US20070281958A1 - Preparation of oxycodone - Google Patents
Preparation of oxycodone Download PDFInfo
- Publication number
- US20070281958A1 US20070281958A1 US11/890,397 US89039707A US2007281958A1 US 20070281958 A1 US20070281958 A1 US 20070281958A1 US 89039707 A US89039707 A US 89039707A US 2007281958 A1 US2007281958 A1 US 2007281958A1
- Authority
- US
- United States
- Prior art keywords
- oxycodone
- composition
- salt
- solution
- hydroxycodeinone
- 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.)
- Abandoned
Links
- QOARLUJWDPPCNZ-PURVWAAKSA-N COC1=CC=C2C[C@@H]3C4=CC=C(OC)[C@@H]5OC1=C2[C@]45CCN3C.COC1=CC=C2C[C@H]3N(C)CC[C@]45C2=C1O[C@H]4C(=O)C=C[C@@]35O.COC1=CC=C2C[C@H]3N(C)CC[C@]45C2=C1O[C@H]4C(=O)CC[C@@]35O Chemical compound COC1=CC=C2C[C@@H]3C4=CC=C(OC)[C@@H]5OC1=C2[C@]45CCN3C.COC1=CC=C2C[C@H]3N(C)CC[C@]45C2=C1O[C@H]4C(=O)C=C[C@@]35O.COC1=CC=C2C[C@H]3N(C)CC[C@]45C2=C1O[C@H]4C(=O)CC[C@@]35O QOARLUJWDPPCNZ-PURVWAAKSA-N 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N COC1=CC=C2C[C@H]3N(C)CC[C@]45C2=C1O[C@H]4C(=O)CC[C@@]35O Chemical compound COC1=CC=C2C[C@H]3N(C)CC[C@]45C2=C1O[C@H]4C(=O)CC[C@@]35O BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
- C07D489/04—Salts; Organic complexes
Abstract
A process for preparing oxycodone or an oxycodone salt, wherein the oxycodone or oxycodone salt has low levels of impurities (especially 14-hydroxycodeinone) is disclosed. The process comprises the steps of: a) preparing a mixture comprising oxycodone and a solvent and adjusting the pH of the mixture to less than 6; and subsequently b) exposing the mixture to hydrogenation reagents for a period of at least 1 hour. This process provides oxycodone with very low levels of α,β-unsaturated ketone impurities. Oxycodone or an oxycodone salt produced according to the process of the invention has low levels of α,β-unsaturated ketones and is advantageously incorporated into pharmaceutical products.
Description
- This application is a continuation of U.S. patent application Ser. No. 11/586,392, filed Oct. 25, 2006, which is a continuation of U.S. patent application Ser. No. 11/234,627, filed Sep. 23, 2005, which claims priority of British Patent Application No. 0421149.6, filed Sep. 23, 2004, the entirety of which applications are incorporated herein by reference.
- The present invention relates to a process for preparing oxycodone having low levels of impurities. In particular, the process is useful for preparing oxycodone with low levels of α,β-unsaturated ketones.
-
- Oxycodone can be manufactured from the natural product thebaine (II) by a well-known process as disclosed in U.S. Pat. No. 6,090,943:
Thebaine (II) or a salt thereof is reacted with hydrogen peroxide in isopropanol, water and formic acid, producing 14-hydroxycodeinone (III). The double bond in the 14-hydroxycodeinone (III) is reduced by reaction with hydrogen in the presence of a Pd/BaSO4 catalyst, providing oxycodone (I). - Recently there has been a concern about the presence of α,β-unsaturated ketone impurities in pharmaceutical products. 14-hydroxycodeinone (III) is an α,β-unsaturated ketone, and unsurprisingly, small quantities of this compound may be found in oxycodone (I). The present inventors have sought to provide a method for preparing oxycodone having low levels of impurities and in particular, low levels of α,β-unsaturated ketone impurities, preferably below 10 ppm.
- Accordingly, the present invention provides a process for preparing oxycodone or an oxycodone salt, wherein the oxycodone or oxycodone salt has low levels of impurities, comprising the steps of:
-
- a) preparing a mixture comprising oxycodone and a solvent and adjusting the pH of the mixture to less than 6; and subsequently
- b) exposing the mixture to hydrogenation reagents for a period of at least 1 hour.
- The inventors have found that this process surprisingly provides oxycodone with low levels of α,β-unsaturated ketone impurities, i.e. 14-hydroxycodeinone at less than 15 ppm. The inventors have found that in order to achieve low levels of 14-hydroxycodeinone, the pH must be adjusted before the hydrogenation step. Suitably the mixture is heated after the pH of the mixture is adjusted, so that the process comprises the steps of:
-
- a) preparing a mixture comprising oxycodone and a solvent, adjusting the pH of the mixture to less than 6 and heating the mixture at the temperature of at least 55° C. for a period of at least 1 hour; and subsequently
- b) exposing the mixture to hydrogenation reagents for a period of at least 1 hour.
- This process provides oxycodone with very low levels of α,β-unsaturated ketone impurities, i.e. 14-hydroxycodeinone at less than 5 ppm.
- The mixture comprising oxycodone and a solvent can be prepared by a number of methods. In a first method, oxycodone base or a salt of oxycodone, prepared and isolated using any of the methods known to those skilled in the art, is mixed with a solvent to form the mixture. In a second method, 14-hydroxycodeinone is hydrogenated in a solvent using known hydrogenation reagents, thereby providing a mixture comprising oxycodone and a solvent. In a third method, a mixture comprising thebaine and a solvent is subjected to oxidation conditions (e.g. hydrogen peroxide in formic acid and water), followed by hydrogenation conditions, thereby providing a mixture comprising oxycodone and a solvent. Other methods of preparing a mixture comprising oxycodone and a solvent may be known to those skilled in the art.
- The pH of the mixture is adjusted to less than 6, suitably less than 5, more suitably less than 3 and preferably about 1. The pH is suitably adjusted by the addition of a strong acid such as concentrated hydrochloric acid to the mixture. Preferably at least one equivalent of acid is added to the mixture.
- The solvent in the mixture is suitably an organic solvent such as isopropanol, ethanol or SD3A (a 95:5 mixture of ethanol:methanol). Preferably the mixture further comprises water.
- After the pH is adjusted, the mixture is suitably heated to a temperature of at least 55° C., preferably at least 60° C. and most preferably about 70-75° C. The temperature is suitably not higher than the boiling point of the solvent. The mixture is suitably heated for a period of at least 1 hour, preferably at least 3 hours and most preferably between 5-10 hours.
- Suitable hydrogenation reagents are well known to the skilled person and typically include a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent, such as sodium hypophosphite. Preferred hydrogenation catalysts are precious metal catalysts such as palladium or platinum dispersed on a support material such as carbon or barium sulfate. In a preferred embodiment, a precious metal catalyst is added to the mixture and hydrogen is passed through the mixture at a pressure of 10 psi or more (162 kPa or more). The hydrogenation step is suitably carried out at a temperature of at least ambient, preferably at a temperature between room temperature and 70° C. The temperature should be sufficient to dissolve the solids in the mixture, thereby providing a solution. The mixture is exposed to the hydrogenation reagents for at least 1 hour, suitably at least 2 hours and preferably about 6 hours.
- The product of step (b) is a mixture comprising oxycodone and a solvent. Hydrogenation catalysts may be removed by filtering the mixture. A purified oxycodone salt may be obtained from the mixture by reducing the temperature, and allowing the salt to crystallise out. For example, if hydrochloric acid was used in step (a), the hydrochloride salt of oxycodone will be produced. Alternatively, oxycodone base may be provided by adding a base such as sodium hydroxide to the mixture and allowing the mixture to cool.
- If precious metal catalysts are used in the hydrogenation step, it is possible that unacceptable levels of the metals will remain in the final product (desirably the heavy metal content of the final product is less than 20 ppm). In one embodiment of the present invention, the oxycodone or oxycodone salt produced in step (b) is subjected to a further process wherein a mixture comprising the oxycodone or oxycodone salt and a solvent is treated with charcoal. Suitably the mixture is heated to a temperature of approx. 60-65° C., the charcoal is added, the mixture is stirred at 60-65° C. for 5 to 10 hours and the hot mixture is filtered to remove the charcoal. Cooling the hot mixture provides the oxycodone salt or oxycodone. Suitably the weight ratio of oxycodone or oxycodone salt to charcoal is between 20:1 and 1:1, preferably about 5:1. The charcoal is suitably a charcoal such as Darco ® G-60 (Norit, USA).
- Oxycodone or an oxycodone salt produced according to the process of the invention has low levels of α,β-unsaturated ketones and is advantageously incorporated into pharmaceutical products.
- The following examples are illustrative but not limiting of the invention.
- Thebaine (15.94 g) was added to a 250 ml flask. Water (18 ml) was added and the mixture was stirred at room temperature. Formic acid (42 ml) was added over 3 minutes and then the mixture was cooled in an ice bath. Hydrogen peroxide (30%, 6.7 g) was added and the mixture was stirred for 1 hour. The mixture was removed from the ice bath, allowed to warm to room temperature and then heated to 48° C. for 2 hours. The mixture was transferred to a hydrogenation bottle. A 5 wt % palladium on carbon catalyst (2 g) was added and hydrogen was passed through the mixture at approximately 20 psi for 15 hours. The catalyst was removed by passing the mixture through a pad of celite and rinsing the filtered solid with water/formic acid (3:1, 8 ml). The mixture was cooled in an ice bath and 25% sodium hydroxide (109 ml) was added dropwise over 50 minutes to increase the pH to 9-10. The mixture was stirred for 1 hour and 15 minutes and the solid product was filtered, rinsed with cold water and dried under vacuum pump for 3 hours. The product was oxycodone base (14.152 g, 87.7% yield) and contained 178 ppm of the α,β-unsaturated ketone impurity, 14-hydroxycodeinone.
- Thebaine (100.0 g dry weight) was dissolved in 85% formic acid (252.3 g). 30% Hydrogen peroxide (43.6 g) was added over a period of about two hours. The mixture was stirred for three hours. Ammonium hydroxide solution was added to the mixture to increase the pH to 8-9. The solid precipitate was filtered and washed with water and ethanol. The solid was dried on the filter and in an oven. The product was 14-hydroxycodeinone (150.52 g damp, 75.32 g dry weight, 75% yield).
- The 14-hydroxycodeinone (39.45 g of the damp solid) was dissolved in water (81.13 ml) and 80% acetic acid (16.17 ml). 10 wt % palladium on carbon catalyst (0.33 g wet weight, 0.16 g dry weight) was added and hydrogen was passed through the mixture for about 6 hours at about 12 psi. The mixture was filtered to remove the catalyst. An ammonium hydroxide solution was added to the mixture up to pH 9. The solid precipitate was washed with water and with ethanol, and was dried. The product was oxycodone (18.8 g, 79% yield).
- 13.257 g of oxycodone prepared via Route A was added to a 250 ml flask. An ethanol/methanol mixture (70 ml) was added to the flask and the mixture was stirred at room temperature, heated to reflux (78° C.) for 1 hour, cooled to room temperature and then stirred at room temperature. The mixture was cooled in an ice bath for 30 minutes and the solid product was filtered and rinsed with an ethanol/methanol mixture. The solid was dried under vacuum for 3 hours. The product was oxycodone base (11.393 g, 85.95%) and contained 210 ppm of the α,β-unsaturated ketone impurity, 14-hydroxycodeinone.
- Dissolving the oxycodone, heating to 78° C. for 1 hour and recrystallising did not reduce the amount of 14-hydroxycodeinone in the oxycodone.
- 11 g of the oxycodone product from comparative example 1 was added to a 250 ml flask. An ethanol/methanol mixture (55 ml) was added to the flask and the mixture was stirred at room temperature, heated to reflux (78° C.) for 1 hour, cooled to room temperature and then stirred at room temperature. The mixture was cooled in an ice bath for 35 minutes and the solid product was filtered and rinsed with an ethanol/methanol mixture. The solid was dried under vacuum overnight. The product was oxycodone base (10.682 g, 97.1%) and contained 165 ppm of the α,β-unsaturated ketone impurity, 14-hydroxycodeinone.
- A second step of dissolving the oxycodone, heating to 78° C. for 1 hour and recrystallising did not significantly reduce the amount of 14-hydroxycodeinone in the oxycodone.
- 5 g of oxycodone product from comparative example 2 was added to a 100 ml flask. Water (10 ml) and isopropanol (10 ml) were added and the mixture was stirred. Concentrated hydrochloric acid (2.64 ml) was added. The mixture was heated to 75° C. for 10 hours and stirred at ambient temperature overnight. The mixture was transferred to a hydrogenation bottle and was heated to 45° C. 5 wt % palladium on carbon catalyst (0.5 g) was added to the mixture and hydrogen was passed through the mixture at about 12 psi for 6.5 hours. The mixture was warmed to 55° C., passed through a filter paper, cooled to room temperature and then placed in an ice bath for 30 minutes. The solid product was filtered, rinsed with cold isopropanol and dried overnight under a vacuum pump. The product was oxycodone hydrochloride (5.533 g, 99.2%) and contained less than 2 ppm 14-hydroxycodeinone (measured by HPLC and MS-SIM (mass spectrometry with selected ion monitoring)).
- 1.2 g of crude oxycodone prepared via Route A was added to a 50 ml flask. Water (3.6 ml), isopropanol (3.6 ml) and formic acid (4.8 ml) were added. Concentrated hydrochloric acid (0.24 ml) was added. The mixture was heated to 75° C. and stirred at 75° C. for 10 hours. The mixture was cooled to room temperature and stirred. HPLC showed that the level of 14-hydroxycodeinone in the oxycodone increased during the heating step. Treatment with acid and heating does not prepare oxycodone with a low level of impurities.
- The mixture was transferred to a hydrogenation bottle. 5 wt % palladium on carbon catalyst (120 mg) was added to the mixture and hydrogen was passed through the mixture at room temperature and about 12 psi for 24 hours. The mixture was passed through a pad of celite and then placed in an ice bath. 50% sodium hydroxide (5.3 ml) was added dropwise over 17 minutes to a pH of 9-10. The mixture was stirred at 0-5° C. for 1 hour and 10 minutes. The solid product was filtered, rinsed with cold water and dried under a vacuum pump for four hours. The product was oxycodone base (1.072 g, 89.33%) and contained approximately 3 ppm 14-hydroxycodeinone (measured by MS-SIM).
- 0.8 g of oxycodone base produced in Example 2a was added to a 50 ml flask. Water (1.6 ml) and isopropanol (3.76 ml) were added. Concentrated hydrochloric acid (0.32 ml) was added and the mixture was heated to 73° C. After 5 minutes at 73° C. the mixture was cooled to room temperature and was then stirred at room temperature for 1 hour. The mixture was placed in an ice bath and stirred for 1.5 hours. The solid product was filtered, rinsed with cold isopropanol and dried under a vacuum pump overnight. The product was oxycodone hydrochloride (0.892 g) and contained approximately 5 ppm 14-hydroxycodeinone (measured by MS-SIM).
- 18.8 g oxycodone prepared via Route B was added to a flask containing ethanol (43.9 ml) and water (10.14 ml). Ethanol (5.71 ml) and concentrated hydrochloric acid (7.37 ml) were mixed and then added to the flask, providing a mixture with a pH of 1. The mixture was heated at 75° C. for 5 hours and was then cooled to 65° C. The mixture was hydrogenated at 10-12 psi for six hours using a 10 wt % palladium on carbon catalyst (175.6 mg wet weight, 88 mg dry weight). The mixture was filtered to remove the catalyst and cooled. The solid product was filtered and washed with ethanol. The product was oxycodone hydrochloride (20.13 g, 75.3%) and contained approximately 0 ppm 14-hydroxycodeinone.
- 3 g of crude oxycodone prepared by essentially the same method as route A and containing 535 ppm 14-hydroxycodeinone was added to a hydrogenation bottle. Isopropanol (9 ml), water (9 ml) and formic acid (12 ml) were added. The mixture was hydrogenated for 23 hours using a 5 wt % palladium on carbon catalyst (0.3 g). The mixture was passed through a pad of celite and the hydrogenation bottle was rinsed with isopropanol and water. The mixture was cooled in an ice bath. 50% sodium hydroxide (14 ml) was added dropwise over 22 minutes to a pH of 9-10. The mixture was stirred at 0-5° C. for 1 hour and 20 minutes. The solid product was filtered, rinsed with cold water and dried under a vacuum pump overnight. The product was oxycodone base (2.822 g, 94.1%) and contained approximately 26 ppm 14-hydroxycodeinone (measured by HPLC). The hydrogenation step reduced the amount of 14-hydroxycodeinone in the oxycodone, but this method, wherein the pH of the mixture was not adjusted before the hydrogenation, did not afford oxycodone with an impurity level of less than 10 ppm.
- 2 g of oxycodone base produced in Comparative Example 3a was added to a 100 ml flask. Water (4 ml) and isopropanol (9.4 ml) were added. Concentrated hydrochloric acid (0.8 ml) was added and the mixture was heated to 70-72° C. After 5 minutes at 70-72° C. the mixture was slowly cooled to room temperature. The mixture was placed in an ice bath and stirred for 1 hour and 20 minutes. The solid product was filtered, rinsed with cold isopropanol and dried under a vacuum pump overnight. The product was oxycodone hydrochloride (2.401 g) and contained approximately 38 ppm 14-hydroxycodeinone (measured by HPLC). Adjusting the pH of the oxycodone to ˜1 and heating did not further reduce the concentration of 14-hydroxycodone. Comparative Examples 3a and 3b demonstrate that oxycodone with very low level of impurities (less than 10 ppm 14-hydroxycodeinone) is not prepared by hydrogenating the oxycodone and then treating with acid.
- 4.35 g oxycodone prepared by essentially the same method as Route B was added to a flask containing ethanol (12.5 ml) and water (2.7 ml). Concentrated hydrochloric acid (approximately 1.5 ml) was added to the flask, providing a mixture with a pH of about 2. The pH of the mixture was increased to 5 by adding ammonia. The mixture was hydrogenated at 45 psi and 50° C. for 1.5 hours and then at 10-12 psi and 50-55° C. for 4 hours using a 10 wt % palladium on carbon catalyst (0.06 g). The mixture was filtered to remove the catalyst and cooled. The solid product was filtered and washed with ethanol. The product was oxycodone hydrochloride (3.706 g, 76.1%) and contained approximately 12 ppm 14-hydroxycodeinone.
- 3 g of oxycodone product from comparative example 2 was added to a 50 ml flask. Water (1.3 ml) and ethanol (5.58 ml) were added and the mixture was stirred. Concentrated hydrochloric acid (1.58 ml) was added. Further water was added so that in total 4.5 ml of water was added. The mixture was heated to 75° C. for 10 hours, slowly cooled to room temperature and stirred overnight. The mixture was heated to 40° C. and transferred to a hydrogenation bottle. 5 wt % palladium on carbon catalyst (0.3 g) was added to the mixture and hydrogen was passed through the mixture at between 11 and 12 psi for 6.5 hours. The mixture was warmed to 56° C. and passed through two layers of filter paper. The bottle and filtrate were rinsed with a hot solution of 1 ml water and 5 ml ethanol, and with 20 ml of hot ethanol. The filtrate was slowly cooled to room temperature and then placed in an ice bath for 30 minutes. The solid product was filtered, rinsed with cold ethanol and dried overnight under a vacuum pump. The product was oxycodone hydrochloride (2.663 g, 79.6% yield). A further 0.334 g of oxycodone hydrochloride was obtained by washing the filter cake and hydrogenation bottle with water and water/ethanol (1:1), giving a combined yield of 2.997 g and 89.5%. Both samples of oxycodone hydrochloride contained 0 ppm 14-hydroxycodeinone (measured by HPLC and MS-SIM (mass spectrometry with selected ion monitoring)).
Claims (117)
1. A composition comprising oxycodone or an oxycodone salt, said oxycodone or oxycodone salt containing less than 15 ppm of 14-hydroxycodeinone.
2. The composition of claim 1 , wherein the oxycodone or oxycodone salt contains less than 10 ppm of 14-hydroxycodeinone.
3. The composition of claim 1 , wherein the oxycodone or oxycodone salt contains less than 5 ppm of 14-hydroxycodeinone.
4. The composition of claim 1 , wherein the oxycodone or oxycodone salt contains less than 2 ppm of 14-hydroxycodeinone.
5. The composition of claim 1 , wherein the oxycodone or oxycodone salt contains about 0 ppm of 14-hydroxycodeinone.
6. The composition of claim 1 , having less than 20 ppm of heavy metal content.
7. The composition of claim 1 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride.
8. The composition according to claim 1 , said oxycodone or oxycodone salt being a purified oxycodone or salt thereof prepared by a process comprising the steps of:
a) preparing a solution comprising oxycodone or a salt thereof in a solvent, said solution having a pH less than 6;
b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour; and
c) contacting the solution with hydrogenation reagents for a period of at least 1 hour;
wherein the step of maintaining is performed in the absence of hydrogenation reagents.
9. The composition of claim 8 , wherein the oxycodone or salt thereof comprises oxycodone hydrochloride.
10. The composition of claim 8 , wherein the pH is less than 5.
11. The composition of claim 8 , wherein the pH is less than 3.
12. The composition of claim 8 , wherein the temperature is at least 60° C.
13. The composition of claim 8 , wherein the temperature is from about 70° C. to 75° C.
14. The composition of claim 8 , wherein the period is at least 3 hours.
15. The composition of claim 8 , wherein the period is at least 5 hours.
16. The composition of claim 8 , wherein the period is from 5 to 10 hours.
17. The composition of claim 8 , wherein the process further comprises after step (c) the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof.
18. The composition of claim 17 , wherein the oxycodone or salt thereof is oxycodone hydrochloride.
19. The composition of claim 17 , wherein the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.
20. The composition of claim 8 , wherein the pH is less than or about 1.
21. The composition of claim 17 , wherein the pH is less than or about 1.
22. The composition of claim 8 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.
23. The composition of claim 8 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.
24. The composition of claim 23 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.
25. The composition of claim 24 , wherein the process further comprises, after step (c), the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;
wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.
26. The composition of claim 25 , wherein step (c) is carried out for about 6 hours at a temperature from about 45° C. to 55° C.
27. The composition of claim 25 , wherein step (b) is carried out for about 10 hours at a temperature of about 75° C.
28. The composition of claim 19 , further comprising, after step (c), removing the hydrogenation catalysts by filtering to provide the product which is crystallized in step (d).
29. The composition of claim 8 , wherein the process further comprises, after step (c), the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;
wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.
30. The composition of claim 29 , wherein step (c) is carried out for about 6 hours at a temperature from about 45° C. to 55° C.
31. The composition of claim 29 , wherein step (b) is carried out for about 10 hours at a temperature of about 75° C.
32. The composition according to claim 1 , said oxycodone or oxycodone salt being prepared by a process comprising the steps of:
a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of at least 55° C. for at least 1 hour, said solution having a pH less than 6; and
b) subsequently exposing the solution to hydrogenation reagents for a period of at least 1 hour.
33. The composition of claim 32 , wherein the solution comprises, after the maintaining step but before the exposing step, a level of 14-hydroxycodeinone that is higher than a level of 14-hydroxycodeinone before the maintaining step.
34. The composition of claim 32 , wherein the pH is less than 5.
35. The composition of claim 32 , wherein the pH is less than 3.
36. The composition of claim 32 , wherein the pH is less than or about 1.
37. The composition of claim 32 , wherein the temperature is at least 60° C.
38. The composition of claim 32 , wherein the temperature is about 70-75° C.
39. The composition of claim 32 , wherein in step a) the period is at least 3 hours.
40. The composition of claim 32 , wherein in step a) the period is 5-10 hours.
41. The composition of claims 32, wherein step b) is carried out at or above about 40° C.
42. The composition of claim 32 , wherein step b) is carried out at a temperature between 40° C. and 70° C.
43. The composition of claim 32 , wherein in step b) the period is at least 2 hours.
44. The composition of claim 32 , wherein in step b) the period is about 6 hours.
45. The composition of claim 32 , wherein in step b) the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.
46. The composition of claim 32 , wherein the process further comprises in sequence the subsequent steps of c) stirring the solution in contact with charcoal at a temperature of approximately 60-65° C. for 5-10 hours, d) filtering the solution to remove the charcoal, and e) cooling the solution.
47. The composition according to claim 1 , said oxycodone or oxycodone salt being prepared by a process comprising the steps of:
a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of about 75° C. for about 10 hours, said solution having a pH less than 6; and
b) subsequently exposing the solution to hydrogenation reagents at or above about 40° C. for about 6.5 hours.
48. The composition of claim 47 , wherein the process further comprises, after step b), a step c) of filtering the solution at a temperature of about 56° C.
49. The composition of claim 47 , wherein the pH is less than 5.
50. The composition of claim 47 , wherein the pH is less than 3.
51. The composition of claim 47 , wherein the pH is less than or about 1.
52. The composition according to claim 1 , said oxycodone or oxycodone salt being prepared by a process comprising the steps of:
a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of about 75° C. for about 5 hours, said solution having a pH of about 1; and
b) subsequently exposing the solution to hydrogenation reagents at about 65° C. for about 6 hours.
53. The composition of claim 32 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.
54. The composition of claim 47 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.
55. The composition of claim 52 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.
56. The composition of claim 32 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.
57. The composition of claim 32 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.
58. The composition of claim 57 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.
59. The composition of claim 47 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.
60. The composition of claim 47 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.
61. The composition of claim 60 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.
62. The composition of claim 52 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.
63. The composition of claim 52 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.
64. The composition of claim 63 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.
65. The composition of claim 57 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride, the pH is less than or about 1, and the maintaining is performed for at least 5 hours at a temperature from about 70° C. to 75° C.
66. The composition of claim 65 , wherein step (b) is performed for about 6 hours from about 45° C. to 55° C.
67. The composition of claim 65 , wherein the maintaining is performed for about 10 hours at a temperature of about 75° C.
68. The composition of claim 32 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride, the pH is less than or about 1, and the maintaining is performed for at least 5 hours at a temperature from about 70° C. to 75° C.
69. The composition of claim 68 , wherein step (b) is performed for about 6 hours from about 45° C. to 55° C.
70. The composition of claim 68 , wherein the maintaining is performed for about 10 hours at a temperature of about 75° C.
71. The composition according to claim 1 , said oxycodone or oxycodone salt being a purified oxycodone or oxyxodone salt prepared by a process comprising the steps of:
a) preparing a solution comprising the oxycodone or salt thereof in a solvent, said solution having a pH less than 6;
b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour; and
c) contacting the solution with hydrogenation reagents for a period of at least 1 hour; and
wherein the solution comprises, after the maintaining step, a level of 14-hydroxycodeinone that is higher than a level of 14-hydroxycodeinone before the maintaining step.
72. The composition of claim 71 , wherein the oxycodone or salt thereof comprises oxycodone hydrochloride.
73. The composition of claim 71 , wherein the pH is less than 5.
74. The composition of claim 71 , wherein the pH is less than 3.
75. The composition of claim 71 , wherein the temperature is at least 60° C.
76. The composition of claim 71 , wherein the temperature is from about 70° C. to 75° C.
77. The composition of claim 71 , wherein the period is at least 5 hours.
78. The composition of claim 71 , wherein the period is from 5 to 10 hours.
79. The composition of claim 71 , wherein the step of maintaining is performed in the absence of hydrogenation reagents.
80. The composition of claim 71 , wherein the process further comprises after step (c) the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof.
81. The composition of claim 80 , wherein the oxycodone or salt thereof is oxycodone hydrochloride.
82. The composition of claim 80 , wherein the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.
83. The composition of claim 80 , wherein the pH is less than or about 1.
84. The composition of claim 71 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.
85. The composition of claim 71 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.
86. The composition of claim 85 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.
87. The composition of claim 85 , wherein the process further comprises, after step (c), the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;
wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.
88. The composition of claim 87 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C.
89. The composition of claim 87 , wherein step (b) is performed at about 75° C. for about 10 hours.
90. The composition of claim 71 , wherein the process further comprises, after step (c), the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;
wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.
91. The composition of claim 90 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C.
92. The composition of claim 90 , wherein step (b) is performed at about 75° C. for about 10 hours.
93. The composition of claim 80 , further comprising, after step (c), removing the hydrogenation catalysts by filtering to provide the product which is crystallized in step (d).
94. A pharmaceutical product comprising a composition comprising oxycodone or an oxycodone salt, said oxycodone or oxycodone salt containing less than 15 ppm of 14-hydroxycodeinone.
95. The pharmaceutical product of claim 94 , wherein the oxycodone or oxycodone salt contains less than 10 ppm of 14-hydroxycodeinone.
96. The pharmaceutical product of claim 94 , wherein the oxycodone or oxycodone salt contains less than 5 ppm of 14-hydroxycodeinone.
97. The pharmaceutical product of claim 94 , wherein the oxycodone or oxycodone salt contains less than 2 ppm of 14-hydroxycodeinone.
98. The pharmaceutical product of claim 94 , wherein the oxycodone or oxycodone salt contains about 0 ppm of 14-hydroxycodeinone.
99. The pharmaceutical product of claim 94 , having less than 20 ppm of heavy metal content.
100. The pharmaceutical product of claim 94 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride.
101. The pharmaceutical product of claim 94 , wherein the oxycodone or oxycodone salt is prepared by a process comprising the steps of:
a) preparing a solution comprising the oxycodone or salt thereof in a solvent, said solution having a pH less than 6;
b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour; and
c) contacting the solution with hydrogenation reagents for a period of at least 1 hour;
wherein the step of maintaining is performed in the absence of hydrogenation reagents.
102. The pharmaceutical product of claim 94 , wherein the oxycodone or oxycodone salt is prepared by a process comprising the steps of:
a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of at least 55° C. for at least 1 hour, said solution having a pH less than 6; and
b) subsequently exposing the solution to hydrogenation reagents for a period of at least 1 hour.
103. The pharmaceutical product of claim 94 , wherein the oxycodone or oxycodone salt is a purified oxycodone or oxycodone salt prepared by a process comprising the steps of:
a) preparing a solution comprising the oxycodone or salt thereof in a solvent, said solution having a pH less than 6;
b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour; and
c) contacting the solution with hydrogenation reagents for a period of at least 1 hour;
wherein the solution comprises, after the maintaining step, a level of 14-hydroxycodeinone that is higher than a level of 14-hydroxycodeinone before the maintaining step.
104. The pharmaceutical product of claim 103 , wherein the process further comprises after step (c) the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof.
105. The pharmaceutical product of claim 104 , wherein the oxycodone or salt thereof is oxycodone hydrochloride.
106. The pharmaceutical product of claim 104 , wherein the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.
107. The pharmaceutical product of claim 104 , wherein the pH is less than or about 1.
108. The pharmaceutical product of claim 103 , wherein the process further comprises, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution.
109. The pharmaceutical product of claim 103 , wherein the process further comprises, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution.
110. The pharmaceutical product of claim 109 , wherein the process further comprises, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol.
111. The pharmaceutical product of claim 109 , wherein the process further comprises after step (c) the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;
wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.
112. The pharmaceutical product of claim 111 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C.
113. The pharmaceutical product of claim 111 , wherein step (b) is performed at about 75° C. for about 10 hours.
114. The pharmaceutical product of claim 103 , wherein the process further comprises after step (c) the step of:
d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;
wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.
115. The pharmaceutical product of claim 114 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C.
116. The pharmaceutical product of claim 114 , wherein step (b) is performed at about 75° C. for about 10 hours.
117. The pharmaceutical product of claim 114 , wherein the process further comprises, after step (c), removing the hydrogenation catalysts by filtering to provide the product which is crystallized in step (d).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/890,397 US20070281958A1 (en) | 2004-09-23 | 2007-08-06 | Preparation of oxycodone |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0421149.6A GB0421149D0 (en) | 2004-09-23 | 2004-09-23 | Preparation of oxycodone |
GB0421149.6 | 2004-09-23 | ||
US11/234,627 US7153966B2 (en) | 2004-09-23 | 2005-09-23 | Preparation of oxycodone |
US11/586,392 US20070037982A1 (en) | 2004-09-23 | 2006-10-25 | Preparation of oxycodone |
US11/890,397 US20070281958A1 (en) | 2004-09-23 | 2007-08-06 | Preparation of oxycodone |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/586,392 Continuation US20070037982A1 (en) | 2004-09-23 | 2006-10-25 | Preparation of oxycodone |
Publications (1)
Publication Number | Publication Date |
---|---|
US20070281958A1 true US20070281958A1 (en) | 2007-12-06 |
Family
ID=33397118
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/234,627 Expired - Fee Related US7153966B2 (en) | 2004-09-23 | 2005-09-23 | Preparation of oxycodone |
US11/586,392 Abandoned US20070037982A1 (en) | 2004-09-23 | 2006-10-25 | Preparation of oxycodone |
US11/752,728 Abandoned US20070219373A1 (en) | 2004-09-23 | 2007-05-23 | Preparation of oxycodone |
US11/890,397 Abandoned US20070281958A1 (en) | 2004-09-23 | 2007-08-06 | Preparation of oxycodone |
US12/192,632 Abandoned US20080306265A1 (en) | 2004-09-23 | 2008-08-15 | Preparation of oxycodone |
US12/193,406 Abandoned US20080312443A1 (en) | 2004-09-23 | 2008-08-18 | Preparation of oxycodone |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/234,627 Expired - Fee Related US7153966B2 (en) | 2004-09-23 | 2005-09-23 | Preparation of oxycodone |
US11/586,392 Abandoned US20070037982A1 (en) | 2004-09-23 | 2006-10-25 | Preparation of oxycodone |
US11/752,728 Abandoned US20070219373A1 (en) | 2004-09-23 | 2007-05-23 | Preparation of oxycodone |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/192,632 Abandoned US20080306265A1 (en) | 2004-09-23 | 2008-08-15 | Preparation of oxycodone |
US12/193,406 Abandoned US20080312443A1 (en) | 2004-09-23 | 2008-08-18 | Preparation of oxycodone |
Country Status (2)
Country | Link |
---|---|
US (6) | US7153966B2 (en) |
GB (1) | GB0421149D0 (en) |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201509943A (en) * | 2004-03-30 | 2015-03-16 | Euro Celtique Sa | Oxycodone hydrochloride composition, pharmaceutical dosage form, sustained release oral dosage form and pharmaceutically acceptable package having less than 25 PPM 14-hydroxycodeinone |
EP1765292B1 (en) | 2004-06-12 | 2017-10-04 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
GB0421149D0 (en) * | 2004-09-23 | 2004-10-27 | Johnson Matthey Plc | Preparation of oxycodone |
SA07280459B1 (en) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic |
EP2073636B1 (en) | 2006-10-17 | 2012-09-05 | Penick Corporation | Process for preparing oxymorphone |
CA2674915C (en) | 2006-10-17 | 2015-06-30 | Penick Corporation | Process for preparing oxymorphone |
US20080125592A1 (en) * | 2006-10-17 | 2008-05-29 | Penick Corporation | Process for preparing oxymorphone, naltrexone, and buprenorphine |
ES2378710T3 (en) * | 2006-12-04 | 2012-04-17 | Noramco, Inc. | Procedure to reduce impurities in the oxycodone base |
WO2008070658A1 (en) * | 2006-12-04 | 2008-06-12 | Noramco, Inc. | Process for preparing oxycodone having reduced levels of 14-hydroxycodeinone |
GB0624880D0 (en) * | 2006-12-14 | 2007-01-24 | Johnson Matthey Plc | Improved method for making analgesics |
FR2923484B1 (en) * | 2007-11-09 | 2012-11-09 | Sanofi Aventis | PROCESS FOR THE PREPARATION OF MORPHINIC COMPOUNDS |
EP2250175B1 (en) * | 2008-02-29 | 2011-08-10 | Mallinckrodt Inc. | Process for the preparation of 3-hydroxymorphinan derivatives |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
EP2377866B1 (en) | 2010-03-23 | 2014-02-26 | Siegfried AG | Preparation of low impurity opiates in a continuous flow reactor |
EP2588481B1 (en) | 2010-07-02 | 2017-11-15 | Johnson Matthey Public Limited Company | Process for the synthesis and purification of oxycodone |
CA2879268C (en) | 2012-07-16 | 2018-05-08 | Rhodes Technologies | Process for improved opioid synthesis |
KR101946103B1 (en) | 2012-07-16 | 2019-02-08 | 로드스 테크놀로지즈 | Process for improved opioid synthesis |
ES2716574T3 (en) * | 2012-08-03 | 2019-06-13 | Johnson Matthey Plc | A method of preparing oxycodone |
BR112016002079A2 (en) | 2013-08-02 | 2017-09-05 | Johnson Matthey Plc | PROCESS FOR PREPARING AN ACID ADDITIVE OF OXYMORPHONE, ACID ADDITIVE OF OXYMORPHONE AQUEOUS SOLUTION, ACID ADDITIVE OF OXYMORPONE SOLID, AND, ACID OF OXYMORPONE SOLID |
US9062062B1 (en) | 2013-12-18 | 2015-06-23 | Cody Laboratories, Inc. | Synthesis of oxycodone hydrochloride |
EP3083632A2 (en) * | 2013-12-18 | 2016-10-26 | Cody Laboratories, Inc. | Sysnthesis of oxycodone hydrochloride |
US8846923B1 (en) | 2013-12-18 | 2014-09-30 | Cody Laboratories, Inc. | Preparation of 14-hydroxycodeinone sulfate |
US10227354B2 (en) | 2013-12-18 | 2019-03-12 | Cody Laboratories, Inc. | Conversion of oxycodone base to oxycodone hydrochloride |
CA2937006C (en) | 2014-01-15 | 2018-12-04 | Rhodes Technologies | Process for improved oxycodone synthesis |
CA2937007C (en) | 2014-01-15 | 2018-11-06 | Rhodes Technologies | Process for improved oxymorphone synthesis |
WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
CA3067718A1 (en) * | 2017-06-20 | 2018-12-27 | Johnson Matthey Public Limited Company | Hydrogenation process for preparing oxycodone hydrochloride from 14-hydroxycodeinone |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4466697A (en) * | 1981-11-12 | 1984-08-21 | Maurice Daniel | Light dispersive optical lightpipes and method of making the same |
US5196005A (en) * | 1991-11-26 | 1993-03-23 | Pdt Systems, Inc. | Continuous gradient cylindrical diffusion tip for optical fibers and method for making |
US5536265A (en) * | 1994-03-25 | 1996-07-16 | Ciba-Geigy Corporation | Light diffuser and process for the manufacturing of a light diffuser |
US5978541A (en) * | 1996-04-16 | 1999-11-02 | Miravant Systems, Inc. | Custom cylindrical diffusion tips |
US6167177A (en) * | 1996-07-05 | 2000-12-26 | Permanova Lasersystem | Optical fiber cable |
US6361530B1 (en) * | 2000-03-22 | 2002-03-26 | Indigo Medical Incorporated | Durable fiber optic diffuser tip and method of making same |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3177567A (en) * | 1963-08-12 | 1965-04-13 | Ivor H Gehrman | Mating tool |
US6067749A (en) * | 1996-07-11 | 2000-05-30 | Tasmanian Alkaloids Pty. Ltd. | Papaver somniferum strain with high concentration of thebaine and oripavine |
US5869669A (en) * | 1996-07-26 | 1999-02-09 | Penick Corporation | Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates |
GB9713703D0 (en) | 1997-06-30 | 1997-09-03 | Johnson Matthey Plc | Preparation of opiates |
US6177567B1 (en) * | 1999-10-15 | 2001-01-23 | Boehringer Ingelheim Chemicals, Inc. | Method for preparing oxycodone |
US6864370B1 (en) * | 2003-06-05 | 2005-03-08 | Zhaiwei Lin | Process for manufacturing oxycodone |
TW201509943A (en) * | 2004-03-30 | 2015-03-16 | Euro Celtique Sa | Oxycodone hydrochloride composition, pharmaceutical dosage form, sustained release oral dosage form and pharmaceutically acceptable package having less than 25 PPM 14-hydroxycodeinone |
GB0421149D0 (en) * | 2004-09-23 | 2004-10-27 | Johnson Matthey Plc | Preparation of oxycodone |
-
2004
- 2004-09-23 GB GBGB0421149.6A patent/GB0421149D0/en not_active Ceased
-
2005
- 2005-09-23 US US11/234,627 patent/US7153966B2/en not_active Expired - Fee Related
-
2006
- 2006-10-25 US US11/586,392 patent/US20070037982A1/en not_active Abandoned
-
2007
- 2007-05-23 US US11/752,728 patent/US20070219373A1/en not_active Abandoned
- 2007-08-06 US US11/890,397 patent/US20070281958A1/en not_active Abandoned
-
2008
- 2008-08-15 US US12/192,632 patent/US20080306265A1/en not_active Abandoned
- 2008-08-18 US US12/193,406 patent/US20080312443A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4466697A (en) * | 1981-11-12 | 1984-08-21 | Maurice Daniel | Light dispersive optical lightpipes and method of making the same |
US5196005A (en) * | 1991-11-26 | 1993-03-23 | Pdt Systems, Inc. | Continuous gradient cylindrical diffusion tip for optical fibers and method for making |
US5330465A (en) * | 1991-11-26 | 1994-07-19 | Laser Therapeutics, Inc. | Continuous gradient cylindrical diffusion tip for optical fibers and method for using |
US5536265A (en) * | 1994-03-25 | 1996-07-16 | Ciba-Geigy Corporation | Light diffuser and process for the manufacturing of a light diffuser |
US5978541A (en) * | 1996-04-16 | 1999-11-02 | Miravant Systems, Inc. | Custom cylindrical diffusion tips |
US6167177A (en) * | 1996-07-05 | 2000-12-26 | Permanova Lasersystem | Optical fiber cable |
US6361530B1 (en) * | 2000-03-22 | 2002-03-26 | Indigo Medical Incorporated | Durable fiber optic diffuser tip and method of making same |
Also Published As
Publication number | Publication date |
---|---|
US20080306265A1 (en) | 2008-12-11 |
US20060111383A1 (en) | 2006-05-25 |
US20070219373A1 (en) | 2007-09-20 |
US20080312443A1 (en) | 2008-12-18 |
GB0421149D0 (en) | 2004-10-27 |
US7153966B2 (en) | 2006-12-26 |
US20070037982A1 (en) | 2007-02-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20070281958A1 (en) | Preparation of oxycodone | |
EP1866308B1 (en) | Preparation of a high purity substituted quinoxaline | |
AU2007298855B2 (en) | Process for preparing N-alkyl naltrexone halides | |
US20140206871A1 (en) | Low abuk oxycodone, its salts and methods of making same | |
EP1140857B1 (en) | Synthesis of histamine dihydrochloride | |
US20140051861A1 (en) | Process for preparing oxymorphone, naltrexone, and buprenorphine | |
US20150133484A1 (en) | Method of preparing oxymorphone | |
EP2328900B1 (en) | PROCESS FOR MAKING MORPHINAN-6 alpha-OLS | |
TWI309651B (en) | Method for the manufacture of anagrelide | |
US5399765A (en) | Enantioselective preparation of optically pure albuterol | |
JPH0212958B2 (en) | ||
EP1682497B1 (en) | Process for purifying mesotrione | |
WO2015111085A2 (en) | Processes for the preparation of eltrombopag and pharmaceutically acceptable salts, solvates and intermediates thereof | |
KR100707050B1 (en) | Method of preparing 10H-Dibenzo[b,f][1,4]thiazepine-11-one | |
AU2018287728B2 (en) | Hydrogenation process for preparing oxycodone hydrochloride from 14-hydroxycodeinone | |
JP4138883B2 (en) | Method for producing acridone derivative and 8-hydroxyimidazoacridinone derivative | |
KR100599028B1 (en) | Preparation method of 6-aminomethyl-6,11-dihydro-5H-dibenz[b,e]azepin | |
JPS636070B2 (en) | ||
KR19990007800A (en) | Method for preparing streptogamine | |
JPH0791252B2 (en) | Process for producing 7-dimethylamino-6-demethyl-6-deoxytetracycline | |
CN115368250A (en) | Method for splitting formoterol chiral intermediate | |
Scaros et al. | The optimization of the catalytic hydrogenation of hydroxybenzamidines to benzamidines | |
JPS63310858A (en) | Manufacture of aminomalonic acid dinitrile salt | |
JPH0713045B2 (en) | 2.5-difluorophenol derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |