EP1891010A2 - A process for the preparation of an injectable solution of (2s)-n-(2;6-dimethyl-phenyl)-1-propyl-2-piperidincarboxamide - Google Patents
A process for the preparation of an injectable solution of (2s)-n-(2;6-dimethyl-phenyl)-1-propyl-2-piperidincarboxamideInfo
- Publication number
- EP1891010A2 EP1891010A2 EP06754189A EP06754189A EP1891010A2 EP 1891010 A2 EP1891010 A2 EP 1891010A2 EP 06754189 A EP06754189 A EP 06754189A EP 06754189 A EP06754189 A EP 06754189A EP 1891010 A2 EP1891010 A2 EP 1891010A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- ropivacaine
- preparation
- propyl
- piperidincarboxamide
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims abstract description 14
- 229940102223 injectable solution Drugs 0.000 title abstract description 4
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 claims abstract description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229960001549 ropivacaine Drugs 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 2
- 229960001813 ropivacaine hydrochloride Drugs 0.000 claims 2
- 238000007796 conventional method Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 5
- VSHFRHVKMYGBJL-CKUXDGONSA-N (S)-ropivacaine hydrochloride hydrate Chemical compound O.[Cl-].CCC[NH+]1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C VSHFRHVKMYGBJL-CKUXDGONSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000004743 Polypropylene Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- -1 polypropylene Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 229960003691 ropivacaine hydrochloride monohydrate Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 238000011045 prefiltration Methods 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
Definitions
- the present invention relates to a process for the preparation of an injectable solution of (2S)-(-)-N-(2;6-dimethyl-phenyl)-l-propyl-2- piperidincarboxamide (I)
- Compound (I) is an active ingredient effective as local anesthetic, cited in the Merck Index, XIII Edition, page 1483, # 8339, Ropivacaine. Its preparation is disclosed in EP 0 151 110, expired on August 1 st , 2003, starting from (S)-pipecolic acid 2,6-xylidide and n-propyl bromide.
- the commercially available formulation is a completely clear solution, which contains Ropivacaine neutralized with hydrochloric acid.
- "Sodium hydroxide” as well as “hydrochloric acid” axe cited among the excipients: this is clearly mistaken, as any skilled chemist knows that the presence of sodium hydroxide excludes that of hydrochloric acid and vice versa.
- the commercially available solution has to be slightly acidic (pH is in fact4.0-6.0) as Ropivacaine is water-insoluble, and would therefore precipitate in an alkali medium.
- Ropivacaine injectable aqueous solutions can be easily prepared starting from the free base, prepared from the same intermediates as in EP O 151 110, but using tetrahydrofuran as the solvent, followed by repeated washings with diisopropyl ether, which completely remove the undesired enantiomer.
- the resulting Ropivacaine base which is perfectly measurable as it is not hygroscopic (contrary to the anhydrous hydrochloride), is directly transformed in situ by addition to the hydrochloric acid solution in water for injectables; after complete dissolution, pH is adjusted to the desired range (5.6-5.8) by addition of sodium hydroxide After the steam sterilization the pH of solution decreases
- Ropivacaine injectable formulations are thereby obtained in a remarkably simpler mode than disclosed in EP 0 239 710.
- the complex preparation of the hydrochloride monohydrate described in such Patent is in fact avoided, and the desired result is directly obtained from Ropivacaine base, without involving other intermediates.
- Ropivacaine is prepared starting from the intermediate (S) pipecolic acid 2,6-xylidide (145 g; 0.624 mols) and n-propyl bromide (766 g; 6.24 mols) in tetrahydrofuran (2.5 L) under reflux for approx. 20-24 hours. Inorganic salts are filtered off and the solvent is evaporated to dryness to obtain a dry- solid, consisting of crude Ropivacaine base. The solid is taken up into the minimum amount of diisopropyl ether (200 ml) and filtered under vacuum.
- the resulting product is a non-hygroscopic solid, that is stable in time and can be used for the formation of the hydrochloride in situ during the preparation of the pharmaceutical product.
- a suitable 10 liters two-necked round-bottom flask (fitted with a stirring shaft and pH meter, placed on a 25.0 kg technique balance) is loaded with about 9.0 kg of water for injectables, 71.1988 g of sodium chloride are dissolved and acidified by addition of 321.7 ml of 1 N hydrochloric acid (equivalent to the theoretical amount to form the hydrochloride, starting from Ropivacaine base), stirring at about 350 rpm, under nitrogen. 88.2684 g of Ropivacaine base are added under the same conditions, stirring is increased to 1000 rpm and kept for approx. 2 hours 30 minutes.
- pH pH is adjusted to 5.5.6-5.8 with 1 N sodium hydroxide under stirring. Afterwards, the solution is adjusted to 10.00 kg with water for injectables, keeping stirring for a further 60 minutes.
- the solution is clear and colorless, pH ranges from 5.5.6 to 5.8and osmolarity is equivalent to that of the reference product.
- the solution is then distributed in polypropylene vials, according to the blow-fill-seal technique, with pre-filtration through 1-0.2 ⁇ m filters and filtration through 0.22 ⁇ m absolute filters, immediately upstream the filling machine. Afterwards, the resulting vials are individually sealed, under high vacuum, with the selected plastic material and steam sterilized at 121°Cfor 15 minutues b) Preparation of Ropivacaine HCl solution bulk 7.5 mg/ml starting from Ropivacaine base by acidification
- Example 2 a The procedure of Example 2 a) is repeated, using 241.3. ml of 1 N hydrochloric acid (equivalent to the theoretical amount to form the hydrochloride from Ropivacaine base), 75.8985 g of sodium chloride and 66.2013 g of Ropivacaine base.
- the procedure of Example 2 a) is repeated, using 64.3 ml of 1 hydrochloric acid (equivalent to the theoretical amount to form the hydrochloride from Ropivacaine base), 86.2378 g of sodium chloride +and 17.6537 g of Ropivacaine base.
- This concentration could be distributed in polypropylene vials, as described in Example 2, and in polypropylene bags with pre-filtration through 1-0.2 ⁇ m filters and filtration through 0.22 ⁇ m absolute filters, immediately upstream the filling machine. Afterwards, the resulting bags are individually sealed, under high vacuum, with the selected plastic material and steam sterilized at 121 0 C for 15 minutes.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Anesthesiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A process for the preparation of an injectable solution of (2S)-(-)-N- (2;6-dimethyl-phenyl)-l-propyl-2-piperidincarboxamide (Ropivacaine) starting from Ropivacaine base substantially free from the dextro enantiomer, by dissolution of the same in water for injectables containing hydrochloric acid in stoichiometric amounts.
Description
A PROCESS FOR THE PREPARATION OF AN INJECTABLE SOLUTION OF (25VN-(2:6-DIMETHYL-PHENYL)-l-PROPYL-2- PIPERIDINCARBOXAMIDE
The present invention relates to a process for the preparation of an injectable solution of (2S)-(-)-N-(2;6-dimethyl-phenyl)-l-propyl-2- piperidincarboxamide (I)
Compound (I) is an active ingredient effective as local anesthetic, cited in the Merck Index, XIII Edition, page 1483, # 8339, Ropivacaine. Its preparation is disclosed in EP 0 151 110, expired on August 1st, 2003, starting from (S)-pipecolic acid 2,6-xylidide and n-propyl bromide.
The presently commercially available specialty (Naropina) is disclosed in "L'Informatore Farmaceutico", Edition 2005. page 852) as follows:
"1 ml of solution contains Ropivacaine hydrochloride monohydrate 2 mg/ml - 7,5 mg/ml - 10 mg/ml. Excipients: sodium chloride, hydrochloric acid, sodium hydroxide, water for injectable preparations " .
It should be noted that the commercially available formulation is a completely clear solution, which contains Ropivacaine neutralized with hydrochloric acid. "Sodium hydroxide" as well as "hydrochloric acid" axe cited among the excipients: this is clearly mistaken, as any skilled chemist knows that the presence of sodium hydroxide excludes that of hydrochloric acid and vice versa. Furthermore, as the commercially available solution is completely clear, it has to be slightly acidic (pH is in fact4.0-6.0) as
Ropivacaine is water-insoluble, and would therefore precipitate in an alkali medium. In addition, the expression "contains Ropivacaine hydrochloride monohydrate" is not true, as the definition "monohydrate" is incongruous in case of an aqueous solution: the exact expression should be "prepared from Ropivacaine hydrochloride monohydrate" , as it can be evinced by a subsequent Patent, EP 0 239 710, expiring on December 15. 2006 (protection extended to September 15. 2010 by the Supplementary Protection Certificate n. 572). The latter Patent evidences the drawbacks of previous EP 0 151 110, in particular that: a) the process for the preparation of Ropivacaine anhydrous hydrochloride affords a product containing 10% of the undesired
(R)-(+) enantiomer; b) the anhydrous hydrochloride is "hygroscopic and therefore instable, and contains about 2% water", whereas one mole of crystallization water would involve 5.5% water; c) a product having variable water content requires the determination of such content each time the pharmaceutical formulation is prepared.
According to EP 0 239 710 said drawbacks are avoided through the preparation of the hydrochloride monohydrate. According to claims 4, 5 and 6, said preparation is carried out treating a hydrochloride aqueous solution
(containing the (R)-(+) enantiomer) with acetone at a temperature ranging from 45°C to the acetone boiling point (56°C). It is evident from said Patent
(see particularly column 2, lines 10-37, and Example 1) that the preparation is remarkably troublesome, in that it requires carefully monitoring water to acetone ratios, as well as acetone temperature; moreover, the operation has to be repeated to obtain an optically pure compound.
It has now been found that Ropivacaine injectable aqueous solutions
can be easily prepared starting from the free base, prepared from the same intermediates as in EP O 151 110, but using tetrahydrofuran as the solvent, followed by repeated washings with diisopropyl ether, which completely remove the undesired enantiomer. According to the invention, the resulting Ropivacaine base, which is perfectly measurable as it is not hygroscopic (contrary to the anhydrous hydrochloride), is directly transformed in situ by addition to the hydrochloric acid solution in water for injectables; after complete dissolution, pH is adjusted to the desired range (5.6-5.8) by addition of sodium hydroxide After the steam sterilization the pH of solution decreases
Ropivacaine injectable formulations are thereby obtained in a remarkably simpler mode than disclosed in EP 0 239 710. The complex preparation of the hydrochloride monohydrate described in such Patent is in fact avoided, and the desired result is directly obtained from Ropivacaine base, without involving other intermediates.
The following examples illustrate the process according to the invention.
Example 1. Preparation of Ropivacaine base
Ropivacaine is prepared starting from the intermediate (S) pipecolic acid 2,6-xylidide (145 g; 0.624 mols) and n-propyl bromide (766 g; 6.24 mols) in tetrahydrofuran (2.5 L) under reflux for approx. 20-24 hours. Inorganic salts are filtered off and the solvent is evaporated to dryness to obtain a dry- solid, consisting of crude Ropivacaine base. The solid is taken up into the minimum amount of diisopropyl ether (200 ml) and filtered under vacuum. The residue is washed on the filter with the same solvent (3 x 150 ml) and dried at 55°C under vacuum to obtain 161 g of Ropivacaine base in a 94% molar yield on the xylidide; HPLC purity = 99.75%; HPLC enantiomeric purity = 99.54%, concentration = 99.5%; loss on drying: 0.3%.
The resulting product is a non-hygroscopic solid, that is stable in time and can be used for the formation of the hydrochloride in situ during the preparation of the pharmaceutical product.
Example 2. Preparation of pharmaceutical formulations a) Preparation of the Ropivacaine HCl bulk solution 10 mg/ml starting from Ropivacaine base by acidification
A suitable 10 liters two-necked round-bottom flask (fitted with a stirring shaft and pH meter, placed on a 25.0 kg technique balance) is loaded with about 9.0 kg of water for injectables, 71.1988 g of sodium chloride are dissolved and acidified by addition of 321.7 ml of 1 N hydrochloric acid (equivalent to the theoretical amount to form the hydrochloride, starting from Ropivacaine base), stirring at about 350 rpm, under nitrogen. 88.2684 g of Ropivacaine base are added under the same conditions, stirring is increased to 1000 rpm and kept for approx. 2 hours 30 minutes. When the solution is completely clear (pH 3.6-3.7), pH is adjusted to 5.5.6-5.8 with 1 N sodium hydroxide under stirring. Afterwards, the solution is adjusted to 10.00 kg with water for injectables, keeping stirring for a further 60 minutes.
The solution is clear and colorless, pH ranges from 5.5.6 to 5.8and osmolarity is equivalent to that of the reference product. The solution is then distributed in polypropylene vials, according to the blow-fill-seal technique, with pre-filtration through 1-0.2 μm filters and filtration through 0.22 μm absolute filters, immediately upstream the filling machine. Afterwards, the resulting vials are individually sealed, under high vacuum, with the selected plastic material and steam sterilized at 121°Cfor 15 minutues b) Preparation of Ropivacaine HCl solution bulk 7.5 mg/ml starting from Ropivacaine base by acidification
The procedure of Example 2 a) is repeated, using 241.3. ml of 1 N hydrochloric acid (equivalent to the theoretical amount to form the hydrochloride
from Ropivacaine base), 75.8985 g of sodium chloride and 66.2013 g of Ropivacaine base. c) Preparation of Ropivacaine HCI solution bulk 2.0 mg/ml starting from Ropivacaine base by acidification The procedure of Example 2 a) is repeated, using 64.3 ml of 1 hydrochloric acid (equivalent to the theoretical amount to form the hydrochloride from Ropivacaine base), 86.2378 g of sodium chloride +and 17.6537 g of Ropivacaine base. This concentration could be distributed in polypropylene vials, as described in Example 2, and in polypropylene bags with pre-filtration through 1-0.2 μm filters and filtration through 0.22 μm absolute filters, immediately upstream the filling machine. Afterwards, the resulting bags are individually sealed, under high vacuum, with the selected plastic material and steam sterilized at 1210C for 15 minutes.
Claims
1. A process for the preparation of (2S)-(-)-N-(2;6-dimethyl-phenyl)-l- propyl-2-piperidincarboxamide (Ropivacaine) injectable solutions, in which Ropivacaine base, containing the R enantiomer in no more than 0.5% by weight, is dissolved in water for injectables containing hydrochloric acid in the stoichiometric amount, and the resulting solutions are then distributed in single-dose containers according to conventional methods.
2. A process as claimed in claim 1, characterized in that the amount of water for injectable preparations is added to obtain injectable solutions containing the desired amount of Ropivacaine hydrochloride.
3. A process as claimed in claims 1 and 2, in which the final single-dose injectable solutions contain 2 to 10 mg/ml of Ropivacaine hydrochloride.
4. A process according to the above claims, in which Ropivacaine containing the R enantiomer in no more than 0.5% is prepared by reaction of
(S) pipecolic acid 2,6-xylidide with n-propyl bromide in tetrahydrofuran, and the resulting crude Ropivacaine is subjected to repeated washings with diisopropyl ether.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT001144A ITMI20051144A1 (en) | 2005-06-17 | 2005-06-17 | "PROCEDURE FOR THE PREPARATION OF AN INJECTABLE SOLUTION OF (2S) -N- (2; 6-DIMETHYL-FENYL) -1-PROPYL-2-PIPERIDINCARBOSSAMIDE" |
| PCT/EP2006/005431 WO2006133837A2 (en) | 2005-06-17 | 2006-06-07 | A process for the preparation of an injectable solution of (2s)-n-(2;6-dimethyl-phenyl)-1-propyl-2-piperidincarboxamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1891010A2 true EP1891010A2 (en) | 2008-02-27 |
Family
ID=37496886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP06754189A Withdrawn EP1891010A2 (en) | 2005-06-17 | 2006-06-07 | A process for the preparation of an injectable solution of (2s)-n-(2;6-dimethyl-phenyl)-1-propyl-2-piperidincarboxamide |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1891010A2 (en) |
| IT (1) | ITMI20051144A1 (en) |
| WO (1) | WO2006133837A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697708A (en) * | 2012-04-17 | 2012-10-03 | 上海禾丰制药有限公司 | Ropivacaine hydrochloride injection and preparation process thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2797241A (en) | 1953-08-28 | 1957-06-25 | Brown Charles Leslie Meredith | Diethyl-glycinexylidide and process |
| GB790762A (en) | 1953-08-28 | 1958-02-19 | Arthur Poole | A hydrate of lignocaine hydrochloride and process for making it |
| WO2006127639A2 (en) * | 2005-05-25 | 2006-11-30 | Navinta Llc | Process for preparation of isotonic aqueous injection of ropivacaine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0151110B1 (en) * | 1983-08-01 | 1989-03-01 | Astra Läkemedel Aktiebolag | L-n-n-propylpipecolic acid-2,6-xylidide and method for preparing the same |
-
2005
- 2005-06-17 IT IT001144A patent/ITMI20051144A1/en unknown
-
2006
- 2006-06-07 WO PCT/EP2006/005431 patent/WO2006133837A2/en not_active Ceased
- 2006-06-07 EP EP06754189A patent/EP1891010A2/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2797241A (en) | 1953-08-28 | 1957-06-25 | Brown Charles Leslie Meredith | Diethyl-glycinexylidide and process |
| GB790762A (en) | 1953-08-28 | 1958-02-19 | Arthur Poole | A hydrate of lignocaine hydrochloride and process for making it |
| WO2006127639A2 (en) * | 2005-05-25 | 2006-11-30 | Navinta Llc | Process for preparation of isotonic aqueous injection of ropivacaine |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI20051144A1 (en) | 2006-12-18 |
| WO2006133837A3 (en) | 2007-04-19 |
| WO2006133837A2 (en) | 2006-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1373207B1 (en) | Novel amlodipine camsylate and method for preparing thereof | |
| AU2002243069A1 (en) | Novel amlodipine camsylate and method for preparing thereof | |
| EP0239710B1 (en) | (s)-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, process for its preparation and pharmaceutical preparation containing it | |
| WO2003043989A1 (en) | Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions | |
| WO2008060093A1 (en) | Crystalline s-(-)-amlodipine maleic acid salt anhydride and preparation method thereof | |
| KR100878698B1 (en) | Crystalline bepotastine metal salt hydrate, preparation method thereof and pharmaceutical composition comprising the same | |
| WO2006133837A2 (en) | A process for the preparation of an injectable solution of (2s)-n-(2;6-dimethyl-phenyl)-1-propyl-2-piperidincarboxamide | |
| CA2653333C (en) | Zofenopril calcium | |
| JP4319491B2 (en) | Amlodipine organic acid salt | |
| US8362263B2 (en) | Crystalline S-(−)-amlodipine adipic acid salt anhydrous and preparation method thereof | |
| WO2004026834A1 (en) | Crystalline organic acid salt of amlodipine | |
| WO2008069469A1 (en) | Crystalline s-(-)-amlodipine camsylate anhydride and preparation method thereof | |
| AU2006251583A1 (en) | Process for preparation of isotonic aqueous injection of ropivacaine | |
| WO2008091085A1 (en) | Crystalline s-(-)-amlodipine orotate anhydrous and preparation method thereof | |
| KR20040016837A (en) | 3-(3-amidinophenyl)-5-[({[1-(1-iminoethyl)-4-piperidyl}amino)methyl]benzoic acid dihydrochloride and process for preparing the same | |
| KR101307712B1 (en) | Crystalline hydrate of bepotastine metal salt, method for preparing same and pharmaceutical composition comprising same | |
| KR20040011751A (en) | An organic acid salt of amlodipine | |
| WO1993014068A1 (en) | Novel salts of a quinolone-carboxylic acid | |
| HK1139073B (en) | 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate, hydrates and polymorphs thereof, and formulations comprising these forms | |
| MXPA03007192A (en) | Novel benzoylguanidine salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20071218 |
|
| AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR |
|
| DAX | Request for extension of the european patent (deleted) | ||
| DAX | Request for extension of the european patent (deleted) | ||
| TPAC | Observations by third parties |
Free format text: ORIGINAL CODE: EPIDOSNTIPA |
|
| 17Q | First examination report despatched |
Effective date: 20101213 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20110427 |