Source: http://www.docstoc.com/docs/78094030/Oxycodone-Hydrochloride-Having-Less-Than-25-PPM-14-hydroxycodeinone---Patent-7674800
Timestamp: 2014-09-21 20:48:52
Document Index: 521941149

Matched Legal Cases: ['application No. 2005230826', 'art 1', 'art 2', 'Application No.\n60', 'Application No.\n60', 'Application No.\n60', 'Application No.\n60', 'Application No.\n60', 'Application No. 60']

Oxycodone Hydrochloride Having Less Than 25 PPM 14-hydroxycodeinone - Patent 7674800
United States Patent: 7674800
In certain embodiments the invention is directed to a process for
preparing an oxycodone hydrochloride composition having less than 25 ppm
of 14-hydroxycodeinone.
Chapman; Robert (North Kingstown, RI), Rider; Lonn S. (Foster, RI), Hong; Qi (Sharon, MA), Kyle; Donald (Newtown, PA), Kupper; Robert (Coventry, RI)
11/729,741
11391897Mar., 2006
11093626Mar., 20057129248
60557492Mar., 2004
60601534Aug., 2004
60620072Oct., 2004
60648625Jan., 2005
60651778Feb., 2005
514/282  ; 546/44; 546/45
A61K 31/485&amp;nbsp(20060101); C07D 489/08&amp;nbsp(20060101)
514/282 546/45,44
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2006138020
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PBS and ARTG entries for OxyContin (oxycodone hydrochloride; PBS codes; 8385H, 8386J, 8387K, 8388L; ARTG IDs; 68187, 68188, 68190, 68189, 68191, 68192, 68193 and 68194, respectively, produced Jun. 25, 2009. cited by other
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11/391,897, filed Mar. 29, 2006, which is a continuation of U.S. patent
application Ser. No. 11/093,626, filed Mar. 30, 2005, now U.S. Pat. No.
7,129,248, which claims priority to U.S. Provisional Application No.
60/651,778, filed Feb. 10, 2005, U.S. Provisional Application No.
60/648,625, filed Jan. 31, 2005, U.S. Provisional Application No.
60/620,072, filed Oct. 18, 2004, U.S. Provisional Application No.
60/601,534, filed Aug. 13, 2004, and U.S. Provisional Application No.
60/557,492, filed Mar. 30, 2004, all of which are hereby incorporated by
1.  A process for preparing an oxycodone salt substantially free of 14-hydroxycodeinone, which process comprises steps of: (a) preparing a mixture of oxycodone free base,
solvent and an acid, the oxycodone free base having an 8.alpha.,14-dihydroxy-7,8-dihydrocodeinone component;  (b) incubating the mixture under conditions suitable to convert the oxycodone free base to an oxycodone salt, wherein said conditions promote an
acid catalyzed dehydration consisting of conversion of the 8.alpha.,14-dihydroxy-7,8-dihydrocodeinone component to 14-hydroxycodeinone;  and (c) preferentially removing the 14-hydroxycodeinone from the oxycodone salt.
2.  The process according to claim 1, wherein in step (b) the mixture is heated to a temperature of about 75.degree.  C.
3.  The process according to claim 1, wherein the mixture has a pH of about 2.5 or less.
4.  The process according to claim 3, wherein the mixture has a pH of about 1.8 or less.
5.  The process according to claim 4, wherein the mixture has a pH of about 1.5 or less.
6.  The process according to claim 5, wherein the mixture has a pH of about 1 or less.
7.  The process according to claim 1, wherein the 14-hydroxycodeinone is preferentially removed by subjecting the oxycodone salt to chromatographic separation.
8.  The process according to claim 1, wherein step (b) is carried out at a temperature of about 20.degree.  C.
9.  The process according to claim 1, wherein step (b) is carried out at a temperature between about 40.degree.  C. to about 85.degree.  C.
10.  The process according to claim 9, wherein in step (c) the mixture is exposed to hydrogenation reagents for at least about 4 hours.
11.  The process according to claim 10, wherein in step (c) the mixture is exposed to the hydrogenation reagents for at least about 5 hours.
12.  The process according to claim 11, wherein in step (c) the mixture is exposed to the hydrogenation reagents for about 21 hours.
13.  The process according to claim 1, wherein the acid in said mixture is present in an amount greater than 1 molar equivalent compared to the amount of oxycodone.
14.  The process according to claim 1, wherein the acid is hydrochloric acid.
15.  The process according to claim 14, wherein the hydrochloric acid is present in an amount greater than 1 molar equivalent compared to the amount of oxycodone.
16.  The process according to claim 15, wherein the hydrochloric acid is present in an amount greater than about 1.2 molar equivalents compared to the amount of oxycodone.
17.  The process according to claim 16, wherein the hydrochloric acid is present in an amount greater than about 1.4 molar equivalents compared to the amount of oxycodone.
18.  The process according to claim 17, wherein the hydrochloric acid is present in an amount greater than about 1.5 molar equivalents compared to the amount of oxycodone.
19.  The process according to claim 1, wherein the resultant oxycodone salt contains less than about 25 ppm 14-hydroxycodeinone.
20.  The process according to claim 19, wherein the resultant oxycodone salt contains less than about 15 ppm 14-hydroxycodeinone.
21.  The process according to claim 20, wherein the resultant oxycodone salt contains less than about 10 ppm 14-hydroxycodeinone.
22.  The process according to claim 21, wherein the resultant oxycodone salt contains less than about 5 ppm 14-hydroxycodeinone.
23.  The process according to claim 1, wherein the 14-hydroxycodeinone is preferentially removed by exposing the oxycodone salt to hydrogenation reagents under conditions sufficient for conversion of the 14-hydroxycodeinone to oxycodone salt.
24.  The process according to claim 23, wherein the hydrogenation reagents are a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.
25.  The process according to claim 1, wherein in step (c) the mixture is exposed to hydrogenation reagents for between about 10 minutes to about 36 hours.
26.  The process according to claim 1, wherein the 14-hydroxycodeinone is preferentially removed by exposing the oxycodone salt to a substance that preferentially removes the 14-hydroxycodeinone compared to the oxycodone salt.
27.  The process according to claim 26, wherein the substance is a gel.
28.  The process according to claim 26, wherein the oxycodone salt is passed through the substance that preferentially removes the 14-hydroxycodeinone.
29.  The process according to claim 26, wherein a slurry is formed with the oxycodone salt and the substance that preferentially removes the 14-hydroxycodeinone.
30.  Oxycodone salt prepared according to the process of claim 1.
31.  Oxycodone salt according to claim 30, wherein the oxycodone salt is oxycodone hydrochloride.
32.  Oxycodone salt according to claim 31 having less than about 25 ppm 14-hydroxycodeinone.
33.  Oxycodone salt according to claim 32 having less than about 15 ppm 14-hydroxycodeinone.
34.  Oxycodone salt according to claim 33 having less than about 10 ppm 14-hydroxycodeinone.
35.  Oxycodone salt according to claim 34 having less than about 5 ppm 14-hydroxycodeinone.
36.  Oxycodone salt according to claim 32, wherein the 14-hydroxycodeinone is derived solely from 8.alpha.,14-dihydroxy-7,8-dihydrocodeinone.
37.  Oxycodone salt according to claim 33, wherein the 14-hydroxycodeinone is derived solely from 8.alpha.,14-dihydroxy-7,8-dihydrocodeinone.
38.  An oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone, the composition prepared by a process comprising: preparing a mixture of oxycodone free base, solvent and hydrochloric acid, the oxycodone free base having
39.  The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed with a hydrogen donor and a catalyst.
40.  The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed under reflux.
41.  The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed in a solvent comprising an alcohol.
42.  The oxycodone hydrochloride composition of claim 41, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropanol.
43.  The oxycodone hydrochloride composition of claim 41, wherein the process further comprises recovering the oxycodone hydrochloride composition having less than 25 ppm from the solvent.
44.  The oxycodone hydrochloride composition of claim 43, wherein the recovering comprises crystallizing the oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone and filtering the crystallized composition from the
45.  The oxycodone hydrochloride composition of claim 43, wherein the process comprises after said recovering further hydrogenating the recovered oxycodone hydrochloride composition.
46.  The oxycodone hydrochloride composition of claim 38 having less than 15 ppm 14-hydroxycodeinone.
47.  The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed with a hydrogen donor.
48.  The oxycodone hydrochloride composition of claim 47, wherein the hydrogen donor is selected from the group consisting of hydrogen gas, formic acid, indoline, cyclohexene, sodium borohydride, tetrahydroquinoline, 2,5-dihydrofuran, phosphoric
49.  The oxycodone hydrochloride composition of claim 38, wherein the hydrogenation is performed with a catalyst.
50.  The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains less than 15 ppm
51.  The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains less than 10 ppm
52.  The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains less than 5 ppm
53.  The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains less than 15 ppm
54.  The oxycodone hydrochloride composition of claim 38, wherein the oxycodone hydrochloride composition having more than 100 ppm 14-hydroxycodeinone is hydrogenated until the oxycodone hydrochloride composition contains between 10 ppm and 15
55.  The composition of claim 38, having a lower limit of the 14-hydroxycodeinone of 0.25 ppm, 0.5 ppm, 1 ppm, 2 ppm or 5 ppm.
56.  The composition of claim 38, which is suitable for use in a commercial oxycodone product.
57.  A process for preparing an oxycodone salt substantially free of 14-hydroxycodeinone, which process comprises steps of: (a) preparing a mixture of oxycodone free base, solvent and an acid, the oxycodone free base having an
8.alpha.,14-dihydroxy-7,8-dihydrocodeinone component;  (b) incubating the mixture under conditions suitable to convert the oxycodone free base to an oxycodone salt, wherein said conditions promote an acid catalyzed dehydration whereby the
8.alpha.,14-dihydroxy-7,8-dihydrocodeinone component is converted to 14-hydroxycodeinone;  and (c) reducing an amount of 14-hydroxycodeinone in the oxycodone salt formed in step (b) to produce an oxycodone salt composition having less than 25 ppm
58.  The process according to claim 57, wherein the acid is hydrochloric acid.
59.  The process according to claim 58, wherein the hydrochloric acid is present in an amount greater than 1 molar equivalent compared to the amount of oxycodone free base.
60.  The process according to claim 59, wherein the hydrochloric acid is present in an amount greater than about 1.2 molar equivalents compared to the amount of oxycodone free base.
61.  The process according to claim 57, wherein the mixture has a pH of about 2.5 or less.
62.  The process according to claim 61, wherein the mixture has a pH of about 1.8 or less.
63.  The process according to claim 62, wherein the mixture has a pH of about 1.5 or less.
64.  The process according to claim 63, wherein the mixture has a pH of about 1 or less.
65.  The process according to claim 57, wherein step (b) is carried out at a temperature between about 40.degree.  C. to about 85.degree.  C.
66.  The process according to claim 57, wherein the amount of 14-hydroxycodeinone is reduced by subjecting the oxycodone salt to chromatographic separation.
67.  The process according to claim 57, wherein the amount of 14-hydroxycodeinone is reduced by exposing the oxycodone salt to hydrogenation reagents under conditions sufficient for conversion of the 14-hydroxycodeinone to oxycodone salt.
68.  The process according to claim 67, wherein the hydrogenation reagents are a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.
69.  The process according to claim 68, wherein in step (c) the mixture is exposed to the hydrogenation reagents for between about 10 minutes to about 36 hours.
70.  The process according to claim 57, wherein the amount of 14-hydroxycodeinone is reduced by exposing the oxycodone salt to a substance that preferentially removes the 14-hydroxycodeinone compared to the oxycodone salt.
71.  The process according to claim 70, wherein the substance is a gel.
72.  The process according to claim 71, wherein the oxycodone salt is passed through the substance that preferentially removes the 14-hydroxycodeinone.
73.  The process according to claim 57, wherein the resultant oxycodone salt contains less than about 25 ppm 14-hydroxycodeinone.
74.  The process according to claim 73, wherein the resultant oxycodone salt contains less than about 10 ppm 14-hydroxycodeinone.
75.  The process according to claim 74, wherein the resultant oxycodone salt contains less than about 5 ppm 14-hydroxycodeinone.
76.  Oxycodone salt prepared according to the process of claim 57.
77.  Oxycodone salt according to claim 76, wherein the oxycodone salt is oxycodone hydrochloride.
78.  Oxycodone salt according to claim 77 having less than about 25 ppm 14-hydroxycodeinone.
79.  Oxycodone salt according to claim 78 having less than about 15 ppm 14-hydroxycodeinone.
80.  Oxycodone salt according to claim 57 having between 0.5 ppm and 25 ppm 14-hydroxycodeinone.
81.  The composition of claim 55 having a lower limit of the 14-hydroxycodeinone of 2 ppm or 5 ppm.  Description
Oxycodone is a semi-synthetic opioid analgesic that exerts an agonist effect at specific, saturable opioid receptors in the CNS and other tissues.  In man, oxycodone may produce any of a variety of effects including analgesia.
Purdue Pharma L.P currently sells sustained-release oxycodone in dosage forms containing 10, 20, 40, and 80 mg oxycodone hydrochloride under the trade name OxyContin.RTM..
U.S.  Pat.  Nos.  5,266,331; 5,508,042; 5,549,912; and 5,656,295 disclose sustained release oxycodone formulations.
Thebaine, a compound derived from opium, although having no medicinal use in itself, is useful as a starting material in synthetic schemes for the production of oxycodone.  In other schemes, codeine can be utilized as the starting material for
the production of oxycodone.  14-hydroxycodeinone is the immediate precursor to oxycodone in these schemes.
Methods of producing thebaine or 14-hydroxy substituted opium derivatives have been reported, e.g. in U.S.  Pat.  No. 3,894,026 and U.S.  Pat.  No. 4,045,440.
The oxidation of codeine to codeinone, an initial step in the synthesis of opium derivatives has been reported in EP 0889045, U.S.  Pat.  No. 6,008,355 and in the J. Am.  Chem. Soc., 1051, 73, 4001 (Findlay).
The reaction of codeinone to 14-hydroxycodeinone has been reported in U.S.  Pat.  No. 6,008,355 and in Tetrahedron 55, 1999 (Coop and Rice).
U.S.  Pat.  No. 6,177,567 describes the hydrogenation of 14-hydroxycodeinone to oxycodone by reduction with diphenylsilane and Pd(Ph3P)/ZnCl2 or with sodium hypophosphite in conjunction with a Pd/C catalyst in aqueous acetic acid.
Krabnig et al. in &quot;Optimization of the Synthesis of Oxycodone and 5-Methyloxycodone&quot; Arch.  Pharm.  (1996), 329(6), (325-326) describes hydrogenating a solution of 14-hydroxycodeinone in glacial acetic acid with a Pd--C-catalyst at 30 psi at the
During the oxidation of thebaine to give 14-hydroxycodeinone, several overoxidized products are formed including 8,14-dihydroxy-7,8-dihydrocodeinone.  In the production of oxycodone free base from the 14-hydroxycodeinone, the
8,14-dihydroxy-7,8-dihydrocodeinone is carried though the process.  During conversion of the oxycodone free base to oxycodone hydrochloride, the impurity undergoes acid-catalyzed dehydration and is converted into 14-hydroxycodeinone.  Thus,
14-hydroxycodeinone is present in the final oxycodone hydrochloride composition.  Oxycodone hydrochloride API (active pharmaceutical ingredient) is available from a variety of manufacturers such as Johnson Matthey and Mallinckrodt.  Current
commercially-available oxycodone hydrochloride API, and oxycodone hydrochloride prepared by known procedures, have a level of 14-hydroxycodeinone of greater than 100 ppm.
It is an object of certain embodiments of the present invention to provide a process for reducing the 14-hydroxycodeinone in an oxycodone hydrochloride composition to an amount of less than 25 ppm, less than about 15 ppm, less than about 10 ppm,
or less than about 5 ppm.
It is an object of certain embodiments of the present invention to provide a process for reacting an oxycodone base composition with hydrochloric acid under conditions to produce an oxycodone hydrochloride composition having an amount of
14-hydroxycodeinone of less than 25 ppm, less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm.
It is a further object of certain embodiments of the present invention to provide an oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm, less than about 15 ppm, less than about 10 ppm, or less than about 5
It is a further object of certain embodiments of the present invention to provide a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm by reacting an oxycodone base composition with
hydrochloric acid under conditions suitable to promote dehydration of 8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone during salt formation and under reducing conditions so as to convert the 14-hydroxycodeinone to oxycodone.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm comprising reacting an oxycodone hydrochloride composition having a
14-hydroxycodeinone level of more than 100 ppm under conditions that reduce the amount of 14-hydroxycodeinone to a level of less than 25 ppm, less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm comprising subjecting an oxycodone hydrochloride composition having a
14-hydroxycodeinone level of greater than 100 ppm to hydrogenation to an extent that the amount of 14-hydroxycodeinone in the composition is reduced to an amount of less than less 25 ppm, less than about 15 ppm, less than about 10 ppm, or less than about
In certain embodiments disclosed herein, the oxycodone composition having a 14-hydroxycodeinone level of less than 25 ppm can be subsequently hydrogenated to further decrease the amount of 14-hydroxycodeinone, e.g., from about 15 ppm to about 10
In one embodiment, where the starting material is an oxycodone hydrochloride composition comprising 14-hydroxycodeinone in an amount of 100 ppm or higher, the final oxycodone hydrochloride composition has a 14-hydroxycodeinone level of less than
25 ppm, less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm. In another embodiment, where the starting material is an oxycodone hydrochloride composition comprising 14-hydroxycodeinone in an amount of between 15 ppm and 25 ppm, the
final oxycodone hydrochloride composition has a 14-hydroxycodeinone level of less than about 10 ppm, or less than about 5 ppm. In another embodiment, where the starting material is an oxycodone hydrochloride composition comprising 14-hydroxycodeinone in
an amount of between 10 ppm and 25 ppm, the final oxycodone hydrochloride composition has a 14-hydroxycodeinone level of less than about 5 ppm.
In certain embodiments of the present invention, the process for preparing the oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm comprises hydrogenating the starting material under reflux.  In certain
embodiments, the process further comprises recovering the resultant oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm comprising hydrogenating under reflux, a starting oxycodone hydrochloride
composition having a 14-hydroxycodeinone level of greater than 100 ppm in a suitable solvent for a time sufficient to produce an oxycodone composition having a 14-hydroxycodeinone level of less than 25 ppm, less than about 15 ppm, less than about 10 ppm,
or less than about 5 ppm; and recovering the oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm by crystallization and removal from the solvent (e.g., by filtration).
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising reacting in a suitable solvent an oxycodone base
composition with hydrochloric acid in an amount greater than 1.0 molar equivalent as compared to the oxycodone base composition, the reacting step being performed under reducing conditions, to form an oxycodone hydrochloride composition having a
14-hydroxycodeinone level in an amount of less than 25 ppm.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising hydrogenating a 14-hydroxycodeinone composition to obtain an oxycodone free
base composition; converting the oxycodone free base composition to oxycodone hydrochloride; and hydrogenating the oxycodone hydrochloride to obtain an oxycodone composition having less than 25 ppm 14-hydroxycodeinone.
base composition; converting the oxycodone free base composition to oxycodone hydrochloride; isolating the oxycodone hydrochloride; and hydrogenating the oxycodone hydrochloride to obtain an oxycodone composition having less than 25 ppm
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising oxidizing a thebaine composition to form 14-hydroxycodeinone composition,
the oxidizing being performed at a suitable pH to minimize or eliminate the production of 8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinone composition; hydrogenating the 14-hydroxycodeinone composition to form an oxycodone base composition;
and converting the oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.
In certain embodiments, the invention is directed to a process for preparing 14-hydroxycodeinone comprising oxidizing a thebaine composition to form 14-hydroxycodeinone composition, the oxidizing being performed at a suitable pH to minimize or
eliminate the production of 8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinone composition;
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition comprising reacting an oxycodone base composition with an acid having a higher pH than hydrochloric acid to form a corresponding
acid addition salt of oxycodone, and converting the acid addition salt of oxycodone to oxycodone hydrochloride.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising contacting an oxycodone base composition having an
amount of 8,14-dihydroxy-7,8-dihydrocodeinone with a substance that preferentially removes the 8,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and converting the oxycodone base composition to an oxycodone hydrochloride composition
having less than 25 ppm 14-hydroxycodeinone.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising subjecting an oxycodone base composition having an
amount of 8,14-dihydroxy-7,8-dihydrocodeinone to chromatographic separation to preferentially removes the 8,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and converting the oxycodone base composition to an oxycodone hydrochloride
composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone, with boronated polystyrene resin; and converting the oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition comprising reacting in a suitable solvent an oxycodone base composition with boronated polystyrene resin; and converting the
oxycodone base composition to an oxycodone hydrochloride composition.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising combining hydrochloric acid and an oxycodone base
composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form a solution; and spray drying the solution to generate oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm.
composition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form a solution; and lyophilizing the solution to generate oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition comprising combining hydrochloric acid and an oxycodone base composition in a solvent to form a solution; and spray drying the
solution to generate oxycodone hydrochloride.
In certain embodiments, the invention is directed to a process for preparing an oxycodone hydrochloride composition comprising combining hydrochloric acid and an oxycodone base composition in a solvent to form a solution; and lyophilizing the
solution to generate oxycodone hydrochloride.  The term &quot;bulk&quot; means an amount of material of at least 1 kg.  In certain embodiments, the amount can be from about 10 kg to about 1000 kg or from about 10 kg to about 500 kg.  In certain embodiments, the
amount is in an amount of from about 20 kg to about 100 kg; about 20 kg or about 50 kg.  Bulk oxycodone hydrochloride composition can be packaged, e.g., in a pharmaceutically acceptable package such as corrugated box containers (made of, e.g., plastic
and/or paper); in drums (made of, e.g., a metal or metal composite material); or in bags of woven fabric generally referred to as flexible intermediate bulk containers (FIBCs).  Each of these approaches use various configurations of liners, typically
made of polyethylene or polypropylene, that fit within the corrugated box, drum, or within the FIBC for preventing contamination of the product being shipped.  Preferably, these packaging approaches use containers configured to be supported by and
carried on pallets.
The term &quot;ppm&quot; as used herein means &quot;parts per million&quot;.  As used to refer to 14-hydroxycodeinone, &quot;ppm&quot; means parts per million of 14-hydroxycodeinone in a particular sample.
The term 8,14-dihydroxy-7,8-dihydrocodeinone includes either 8.alpha.,14-dihydroxy-7,8-dihydrocodeinone; or 8.beta.,14-dihydroxy-7,8-dihydrocodeinone or can include a mixture of both compounds.
The oxycodone hydrochloride preparation can be, e.g., an oxycodone active pharmaceutical ingredient (API), such as oxycodone hydrochloride U.S.P., uncombined or combined with one or more other ingredients.  For example, the oxycodone preparation
can be a final pharmaceutical dosage form, or an intermediate preparation for a final dosage form, that can be tested for the presence of 14-hydroxycodeinone and/or codeinone, e.g., for quality assurance purposes.  Preferably, the oxycodone hydrochloride
preparation is oxycodone hydrochloride API and contains at least 95% oxycodone hydrochloride, at least 98% oxycodone hydrochloride, at least 99% oxycodone hydrochloride, or at least 99.9% oxycodone hydrochloride.
The method of detecting the presence of 14-hydroxycodeinone in an oxycodone preparation can be performed in accordance with commonly assigned U.S.  Provisional Application Ser.  No. 60/557,502, entitled &quot;Methods For Detecting 14-Hydroxycodeinone&quot;
filed Mar.  29, 2004 and in accordance with U.S.  Provisional Application entitled &quot;Methods For Detecting 14-Hydroxycodeinone&quot; filed Jan.  31, 2005.
In certain embodiments, the invention is directed to a process for reducing the amount of 14-hydroxycodeinone in an oxycodone hydrochloride composition (e.g., oxycodone hydrochloride API), and to the resultant oxycodone hydrochloride composition
having a 14-hydroxycodeinone level of less than 25 ppm recovered from that process.  In certain embodiments, the present invention is directed to a process for reducing the amount of 14-hydroxycodeinone in an oxycodone hydrochloride composition
comprising reacting the oxycodone hydrochloride composition with a catalytically effective amount of a transition metal compound and a gas comprising hydrogen, at a temperature and for a period of time sufficient to reduce the content of
14-hydroxycodeinone to a level wherein the resultant oxycodone hydrochloride composition comprises 14-hydroxycodeinone in an amount less than 25 ppm, less than about 15 ppm; less than about 10 ppm, or less than about 5 ppm.
In accordance with certain embodiments of the present invention, an oxycodone hydrochloride composition (e.g., oxycodone hydrochloride API), and a solvent, are fed into a reaction apparatus.  The composition is then hydrogenated under adequate
conditions for a sufficient period; the catalyst is removed from the solvent; and the oxycodone hydrochloride composition having a 14-hydroxycodeinone level of less than 25 ppm is isolated and removed, e.g., by crystallization and filtration.
Hydrogenation of the 14-hydroxycodeinone in the processes of the present invention can be accomplished by using, e.g., pressurized-catalytic hydrogenation or catalytic transfer hydrogenation in an appropriate acid, e.g., acetic acid.  A
particular hydrogenation reaction employs hydrogen gas or NaHPO.sub.2 along with a palladium-carbon catalyst.  In certain embodiments, a hydrogen donor for use in the hydrogenation of the 14-hydroxycodeinone can be selected from hydrogen, primary and
secondary alcohols, primary and secondary amines, carboxylic acids and their esters and amine salts, readily dehydrogenatable hydrocarbons (e.g., lower alkyl-substituted aromatic hydrocarbons such as ethylbenzene, diethylbenzene, isopropylbenzene,
diisopropylbenzene, o-ethyltoluene, m-ethyltoluene, p-ethyltoluene, o-isopropyltoluene, m-isopropyltoluene, p-isopropyltoluene, ethylnaphthalene, propylnapththalene, isopropylnaphthalene, and diethylnaphthalene; paraffins such as ethane, propane,
n-butane, isobutane, n-pentane, isopentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, and branched chain isomers thereof; cycloparaffins such as cyclobutane, cyclopentane, cyclohexane, methylcyclopentane, methylcyclohexane, and
ethylcyclopentane; olefins such as ethylene, propylene, 1-butene, 2-butene, 1-pentene, 2-pentene, 1-hexene, 2-hexene, 3-hexene, and branched chain derivatives thereof), clean reducing agents (e.g., polymer-supported organotin hydrides, and any suitable
combination thereof.  In certain embodiments, the hydrogenation can be performed as disclosed in U.S.  Provisional Application No. 60/477,968, filed Jun.  12, 2003, entitled &quot;Hydrogenation of Opioids Without Hydrogen Gas Feed.&quot;
In certain embodiments, the hydrogenation is carried out at a pressure from about 5 PSIG to about 200 PSIG, or from about 40 PSIG to about 60 PSIG.  In certain embodiments, the hydrogenation is carried out at a temperature of from about
20.degree.  C. to about 100.degree.  C., or from about 40.degree.  C. to about 85.degree.  C.
In certain embodiments of the present invention, the 14-hydroxycodeinone is converted to oxycodone by hydrogenation utilizing diphenylsilane and Pd(Ph.sub.3P)/ZnCl.sub.2 and sodium hypophosphite in conjunction with a Pd/C catalyst in aqueous
organic acid; or Pd/C catalytic transfer hydrogenation.
The total reaction time of the hydrogenation reaction is for a duration sufficient to reduce the content of the 14-hydroxycodeinone to a level that is less than 25 ppm, less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm. The
actual reaction time can vary depending upon the temperature and efficiency of the hydrogenation system.  Depending on the hydrogenation conditions (e.g., temperature and pressure), the total reaction time to achieve the desired reduction in
14-hydroxycodeinone can be, e.g., from about 10 minutes to about 36 hours.  The hydrogenation of the 14-hydroxycodeinone can be carried out in the presence of a noble metal catalyst.  In certain embodiments, suitable catalysts can be selected from Raney
cobalt, Raney nickel, palladium on carbon, platinum on carbon, palladium on alumina, platinum oxide, ruthenium on alumina, rhodium on alumina, or rhodium on carbon, among others.  One particular catalyst for this reduction is 5% palladium on carbon.  The
quantity of palladium on carbon catalyst can be from about 0.05% w/w to about 50% w/w, or from about 0.5% w/w to about 5%, in relation to the treated composition.
The reaction may be carried out in a solvent such as water; an alcohol (such as, e.g., isopropanol, methanol or ethanol); tetrahydrofuran; an aromatic hydrocarbon (such as benzene); an ether (such as dioxane); an ester of a lower alkanoic acid
(such as methyl acetate or ethyl acetate); an amide (such as, e.g., dimethylformamide, diethylformamide, dimethylacetomide, or other N-alkyl substituted lower fatty acid amides); N-methylpyrrolidone; formylmorpholine; .beta.-methoxypropionitrile; a
carboxylic acid (such as formic, acetic, propionic acid or other lower alkanoic acid) or an appropriate mixture of any two or more of the aforementioned solvents.  One particular co-solvent combination is isopropanol/water.
In certain embodiments, the invention is directed to the conversion of an oxycodone free base composition (with an 8,14-dihydroxy-7,8-dihydrocodeinone component) to oxycodone hydrochloride.  During salt formation reactions known in the art, the
8,14-dihydroxy-7,8-dihydrocodeinone component is converted to 14-hydroxycodeinone by acid-catalyzed dehydration.  Thus, 14-hydroxycodeinone is increased in the final product.  By virtue of the present invention, this can be reduced by overloading the
amount of hydrochloric acid in the salt formation to promote the reaction of 8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone and providing reducing conditions sufficient for the 14-hydroxycodeinone to be readily converted to oxycodone.  In
such an embodiment, the amount of hydrochloric acid is an amount of greater than 1 molar equivalent as compared to the oxycodone free base.  In certain embodiments, the molar equivalent amount of hydrochloric acid can be greater than about 1.2 molar
equivalents or greater than about 1.4 molar equivalents.  In certain embodiments, the amount of hydrochloric acid can be about 1.5 molar equivalents.  The reducing conditions sufficient to drive the 14-hydroxycodeinone to oxycodone can be provided, e.g.,
by a catalyst with a hydrogen donor.
Further, during salt formation, the rate of dehydration of 8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone is reduced as the pH of the solution increases.  Therefore, in certain embodiments, the pH of the solution can be adjusted to a
pH of from about 1.5 to about 2.5, preferably to about 1.8, (e.g., from a pH of less than 1) with a suitable basic agent, e.g., sodium hydroxide.  This further minimizes the formation of 14-hydroxycodeinone from 8,14-dihydroxy-7,8-dihydrocodeinone during
crystallization.  Preferably, the pH adjustment is performed after the hydrogenation step and prior to removal of catalyst and isolation of the oxycodone having a 14-hydroxycodeinone level of less than 25 ppm.
In certain embodiments it may be necessary to perform the process of the present invention, or one or more relevant steps in the process of the present invention, more than once in order to reduce the amount of 14-hydroxycodeinone to a desired
level, e.g., less than about 10 ppm, or less than about 5 ppm.
In certain embodiments of the present invention, oxycodone hydrochloride compositions can be prepared by certain alternative processes.  Such alternative processes preferably result in an oxycodone hydrochloride composition having a
14-hydroxycodeinone level in an amount of less than 25 ppm. One such alternative process is directed to a process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising oxidizing a thebaine composition
to form 14-hydroxycodeinone composition, the oxidizing being performed at a suitable pH to minimize or eliminate the production of 8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinone composition; hydrogenating the 14-hydroxycodeinone
composition to form an oxycodone base composition; and converting the oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.
Another alternative process is directed to a process for preparing 14-hydroxycodeinone comprising oxidizing a thebaine composition to form a 14-hydroxycodeinone composition, the oxidizing being performed at a suitable pH to minimize or eliminate
the production of 8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinone composition.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition comprising reacting an oxycodone base composition with an acid having a higher pH than hydrochloric acid to form a corresponding acid
addition salt of oxycodone, and converting the acid addition salt of oxycodone to oxycodone hydrochloride.  In such an embodiment, the acid may be selected from the group consisting of tartaric acid, oxalic acid, fumaric acid, phosphoric acid, sulfuric
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising contacting an oxycodone base composition having an amount of
8,14-dihydroxy-7,8-dihydrocodeinone with a substance that preferentially removes the 8,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and converting the oxycodone base composition to an oxycodone hydrochloride composition having
less than 25 ppm 14-hydroxycodeinone.  In preferred embodiments the contacting substance can be a gel.  In further embodiments, the contacting can comprise passing a solution comprising the oxycodone base composition through the substance or can comprise
forming a slurry with the oxycodone base composition and the gel.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising subjecting an oxycodone base composition having an amount of
8,14-dihydroxy-7,8-dihydrocodeinone to chromatographic separation to preferentially remove the 8,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base; and converting the oxycodone base composition to an oxycodone hydrochloride composition
having less than 25 ppm 14-hydroxycodeinone.  In preferred embodiments, the chromatographic separation is a simulated moving bed.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising contacting an oxycodone hydrochloride composition having an
amount of 14-hydroxycodeinone with a substance that preferentially removes the 14-hydroxycodeinone as compared to the oxycodone hydrochloride; and recovering an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.  In
preferred embodiments the contacting substance can be a gel.  In further embodiments, the contacting can comprise passing a solution comprising the oxycodone hydrochloride composition through the substance or can comprise forming a slurry with the
oxycodone hydrochloride composition and the gel.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising subjecting an oxycodone hydrochloride composition having an
amount of 14-hydroxycodeinone to chromatographic separation to preferentially remove the 14-hydroxycodeinone as compared to the oxycodone hydrochloride; and recovering an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.
In preferred embodiments, the chromatographic separation is a simulated moving bed.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising reacting in a suitable solvent an oxycodone base composition
having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone, with boronated polystyrene resin; and converting the oxycodone base composition to an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone.  Preferably the reacting is
performed at a temperature below about 20 degrees C.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition comprising reacting in a suitable solvent an oxycodone base composition with boronated polystyrene resin; and converting the oxycodone base
composition to an oxycodone hydrochloride composition.  Preferably the reacting is performed at a temperature below about 20 degrees C.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm comprising combining hydrochloric acid and an oxycodone base composition
having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form a solution; and spray drying the solution to generate oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm.
having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form a solution; and lyophilizing the solution to generate oxycodone hydrochloride composition having a 14-hydroxycodeinone level in an amount of less than 25 ppm.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition comprising combining hydrochloric acid and an oxycodone base composition in a solvent to form a solution; and spray drying the solution to
generate oxycodone hydrochloride.
Another alternative process is directed to a process for preparing an oxycodone hydrochloride composition comprising combining hydrochloric acid and an oxycodone base composition in a solvent to form a solution; and lyophilizing the solution to
The oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm can be incorporated into pharmaceutical dosage forms, e.g., by admixtures of the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm
with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances.  For oral formulations, the dosage forms can provide a sustained release of the active.  Suitable pharmaceutically acceptable carriers include but
are not limited to, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides
and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, disintegrants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.  The compositions intended for oral use may be prepared according to any method known in the art and
such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.  Such excipients include, for example an inert diluent such
as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.  The tablets may be uncoated or they may be coated by known techniques for elegance or to delay
release of the active ingredients.  Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.  The oral dosage forms of the present invention may be in the form of tablets
(sustained release and/or immediate release), troches, lozenges, powders or granules, hard or soft capsules, microparticles (e.g., microcapsules, microspheres and the like), buccal tablets, suppositories, solutions, suspensions, etc.
When the dosage form is oral, the dosage form of the present invention contains from about 10 mg to about 320 mg of oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm. Particularly preferred dosages for twice daily
dosing are about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, or about 160 mg.  Particularly preferred dosages for once daily dosing are about 10 mg, about 20 mg, about 30 mg,
about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg, or about 320 mg.  The oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm can also be formulated with suitable pharmaceutically acceptable
excipients to provide a sustained release of the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm. Such formulations can be prepared in accordance with U.S.  Pat.  Nos.  5,266,331; 5;508,042; 5,549,912; and 5,656,295.
The sustained release dosage from may include a sustained release material which is incorporated into a matrix along with the oxycodone or salt thereof.
The sustained release dosage form may optionally comprise particles containing oxycodone having a 14-hydroxycodeinone level of less than 25 ppm. In certain embodiments, the particles have a diameter from about 0.1 mm to about 2.5 mm, preferably
from about 0.5 mm to about 2 mm.  Preferably, the particles are film coated with a material that permits release of the active at a sustained rate in an aqueous medium.  The film coat is chosen so as to achieve, in combination with the other stated
properties, desired release properties.  The sustained release coating formulations of the present invention should preferably be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating
additives, non-toxic, inert, and tack-free.
capsule in an amount sufficient to provide an effective sustained release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media.
The sustained release bead formulations of the present invention slowly release the active of the present invention, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.  The sustained release profile of the
Spheroids or beads coated with the agent(s) of the present are prepared, e.g., by dissolving the agent(s) in water and then spraying the solution onto a substrate, for example, nu pariel 18/20 beads, using a Wuster insert.  Optionally, additional
ingredients are also added prior to coating the beads in order to assist the binding of the active to the beads, and/or to color the solution, etc. For example, a product which includes hydroxypropylmethylcellulose, etc. with or without colorant (e.g.,
optionally overcoated with a barrier agent, to separate the active(s) from the hydrophobic sustained release coating.  An example of a suitable barrier agent is one which comprises hydroxypropylmethylcellulose.  However, any film-former known in the art
may be used.  It is preferred that the barrier agent does not affect the dissolution rate of the final product.
3,916,899; 4,063,064; and 4,088,864.
polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride) and glycidyl methacrylate copolymers.  In other embodiments, the hydrophobic material is selected from materials such as hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and
Preferred hydrophobic materials are water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends.  Preferably, the hydrophobic materials useful in the invention have a melting point from about 2530.degree.  to about
present oral dosage form will be determined, inter alia, by the precise rate of oxycodone hydrochloride release required.  The at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol.  In particularly
preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol.  The amount of the at least one aliphatic alcohol in the present oral dosage form will be determined, as above, by
the precise rate of opioidoxycodone release required.  It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form.  In the absence of at least one polyalkylene glycol, the oral dosage form preferably
contains between 20% and 50% (by wt) of the at least one aliphatic alcohol.  When at least one polyalkylene glycol is present in the oral dosage form, then the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol
Matrix--Particulates
matrix may be effected, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose, and the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm; (b) mixing the hydroxyalkyl cellulose
In yet other alternative embodiments, a spheronizing agent, together with the active can be spheronized to form spheroids.  Microcrystalline cellulose is a preferred spheronizing agent.  A suitable microcrystalline cellulose is, for example, the
material sold as Avicel PH 101 (Trade Mark, FMC Corporation).  In such embodiments, in addition to the active ingredient and spheronizing agent, the spheroids may also contain a binder.  Suitable binders, such as low viscosity, water soluble polymers,
will be well known to those skilled in the pharmaceutical art.  However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, are preferred.  Additionally (or alternatively) the spheroids may contain a water insoluble polymer,
especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.  In such embodiments, the sustained release coating will generally include a hydrophobic material such as (a) a wax, either
The additional hydrophobic material may comprise one or more water-insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like
substances.  In order to achieve constant release, the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases.  Useful water-insoluble wax-like
substances may be those with a water-solubility that is lower than about 1:5,000 (w/w).
The preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm together with at least one
hydrophobic material and preferably the additional hydrophobic material to obtain a homogeneous mixture.  The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same.  The resulting
homogeneous mixture is then extruded to form strands.  The extrudate is preferably cooled and cut into multiparticulates by any means known in the art.  The strands are cooled and cut into multiparticulates.  The multiparticulates are then divided into
unit doses.  The extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the therapeutically active agent for a time period of from about 8 to about 24 hours.
An optional process for preparing the melt extrusions of the present invention includes directly metering into an extruder a hydrophobic material, the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm, and an optional
In one preferred embodiment, oral dosage forms are prepared to include an effective amount of melt-extruded multiparticulates within a capsule.  For example, a plurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in
an amount sufficient to provide an effective sustained release dose when ingested and contacted by gastric fluid.
Optionally, the sustained release melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule containing the multiparticulates can be further coated, with a sustained release coating such as the sustained release
coatings described above.  Such coatings preferably include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the overcoat may be greater depending upon the desired release rate, among
The melt-extruded unit dosage forms of the present invention may further include combinations of melt-extruded particles before being encapsulated.  Furthermore, the unit dosage forms can also include an amount of an immediate release agent for
prompt release.  The immediate release agent may be incorporated, e.g., as separate pellets within a gelatin capsule, or may be coated on the surface of the multiparticulates after preparation of the dosage forms (e.g., sustained release coating or
matrix-based).  The unit dosage forms of the present invention may also contain a combination of sustained release beads and matrix multiparticulates to achieve a desired effect.
The sustained release formulations of the present invention preferably slowly release the agent(s), e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.  The sustained release profile of the melt-extruded formulations
of the invention can be altered, for example, by varying the amount of retardant, i.e., hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the
method of manufacture, etc.
In other embodiments of the invention, the melt extruded material is prepared without the inclusion of the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm, which can be added thereafter to the extrudate.  Such
formulations typically will have the agents blended together with the extruded matrix material, and then the mixture would be tableted in order to provide a slow release formulation.
The dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation.  In one embodiment, coatings are provided to permit either pH-dependent
or pH-independent release.  A pH-dependent coating serves to release the active in desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an absorption profile is provided which is capable of providing at least
about eight hours and preferably about twelve hours to up to about twenty-four hours of analgesia to a patient.  When a pH-independent coating is desired, the coating is designed to achieve optimal release regardless of pH-changes in the environmental
fluid, e.g., the GI tract.  It is also possible to formulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small
In certain preferred embodiments, the substrate: (e.g., tablet core bead, matrix particle) containing the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm thereof is coated with a hydrophobic material selected from
(i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.  The coating may be applied in the form of an organic or aqueous solution or dispersion.  The coating may be applied to obtain a weight gain from about 2 to about 25% of the
substrate in order to obtain a desired sustained release profile.  Coatings derived from aqueous dispersions are described, e.g., in detail in U.S.  Pat.  Nos.  5,273,760 and 5,286,493.
Other examples of sustained release formulations and coatings which may be used in accordance with the present invention include those described in U.S.  Pat.  Nos.  5,324,351; 5,356,467, and 5,472,712.
Sustained release dosage forms according to the present invention may also be prepared as osmotic dosage formulations.  The osmotic dosage forms preferably include a bilayer core comprising a drug layer (containing the oxycodone hydrochloride
having a 14-hydroxycodeinone level of less than 25 ppm) and a delivery or push layer, wherein the bilayer core is surrounded by a semipermeable wall and optionally having at least one passageway disposed therein.
The expression &quot;passageway&quot; as used for the purpose of this invention, includes aperture, orifice, bore, pore, porous element through which oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm can be pumped, diffuse or
polysaccharides, acids, salts or oxides.  A passageway can be formed by leaching a compound from the wall, such as sorbitol, sucrose, lactose, maltose, or fructose, to form a sustained-release dimensional pore-passageway.  The dosage form can be
manufactured with one or more passageways in spaced-apart relation on one or more surfaces of the dosage form.  A passageway and equipment for forming a passageway are disclosed in U.S.  Pat.  Nos.  3,845,770; 3,916,899; 4,063,064 and 4,088,864.
Passageways comprising sustained-release dimensions sized, shaped and adapted as a releasing-pore formed by aqueous leaching to provide a releasing-pore of a sustained-release rate are disclosed in U.S.  Pat.  Nos.  4,200,098 and 4,285,987.
In certain embodiments the drug layer may also comprise at least one polymer hydrogel.  The polymer hydrogel may have an average molecular weight of between about 500 and about 6,000,000.  Examples of polymer hydrogels include but are not limited
to a maltodextrin polymer comprising the formula (C.sub.6H.sub.12O.sub.5).sub.n.H.sub.2O, wherein n is 3 to 7,500, and the maltodextrin polymer comprises a 500 to 1,250,000 number-average molecular weight; a poly(alkylene oxide) represented by, e.g., a
ethacrylic acid of 10,000 to 500,000 number-average molecular weight.
swelling and expanding as an osmotic hydrogel (also known as osmogel), whereby they push the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm thereof from the osmotic dosage form.
In certain alternative embodiments, the dosage form comprises a homogenous core comprising oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm, a pharmaceutically acceptable polymer (e.g., polyethylene oxide),
optionally a disintegrant (e.g., polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fatty acid, a surfactant, a chelating agent, a bile salt, etc.).  The homogenous core is surrounded by a semipermeable wall having a passageway (as defined
above) for the release of the oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm.
In certain embodiments, preferably the semipermeable wall is nontoxic, inert, and it maintains its physical and chemical integrity during the dispensing life of the drug.  In certain embodiments, the dosage form comprises a binder.  An example of
a binder includes, but is not limited to a therapeutically acceptable vinyl polymer having a 5,000 to 350,000 viscosity-average molecular weight, represented by a member selected from the group consisting of poly-n-vinylamide, poly-n-vinylacetamide,
poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone, poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n-vinyl -pyrrolidone copolymers with a member selected from the group consisting of vinyl acetate, vinyl alcohol,
vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laureate, and vinyl stearate.  Other binders include for example, acacia, starch, gelatin, and hydroxypropylalkylcellulose of 9,200 to 250,000 average molecular weight.
In certain preferred embodiments, the present invention includes a therapeutic composition comprising an amount of oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm equivalent to 10 to 40 mg oxycodone hydrochloride,
25 to 500 mg of poly(alkylene oxide) having a 150,000 to 500,000 average molecular weight, 1 to 50 mg of polyvinylpyrrolidone having a 40,000 average molecular weight, and 0 to about 7.5 mg of a lubricant.
The sustained release formulations of the present invention may be formulated as a pharmaceutical suppository for rectal administration comprising a suitable suppository base, and oxycodone hydrochloride having a 14-hydroxycodeinone level of less
than 25 ppm. Preparation of sustained release suppository formulations is described in, e.g., U.S.  Pat.  No. 5,215,758.
Prior to absorption, the drug must be in solution.  In the case of suppositories, solution must be preceded by dissolution of the suppository base, or the melting of the base and subsequent partition of the drug from the suppository base into the
rectal fluid.  The absorption of the drug into the body may be altered by the suppository base.  Thus, the particular suppository base to be used in conjunction with a particular drug must be chosen giving consideration to the physical properties of the
drug.  For example, lipid-soluble drugs will not partition readily into the rectal fluid, but drugs that are only slightly soluble in the lipid base will partition readily into the rectal fluid.
The suppository base chosen should be compatible with the active of the present invention.  Further, the suppository base is preferably non-toxic and nonirritating to mucous membranes, melts or dissolves in rectal fluids, and is stable during
Examples of suitable commercially available mono-, di- and triglycerides include saturated natural fatty acids of the 12-18 carbon atom chain sold under the trade name Novata.TM.  (types AB, AB, B, BC, BD, BBC, E, BCF, C, D and 299), manufactured
by Henkel, and Witepsol.TM.  (types H5, H12, H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58, E75, E76 and E85), manufactured by Dynamit Nobel.
The oxycodone hydrochloride having a 14-hydroxycodeinone level of less than 25 ppm may be used as a substitute for the oxycodone hydrochloride in any existing commercial product such as, e.g., Tylox.RTM., Roxilox.RTM., Roxicet.RTM.,
Percocet.RTM., Oxycet.RTM., Percodan.RTM., Roxycodone.RTM., OxyContin.RTM.  and OxyIR.RTM..  Such formulations are listed in the PDR 58th Edition (2004) and the FDA Orange Book.
In Example 1, 37.7 g of oxycodone HCl (35.4 g dry basis, ca.  500 ppm 14-hydroxycodeinone) was placed in a 500 mL Parr reaction bottle and combined with 0.55 g 5% Pd/C catalyst, 50% water wet (Johnson Matthey type 87L), and 182.2 g of 61.9%
isopropanol/water (w/w).  The mixture was placed under an inert atmosphere and heated with shaking to 45-50.degree.  C. Upon dissolution of all starting material, the pressure in the bottle was vented to the atmosphere and hydrogen pressure was applied
(45 PSIG) for 4 hours.  At the end of the hydrogenation, the hydrogen was vented off and the solution was allowed to cool to room temperature.
The next day, the mixture was heated to 75.degree.  C. to dissolve the crystallized solids and then suction filtered over a 0.2 .mu.m PTFE membrane into a 1 L jacketed cylindrical flask (equipped with a condenser, a nitrogen atmosphere, a
mechanical stirrer, a type K thermocouple, and a programmable refrigerated recirculator).  The Parr bottle was rinsed with deionized water (11.7 g), which was added to the 1 L flask through the filter.  Isopropanol (334.7 g) was added to the flask and
the mixture was re-heated with stirring to 75.degree.  C. and held to dissolve any crystallized solids.  The solution was cooled with stirring to 0-10.degree.  C. over 8 hours (linear ramp) and held at 0-10.degree.  C. for 20 hours.  The crystallized
solid was then collected by suction filtration and washed with 107 g of cold 95:5 isopropanol/water (w/w).
To remove isopropanol from product, the solvent-wet material was transferred to a drying dish and placed in a vacuum desiccator with an open container of deionized water.  The solid was held in this manner, under vacuum, overnight.  The material
was then dried under vacuum at 60.degree.  C.
Analysis of the dried material using the method of Example 6 below gave a result of &amp;lt;5 ppm of codeinone and 8 ppm of 14-hydroxycodeinone.
In Example 2, 35.0 g of oxycodone HCl (33.3 g dry basis, ca.  4000 ppm 14-hydroxycodeinone) was placed in a 500 mL Parr reaction bottle and combined with 0.49 g 5% Pd/C catalyst, 50% water wet (Johnson Matthey type 87L), and 159.9 g of 62.3%
isopropanol/water.  The mixture was placed under an inert atmosphere and then heated with shaking to 45-50.degree.  C. Upon dissolution of the starting material, the pressure in the bottle was vented to the atmosphere and hydrogen pressure was applied
(45 PSIG).  After 5.25 hours of shaking, the hydrogen was vented off, and the solution was allowed to cool to room temperature.  The mixture was re-heated the next day and hydrogenation was continued for 4.75 hours.
The mixture was heated to 75.degree.  C. and then suction filtered over a 0.2 .mu.m PTFE membrane into a 1 L jacketed cylindrical flask (equipped with a distillation head, a nitrogen atmosphere, a mechanical stirrer, a type K thermocouple, and a
programmable refrigerated recirculator).  The Parr bottle was rinsed with deionized water (11.7 g), which was added to the 1 L flask through the filter.
Isopropanol (295.6 g) was added to the flask and the mixture was heated to boiling (ca.  81.degree.  C.).  To remove water and increase the yield, isopropanol/water azeotrope was distilled from the flask until 305.7 g had been collected.  Fresh
isopropanol (305.6 g) was added and the distillation head was removed and replaced with a condenser.
The mixture was cooled with stirring from boiling to 0-10.degree.  C. over 8 hours (linear ramp) and held at 0-10.degree.  C. for 20 hours.  The crystallized solid was then collected by suction filtration and washed with 107 g of cold 95:5
isopropanol/water.  The material was dried as described in Example 1.
Analysis of the dried material using the low 14-hydroxycodeinone method of Example 4 below gave a result of &amp;lt;5 ppm of 14-hydroxycodeinone.
Analysis of the dried material using the method of Example 6 below gave a result of &amp;lt;5 ppm of codeinone and &amp;lt;5 ppm of 14-hydroxycodeinone.
In Example 3, 27.83 g of oxycodone free-base, water wet (24.57 g dry basis, 0.0779 mol, ca.  3000 ppm 14-hydroxycodeinone), 39.8 g of deionized water, 81.9 g of isopropanol, 0.49 g 5% Pd/C catalyst, 50% water wet (Johnson Matthey type 87L), and
conc. HCl (11.3 g, 0.117 mol, 1.50 equivalents based on 37.7% HCl assay) were combined in a 500 ml Parr shaker bottle.
The mixture was placed under an inert atmosphere and heated to 75.degree.  C. with shaking.  The pressure in the bottle was relieved, and the system was pressurized with hydrogen (45 PSIG).  The solution was held under these conditions for 21.7
hours.  Analysis by HPLC showed that the ratio of the area of the 8,14-dihydroxy-7,8-dihydrocodeinone peak to that of oxycodone was reduced from 0.29% to 0.04% during this time.
The hydrogen pressure was vented and the system was placed under an inert atmosphere.  In order to prevent further dehydration of any residual 8,14-dihydroxy-7,8-dihydrocodeinone, the pH of the solution was adjusted from 0.5 to 1.8 with 20.7 g
NaOH saturated isopropanol (some solid sodium hydroxide was also present).
The solution was re-heated to 75.degree.  C. and then pressure filtered through a 0.2 .mu.m PTFE membrane filter housed in heat-traced 47 mm SS filter holder into a 500 ml jacketed cylindrical reactor (condenser, N.sub.2, mechanical stirrer,
programmable refrigerated recirculator).  The Parr bottle was rinsed with 8.6 g of deionized water, which was added to the flask through the filter.
Isopropanol (222.5 g) was added to the solution in the flask and the resulting slurry was heated to approximately 75.degree.  C. to re-dissolve the solids.  After reaching the desired temperature, the solution was held for two hours (to simulate
typical processing times).  No 14-hydroxycodeinone was detected in a sample of the crystallization mixture after this hold.
The circulator was set to cool from 80.degree.  C. to 0.degree.  C. over 8 hours.  Approximately 24 hours after starting the cooling program, the solids were collected by suction filtration and washed three times with 95:5 isopropanol/water
(232.8 g total).  The material was dried as described in Example 1.
Analysis of the dried material using the method of Example 6 below gave a result of &amp;lt;5 ppm of codeinone and 10 ppm of 14-hydroxycodeinone.
The products of Examples 1-3 were analyzed to determine the level of 14-hydroxycodeinone under 100 parts per million (PPM) level by a HPLC method using a Waters Atlantis 5 .mu.m dC18, 3.times.250 mm column maintained at 50.degree.  C. and
isocratic elution using pH 9.35, 17 mM ammonium carbonate buffer and methanol (60:40).  Quantitation was achieved by measuring the peak area response with UV detection at 220 nm using external standard.  This method utilized mobile phase with volatile
components that are compatible with LC/MS analysis.
1.  Ammonium carbonate, analytical reagent grade (Aldrich);
2.  Water, HPLC grade;
3.  Methanol, HPLC grade;
4.  Acetic acid, reagent grade (J. T Baker Glacial Acetic Acid);
5.  Ammonium hydroxide, reagent grade;
6.  Phosphoric acid, about 85%, A.C.S.  reagent;
7.  14-Hydroxycodeinone reference material from Albany Molecular Research, Inc.
1.  HPLC system capable of delivering 0.4 mL/minute of mobile phase (Waters Alliance);
2.  UV/Visible detector set to monitor the eluant at 220 nm (Waters 2487 UV/Vis);
3.  Autosampler capable of injecting 6 .mu.L;
4.  Integrator or suitable data recording system (Waters Millennium 32 chromatograph system.);
5.  Waters, Atlantis dC18 column, 3.times.250 mm, 5 .mu.m;
6.  Column heater capable of maintaining a constant temperature of 50.degree.  C.;
7.  On-line vacuum degasser.
1.  pH meter, preferably with automatic temperature compensation (ATC);
2.  Ultrasonic bath, Model 5200, Branson;
3.  0.45-.mu.m membrane filters for aqueous solvent, Whatman or Millipore, Cellulose acetate or Nylon.
1.6.+-.0.1 g of ammonium carbonate was weighed and placed into a 1-L beaker.  1000 mL of water was added to the beaker and stirred with a magnetic stirrer until the ammonium carbonate was dissolved.  The pH was adjusted to 9.35-9.40 with ammonium
400 mL of HPLC-grade methanol was mixed with 600 mL of 17 mM ammonium carbonate, pH 9.35-9.40 prepared above.  The mixture was filtered through solvent membrane filters and then degassed using an on-line vacuum degasser in the HPLC system.
10.0 mL of 85% H.sub.3PO.sub.4 was pipetted into a 1 liter volumetric flask and diluted to volume with water and mixed thoroughly.
A stock 14-hydroxycodeinone standard solution was prepared by weighing 25.+-.2 mg of 14-hydroxycodeinone reference material and transferring it into a 250-mL volumetric flask.  Approximately 100 mL of 0.85% H.sub.3PO.sub.4 solution was added to
the flask and sonicated for approximately 2 minutes or until dissolved.  The solution was diluted to volume with 0.85% H.sub.3PO.sub.4 solution and mixed thoroughly.  This was the stock 14-hydroxycodeinone standard solution.
A working solution of 100 ppm 14-hydroxycodeinone standard solution for system suitability was prepared by pipetting 5.0 mL of the stock 14-hydroxycodeinone standard solution into a 100-mL volumetric flask, diluting the solution to volume with
water and mixing thoroughly.
A working solution of 10 ppm 14-hydroxycodeinone standard solution for sensitivity was prepared by pipetting 5.0 mL of working 100 ppm 14-hydroxycodeinone standard solution into a 50-mL volumetric flask, diluting the solution to volume with water
and mixing thoroughly.
A stock hydrocodone standard solution was prepared by weighing 25.+-.2 mg of hydrocodone reference material and transferring contents into a 250-mL volumetric flask.  Approximately 100 mL of 0.85% H.sub.3PO.sub.4 solution was added to the flask
and sonicated for approximately 2 minutes or until dissolved.  The solution was diluted to volume with 0.85% H.sub.3PO.sub.4 solution and mixed thoroughly.
Stock Hydrocodone Standard Solution was prepared by weighing 25.+-.2 mg of Hydrocodone reference material and transferring contents into a 250-mL volumetric flask.  Approximately 100 mL of 0.85% H3PO4 solution was added to the flask and sonicated
for approximately 2 minute or until dissolved.  The solution was diluted to volume with 0.85% H3PO4 Solution and mixed thoroughly.
A sample solution was prepared by weighing about 250 mg oxycodone API sample into a scintillation vial.  5.0 mL of water was pipetted into the vial to dissolve the sample.  The vial was tightly capped and sonicated for approximately 5 minutes or
until the sample was dissolved.  The contents were then shaken and mixed thoroughly.
The Resolution Test Mixture (RTM) was prepared by pipetting separately 10.0 mL of each stock standard solution of hydrocodone above and 14-hydroxycodeinone above into the same 100 mL volumetric flask and diluted to volume with a sufficient amount
of water and mixed thoroughly.
Column: Waters, Atlantis dC18, 3.times.250 mm, 5 .mu.m.
Column temperature: 50.degree.  C.
Injection volume: 6 .mu.l
Before performing the system suitability test, a new column was equilibrated over night (at least 12 hours) by pumping mobile phase through it at 0.4 mL/min. After the new column was equilibrated, 6 .mu.L of RTM solution was injected into the
equilibrated system to ensure that the two eluted component peaks did not interfere with one another.  A typical separation of the system suitability testing solution is shown in FIG. 3.
A system suitability test was performed by injecting the Working 100 ppm 14-hydroxycodeinone standard solution into the system and by performing the system suitability test as described in the USP &amp;lt;621&amp;gt; by making six different runs of 6
.mu.L injections.  The system suitability test results met the following criteria listed in Table 1 below.
TABLE-US-00001 TABLE 1 Test No. System Suitability Test Specification 1 RSD of peak areas for 14- RSD .ltoreq.  3.0% hydroxycodeinone (1) 2 RSD of retention time for RSD .ltoreq.  2.0% 14-hydroxycodeinone (1) 3 Column Efficiency N .gtoreq.  2000
(Theoretical Plates of 14- hydroxycodeinone) (1) 4 Resolution between 14- R .gtoreq.  1.5 hydroxycodeinone and Hydrocodone (2) 5 Signal to noise ratio (3) .sup.  S/N .gtoreq.  10 Note: (1) the working 100 ppm 14-hydroxycodeinone standard solution for
Test Nos.  1 to 3 was used.  (2) the RTM for Test No. 4 was used.  (3) the working 10 ppm 14-hydroxycodeinone standard solution for Test No. 5 was used.
Before starting the experiment, 6 .mu.L of water was injected to ensure that there were no interfering peaks co-eluting with the peak for 14-hydroxycodeinone.  The following procedure was then conducted.
The working 100 ppm 14-hydroxycodeinone standard solution was injected six times in different runs, and the system was checked to verify that it met the system suitability test specifications as listed for Test Nos.  1, 2 and 3 in Table 1 above.
The working 10 ppm 14-hydroxycodeinone standard solution was injected and run once in the HPLC system to confirm that the system had signal-to-noise ratio S/N greater than or equal to 10, as listed in the specification for Test No. 5 in Table 1
The working 100 ppm 14-hydroxycodeinone standard solution and the working 10 ppm 14-hydroxycodeinone standard solution were each injected separately.  Both working standard solutions were used to quantitate the samples.  The setting and
integration parameters are listed in Table 2 below.
TABLE-US-00002 TABLE 2 Integration Setting Parameters Minimum area 0 Minimum height 0 Threshold 2 Peak width 90.00 Inhibit integration: 0.01 to 20 minutes Eliminates solvent front
Typical HPLC chromatograms for the working 100 ppm 14-hydroxycodeinone standard solution and the oxycodone API sample solution are shown in FIG. 4 and FIG. 5 respectively.  Retention times of the 14-hydroxycodeinone and other related substances
are presented in Table 3 below.
TABLE-US-00003 TABLE 3 Relative Retention Time vs.  Oxycodone Peak ID (RRT) Oxycodone-N-Oxide (ONO) 0.16 Noroxycodone 0.31 Oxymorphone 0.45 7,8-Dihydro-8,14-Dihydroxycodeinone (DDC) 0.58 14-Hydroxycodeine 0.73 14-Hydroxycodeinone 0.79
6-.alpha.-Oxycodol 0.96 Hydrocodone 0.95 Oxycodone 1.0 Thebaine 1.89
The following calculations were performed using the results obtained above.  Using Millennium.RTM., software, the parameters were entered as follows: In the sample set, the standard concentrations for both working standards (10 and 100 ppm) were
.times..times..times..times..times..times..times..times..times..times..tim- es..times.  ##EQU00001## .times..times..times..times..times..times..times..times..times..times..ti- mes..times.  ##EQU00001.2## where W.sub.std is the weight of standard.
.times..times..times..times..times..times..times..times.  ##EQU00002## where: A.sub.sam=peak area of 14OHC Y.sub.intercept=Y intercept from a linear regression line using the two standards Slope=slope from a linear regression line using the two
standards D=5.0 (sample dilution factor) W.sub.sam=sample weight in mg 1000000=Convention factor to convert the result to PPM
3.0 g of oxycodone hydrochloric salt containing 154 ppm 14-hydroxycodeinone was dissolved in 20 mL water to afford a clear solution in a 250 mL Parr reaction bottle.  To the solution, 0.05 g 5% Pd/C catalyst, 50% water wet (Johnson Matthey type
87L) and 1 mL formic acid 88% were added.  The mixture was placed under inert atmosphere without hydrogen feed and then heated to 45.degree.  C.-50.degree.  C. After 2 hours of shaking, a sample was taken to check the disappearance of
14-hydroxycodeinone.  The sample showed no 14-hydroxycodeinone by the HPLC method described in Example 4 above.
The solution was then suction filtered over a 0.2 micron PTFE membrane to remove the catalyst.  An aliquot of 2 mL was taken out of about 18 mL filtrate solution.  To this solution, 2.0 mL isopropyl alcohol was added to obtain a clear solution,
followed by 4.0 mL of ethyl acetate.  The solution was stirred, cooled and kept at 0-5.degree.  C. for 20 hours to afford oxycodone hydrochloride crystals.  The crystalline solid was isolated by suction filtration.  The wet solid was dried in an oven at
50.degree.  C. and 10 mmHg pressure.  The dried solid weighed 0.12 g.
Analysis using the HPLC method in Example 4 above indicated that about 11 ppm 14-hydroxycodeinone were present in the oxycodone hydrochloride salt composition.  In another aliquot of 2 mL of the filtrate solution, 16-18 mL of isopropyl alcohol
was added to the concentrated oxycodone hydrochloride solution followed by crystallization and drying.  The procedure afforded oxycodone hydrochloride salt containing about 6.8 ppm 14-hydroxycodeinone.
The products of Examples 1-3 were analyzed by the following alternative method to determine the amount of codeinone and 14-hydroxycodeinone present.  This method uses a Waters Symmetry C.sub.18 column maintained at 40.degree.  C. with isocratic
elution using a mobile phase of sodium phosphate buffer, sodium dodecyl sulfate (SDS), acetonitrile (ACN), and methanol (MeOH).
The reagents used were as follows: 1.  Water, HPLC grade or equivalent; 2.  Phosphoric acid, 85%, HPLC reagent grade or equivalent; 3.  Sodium phosphate monobasic, monohydrate, Enzyme grade or equivalent; 4.  Sodium dodecyl sulfate (99%+),
Ultrapure, Fluka or equivalent; 5.  Acetonitrile, HPLC grade or equivalent; 6.  Methanol, HPLC grade or equivalent; 7.  Sodium hydroxide, ACS reagent grade or equivalent; 8.  Oxycodone HCl with low ABUK to be used as part of the matrix in standard
preparation; 9.  Codeinone reference material from Rhodes Technologies or equivalent; 10.  14-Hydroxycodeinone reference material from Albany Molecular Research or equivalent
For this analysis, an HPLC system with a dual wavelength detector was used that was able to operate under isocratic conditions at a flow rate of 0.7 mL per minute with UV detection @ 220 nm, and a column temperature of 40.degree.  C.
For this analysis, an HPLC vacuum filtration apparatus with a nylon membrane filter (0.45 .mu.m) was used.
50 g of sodium hydroxide pellets were weighed and transferred into a 100-mL volumetric flask.  60-mL of water was then added and sonicated until the pellets were completely dissolved.  The pellets were diluted to volume with water and mixed well. (Commercially available 50% w/v NaOH solution may also be used.)
ii.  Phosphoric Acid Solution I (.about.8.5% H.sub.3PO.sub.4)
10 ml of concentrated phosphoric acid (85%) was transferred into a 100 ml volumetric flask containing approximately 50 ml of water.  The volume was diluted with water and then mixed.
iii.  Phosphoric Acid Solution II (0.85% H3PO4)
10-mL of 85% phosphoric acid was pipetted into a 1000-mL volumetric flask, diluted to volume with water and mixed well.  This was the diluent for the sample and standard preparation.
iv.  Mobile Phase
3.45 g.+-.0.1 g of sodium phosphate monobasic monohydrate was weighed into a 1-L flask.  1000 mL of water was added and then stirred with a magnetic stirrer until dissolved.  5.41 g.+-.0.1 g of sodium dodecyl sulfate was added and mixed well
until dissolved.  This solution was filtered using vacuum filtration with a 0.45-.mu.m nylon membrane filter.  The pH of this solution was adjusted with 50% NaOH solution to a final pH of 7.50.+-.0.05.
722.5 ml of the above solution was then mixed with 157.5 mL of acetonitrile, then 120 mL of methanol was added to the solutions and mixed well.  The final pH was adjusted to 7.80.+-.0.01 with .about.8.5% phosphoric acid solution.  The mobile
phase was sonicated for about 5 minutes to remove dissolved air.
25.+-.1 mg of both codeinone and 14-hydroxycodeinone reference materials were weighed and transferred into a 100-mL volumetric flask, diluted to volume and dissolved with .about.0.85% phosphoric acid solution II.
ii.  100 ppm Stock Standard II
1-ml of stock solution I was pipetted into a 50-ml volumetric flask, diluted to volume with .about.0.85% phosphoric acid solution II and then mixed.
iii.  10 ppm Working Standard III
500.+-.5 mg of Oxycodone low ABUK material was weighed into a 10-ml volumetric flask.  1-ml of stock standard II was pipetted and diluted to volume with .about.0.85% phosphoric acid solution II and mixed.
iv.  Unspiked Oxycodone Solution
500.+-.5 mg of Oxycodone low ABUK material was weighed into a 10-ml volumetric flask, diluted to volume with .about.0.85% phosphoric acid solution II and mixed.  (This solution was used to calculate the residual content of both Codeinone and
14-Hydroxycodeinone in the working standard).
1.0-ml of the Codeinone/14-Hydroxycodeinone stock solution I was pipetted into a 50-ml volumetric flask.  Using a micropipette, 100 .mu.l of the unspiked Oxycodone solution was transferred and diluted to volume with .about.0.85% phosphoric acid
solution II.  The concentration of Codeinone, 14-Hydroxycodeinone, and Oxycodone was approximately 100 ppm.
500.+-.5 mg of Oxycodone HCl was weighed, in duplicate, into separate 10-mL volumetric flasks for each of Examples 1, 2 and 3.  The Oxycodone HCl was then diluted to volume with the .about.0.85% phosphoric acid solution II and swirled to dissolve
the sample.  A sufficient amount of this sample was transferred to an HPLC vial for injection.
TABLE-US-00004 TABLE 4 HPLC Conditions Parameter Condition HPLC Column Symmetry C.sub.18, 3.0 .times.  150 mm, 3.5 .mu.m particle size Mobile Phase 18 mM phosphate/13 mM SDS pH = 7.50:ACN:MeOH (72.25:15.75:12.0) pH = 7.80 .+-.  0.01 Flow Rate*
0.7 mL/min Column Temperature 40.degree.  C. Detection 220 nm Injection Volume 5 .mu.L Run Time 50 minutes *Parameter may be adjusted to achieve retention times.
One injection (5-.mu.L) of a blank solution (.about.0.85% phosphoric acid solution II) was made, followed by one injection of the RTM to determine if there was any interfering peaks in the blank solution.  6 injections of the working standard III
were made.  The system suitability injections were then tested to verify that they met the system suitability criteria as shown in Table 2.
TABLE-US-00005 TABLE 5 System Suitability Criteria Acceptance Parameter Criteria Resolution between Codeinone and 14-Hydroxycodeinone NLT 8 Resolution between 14-Hydroxycodeinone and Oxycodone NLT 2 Tailing factor for Oxycodone 0.7-2.0 Relative
retention times for Codeinone based on Oxycodone Approx. 0.44 Relative retention times for 14-Hydroxycodeinone Approx. 0.85 based on Oxycodone % RSD of 6 system suitability injections for NMT 20% Codeinone and 14-Hydroxycodeinone
TABLE-US-00006 Expected Retention Components Times Codeinone 14 .+-.  2 min 14-Hydroxycodeinone 27 .+-.  4 min Oxycodone 32 .+-.  6 min
TABLE-US-00007 TABLE 6 Blank (diluent) 1 injection Resolution solution 1 injection Working Standard III 6 injections for RSD, last 2 injections for calibration Blank (diluent) 2 injections Unspiked Oxycodone solution 2 injections Sample 1 Prep#
1 2 injections Working Standard III 2 injections Sample 1 Prep# 2 2 injections Sample 2 Prep# 1 2 injections Sample 2 Prep# 2 2 injections Working Standard III 2 injections Sample 3, Prep# 1 2 injections Sample 3, Prep# 2 2 injections Working Standard
III 2 injections
The responses of Codeinone and 14-Hydroxycodeinone peaks were measured and recorded.  The content of Codeinone and 14-Hydroxycodeinone was calculated in ppm using the following equation:
.times..times..times..times..times..times..times.  ##EQU00003## .times..times..times.  ##EQU00003.2## Where: ppm=Parts per millions of codeinone or 14-Hydroxycodeinone in Oxycodone HCl Rs=Response of Codeinone or 14-Hydroxycodeinone in Sample
Solution.  Rstd=Response of Codeinone or 14-Hydroxycodeinone in Standard Solution minus the response of unspiked standard Wstd=Weight of Standard, corrected for purity, mg Ws=Weight of Sample, mg 1000000=Conversion Factor for ppm %
Codeinone/14-hydroxycodeinone=ppm/10,000
The results for Example 1 utilizing the procedure of Example 6, gave a result of &amp;lt;5 ppm of codeinone and 8 ppm of 14-hydroxycodeinone.
The results for Example 2 utilizing the procedure of Example 6 gave a result of &amp;lt;5 ppm of codeinone and &amp;lt;5 ppm of 14-hydroxycodeinone.
The results for Example 3 utilizing the procedure of Example 6 gave a result of &amp;lt;5 ppm of codeinone and 10 ppm of 14-hydroxycodeinone.
Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone, Chapman, et al., Robert Chapman, Lonn S. Rider, Qi Hong, Donald Kyle, Robert Kupper, Application number 11 729-741, Drug Bio-Affecting And Body Treating Compositions, Organic Compounds -- Part Of The Class 532-570 Series, oxycodone hydrochloride, present invention relates, Patent Search, present invention provides, Patent Agent, dosage form, Purdue Pharma L.P, generic version, Rhode Island, Purdue Pharmaceuticals
The present invention relates to a process for reducing the amount of 14-hydroxycodeinone in an oxycodone hydrochloride preparation.BACKGROUND OF THE INVENTIONOxycodone is a semi-synthetic opioid analgesic that exerts an agonist effect at specific, saturable opioid receptors in the CNS and other tissues. In man, oxycodone may produce any of a variety of effects including analgesia.Purdue Pharma L.P currently sells sustained-release oxycodone in dosage forms containing 10, 20, 40, and 80 mg oxycodone hydrochloride under the trade name OxyContin.RTM..U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912; and 5,656,295 disclose sustained release oxycodone formulations.Thebaine, a compound derived from opium, although having no medicinal use in itself, is useful as a starting material in synthetic schemes for the production of oxycodone. In other schemes, codeine can be utilized as the starting material forthe production of oxycodone. 14-hydroxycodeinone is the immediate precursor to oxycodone in these schemes.Methods of producing thebaine or 14-hydroxy substituted opium derivatives have been reported, e.g. in U.S. Pat. No. 3,894,026 and U.S. Pat. No. 4,045,440.The oxidation of codeine to codeinone, an initial step in the synthesis of opium derivatives has been reported in EP 0889045, U.S. Pat. No. 6,008,355 and in the J. Am. Chem. Soc., 1051, 73, 4001 (Findlay).The reaction of codeinone to 14-hydroxycodeinone has been reported in U.S. Pat. No. 6,008,355 and in Tetrahedron 55, 1999 (Coop and Rice).The methylation of codeinone to thebaine has been reported in Heterocycles, 1988, 49, 43-7 (Rice) and EP0889045.U.S. Pat. No. 6,177,567 describes the hydrogenation of 14-hydroxycodeinone to oxycodone by reduction with diphenylsilane and Pd(Ph3P)/ZnCl2 or with sodium hypophosphite in conjunction with a Pd/C catalyst in aqueous acetic acid.Krabnig et al. in "Optimization of the Synthesis of Oxycodone and 5-Methyloxycodone" Arch. Pharm. (1996), 329(6), (325-326) descr
buspirone hydrochloride buspirone hydrochloride contains not less Doxepin Hydrochloride Doxepin Hydrochloride an and
Effects of Carbamazepine Oxycodone Coadministration in the
Methadose Oral Concentrate methadone hydrochloride oral