DD298099A5 - Form 2 of ranitidine hydrochloride and its use - Google Patents

Abstract

A new crystal form of ranitidine * & *, referred to as Form 2, is described. This form has favorable filtration and drying properties and is characterized by a special infrared spectrum and / or X-ray diffraction pattern. {Form 2; ranitidine hydrochloride; Use; Drug}

Description

The invention relates to the form 2 of the hydrochlorides of the H ₂ -antagonist N- [2- | ((5- (dimethylamino) -methyl) -2-furanyl] -methylthiol-ethyl-N'-methyl-nitro-ii-ethenediamine , which has been given the name "ranitidine." The invention also relates to the use of this compound.

Ranitidine, which is described in GB-PS 1565966, exhibits a potent histamine Hj-blocking activity and can be used to treat conditions in which, advantageously, the gastric acidity is lowered, in particular of gastric and intestinal ulcers, for prophylaxis in surgical interventions and Treatment of histamine-induced allergic and inflammatory conditions.

The hydrochloride salt of ranitidine (hereinafter referred to as ranitidine hydrochloride) is particularly desirable because it allows the convenient formulation of ranitidine, for example, in the form of tablets for oral administration. There is therefore a need to prepare ranitidine hydrochloride in pure and highly crystalline form to meet exact pharmaceutical requirements and specifications.

The production process for ranitidine hydrochloride must also be feasible on an industrial scale. In particular, it is desirable that the hydrochloride be prepared with concentrated hydrochloric acid and that the crystallization solvent can be easily recovered.

Add to this that the product should be in a form that can be easily filtered off and dried easily. Furthermore, if necessary, the product should be recrystallizable from the same solvent system.

Ranitidine hydrochloride is prepared in a crystalline form, designated Form 1, by dissolving ranitidine in technical methylated petrol containing hydrogen chloride and adding ethyl acetate to the resulting solution, as described in the above-referenced GB patent 1565966 is described. However, this procedure does not have the desirable characteristics of a manufacturing process described above and Form 1 of the hydrochloride salt has unfavorable filtration and drying properties.

It has now been found that ranitidine hydrochloride can be prepared in a novel crystalline form having better properties, with the production process for the new crystalline form satisfying the desirable requirements described above. The invention therefore provides ranitidine hydrochloride in a novel crystal form, referred to as Form 2. It has been found that the mold 2 in general has larger crystals than the previously known Form 1 and that has the more favorable filtration and drying properties. In addition, the form 2 is less hygroscopic than the form 1, which represents a further advantage in terms of the moisture sensitivity of the ranitidine hydrochloride.

The invention relates to the form 2 of ranitidine hydrochloride, which is characterized by an infrared spectrum as a paste in mineral oil with the following main peaks:

3260 1075 3190 1045 3100 1021 2 560 1006 2510 991 2470 972 1620 958 1590 810 1570 800 1263 760 1230 700 1220 660 1195 640 1163 620 cm 1130

The invention further relates to the use of form 2 of ranitidine hydrochloride for the preparation of an agent. The form 2 of ranitidine hydrochloride can thus be characterized by its infrared spectrum in mineral oil and / or by its X-ray powder diffraction pattern, as explained in more detail below.

The infrared spectrum of the product of Example 1 thus obtained is shown in the drawing. The ordinate indicates the permeability in% and the abscissa the wavenumber in cm ' ¹ .

X-ray diffraction

The X-ray diffraction pattern of form 2 of ranitidine hydrochloride can be obtained by placing the material in a glass capillary having a diameter of 0.3 mm and the image or pattern by the Debye-Scherrer method with a camera having a diameter of 114, 6 mm by exposure for 12 hours with a CoK, radiation and 3 hours exposure to a CuK _a radiation (for "d" 0.3 nm (3A)) .The measured average values of X-ray wavelengths used for the calculations were CuK, 0.154171 nm [1.54171 A] and CoK.0.179024nm [1.79024A].

The X-ray powder diffraction pattern of form 2 of ranitidine hydrochloride, expressed as "d spacings and relative intensities (I), follows w * ··" (s = strong, m = medium, w = weak, ν = very, d = diffuse ):

d (nm) = (A) I d (nm) = (A) I

1,073 10.73 m 0.34 3.4-J 2 ▲ ▼ 0.65 6.50 3vwd 0.335 3,3- 2 vwd 0,613 6.13 m 0,325 3.25 wd 0.583 5.83 S 0.312 3.12 2 vw 0.563 5.63 3 vwd 0.304 3.04 2 vwd 0.542 5.42 S 0.297 2.97 3 vwd 0.506 5.06 2 vw 0.293 2.93 3vwd 0.492 4.92 W 0,288 2.88 3 vwd 0.459 4.59 2 vw 0.281 2.81 vwd 0.44 4.40 S 0.272 2.72 vwd 0.428 4.28 W 0.266 2.66 3 vwd 0.391 3.91 wd 0.247 2.47 2 vwd 0.379 3.79 S 0.244 2.44 VW 0.371 3.71 m 0.234 2.34 2 vwd 0.36 3.60 vwd 0.23 2.30 3 vwd 0.346 3.46 m 0.221 2.21 2 vwd

The form 2 of ranitidine hydrochloride may be formulated for administration in any manner. The invention therefore also encompasses the use of form 2 of ranitidine hydrochloride for the preparation of medicaments suitable for human or veterinary medicine. Such drugs may be formulated in a conventional manner with pharmaceutically acceptable carriers or diluents. Thus, the hydrochloride salt of the invention may be formulated for oral, buccal, topical, parenteral or rectal administration. Oral administration is preferred, especially in the form of tablets and capsules.

For oral administration, the medicament may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions, which may be formulated in a conventional manner using suitable carriers. For buccal administration, the medicaments may take the form of tablets or briefrhen formulated in a conventional manner.

The form of ranitidine hydrochloride may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form as vials or in multi-dose containers with an added preservative. The pharmaceutical compositions may also take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory aids such as suspending, stabilizing and / or dispersing agents. Alternatively, the active compound may also be used in powder form for the purpose of rekor- titution with a suitable carrier, eg. As sterile pyrogen-free water, before use. The Forr .. ι ranitidine hydrochloride may be formulated which may include, for example, conventional suppository bases such as cocoa butter or other glycerides for rectal administration forms, such as suppositories or retention enemas.

For topical application, form 2 of ranitidine hydrochloride in the form of ointments, cis, gels, lotions, powders or sprays may be formulated in a conventional manner.

For internal administration, a suitable daily dosage form of ranitidine hydrochloride 2 is 1 to 4 doses to a total of about 40 mg to 1.2 g per day, depending on the condition of the patient.

In the process for preparing form 2 of ranitidine hydrochloride, one proceeds by crystallizing ranitidine hydrochloride from a solution in a solvent under conditions which yield form 2 of ranitidine hydrochloride.

The precise conditions in which form 2 of ranitidine hydrochloride is formed can be determined empirically and at this point only a number of methods which have been found to be suitable for the practice should be indicated.

For example, Form 2 of ranitidine hydrochloride can be prepared by crystallization under controlled conditions. In particular, it can be prepared either from the corresponding free base by reaction with hydrochloric acid or by recrystallization of the previously isolated ranitidine hydrochloride. In general, the use of a hydroxyl group-containing solvent, for example a lower alkanol, is preferred. In order to dissolve the starting material, it may be desirable to heat and / or add some water to the solvent system. In some cases, it will be necessary to add another organic solvent or a special anti-solvent, such as acetone, to obtain Form 2 crystals from the solution.

When the starting material for the preparation of the desired form 2 of ranitidine hydrochloride is the free base, a preferred method of preparation is to treat a solution of ranitidine in propan-2-ol with hydrochloric acid and then crystallize the desired form of the hydrochloride salt , preferably at an elevated temperature of up to 7O ⁰ C, eg 40 to 60 ° C, ^0, indam one further quantities of propan-2-ol is added and in particular 48 to 52 C.

Alternatively, one can also treat a solution of ranitidine in 2-methylpropan-2-ol, butan-2-ol or ethanol with hydrochloric acid and the desired Form 2 of ranitidine hydrochloride at a temperature of up to 7O ⁰ C, for example from room temperature to 6O ⁰ C, kristai, let adorn. It is preferred to use concentrated hydrochloric acid (eg to 38% w / w). In general, molar equivalent ratios of hydrochloric acid and ranitidine should be used. In these conditions, salt formation, such as crystallization, should preferably be carried out at elevated temperature, for example at a temperature within the abovementioned temperature range. It has been found that it may be advantageous to add to the starting solution a small amount of water in addition to the water contained in the hydrochloric acid, for example up to 7%, preferably about 3% volume / volume. For example, when ethanol is used as the solvent, it may be used in the form of engineering methylated gas containing about 2% volume / volume of water.

When the starting material ranitidine hydrochloride, e.g. Form 1 or Form 2, then the salt of the desired Form 2 can be crystallized using similar conditions for crystallization as described above.

Alternatively, the salt may be dissolved, for example, by heating in an organic solvent such as methanol or ethanol, and then the resulting solution may be cooled to 10 to 40 ° C, for example, followed by stirring until crystallization of the intended shape is complete. In the case of some solvents, eg. As methanol, it may be advantageous to use a miscible anti-solvent, for. Acetone or ethyl acetate, to the solution to complete the crystallization.

It has often been found convenient to add "seed 2" seeds of ranitidine hydrochloride to the crystallization solution to induce crystallization.

The form 2 of ranitidine hydrochloride has been found to be readily isolatable and, if desired, it may be cooled, washed and dried after cooling from the crystallization medium.

If desired, the form 2 of ranitidine hydrochloride prepared in the above manner can be recrystallized using similar crystallization conditions as described above.

The invention is illustrated in the examples. All temperatures are given in ° C. The concentrated hydrochloric acid has a concentration of 35% weight / weight and the technical methylated fuel has a boiling point of 74 ⁰ C and contains 2% volume / volume of water.

example 1 Preparation of Form 2 of ranitidine hydrochloride

1 equivalent (about 5.3 ml) of concentrated hydrochloric acid was added to a solution of ranitidine (20 g) in a mixture of propan-2-ol (130 ml) and water (4 ml) at 45 ° C The mixture was 5O ⁰ C. while adding another amount of propan-2-ol (68 ml). Then, the resulting solution was stirred at 50 ^° C to allow the product to crystallize. The slurry was cooled to 10 to 12 ⁰ C and the product was filtered off, washed with propan-2-ol (2x 27 ml) and dried at 50 ° under reduced pressure, whereby the form 2 of ranitidine hydrochloride (21 g), Vp 139 to 141 "C, was obtained.

Example 2

Recrystallization of ranitidine hydrochloride

The form 2 of ranitidine hydrochloride (25g) was heated in a mixture of propan-2-ol (66ml) and water (9ml) and the resulting solution was stirred at 50 ^° C. A further quantity of propan-2-ol (150ml) was added over 5 to 10 minutes and the product was dried at 5O ⁰ C allowed to crystallize. The slurry was cooled to 10 and 1? ° C and the product was filtered off, washed with propan-2-ol (2 x 30) and then at 5O ⁰ C dried under reduced pressure to give the Form 2 ranitidine hydrochloride (23,6g) , Mp 139 to 141 ^° C.

Example 3

Recrystallization of ranitidine hydrochloride

The form 2 of ranitidine hydrochloride (50 g) was warmed in a mixture of propar-2-ol (132 ml) and water (18 ml) and the resulting solution was stirred at 55 ° C. An additional amount of propan-2-ol (300 ml) was added over 5 to 10 minutes and the product was allowed to crystallize at 55 ° C. The slurry was cooled to 10 to 121 ⁰ C and the

Product was abfiltrieit, washed with propan-2-ol (2x 60ml) and then dried at 50 ° C under reduced pressure to give the Form2 ranitidine hydrochloride (48g), mp was 141-142 ⁰ C is obtained.

Example 4

Recrystallization of the ranitldine hydrochloride

The Form 2 ranitidine hydrochloride (50g) was dissolved in industrial methylated spirit (200ml) at 7O ⁰ C. The solution was allowed to cool and the product crystallized at 4O ⁰ C from. The resulting Aufschlämung was cooled to 0 ° C and the product was filtered off, washed with industrial methylated spirit (20ml) and dried at 5O ⁰ C under reduced pressure to give the Form 2 ranitidine hydrochloride (47,7g), mp 140 to 142 ⁰ C, was obtained.

Example 5

Preparation of Form 2 of ranitidine hydrochloride

Concentrated hydrochloric acid (1.4 ml) was added to a solution of ranitidine (6 g) in 2-methylpropan-2-ol. The mixture was stirred at 40 ° C to allow the product to crystallize. The resulting slurry was cooled to 20 ° C. More concentrated hydrochloric acid (about 0.2 ml) was added to the mixture. After stirring at 2O ⁰ C, the product was filtered off, washed with 2-methylpropan-2-ol and dried at 50 ⁰ C under reduced pressure to give the Form 2 ranitidine hydrochloride (5,96g), mp 141-142 ⁰ C, was obtained.

Examples

Preparation of Form 2 of ranitidine hydrochloride

The procedure was as in Example 5, wherein butan-2-ol was used instead of 2-methylpropan-2-ol and the mixture was stirred at 55 ⁰ C. In this way Form 2 was obtained from ranitidine hydrochloride (6.1 g), mp 140-141 ° C.

Example 7

Reaction of form 1 of ranitidine hydrochloride to produce form 2 of ranitidine hydrochloride Form 1 of ranitidine hydrochloride (25 g) was warmed in a mixture of propan-2-ol (66 ml) and water (9 ml) and the resulting solution became 50 ° C stirred. An additional amount of propan-2-ol (150 ml) was added over 5 to 10 minutes and the product was allowed to crystallize at 50 ° C. The slurry was cooled to 10 to 12 ^° C. and the product was filtered off with propane -2 oil (2x 30 ml) and dried at 5O ⁰ C under reduced pressure to give the form 2 ranitidine hydrochloride (22,7g), mp was 139 to 14O ⁰ C, was obtained.

Examples

Recrystallization of Formula 1 from ranitidine hydrochloride to produce Form 2 ranitidine hydrochloride Form 1 ranitidine hydrochloride (10g) was heated in a mixture of methanol (15ml) and acetone (15ml). The solution was stirred at 5O ⁰ C, while a further quantity of acetone (45ml) was added, and then the resulting solution at 5O ⁰ C was stirred to crystallize the product. The slurry was cooled to 2O ⁰ C and the product was filtered, washed with acetone (2x 10ml) and dried at 5O ⁰ C under reduced pressure to give the Form 2 ranitidine hydrochloride (9.5 g), mp 141-142 ⁰ C, was obtained.

Example 9

Preparation of Form 2 of ranitidine hydrochloride

Ranitidine (6 g) was dissolved in technical methyliorten fuel (42ml) at ambient temperature (about 20 ⁰ C) dissolved. 1 equivalent (about 1.6 ml) of concentrated hydrochloric acid was added to the solution. The temperature rose to about 27 ⁰ C and the solution was seeded at this temperature to induce crystallization. The product crystallized out to form a thick slurry at 25 to 27 ° C. After 0.5h the slurry was cooled C 0.5h heated at 10 to 12 ^0th The product was then filtered, washed with industrial methylated spirit (5 ml) and dried at 5O ⁰ C under reduced pressure to give the Form 2 ranitidine hydrochloride (5.4 g), mp 139 to 14O ⁰ C was obtained.

Examples 10 to 12

Preparation of Form 2 of ranitidine hydrochloride

Ranitidine (50 g) was dissolved in propan-2-ol (225 ml) at 45 to 55 ⁰ C dissolved. Celite (0.6 g) was added and the reaction mixture was filtered. Propan-2-ol (100 mL) heated to 45-55 ° C, water used to wash the filter (Table 8 omitted in Example 12) was added to the combined filtrate and the reaction solution was added to the Crystallization temperature (see table) set.

Concentrated hydrochloric acid (approximately 14 ml) was added until reaching the endpoint, ie, until an aliquot of the reaction mixture changed bromothymol blue from green to yellow. Propan-2-ol (168 mL) warmed to 45-55 ^° C was added and the temperature of the solution was adjusted to the selected crystallization temperature. The solution was inoculated with form 2 of ranitidine hydrochloride if necessary and stirred for 3 hours.

The reaction mixture was then cooled to room temperature and stirred overnight. Prior to filtration, the mixture was cooled at 8 to 12 ⁰ C for 1.5 hours. The mixture was filtered and the product was washed with cold (8 to 12 ⁰ C) propan-2-ol (2x 62 ml). The obtained product as Form 2 ranitidine hydrochloride was dried in vacuum oven at 5O ⁰ C.

table added water crystallization Yield (g) example quantity (ml) temperature ( ⁰ C) No. 2.1 40 52.2 10 2.1 55 51.0 11 _ 50 54.0 12

Claims (2)

1. Form 2 of ranitidine hydrochloride, characterized by an infrared spectrum as a paste in mineral oil with the following main peaks: -1 2. Use of the form 2 of ranitidine hydrochloride according to claim 1 for the preparation of a medicament. For this 1 page drawing