Patent Application
20070281957
The present invention describes several novel polymorphic forms of levorphanol, and methods of making them.
Several crystalline forms of levorphanol were prepared and subsequently characterized. These crystalline forms include three non-solvated/non-hydrated polymorphs (herein denoted Forms I, II, and IX), an acetonitrile solvate (Form III), a methylene chloride solvate (Form IV), two chloroform solvates (Forms V and VI), a methyl alcohol solvate (Form VII), and hydrated polymorphs (Forms VIII and X). The methods used to produce each of the crystalline forms from levorphanol base and/or levorphanol tartrate are set forth in Table 1. Each crystalline form exhibited a distinctly different powder X-ray diffraction pattern.
A TA Instruments Q100—differential scanning calorimeter was used. The samples were weighed into an aluminum, hermetic sample pan and were crimped with a pinhole lid. The samples were heated from 25° C. to 220° C. at a rate of 10° C. per minute (unless otherwise noted).
Form I was discovered to melt/decompose at a temperature of approximately 200° C. by DSC and hot-stage microscopy, while Form II was observed to first melt/recrystallize from 160° C. to 180° C., and then melt/decompose at approximately 200° C.
Form II exhibited a series of phase transitions (melt and recrystallization—conversion of one crystalline form to another) from approximately 160° C. to 180° C. by DSC. Different scanning rates were observed to have a dramatic effect on these transitions. Form II exhibited an exothermic transition likely associated with recrystallization (following desolvation) by DSC. The sample appeared to melt/decompose at approximately 200° C. These transitions were confirmed by hot-stage microscopy.
Form III exhibited a broad endothermic transition from 80-145° C., and was discovered to melt/decompose at approximately 200° C.
Form IV exhibited consecutive endothermic/exothermic transitions from 100-170° C. Final melting/decomposition occurred in an endothermic transition at approximately 200° C.
Form V exhibited several overlapping endothermic/exothermic transitions from 60-145° C. Final melting/decomposition occurred in an endothermic transition from 175-200° C.
Form VI exhibited two endothermic transitions from 100-150° C. Final melting/decomposition occurred in an endothermic transition at approximately 200° C.
Form VII exhibited a small endothermic transition from 145-155° C. Final melting/decomposition occurred in an endothermic transition at approximately 200° C.
Form VIII exhibited two exothermic transitions subsequent to desolvation, including a broad endothermic transition from 30-100° C., and a small exothermic transition from 145-155° C. Final melting/decomposition occurred in an endothermic transition at approximately 200° C.
Form IX exhibited an exothermic transition from 145-155° C. Final melting/decomposition occurred in an endothermic transition at approximately 200° C.
For Form X, no DSC data was collected.
A TA Instruments Q50—thermogravimetric analyzer equipped with a quartz lined evolved gas furnace was used to conduct thermogravimetric analysis-Fourier transform infrared spectroscopy (TGA-FTIR). The furnace was coupled to a Nicolet Nexus 470 equipped with a TGA interface furnace, gas cell, and transfer line. The samples were heated from 10° C. per minute to approximately 200° C. (unless otherwise noted). The transfer line and TGA interface furnace were held at 150° C. A total nitrogen flow rate of 50 mL/min was used for all experiments. A Gram-Schmidt plot/analysis was attained for the experiments, with individual spectra of evolved gases analyzed as follows: 16 scans, 8 cm−1. A background (16 scans) was acquired prior to analyses.
Form I and Form II exhibited no loss of mass associated with a bound solvent by TGA, prior to sublimation above 135° C.
Form III exhibited 6-7% loss of mass from 80-145° C. The lost material was identified as acetonitrile by TGA-FTIR. This sample is therefore present, at least in part, as an acetonitrile solvate.
Form IV exhibited a 7-8% loss of mass from 110-140° C. The lost material was identified as methylene chloride by TGA-FTIR. This sample is therefore present, at least in part, as a methylene chloride solvate.
Form V exhibited two consecutive losses from 50-150° C., for a total loss of approximately 18%. The lost material was identified as chloroform by TGA-FTIR. This sample is therefore present, at least in part, as a chloroform solvate.
Form VI exhibited a 9-11% loss of mass from 80-140° C. The lost material was identified as chloroform by TGA-FTIR. This sample is therefore present, at least in part, as a chloroform solvate.
Form VII exhibited a 1-2% loss of mass from 80-150° C. The lost material was identified as methyl alcohol by TGA-FTIR. This sample is therefore present, at least in part, as a methyl alcohol solvate.
Form VIII exhibited losses of mass of 1.4% from 40° C. to 130° C. and approximately 2% from 30-100° C. The lost material was identified as water by TGA-FTIR, thus indicating that Form VIII is a hydrated crystalline form.
Form IX exhibited no significant loss of mass prior to sublimation, which occurred above approximately 135° C.
No TGA data was collected for Form X. Single crystal x-ray structure indicated a 1:1 molar ratio between levorphanol base and water. Form X is therefore a monohydrate crystalline form (approximately 4.2% water, by mass).
Analysis was conducted using a Siemens D500 X-ray Diffractometer. Samples of each of Forms I-X were uniformly crushed with a spatula edge, and placed on a quartz, zero-background holder. The following instrument parameters were utilized: Scan range −2.0 to 40.0°2θ, Step size—0.02°2θ, Scan time per step −1.0 seconds, Radiation source—copper Kα (1.5406 Å), X-ray tube power—40 kV/30 mA. The results are shown in
Additional information obtained from the powder X-ray diffraction analysis of Forms I-X is set forth in Tables 2-11. Crystalline levorphanol forms having at least four of the peaks indicated by an asterix (±0.2 deg 2θ) within any one of Tables 2-11 are preferred embodiments of the invention. More preferable are forms having at least eight of the peaks that are indicated by an asterix (±0.2 deg 2θ). Even more preferable are forms having at least ten of the peaks that are indicated by an asterix (±0.2 deg 2θ). Most preferable are forms having all of the peaks that are indicated by an asterix (±0.2 deg 2θ).
In accordance with the present invention, these novel crystalline polymorphs of levorphanol may be prepared as pharmaceutical compositions that are particularly useful for the management of pain, particularly chronic and/or severe pain. Such compositions comprise one of the new polymorphic forms of levorphanol with pharmaceutically acceptable carriers and/or excipients that are known to those skilled in the art.
Preferably, these compositions are prepared as medicaments to be administered orally. Suitable forms for oral administration include tablets, compressed or coated pills, hard or gelatin capsules, sub-lingual tablets, syrups, and suspensions. While one of skill in the art will understand that dosages will vary according to indication, age of patient, etc., generally the polymorphic forms of levorphanol of the present invention will be administered from about 2 mg to about 4 mg every 4-6 hours, for a total of about 8 mg to about 24 mg per day, and preferably from about 12 mg to about 20 mg per day.
Additional uses for the crystalline polymorphs described herein, as well as the compositions containing these polymorphs, and the methods of administering the compositions, are also envisioned. For example, and without limitation, the crystalline polymorphs and related pharmaceutical compositions of the present invention may also be useful in treating any conditions that may be alleviated by administration of opioid analgesics. The principles applied to the formation of the oral pharmaceutical compositions disclosed herein may also be applied to the formation of other delivery vehicles, such as sublingual, vaginal, rectal, etc.
While the present invention has been described for what are presently considered the preferred embodiments, the invention is not so limited. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the detailed description provided above.
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/810,975, filed Jun. 5, 2006, entitled “Crystalline Forms of Levorphanol” which is incorporated herein in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 60810975 | Jun 2006 | US |
