan inhibits the effect

AII on its receptors on the target cell and, thus, prevents the increase in blood pressure caused by the interaction of the hormone-receptor. By administering losartan to mammalian species with atherosclerosis and/or high cholesterol retention and/or hypertension due to exposure to AI, their blood pressure decreases. Losartan t is also suitable for the treatment of high cholesterol retention by lowering total cholesterol retention. Administration of losartan together with a diuretic such as urosemide or hydrochlorothiazide or as a stepwise combination therapy (diuretic first) or as a physical mixture improves the antihypertensive effect of losartan in the simultaneous treatment of atherosclerosis and lowering the level of cholesterol retention. Administering losartan with a nonsteroidal anti-inflammatory drug may prevent kidney failure that sometimes results from the administration of this drug.

Figure. Schematic layout of the equipment for the proposed method of crystallization.

The present invention relates to a method of controlled crystallization of losartan potassium using the addition of an antisolvent in combination with the mass introduction of seeds in order to obtain the desired crystal morphology and bulk physical properties necessary for a successful drug preparation technology. c 29 The method of crystallization of losartan potassium includes the following stages: Ge) a) distillation of the isopropanol-water mixture containing losartan potassium to a water content of approximately 2.4 to approximately 2.890; b) cooling the mixture to a temperature of from about 65 to about 707C; c) addition of approximately 0.5 wt.9o of finely ground losartan potassium to a suspension of cyclohexane at a temperature of approximately 607°C to approximately 65°C at a rate of approximately 0.3l/min. until a cloud point is reached at a water content of about 1.8 to about 2.395; d) keeping the mixture for about ten minutes; o e) adding from about 3 to about 1Omas.9o of finely ground losartan potassium to introduce the seed into the mixture in the temperature range from about 607C to about 707C;

Zo f) keeping the seeded mixture for a period of about one to about 2 hours, in the range of temperatures from about 607C to the boiling temperature, with stirring; g) addition at a temperature of approximately 60 - 65"C of a cyclohexane solution over a period of time of approximately two hours while maintaining the temperature of the mixture at approximately 687; "h) distillation of the mixture at a constant volume to a water content of approximately 0.595 while maintaining a constant volume of З7З 70 due to the addition of a mixture of cyclohexane and isopropanol in a ratio of about 50:50 to 80:20 by volume; "c i) distillation of the mixture to a suspension density of about 200 g/l and a water content of less than about 0.195, when adding, if this of cyclohexane, as needed, so as to maintain a cyclohexane:isopropanol ratio of about 50:50 to about 60:40 by volume; q) cooling the mixture to a temperature from about 207C to about 30"; o l) filtering the mixture to isolate crystalline losartan potassium; -I m) washing the crystalline material with a mixture of cyclohexane:isopropanol in the ratio 75:25; n) washing the crystalline material with cyclohexane; and o o) drying crystalline losartan potassium under vacuum at a temperature from about 457C to about 70 Bo.

A variant of the method described above is proposed, in which from approximately 3 to 100 grams of seed is added in the form of finely ground losartan potassium.

A variant implementation of the method described above is proposed, in which the stage of distillation of the isopropanol-water mixture proceeds until a water content of from about 2.6 to about 2.895 is reached. 99 A variant of the method described above is proposed, in which a suspension of potassium

HF) of losartan in cyclohexane is added until a cloud point is reached at a water retention of about 1.8 to about 2.095.

A variant of the method described above is proposed, in which the temperature at the stage of inoculation is from approximately 657C to approximately 70"C. 60 A variant of the method described above is proposed, in which distillation at a constant volume is carried out until the water content is less than approximately 0.595.

In the best variant of the implementation of the method described above, approximately 5 wt. 90% of seed is added in the form of finely ground potassium-losartan.

A variant of the method described above is proposed, in which the size of the seed particles in the form of finely ground losartan potassium is from about 8 to about 100 μm.

Losartan, well known as 2-butyl-4-chloro-1-((2-(tetrazol-5-yl)-biphenyl-4-yl)umethylyl-5-(hydroxymethyl)imidazole potassium salt (Formula 1!) is useful for the treatment of hypertension as a selective angiotensin II antagonist

Mm-M m s potassium-pozartan

Losartan potassium can be obtained using the reactions and methods described in US patent Mo5138069 and UMO 93/10106 or in one of its three analogues in the USA, namely US patent Mo5130439, issued on July 14, 1992, US patent Mo5206374, issued April 27, 1993, and US Doc. Mo. 07/911813, registered on July 10, 1992.

A method was developed for the preparation of preparations based on losartan potassium using a material that was crystallized by nucleation using an uncontrolled distillation process. The morphology of the crystals was the morphology of small flat rods. In an attempt to make the existing crystallization technique more controllable, the "distillation" process was somewhat refined to include seeding and maintaining a constant solvent composition. However, the resulting morphology was the morphology of large three-dimensional crystals. This material cannot be used for the preparation of medicinal products using the existing preparation technology. Experiments in i) comparing the properties of small flat rods, obtained using another experimental method of crystallization, related to the technology of preparation of medicinal preparations, with the properties of clusters convincingly proved the importance of the size of crystals and their morphology in the technology of preparation of medicinal preparations. This leads to strictly specified characteristics of particle size and bulk density of losartan potassium. -

The use of an antisolvent controlled seeding process stems from our previous work and the need for improvement. The primary driving force for crystallization was cyclohexane as an antisolvent, rather than distillation. This allows for greater control over the approach to saturation than distillation. (Cyclohexane is used as an antisolvent. Seeding cyclohexane has been used, but not for cloud point purposes.) However, using an antisolvent by itself or with some amount of seed in it still results in different physical properties due to the existing tendency of the K-salt to form a supersaturated solution and then spontaneous nucleation. Improvements to this process included tighter control over " temperature, tighter control over water content, and mass application of the seed at saturation. It was this 7-3 s that became the essence of the method, by virtue of which he is able to give crystals having the desired particle size distribution. and morphology, necessary for the successful preparation of medicinal preparations. and?" In the method according to the invention, a more traditional concept of crystallization is used, that is, the addition of an antisolvent is used to control the approach to saturation and to control crystal growth. In this method, a solution of the potassium salt of losartan in a mixture of isopropanol:water is distilled to a value of KE (water content according to Karl Fischer titration) of approximately 2.695. Cyclohexane, containing a small amount of seed (0.590 seed is 5% by weight of the expected K-salt product in the solution, i.e. 595% of the amount expected as a result of crystallization), is added up to the moment of the beginning of crystallization, called the "cloud point" . The seed is added to cyclohexane in order to prevent supersaturation in the loaded portion of the material. Thus, the seed will dissolve during the initial stages of addition of cyclohexane, but as the treated portion of material reaches saturation, the seed will cease to dissolve and the portion of material will become turbid. During some of the experiments, it was difficult to determine the cloud point. Some portions of the material became cloudy at a KE value of approximately 2.495. When a seed was introduced into such a portion of the material at a KE value equal to 2.2595, the seed dissolved. Thus, the cloud point alone cannot be used as the only indication of the saturation point. As the experimental data accumulate during the process, the intervals of the KE indicator

F) were narrowed, thereby minimizing the need to determine the cloud point. Preferably, the introduction of 590 ka seed was carried out based on the value of KE, after a given amount of suspension in cyclohexane was added. Thus, when enough of the cyclohexane/seed mixture had been added to reduce the KE of the 60 treated portion to a size of about 1.895 to about 2.095, a portion of the material was seeded with a finely ground seed of 596. In prior methods, the use of finely ground seed resulted in cluster formation . In the method according to the invention, a "hardening" hold is introduced after the addition of the seed, with the help of which there is a release from the stress cells introduced into the crystal as a result of grinding due to the dynamic equilibrium of the dissolution process in the system. At the end of 65 Aging, the rest of the cyclohexane is slowly added to the processed portion, so as to bring the volume ratio of cyclohexane: isopropanol to a value of approximately 55:45. From this point on, processing continues in the same way as in the case of a process based entirely on distillation. The advantage, however, is that the indicator

KE has a much smaller value (from 1.2 to 1.395 vs. from 1.5 to 1.695), so that a larger part of the processed portion turns out to be crystallized. In fact, at this value of KE, approximately 5095 processed portions of the material crystallized. Therefore, the time of the distillation cycle becomes a less critical factor in crystal nucleation and growth. And volume) water approximately 1,995) 00000000 Child CPU CPU 75:25 PM CC: Inn vessimdvuvs000000000000 ././//::/AT-/

The following examples further illustrate the preparation of losartan potassium and, as such, should not be considered or construed as limiting the invention set forth in the appended claims. "

EXAMPLE 1

Potassium salt of 2-n-butyl-4-chloro-1-(2'-(tetrazol-5-yl)-1,1"-biphenyl-4-yl)umethyl)-1H-imidazole-5-methanol o

Isopropanol (23.4 kg) was loaded into a container with a volume of 189.3 l, and then 7.5 kg was added to it

3-n-butyl-4-chloro-1-((2'-(tetrazol-5-yl)-1,1'-biphenyl-4-yl)umethyl|-1H-imidazole-b-methanol in the form of free

From acid (purity 98.695 wt.). The entire processed portion of the material was heated to 35 - 457 and 1.864 kg and) 8.91 N were added. KOH followed by holding for one hour.

8Oml of 8.91n was added. KOH and after holding for a further 15 minutes, the retention of free acid decreased to 2.0295. Finally, with the help of Zb5 ml of KOH, the residual level of the free acid content was brought to 0.195 (degree of conversion into potassium salt 99.9965). The processed portion of the material was moved into the field-drum using nitrogen under a pressure of 48.3 - 103.4 kPa. The 189.3 L initial vessel was washed with 18.9 liters of a cyclohexane:isopropanol mixture, which was discarded, and the treated portion was reloaded into the vessel through a 1-μm pore size filter and then through a 0.bμm pore size filter using residual vacuum." The treated portion was distilled at constant volume with the concomitant addition of isopropanol to reduce the water content. A total of 21.5 liters were passed. The distillation temperature was 82°C. The KE of the treated portion was 2.569; 30 ml of water was added to bring the KE to 2.6495. -1 During the distillation of isopropanol, 12.4 kg of cyclohexane and 40 g of finely ground K-salt were loaded into a vessel with a volume of 75.7 L and heated to 60 - 657 C. Then the suspension was subjected to recirculation through a container with a volume of 74.7 L in the preparation process before moving into a crystallizer with a volume of 189.ZL. When the transfer process began, there were 250 of them and it was observed that the K-salt solution was transparent. The transfer rate was approximately 0.ZL/min. The temperature in the 75.7L container was 55 - 60"C, while in a container with a volume of 189.3 liters it was 65 - 747. A total of 10.6 bkg of suspension was needed to reach the cloud point (the KE value of the portion was 1.9496).

The amount of added suspension was determined by emptying a container with a volume of 75.7 liters and weighing the remaining material. Using gas chromatography, it was established that the volume ratio of cyclohexane/isopropanol is 25/75.

GF! Four hundred grams of finely ground K-salt was added to the processed portion and kept at 687C for two hours. o Cyclohexane (20.5 kg) was loaded into a container with a volume of 75./l and heated to 60 - 65 "C. This substance was loaded into a container with a volume of 189.3 l using nitrogen pressure for an extended period of time of two hours at 60 maintaining the temperature of the processed portion equal to 682C.

The processed portion was subjected to distillation at a constant volume with the concomitant addition of a mixture of cyclohexane:isopropanol in the ratio of 75:25. A total of 57 liters were distilled and 45 kg of the 75:25 mixture was added.

The treated portion was evaporated to a volume of approximately 38 liters by distilling 47.3 liters and loading again b.0 kg of cyclohexane. 65 Using gas chromatography, it was established that the volume ratio of cyclohexane/isopropanol is 64.6:35 4.

An additional 22.7 liters of distillate was collected with the simultaneous addition of 18 kg of a mixture of cyclohexane:isopropanol in the ratio of 75:25, so as to lower the final value of KE in the portion to 0.0295. The concentration of K-salt was 2.3 g/l.

Then the processed portion was cooled to 20 - 30"C, filtered on a filter tank with a diameter of 48.3 cm, lined with fabric/paper/fabric, and washed with 20 kg of a mixture of cyclohexane:isopropanol 75:25, and then with 20 kg of cyclohexane. The portion dried on trays under vacuum while removing nitrogen at a rate of 14.16 normal l/min at 45 - 50"C for 8 hours. Only 7.bkg of the product with a purity of 99.990wt was obtained. According to the submitted ЭЖХ. 70 EXAMPLE 2

Potassium salt of 2-n-butyl-4-chloro-1-(2'-(tetrazol-5-yl)-1,1'-biphenyl-4-yl)umethyl|-1H-imidazole-5-methanol 25.4 kg of isopropanol and kg of K-salt were loaded into a container with a volume of 189.3 liters together with 90 ml of deionized water.

The KE index of the prepared solution was 2.4895. In a container with a volume of 75.7 liters, 12 4 kg of cyclohexane and 40 g of finely ground K-salt were heated to 60 - 65"7C and added to a container with a volume of 189.3 liters over a period of 40 /5 minutes, until the solution In the process of this addition, the contents of the container with a volume of 189.3 ml were kept boiling (the boiling temperature decreased from 747°C to 68°C). The EC at which the cloud point occurred was 1.9095, and the amount of cyclohexane slurry used to reach the cloud point was 6.2 kg. Then the treated portion was cooled to 60"C and 400g of seed in the form of finely ground K-salt was added and kept at a boiling state (70"C) for one hour. During 1 hour, cyclohexane (24.9 kg) was added to the portion, which was heated to 65"C. During this addition, the portion was kept at a boiling state. After the addition, the KE index of the processed portion was 1.2195. The portion was subjected to distillation at a constant volume with the simultaneous addition of 35 kg of a mixture of cyclohexane:isopropanol 75:25, so as to achieve a KE indicator of the portion equal to 0.5495. 41.bl of distillate was collected when adding bkg of cyclohexane to the processed portion at the stage of evaporation. The KE indicator at the end of this evaporation was about was 0.1195. After cooling to 20 - 25"C, the charge was filtered in a 48.3cm filter tank unit supplied with a cloth/paper/cloth filter layer, and the filtration was carried out under i) nitrogen atmosphere. The filter cake was washed with 20 kg of a mixture of cyclohexane:isopropanol 75:25, and then with 20 kg of cyclohexane. The load was dried on trays at 45-50"C under vacuum.

EXAMPLE C yuzo Potassium salt 2-n-butyl-4-chloro-1-(2'-(tetrazol-5-yl)-1,1'-biphenyl-4-yl)umethyl|-1H-imidazol-5- of methanol, 25.5 kg of isopropanol, 9400 ml of deionized water and kg of K-salt were loaded into a container with a volume of 189.3 liters. "

The KE index of the prepared solution was 2.69905. In a container with a volume of 7.57 l, 12 4 kg of cyclohexane and 40 g of finely ground K-salt were heated to 57 "C. A portion of the material to be processed in a container with a volume of 189.3 l was heated to boiling (82 "C) and added to her suspension in cyclohexane for an extended period of time of 1 hour and 10 minutes. In the process of this addition, the processed portion was kept in a boiling state (during this addition, the boiling temperature dropped from 827C to 72"C). The KE index at the cloud point was 2.195, and 400g of seed in the form of finely ground K-salt was added and kept in a state of boiling (697) for a further 2 hours.

The amount of cyclohexane suspension added before the cloud point was reached was 10.4 kg. After standing, an additional 20.7 kg of cyclohexane was added to the processed portion for 1 hour while maintaining the temperature of the portion equal to 657C. At the end of adding cyclohexane, the KE was 1.399. shsh s The processed portion was subjected to distillation at a constant volume with the addition of 73 kg of a mixture of cyclohexane: isopropanol 75:25 to the value of the KE indicator, which is equal to 0.2395, with subsequent evaporation at ;" half of the volume (56b.8l of distillate was collected, with the addition of 7.5kg of cyclohexane). At the end of the evaporation process, no water was detected. The charge was cooled to 20 - 30"C, filtered and washed, as before, with 20 kg of a mixture of cyclohexaneisopropanol 75:25, and then with 20 kg of cyclohexane. Purity of the product according to HPLC data was 99.59 by mass, purity by area in bo - 99.995. The KE indicator was 0.390.

EXAMPLE 4

Ш- Potassium salt of 2-n-butyl-4-chloro-1-((2'-(tetrazol-5-yl)-1,1-bidenyl-4-ylylmethyl|-1H-imidazole-5-methanol) about 25, 4 kg of isopropanol, 100 Oml of deionized water and 8 kg of K-salt were loaded into a container with a volume of 189.3 liters.

Since the KE index was 3.150, the treated portion was subjected to distillation at a constant volume with the concomitant addition of 4.1 L of isopropanol until the KE index value was reached, which was equal to 2.7395. 12 4 kg of cyclohexane and 40 g of seed in the form of finely ground K-salt were loaded into a container with a volume of 75.7 l and heated to 5570.

The suspension was added to the treated portion over a period of 2 hours while maintaining the temperature of the portion equal to 70"7s.

Turbidity was noted at the time of addition of cyclohexane, when a KE of 2.495 was reached. However, the inoculation in the treated portion was carried out with a KE indicator of 2.25905. The amount of suspension (F) added before reaching this KE value was 9.9 kg. The portion was kept for two hours at 68°C. At the end of the keeping time, it turned out that the seed had dissolved.

Five liters of cyclohexane containing 25 g of seed in the form of finely ground K-salt was added at room temperature over a period of one minute to the crystallizer through a subsurface injection line. In the process of this addition, the temperature of the processed portion dropped from 68"C to 647C. The KE index of the portion was 1.9395. After a 10-minute exposure, 400g of seed was added in the form of finely ground

K-salt, the portion was kept for two hours at 69"7C and 21.2 kg of cyclohexane (at 627) was charged for 1 hour while maintaining the temperature of the portion equal to 68"C. The KE indicator was 1.23905. 65 The portion was subjected to distillation at a constant volume with the addition of 42 kg of a mixture of cyclohexane:isopropanol 75:25 (56.8 liters of distillate was collected). The KE indicator was 0.495. Then the portion was evaporated to half the volume by adding 1 kg of cyclohexane (56.8 l of distillate was collected). The KE indicator was 0.1495. Finally, in order to further reduce the KE index, an additional 56b.8l of distillate was collected with the simultaneous addition of 45 kg of a mixture of cyclohexane:isopropanol 75:25 to the final value of the KE indicator, which was equal to 0.0295. The load was filtered on a 48.3 cm filter tank, washed with 20 kg of a mixture of cyclohexane: isopropanol 75:25 and 20 kg of cyclohexane and dried under vacuum at 45 - 5070. A total of 7.59 kg of product with a purity of 99.390 wt. ., 99.990 in area and the value of the KE indicator, which is equal to 0.290.

EXAMPLE 5

Potassium salt of 2-n-butyl-4-chloro-1-(2'-(tetrazol-5-yl)-1,1'-biphenyl-4-yl)umethyl|-1H-imidazole-5-methanol 70 25, 4 kg of isopropanol, 1044 ml of water and 8.0 kg of K-salt were loaded into a container with a volume of 189, PLN. The KE indicator was 2.61. 12.4 kg of cyclohexane together with 40 g of seed in the form of finely ground K-salt were loaded into a vessel with a volume of 7.57 l and heated to a temperature of approximately 73"C. The suspension in cyclohexane was added over a period of 45 minutes.

The temperature of the treated portion at the beginning of the process was 73°C and during transfer it dropped to 70°C. 7/5 The temperature of cyclohexane was 5572. After a 10-minute exposure, 400 g of seed was added in the form of finely ground K-salt. The portion was kept for a further 2 hours while maintaining a temperature equal to 60 - 657. 18.7 kg of cyclohexane heated to 65"C was added to the portion for a further 70 minutes while the temperature of the portion was maintained equal to 64"C. The KE indicator at the end of the addition was 1.36905.

The processed portion was subjected to distillation at a constant volume with the concomitant addition of 5 kg of a mixture of cyclohexane:isopropanol 75:25 (71.9 l of distillate was collected). The KE indicator was 0.5195. Then the portion was evaporated to half the volume, as in the case of the previous portions, and the final value of the KE indicator was 0.0295. The portion was filtered, washed and dried as described above, and then ground at low speed and mixed. 7 4 kg of K-salt was obtained, which has a purity of 99.990 mass, a purity of 99.995 by area and a KE value of 0.196. s shchi o yu zo Meaning. KE at turbidity 18495 1.805 2.109 2.0096 on MON PODEO MON pos ah NOW WHAT about

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Chasularevanya 10000000000001todia 000javo 0000046 0000pja 030 no) x :z» 0.595 to reach the second value of KE, and 595 seeds were added. 16 1 of the Formula of the invention (c) i) 20 1. The method of crystallization of kalilosartan, in which the following stages are carried out: a) distillation of an isopropanol-water mixture containing kalilosartan to a water content of about 2.4 to about 2.890 ml; b) cooling the mixture to a temperature of about 657C to about 707C; c) adding approximately 0.5 wt. 95 suspension of finely ground potassium sartan in cyclohexane at 59 from about 07°C to about 657°C at a rate of about 0.3 L/min until

F! a cloud point reached at a water content of from about 1.8 to about 2.395; d) keeping the mixture for about ten minutes; and d) adding from about 3 to about 10 wt. 95 finely ground potassium sartan for inoculating the mixture in the temperature range from about 607C to about 707C; 60 e) keeping the seeded mixture for about 1 to about 2 hours, in the temperature range from about 60"C to the boiling temperature, with stirring; g) adding at a temperature of about 60-657C cyclohexane solution for about two hours while maintaining the temperature of the mixture for about 687; h) distillation of the mixture at a constant volume to a water content of approximately 0.595 while maintaining a constant volume by adding a mixture of cyclohexane and isopropanol in a volume ratio of approximately 50:50 to

Claims (8)

80:20; (i) Distilling the mixture to a slurry density of about 200 g/L and a water content of less than about 0.195, adding, if necessary, cyclohexane to maintain a cyclohexane:isopropanol ratio of about 50:50 to about 60:40 by volume ; k) cooling the mixture to a temperature of about 207C to about 30"; l) filtering the mixture to isolate crystalline potassium sartan; m) washing the crystalline material with a mixture of cyclohexane:isopropanol in the ratio 75:25; n) washing the crystalline material with cyclohexane; and 70 o) drying of crystalline potassium sartan under vacuum at a temperature of about 4573 to about BOSS. 2. The method according to claim 1, which is characterized by adding finely ground kalilosartan in an amount from about 3 to about 8 wt. 95. C. The method according to claim 2, characterized in that the step of distillation of the isopropanol-water mixture is carried out /5 Until a water content of from about 2.6 to about 2.890 is reached 4. The method according to item C, which is characterized in that the cyclohexane-kalilosartan suspension is added until the cloud point is reached at a water content of from about 1.8 to about 2.095. 5. The method according to claim 4, which is characterized by the fact that the temperature at the stage of inoculation is maintained from approximately 65"7C to approximately 707C. 6. The method according to claim 5, characterized in that distillation at constant volume is carried out until the water content is less than about 0.595. 7. The method according to point b, which differs in that approximately 5 wt. 95 finely ground potassium sartan. 8. The method according to claim 7, which is characterized by the fact that the particle size of finely ground potassium sartan is from about 8 to about 10 μm. o I c) "I (av) cha Io) - with . a 1 -I (av) t» sl ko bo b5