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Levalbuterol hydrochloride polymorph aRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Nitrogen Containing Other Than Solely As A Nitrogen In An Inorganic Ion Of An Addition Salt, A Nitro Or A Nitroso Doai, Benzene Ring Containing, Amino Nitrogen Attached To Aryl Ring Or Aryl Ring System By An Acyclic Carbon Or Acyclic ChainLevalbuterol hydrochloride polymorph a description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050272821, Levalbuterol hydrochloride polymorph a. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefits of U.S. Provisional Patent Application Nos. 60/573,025, filed May 20, 2004, 60/577,979, filed Jun. 7, 2004, 60/646,803, filed Jan. 25, 2005, 60/577,819, filed Jun. 7, 2004, 60/583,777, filed Jun. 28, 2004, 60/583,642, filed Jun. 28, 2004, 60/587,673, filed Jul. 13, 2004 and 60/632,625, filed Dec. 2, 2004, the contents of all of which are incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention encompasses processes for the preparation of levalbuterol hydrochloride Polymorph A and to pure forms thereof. BACKGROUND OF THE INVENTION [0003] Activation of .beta..sub.2-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 chemical name for levalbuterol HCl is (R)-.alpha..sup.1-[[(1,1-dimethylethyl)amino]methyl]-- 4-hydroxy-1,3-benzenedimethanol hydrochloride. [0004] Levalbuterol HCl has been synthesized 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. 1 [0005] Thereafter, the crystal undergoes debenzylation deprotection, followed by ester reduction to yield levalbuterol. [0006] 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, the collected organic layer is dried and levalbuterol free base crystallizes overnight. The crystalline levalbuterol free base is dissolved in anhydrous alcohol, followed by addition of HCl to obtain crystalline levalbuterol HCl. Also, levalbuterol HCl is synthesized by acid displacement from (R)-albuterol D-dibenzoyltartaric acid salt suspended in acetone and the addition of an ether solution of HCl. [0007] Despite the many attempts of the prior art to synthesize pure levalbuterol, still novel synthetic processes of preparing polymerically pure levalbuterol are needed to reduce the steps necessary for synthesis. SUMMARY OF THE INVENTION [0008] The invention encompasses processes for making levalbuterol HCl Polymorph A comprising suspending or forming a first slurry of (R)-SLB(D)-DBTA (((R)(-).alpha..sup.1-[[(1,1-dimethylethyl)amino]methyl]-- benzenedimethanol.(D)-Dibenzoyltartrate) in at least a first organic solvent; adding HCl to the suspension or slurry of the solid (R)-SLB.D-DBTA until the (R)-SLB.D-DBTA forms pure levalbuterol HCl Polymorph A; and isolating the pure levalbuterol HCl Polymorph A. The first solvent may be at least one linear or branched C.sub.3-C.sub.10 ester, linear or branched C.sub.3-C.sub.10 ketone, linear or branched C.sub.3-C.sub.10 ether, C.sub.6-C.sub.10 aromatic hydrocarbon, linear or branched C.sub.1-C.sub.4 alcohol, dimethylsulfoxide, dimethylformamide, methylene chloride, or acetonitrile. Preferably, the first solvent is at least one of ethyl acetate, tetrahydrofuran, dimethyl carbonate, acetonitrile, toluene, methanol, dimethylsulfoxide, or dimethylforamide. [0009] Preferably, the process further comprises chemical purification of the pure levalbuterol HCl Polymorph A by suspending or forming a second slurry of the pure levalbuterol HCl Polymorph A in a second solvent; and isolating the pure levalbuterol HCl Polymorph A. Preferably, the second solvent comprises 95% ethylacetate and about 5% methanol by volume. [0010] The invention also encompasses processes for making pure levalbuterol HCl Polymorph A by the conversion of levalbuterol HCl Polymorph B into pure levalbuterol Polymorph A comprising forming a slurry or suspension of levalbuterol HCl Polymorph B with a first organic solvent mixture as described above; and isolating pure levalbuterol Polymorph A from the slurry or suspension. [0011] The invention also encompasses levalbuterol HCl polymorph A having levalbuterol HCl Polymorph B in an amount of not more than about 5% by weight. Preferably, the levalbuterol HCl Polymorph A has levalbuterol HCl Polymorph B present in an amount of not more than 3%, and more preferably, in an amount of not more than 1% by weight. BRIEF DESCRIPTION OF THE FIGURES [0012] FIG. 1 illustrates levalbuterol HCl Polymorph A in a crystalline particle size having a maximum particle size of about 150 microns. DETAILED DESCRIPTION OF THE INVENTION [0013] The present invention relates to the solid state physical properties of levalbuterol HCl. These properties can be influenced by controlling the conditions under which levalbuterol HCl is obtained in 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 processing into a pharmaceutical product. When particles of the powdered compound do not 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 use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate. [0014] 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 imposes 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. [0015] 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, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. [0016] As used herein, the term: "(R)-SLB(D)-DBTA" refers to R enantiomer of albuterol D-DBTA complex. [0017] Polymorph A may be characterized either by x-ray diffraction (XRD); infrared spectroscopy; or by differential scanning calorimetry (DSC). Polymorph A is characterized using x-ray diffraction by peaks at 10.7, 15.3, 15.6, 19.1, and 23.9 degree two-theta, .+-.0.2 two-theta. Polymorph A may be further characterized using x-ray diffraction peaks at 6.9, 20.7, 27.4, and 32.4 degree two-theta, .+-.0.2 two-theta. Alternatively, Polymorph A is characterized by infrared peaks at 3534, 3414, 3087, 1437, 1304, and 1087 cm.sup.-1. Polymorph A may be further characterized by IR peaks at 2979, 2797, 1613, 1547, 1505, 1481, 1397, 1365, 1325, 1243, 1199, 1152, 1109, 1076, 1056, 1030, 990, 920, 839, 792, and 640 cm.sup.-1. Polymorph A is characterized by DSC data having one endothermic peak due to melting at about 171.degree. C. to 193.degree. C. Polymorph A is also characterized by a Loss On Drying (L.O.D.) of about 0.09% to 1.2% or a water content of 0.09 to 0.3% by weight. [0018] The amount of levalbuterol HCl Polymorph B present in the Polymorph A can easily be determined by comparing the characteristic peak at 8.7 degree two-theta in an X-ray diffraction pattern. As used herein, the term "pure levalbuterol HCl Polymorph A" refers to levalbuterol HCl Polymorph A having levalbuterol HCl Polymorph B in an amount less than about 5% by weight. Preferably, the levalbuterol HCl Polymorph A does not contain more than 3% of levalbuterol HCl Polymorph B, and most preferably not more than 1% by weight. Continue reading about Levalbuterol hydrochloride polymorph a... Full patent description for Levalbuterol hydrochloride polymorph a Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Levalbuterol hydrochloride polymorph a patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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