ZA200605945B - Levalbuterol hydrochloride polymorph A - Google Patents
Levalbuterol hydrochloride polymorph A Download PDFInfo
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- ZA200605945B ZA200605945B ZA200605945A ZA200605945A ZA200605945B ZA 200605945 B ZA200605945 B ZA 200605945B ZA 200605945 A ZA200605945 A ZA 200605945A ZA 200605945 A ZA200605945 A ZA 200605945A ZA 200605945 B ZA200605945 B ZA 200605945B
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- OWNWYCOLFIFTLK-YDALLXLXSA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;hydron;chloride Chemical compound Cl.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 OWNWYCOLFIFTLK-YDALLXLXSA-N 0.000 title claims description 17
- 229940087642 levalbuterol hydrochloride Drugs 0.000 title description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 38
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 claims description 30
- 229950008204 levosalbutamol Drugs 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
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- 238000002441 X-ray diffraction Methods 0.000 claims description 12
- 229940093499 ethyl acetate Drugs 0.000 claims description 12
- 235000019439 ethyl acetate Nutrition 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
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- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims 1
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- MVODTGURFNTEKX-UHFFFAOYSA-N 2-bromo-n-(2-bromoethyl)-n-(thiophen-2-ylmethyl)ethanamine;hydrobromide Chemical compound Br.BrCCN(CCBr)CC1=CC=CS1 MVODTGURFNTEKX-UHFFFAOYSA-N 0.000 description 3
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- UPJKSWLLCONYMW-UHFFFAOYSA-N 5'-Adenosine monophosphate Natural products COc1cc(O)c(C(=O)C)c(OC2OC(COC3OC(C)C(O)C(O)C3O)C(O)C(O)C2O)c1 UPJKSWLLCONYMW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 101150105088 Dele1 gene Proteins 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
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- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 239000004044 bronchoconstricting agent Substances 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
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- 238000005056 compaction Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 210000003437 trachea Anatomy 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
Description
LEVALBUTEROL HYDROCHLORIDE POLYMORPH B
Cross-Refereence To Related Applications
This application claims the benefits of U.S. Provisional Patent Application Nos. 60/573,025, filed May 20, 2004, 60/577,979, filed June 7, 2004, 60/646,803, filed January 25, 2005, 60/577,819, filed June 7, 2004, 60/583,777, filed June 28, 2004, 60/583,642, filed June 28, 2004, 60/587,673, filed July 13, 2004 and 60/632,625, filed December 2, 2004, the contents of all of which ares incorporated herein by reference.
The present invention encompasses levalbuterol hydrochloride polymorph B and processes for the preparation thereof.
Activation of B,-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an. increase in the intracellular concentration of cyclic- © 3’,5’-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which_ inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levalbuterol relaxes the smooth muscles of the airways from the trachea to the terminal bronchioles.
Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. The clemical name for levalbutero] HCl is (R)-a'-[[(1,1- dimethylethyl)amino]methyl]-4-hydr-oxy-1,3-benzenedimethanol hydrochloride.
Levalbuterol HCI has been sy=nthesized using a variety of synthetic schemes. For example, Great Britain patent No.1298494 discloses synthesizing levalbuterol first by crystallizing the alkyl acetate of the 4-carboxylate derivative (Formula 1) using ditolyltartaric acid and isolating the selected crystalline fraction.
[e] OH ee
SO ao ~<C 0 oY Formula
Thereafter, the crystal undergoes debenzylation depro tection, followed by ester reduction to yield levalbuterol.
In Chinese patent No. 1,273,966, the salt of (R)-albuterol D-dibenzoyltartaric acid is treated with potassium carbonate in water and an organic solvent, such as ethylacetate.
After phase separation and extraction of the aqueous layer, th.e collected organic layer is dried and levalbuterol free base crystallizes overnight. The cxystalline levalbuterol free base is dissolved in anhydrous alcohol, followed by addition of HCI to obtain crystalline levalbuterol HCl. Also, levalbuterol HCI is synthesized by acid displacement from (R)- albuterol D-dibenzoyltartaric acid salt suspended in acetone and the addition of an ether solution of HCL
Despite the many attempts of the prior art to synthesize enantiomerically pure levalbuterol, still novel synthetic processes for preparing polymerically pure levalbuterol
HCI are needed to reduce the steps necessary for synthesis amd purification without sacrificing compound purity.
On embodiment of the invention encompasses levalbuiterol hydrochloride Form B characterized by at least one of x-ray diffraction by peaks at 8.7, 14.5, 19.0, and 19.6 degree two-theta, + 0.2 degree two-theta; IR peaks at 2970, 2 802, 1615, 1599, 1560, 1546, 1507, 1482, 1444, 1364, 1313,1199, 1151, 1111, 1094, 1034, 992, 829, 697, 653, 597, 537, and 454 cm’; or DSC curves of small endothermic event in the temperature range of 144°C to 169°C and decomposes during melting in the temperature range of 181°C to 188°C. The levalbuterol hydrochloride Form B may be further characterized by x-ray diffraction peaks at 20.6, 22.6, 30.9, and 35.0 degree two-theta, + 0.2 degree two- theta. The levalbuterol hydrochloride Form B may be further characterized by infrared peaks at 3137, 2865, 2437, 23 64, 1268, and 1071 cm”. Another embodiment of the invention encompasses levalbuterol hydrochloride Polymorph B in about 98% purity as determined by HPLC.
Another embodiment of the invention encompasses processes for preparing levalbuterol HCl Polymorph BB comprising suspending (R)-SLB(D)-DBTA ((R)(-) a’ [[(1,1-dimethylethyl)aminoJmmethyl]-benzenedimethanol.(D)-Dibenzoyitartrate in at least one solvent; adding HCI in a C-C4 alcohol to the suspension of the solid (R)-SLB(D)-
DBTA until levalbuterol HCl Polymorph B is obtained; and isolating the levalbuterol HCI
Polymorph B. The solvent includes at least one linear or branched C3-Cjg ester, linear or branched C3-Ciq ketone, lineax or branched C3-Cyg ether, Cs-Cyo aromatic hydrocarbon, or linear or branched C;-Cs alcohol.
Preferably, the solvent comprises 95% ethylacetate and about 5% methanol by volume,
Baief Description of the Drawings
Figure 1 illustrates the hygroscopicity levels of levalbuterol HCI Polymorph A and Polymorph B after a one-week exposure to various percentages of relative humidity.
Figure 2 is a charactersistic powder X-ray diffraction pattern of levalbuterol HC]
Polymorph B.
Figure 3 is a characteristic FT-IR spectrum of levalbuterol HCI Polymorph B.
Figure 4 is a characterdistic DSC curve of levalbuterol HC] Polymorph B.
One embodiment of the invention encompasses levalbuterol HCl Polymorph B.
The invention also encompasses processes for preparing levalbutero! Polymorph B with considerable simplicity and to the novel levalbuterol HCI Polymorph B obtained by using this process.
The present invention xelates to the solid state physical properties of levalbuterol
HCI. These properties can be influenced by controlling the conditions under which levalbuterol HCI is obtained ira solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during pro cessing into a pharmaceutical product. When particles of the powdered compound do newt flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the usc of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient’s stomach fluid can have therapeutic consequences since it im-poses an upper limit on the rate at which an orally-administered active ingredient can reach the patient’s bloodstream.
The rate of dissolution is also a consideration in formulating: syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. These conformational and orientational factors in turn result in particular intramolecular interactions and intermolecular interactions with adjacent molecules that influence the macroscopic properties of the bulk compound. A particular polymorphic form may give rise to distinct spectroscopic properties that may be detectable by powder
X-ray diffraction, solid state. 13C NMR spectrometry and infrared spectrometry. The polymorphic form may also give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thexmogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can "be used to distinguish some polymorphic forms from others.
As used herein, the term: "(R)-SLB(D)-DBTA" refers to R enantiomer of albuterol D-DBTA complex.
In one embodiment the invention encompasses processes for preparing levalbuterol HCl Polymorph B which comprise suspending or forming a slurry of (R)-
SLB.D-DBTA in at least one organic solvent; adding HC] with a C;-C, alcohol to the suspension or slurry of the solid SLB.D-DBTA until levalbuterol HCI Polymorph B is obtained; and isolating the levalbuterol HC] Polymorph B. Not to be limited by theory, it is believed that the process occurs by a solid to solid transformation.
The organic solvent includes, but is not limited to, at Teast one linear or branched
Cs-Cyo ester, linear or branched C3-C)o ketone, linear or branched C3-C)q ether, C¢-Cio aromatic hydrocarbon, linear or branched C,-C4 alcohol, dim ethylsulfoxide, dimethylformamide, acetonitrile, or dichloromethane. Optiomally, water is added to the solvent. Preferably, the solvent includes, but is not limited to, at least one of ethylacetate, acetone, tetrahydrofuran, dimethuylcarbonate, acetonitrile, toluene, xylene, methanol, ethanol, isopropanol, dimethylsulfoxide, or dimethylformamide. More preferably, the solvent is ethylacetate. Preferably, the ratio of the organic solvent to the C;-C4 alcohol, which is added with the HCl, is about 90% to about 10% by volume, more preferably, the ratio of solvents is about 95% to about 5% by volume, and most preferably, the ratio of solvents is about 95% ethylacetate and about 5% methanol by volume. Preferably, the solvent is present in an amount of about 5 ml/g to about 20 ml/g of the (R)-SLB.D-
DBTA.
The reaction may be carried out at temperatures of about -10°C to about 40°C, preferably the temperature is about room temperature. Alternatively, the slurry may be cooled, preferably at a temperature of about -10°C to about 10°C, more preferably at about -5°C to about 5°C, and most preferably at a about -2°C to about 2°C.
The HCl is added with a C;-C, alcohol. Preferably, the Cy-C4 alcohol is methanol.
For example, methods for adding HCI include, but are not limited to, adding aqueous HCl (37%), HCl gas, HCI in methanol, HCl in DMF, or HCl in ethereal solutions. Typically,
HCl is added in an amount of about 1.2 equivalents of HCI per equivalent of SLB.D-
DBTA.
In another embodiment, the invention encompasses levalbuterol HCl Polymorph B. Polymorph B is characterized using x-ray diffraction by peaks at 8.7, 14.5, 19.0, and 19.6 degree two-theta, + 0.2 degree two-theta. Polymorph B may be further characterized by x-ray diffraction peaks at 20.6, 22.6, 30.9, and 35.0 degree two-theta, + 0.2 degree two-theta. Alternatively, Polymorph B is characterized by infrared peaks at 3137, 2865, 2437, 2364, 1268, and 1071 cm”. Polymorph B may be further characterized by IR peaks at 2970, 2802, 1615, 1599, 1560, 1546, 1507, 1482, 1444, 1364, 1313, 1199, 1151, 1111, 1094, 1034, 992, 829, 697, 653, 597, 537, and 454 cm”. DSC curves of Levalbuterol
HCI polymorph forrn B has an additional small endothermic event in the temperature range of 144°C to 169°C and decomposes during melting in the temperature range of 181°C to 188°C. Additionally, the levalbuterol hydrochloride Polymorph B has an L.O.D. of about 0.1% or 0.6% TGA by weight or a water content of 0.12 to 0.23% by weight.
Table 1 summarizes the loss on drying (LOD) as a percentage of weight over a temperature range, as well as the water content for a sampling of polymorphs. [Sample [CrystalForm [ ~~~ TGA ~~ | Water Content
1 |B | 004 | 31-100 | 033 | 145159 | 014 2 | 2B] 015 31-102 4B [005 | dele | 054 | 13610
C5 |B | 003 [ sre | | | 016 7 |B | 006 | 33102 | 042 | 130.150 | 023 [9 1 B® | 008 | ses | 033 | 15371 | 012
Tabole 2 summarizes the hygroscopicity and crystal structure of a 100% sample of either leval buterol HC1 Polymorph A or Polymorph B after each same was individually exposed to different levels of humidity for one week. After each exposure the wvater content was determined by Thermal Gravimetric Analysis (TGA) and reported as loss on drying (LOD) as a weight percentage and the crystal structure was determined by X-ray
Diffractiom (XRD). After exposure of each sample up to about 80% relative humidity, it was determined that the water content of Polymorph A was about 0.23 to 0.97 percent and the warter content of Polymorph B was about 0.21 to 0.48 percent. After exposure of each sample at about 100% relative humidity for one week, the water content of
Polymorplm A was about 34 percent and that of Polymorph B was about 36 percent.
Table 2: Results of hygroscopicity test of levalbuterol HCI Polymorph B
RH (%) LOD (%)® (Polymorph B) Polymorph by XRD® (Polymorph TB) oo | — 0a [— ~~ 0B 00 ———-.-+iii:i...
OR A - 6 | 03% 1 BA so | 04 [© A>»B
TS I
® The water content of each individual sample of Polymorph B after being exposed tos the various levels of relative humidity (RH %), equilibrated and analyzed by thermal gravimetric analysis. ® The crystal structure of each individual sample of Polymorph B after “being exposed tos the various levels of relative humidity (RH %) of column one, equil ibrated and analyzed by x-ray diffraction.
Figzure 1 illustrates the results in graphical form, which graphs correlate: the water content by weight percentage to the increasing levels of relative humidity for a sample of levalbuterol HC] Polymorph A or Polymorph B. After exposure of each sample up to about 80% relative humidity, the water content of each sample was less than atwout one percent. For each sample after exposure at about 100% relative humidity for ome week, the water content of each sample was more than about 30%. Thus, based on the results of
Table 3 an d Figure 1, samples of Polymorph A or Polymorph B absorbed sufficient water to dissolve the polymorph after one-week exposure at 100% relative humidity. At higher relative humidities, Polymorph A was detected in samples of Polymorph B. For example, at a relative humidity of 60%, the amount of Polymorph A was greater than the amount of
Polymorph B. At 100% relative humidity, only Polymorph A was detected and
Polymorph B was not detected at all.
The heat stability of the crystal Polymorph B of levalbuterol HCl was examined using XRD. Samples of 100% Polymorph B that were stored in an oven at 160°C for about 15 or 30 minutes. After each time interval, a sample was analyzed by XRD. After about 15 minutes, levalbuterol HCl Polymorph A was detected in the sample of
Polymorph B.
While the present invention is described with respect to particular examples and preferred embodiments, it is understood that the present invention is not limited to these examples and embodiments. The present invention, as claimed, therefore includes variations from the particular examples and preferred embodiments described herein, as will be apparent to one of skill in the art.
The X-Ray diffraction (XRD) analysis was conducted using an ARL X-Ray powder diffractometer (model X"TRA-030) equipped with a PPeltier detector, round standard aluminum sample holder with round zero background, and quartz plate. The scanning parameters were from a range of about 2-40 degree two 6 (+ 0.2 degrees) and a continuous scan at a rate of about 3 degrees/min.
Fourier transform infrared (FT-IR) spectroscopy was conducted using a Perkin-
Elmer Spectrum 1000 Spectrometer at about 4 cm! resolution. with about 16 scans in the range of 4000-400 cm. Samples were analyzed in KBr pellet and the instrument was calibrated using an empty cell as a background.
Differential scanning calorimetry (DSC) was conducted using a Mettler Toledo
DSC 822%/700 with a sample weight of about 3-5 mg, a heating rate of about 10°C/min., using a 3 holed crucible, under a stream of N; at a flow rate of about 40 ml/min. The sample was scanned between a range of about 30°C to about 250°C at a heating rate of about 10°C/minute.
Thermal Gravimetric Analysis (TGA) was conducted wsing a Mettler Toledo
TGA/SDTA 851° using a sample weight of about 7-15 mg, a heating rate of about 10 °C/
min. under a N stream at a N; flow rate of about 50 ml/min. The samples were scanned at a range between about 30°C to about 250°C.
Example 1
In a 500 ml reactor equipped with a coendenser, thermometer, and mechanical stirrer loaded at room temperature and under nitrogen a suspension of wet pure (R)-
SLB.(D)-DBTA (39.73 g wet, 30 g at 100%; ©.05 moles), in ethylacetate (331 ml) was formed. The suspension was cooled to 0°C = 2°C, the temperature was maintained, and in about 5 minutes HCl (37%, 5.89 g, 0.06 moles, 1.2 eq. in MeOH 18 ml) was added.
The suspension was stirred at 0°C + 2°C for 1 hour, the solid was collected by filtration, and washed with ethylacetate (3 x 16 ml). Thee wet solid (18.1 g) was suspended in an ethylacetate and methanol mixture (90 ml, 90 :10 v/v) and the suspension was stirred at 20°C to 25°C for 4 hrs. The solid was collected by filtration and washed with ethylacetate to obtain levalbuterol HCI polymorph B (12.9 g dry weight, 94%).
Example 2
In a 250 ml reactor equipped with a condenser, thermometer, and mechanical stirrer loaded at room temperature and under mitrogen a suspension of wet pure (R)-
SLB.(D)-DBTA (20 g, 0.0335 moles) and eth ylacetate (150 ml). The suspension was cooled at 7°C to 8°C, the temperature was maintained, and in about 3 minutes HCI (34%, 3.6 g, 0.0335 moles, 1 eq. in MeOH) and ethy-lacetate (10 ml) were added.
The suspension was warmed to 15°C to 20°C and after 1 hour, the solid was collected by filtration, and washed with ethylacetate (3 x 1 0 ml), and the solid was collected by filtration. Levalbuterol Polymorph B was col lected (8.68 g).
Example 3
Table 3 also summarizes the results following example 18 of CN 1273966 and example 7 of WO 95/32178, as illustrated in Examples 1-5.
Form C, J/g
HCl in Et,0 + Et:O
EtOH-MTBE
HCl in Et,0 + MTBE
> TXtl sample 3 from According to WO 95/32178 example 7 196 (146)
EtOH-MTBE
Xtl. sample 3 from According to CN 1273966 example 19 194 (131)
EtOH-MTBE ® The starting material was a crude sample of levalbuterol base. ® The starting material was a purified sample of levalbuterol HC] A.
Claims (14)
1. Leva®buterol hydrochloride Form B characterized by at least one of x-ray” diffraction by peaks at 8.7, 14.5, 19.0, and 19.6 degree two-theta, + 0.2 degree two-Eheta; IR peaks at 2974), 2802, 1615, 1599, 1560, 1546, 1507, 1482, 1444, 1364, 1313, 1199, 1151, 1111, 1094, 1034, 992, 829, 697, 653, 597, 537, and 454 cm’; or DSC curves of small endotherrmic event in the temperature range of 144°C to 169°C and decomposses during melting Jin the temperature range of 181°C to 188°C.
2. The Revalbuterol hydrochloride Form B according to claim 1 further characterized by x-ray diffraction peaks at 20.6, 22.6, 30.9, and 35.0 degree two-the>ts, +
0.2 degree two—theta.
3. The Mevalbuterol hydrochloride Form B according to claim 1 further characterized boy infrared peaks at 3137, 2865, 2437, 2364, 1268, and 1071 cm’,
4. A preocess for preparing levalbuterol HCI Polymorph B comprising: suspending or forming a slurry of (R)-SLB(D)-DBTA in at least one solvent; adding HC] in & C;-Cy alcohol to the suspension or slurry until levalbuterol HCI Polymorph B is obtained; and isolating the levalbuterol HCl Polymorph B.
5. The process according to claim 4 further comprising adding water to the organic solvent.
6. The -process according to claim 4, wherein solvent includes at least one 1-inear or branched C3—Cy ester, linear or branched Ci-Cjq ketone, linear or branched C3-Cyg ether, C4-Co amomatic hydrocarbon, or linear or branched C,-C; alcohol.
7. The process according to claim 4, wherein the solvent includes at least o:ne of ethylacetate, acetone, tetrahydrofuran, dimethylcarbonate, acetonitrile, toluene, xyl ene, methanol, ethamol, isopropanol, dimethylsulfoxide, or dimethylformamide.
8. The process according to claim 4, wherein the ratio of the organic solverat to the C;-C,4 alcobol, which is added with the HCI, is about 90% to about 10% by voltame.
9. The process according to claim 8, wherein the ratio of the organic solvent to the C;-Cy alcohol, which is added with the HCY, is about 95% to about 5% by volume.
10. The process according to claim 8 or 9, wherein the organic solvent is ethyl acetate and the C,-C, alcohol is meethanol in a ratio of about 95% to about 5% by volume.
11. The process according to claim 4, wherein the reaction is carried out at temperature of about -10°C to about 40°C.
12. The process according to claim 4, wherein the reaction is carried out at room temperature.
13. The process according to claim 4, wherein the HCl is added as a solution or a gas in a C;-C4 alcohol.
14. The process according to claim 4, wherein the HCl is added in an amount of about 1.2 equivalents of HCI per equivalent of (R)-SLB.D-DBTA.
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| US57302504P | 2004-05-20 | 2004-05-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| ZA200605946A ZA200605946B (en) | 2004-05-20 | 2005-05-20 | Levalbuterol hydrochloride polymorph B |
| ZA200605945A ZA200605945B (en) | 2004-05-20 | 2005-05-20 | Levalbuterol hydrochloride polymorph A |
| ZA200605947A ZA200605947B (en) | 2004-05-20 | 2005-05-20 | Preparation of levalbuterol hydrochloride |
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| CN115109026A (en) * | 2022-06-28 | 2022-09-27 | 北京云鹏鹏程医药科技有限公司 | Preparation method of levalbuterol intermediate and hydrochloride with high ee value |
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