IE19990301A1 - Tilidene salts - Google Patents
Tilidene saltsInfo
- Publication number
- IE19990301A1 IE19990301A1 IE1999/0301A IE990301A IE19990301A1 IE 19990301 A1 IE19990301 A1 IE 19990301A1 IE 1999/0301 A IE1999/0301 A IE 1999/0301A IE 990301 A IE990301 A IE 990301A IE 19990301 A1 IE19990301 A1 IE 19990301A1
- Authority
- IE
- Ireland
- Prior art keywords
- tilidine
- salicylate
- acetylsalicylate
- salts
- hydrochloride hemihydrate
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title description 18
- 239000011780 sodium chloride Substances 0.000 title description 18
- 229960001402 tilidine Drugs 0.000 abstract description 74
- WDEFBBTXULIOBB-WBVHZDCISA-N Tilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 abstract description 62
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 abstract description 32
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 abstract description 23
- 229960001860 salicylate Drugs 0.000 abstract description 23
- 229940068372 Acetyl salicylate Drugs 0.000 abstract description 22
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 abstract description 16
- WHYVWQHDUOALSV-UMJMSJQKSA-N ethyl (1S,2R)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate;hydrate;dihydrochloride Chemical compound O.Cl.Cl.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WHYVWQHDUOALSV-UMJMSJQKSA-N 0.000 abstract description 15
- 229960001138 acetylsalicylic acid Drugs 0.000 abstract description 8
- 229960004889 salicylic acid Drugs 0.000 abstract description 7
- 238000000034 method Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000000875 corresponding Effects 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 230000000202 analgesic Effects 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000000240 adjuvant Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000001741 anti-phlogistic Effects 0.000 description 2
- 230000001754 anti-pyretic Effects 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 230000003111 delayed Effects 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZGZWRSASDRZAIL-UHFFFAOYSA-N 2-acetyloxybenzoic acid;azane Chemical class N.CC(=O)OC1=CC=CC=C1C(O)=O ZGZWRSASDRZAIL-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-M Acetylsalicylate Chemical compound CC(=O)OC1=CC=CC=C1C([O-])=O BSYNRYMUTXBXSQ-UHFFFAOYSA-M 0.000 description 1
- 229940063284 Ammonium salicylate Drugs 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 230000003466 anti-cipated Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- BOFZOTMTKBQRAB-UHFFFAOYSA-N azanium;2-carboxyphenolate Chemical compound N.OC(=O)C1=CC=CC=C1O BOFZOTMTKBQRAB-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Abstract
Abstract Tilidine Acetylsalicylate and Tilidine Salicylate are formed by reacting Tilidine Hydrochloride Hemihydrate with Acetylsalicylic or Salicylic acid respectively.
Description
Abstract
Tilidine Acetylsalicylate and Tilidine Salicylate are formed by reacting Tilidine
Hydrochloride Hemihydrate with Acetylsalicylic or Salicylic acid respectively.
Introduction
The invention relates to novel salts of Tilidine, processes for their preparation and
their use in pharmaceutical products.
(i)-Ethyl-trans(dimethyIamino)pheny1-3—cyclohexene-l-carboxylate
(Tilidine) is a pharmaceutically active substance with strong analgesic properties.
Trans—Tilidine Base (1) is known to be a compound with a very low melting point
(Pharm. Ind. 40(6), 657-664 [l978]; Cienc. Ind. Farm. 8(1). 4-11 [l976]). This
creates problems for the manufacture of final pharmaceutical products.
go... (I)
Therefore, T ilidine is generally used in pharmaceuticals in the form of
Hydrochloride Hemihydrate, a more stable compound than Tilidine base itself. As
the Hydrochloride Hemihydrate is very soluble in water it is suitable for the
preparation of solutions which can be administered for fast pain relief. Certain
types of soft capsules can also be manufactured using Tilidine Hydrochloride
Hemihydrate as an active ingredient. However, the Hydrochloride Hemihydrate
is not suitable for “solid formulations" required for the production of tablets.
F urtherrnore it seems to be unsuitable for the manufacture of Tilidine containing
products with a retard profile. g
OPEN TO PUBLIC lNSPECTlON r
is/rt»
Salts other than Tilidine Hydrochloride Hemihydrate are described in WO-A-
94/ 10129. The compound disclosed is Tilidine Dihydrogen Orthophosphate,
which is said to be stable and therefore suitable for the preparation of solid
pharmaceutical 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, easily producible in high quality and good yields and which can be
formulated to provide a range of different delivery routes.
This invention is directed towards providing such a new entity.
ts of Invention
According to the invention there is provided an acid base salt adduct of Tilidine
formed by reacting Tilidine with acetylsalicylic acid or salicylic acid as their
corresponding salts.
Preferably the Tilidine is introduced in the form of Tilidine Hydrochloride
Hemihydrate.
One aspect of the invention provides Tilidine Acetylsalicylate.
Yet another aspect of the invention provides Tilidine Salicylate.
In one embodiment the invention provides a process for the preparation of
Tilidine Acetylsalicylate comprising:-
reacting Tilidine Hydrochloride Hemihydrate with an Acetylsalicylic Acid
salt and isolating the desired salt.
IE 990301
In another embodiment the invention provides a process for the preparation of
Tilidine Salicylate comprising:-
reacting Tilidine Hydrochloride Hemihydrate with a Salicylic Acid salt and
isolating the desired salt.
The reaction is preferably carried out in the presence of a base such as an amine
base for example ammonia. triethylamjne, Htinigs base or hydroxides such as
alkali hydroxides.
Most preferably the reaction is carried out in an appropriate solvent, typically
MIBK, MEK, acetone, THF, or rz-butanol. However other solvents may be used.
Preferably the reaction temperature is from 0 to 80°C, most preferably from 0 to
°C.
The invention further provides a pharmaceutical composition containing Tilidine
Acetylsalicylate as an active ingredient.
The invention further provides a pharmaceutical composition containing Tilidine
Salicylate as an active ingredient.
The composition may be in a solid form. Typically the composition is in the form
of a tablet, dragee, capsule, suppository, granulate or plaster.
The composition may be used as a retard formulation for sustained release or for
dual action applications.
The invention will be more clearly understood from the following description
thereof given by way of example only.
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Description of the Invention
It has been found that Tilidine Acetylsalicylate and Tilidine Salicylate can be
obtained via a simple process. The salts are very stable, show unusual solubility
and pH properties and are suitable for solid formulations. Furthermore Tilidine
Acetylsalicylate and Tilidine Salicylate can be used in plasters for percutaneous
applications in the form of a transderrnal patch and for dual action applications.
According to the literature (WO—A—94/ 10129) Tilidine salts are difficult to
crystallise. Surprisingly therefore we have found that Tilidine Acetylsalicylate and
Tilidine Salicylate can be crystallised as l:l-adducts by reacting Tilidine
Hydrochloride Hemihydrate and salts of Acetylsalicylic Acid or Salicylic Acid, for
Tilidine
Acetylsalicylate and Tilidine Salicylate can be isolated as a white to ofi-white,
example in organic or organic/aqueous or aqueous media.
odourless powder in high yield. Both salts show a pH value of 5-6 (~1% aqueous
solution) which is, compared to the Hydrochloride Hemihydrate and Dihydrogen
Orthophosphate, more basic, almost in the neutral range. It was found that the
Acetylsalicylate and the Salicylate are very stable over a long period of time.
Furthermore the Acetylsalicylate and the Salicylate are non-hygroscopic in
contrast to known Tilidine salts such as Tilidine Hydrochloride Hemihydrate and
Dihydrogen Orthophosphate.
As Tilidine Acetylsalicylate and Tilidine Salicylate are very stable and non-
hygroscopic they are very suitable for the manufacture of granulates which are
readily convertible into tablets, dragees or pills. A delayed action of the active
compound Tilidine may be obtained by incorporation in a suitable retard
formulation.
Due to poor water solubility the compounds may be used for the manufacture of
plastets/ patches for percutaneous applications with a delayed and slow release of
the active ingredients.
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In preparing such compositions any of the various adjuvant or excipient materials
customarily employed in the art may be used. 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 rnedicaments.
As Tilidine Acetylsalicylate and Tilidine Salicylate are combinations of two active
compounds either may be used for dual action applications.
Tilidine is lcnown to be a highly potent analgesic which is used for the treatment
of severe pain. Salicylic acid and Acetylsalicylic acid can be used as a mild
analgesic with an additional antipyretic and antiphlogistic profile. Moreover in
particular Acetylsalicylic acid is known for its antithrombotic activity. Therefore it
can be anticipated that the salts Tilidine Acetylsalicylate and Tilidine Salicylate
respectively show an advanced pharmacological profile over Tilidine
Hydrochloride Hemihydrate. The salts are therefore useful if a tandem therapy is
required in the sense of additional antipyretic, antithrombotic or antiphlogistic
effectiveness.
The process for the preparation of Tilidine Acetylsalicylate and Tilidine Salicylate
is extremely simple and efficient. The product is isolated in a simple procedure at
high yields, greater than 50% and at a very high level of purity, greater than 99%.
Tilidine Salicylate
R‘, R’ and R’ are hydrogen or C.-C4 alkyl groups. In addition to the ammonium
acetylsalicylates and salicylates the corresponding earth alkali salts may also be
utilised in the process. Preferred salts, in these cases, are sodium or potassium
analogues.
IE 990301
Example 1
Preparation of Tilidine Acetvlsalicvlate
l0.2g (0.056 mol) of Acetylsalicylic Acid were dissolved in 100-150 ml of a
suitable organic solvent such as methanol, ethanol, acetone, THF or mixtures
thereof. The solution was treated with one equivalent of base. The base may
typically be triethylamine, Htinigs base or ammonia. The mixture was agitated
and 18.lg (0.056 mol) of Tilidine Hydrochloride Hemihydrate were added.
Agitation was continued for 0.5-2 hours, preferably at room temperature. The by-
product formed was removed by filtration. The solvent was removed from the
mother liquor by distillation, preferably under vacuum conditions providing the
crude product in almost quantitative yield. The product may be purified by
crystallisation from a suitable solvent such as ether, petroleum ether or mixtures
thereof. Typically a yield of >50°/o of the purified material is obtained.
FT-IR (KBr): '\7[cm“] = 2978, 1727, 1588, 1485, 1453, 1371, 1321, 1237, 1200,
1l46,729,704.
Stamlfiliti
Tilidine Acetylsalicylate was found to be stable when stored over a long period of
time under standard conditions. No critical change in purity was observed and no
significant amounts of degradation product was detected.
Example 2
Preparation of Tilidine Salicvlate
Aqueous ammonia was added to 43.43 (0.31 mol) of Salicylic Acid until complete
dissolution was obtained. The excess of ammonia can then be removed under
vacuum. 100g (0.31 mol) of Tilidine Hydrochloride Hemihydrate were dissolved
in 200-250 ml of water and mixed with the previously prepared ammonium
salicylate. The mixture was stirred at room temperature for 0.5-1 hour. The
IE 990301
product was extracted from the aqueous phase with a suitable solvent such as
MIBK or CHCl;. After removing the organic solvent the product was crystallised
from the obtained oil by treatment with MIBK/ Petroleum Ether.
A typical yield of 90g corresponding approximately to 70% is obtained with a
melting point of 99.7°C.
‘H-NMR (CDCl3, 60 MHz): 8 = 1.05 (t, 3H,CH2C_H3)S 2.25-2.60 (m, 10H,
N(CH3)2, CH2CH2); 4.05 (q, 2H,Cfl2CH3); 4.45 (db,_1H, NCH); 5.95-6.15 (tn, 2H,
CH=CI-I), 6.75- 7.85, (m, 10H, aryl—H, NH); 12.0 (s, 1H, OH).
FT-IR (KBI): '\7[cm"] = 2977, 2476, 1728, 1624, 1587, 1485, 1459, 1371, 1322,
1294, 1237, 1147, 854, 770, 729, 704.
Stability
Tilidine Salicylate was found to be stable when stored over a long period of time
under standard conditions. No critical change in purity was observed and no
significant amounts of degradation product was detected.
Example 3
Retard Formulation of Tilidine Salicvlate
1070g Tilidine Salicylate prepared as in example 2 was added to 70.4g Naloxon
Hydrochloride Dihydrate, 740g lactose and 700g hydrated castor oil, slowly
stirred and heated up to a temperature of 50-85°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 1 mm. 273.6g of
ammonia methyl acrylate co-polymer, 32 g magesium stearate and 24 g silicon
dioxide were added to the mixture. The resultant mixture was then compressed
into tablet form. Retard formulations of Tilidine Acetylsalicylate may be prepared
using an analogous protocol.
The invention is not limited to the embodiments hereinbefore described which
may be varied in detail.
IE 990301
&ti_rn_s
An acid base salt adduct of Tilidine formed by reacting Tilidine with
acetylsalicylic acid or salicylic acid as their corresponding salts.
An acid base salt adduct as claimed in claim 1 wherein the Tilidine is
introduced in the form of Tilidine Hydrochloride Hemihydrate.
Tilidine Acetylsalicylate.
Tilidine Salicylate.
A process for the preparation of Tilidine Acetylsalicylate comprising:-
reacting Tilidine Hydrochloride Hemihydrate with an
Acetylsalicylic Acid salt and isolating the desired salt.
A process for the preparation of Tilidine Salicylate comprising:-
reacting Tilidine Hydrochloride Hemihydrate with a Salicylic Acid
salt and isolating the desired salt.
A process as claimed in claim 5 or 6 wherein the reaction is carried out in
the presence of a base such as ammonia, Hiinigs base or triethylamine.
A process as claimed in any of claims 5 to 7 wherein the reaction is carried
out in an appropriate solvent.
A process as claimed in any of claims 5 to 8 wherein the process carried
out at a temperature of from 0 to 80°C.
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A process as claimed in claim 9 wherein the process is carried out at a
temperature of from 0 to 30°C.
A process as claimed in any of claims 8 to 10 wherein the solvent is MIBK.
A process for the preparation of Tilidine Acetylsalicylate substantially as
herein before described with reference to the example.
A process for the preparation of Tilidine Salicylate substantially as
hereinbefore described with reference to the example.
Tilidine Acetylsalicylate whenever prepared by a process as claimed in any
ofclaims 5 or 7 to 12.
Tilidine Salicylate whenever prepared by a process as claimed in any of
claims 6 to 12 or 13.
A pharmaceutical composition containing Tilidine Acetylsalicylate as an
active ingredient.
A pharmaceutical composition containing Tilidine Salicylate as an active
ingredient.
A pharmaceutical composition as claimed in claim 16 or 17 in a liquid
form.
A pharmaceutical composition as claimed in claim 16 or 17 in a solid
form.
A pharmaceutical composition as claimed in any of claims 16 to 19 which
is formulated to provide a retard formulation.
IE 990301
A pharmaceutical composition as claimed in any of claims 16 to 20 which
is in a form for percutaneous application.
A pharmaceutical composition as claimed in any of claims 16 to 21 which
is in the form of a transdermal patch.
A pharmaceuticalcomposition substantially as hereinbefore described with
reference to the examples.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE1999/0301A IE83591B1 (en) | 1999-04-09 | Tilidene salts |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IEIRELAND14/07/19981998/0564 | |||
| IE980564 | 1998-07-14 | ||
| IE1999/0301A IE83591B1 (en) | 1999-04-09 | Tilidene salts |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IE19990301A1 true IE19990301A1 (en) | 2000-03-08 |
| IE990301A1 IE990301A1 (en) | 2000-03-08 |
| IE83591B1 IE83591B1 (en) | 2004-09-22 |
Family
ID=
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