WO1999065890A1

WO1999065890A1 - Ranitidine adduct

Info

Publication number: WO1999065890A1
Application number: PCT/IE1999/000041
Authority: WO
Inventors: Helmut Schickaneder; Aggelos Nikolopoulos; Gesine Hermann
Original assignee: Russinsky Limited
Priority date: 1998-06-17
Filing date: 1999-05-13
Publication date: 1999-12-23
Also published as: IE990387A1; AU4055699A

Abstract

A novel Ranitidine Base water adduct is more stable than the anhydrous base. Also claimed are pharmaceutical compositions including Ranitidine Base water adduct. The adduct is prepared by dissolving Ranitidine Base (anhydrous) in water and precipitating the desired water adduct.

Description

RANITIDINE ADDUCT

Introduction

Ranitidine (I), (N-{2-[({5-[(dimethylarr_ino)rnethyl]-2-furanyl}-methyl)thio]ethyl}- N^I-methyl-2-nitro-l,l-ethenediamine), is a selective Histamine H₂-receptor antagonist which is very effective in the treatment of peptic ulcers and related disorders [Drugs 24, 267 (1982), Drugs Fut. 20, 480 (1995), Pharmacol. Rev. 49, 253 (1997)]. It has the following structure:

British Patent 1 565 966 describes Ranitidine Hydrochloride and a process for the preparation of Ranitidine Base (page 18, lines 6-17).

During the process for producing Ranitidine Base a number of by-products are obtained. These by-products produce unpleasant odours and create processing difficulties. Various purification steps are required to minimise the impurities prior to the conversion of Ranitidine Base into the final salts required, such as Ranitidine Hydrochloride. However, patients often complain about the adverse taste and/ or malodour associated with Ranitidine formulations. Various attempts have been made to produce formulations and delivery systems which mask these properties.

WO96/06608-A describes a purification process which is said to reduce adverse taste and malodour associated with cimetidine, famotidine and nizatidine by forming an aqueous solution which is heated to about 100"C. However, this process does not work for Ranitidine. Ranitidine Base is also known to be moisture and temperature sensitive. Environmental conditions such as the influence of light and air can lead to the decomposition of the Base which releases compounds with an unpleasant odour. The colour of the Base changes in storage.

There is therefore a need for a product and/ or process which will overcome at least some of these difficulties.

Statements of Invention

The invention provides a novel water adduct of Ranitidine. Preferably the Ranitidine Base water adduct contains up to three equivalents of water.

The invention also provides a process for preparing Ranitidine Base water adduct comprising the steps of: dissolving Ranitidine Base (anhydrous) in water; and precipitating the desired water adduct.

Ideally the process has a crystallisation temperature of-10°C to +25°C. Preferably the crystallisation temperature is from 0°C to 5°C.

A further embodiment of the invention provides a pharmaceutical composition including Ranitidine Base water adduct. Preferably the composition is in the form of a solution.

Another aspect of the invention provides a process for preparing Ranitidine or pharmaceutically acceptable salts thereof including the step of converting Ranitidine Base adduct into Ranitidine Base or a pharmaceutically acceptable salt thereof. Ideally the salt is Ranitidine Hydrochloride. Detailed Description of the Invention

It has been found that Ranitidine Base can be crystallised as a hydrate from water. This is surprising as Ranitidine "free" Base is known to be hygroscopic and highly water-soluble. The novel adduct can be isolated as a white to off-white coarse material containing up to three equivalents of water. Upon gentle heating under vacuum the H₂0 adduct can be converted back into the more sensitive "free" Ranitidine Base, if required. The H₂0 adduct may also be converted directly into pharmaceutically acceptable salts or formulated into a solution.

The novel form of Ranitidine Base is much more stable than the anhydrous Base. It can be stored over a long period of time without decomposition and loss of quality.

The product can be crystallised from water in high yield (>80%) and very high quality (purity greater than 99.5%). The adduct formation prevents Ranitidine Base from decomposition which is a major problem with the handling and especially the storage of the anhydrous form.

The crystallisation procedure is an excellent purification method as most impurities from previous reaction steps can be eliminated without significant loss of product yield. The procedure can be undertaken at a temperature range between -10°C and +25°C, preferably 0°C to +5°C.

The novel form of Ranitidine Base can be converted into Ranitidine

Hydrochloride or any other pharmaceutically acceptable salts of very high quality. The H₂0 adduct of Ranitidine Base can also be used for the preparation of Ranitidine Hydrochloride solutions.

The invention will be more clearly understood from the following examples. Reaction Scheme

+ x H₂O - x H,0/ ΔT

Example 1

Preparation of Ranitidine Base H;Q Adduct

100 g (0.32 mol) of Ranitidine Base were dissolved at room temperature in 300 ml of water. The mixture was stirred for one to three hours at -10°C to +25°C, preferably 0°C to +5°C. The precipitated product was then filtered off, washed with some cold water and dried at ambient temperature. 103 g of product containing approximately 1.5 equivalents of water were obtained, yield 96% (0.32 mol).

Identification data for the adduct are as follows: 'H-NMR-spectrum (Figure 1), ¹³C-NMR-spectrum (Figure 2), IR-spectrum (Figure 3).

Η-NMR (270 MHz, room temperature, CDC1₃): δ = 2.18 (s, 6H, N(CH₃)₂); 2.72- 2.77 (m, 2H, CH₂); 2.85-2.98 (m, 4H, CH₂); 2.95 (crystal water); 3.23-3.25 (m, IH, CH₂N); 3.41 (s_br, IH, CH₂N); 3.41 and 3.71 (s each, 3H, NHCHj, both tautomers); 6.13 (d, IH, CH); 6.16 (d, IH, CH); 6.59 (s, CHN0₂); 6.74, 7.30, 10.20 and 10.28 (each s_br, NH, both tautomers).

^I3C-NMR (67.5 MHz, room temperature, CDC1₃): δ = 27.67-29.03 (CH₃NH, CH₂); 30.97 (CH₂); 41.00 (CH₂); 45.00 (N(CH₃)₂); 55.91 (CH₂N(CH₃)₂); 98.21 (CHN0₂); 108.53, 109.72 (C=C-C=C); 150.76, 152.19 (C-O); 156.85 (N-C-N).

FT-IR (Paraffin Oil): v [cm ¹] = 3210, 2971, 1616, 1576, 1457, 1377, 1233, 1013, 758, 621.

In the case of crystallisation failure, seeding material may be added. Optionally, a treatment with activated carbon may be undertaken for colour improvement.

Depending on the drying process, Ranitidine Base may also be isolated with a content of water higher than 1.5 equivalents, up to approximately 3 equivalents.

The water adduct can also be converted back into the anhydrous form of Ranitidine Base upon heating under normal pressure or preferably vacuum.

Identification data for the Ranitidine base formed in this way are as follows: H- NMR-spectrum (Figure 4), ¹³C-NMR-spectrum (Figure 5), IR-spectrum (Figure

6).

Η-NMR (270 MHz, room temperature, CDC1₃): δ = 2.21 (s, 6H, N(CH₃)₂); 2.73- 2.78 (m, 2H, CH₂); 2.86-2.99 (m, 4H, CH₂); 3.26-3.27 (m, IH, CH₂N); 3.44-3.47 (m, IH, CH₂N); 3.41 and 3.73 (s each, 3H, NHCH₃, both tautomers); 6.13 (d, IH,

CH); 6.16 (d, IH, CH); 6.59 (s, IH, CH and NH of one tautomer); 7.01, 10.20 and 10.28 (s^ each, NH, both tautomers).

^I3C-NMR (67.5 MHz, room temperature, CDC1₃): δ = 27.45-29.26 (CH₃NH, CH₂); 30.95 (CH₂); 41.07 (CH₂); 45.06 ((CH₃)₂N); 55.96 (CH₂N(CH₃)₂); 98.23

(CHN0₂); 108.53, 109.58 (C=C-C=C); 150.68, 152.39 (C-O); 156.83 (N-C-N). FT-IR (Paraffin Oil): v [cm ¹] = 3273, 3207, 2966, 2930, 2774, 1622, 1577, 1442, 1372, 1260, 1163, 1018, 988, 790, 753, 594, 528.

Example 2 Preparation of Ranitidine Hydrochloride (Form 1

65 g of Ranitidine Base 1.5 H₂0 were dissolved in 300 ml of isopropanol or ethanol. 1.0-1.1 equivalents of cone. HCl were added. The mixture was stirred at room temperature. After addition of a reasonable amount of seeding material (Ranitidine Hydrochloride Form 1), stirring was continued for four to six hours.

The mixture was cooled to 0-5°C. The product, Ranitidine Hydrochloride Form 1, was filtered off, washed with isopropanol and dried under vacuum. Yield 32 g (0.091 mol, 54%).

The invention is not limited to Form 1 Ranitidine Hydrochloride. It is believed that it also applies to Form 2.

Stability Test

Ranitidine hydrate was found to be stable over a long period of time stored under standard conditions. No significant change in the purity profile was found. The compound remained a white to off white colour and quite odourless.

The Ranitidine Base water adduct prepared as hereinbefore described may be used in the manufacture of effervescent tablets, injectables and Ranitidine Bismuth Citrate as described in the following examples. Example A

Preparation of effervescent tablets containing Ranitidine

The following is a typical formulation:

Ranitidine Base H₂0 Adduct (1.5 eq. H₂0): 163.5mg

Anhydrous Monosodium Citrate: 840.0mg

Sodium Hydrogen Carbonate: 836.0mg

Polyvinylpyrrolidone: 40.0mg 10% [w/w] Siliconed Sodium Benzoate: 80.0mg

Flavour: 36.0mg

Ranitidine Base H₂0 Adduct, Anhydrous Monosodium Citrate, Sodium Hydrogen Carbonate and Polyvinylpyrrolidone were blended in the presence of a suitable amount of alcohol in a mixer-granulator. The resulting granules were dried and mixed with Sodium Benzoate and flavouring. The obtained material can be pressed into tablets.

Example B Preparation of Ranitidine iniectable

lO.Og of Ranitidine Base 1.5 H₂0 Adduct were dissolved in 100ml of water. The obtained solution was titrated with diluted hydrochloric acid to pH 5. The mixture was then saturated with nitrogen gas and filtered thoroughly through a membrane to remove solid fibres or particles. The solution can then be transferred into ampoules containing typically 200mg of the active compound. The filled ampoules were sterilised. The solution can be used for intravenous injection. Example C

Preparation of Ranitidine Bismuth Citrate Polymorph 2 from Ranitidine Base 1.5

H.O Adduct.

16.6g of Ranitidine Base 1.5 H₂0 Adduct and 20.8g of Bismuth Citrate were mixed with 150-200ml of water. The mixture was heated to 60-90°C to perform a neutralisation process. The mixture was then cooled to ambient and unreacted Bismuth Citrate filtered off. The filtrate was evaporated to dryness affording a viscous oil. The residue was treated with 400-600 ml of alcohol to precipitate the product. After filtration an additional wash with 200-300 ml of alcohol the product was dried under vacuum. A typical yield of 65-80% is obtained.

The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims

1. Ranitidine base water adduct.

2. Ranitidine Base water adduct containing up to three equivalents of water.

3. A process for preparing Ranitidine Base water adduct comprising the steps of: dissolving Ranitidine Base (anhydrous) in water; and precipitating the desired water adduct.

4. A process as claimed in claim 3 wherein the crystallisation temperature is from -10°C to +25°C.

5. A process as claimed in claim 3 or 4 wherein the crystallisation temperature is from 0°C to 5°C.

6. A process for preparing Ranitidine Base water adduct substantially as hereinbefore described with reference to the examples.

7. Ranitidine Base water adduct whenever prepared by a process as claimed in any of claims 3 to 6.

8. A pharmaceutical composition including Ranitidine Base water adduct.

9. A composition as claimed in claim 8 in the form of a solution.

10. A process for preparing Ranitidine or pharmaceutically acceptable salts thereof including the step of converting Ranitidine Base adduct into Ranitidine Base or a pharmaceutically acceptable salt thereof. - lO - ll. A process as claimed in claim 10 wherein the salt is Ranitidine Hydrochloride.

12. A process for preparing Ranitidine or pharmaceutically acceptable salts thereof substantially as hereinbefore described with reference to the examples.

13. Ranitidine or pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in any of claims 10 to 12.