PROCESS FOR THE FORMATION OF HYDROCODONE BITATRATE
20170327511 · 2017-11-16
Assignee
Inventors
Cpc classification
C07D489/00
CHEMISTRY; METALLURGY
A61K31/00
HUMAN NECESSITIES
International classification
Abstract
There is provided a novel process for the preparation of a hydrocodone salt. In particular, there is provided a novel process for the preparation of a free-flowing slurry of a hydrocodone salt, for example, a free-flowing slurry of hydrocodone bitartrate hemipentahydrate.
Claims
1. A process for the formation of hydrocodone bitartrate, which process comprises the steps: (i) providing a solution comprising hydrocodone and a first portion of tartaric acid; (ii) adjusting the temperature of the solution to less than about 50° C. and forming a precipitate comprising a tartaric acid salt of hydrocodone from said solution; and (iii) adding a second portion of tartaric acid to the product formed in step (ii).
2. The process as claimed in claim 1, wherein the precipitate in step (ii) is formed as a free flowing slurry.
3.) The process as claimed in claim 1, wherein the product of step (ii) comprises a tartaric acid salt of hydrocodone having a bulk density of from about 0.60 g/ml to about 0.70 g/ml.
4. The process of claim 1, wherein the product of step (ii) comprises a tartaric acid salt of hydrocodone in which at least 80% by volume of the particles of the tartaric acid salt of hydrocodone have a diameter that is from about 0.5 μm to about 2000 μm, preferably from about 1 μm to about 1000 μm.
5. The process of claim 1, wherein in step (ii) the solution of step (i) is adjusted to less than about 40° C. or less than about 30° C.
6. The process of claim 1, wherein, in step (i), the solution is heated to a temperature of from about 40° C. to about 100° C.
7. The process of claim 1, wherein, in step (i), the first portion of tartaric acid comprises from about 0.2 to about 0.8 (e.g. from about 0.4 to about 0.6) molar equivalents of tartaric acid with respect to the hydrocodone.
8. The process of claim 1, wherein the second portion of tartaric acid comprises from about 0.2 to about 0.8 (e.g. from about 0.5 to about 0.6) molar equivalents of tartaric acid with respect to the hydrocodone.
9. The process of claim 1, wherein, in the product of step (i), greater than about 90% by weight of the hydrocodone is dissolved in the solution.
10. The process of claim 1, wherein, in the product of step (ii), from about 30% to about 90% by weight of the hydrocodone is present in solid form.
11. The process of claim 1, wherein the second portion of tartaric acid is added continuously over a period of at least 0.25 hr.
12. The process of claim 1, where the total amount of tartaric acid added in step (i) and step (iii) is from about 1.0 to about 1.2 molar equivalents with respect to the hydrocodone.
13. The process of claim 1, wherein said process further comprises the step of isolating the hydrocodone bitartrate from the product of step (iii).
14. The process of claim 13, wherein said process further comprises the steps of: (i) reslurrying the hydrocodone bitartrate obtained following the isolation step in a solvent or solvent mixture; (ii) isolating the solid hydrocodone bitartrate from that slurry; and (iii) optionally repeating steps (i) and (ii) one or more times.
15. A process for the formation of a pharmaceutical composition comprising hydrocodone bitartrate which process comprises the steps: (i) obtaining hydrocodone bitartrate according to a process of claim 1; and (iii) bringing the hydrocodone bitartrate into association with one or more pharmaceutically acceptable excipients, diluents or carriers.
16. A mixture of hydrocodone bitartrate and a solvent obtainable by the process of claim 1, wherein said mixture is a free flowing slurry.
17. A pharmaceutical composition comprising hydrocodone bitartrate obtained by a process of claim 1 and one or more pharmaceutically acceptable excipients, diluents or carriers.
Description
EXAMPLES
[0103] The invention is illustrated by the following examples in which:
[0104]
[0105]
[0106]
[0107]
[0108]
Example 1
[0109] Preparation of a Free-Flowing Slurry of Hydrocodone Bitartrate Hemipentahydrate
##STR00001##
[0110] Hydrocodone free-base (636.8 g, 2.127 mol) and L-(+)-tartaric acid (159.6 g, 1.063 mol, 0.5 eq.) were dissolved in EtOH (3768 g, 4776 mL) and water (701 g, 701 mL), and the resulting mixture was heated to about 65° C. The solution was hot polish filtered (5 μm filter) and rinsed with EtOH/water and then EtOH/MeOH. The solution was cooled to about 30° C. to induce precipitation of a tartrate salt of hydrocodone in the form of a thin slurry. In another vessel L-(+)-tartaric acid (191.5 g, 1.276 mol) was dissolved in water (159.2 g, 159.2 mL), EtOH (1068 g, 1353 mL) and MeOH (63.0 g, 79.6 mL) and polish filtered at ambient temperature. This tartaric acid solution was slowly added to the slurry over about 4 hr. As the tartaric acid solution was added to the slurry, the temperature was increased to about 60° C. and then held for about 1 hr at about 60° C. after the addition was completed. The slurry was cooled at a rate of 5° C./hr to 10° C. and held for about 2 hr at 10° C.
Example 2
[0111] Isolation of Hydrocodone Bitartrate Hemipentahydrate
[0112] The slurry of hydrocodone bitartrate hemipentahydrate obtained in Example 1 was filtered. The solid was washed twice with ethanol and dried under reduced pressure (about 78 kPa) at about 20° C. for 24 hr. The solid was purged with wet nitrogen at 20° C. for 24 hr after which it was dried a second time under reduced pressure (about 78 kPa) at about 20° C. for 24 hr. This resulted in hydrocodone bitartrate hemipentahydrate as an off white crystalline solid (1031.6 g, 98%).
Example 3
[0113] Preparation of a Free-Flowing Slurry of a Hydrocodone Bitartrate Hemipentahydrate (Ethanol Reslurry)
[0114] Hydrocodone free-base (25.3 kg, 76.5 mol, 90% assay) and L-(+)-tartaric acid (5.8 kg, 38.6 mol, 0.5 eq.) were dissolved in EtOH (135.8 kg) and water (24.7 kg), and the resulting mixture was heated to about 65° C. The solution was hot polish filtered (5 μm filter) and rinsed with EtOH (26.7 kg)/water (3.3 kg) and then EtOH (30.0 kg)/MeOH (11.7 kg). The solution was hot polish filtered (5 μm filter). The combined solution was cooled to about 25° C. to induce precipitation of a tartrate salt of hydrocodone in the form of a thin slurry. In another vessel L-(+)-tartaric acid (6.9 kg, 45.9 mol, 0.6 eq.) was dissolved in water (5.8 kg), EtOH (38.7 kg) and MeOH (2.4 kg). This tartaric acid solution was slowly added to the slurry through a polish filter (5 μm filter) at ambient temperature over about 4 hr. As the tartaric acid solution was added to the slurry, the temperature was increased to 55° C. The slurry was held 1 hr at about 55° C. and cooled to about 10° C. over about 6 hr and held for about 2 hr at about 10° C. and filtered. The solid was reslurried twice with ethanol (62.1 kg) and dried under reduced pressure (about −10 psig) at about 20° C. for 24 hr. The solid was purged with wet nitrogen at 20° C. for 24 hr. This resulted in hydrocodone bitartrate hemipentahydrate as an off white crystalline solid (35.2 kg, 93%).
Example 4
[0115] Preparation of a Free-Flowing Slurry of a Hydrocodone Bitartrate Hemipentahydrate (Acetone/Water Reslurry)
[0116] Hydrocodone free-base (19.6 kg, 58.3 mol, 89% assay) and L-(+)-tartaric acid (4.4 kg, 29.2 mol, 0.5 eq.) were dissolved in EtOH (103.6 kg) and water (19.1 kg), and the resulting mixture was heated to about 65° C. The solution was hot polish filtered (5 μm filter). To the reactor was charged EtOH (43.1 kg), MeOH (8.6 kg), and water (2.6 kg) and heated to about 50° C. The solution was hot polish filtered (5 μm filter). The combined solution was cooled to about 25° C. to induce precipitation of a tartrate salt of hydrocodone in the form of a thin slurry. In another vessel L-(+)-tartaric acid (5.3 kg, 35.0 mol, 0.6 eq.) was dissolved in water (4.2 kg), EtOH (29.5 kg) and MeOH (1.7 kg). This tartaric acid solution was slowly added to the slurry through a polish filter (5 μm filter) at ambient temperature over about 4 hr. As the tartaric acid solution was added to the slurry, the temperature was held at about 30° C. The slurry was held for about 1 hr at about 30° C. and cooled to about 5° C. over about 4 hr and held for about 2 hr at about 5° C. and filtered. The solid was reslurried twice in acetone (131.9 kg)/water (8.8 kg) and dried under reduced pressure (about −10 psig) at about 20° C. for 24 hr. The solid was purged with wet nitrogen at 20° C. for 24 hr. This resulted in hydrocodone bitartrate hemipentahydrate as an off white crystalline solid (26.7 kg, 92%).
Example 5
[0117] The product of Example 4 was obtained in triplicate (Examples 5a to 5c) and subjected to particle size analysis using a Malvern Mastersizer 2000 analyser according to the process outlined above.
[0118] The dispersant used was Miglyol 812, and the instrument parameters were set as follows.
TABLE-US-00002 Parameter Value Dispersant Miglyol 812 Dispersant RI 1.450 Particle RI, Absorption 1.663, 0.1 Pump Speed 2000 (±10%) rpm Sonication 10 minutes prior to sample addition to instrument Pre-measurement Delay 2.0 Minutes Measurement Time 12 Seconds (12000 snaps) Background Time 12 Seconds (12000 snaps) Delay between measurement 60 Seconds Obscuration Limits Lower 5% and Upper 15%
[0119] The following particle size data were obtained for these products.
TABLE-US-00003 D D D % Sample (0.1) μm (0.5) μm (0.9) μm Residual Obscuration Example 3.165 14.475 58.817 0.164 8.12 5a Example 6.608 72.361 698.343 0.911 5.77 5b Example 2.201 6.932 456.24 0.389 13.78 5c
[0120] Observations:
[0121] The amount of sample weighed for each of the above samples was similar, however the % obscuration varied from 6-50%. The entire sample was added to the instrument and if the obscuration was too high then more Miglyol was added.
[0122] Particle size distribution curves for Examples 5a, 5b and 5c are shown in
Example 6
[0123] Two further samples of a product obtained according to the process of Example 4 were produced and subsequently comilled (delumped) using a comill (Examples 6a and 6b).
[0124] The products obtained by this process were subjected to particle size analysis according to the process outlined above in respect of Example 5.
[0125] The following particle size data were obtained for these products.
TABLE-US-00004 D D D % Sample (0.1) μm (0.5) μm (0.9) μm Residual Obscuration Example 2.731 18.446 91.584 0.546 8.31 6a Example 4.867 50.417 147.282 0.321 10.72 6b
[0126] Particle size distribution curves for Examples 6a and 6b are shown in
ABBREVIATIONS
[0127] Mol moles
[0128] g grams
[0129] mg milligrams
[0130] μg micrograms
[0131] eq. molar equivalents
[0132] mL millilitres
[0133] hr hours
[0134] EtOH ethanol
[0135] MeOH methanol
[0136] kPa kilopascals