SI21424A - Procedure of purification of losartan - Google Patents

Abstract

Procedure of purification of 2-n-butyl-4-chloro-5-hydroxymethyl-1-((2'-1H-tetrazole-5-yl)(1,1' biphenyl)-4-yl)-1H-inidazole by the transition amphoteric compound - alkali or earth alkali salt - amphoteric compound, which is led over new isolated alkali or earth alkali salts of losartan.

Description

The process of purification of losartan

Field of the Invention (IPC ⁷ B01D, A61K)

The present invention falls within the field of chemistry of heterocyclic compounds and the pharmaceutical industry and relates to a novel method of purifying 2-n-butyl-4-chloro-5-hydroxymethyl-1 [[2 '- (1H-tetrazol-5-it) [1 , 1'-biphenyl] -4-yl] methyl] -1H-imidazole, commonly known as the losartan generic name and the preparation of the losartan alkali and alkaline earth salts useful in the new purification process.

A technical problem

2-n-Butyl-4-chloro-5-hydroxymethyl-1 - [[2 ^J - (1H-tetrazol-5-yl) [1,1-T-biphenyl] -4-yl] methyl] -1 the last stage of the renin-angiotensin cascade system by binding to the angiotensin II receptor. Taking advantage of this biochemical effect, losartan is generally used as an effective antihypertensive agent in the form of potassium salt (henceforth losartan potassium).

There is a need for high-purity losartan or losartan potassium, and the new process would be cleaned in an easy-to-implement and robust manner, with high yield and high purity. It is also desirable to have the active substance in such a form that it is readily incorporated into a pharmaceutical formulation that ensures high bioavailability. For incorporation into the pharmaceutical form, the active ingredients must have certain desired physicochemical properties.

The state of the art

Substituted imidazoles acting on the renin-angiotensin blood pressure regulation system, including losartan, have been disclosed in patents EP 253310 and US 5138069.

Applicants for EP 253310 have generally protected various substituted imidazoles and their salts, generally listing ammonium, calcium, potassium and sodium salts, and specifically describing the reactions leading to the potassium and sodium salts of some substituted imidazoles and characterizing their products . Surprisingly, the compound is 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5yl) [1,1'-biphenyl] -4-yl] methyl] - 1 H-imidazole, later called losartan, was described in the experimental section only in non-saline, i.e. amphoteric form. The experimental part of this patent thus states that in the synthesis of losartan from a cyanobiphenyl intermediate (i.e. from 2-n-butyl-4-chloro-1 - [(2'-cyanobiphenyl-4-yl) -methyl] -5 (hydroxymethyl) imidazole ) Losartan in the form of slightly yellow crystals is released by sodium azide. The patent application also mentions that the effectiveness of reducing the blood pressure of the sodium salt of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5yl) [1, r-biphenyl] - was compared 4-yl] methyl] -1H-imidazole before and after administration of furosemide to animals, but the compound is not characterized in the patent or any other publication or entered in the Chemical Abstracts Register.

The Chemical Abstracts Register lists losartan in its basic, i.e. amphoteric, form between the compounds of the losartan structural formula or their salts; tetrahydrofuran and pyridine compounds; a mixture with hydrochlorothiazide, the acid addition complexes hydrochloride and hydrobromide, and from the salts p-toluenesulfonate and potassium salt and potassium hydrochloride. This indicates that the other alkaline and alkaline earth salts of losartan have not been characterized and thus their known properties are unknown.

For incorporation into the pharmaceutical form, the active pharmaceutical ingredients must have certain desired physicochemical properties, such as: solubility in water and certain solvents, suitable particle size, stability, non-hygroscopicity; which can be regulated by choosing the right salt, adduct, complex and form to achieve effective bioavailability.

The alkali or alkaline earth salts of losartan can be prepared because of an acidic hydrogen atom on the tetrazole ring which can be cleaved with a sufficiently strong base, that is, with which the pH of the aqueous solution is reached at an equivalent point of about pH = 10 according to US 5310928. EP 324377 disclosed a process for the formation of the potassium salt of losartan with potassium hydroxide, after which the potassium salt was adopted as the most suitable form of the molecule for pharmaceutical use.

A similar process for the preparation of losartan potassium is provided by patent application WO 02094816, where, unlike the said process, they do not use an aqueous solution of potassium hydroxide but add solid potassium hydroxide to an alcoholic solution of losartan.

According to the synthesis process described in US Patents 5130439 and US 5310928, substituted boron salts are formed by hydrolysis of 2-n-butyl-4-chloro-5-hydroxymethyl-1- [2 '(2-triphenylmethyl-2H-tetraz: ol-5- il) [1,1'-Biphenyl-4-yl] methyl] -1H-imidaz: ol with sulfuric acid in tetrahydrofuran and subsequent rinsing on a column of dical hydrogen phosphate, and crystalline losartan potassium by concentrating the washed aqueous solution with / propanol. This patent also mentions the process of preparing losartan potassium by spray drying.

It is clear from the foregoing that potassium hydroxide and dicalium hydrogen phosphate are commonly used as a base for the conversion of losartan to losartan potassium. Under anhydrous conditions, it is generally possible to prepare some salts also with alkali or alkaline earth alkalis, which is already known for some heterocyclic compounds according to EP 495626 but not for losartan itself.

Losartan potassium has been found to occur in two polymorphic forms [Pharm. Really. 10 (1993), 900]. The authors of US 5608075 state that polymorphic Form I, which is characterized by a DSC endotherm at 229.5 ° C, undergoes heating upon polymorphic Form II, characterized by an endothermic maximum melting point at 273.2 °.

It is apparent from the description of US patent 5859258 that a particular form of polymorph does not necessarily provide suitable physicochemical properties. It has been found that uncontrolled crystallization can lead to the formation of large three-dimensional clusters, which are unfit for incorporation into the pharmaceutical form, and according to the invention, state a very strictly controlled process in which, surprisingly, as many as fourteen different conditions have to be fulfilled to ensure a suitable particle shape for pharmaceutical use. The need for such a tightly controlled process due to its rigidity can lead to a greater number of defects in industrial production conditions, which can significantly affect the final product.

Crystalline forms are identified by physicochemical methods that measure parameters that depend on the molecular neighborhood. The most commonly used methods are differential thermal analysis, infrared spectroscopy, solid-state nuclear magnetic resonance, and x-ray diffraction.

Infrared spectroscopy is a method that, based on the absorption of IR light, detects low-energy transitions mainly at the bond level, which are the result of molecular vibrations and vibrations. These are primarily dependent on the nature of the molecule and its bonds, and may be influenced by the neighborhood of the molecule. Therefore, it has become a widely accepted method for the characterization of polymorphs. However, it is not always necessary that different crystal patterns are also expressed in different IR spectra. Differences can be manifested in the presence or absence of certain oscillations or vibrations, in amplified or weakened bands, and in the wavelength movements of individual oscillations or vibrations.

¹³ C magnetic resonance of solid samples is a suitable method for determining the structures of solid samples. Individual polymorphic modifications can thus be determined. Solvates can be determined in a simple way, and conformational polymorphs can also be studied in a simple way. High resolution spectra and good intensity signals are obtained by CP / MAS (cross-polarization / magic angle spinning spectrum) recording technique [Sedon KR et al, Crystal Engineering: The

Design and Application of Functional Solids, Kluvver Academic Publishers, 1999]. When measuring two different polymorphs, we would expect to get two identical spectra, since the two carbons in each case are connected in the same way. The difference, however, is indeed shown because otherwise the same compounds are found in different chemical environments [Bugay D.E.: Magnetic Resonance Spectrometry in: Brittain H.G., Physical Characterization of Pharmaceutical Solids]. The structure is most easily determined by samples that are pure and contain only one crystalline form. If we have a mixture of different shapes, we get chemical shifts that can overlap and mislead us in determining the crystal structure. Thus, we may wrongly conclude that we have a new polymorphic modification.

Significantly more accurate than X-ray diffraction can be defined by infrared spectroscopy and NMR methods for solid samples whose changes are detected only on those atoms and bonds that directly interfere with adjacent molecules. From the X-ray diffraction image of a well-ordered large crystal, the spatial image of the molecule can be precisely defined, and when measuring the powder sample, differences between different crystal lattices can be detected, and the position of the individual atoms cannot be determined precisely. In addition to identifying different ordering of molecules into a crystal, which is a sign of a different crystal form, information on the degree of orderliness or crystallinity can also be obtained from the powder diffractogram, with a worse orderliness reflected in the expansion of the bands in the diffractogram. The extreme form of a disordered solid is an amorphous state that does not show a repetition of the molecular orientation pattern in the solid, and therefore diffuse X-ray scattering occurs, which is reflected in the continuous removal in the diffractogram throughout the measured range. With the described method we can discover that there are several different crystalline forms in the substance, we can even determine their mass ratio. X-ray powder diffraction is a method for distinguishing between different crystalline forms and distinguishing between amorphous and polymorphic forms.

It is well known that, because of the introduction into the body, of pharmaceutical active ingredients, particularly pure substances are required to avoid undesirable and toxic effects. Substances are purified by various methods, such as for solids, including thermal and other recrystallization, solvent or reagent digestion, extraction and washing, pH regulation, chromatographic methods. Applicants for EP 2533310 purified the final product by recrystallizing the acetonitrile amphoter. Subsequent publications such as WO 9310106 and WO 9517396 list more complicated and lengthy processes for ensuring high purity of losartan potassium, covering thermal crystallization of amphoter and potassium salts, use of column chromatography and use of adsorption media. Applicants EP 1106611 and US 6350880 state that these methods are unsatisfactory and propose purification via losartan salts with monobasic acids such as chlorides, bromides and p-toluenesulfonates. However, ultimately, it is a one-step recrystallization from an acid salt to an alkali salt with potassium hydroxide, resulting in the formation of large amounts of the potassium salt of the anion moiety of losartan, which can be coprecipitated onto losartan potassium as impurity, and the crystallization itself is carried out in acetonitrile, which is not a recommended solvent for toxicity due to the latter stage.

EP 324377 describes pharmaceutical preparations in which 1 to 500 mg of losartan is combined daily with other substances, for example diuretics, and provides an indication of hypertension. However, patent application WO 9219228 describes optimized tablet compositions suitable for direct compression.

Description of the pictures

Figure 1: DSC curve of losartan potassium salt, recognized as form I Figure 2: DSC curve of losartan sodium salt, isolated in crystalline form

Figure 3: DSC curve of the losartan magnesium salt

Figure 4: DSC curve of the calcium salt of losartan

Figure 5: The IR spectrum of the losartan potassium salt, which we recognized as Form I Figure 6: a section of the IR spectrum shown in Figure 5

Figure 7: IR spectrum of losartan sodium salt isolated in crystalline form Figure 8: excerpt of the IR spectrum shown in Figure 7 Figure 9: IR spectrum of losartan magnesium salt Figure 10: Losartan calcium salt IR spectrum

Figure 11: ¹³ C CP / MAS NMR measurement of the losartan potassium sample we recognized as Form I

Figure 12: X-ray powder diffractogram of the losartan potassium salt identified as Form I

Figure 13: X-ray powder diffractogram of the losartan sodium salt isolated in crystalline form

Figure 14: X-ray powder diffractogram of the losartan sodium salt prepared in amorphous form

Figure 15: X-ray powder diffractogram of losartan magnesium salt Figure 16: X-ray powder diffractogram of losartan calcium salt

Description of solution to a technical problem with implementation examples

The present invention describes the purification of losartan by passage of an amphoter - its salt amphoter.

High-purity amphoteric losartan is used to prepare high-quality losartan salts for pharmaceutical use. In the preparation of high-quality losartan or high-purity potassium losartan for the preparation of finished pharmaceutical preparations, it has surprisingly been shown that effective purification is achieved by the amphoter alkali salt-amphoter itself, without particularly purifying them by crystallization. Processes through concrete salts give different scopes, the most effective being the processes via the sodium and potassium salts, which fall out of solvents as crystalline salts.

The object of our invention is a purification process for losartan and the preparation of salts useful in the described purification process, and has a significant advantage in the prior art, since losartan potassium prepared from losartan purified via these two salts has proved to be more pure than losartan potassium, which is was prepared according to the description of WO 9310106, which does not reach a pharmaceutical quality, but does not specify any process to further purify this product. As can be seen from the exemplary examples, purification via sodium salt and potassium salt proved to be an effective method, since very pure amphoteric losartan was obtained from which pure pure losartan potassium could be prepared as in the prior art. Surprisingly, the sodium salt process is more robust, since the effect of the change in p H on the yield is significantly less than in the preparation of the potassium salt, and the yield itself is better in the preparation of the sodium salt than in the preparation of Table 1.

cleaning over Na salt via K salt via Ca salt phase cleanliness efficiency cleanliness efficiency cleanliness efficiency ex. losartan 98.44% 98.44% 98.44% sol 99,42% 82% 99.67% 77% 98.16% 91.9% losartan 99.74% 94% 99,82% 93% 98.98% 91.0% [losartan K 99.91% 94% 99,88% 96% 99,81% 88.9%

Table 1: Comparison of the yields and purities of losartan purified over different salts

This conversion of the substance is efficiently purified so that the amphoteric losartan obtained has a low impurity level and is suitable for the preparation of potassium salt for pharmaceutical use, and such high-quality alkaline and alkaline earth salts of losartan can be prepared from such amphoteric losartan.

In accordance with the object of our invention, crude losartan was purified by the following procedure: losartan dissolved in alcohol was converted to losartan potassium or sodium, the resulting salt was isolated in crystalline form, the isolated salt obtained was dissolved in water or a mixture of water and an organic solvent, the solution was added inorganically acid to a pH between about 3.6 and about 3.8, the resulting solution was cooled below about 10 ° C, with losartan precipitated or crystallized and the resulting losartan further digested with an organic solvent.

The losartan thus purified can then be used to prepare losartan potassium by known methods. For example, by adding potassium hydroxide solution. Other alkaline and earth alkali salts of losartan, which have significantly less admixture than in the case of amphoteric losartan, can be obtained in an analogous manner, which would be isolated directly from the reaction. Such salts are suitable for pharmaceutical use.

The process of purification of losartan by passage of an amphoter - alkali salt or an alkaline earth salt - amphoter involves two subprocesses, namely the preparation of the salt and its isolation and the subsequent preparation of the amphoter from this salt.

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Preparation of the alkali or alkaline earth salt of losartan and its isolation:

We have found that, according to the first part of the process, the alkaline or alkaline earth salts of losartan can be prepared if dissolved in a suitable solvent such as alcohol or a mixture of alcohol and a non-protic solvent, preferably in / -propanol, such that losartan concentration is around 170 g / l and at a temperature between about 38 ° C and about 40 ° C, an aqueous alkali or alkaline earth metal hydroxide solution is added to a pH of between about 9 and about 12.5, preferably to a pH of about 10, for about 15 minutes to about 1 hours, preferably for half an hour, then distill until all the azeotropic mixture is removed.

The process of preparing the alkaline earth alkaline salts was further investigated and prepared by adding anhydrous alkaline earth metal alcohol to a solution of losartan in a suitable solvent or solvent mixture, for example in / -propanol prepared so that the losartan concentration was about 170 g / l. or alkaline earth metal hydroxide and the reaction mixture was stirred at elevated temperature between about 40 ° C and about 85 ° C, preferably at reflux temperature.

In all cases, the thus prepared alkali or alkaline earth alkali salts of losartan from solutions / -propanol were precipitated with a non-polar solvent, preferably n-heptane at low temperature, preferably at a temperature below about 10 ° C and isolated by conventional methods. The result of such preparation are crystalline potassium and sodium salts and surprisingly amorphous magnesium and calcium salts. Crystalline potassium salt is a known form of losartan by the present state of the art and has been proven to be crystalline form I, while the sodium salt has not yet been characterized. Surprisingly, losartan sodium crystals are larger and more beautifully formed if the solvent mixture they fall out of contains some water. Losartan salts of the present invention can also be formulated in bound water, which can be influenced by the choice of conditions, such as pH. Crystalline losartan sodium, prepared at a pH of about 12, retains between about 3.5% and about 4.5% of water even after drying and releases water only above about 100 ° C.

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Preparation of magnesium salt with magnesium alcoholate, for example with magnesium ethoxide, is preferable since the use of magnesium hydroxide is very impractical due to the poor solubility and predominant conversion to insoluble magnesium oxide. Surprisingly, we have found that better results, both in terms of yield and quality, are also obtained by using sodium or potassium alcohols in non-aqueous media, such as alcohol, instead of using aqueous sodium or potassium hydroxide, and the process itself is less time consuming, since does not require expulsion of water by azeotropic distillation. Only a solution of sodium and potassium alcoholate is most readily obtained by dissolving commercially available sodium or potassium f-butoxide, and may also be added by the addition of metallic sodium to alcohol, but this solution must be prepared before the addition of losartan, whereas potassium ί-butoxide can be added directly to the solution. losartan in alcohol. In the known hydroxide method, the yield is sensitive to pH and the presence of water, and the effect of these two factors is almost nullified in this method, which is especially evident in the preparation of the potassium salt.

The most suitable process for the preparation of losartan potassium is that dissolve losartan in a suitable solvent, for example in alcohol, preferably in / -propanol, so that the concentration is about 370 g / l and then the potassium salt of losartan is excreted after the addition of potassium tbutoxide a non-polar solvent, for example a hydrocarbon, preferably n-heptane, and the recovery of salt from the solution is further increased. Losartan potassium is isolated by simple filtration and drying. The sodium salt of losartan is also prepared analogously by this method, except that sodium f-butoxide is used in this conversion.

Preparation of losartan from its earthquake or alkali salt

In accordance with the process of purification of losartan with the passage of amphoter-alkali salt or earth-alkaline salt-amphoter, the further selected salt prepared by one of the described procedures was dissolved in about 5 to about 20 times the amount of water, preferably at a concentration of about 100 g / l, at an temperature of from about 5 ° C to about 25 ° C, preferably in the interval between 21 ° C and 25 ° C, added an organic solvent, preferably ethyl acetate, and acidified with inorganic acid, preferably with

-1212 concentrated inorganic acid, especially preferably with sulfuric acid to a pH between about 3.6 and about 3.8, preferably to a pH of about 3.7, after which the reaction mixture is cooled to a temperature of about 0 ° C to about 15 ° C, preferably below 10 ° C and losartan was isolated by conventional methods.

From the above-described procedures for the preparation of losartan salts, the magnesium and calcium salts were found to be amorphous, which was proved by X-ray powder analysis. On the other hand, potassium salt in crystalline Form I, which is known in the art, has been shown to be isolated, while the sodium salt, previously unknown, was found to be crystalline, but lyophilized its aqueous solution, however. amorphous losartan sodium was also obtained.

The present invention also provides pharmaceutical compositions containing novel high purity alkali or alkaline earth salts and pharmaceutically acceptable excipients. The pharmaceutical composition may be in a form suitable for oral or parenteral use and may be used, for example, for the treatment of hypertension, the pharmaceutical composition of the present invention may thus be in the form of tablets, capsules, pellets, granules and suppositories, for example.

Solid pharmaceutical forms may be coated, for example, to increase pelletability or to regulate degradation or absorption.

In accordance with the object of the present invention, tablets may be prepared which may be coated, for example by the direct dry blend process or by the dry granulation process, for example. The pharmaceutically useful alkaline and earth alkali salts of losartan, purified by the process described above, are, for example, mixed with acceptable excipients, for example: lactose, microcrystalline cellulose, starch and aerosil, magnesium stearate and tableted.

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The experimental part

The prepared amorphous form of losartan potassium was compared and measured with the following physicochemical methods, comparing the measured properties with the literature data, or with the crystalline potassium salt of losartan prepared according to US patent 5608075 or as described in the experiments:

- melting point measurement

- differential thermal calorimetry

- NMR spectroscopy

- IR spectroscopy

- X-ray powder diffraction.

The crystalline potassium salt prepared according to the methods of the invention through an amphoteric-potassium salt-amphoteric conversion process was recognized as Form I and was identical to that prepared according to U.S. Pat. No. 5608075.

The sodium, magnesium and calcium salts prepared as intermediate salts in the purification process of losartan and which are unknown in the present state of the art have also been characterized by the aforementioned physicochemical methods. We have determined that losartan sodium prepared by the above procedures, which are described in more detail in the embodiments, exists in crystalline and amorphous form, and losartan calcium and magnesium were identified only in amorphous form.

1. Melting point

To measure the melting point, we used the visual monitoring method on a microscope with a heating table and the Thiele method.

In crystalline losartan potassium, a change of about 230 ° C is visible, a temperature known from the literature as the Form II conversion zone.

The difference between melting points of crystalline and amorphous losartan sodium is recognizable. The crystalline form has a melting point of 191-196 ° C and an amorphous one of 171-177 ° C.

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The melting of calcium and magnesium salts below 300 ° C was not detected.

2. Differential thermal analysis

We used a Perkin Elmer Pyris 1 DSC differential dynamic calorimeter.

Losartan potassium has a first endothermic change above 230 ° C which would be consistent with the temperature of Form I to Form II transition, which is known from the literature. Above 190 ° C, the samples are already decaying and are very visually altered.

Crystalline losartan sodium has a melting point according to the DSC method at 195 ° C, which corresponds to the measurement on a Kofler microscope. However, a major endothermic change can be detected already in the region of about 110 ° C and the loss of crystalline water is inferred. Amorphous losartan sodium does not have these changes, and conversions above 240 ° C characterize the breakdown of the samples. Already above 150 ° C, a very elongated passage is barely noticeable, which can be seen in the Kofler microscope as a melting-like visible change between 170 and 180 ° C.

DSC thermograms of losartan calcium and losartan magnesium samples are similar to thermograms of amorphous losartan sodium at temperatures above 200 ° C; only the decomposition of the samples in approximately the same temperature range with slightly different heat flux dynamics is observed.

DSC thermograms are shown in Figures 1 to 4.

3. ¹³ C CP / MAS NMR spectroscopy of a solid

A Varian NMR Spectrometer Unity plus 300 was used to record samples using the ¹³ C-NMR Solid-State CP-MAS method. Samples were shifted with TOSS at a rotation of 10 kHz, a pulse (90) of 4.4 ps (tpwm = 3600 ).

The crystalline form of the potassium salt shows sharp peaks, as shown in Figure 11, an inventory of all chemical shifts is given in Table 1:

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chemical shift (ppm) 14.1 17,1 21.0 27.8 30.4 / 50.0 (wide) 123,8 126.5 130.3 131.7 134.6 136,1 141.7 146.6 148.1 163,0

Table 1: Chemical shifts of a solid losartan potassium sample recorded by the NMR method of CPMAS

4. IR (infrared) spectroscopy

We used an infrared spectrometer "Bio-Rad FTS-60, Digilab-Division".

The recorded IR spectra are shown in Figures 5 to 10, and the most pronounced absorption maxima between 1510 and 700 cm ^-1 are listed in the following table, with values for Form II crystalline potassium salts taken from the literature [Pharm. Really. 10 (1993), 900]:

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krist. losartan potassium (Form I) krist. losartan potassium (Form II.) krist. losartan sodium amorphous losartan sodium losartan magnesium losartan calcium 1507 1507 1507 1507 1508 1497 1498 1494 1495 1494 1472 1474 / / / 1460 1461 1460 1461 1461 1423 1426 1425 1426 1426 1406 1408 1408 1409 1409 1378 weak 1380 1380 1380 1358 1357 1360 1358 1359 1358 1342 / 1342 / / / 1260 1264 1256 1258 1258 / 1140 1144 1150 1148 1133 1132 alloy alloy alloy 1113 1109 1108 1108 1108 1074 1080 1074 1075 1075 / 1011 1013 1014 1014 1008 1008 1006 1006 1006 996 / / / / 954 / 958 954 953 954 / 949 / / / 934 940 937 933 934 934 886 / / weak weak 878 844 / / / / 841 839 / i / 826 820 824 824 824 789 785 787 787 786 763 754 753 761 760 760 alloy s763 740 743 alloy with 760 743 713 / weak weak 714 714

Table 3: Characteristic bands [cm ' ¹ ] in the IR spectra of various losartan salts in the range between 1550 and 700 cm' ¹

The IR spectrum of crystalline losartan sodium is more similar to crystalline losartan potassium Form I than to amorphous losartan sodium, but clearly different from potassium salt with the absence of peaks at wavelength intervals 995-1000 and 870-890 cm ' ¹ and changes in the range between 820 and 850 cm ' ¹ , identified by the presence of peaks 839 ± 1 and 820 ± 1 cm' ¹ . Amorphous losartan sodium from

The -1717 crystalline losartan sodium differs in the absence of peaks in the wavelength range 1472 ± 5.1342 ± 5 and between 835 and 845 cm ^-1 .

All amorphous forms of losartan sodium, magnesium and calcium salts have the same IR spectrum, the differences are within the error of the analytics and software detect the value of the peak bandwidth and differ from the other crystalline salts in the absence of absorption bands in the 1472 ± 5, 1342 band ± 5 and between 835 and 845 cm ^-1 . This can be explained by the fact that there are no specific bands in the spectrum that result from the influence of the cation on the bond energy states, and the other bands are merely a result within molecular events, since intermolecular effects due to disordered amorphous state are scattered and therefore undetectable in the IR spectrum.

5. X-ray powder analysis

Samples were taken on a Philips PW1710 apparatus with the reflection technique under the following conditions: CuKa radiation, range 2 ° to 37 ° 2θ, step 0.04y 2Θ, integration time 1 second).

The X-ray powder diffractogram of losartan potassium shown in Figure 12 shows pronounced bands at angles characteristic of polymorphic Form I from the prior art.

X-ray powder diffractograms of losartan sodium show for amorphous losartan sodium the percentage of dips and undoubtedly amorphous material, unlike the crystalline pattern showing sharp bands indicating high crystallinity. Both diffractograms are shown in the attached Figures 13 and 14.

X-ray powder diffractograms of losartan magnesium and calcium show the apparent amorphous structure of the samples, regardless of how they were prepared. The diffractograms of typical magnesium and calcium salt samples are shown in the accompanying Figures 15 and 16.

In the following embodiments, which explain, but do not limit in any way our invention, we give us the best known ways of preparing new

-1818 pharmaceutically usable formulations of losartan with novel purification and isolation methods according to the present invention.

Experiment 1

Losartan crude (2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] methyl] -1H-imidazole)

A mixture of 129.80 g of 5- [2- (4-bromomethylbiphenyl)] -2-triphenylmethyl-2H-tetrazole, 43.4 g of 2-butyl-4-chloro-5-hydroxymethyl-1 H-imidazole and 38.27 g of potassium carbonate in 550 ml of Ν, Ν-dimethylacetamide was stirred at 0-5 ° C for 8 hours and at room temperature overnight. To the mixture was added 8.02 g NaBH ₄ and 18 ml water. Cool to room temperature and stir for 3 hours. The reaction mixture was poured under vigorous stirring into 1.1 I of water, filtered and the precipitate was washed with 550 ml of water. Vacuum was dried overnight at room temperature over silica gel.

2-n-Butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (triphenylmethyl-2H-tetrazol-5-yl) [1,1'biphenyl-4-yl] methylimidazole is obtained which is recrystallized from of chlorobutane and ethyl acetate with a final reaction and purification yield after drying 66.77 g.

A solution of 67.77 g of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2- (triphenylmethyl-2H-tetrazol-5yl) [1,1 'biphenyl-4-yl] methyl] imidazole in 316 ml of tetrahydrofuran (THF) was added while stirring 105.9 g of 12% HCl at 23 ° C for one hour. The mixture was stirred at room temperature overnight. 30% NaOH was added at a temperature of up to 22 ° C for one hour until a pH of 12.5 (approx. 100 ml) was reached. Evaporate THF at 60 ° C and add demineralized water to its original volume. The resulting precipitate was filtered off, washed with 2 x 50 ml of demineralized water and discarded. The aqueous phase is extracted with 1 x 50 ml of toluene. The organic layer was separated and 124 ml of ethyl acetate were added to the aqueous phase. The mixture is acidified with concentrated H2SO4 at a temperature of 21-25 ° C to pH 3.63.8 during vigorous stirring. Cool below 10 ° C and stir for 1 hour. The precipitate formed is filtered off, digested with

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With 130 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 40.8 g of losartan in amphoteric form.

Experiment 2

Losartan sodium salt formation - method 1

A solution of 5.5 g of sodium hydroxide in 5.7 ml of water was added to 40.81 g of losartan from Experiment 1 in 235 ml / -propanol at a temperature of 38-40 ° C to pH 12 for half an hour. Distill off about 35 ml of azeotropic / propanol / water mixture. Add 140 ml of n-heptane and stir at room temperature until a white precipitate disappears. It is diluted with 55 ml of n-heptane, filtered, washed with 110 ml of n-heptane and dried in vacuo at 50 ° C to give 35.0 g of the losartan sodium salt.

Melting point: 191-196 ° C

Karl-Fisher water: 4.2%.

Sodium content 4.4% (5.0% on dry matter)

Experiment 3

Losartan sodium salt formation - method 2

To a solution of 40.81 g of losartan from Experiment 1 in 235 ml / -propanol was added a solution of 5.5 g of sodium hydroxide in 5.7 ml of water at a temperature of 38-40 ° C to pH 10 for half an hour. Distill off about 35 ml of azeotropic / propanol / water mixture. Add 140 ml of n-heptane and stir at room temperature until a white precipitate disappears. Dilute with 55 ml of n-heptane, filter, wash with 110 ml of n-heptane and dry under vacuum at 50 ° C to give 37.0 g of the losartan sodium salt.

Melting point: 190-198 ° C Karl-Fisher water: 0.3%.

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Experiment 4

Losartan sodium salt formation - method 3

To 40.31 g of losartan from Experiment 1 in 120 ml / -propanol was added 9.28 g of sodium f-butoxide. The reaction mixture was clarified. 145 ml of n-heptane was added and stirred at room temperature until a white precipitate disappeared. It is filtered and washed with 165 mi of nheptane. It is dried at 40 ° C in vacuo to give 37.0 g of the losartan sodium salt.

Melting point: 191-196 ° C

Sodium content of 4.7% (5.2% on dry matter)

Experiment 5

Losartan potassium salt formation - method 1

A solution of 5.5 g of potassium hydroxide in 5.7 ml of water at a temperature of 38-40 ° C to pH 12 for half an hour is added to 40.81 g of losartan from Experiment 1 in 235 ml / -propanol. Distill off about 35 ml of azeotropic / propane / water mixture. 141.5 ml of n-heptane is added and stirred at room temperature until a white precipitate disappears. It is diluted with 54 ml of n-heptane, filtered, washed with 108 ml of n-heptane and dried in vacuo at 50 ° C to give 21.36 g of losartan potassium.

Experiment 6

Losartan potassium salt formation - method 2

To 10.2 g of losartan From Experiment 1 dissolved in 59 ml of i-propanol, add a solution of 1.4 g of potassium hydroxide in 1.5 ml of water at a temperature of 38-40 ° C to pH

-2121 for half an hour. Distill off about 19 ml of azeotropic / propanol / water mixture. 36 ml of n-heptane was added and stirred at room temperature until a white precipitate disappeared. It is diluted with 14 ml of n-heptane, filtered, washed with 26 ml of nheptane and dried in vacuo at 50 ° C to give 8.57 g of losartan potassium.

Experiment 7

Losartan potassium salt formation - method 3

To 40.81 g of losartan from Experiment 1 in 110 ml / -propanol was added 10.86 g of potassium f-butoxide at a temperature between 10 ° C and 25 ° C. The reaction mixture was clarified and a white precipitate was dropped. Add 150 ml of n-heptane and stir at room temperature for 1 hour. Filter and wash with 75 ml of n-heptane. Vacuum was dried at 50 ° C overnight to give 43.25 g of losartan potassium

Experiment 8

Magnesium salt formation of losartan

To 40.81 g of losartan from Experiment 1 in 235 ml / -propanol was added 6.07 g of magnesium ethoxide and stirred at reflux overnight. Hot filtered, 650 ml of n-heptane were added and cooled to room temperature to produce the isobort. Filter and wash with 110 ml of n-heptane. The mixture was dried in vacuo at 50 ° C to give 37.9 g of the losartan magnesium salt.

Melting point: above 300 ° C

Magnesium content 2.9% (3.2% on dry matter).

-2222

Experiment 9

Calcium salt formation of losartan

3.92 g of calcium hydroxide was added to 40.81 losartan from Experiment 1 in 235 ml / propanol. The mixture was stirred at reflux for 1 hour and filtered hot. 410 ml of n-heptane was added to the filtrate and cooled to room temperature. Decant the solvent from the resinous residue and add 820 ml of n-heptane. Stir at 10 ° C until a white precipitate crystallizes. It was filtered, washed with 110 ml of nheptane and dried in vacuo at 50 ° C to give 39.2 g of the calcium salt of losartan.

Melting point: above 300 ° C.

Calcium content 4.0% (4.7% on dry matter).

Experiment 10

Losartan purified - Dissolve 1 g of losartan sodium salt in 350 ml of water, add 106 ml of ethyl acetate and acidify at a temperature of 21-25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° and stir for 1 hour. The resulting precipitate was filtered off, digested with 120 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 29.3 g of losartan.

Experiment 11

Losartan purified - Method 2

Dissolve 42.66 g of the losartan potassium salt in 430 ml of water, add 130 ml of ethyl acetate and acidify at 21 ° C-25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° C and stir for 1 hour. The resulting precipitate is filtered off, digested

-2323 with 145 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 36.6 g of losartan.

Experiment 12

Losartan Purified ~ Method 3

Dissolve 37.9 g of the losartan magnesium salt in 388 ml of demineralized water, add 120 ml of ethyl acetate and acidify at a temperature of 21 ° -25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° C and stir for 1 hour. The precipitate which was formed was filtered off, digested with 130 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 32.3 g of losartan.

Experiment 13

Losartan purified - Method 4

38.0 g of the calcium salt of losartan are dissolved in 380 ml of water, 115 ml of ethyl acetate are added and acidified at a temperature of 21 ° - 25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° C and stir for 1 hour. The resulting precipitate was filtered off, digested with 130 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 36.2 g of losartan.

Experiment 14

Preparation of pharmaceutically useful losartan potassium via crystalline losartan sodium

A solution of 2.75 g of sodium hydroxide in 2.9 ml of water was added to 20.4 g of crude losartan (chromatographic purity 98.73%) in 120 ml / -propanol at a temperature of 38-40 ° C to pH 10 for half an hour. Distill off about 18 ml of azeotropic / propanol / water mixture. Add 70 ml of n-heptane and stir at

-2424 room temperature until white precipitate drops. Diluted with 28 ml of n-heptane, filtered, washed with 55 ml of n-heptane and dried in vacuo at 50 ° C to give 18.5 g of crystalline losartan sodium salt (yield 87%, chromatographic purity 99.42%).

The resulting substance was dissolved in 185 ml of water, 56 ml of ethyl acetate was added and acidified at a temperature of 21-25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° and stir for 1 hour. The precipitate which was formed was filtered off, digested with 64 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 16.5 g of losartan (phase efficiency 94%, chromatographic purity 99.74%).

The resulting product was dissolved in 45 ml / -propanol and 4.39 g of potassium tbutoxide was added at a temperature between 10 ° C and 25 ° C. The reaction mixture was clarified and a white precipitate was dropped. 60 ml of n-heptane are added and stirred at room temperature for 1 hour. Filter and wash with 30 ml of n-heptane. Vacuum was dried at 50 ° C overnight to give 16.9 g of losartan potassium (phase yield 94%, chromatographic purity 99.91%, total yield 77%).

Experiment 15

Preparation of pharmaceutically useful losartan potassium via crystalline losartan potassium

As described in Experiment 4, a solution of 1.4 g of potassium hydroxide in 1.5 ml of water at a temperature of 38-40 ° is added to 4 to 10.2 g of losartan from Experiment 1 (chromatographic purity 98.73%) in 59 ml of i-propanol. C to pH 10 for half an hour. Distill off about 19 ml of azeotropic / propanol / water mixture. 36 ml of n-heptane was added and stirred at room temperature until a white precipitate disappeared. It is diluted with 14 ml of n-heptane, filtered, washed with 26 ml of n-heptane and dried in vacuo at 50 ° C to give 8.57 g of losartan potassium, (yield: 77%, chromatographic purity 99.67%).

-2525

The resulting losartan potassium salt was dissolved in 86 ml of water, 26 ml of ethyl acetate were added and acidified at 21 ° -25 ° C to pH 3.6-3.8 with concentrated sulfuric acid. Cool below 10 ° C and stir for 1 hour. The resulting precipitate was filtered off, digested with 29 ml of ethyl acetate, filtered again and vacuum dried at 50 ° C overnight to give 7.35 g of losartan (93% yield, chromatographic purity 99.82%).

The resulting product was dissolved in 20 ml / -propanol and 1.96 g of potassium tbutoxide was added at a temperature between 10 ° C and 25 ° C. The reaction mixture was clarified and a white precipitate was dropped. 27 ml of n-heptane are added and stirred at room temperature for 1 hour. It is filtered and washed with 13 mi of n-heptane. Vacuum was dried at 50 ° C overnight to give 7.66 g of losartan potassium (phase yield 96%, chromatographic purity 99.88%, total yield 69%).

Experiment 16

Comparative attempt to prepare potassium salt according to the prior art

To 40.81 g of losartan (chromatographic purity 98.73%) in 153 ml of i-propanol was added a mixture of 10 g of potassium hydroxide, 5.1 ml of water and 100 ml / -propanol at a temperature of 38-40 ° C to pH 10-11 for half an hour. Distill off about 140 ml of solvent (mixture / propanol / water) and add 92 m of n-heptane. Stir at room temperature until a white precipitate disappears. It is diluted with 54 ml of n-heptane, filtered, washed with 70 ml of n-heptane and dried in vacuo at 50 ° C to give 38.4 g of losartan potassium (yield: 86%, chromatographic purity: 99.67%).

Claims (24)

Patent claims 1. Losartan sodium salt. Losartan sodium salt according to claim 1, characterized in that it exists in crystalline form and has its X-ray powder diffraction patterns at 2Θ = 6.2 °, 14.5 °, 18.2 °, 18.8 °, 21, 6 °, 23.5 °, 24.8 ° and 25.5 °. Losartan sodium salt according to claim 1, characterized in that it exists in crystalline form and has a melting point between 190 and 200 ° C. Losartan sodium salt according to claim 1, characterized in that it exists in crystalline form with bound water, the amount of water being between about 3.5% and about 4.5%, and the loss of bound water upon drying between about 100 and about 120 ° C. 5. Salts of alkaline earth metals of losartan. 6. The alkaline earth metal salt of losartan according to claim 5, selected from a magnesium or calcium salt. 7. A process for the preparation of alkaline earth or alkali salts of losartan, characterized in that it contains the following steps: a) an alkali metal or alkaline earth metal alcoholate is added to the solution of losartan in alcohol or a mixture of alcohol and a non-protic solvent; b) the resulting salt is precipitated or crystallized; c) that the precipitated or crystallized salt obtained is isolated by filtration or centrifugation. The process of claim 7 wherein the alkaline earth salt is selected from magnesium or calcium salts; and the alkali salt is selected from potassium salt or sodium salt. Process according to claims 7 and / or 8, characterized in that the alkali metal alcoholate is selected from sodium or potassium f-butoxide. -2727 A process according to any one of claims 7 to 9, characterized in that alcohol / -propanol is used. A process according to any one of claims 7 to 10, characterized in that the alkali metal or alkaline earth salt is precipitated or crystallized by the addition of a non-protic solvent. 12. The process for the preparation of the sodium salt is indicated by the following steps: a) adding a solution of sodium hydroxide to a solution of losartan to a pH of between about 9 and about 12; b) the resulting salt is precipitated or crystallized by the addition of a non-protic solvent; c) that the precipitated or crystallized salt obtained is isolated by filtration or centrifugation. Process according to any one of claims 7 to 12, characterized in that the non-protic solvent is n-heptane. 14. The process of purification of losartan is characterized by the following steps: conversion of losartan to salt; further isolation of this salt; conversion of isolated salt to losartan. 15. The purification process of losartan, characterized in that it contains the following steps: a) to prepare the alkaline or earth alkali salt of losartan according to any one of claims 7 to 11 or to prepare the sodium salt of losartan according to claims 12 and / or 13; b) Losartan is prepared from the resulting isolated salt by acidification with inorganic acid in an organic solvent. Process according to claim 15, characterized in that the losartan alkali salt is selected from the potassium or sodium salt and that the named losartan salt is isolated in crystalline form, and that the preparation of losartan from said isolated salt by acidic acid in an organic solvent is indicated with the following steps: a) that the isolated salt is dissolved in water or a mixture of water and an organic solvent; b) inorganic acid is added to the resulting solution to a pH between about 3.6 and about 3.8; -2828 c) to cool the resulting solution to below 10 ° C with losartan precipitating; d) that the resulting losartan precipitated is further digested with an organic solvent. Process according to claims 15 and / or 16, characterized in that the inorganic acid is sulfuric acid (VI). 18. The process according to claims 15 and / or 16, characterized in that the organic solvent is ethyl acetate. Use of the alkali or alkaline earth salt of losartan in the purification process of losartan according to claim 14 and / or 15. Use of crystalline losartan sodium salt in the purification process of losartan according to any one of claims 14 to 18. 21. Pharmaceutical preparation containing as active ingredient the crystalline sodium salt of losartan and pharmaceutically acceptable excipients. 22. Pharmaceutical preparation containing as active ingredient the alkaline earth salt of losartan and pharmaceutically acceptable excipients. 23. Use of the crystalline losartan sodium salt for the preparation of a medicament. Use of the crystalline losartan sodium salt according to claim 23 for the preparation of a medicament for the treatment of hypertension.