SI21509A - Preparation of tetrazole derivative in new crystalline form - Google Patents

Abstract

A new crystalline form of pharmaceutically applicable crystalline salt of 2-n-butyl-4-chloro-5-hydroxymethyl-1-((2'-(1H-tetrtazole-5-yl)(1,1' biphenyl)-4-yl)methyl)-1H-imidazole indicated by strongest diffractions in X-ray powder diffractogram at 2-theta around 6.9, 13.8, 20.6, 24.0, 24,8, 28.7 and 29.2 degrees was prepared from known polymorphous forms from a solvent combination containing methanol.

Description

Preparation of the tetrazole derivative in a new crystalline form

Field of the Invention (IPC ⁷ C 07 D 403/10, 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 crystalline form of the pharmaceutically useful crystalline potassium salt of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5yl) ) [1,1'-biphenyl] -4-yl] methyl] -1H-imidazole and a new method of its preparation.

A technical problem

2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1 ^] -biphenyl] -4-yl] methyl] -1 Hymidazo! with the generic name losartan, it acts on the last stage of the cascade renin-angiotensin system by binding to the angiotensin receptor ll. Utilizing this biochemical effect, it is generally used as an effective antihypertensive agent in the form of potassium salt (henceforth losartan potassium). In pharmaceuticals, it is often combined with diuretics.

There is a need for losartan or its high-purity salt in such a form that it can be easily incorporated into a pharmaceutical formulation that ensures high bioavailability. For incorporation into the pharmaceutical form, the active ingredients must have certain desired physicochemical properties, in addition to high purity, we require stability, non-hygroscopicity, adequate solubility and compatibility with excipients.

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.

Losartan potassium is known to exist in several polymorphic forms [K. Raghavan et al., Pharm. Res., 1993, 103 900-904; L. S. Wu et al., Pharm. Res., 1993, 10, 17931795]. 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 °. Form I is stable at room temperature, while Form II is stable at higher temperatures. Because of this, Form II gradually transforms into thermodynamically more stable Form I under normal operating conditions.

Fig. 200300145 gives losartan potassium in polymorphic form with bound water (wherein the water was 7 to 12 weight percent), named Form III. The patent states that the ill form was isolated in the form of three bound molecules of water per losartan potassium molecule, and upon heating a polymorphic form was formed with two bound molecules of water per molecule of losartan potassium. Physical analyzes of this form have shown that it is a polymorphic form in the form of a dihydrate, with two crystalline bound molecules of water per molecule of losartan potassium. A similar substance was prepared by the authors of patent application WO 03048135, which prepared a polymorphic form with bound between 12% and 16% water (percent by weight). The foregoing patent application also gives the further two polymorphic forms of losartan characterized by the strongest X-ray powder diffraction patterns for the form named Form IV about 2 Θ: 4.3, 15.6 and 23.4 ° and the further polymorph form named Form V characterized by with the strongest X-ray powder diffraction patterns around 2 Θ: 6.4, 12.2, 20.7, 21.5 and 22.5 °.

It is also known from the patent of Sl 200300025 that alkaline or alkaline earth salts of losartan can be prepared in the form of fine amorphous powder by lyophilization of an aqueous solution of alkaline or alkaline earth salts of losartan or identical with respect to Sl 200200145 by evaporation.

It is well known that a particular form of polymorph does not necessarily provide suitable physicochemical properties. Losartan polymorphic Form I crystallized from US / 5859258 from a mixture of / -propanol and 2.4 - 2.6% water. 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 they state a very strictly controlled process in which as many as 14 different conditions must be fulfilled in order to provide a suitable pharmaceutical particle shape use.

It is apparent from the prior art that an essential element in the preparation of crystalline forms of losartan potassium with bound water is the presence of water in combination with a suitable solvent in an appropriate ratio or the presence of water in the form of atmospheric moisture. The crystalline form of about 7 to about 12% water was isolated from the combination of solutes! and water, or by exposing the amorphous substance to atmospheric moisture, and crystalline form from 12 to 16% of water was prepared solely by exposing amorphous losartan potassium or losartan potassium form I with a relatively long exposure to controlled humidity above 80% relative humidity.

Unlike US 5859258, where crystallized losartan potassium Form I from a combination of alcohol and water, polymorphic Form IV can be prepared according to WO 03048135 by dissolving losartan potassium in a solvent with a boiling point below 135 ° C and the addition of a suspension. , and the Form V polymorph by dissolving losartan potassium in a solvent with a boiling point below 135 ° C and the addition of hexane. For both processes, the patent application cites C 1 to C ₆ alcohols, and in cases only ethanol.

Description of the pictures

Figure 1: X-ray powder diffractogram of the losartan potassium X polymorphic form X.

Figure 2: DSC diagram of the losartan potassium polymorphic form obtained by the procedure described in Experiment 4.

Description of solution to a technical problem with implementation examples

The object of our invention is a completely new crystalline form of losartan potassium.

According to the process described in WO 03048135, which teaches Form V formation from a solvent system containing one of the Ci C ₆ alcohols and hexane, one would also expect that a solvent with a strong X-ray powder diffraction pattern would be isolated from the methanol-hexane solvent system at 2Θ about 6.4, 12.2, 20.7, 21.5 and 22.5 °.

Surprisingly, it turned out that when dissolved formartan I potassium salt of methanol was dissolved in methanol and the resulting solution concentrated to a dense glass mass, it was poured into hexane while stirring and the resulting precipitate filtered and carefully dried to give a completely new polymorphic form with the strongest X-ray powder diffractions at 20 about 6.9, 13.8, 20.6, 24.0, 24.8, 28.7 and 29.2 °.

Interestingly, the same crystalline form is formed together with the already known polymorphic Form I when losartan potassium Form I was dissolved in a mixture of methanol and water and the resulting solution was concentrated and poured into diisopropyl ether while stirring at room temperature.

The crystalline form of losartan potassium characterized by the strongest X-ray powder diffraction patterns at 2Θ about 6.9, 13.8, 20.6, 24.0, 24.8, 28.7 and 29.2 ° was named polymorphic form X. According to the method of isolation, solvates of polymorphic form X are also the object of the invention. losartan potassium.

The present invention also provides pharmaceutical compositions containing the polymorphic form X losartan potassium or solvates of the polymorphic form X losartan potassium. A suitable daily dose contains 1 to 500 mg of polymorphic form X losartan potassium and may contain other suitable ingredients, for example a diuretic.

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 subject matter of our invention, film-coated tablets can be prepared by the direct dry mixture process or by the wet granulation process or by any suitable method known in the pharmacy.

The experimental part

X-ray Powder Analysis (XRD)

We used a Philips PVV1710 apparatus with reflection technique under the following conditions: CuKa radiation, range 2 ° to 37 ° 20, step 0.04y 2Θ, integration time 1 second).

A typical diffractogram of polymorphic form X losartan potassium is shown in the accompanying Figure 1.

Differential thermal analysis (DSC)

The DSC thermogram of the sample isolated according to the procedure described in Experiment 4 is shown in Figure 2. Re-recording the dried sample yielded essentially the same DSC thermogram.

In the following embodiments, which explain, but in no way limit, our invention, we are provided with known best methods of preparing a new pharmaceutically useful polymorphic form of losartan in accordance with the present invention.

Experiment 1 (preparation of losartan amorphous potassium salt)

Suspend 29.3 g of purified losartan 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.

An experiment of 2 g of losartan Form I potassium salt was dissolved in a mixture of 200 m methanol and 1.2 ml of water. The resulting solution was concentrated to a volume of 13 ml and poured into 500 ml of diethyl ether while stirring at room temperature. The resulting precipitate was stirred at room temperature for 1 hour and filtered. Dry at 45 ^D C in vacuo. Yield 9.3 g.

Experiment 3 (Preparation of losartan kale salt polymorphic form X) Dissolve g of losartan form I potassium salt in a mixture of 200 ml of methanol and 1.2 ml of water. The precipitate was stirred at room temperature for 1 hour and filtered and dried. Yield 9.93 g.

Experiment 4 (Preparation of polymorphic form X of the losartan kail salt) dissolved g of losartan form l in 20 ml of methanol. The concentrated solution was concentrated to a thick glassy mass and poured into 100 ml of n-hexane while stirring at room temperature. The resulting precipitate was stirred at room temperature for 1 hour and filtered. Carefully dry. Yield 0.92 g.

Claims (8)

Patent claims 1. The polymorphic form X of the losartan potassium salt, characterized in that it exists in crystalline form and has an X-ray powder diffraction pattern at 2Θ about 6.9, 13.8, 20.6, 24.0, 24.8, 28.7 and 29.2 °. The losartan potassium polymorphic form X of claim 1, characterized in that it has an X-ray powder diffractogram essentially as shown in Figure 1. The polymorphic form X of the losartan potassium salt according to claim 1, characterized in that it exists in solvate crystalline form. 4. A process for the preparation of the polymorphic form X of the potassium salt of losartan and its solvates, characterized by isolation from a mixture of methanol and hexane. 5. The method according to claim 4, characterized in that it comprises the following steps: a) to prepare a methanolic solution of losartan potassium salt, b) concentrate the resulting solution, c) mix the resulting concentrated solution with hexane, d) isolate polymorphic form X losartan potassium. 6. Pharmaceutical preparation containing as active ingredient polymorphic form X of the potassium salt of 2-n-butyl-4-chloro-5-hydroxymethyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1 '-biphenyl4-yl] methyl] -1H-imidazole or solvates thereof. Use of polymorphic form X of the losartan potassium salt for the preparation of a medicament. Use of the losartan potassium salt polymorph X of claim 7 for the preparation of a medicament for the treatment of hypertension.