SI21423A - Preparation of new pharmaceutically applicable forms of losartan by new methods of purification and isolation - Google Patents

Abstract

Pharmaceutically applicable alkali and earth alkali salts of 2-n-butyl-4-chloro-5-hydroxymethyl-1-((2'-1H-tetrazole-5-yl)(1,1' biphenyl)-4-yl)-1H-inidazole were prepared by liophilization of water solution of its salt prepared from losartan, which can be purified effectively during the transition amphoteric compound - alkali or earth alkali salt - amphoteric compound.

Description

Preparation of new pharmaceutically useful forms of losartan with new methods of purification and isolation

Field of the Invention (1PC ⁷ A61 K, A 61 K 9/19)

The present invention falls within the field of chemistry of heterocyclic compounds and the pharmaceutical industry and relates to a novel method of preparing pharmaceutically useful crystalline and amorphous alkali and earth alkali salts of 2-n-butyl-4-chloro-5h idroxymethyl-1 - [[2 '- (1H -tetrazol-5-yl) [1,1 '-biphenyl] -4-yl] methyl] -1H-imidazole, commonly known as losartan, and a new process of isolating and purifying these salts to ensure high purity.

A technical problem

2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1' -biphenyl] -4-yl] methyl] -1 to 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 losartan and / or losartan potassium of high purity and a new process for its preparation to obtain the desired substance in an easily feasible 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 2533310 and US 5138069.

Applicants for EP 2533310 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- [7-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) [1,1'-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 crystalline 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 procedure 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-tetrazol-5-yl) ) [1,1 '-biphen and 1-4-Ihtim I] -1 H-imidazole with sulfuric acid in tetrahydrofuran and subsequent rinsing on a dicalium hydrogen phosphate column and by concentrating the washed aqueous solution with crystalline losartan potassium in addition / propanol. This patent also mentions the process of preparing losartan potassium by spray drying, but it does not state that the substance thus obtained is not crystalline.

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 salts of some heterocyclic compounds also with alkali or alkaline earth alcohols, which is already known for some tetrazole 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 as many as 14 different conditions are surprisingly fulfilled in order to provide 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.

The authors of US patent 5128355 have prepared and characterized some compounds that are structurally very similar to losartan. Surprisingly, bromo and iodine are losartan analogs: 2-n-butyl-4-bromo-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1, T-biphenyl] - 4yl] methyl] -1H-imidazole and 2-n-butyl-5-hydroxymethyl-4-iodo-1 - [[2 '- (1H-tetrazol-5-yl) [1,1' biphenyl] -4 -yl] methyl] -1H-imidazole amorphous substances, while 2-n-butyl-4-chloro-5hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1' -biphenyl] -4-yl] methyl 1] -1H-imidazole (losartan) crystalline. It is also surprising that compound 2-n-propyl-4-chloro-5hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1-biphenyl] -4-yl] methyl] -1 H-imidazole described in this patent, which differs from losartan by one side chain, is amorphous.

Surprisingly, the amorphous form of losartan potassium alone could not be prepared by the present state of the art. Losartan has been a crystalline product in all its forms [Egypt. J. Pharm. Sci. 40, (1999), 49]. It is known that in some cases where pure compounds cannot be obtained in amorphous form, pharmaceutically acceptable admixtures are added to remove the active substance into the solid state without forming a recurrent crystal lattice, which is characteristic of the amorphous state. Thus, it is known from WO 0142221 that celecoxib, which is otherwise known in several polymorphic forms, was only able to be obtained in amorphous form by the addition of crystallization inhibitors such as polyvinylpyrrolidone or hydroxypropylmethylcellulose, and the resulting composites had increased bioavailability due to the amorphous nature of the compound. In the patent

US 6284277 discloses pharmaceutical formulations prepared by lyophilization, which is a combination of an amorphous and crystalline phase and in which the predominantly amorphous active ingredients and mannitol are combined with predominantly crystalline alanine. Among the many active ingredients listed by the patent name, it is also called losartan but is not mentioned in any embodiment, nor is it mentioned in the case of potassium salt.

Crystalline forms are identified by physicochemical methods that measure molecular-dependent parameters. 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 for different crystal forms to be 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. Also, for an amorphous substance, the IR spectrum does not necessarily have to be distinguished from the crystalline form, but usually it is the absence of some bands that are a function of the intermolecular bonds present due to the orderliness of the crystal.

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, Kluwer 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 DE: Magnetic Resonance Spectrometry in: Brittain HG, 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 mistakenly conclude that we have a new polymorphic modification. The spectrum of the amorphous form is usually simpler because of the absence of some information that, in crystalline forms, was a function of the specific environment in which the nuclei are located, and this environment is non-repetitive in the amorphous form, and peaks are usually wider in amorphous forms.

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 key method for distinguishing different crystalline forms and distinguishing amorphous from crystalline form even in cases where other methods, such as IR and ¹³ C CP / MAS NMR spectroscopy, show no differences between the samples.

After characterization of the substance by various analytical techniques, X-ray diffraction is a key method for distinguishing amorphous from crystalline form, since

The -7I is defined as amorphous based on the absence of deviations at all angles in its X-ray powder diffraction pattern.

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 anionic 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 toxic solvent for the last 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 crystalline potassium salt of losartan

Figure 2: DSC curve of the amorphous potassium salt of losartan

Figure 3: DSC curve of crystalline sodium salt of losartan

Figure 4: DSC curve of amorphous losartan sodium salt

Figure 5: DSC curve of the losartan magnesium salt

Figure 6: DSC curve of the calcium salt of losartan

Figure 7: IR spectrum of crystalline potassium salt of losartan

Figure 8: a section of the IR spectrum shown in Figure 7

Figure 9: IR spectrum of the amorphous potassium salt of losartan

Figure 10: a section of the IR spectrum shown in Figure 9

Figure 11: IR spectrum of crystalline sodium salt of losartan

Figure 12: a section of the IR spectrum shown in Figure 11

Figure 13: IR spectrum of the amorphous sodium salt of losartan

Figure 14: a section of the IR spectrum shown in Figure 13

Figure 15: IR spectrum of the losartan magnesium salt

Figure 16: IR spectrum of the calcium salt of losartan

Figure 17: ¹³ C CP / MAS NMR measurement of losartan crystalline potassium salt sample Figure 18: ¹³ C CP / MAS NMR measurement of losartan amorphous potassium saline sample Figure 19: Losartan crystalline potassium X-ray powder diffraction pattern

Figure 20: X-ray powder diffractogram of losartan potassium amorphous potassium Figure 21: X-ray powder diffractogram of losartan crystalline sodium salt Figure 22: X-ray powder diffractogram of losartan magnesium salt Fig. 24: X-ray powder diffractogram of losartan

Description of solution to a technical problem with implementation examples

The present invention describes the formation of completely amorphous alkaline or earth alkali salts of losartan without additional pharmaceutically acceptable admixtures. In our research work, it was surprisingly found that by lyophilization of an aqueous solution of the alkaline or alkaline earth alkali salt of losartan, the active substance is obtained in the form of a fine amorphous powder, thus a hitherto unknown form. With this short and fairly robust method, without the long and rigorously controlled crystallization process, it was easy to obtain losartan potassium with suitable physicochemical properties for incorporation into the pharmaceutical form. The amorphous form has many times better bioavailability than the crystalline forms, as seen in the cases mentioned above for celecoxib [WO 0142221] and some other examples described in US 6284277. In the end, isolation of water as a solvent also solved the problem unwanted solvent residues.

For the preparation of high-quality amorphous salts for pharmaceutical use, high purity amphoteric losartan is used since lyophilization as a method of depreciation of the substance cannot be further purified. When preparing high-quality losartan or losartan high-purity potassium for entry into lyophilization, it was surprising that effective purification was achieved by the amphoter-alkali or alkaline-earth amphoter transition alone, 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 process of preparation of losartan potassium of the present invention has a significant advantage in the prior art, since losartan potassium purified through these two salts has proven to be more pure than losartan potassium prepared according to the description of WO 9310106, which does not achieve pharmaceutical grade, but there is no process listed here 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 because of the impact of the change

The -1010 p H yield is significantly lower than that of potassium salt preparation, and the yield itself is better in the preparation of the sodium salt than in the preparation of the potassium salt as given in Table 1.

j 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 potassium 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 effectively purified so that the amphoteric losartan obtained has a low impurity level and is suitable not only for the preparation of amorphous potassium salt for pharmaceutical use, but also for the preparation of crystalline potassium salt for pharmaceutical use, and other high amphoteric losartan can be prepared quality alkaline and alkaline earth salts of losartan.

In accordance with the object of our invention, losartan potassium salt in amorphous form was prepared from crude losartan according to the following procedure: losartan was first purified by the procedure in the following steps: losartan dissolved in alcohol was converted to losartan potassium or sodium salt, the resulting salt was isolated in crystalline form , the resulting isolated salt was dissolved in water or a mixture of water and an organic solvent, the inorganic acid was added to the solution to a pH of between about 3.6 and about 3.8, the resulting solution was cooled below about 10 ° C while the losartan was precipitated or crystallized and the resulting losartan was further digested with an organic solvent; then losartan potassium was prepared in an amorphous form by suspending the purified losartan in water, dissolving the resulting suspension by adding an aqueous potassium hydroxide solution at a temperature of 0 to 30 ° C until the pH of the solution reached at least 9.3; the resulting solution was frozen and the resulting frozen solution was lyophilized in the last step.

-1111

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.

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, crystals of losartan sodium have been found to be larger and more beautifully formed if the solvent mixture from which they fall out 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

-1212 retains between about 3.5% and about 4.5% of water even after drying and releases water only above about 100 ° C.

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, but may also be added by the addition of metallic sodium to the alcohol, but this solution must be prepared before the addition of losartan, whereas potassium f-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 alkaline earth or alkali salts

In accordance with the process of purification of losartan with the passage of amphoter-alkali salt or earth-alkali salt-amphoter, the further selected salt prepared according to one of the described procedures was dissolved in about 5 to about 20 times the amount of water,

-1313, preferably at a concentration of about 100 g / l, at a 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 an acid, preferably with concentrated inorganic acid, especially preferably with sulfuric (VI) acid, to a pH of between about 3.6 and about 3.8, preferably to a pH of about 3.7, and then 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.

Preparation of amorphous forms of alkaline or alkaline earth salts of losartan

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, known from the prior art, was found to be so isolated, while the sodium salt so far unknown was found to be crystalline. Therefore, the crystallization method of losartan salts from alcohols or mixtures of alcohol and other organic solvents cannot be a general method for the preparation of amorphous salts.

In the search for a more general method for the preparation of losartan amorphous salts, we have found that amorphous forms of the alkaline or alkaline earth alkaline salts of losartan can be prepared by lyophilization according to the following procedure. Losartan, for example obtained by the process described, was suspended in water by adding from about 5 to about 20 times the weight of water, preferably 10 times the weight of water, and at a temperature of from about 5 ° C to about 25 ° C at room temperature, an aqueous solution of an alkali metal or alkaline earth metal hydroxide was added, preferably in the preparation of the potassium salt, a 10% aqueous potassium hydroxide solution, to a pH of between about 9 and about 10, preferably to a pH of about 9.3, whereby the reaction mixture was clarified, the solution was filtered, frozen and lyophilized, i.e. freeze-dried under reduced pressure between about 0.1 and about 0.01 bar.

However, if suitable and sufficiently pure alkaline or alkaline earth alkali salts of losartan are already available for pharmaceutical use, their amorphous forms can be prepared by lyophilization of their frozen aqueous solutions.

-1414

The present invention also relates to pharmaceutical preparations containing an alkali or alkaline earth salt, preferably a potassium salt, losartan in an amorphous form. The pharmaceutical composition may be in a form suitable for oral or parenteral use and is indicated, 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 our invention, film-coated tablets were prepared by the direct dry mixture process. Losartan potassium was mixed with lactose, microcrystalline cellulose, starch and aerosil and the mixture was screened. Magnesium stearate was added and mixed again. 160 mg tablets were tableted. A film coating prepared as an aqueous suspension containing the following essential ingredients was applied to the cores: hydroxypropyl methylcellulose, hydroxypropylcellulose, polyethylene glycol and titanium dioxide, and the film-coated tablets were talc-coated. Pharmaceutical preparations containing the amorphous alkali or alkaline earth salts of losartan can also be prepared by other suitable methods, for example by the dry granulation process.

The experimental part

The prepared amorphous form of losartan potassium salt was compared and measured using the following physicochemical methods, comparing the measured properties with the literature data, or with the crystalline potassium salt of losartan prepared according to US Pat. No. 5608075 or as described in the experiments:

- melting point measurement

- differential thermal calorimetry

- NMR spectroscopy

- IR spectroscopy

-1515

- X-ray powder diffraction.

The crystalline potassium salt prepared according to the methods of the invention through the process of conversion of amphoter - potassium salt - amphoter was recognized as form L and was the same as that prepared according to patent US 5608075. The amorphous compound was mentioned by said physicochemicals. by methods have been compared with the literature references for crystalline forms [US 5608075, Pharm. Really. 10, (1993), 900], and was also compared to the crystalline potassium salt of losartan prepared according to patent US 5608075.

Sodium, magnesium and calcium salts, which are unknown in the present state of the art, were also 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.

The measured melting point of amorphous losartan potassium does not differ significantly from that of crystalline losartan potassium, the samples melting between 265 and 275 ° C, only the visual processes above 200 ° C on the amorphous salt are more continuous and more pronounced in terms of merging and coloring of the sample, while in crystallinity, a significant change of magnitude is only around 230 ° C, which is the temperature known from the literature as the Form II conversion zone.

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

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

-1616

2. Differential thermal analysis

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

Crystalline 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. The amorphous potassium salt does not have this transition, but significant changes are observed even at a lower temperature, so a wider exothermic transition between 190 and 210 ° C can be detected. Above this temperature, the specimens are already decaying and visibly 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 6.

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

A Varova INOVA 600 spectrometer at 150 kHz was used to record samples from ¹³ C-NMR spectra using the CP-MAS method. Samples were shifted with TOSS at 10 kHz rotation, pulse (90) 4.4 μ.

We recorded two forms of losartan potassium salt. The crystalline potassium salt exhibits sharp peaks and the amorphous form is characterized by broader signals, some of which are

-1717 fused with adjacent tip or absent. The spectra are shown in Figures 17 and 18, the inventory of chemical shifts is given in Table 2:

Crystalline losartan potassium (ppm) Amorphous Losartan Potassium (ppm) 14.1 13,8 17,1 / 21.0 22.3 27.8 26,8 30.4 29.0 / 47.1 (wide) 50.0 (wide) 52.0 (wide) 123,8 / 126.5 127.4 130.3 129,2 131.7 alloy 134.6 / 136,1 135.6 141.7 140,9 146.6 / 148.1 148.7 163,0 162,4

Table 2: Chemical shifts of solid losartan potassium samples recorded by NMR CP / MAS method

The table shows that the amorphous shape is indicated by the absence of peaks 146.6, 134.6 and 17.1 ppm and the presence of a wide peak at 47.1 ppm, with the other peaks being smaller shifts in both directions, line extensions and more tops in a group.

4. IR (infrared) spectroscopy

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

The recorded IR spectra are shown in Figures 7 to 14, 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]:

-1818

krist. losartan potassium (Form 1) krist. losartan potassium (Form II.) amorphous losartan potassium krist. losartan sodium amorphous losartan sodium losartan magnesium losartan calcium 1507 1506 1507 1507 1507 1508 1497 1495 1498 1494 1495 1494 1472 / 1474 / / / 1460 1459 1461 1460 1461 1461 1423 1424 1426 1425 1426 1426 1406 1408 1408 1408 1409 1409 1378 1380 weak 1380 1380 1380 1358 1357 1356 1360 1358 1359 1358 1342 / / 1342 / / / 1260 1255 1264 1256 1258 1258 / 1144 1140 1144 1150 1148 1133 1126 1132 alloy alloy alloy 1113 1107 1109 1108 1108 1108 1074 1073 1080 1074 1075 1075 / 1011 1011 1013 1014 1014 1008 1005 1008 1006 1006 1006 996 / / / / / 954 / 954 958 954 953 954 / / 949 / / / 934 940 933 937 933 934 934 886 / 879 / weak weak 878 844 / / / / / 841 / 839 / / / 826 825 820 824 824 824 789 786 785 787 787 786 763 754 760 753 761 760 760 alloy S763 742 740 743 alloy with 760 743 713 / 715 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 spectra of the amorphous and crystalline potassium salts differ significantly, more or less along the whole scale, mainly in the forms of absorption bands and minor displacements of the values of absorption maxima, but in the amorphous potassium salt the absence of absorption maxima at 1472 ± 5 is the most prominent feature in the IR spectrum. 1342 ± 5 and between 835 and 845 cm ^-1 . On the other hand, since Form II. amorphous form

-1919 distinguishes by the presence of bands, which, however, this crystal form does not have, which are the regions 954 + 5, 949 ± 5. 870-890 and 715 + 5 cm ' ¹ .

The IR spectrum of crystalline losartan sodium is more similar to crystalline L-formartan potassium than to amorphous losartan sodium, but is distinctly 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 differs from crystalline losartan sodium 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 salts, both potassium, sodium, magnesium and calcium, have the same IR spectrum, the differences are within the error of the analytics and software detect the value of the wave number of the peak band and differ from the other crystalline salts in the absence of absorption bands in the 1472 ± 5 , 1342 ± 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 PVV1710 apparatus with the reflection technique under the following conditions: CuKa radiation, range 2 ° to 37 ° 2Θ, step 0.04y 2Θ, integration time 1 second).

X-ray powder diffractograms of losartan potassium show for amorphous losartan potassium the percentage of discrete defects characteristic of crystalline forms and continuous removal throughout the measured area, which is undoubtedly a confirmation of the material amorphousness, unlike the crystalline sample, which shows pronounced bands at angles from the prior art. characteristic of polymorphic form l. Both diffractograms are shown in the accompanying Figures 19 and 20.

-2020

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 21 and 22.

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 23 and 24.

In the following embodiments, which explain, but do not limit in any way, our invention, we give us the best known methods of preparing new pharmaceutically useful forms of losartan with new methods of purification and isolation in accordance with the present invention.

Experiment 1

Losartan crude (2 - / - 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.

-2121

A solution of 67.77 g of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2- (triphenylmethyl-2H-tetrazol-5yl) [1,2-biphenyl-4-yl] methyl] imidazole in 316 m 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 precipitated 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 resulting precipitate was filtered off, digested 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 the beta 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)

-2222

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%.

Experiment 4

Losartan sodium salt formation - method 3

To 40.81 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. Filter and wash with 165 ml 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)

-2323

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 / propanol / water mixture. 141.5 mi of n-heptane was added and stirred at room temperature until a white precipitate disappeared. 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 a solution of 10.2 g of losartan from Experiment 1 dissolved in 59 ml of i-propanol was added a solution of 1.4 g of potassium hydroxide in 1.5 ml of water at a temperature of 38-40 ° 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 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

-2424

Experiment 8

Magnesium salt formation of losartan

6.07 g of magnesium ethoxide are added to 40.81 g of losartan from Experiment 1 in 235 ml / -propanoia and stirred at reflux overnight. Hot filtered, 650 ml of n-heptane was added and cooled to room temperature to precipitate the product. 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).

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 / -propanoia. 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).

-2525

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 was filtered off, digested 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.

-2626

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 room temperature until a white precipitate disappears. 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%).

-2727

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 ΐ-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%).

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. Filter and wash with 13 ml of n-heptane. Vacuum drying at

-2828 at 50 ° C overnight, yielding 7.66 g of losartan potassium (phase yield 96%, chromatographic purity 99.88%, overall 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 ml 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%).

Experiment 17

Losartan amorphous potassium salt - method 1

29.3 g of purified losartan from one of experiments 8 to 11 were suspended in 293 ml of water. At room temperature, the pH was adjusted to 9.3 with 10% aqueous potassium hydroxide solution. The reaction mixture was clarified. The solution was filtered and lyophilized. A white, completely amorphous product of losartan potassium is obtained in an amount of 31.8 g

Experiment 18

Losartan amorphous potassium salt - method 2

20.0 g of the crystalline potassium salt of losartan are dissolved in 200 ml of distilled water. The clear solution was filtered and lyophilized. The amorphous potassium salt of losartan is obtained in an amount of 20.0 g.

-2929

Experiment 19

Losartan amorphous sodium salt - method 1

Suspend 5.0 g of purified losartan from Experiment 8 in 50 ml of water. At room temperature, the pH was adjusted to 9.62 with 10% aqueous sodium hydroxide solution. The reaction mixture was clarified. The solution was filtered and lyophilized. The amorphous sodium salt of losartan is obtained in an amount of 5.2 g.

Experiment 20

Losartan amorphous sodium salt - method 2

3.10 g of the crystalline losartan sodium salt are dissolved in 31 ml of water. The clear solution was filtered and lyophilized. The amorphous sodium salt of losartan is obtained in an amount of 3.10 g.

Melting point: 171-177 ° C

Experiment 21

A solid pharmaceutical preparation containing the losartan potassium salt

We have prepared film-coated tablets containing:

losartan potassium 50.00 mg lactose monohydrate 28,52 mg microcrystalline cellulose 60,00 mg pregelatinized starch 20,00 mg aerosil 0.48 mg magnesium stearate 1.00 mg we used: hydroxypropylmethylcellulose 1,984 mg hydroxypropylcellulose 0,496 mg polyethylene glycol 0,400 mg

-3030 titanium dioxide talc

0,920 mg 0,200 mg

The tablets were prepared by the direct dry mixture process. The active substance was mixed with lactose, microcrystalline cellulose, starch and aerosil and the mixture was screened. Magnesium stearate added and mixed again. 160 mg tablets were tableted. A film coating prepared from the above ingredients was applied to the cores as a suspension in demineralized water. The coated tablets were polished with talc.

Experiment 22

A solid pharmaceutical preparation containing the losartan potassium salt and hydrochlorothiazide

Tablets containing the following ingredients at the core:

losartan potassium 50.00 mg hydrochlorothiazide 12.50 mg lactose monohydrate 26,90 mg microcrystalline cellulose 60,00 mg pregelatinized starch 23.60 mg aerosil 0,50 mg magnesium stearate 1,50 mg and in the lining: hydroxypropylmethylcellulose 1,925 mg hydroxypropylcellulose 1,925 mg titanium dioxide 1,130 mg iron oxide E 172 0,020 mg we prepared according to the procedure dry granulation, that is by briquetting. The active ingredients losartan potassium and hydrochlorothiazide were first mixed with starch and aerosil and the mixture screened. Added lactose, microcrystalline cellulose and the remaining amount of aerosil, sift and briquette the mixture. The briquettes were ground, magnesium stearate added and

granulate homogenized. 175 mg tablets were tableted. A film coating prepared from the above ingredients was applied to the cores as a suspension in demineralized water. The film-coated tablets were polished with talc.

Claims (26)

Patent claims 1. Salts of the alkali or alkaline earth metals of losartan in amorphous form. Losartan alkali salt according to claim 1, characterized in that it is selected from the losartan sodium salt in amorphous form or the losartan potassium salt in amorphous form. Losartan potassium salt in amorphous form according to claim 2, characterized in that its X-ray powder diffractogram does not have discrete deflections in the range 2Θ from 2 ° to 37 °. Losartan potassium salt in amorphous form according to claim 2, characterized by the continuity of removal in its X-ray powder diffraction pattern shown in Figure 20. Losartan potassium salt in amorphous form according to claim 2, characterized in that its IR spectrum does not show typical absorption bands at wave numbers of about 1472 ± 5 cm ^-1 , about 1342 + 5 cm ^-1, and between about 835 cm ¹ and about 845 cm ¹ . 6. Process for the preparation of the alkaline or alkaline earth salts of losartan in amorphous form. Process according to claim 6, characterized in that the alkaline salt of losartan in amorphous form is selected from the losartan sodium salt in amorphous form or the potassium salt of losartan in amorphous form; the alkaline earth salt of losartan in amorphous form is selected from the magnesium salt of losartan in amorphous form or the calcium salt of losartan in amorphous form. Process according to claim 6 and / or 7, characterized in that the last step of the process is the lyophilization of the frozen aqueous solution of the alkaline or alkaline earth salt of losartan. A method according to claim 6 and / or 7, characterized in that it comprises the following steps: a) freeze the solution of the alkaline or alkaline earth salt of losartan; b) the resulting frozen solution is lyophilized. -3232 A process according to claim 9, characterized in that the losartan alkali salt in amorphous form is the losartan potassium salt in the amorphous form and that the losartan alkali salt solution is an aqueous solution of losartan potassium salt. The process of claim 10, wherein the preparation of the aqueous solution of losartan potassium salt comprises the following steps: a) that losartan is suspended in water; b) dissolve the resulting suspension by adding an aqueous solution of potassium hydroxide at a temperature of 0 to 30 ° C until the pH of the solution reaches at least about 9.3. A process according to any one of claims 6 to 11, characterized in that the alkaline or alkaline earth alkali salts of amorphous form of losartan have been prepared, which has been purified by a process comprising the steps of: converting losartan to a salt; further isolation of this salt; conversion of isolated salt to losartan. A process according to any one of claims 6 to 11, characterized in that the alkaline or alkaline earth alkali salts of amorphous form are prepared from losartan, which is purified by a process comprising the following steps: a) that losartan is converted to the alkaline or alkaline earth salt of losartan; b) isolate the resulting salt of losartan; c) that the resulting isolated soy be converted to losartan by acidification with inorganic acid in an organic solvent. A process according to any one of claims 6 to 9, characterized in that the alkali or alkaline earth alkali salts of losartan in amorphous form are prepared from losartan, which has been purified by a process comprising the following steps: a) losartan is converted to losartan potassium or sodium salt; b) that the resulting salt of losartan is isolated in crystalline form; c) that the resulting isolated salt is dissolved in water or a mixture of water and an organic solvent; d) inorganic acid is added to the resulting solution to a pH between about 3.6 and about 3.8; -3333 e) to cool the resulting solution below about 10 ° C with losartan precipitating; f) that the resulting losartan precipitated is further digested with an organic solvent. 15. The method of claims 10 and / or 11, characterized in that the potassium salt of losartan in amorphous form is prepared from losartan, which has been purified by a process comprising the following steps: a) that losartan is converted to losartan potassium or sodium salt; b) that the resulting salt of losartan is isolated in crystalline form; c) that the resulting isolated salt is dissolved in water or a mixture of water and an organic solvent; d) inorganic acid is added to the resulting solution to a pH of between 3.6 and 3.8; e) to cool the resulting solution to below 10 ° C with losartan precipitating; f) that the resulting losartan precipitated is further digested with an organic solvent. 16. The process according to claim 14 and / or 15, characterized in that the conversion of losartan to the potassium salt and its isolation in the purification process are characterized by the following steps: a) potassium alcoholate is added to a 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 resulting precipitate or crystallized salt is isolated by filtration or centrifugation. 17. The process according to claim 14 and / or 15, characterized in that the conversion of losartan to the sodium salt and its isolation in the purification process are characterized by the following steps: a) to the solution of losartan in alcohol or a mixture of alcohol and a non-protic solvent, sodium alcoholate or sodium hydroxide is added to a pH of between about 9 and about 12; b) the resulting salt is precipitated or crystallized; c) the resulting precipitate or crystallized salt is isolated by filtration or centrifugation. -3434 Process according to any one of claims 13 to 15, characterized in that the inorganic acid is sulfuric acid (VI). A process according to any one of claims 13 to 15, characterized in that the organic solvent is ethyl acetate. Use of the crystalline alkali or alkaline earth salt of losartan in the process of preparing the alkaline or alkaline earth salt of losartan in an amorphous form according to any of claims 12 to 19. Use of crystalline losartan sodium salt in the process of preparing losartan potassium salt in amorphous form according to any one of claims 12,13,14,15,17,18, 19. 22. A pharmaceutical composition comprising, as an active ingredient, an alkaline alkaline earth salt of losartan in amorphous form and pharmaceutically acceptable excipients. 23. Pharmaceutical preparation according to claim 22, characterized in that the active ingredient is selected from the losartan potassium salt in amorphous form or the losartan sodium salt in amorphous form. Use of the alkali or alkaline earth salt of losartan in amorphous form for the preparation of a medicament. 25. Use of the alkaline or alkaline earth salt of losartan in an amorphous form for the preparation of a medicament for the treatment of hypertension. Use of the alkaline or alkaline earth salt of losartan in amorphous form for the preparation of a medicament for the treatment of hypertension according to claim 25, characterized in that said salt is the potassium salt of losartan in amorphous form.