WO2006023659A2 - Novel polymorphs of azabicyclohexane - Google Patents
Novel polymorphs of azabicyclohexane Download PDFInfo
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- WO2006023659A2 WO2006023659A2 PCT/US2005/029420 US2005029420W WO2006023659A2 WO 2006023659 A2 WO2006023659 A2 WO 2006023659A2 US 2005029420 W US2005029420 W US 2005029420W WO 2006023659 A2 WO2006023659 A2 WO 2006023659A2
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- addition salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the (+) optical antipode of the compound of formula 1 as prepared in Lippa et al., U.S. Patent 6,372,919 exists as a mixture of two crystalline polymorphic structures, one being the hemi-hydrate form, which is designated as polymorph form A, and the other being the anhydrous form, which is designated as polymorph form B.
- a dehydrated form designated as polymorph form C has also been found.
- polymorph form A of the (+) optical antipode of the compound of formula I in its pure crystalline structure produced in accordance with this invention is a thermodynamically stable polymorph form. Therefore, form A is the preferred crystalline form of the (+) optical antipode of the acid addition salt of the compound of formula I for formulation into pharmaceutical drug products.
- Polymorph form A may be characterized as the hemi-hydrate of acid addition salts of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. It is the hemi-hydrate crystalline form, which uniquely characterizes polymorph form A from polymorph form B and polymorph form C of acid addition salts of the compound of formula I. Polymorph form B and polymorph form C of acid addition salts of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane do not exist as hemi-hydrates.
- the polymorphs of acid addition salts of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane may also be characterized by their X-ray powder diffraction patterns (XRPD) and/or their Raman spectroscopy peaks.
- XRPD X-ray powder diffraction patterns
- the relative intensities of the X-ray powder diffraction peaks of a given polymorph may vary depending upon the crystal size of the polymorph used to determine the pattern. This is a phenomenon of preferred orientation. Preferred orientation is caused by the morphology of crystals.
- the XRPD analysis should be carried out with the sample spinning in the sample holder during XRPD analysis to reduce the preferred orientation effects.
- Samples for XPRD analysis for determination of the presence and nature of their polymorph status in accordance with this invention should be lightly ground and/or sieved to a crystal size of from about 10 to 40 microns for XPRD analysis.
- a Bragg-Brentano instrument which includes the Shimadzu system, used for the X-ray powder diffraction pattern measurements reported herein, gives a systematic peak shift (all peaks can be shifted at a given "°2 ⁇ " angle) which result from sample preparation errors as described in Chen et al.; J Pharmaceutical and Biomedical Analysis, 2001; 26, 63. Therefore, any "°2 ⁇ ” angle reading of a peak value is subject to an error of about ( ⁇ ) 0.2°.
- the X-ray powder diffraction pattern (XRPD) analyses of polymorph forms A, B and C were performed with a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Ka radiation.
- the compound as a hydrochloride salt was loaded onto the machine as a crystalline powder.
- the instrument was equipped with a long fine focus X- ray tube.
- the tube voltage and amperage were set to 40 kV and 40 mA, respectively.
- the divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm.
- Diffracted radiation was detected by a NaI scintillation detector.
- a theta-two theta continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5 to 40 °2 ⁇ was used.
- a silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6000 v. 4.1.
- Table 1 shows the peaks of the X-ray powder diffraction pattern of purified polymorph form A of the hydrochloride salt of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
- This pattern is given in terms of the "°2 ⁇ " angles of the peaks subject to the angle error set forth above.
- I/lo represents the value of the maximum peak determined by XRPD for the sample for all "°2 ⁇ " angles and I represents the value for the intensity of a peak measured at a given "°2 ⁇ " angle".
- the angle "°2 ⁇ ” is a diffraction angle which is the angle between the incident X-rays and the diffracted X-rays.
- the values for the relative intensities for a given peak set forth in percent and the "°2 ⁇ " angles where said peaks occur are given in Table 1 below.
- Table 2 shows the peaks of the X-ray powder diffraction pattern of purified polymorph form B of the hydrochloride salt of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
- the values for the relative intensities for a given peak set forth in percent and the "°2 ⁇ " angles where said peaks occur for polymorph form B of the hydrochloride salt of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystal size of about 10 to 40 microns are given in Table 2 below.
- Table 3 shows the peaks of the X-ray powder diffraction pattern of purified polymorph form C of the hydrochloride salt of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
- the values for the relative intensities for a given peak set forth in percent and the "°2 ⁇ " angles where said peaks occur for polymorph form C of the hydrochloride salt of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystal size of about 10 to 40 microns are given in Table 3 below.
- polymorph form B there are key major peaks at given angles in the XRPD of polymorph form B which are unique to polymorph form B as the hydrochloride salt having a crystal size of about 10 to 40 microns that are typically present in the XRPD pattern of polymorph form B as the hydrochloride salt irrespective of the particle size. Any of these major peaks, either alone or in any distinguishing combination, are sufficient to distinguish polymorph form B from the other two polymorph forms.
- the "°2 ⁇ " angles of these major peaks which characterize polymorph form B, subject to the error set forth above, are as follows:
- Raman spectra were obtained using a FT-Raman 960 (or 860) spectrometer (Thermo Nicolet) interfaced to an 860 FT-IR. This spectrometer uses an excitation wavelength of 1064 nm. Approximately 0.912 W of Nd: YVO 4 laser power was used to irradiate the samples. The Raman spectra were measured with an indium gallium arsenide (InGaAs) detector. The samples were pressed into pellets for analysis. A total of 128 sample scans were collected from 3600 or 3700 - 98 cm "1 at a spectral resolution of about ( ⁇ ) 4 cm "1 , using Happ-Genzel apodization.
- InGaAs indium gallium arsenide
- Wavelength calibration was performed using sulfur and cyclohexane.
- the Raman spectra peak positions given below in wavenumbers (cm "1 ) for the purified polymorph forms A, B and C of the hydrochloride salt of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are subject to an error of about ( ⁇ ) 4 cm "1 .
- Table 4 Table 5 and Table 6 provide the complete patterns of the Raman peak positions with respect to the hydrochloride salts of polymorph forms A, B and C respectively. However, there are certain key peaks, within these patterns, which are unique to each of the hydrochloride salts of these polymorphs. Any of these key peaks, either alone or in any distinguishing combination, are sufficient to distinguish one of the polymorph forms from the other two polymorph forms. These peak positions, expressed in wavenumbers (cm "1 ) for the hydrochloride salt of polymorph form A are:
- each of the crystalline polymorph forms of the acid addition salt (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane can be obtained substantially free of its other enantiomeric, geometric and polymorphic isomeric forms.
- the term "substantially free" of its other enantiomeric, geometric and polymorphic isomeric forms designates that the crystalline material is at least about 95% by weight pure in that it contains no more than about 5% w/w of its other enantiomeric, geometric and polymorphic isomeric forms.
- B and C of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, particularly as hydrochloride acid addition salts, can each be prepared substantially free of its other enantiomeric, geometric and polymorphic isomeric forms through re-crystallization of a mixture of the A and B polymorph forms produced in accordance with prior art procedures.
- polymorph form A which is the hemi -hydrate of the acid addition salt of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane
- solvent medium to dissolve a solid containing polymorph form A such as a mixture of polymorph forms A and B in an organic solvent which contains water.
- the preferred organic solvents that can be utilized in this procedure include lower alkanol solvents such as methanol, butanol, ethanol or isopropanol as well as other solvents such as acetone, dichlorom ethane and tetrahydrofuran.
- lower alkanol solvents such as methanol, butanol, ethanol or isopropanol
- other solvents such as acetone, dichlorom ethane and tetrahydrofuran.
- Polymorph form B is the anhydrous form of the acid addition salt of (+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
- Polymorph form B of the acid addition salt of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.Ojhexane can be prepared from a solid containing polymorph form A such as a mixture of polymorph forms A and B by dissolving the polymorph form A or the mixture of polymorph forms A and B, preferably as the hydrochloride salt, utilizing anhydrous conditions.
- this solid is in crystalline form and is re-crystallized by utilizing an anhydrous organic solvent. Any of the organic solvents mentioned hereinbefore can be utilized in their anhydrous form to produce polymorph form B.
- the removal of solvent to produce the crystalline form of polymorph B take place at elevated temperatures, i.e. from about 50°C to 8O 0 C, under anhydrous conditions.
- the solvent can be removed by filtering or decanting to leave polymorph form B substantially free of other polymorph forms.
- the formation of the crystallizing medium containing the mixture of forms A and B for re-crystallization can take place at elevated temperatures, if desired, i.e. from 50 0 C to 8O 0 C.
- Polymorph form C can be prepared from either polymorph form A or polymorph form B or mixtures thereof.
- Polymorph form C is prepared by extensive heating of either polymorph form A or polymorph form B, or mixtures thereof, at temperatures of at least 50 0 C, preferably from 60 0 C to 80 0 C. Heating can be continued until polymorph form C substantially free of other polymorph forms is formed. This heating can, if desired, take place over long periods of time i.e. from 12 hours to 4 days of longer, until the polymorph forms of the starting material are converted to polymorph form C substantially free of other polymorph forms.
- the acid addition salt having the crystalline structure of polymorph form C substantially free of other polymorph forms is produced by extensive heating, usually not in the presence of a solvent, of the acid addition salts of polymorph forms A and B.
- the preferred acid addition salt in this preparation is the hydrochloride acid addition salt form.
- a mixture of polymorph form A and polymorph form B containing the desired amount of each polymorph can be prepared by subjecting polymorph form A substantially free of other polymorph forms and prepared as described above to the procedure for preparation of polymorph form B described above for the period of time needed to produce the desired amount of polymorph form B.
- a mixture of polymorph form A and polymorph form C containing the desired amount of each polymorph can be prepared by subjecting polymorph form A substantially free of other polymorph forms and prepared as described above to the procedure for preparation of polymorph form C described above for the period of time needed to produce the desired amount of polymorph form C.
- a mixture of polymorph form B and polymorph form C containing the desired amount of each polymorph can be prepared by subjecting polymorph form B substantially free of other polymorph forms and prepared as described above to the procedure for preparation of polymorph form C described above for the period of time needed to produce the desired amount of polymorph form C.
- mixtures of polymorph form A and either polymorph form B or polymorph form C, polymorph form B and polymorph form C, and polymorph form A, polymorph form B and polymorph form C containing the desired amount of each polymorph can be prepared by combining the desired polymorphs substantially free of other polymorph forms and prepared as described above so that the desired mixture is obtained.
- mixtures containing specific percentages of the individual polymorphic forms of the acid addition salt of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane can be obtained.
- mixtures containing from about 10% to about 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% and up to 95-99% or greater (by weight) of polymorph form A, with the remainder of the mixture being either or both polymorph form B and polymorph form C, can be prepared.
- mixtures containing from about 10% to about 10-20%, 20-35%, 35-50%, 50-70%, 70- 85%, 85-95% and up to 95-99% or greater (by weight) of polymorph form B, with the remainder of the mixture being either or both polymorph form A and polymorph form C can be prepared.
- mixtures containing from about 10% to about 10- 20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% and up to 95-99% or greater (by weight) of polymorph form C, with the remainder of the mixture being either or both polymorph form A and polymorph form B, can be prepared.
- pseudopolymorphs can also be referred to as solvates. All of these additional forms of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are likewise contemplated by the present invention.
- the polymorph forms A, B and C of the present invention can be prepared as acid addition salts formed from an acid and the basic nitrogen group of (+)-l-(3,4- dichlorophenyO-S-azabicyclop.l.Ojhexane.
- Suitable acid addition salts are formed from acids, which form non-toxic salts, examples of which are hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate.
- Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts.
- the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; organic acid salts such as acetate, citrate, lactate, succinate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparginate, glutamate, tartrate, gluconate and the like.
- Suitable routes of administration for the above individual polymorph forms and mixtures of polymorph forms of an acid addition salt of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane include, but are not limited to, oral, buccal, nasal, pulmonary, aerosol, topical, transdermal, mucosal, injectable, slow release and controlled release delivery, although various other known delivery routes, devices and methods can likewise be employed.
- Useful parenteral delivery methods include, but are not limited to, intravenous, intramuscular, intraperitoneal, intraspinal, intrathecal, intracerebroventricular, intraarterial, and subcutaneous injection.
- Suitable effective unit dosage amounts for the above individual polymorphic forms and mixtures of polymorphic forms of an acid addition salt of (+)-l-(3,4-dichlorophenyl)- 3-azabicyclo[3.1.OJhexane for mammalian subjects may range from about 1 to 1200 mg, 50 to 1000 mg, 75 to 900 mg, 100 to 800 mg, or 150 to 600 mg.
- the effective unit dosage will be selected within narrower ranges of, for example, about 10 to 25 mg, 30 to 50 mg, 75 to lOOmg, 100 to 150 mg, 150 to 250 mg or 250 to 500 mg.
- dosages of about 10 to 25 mg, 30 to 50 mg, 75 to 100 mg, 100 to 200 (anticipated dosage strength) mg, or 250 to 500 mg are administered one, two, three, or four times per day.
- dosages of about 50-75 mg, 100-150 mg, 150-200 mg, 250-400 mg, or 400-600 mg are administered once, twice daily or three times daily.
- dosages are calculated based on body weight, and may be administered, for example, in amounts from about 0.5mg/kg to about 30mg/kg per day, lmg/kg to about 15mg/kg per day, lmg/kg to about lOmg/kg per day, 2mg/kg to about 20mg/kg per day, 2mg/kg to about lOmg/kg per day or 3mg/kg to about 15mg/kg per day.
- the individual polymorph forms and mixtures of polymorph forms of the present invention can be used for the prevention and treatment of various diseases and conditions in humans.
- depression in the case of depression, this is accomplished by administering to a patient in need of said treatment who is suffering from depression a composition containing one of the above polymorph forms substantially free of other polymorph forms or mixtures of polymorphs and an inert carrier or diluent, said composition being administered in an effective amount to prevent or treat said depression.
- a composition containing one of the above polymorph forms substantially free of other polymorph forms or mixtures of polymorphs and an inert carrier or diluent said composition being administered in an effective amount to prevent or treat said depression.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is administered in an effective amount to prevent or treat depression.
- any effective amount of such polymorph form substantially free of other polymorph forms or mixtures of polymorph forms needed to prevent or treat depression can be utilized in this composition.
- dosages of from about 0.5 mg/kg to about 5.0 mg/kg of body weight per day are used.
- amount of such polymorph form substantially free of other polymorph forms or mixtures of polymorph forms in the oral unit dose to be administered will depend to a large extent on the condition of depression and the weight of the patient and of course be subject to the physician's judgment.
- the oral unit dosage form containing the given polymorph form substantially free of other polymorph forms or mixtures of polymorph forms can be preferably administered at a dosage of from about 30 mg to 300 mg per day, more preferably from about 50 mg to about 200 mg per day, administered once or twice during the day or as needed.
- the present invention includes pharmaceutical dosage forms for the above individual polymorph forms and mixtures" of polymorph forms of an acid addition salt of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
- Such pharmaceutical dosage forms may include one or more excipients or additives, including, without limitation, binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents and other conventional excipients and additives.
- compositions of the present invention can thus include any one or a combination of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives; diluents; and various other pharmaceutical additives and agents known to those skilled in the art.
- additional formulation additives and agents will often be biologically inactive and can be administered to patients without causing deleterious side effects or interactions with the active agent.
- polymorph form A is a thermodynamically stable polymorph of an acid addition salt of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Therefore, it is preferred that polymorph form A be used in pharmaceutical dosage forms without the presence of other geometrical, optical and polymorphic isomers of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane.
- polymorph forms B and C can also be included in pharmaceutical product formulations with less positive results concerning formulation and stability.
- the individual polymorph forms or mixtures of polymorph forms of the present invention can be administered in a controlled release form by use of a slow release carrier, such as a hydrophilic, slow release polymer.
- a slow release carrier such as a hydrophilic, slow release polymer.
- exemplary controlled release agents in this context include, but are not limited to, hydroxypropyl methyl cellulose, having a viscosity in the range of about 100 cps to about 100,000 cps.
- Suitable carriers common to pharmaceutical formulation technology include, but are not limited to, microcrystalline cellulose, lactose, sucrose, fructose, glucose, dextrose, other sugars, di-basic calcium phosphate, calcium sulfate, cellulose, methylcellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, other sugar alcohols, dry starch, dextrin, maltodextrin, other polysaccharides, or mixtures thereof.
- Exemplary oral unit dosage forms for use in the present invention include tablets, capsules, powders, solutions, syrups, suspensions and lozenges, which may be prepared by any conventional method of preparing pharmaceutical oral unit dosage forms.
- Oral unit dosage forms such as tablets, may contain one or more of the conventional, pharmaceutically acceptable additional formulation ingredients, including but not limited to, release modifying agents, glidants, compression aides, disintegrants, effervescent agents, lubricants, binders, diluents, flavors, flavor enhancers, sweeteners and preservatives. These ingredients are selected from a wide variety of excipients known in the pharmaceutical formulation art. Depending on the desired properties of the oral unit dosage form, any number of ingredients may be selected alone or in combination for their known use in preparing such dosage forms as tablets.
- Suitable lubricants include stearic acid, magnesium stearate, talc, calcium stearate, hydrogenated vegetable oils, sodium benzoate, leucine carbowax, magnesium lauryl sulfate, colloidal silicon dioxide and glyceryl monostearate.
- Suitable glidants include colloidal silica, fumed silicon dioxide, silica, talc, fumed silica, gypsum and glyceryl monostearate.
- Substances which may be used for coating include hydroxypropyl cellulose, titanium oxide, talc, sweeteners and colorants.
- the aforementioned effervescent agents and disintegrants are useful in the formulation of rapidly disintegrating tablets known to those skilled in the art. JThese typically disintegrate in the mouth in less than one minute, and often in less than thirty seconds.
- effervescent agent is meant a couple, typically an organic acid and a carbonate or bicarbonate.
- This example is directed to preparing the hydrochloride salt of (+)-l-(3,4 dichlorophenyl)-3-azabicyclo[3.1.0] hexane from the free base of (+)-l-
- Example 1 Duplicate samples of the hydrochloride salt of (+)-l-(3,4dichlorophenyl)-3- azabicyclo[3.1.0] hexane produced in Example 1 and containing a 50% (by weight) mixture of polymorph form A and polymorph form B were placed on informal stability to test storage in desiccators placed at ambient temperature and at 50°C in a programmable heating bloc. The samples were examined after 1 week and while both samples contained mixtures of polymorph form A and polymorph form B, the ratios observed showed some conversion of forms. The mixture subjected to ambient temperature was observed to contain 40% (by weigh) of polymorph form A and 60% (by weight) of polymorph form B (as determined by XPRD analysis?).
- Step 1 Synthesis of ⁇ -bromo-3.4-dichlorophenylacetic acid methyl ester 100 kg 3,4-dichlorophenylacetonitrile was added in portions over 1.25 hours to a mixture of 12 kg water and 140 kg 98% sulfuric acid. Exotherm was allowed to 65°C maximum, and the reaction mix was maintained at 60-65 0 C for 30 minutes. After cooling to 50 0 C, 80 kg methanol was slowly added over 25-30 minutes. The mixture was warmed to 92-98 0 C, and maintained at this temperature for an additional three hours. After cooling to 35 0 C, the reaction mixture was quenched into an agitated mixture (precooled to 0-5 0 C) of 150 L ethylene dichloride and 250 L water.
- the reactor and lines were washed with water into the quench mix, which was agitated 5 minutes and allowed to stratify.
- the lower organic phase was separated, and the aqueous phase washed with 2 x 150 L ethylene dichloride.
- the combined organic phases were washed with 100 L water and then with aqueous sodium carbonate (3 kg sodium carbonate in 100 L water).
- the solution of crude ester was azeotropically "dried" in vacuo at 60-620C, resulting in the collection of 100 L ethylene dichloride. A theoretical yield was assumed without isolation and the solution was used "as is" in the following bromination reaction.
- the mixture was allowed to stratify, the lower organic phase was separated and the aqueous phase was washed with 50 L ethylene dichloride.
- the combined organic phases were washed with aqueous thiosulfate (5.0 kg sodium thiosulfate in 150 L water), aqueous sodium carbonate (2.5 kg sodium carbonate in 150 L water), and dilute hydrochloric acid (5.4 L 32% HCI in 100 L water).
- the organic phase was line-filtered and distilled in vacuo to "dryness" (full vacuum to 83°C). Residual ethylene dichloride was chased with 20 kg toluene (full vacuum at 83°C).
- Step 2 Synthesis of l-(3,4-dlchlorophenyl-l,2-cvclopropane-dicarboxylic acid dimethyl ester
- the crude ⁇ -bromo-3,4-dichlorophenylacetic acid methyl ester from Step 1 was mixed well with 55.6 kg methyl acrylate, and then the mixture was added to a precooled (- 2°C) mixture of 54.4 kg potassium methoxide in 500 L toluene (argon blanket) over 5.5 hours with good agitation and maintained at ⁇ +10°C.
- the cold reaction mixture was quenched into a mix of 250 L water and 30 kg 32% hydrochloric acid with good agitation. 200 L water and 2.5 kg potassium carbonate were added to the mixture with good agitation for an additional 30 minutes. After stratification, the lower aqueous phase was separated, and 150 L water and 1.0 kg potassium carbonate were added to the organic phase. The mixture was agitated 5 minutes and stratified. The lower aqueous phase was separated and discarded, as well as the interfacial emulsion, and the organic phase was washed with 100 L water containing 1 L 32% hydrochloric acid.
- Step 3 Synthesis of l-(3.4-dichlorophenvD-l,2-cvclopropane-dicarboxylic acid
- 120 kg ethyl acetate was added, and the mix warmed to 40-50 0 C to effect solution.
- the lower aqueous phase was separated and washed with 20 kg ethyl acetate.
- the l-(3,4- dichlorophenyl)-l,2-cyclopropane-dicarboxylic acid cake was washed with cold ethylene dichloride (2 x 5 L), followed by ambient ethylene dichloride (4 x 5 L).
- the dicarboxylic acid product was suction dried for 15 minutes and air-dried on paper (racks).
- Step 4 Synthesis and Recrvstallization of l-(3,4-dichlorophenylV3-azabicyclo[3.1.0] hexane-2.4-dione
- the slurry of l-(3,4-dichlorophenyl)-l,2-cyclopropane-dicarboxylic acid (from Step 3) was added to 45.6 kg warm (68°C) formamide, and residual ethyl acetate was distilled with full vacuum at 68-73°C.
- An additional 14.4 kg formamide was added to the mixture, followed by 11.2 kg of the dicarboxylic acid (derived from the disodium salt, Step 3).
- An argon blanket on the mixture was maintained for the following operation.
- the mixture was agitated 15 minutes at 73-75 0 C to effect a complete solution, and then heated over a 1 hour period to 140-145°C and maintained at this temperature for an additional 2.25 hours. Heating was discontinued, and the mixture was cooled to 7O 0 C and 10 L water containing 20 ml 32% HCI was slowly added over 30 minutes. The mixture was seeded and crystallization commenced. An additional 20 L water was slowly added to the heavy suspension over a 2 hour period. After standing overnight at ambient conditions, the mixture was agitated for 1.25 hours at ambient temperature and then suction-filtered (Nutsche).
- the clear light yellow solution was concentrated in vacuo at 75-80°C to 100 L final volume and slowly cooled, with seeding at 7O 0 C.
- the heavy crystalline suspension was cooled to -5°C, held 30 minutes at this temperature and suction-filtered (Nutsche).
- the cake of purified l-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane-2,4-dione was washed with 2 x 10 L cold (-10 0 C) toluene, and then 2 x 20 L hexane. After suction drying for 30 minutes, the 2,4-dione product was dried in vacuo ( ⁇ 62°C).
- [3.1.0]hexane hydrochloride BH3-THF complex is charged into a 2 L addition funnel (9 x 2 L, then 1 x 1.5 L) and drained into a 50 L flask. 1000 g of ( ⁇ )-l-(3,4 dichlorophenyl)-3-azabicyclo[3.1.0]-hexane-2,4-dione is dissolved in 2 L of THF and added to the BH3-THF dropwise over a period of 2 hours. The reaction mixture is heated to reflux and held at this temperature overnight. The mixture is then cooled to ⁇ 10°C, adjusted to pH 2 with the addition of 1200 mL of 6N HCI dropwise at ⁇ 20°C, and stirred for a minimum of 1 hour.
- the reaction mixture is then transferred to a 10 L Buchi flask, concentrated to a milky white paste, and transferred again to a 5 -gallon container.
- the mixture is diluted with 4 L of cold water and adjusted to pH 10 with 2000 mL of a 25% sodium hydroxide solution. A temperature of ⁇ 20°C is maintained. Following this, 4.5 L of ethyl acetate is added and the mixture is stirred for 15 minutes. The solution is then filtered through a 10 inch funnel with a filter cloth and washed with ethyl acetate (2 x 250 mL).
- the filtrate is then transferred into a 40 L separatory funnel and the phases are allowed to separate. Each phase is then drained into separate 5-gallon containers. The aqueous layer is returned to the 40 L separatory funnel and extracted with ethyl acetate (2 x 2 L). The organic phases are combined. The aqueous layer is discarded.
- HCI gas is bubbled through a 12 L flask containing 10 L of ethyl acetate to make an approximately 2.3 M solution of HCI/ethyl acetate.
- This HCI/ethyl acetate solution is added to the oil dropwise at a rate that maintains a temperature of ⁇ 20°C using an ice/water bath.
- the solution is then stirred at ⁇ 10°C for a minimum of 2 hours in the ice/water bath.
- the material is chilled in a cold room overnight.
- the material is then filtered through a 18.5 cm funnel utilizing a filter pad and transferred to a 22 L flask.
- the solution is then stirred at room temperature for 1 hour.
- the solution is then chilled to 4°C with an ice/water bath and stirred for 3.75 hours.
- the product is then placed in a cold room overnight.
- the solids are then filtered through a 13 inch filter using a filter cloth and washed with ethyl ether (3 x 633 mL).
- the product is then air dried for 2 hours.
- the L-(-)-dibenzoyl tartaric acid solution in methanol is added via addition funnel to the reactor containing the filtrate, over a period of approximately 1 hour, maintaining the temperature at 15-25°C. After the addition is complete the mixture is stirred for approximately 16 hours at 15-25°C. Following stirring, 50 L of methanol is added to the mixture and it is stirred again for 30 additional minutes. The resulting solids are filtered onto a plate filter. The solids are then washed with methanol (3 x 5 L) and pressed dry. The crude solids are weighed and transferred to a 50-gallon reactor to which 80 L of methanol is added. The mixture is heated to reflux and stirred at reflux for approximately 30 minutes.
- the mixture is then cooled to 15-20 0 C and stirred at this temperature for approximately 2 hours.
- the resulting solids are filtered onto a plate filter using a polypropylene filter cloth.
- the cake is washed with methanol (3 x 5 L) and pressed dry.
- the solids are transferred to a tarred 5-gallon container and weighed (yield ⁇ 20 kg).
- the solids are then added (over a period of approximately 1 hour) to a 50 gallon reactor vessel containing 60 L of 15% NaOH while maintaining the temperature at approximately 20°C. Once the addition of the solids is complete the reaction mixture is stirred for approximately 19 hours.
- HCl gas is bubbled through 12 L of ethyl acetate to make an approximately 2.3 M solution of HCI/ethyl acetate.
- the solution is adjusted to exactly 2.3 M by adding either ethyl acetate or HCI gas. 8.2 L of the 2.3 M solution of HCI/ethyl acetate is added (over a period of approx.
- Step 6a Recrystallization of (+)-l-(3.4-dichloroPhenyl)-3-azabicvclor3.1.01hexane hydrochloride from isopropanol
- the solids (from Step 6, above) are transferred to a 50-gallon reactor and isopropanol is added (8-10 mL/g of solid). The mixture is heated to reflux. The solution is filtered through an in-line filter into another 50 gallon reactor. The solution is cooled to 0 to -5°C and maintained at this temperature with stirring for approximately 2 hours. The resulting solids are filtered onto a plate filter using a polypropylene filter cloth. The solids are then washed with ethyl acetate (2 x 2 L), acetone (2 x 2 L) and ethyl ether (2 x 2 L). The solids are dried under vacuum.
- (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride is transferred into clean, tarred drying tray(s).
- the tray(s) are placed in a clean, vacuum drying oven.
- the product is dried at 50°C to constant weight.
- the material is dried for a minimum of 12 hours at ⁇ 10mm Hg.
- This product was a mixture of polymorph form A and polymorph form B, with each polymorph present in the mixture in an amount of about 50% by weight. This product was used as the starting material for Examples 4 through 8 below.
- Example 6 51 mg of the 50% by weight mixture of polymorph form A and polymorph form B of the hydrochloride salt of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane was weighed into a vial. The vial was covered with aluminum foil perforated with pinholes and placed in an oven at 8O 0 C for 4 days to produce the pure polymorph C crystals of the hydrochloride salt of (+)-l-(3, 4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as demonstrated by Raman spectroscopy and XRPD analysis as described above.
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05785506A EP1786417A4 (en) | 2004-08-18 | 2005-08-17 | Novel polymorphs of azabicyclohexane |
KR1020137024105A KR20130108489A (en) | 2004-08-18 | 2005-08-17 | Novel polymorphs of azabicyclohexane |
BRPI0515193-7A BRPI0515193A (en) | 2004-08-18 | 2005-08-17 | new azabicyclohexane polymorphs |
JP2007528015A JP2008510715A (en) | 2004-08-18 | 2005-08-17 | A new polymorph of azabicyclohexane |
AU2005277351A AU2005277351A1 (en) | 2004-08-18 | 2005-08-17 | Novel polymorphs of azabicyclohexane |
KR1020127030289A KR20130004370A (en) | 2004-08-18 | 2005-08-17 | Novel polymorphs of azabicyclohexane |
CA002619817A CA2619817A1 (en) | 2004-08-18 | 2005-08-17 | Thermodynamically stable polymorph of an azabicyclohexane |
MX2007001827A MX2007001827A (en) | 2004-08-18 | 2005-08-17 | Novel polymorphs of azabicyclohexane. |
IL181185A IL181185A (en) | 2004-08-18 | 2007-02-06 | Composition containing polymorphs a, b and c of azabicyclohexane, said polymorphs, process for their preparation and pharmaceutical compositions containing them |
NO20071372A NO20071372L (en) | 2004-08-18 | 2007-03-14 | New polymorphs of azabicyclohexane |
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US92074804A | 2004-08-18 | 2004-08-18 | |
US10/920,748 | 2004-08-18 |
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WO2006023659A2 true WO2006023659A2 (en) | 2006-03-02 |
WO2006023659A3 WO2006023659A3 (en) | 2006-12-07 |
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PCT/US2005/029420 WO2006023659A2 (en) | 2004-08-18 | 2005-08-17 | Novel polymorphs of azabicyclohexane |
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EP (1) | EP1786417A4 (en) |
JP (1) | JP2008510715A (en) |
KR (3) | KR20070054208A (en) |
CN (1) | CN101052393A (en) |
AU (1) | AU2005277351A1 (en) |
BR (1) | BRPI0515193A (en) |
CA (1) | CA2619817A1 (en) |
IL (1) | IL181185A (en) |
MX (1) | MX2007001827A (en) |
NO (1) | NO20071372L (en) |
NZ (1) | NZ589033A (en) |
RU (1) | RU2007109817A (en) |
WO (1) | WO2006023659A2 (en) |
ZA (1) | ZA200701570B (en) |
Cited By (6)
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EP2061318A1 (en) * | 2006-04-28 | 2009-05-27 | DOV Pharmaceutical, Inc. | Process for the synthesis of (+) and (-) -1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
US8138377B2 (en) | 2006-11-07 | 2012-03-20 | Dov Pharmaceutical, Inc. | Arylbicyclo[3.1.0]hexylamines and methods and compositions for their preparation and use |
US8765801B2 (en) | 2004-08-18 | 2014-07-01 | Euthymics Bioscience, Inc. | Polymorphs of azabicyclohexane |
US8877798B2 (en) | 2005-07-27 | 2014-11-04 | Neurovance, Inc. | 1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders |
US9133159B2 (en) | 2007-06-06 | 2015-09-15 | Neurovance, Inc. | 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments |
US9708261B2 (en) | 2015-06-17 | 2017-07-18 | Neurovance, Inc. | Crystalline compounds |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2834713A1 (en) * | 2010-12-03 | 2012-06-07 | Anthony Alexander Mckinney | Preparation and use of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in the treatment of conditions affected by monoamine neurotransmitters |
JP2016518406A (en) * | 2013-05-07 | 2016-06-23 | ユーシミクス・バイオサイエンス・インコーポレイテッドEuthymics Bioscience,Inc. | Use of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane to treat addictive and alcohol related disorders |
KR101567003B1 (en) | 2013-12-27 | 2015-11-06 | 경희대학교 산학협력단 | Fixing Device for Splinters of a Bone and Drill Assembly for Cutting Splinters of a Bone |
Family Cites Families (2)
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US4435419A (en) * | 1981-07-01 | 1984-03-06 | American Cyanamid Company | Method of treating depression using azabicyclohexanes |
US6372919B1 (en) * | 2001-01-11 | 2002-04-16 | Dov Pharmaceutical, Inc. | (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as an anti-depressant agent |
-
2005
- 2005-08-17 EP EP05785506A patent/EP1786417A4/en not_active Withdrawn
- 2005-08-17 ZA ZA200701570A patent/ZA200701570B/en unknown
- 2005-08-17 WO PCT/US2005/029420 patent/WO2006023659A2/en active Application Filing
- 2005-08-17 RU RU2007109817/04A patent/RU2007109817A/en not_active Application Discontinuation
- 2005-08-17 KR KR1020077006293A patent/KR20070054208A/en not_active Application Discontinuation
- 2005-08-17 MX MX2007001827A patent/MX2007001827A/en active IP Right Grant
- 2005-08-17 CN CNA2005800279269A patent/CN101052393A/en active Pending
- 2005-08-17 AU AU2005277351A patent/AU2005277351A1/en not_active Abandoned
- 2005-08-17 CA CA002619817A patent/CA2619817A1/en not_active Abandoned
- 2005-08-17 BR BRPI0515193-7A patent/BRPI0515193A/en not_active IP Right Cessation
- 2005-08-17 NZ NZ589033A patent/NZ589033A/en not_active IP Right Cessation
- 2005-08-17 JP JP2007528015A patent/JP2008510715A/en active Pending
- 2005-08-17 KR KR1020137024105A patent/KR20130108489A/en not_active Application Discontinuation
- 2005-08-17 KR KR1020127030289A patent/KR20130004370A/en not_active Application Discontinuation
-
2007
- 2007-02-06 IL IL181185A patent/IL181185A/en not_active IP Right Cessation
- 2007-03-14 NO NO20071372A patent/NO20071372L/en not_active Application Discontinuation
Non-Patent Citations (1)
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Also Published As
Publication number | Publication date |
---|---|
JP2008510715A (en) | 2008-04-10 |
AU2005277351A1 (en) | 2006-03-02 |
KR20130108489A (en) | 2013-10-02 |
IL181185A (en) | 2012-10-31 |
IL181185A0 (en) | 2007-07-04 |
EP1786417A2 (en) | 2007-05-23 |
KR20130004370A (en) | 2013-01-09 |
NZ589033A (en) | 2012-06-29 |
WO2006023659A3 (en) | 2006-12-07 |
EP1786417A4 (en) | 2009-05-20 |
KR20070054208A (en) | 2007-05-28 |
BRPI0515193A (en) | 2008-07-08 |
NO20071372L (en) | 2007-05-18 |
CA2619817A1 (en) | 2006-03-02 |
RU2007109817A (en) | 2008-09-27 |
CN101052393A (en) | 2007-10-10 |
MX2007001827A (en) | 2007-04-23 |
ZA200701570B (en) | 2008-08-27 |
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