GB2336840A - Tilidine embonate - Google Patents

Abstract

Tilidine Embonate has high stability, an improved taste, and may be manufactured by a simple efficient process. It may be presented in solid formulations, particularly with a retard profile.

Description

2336840 1 "A compound"

Introduction

The invention relates to a salt of Tilidine, processes for its preparation and its use in pharmaceutical products.

( )-Ethyl-trans-2-(dimethylamino)-1-phenyl-3-cyclohexene-l-carboxylate (Tilidine) is a pharmaceutically active substance with strong analgesic properties. Tilidine Base (l) is known to be a compound with a very low melting point [Pharm. Ind.

40(6), 657-664 [1978]; Cienc. Ind. Farm. 8(1), 4-11 [197611. This creates problems for the preparation of final pharmaceutical products.

/ CH3 0 CH3 H3C H Therefore, Tilidine is generally used in pharmaceuticals in the form of the Hydrochloride Sernihydrate salt which is a more stable compound than Tilidine base. However the Hydrochloride Sernihydrate is only suitable for the preparation of solutions and certain types of soft capsules. The Hydrochloride Sernihydrate is unsuitable for "solid formulations" required for the production of tablets. In addition, the taste of the Hydrochlonide is bitter which is an unpleasant side effect.

Attempts have been made to develop more stable salts of Tilidine. WOA94/10129 describes Tilidine Dihydrogen Orthophosphate, which is said to be stable and therefore suitable for the preparation of solid pharmaceutical 2 formulations such as tablets or dragees. However, the process for the preparation of Tilidine Dihydrogen Orthophosphate appears to be critical and complicated.

There is therefore a need for a new chemical entity based on Tilidine which is stable and can be easily produced in high yield and good quality.

This invention is directed towards providing such a new entity.

Statements of Invention

According to the invention there is provided Tilidine Embonate.

The invention also provides a process for preparing Tilidine Embonate wherein Tilidine Hydrochloride Semihydrate of the formula A:- CH3 H3C_ 0 CH3 \\10 (A) HC1.0.5H20 is reacted with Ammonium Embonate or alkyl substituted Ammonium Embonate of the formula B:

e (D Io OH (B) OH G) (D 0 NWR2R 3 0 3 wherein R', R' and W are selected from one or more of the same or different of Hydrogen and alkyl.

In one case all of R', R' and R' are hydrogen. One or more of R', R' and R' may be Cl to C4 alkyl, preferably ethyl or isopropyl. In one case one of R', R' and R' is ethyl and the other two of R', R' and R' is isopropyl. This corresponds to HOnigs base, diisopropyl ethyl amine.

In a preferred embodiment of the invention Embonic Acid is reacted with two molar equivalents of ammonia or an appropriate amine to form an intermediate of formula B. Preferably the suspension of Embonic Acid and aqueous Ammonia is heated to a temperature of from 35 to 80T, most preferably 45 to 50T, prior to addition of a solution of Tilidine Hydrochloride Sernihydrate. Ideally, the desired salt is isolated by addition of a suitable solvent, especially acetone.

In another embodiment a suspension of Embonic Acid and aqueous Ammonia is added to a solution of Tilidine Hydrochloride Sernihydrate and a solvent is added prior to heating the mixture to a temperature of from 40 to 80T, preferably 50 to 55T. Preferably the solvent is n-butanol. The desired salt may be isolated by evaporation of the solvent from the organic phase.

In one embodiment of the invention Embonic Acid is treated with Triethylamine at a temperature of from 30 to 80T, preferably 40 to 60T, prior to the addition of a solution of Tilidine Hydrochloride Sernihydrate.

Optionally the Tilidine Hydrochoride can be formed in situ from Tilidine base by addition of hydrochloric acid. Further reaction with ammonium, sodium or potassium embonate produces Tilidine embonate.

4 Alternatively other Tilidine acid salts may be used for the preparation of Tilidine Embonate. It is anticipated that these Tilidine acid salts can conveniently be prepared, preferably in situ, by reaction of Tilidine base with suitable acids such as sulphuric acid or hydrobromic acid. Subsequent conversion into Tilidine Embonate may also be performed with ammonium, sodium or potassium embonate.

The invention further provides pharmaceutical compositions containing Tilidine Embonate as the active ingredient. The Tilidine Embonate may be in a solid form. The composition may be a retard formulation. The composition may be in any suitable form including a tablet, capsule, suppository, dragee or granulate.

The invention will be more clearly understood from the following description given by way of example only.

Description Qf the Invention

It has been found that Tilidine Embonate shows extraordinary stability and remarkable properties for the preparation of various pharmaceutical products, especially for those having a retard profile. It has a neutral taste and the process for making Tilidine Embonate is extremely efficient and simple.

The invention provides a novel Tilidine salt which shows high stability and a 'neutral' non-bitter taste in comparison to other known Tilidine salts.

The invention also provides pharmaceutical formulations, especially with a retard profile.

Surprisingly it was found that Tilidine Embonate can be crystallised as a 2:1adduct from aqueous or organic solutions. The product isolated in high yields (-:--80%), is non-hygroscopic and shows, in comparison to other known Tilidine salts such as the Hydrochloride Sernihydrate and the Dihydrogen Orthophosphate, a non-bitter, neutral taste. As the novel salt is very stable, non-hygroscopic and has a high melting point (161-162'C) it is suitable for the manufacture of granulates which are readily converted into tablets, dragees or suppository. A delayed action or retard formulation containing Tilidine Embonate can be readily prepared.

In preparing such compositions there can be employed any of the various adjuvant or excipient materials customarily employed in the art. These adjuvants or excipients include, for example, inert substances such as water, gelatine, lactose, vegetable oil, as well as many of the other compatible materials conventionally used in the preparation of medicaments.

The process for production of Tilidine Embonate is very simple and efficient. The product obtained has high yields (80%) and a very high level of purity (:99%).

Tilidine Embonate may be administered in suitable quantities, depending on the amount of Tilidine to be provided. Typically, Tilidine Hydrochloride is administered in doses of up to 40Orng/day, usually in 5Orng units; in the form of capsules or drops. To achieve a similar profile a single dose of Tilidine Embonate [2:1] salt, is approximately 150mg and the maximum amount administered per day is in the range of 120Orng. In the case of formulations, preferably Naloxon Hydrochloride Dihydrate is used as an opiate antagonist in the formulation.

6 Reaction Scheme 0 ee 0 NHIR 1 R 2 R 3 0OH OH e@ 1 2 3 0 NHR R R 0 J,ie 0 OH 2 CH3 1 0 H3C- N.H /_-CH3 0 HCI. 112H20 L CH3 0 H 3C /-CH3 0 OH 1 e 2 0 re 1 2 3 Cl +1 NHR R R)I Tifidine Embonate 0 The ammonium salt by-product is washed out with solvent preferably water.

In addition to ammonium embonates, earth alkali salts of embonic acid may also be utilised, preferably the sodium or potassium salts. They can be prepared by reacting embonic acid with two equivalents of sodium hydroxide and potassium hydroxide respectively. The reaction scheme is as follows:

is 2 L CH3 1 0 N H H3C /'--CH3 C) HCl. 112H20 CH3 1 0 N H3C H 0 /-CH3 Tilidine Embonate 7 0 0 m OH OH 0 m 0 0 0 OH OH 2 0 0 wherein M is an earth alkali metal, preferably Na or K.

(D E) + m cl The earth alkali chloride by-products such as NaCI or KG are washed out with water.

Example 1

Preparation of Tilidine Embonate (2: 1 -salt) A suspension of 10 g (0.026 mol) of Embonic Acid in 40 nil of water was treated with 2 equivalents (0.052 mol) of aqueous Ammonia. The suspension was heated to 35-80'C preferably 45-50'C and a solution of 16.6 g (0.052 mol) Tilidine Hydrochloride Sernihydrate in 30 mI of water was slowly added. The mixture was stirred for one to three hours. After addition of 70 nil of acetone the off-white precipitate was filtered off, and washed with an acetone/water mixture (v/v L2).

The product was dried under vacuum at 6WC. A typical yield of 19.4 g or approximately 80% was obtained with a melting point of 161-162'C. Figs 1, 2, 3 8 and 4 show respectively, the 'H-NMR-spectrum, 'C-NMR-spectrum, DEPT and the IR-spectrum. Microanalysis of the compound revealed the following: Calculated: C:73.21, H:6.68, N:100 Found: C:73.00, H:631, N2.98 Stabili Tilidine Embonate was found to be stable over a long period of time stored as a solid under standard conditions. No significant change in the purity profile was found. No critical amounts of degradation products were observed Taste Organoleptic tests with human volunteers found that Tilidine Embonate has a neutral, non-bitter taste in comparison to Tilidine Hydrochloride Hemihydrate.

ExaLnple 2 A suspension of 30g (0.077 mol) of Embonic Acid in 120rnI of water was treated with 2 equivalents (0. 154 mol) of aqueous Ammonia. The mixture was added to a solution of Tilidine Hydrochloride Sernihydrate (49g, 0. 154 mol) in 10OmI of water. 15Orril of n-Butanol was added and the mixture heated to 40-80'C, preferably 50-55'C. The obtained two phases were separated and the organic layer was washed with water. After evaporation of the solvent the crude material was re-crystallised from ethanol. A typical yield of 63.2g or approximately 88% is obtained of Tilidine Embonate with the characteristics of Example 1.

ExaInple 3 A suspension of Embonic Acid (270 g, 0.695 mol) in 1.1 litres of water was treated with 2 equivalents of Ammonia (1.39 mol). The n-dxture was heated to 40-800C, preferably 50-60T. A mixture of Tilidine Base (380 g, 1.39 mol) in 900 ml of 9 water acidified with one equivalent of conc. HCl (1.39 mol) was added. Heating was continued for one to three hours. On cooling to room temperature the product precipitated quantitatively, was filtered off, washed with some water and dried under vacuum. The product is re- crystallised from ethanol forming Tilidine Embonate with the characteristics of Example 1.

Example 4

A suspension of 10 g (0.026 mol) of Embonic Acid in water was treated with 2 equivalents of Triethylamine (5.26 g, 0.052 mol) at a temperature of 3080'C, preferably 40-60'C. A solution of 16.6 g (0.052 mol) of Tilidine Hydrochloride Sernihydrate in 30 ml of water was added. The mixture was stirred for two to four hours. The product was filtered off, washed with some water and dried under vacuum. A quantitative yield of Tilidine Embonate was obtained. The product was re-crystallised from ethanol forming Tilidine Embonate with the characteristics of Example 1.

Example 5 -Retard Formulation 960g Tilidine Embonate prepared as in example 1 was added to 70.4g Naloxon hydrochloride dihydrate, 740g lactose and 700g hydrated castor oil, and the solution slowly stirred and heated up to a temperature of 60- 85'C. The mixture was filtered through a filter with a pore size of 2.5mm. After cooling to room temperature the mixture was further filtered through a filter with a pore size of Imm. 273.6g of Ammonia methyl Acrylate co-polymer, 32g Magnesium Stearate and 24g Silicon Dioxide were added to the mixture. The resultant mixture was then compressed into tablet form.

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

Claims (23)

Claims

1. Tilidine Embonate.

2. A process for the preparation of Tilidine Embonate wherein Tilidine Hydrochloride Semihydrate of the formula A:- / CH3 H3C H (A) HCL0.5H20 is reacted with Ammonium Embonate or alkyl substituted Ammonium Embonate of the formula B:

0 G) 1 2 3 0 NHR R R OH OH (D0 0 NHR 1 R 2 R 3 0 (B) wherein R', R2 and R' are selected from one or more of the same or difFerent of Hydrogen and alkyl.

3. A process as claimed in claim 2 wherein all of R, W and R' are hydrogen.

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4.

5.

A process as claimed in claim 2 wherein one or more of R', R 2 and R' is Cl to C4 alkyl.

A process as claimed in claim 3 wherein one or more of R', R' and R' is ethyl.

6.

A process as claimed in claim 4 or 5 wherein one or more of R', R2and R 3 is isopropyl.

7. A process as claimed in any of claims 4 to 6 wherein one of R', R2 and R' is ethyl and the other two of R', R2and R' is isopropyl.

8. A process as claimed in any of claims 2 to 7 wherein Embonic Acid is reacted with two molar equivalents of ammonia or an appropriate amine to form an intermediate of the formula B as defined in claim 2.

9. A process as claimed in claims 2 to 8 wherein the suspension of Embonic Acid and aqueous Ammonia is heated to a temperature of from 35 to 8TC, preferably 45 to STC, prior to addition of a solution of TilidMic Hydrochloride Sernihydrate.

10. A process as claimed in claim 9 wherein the desired salt is isolated by addition of a suitable solvent.

11.A process as claimed in claim 10 wherein the solvent is acetone.

12. A process as claimed in any of claims 2 to 8 wherein a suspension o Embonic Acid and aqueous Ammonia is added to a solution of Tilidine Hydrochloride Sernihydrate and a solvent is added prior to heating the mixture to a temperature of from 40 to 800C, preferably 50 to 55'C.

13. A process as claimed in claim 12 wherein the solvent is n-Butanol.

14. A process as claimed in claim 12 or 13 wherein the desired salt is isolated by evaporation of the solvent from the organic phase.

15. A process as claimed in any of claims 2 to 8 wherein Embonic Acid is treated with Triethylamine at a temperature of from 30 to 801C, preferably 40 to WC, prior to the addition of a solution of Tilidine Hydrochloride Sernihydrate.

16. A process for preparing Tilidine Embonate by forming Tilidine hydrochloride in situ by addition of hydrochloric acid to Tilidine base and reacting Tilidine hydrochloride with a suitable embonate, especially ammonium, sodium or potassium embonate.

is

17.

A process for preparing Tilidine Embonate by forming a Tilidine acid salt with suitable acids and converting the acid salt into Tilidine Embonate using a corresponding embonate salt.

18. A process as claimed in claim 17 wherein the Tilidine acid salt is prepared in situ by reaction of Tilidine base with an appropriate acid.

19. A process for preparing Tilidine Embonate substantially as hereinbefore described with references to the examples.

20. Tilidine Embonate whenever prepared by a process as claimed in any of claims 2 to 19.

21. A pharmaceutical composition containing Tilidine Embonate as an active ingredient.

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22. A composition as claimed in claim 21 wherein the composition is in a solid form.

A composition as claimed in claim 21 or 22 wherein the composition is in the form of a tablet, dragee, capsule, suppository or granulate.

24. A composition as claimed in any of claims 21 to 23 wherein the composition is a retard formulation for sustained release.

23.A composition substantially as hereinbefore described with reference to the examples.