Abstract:
This invention discloses a new dihydrate polymorph of Olanzapine (hereinafter referred to as “dihydrate C”), and process for recovering anhydrous Form I of Olanzapine from this novel Dihydrate C.

Description:
FIELD OF THE INVENTION  
       [0001]     The present invention relates to novel dihydrate C of Olanzapine, and a process for its conversion to Form I of Olanzapine.  
       BACKGROUND OF THE INVENTION  
       [0002]     Olanzapine is an antipsychotic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-1OH-thieno[2,3-b][1,5]benzodiazepine.  
         [0003]     U.S. Pat. No. 5,736,541 discloses that Olanzapine can exist in two different crystalline polymorphs namely Form I and Form II, wherein the two polymorphs are characterized by their different X-ray power diffraction pattern and are represented by the following interplanar spacings and typical relative intensities as shown in Table—1.  
                                                                                 TABLE 1                           X-Ray powder diffraction spectrums of Form I and Form II                Form II       Form I                    d   I/I 1     d   I/I 1                              9.9463   100.00   10.2689   100.00           8.577   7.96   8.5579   15.18           7.4721   1.41   8.2445   1.96           7.125   6.50   6.8862   14.73           6.1459   3.12   6.3787   4.25           6.071   5.12   6.2439   5.21           4.4849   0.52   5.5895   1.10           5.2181   6.86   5.3055   0.95           5.1251   2.47   4.9815   6.14           4.9874   7.41   4.8333   68.37           4.7665   4.03   4.7255   21.88           4.7158   6.80   4.6286   3.82           4.4787   14.72   4.533   17.83           4.3307   1.48   4.4624   4.02           4.2294   23.19   4.2915   9.19           4.141   11.28   4.2346   18.88           3.9873   9.01   4.0855   17.29           3.7206   14.04   3.8254   6.49           3.5645   2.27   3.7489   10.64           3.5366   4.85   3.6983   14.65           3.3828   3.47   3.5817   4.04           3.2516   1.25   3.5064   9.23           3.134   0.81   3.3392   4.67           3.0848   0.45   3.2806   1.96           3.0638   1.34   3.2138   2.52           3.0111   3.51   3.1118   4.81           2.8739   0.79   3.0507   1.96           2.8102   1.47   2.948   2.40           2.7217   0.20   2.8172   2.89           2.6432   1.26   2.7589   2.27           2.6007   0.77   2.6597   1.86                      
 
         [0004]     It is well known from prior art that Form I of Olanzapine can be crystallized from methylene chloride. However, this is associated with problems of removing residual methylene chloride from the final product (limit of not more than 600 ppm) in spite of increasing drying temperatures around 70° C. for a sufficiently long time. This is surprising considering that methylene chloride has a relatively lower boiling point.  
         [0005]     Another problem associated with obtaining Form I of Olanzapine from methylene chloride is the formation of the following impurity: 1-Chloromethyl-1-methyl-4-(2-methyl-10H-thieno-[2,3-b][1,5]benzodiazapine-piperazinium chloride (hereinafter referred to as “impurity C”), and having the following structure:  
                         
 
         [0006]     This impurity C is difficult to remove even upon multiple re-crystallizations from methylene chloride, and in fact the level of impurity increases with each re-crystallization, as this impurity C is a product formed by the reaction of Olanzapine in methylene chloride. Thus, there is a need for finding alternate ways of making pharmaceutically acceptable Form I of Olanzapine while attempting to solve the problem of impurity C formation.  
       SUMMARY OF THE INVENTION  
       [0007]     The present invention provides a novel Dihydrate C of Olanzapine.  
         [0000]     The invention also provides for a pharmaceutical formulation comprising the novel Dihydrate C of Olanzapine.  
         [0008]     The invention further provides a process for obtaining substantially pure Form I of Olanzapine with lower organic residues comprising drying Olanzapine Dihydrate at about 40° C. to about 70° C., until the desired Form I is obtained.  
         [0009]     The instant invention also provides a novel process for obtaining substantially pure Form I of Olanzapine with lower organic residues comprising drying Olanzapine Dihydrate C. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0010]      FIG. 1 . shows a typical powder X-ray diffraction pattern of Dihydrate C of Olanzapine.  
         [0011]     Note: vertical axis represents intensity (CPS) and horizontal axis represents 2-theta degrees).  
         [0012]      FIG. 2 . shows a typical infrared spectrum of Dihydrate C of Olanzapine  
         [0013]      FIG. 3 . shows a typical differential scanning calorimetric pattern of Dihydrate C of Olanzapine 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0000]     Definitions  
         [0014]     As used herein, the term “technical grade” refers to Olanzapine having less than 5% undesired related substances. Such technical grade may contain less than about 1% undesired related substances. The term “crude” refers to form of Olanzapine having typically associated with less than 5% of undesired polymorph and/or undesired related substances. Such crude grade Olanzapine may contain less than about 1% of undesired related substances.  
         [0015]     As used herein, term “substantially pure” refers to olanzapine associated with less than 5%, preferably less than 2% and most preferably less than 1% of the other crystalline form, as may be detected by typical spectroscopic methods. Further, “substantially pure” relates to a chemical compound which preferably contains less than about 2%, more preferably less than 1%, most preferably less than 0.5% of undesired chemical impurities, i.e. unrelated substrates, residual solvents or water.  
         [0000]     Substantially Pure Olanzaoine Form I  
         [0016]     Applicants have discovered that Olanzapine Form I that is substantially free from all organic residues can be prepared using an eco-friendly process, which comprises of 
        i) Obtaining crude Form I of Olanzapine by crystallization of technical grade Olanzapine from methylene chloride     ii) treatment of crude Form I of Olanzapine with water by stirring at 25-35 C.. for about 15 minutes to about 3 hours.     iii) subsequent filtration to obtain Olanzapine Dihydrate C     iv) drying the Olanzapine Dihydrate C, for instance in a vacuum oven, at about 40° C. to about 70° C., until the desired Form I is obtained.        
 
         [0021]     Previous attempts by industry have resulted in Olanzapine Dihydrate being converted to Olanzapine form II without conversion to form I. The present inventor has successfully achieved conversion of olanzapine dihydrate to olanzapine form I, without conversion to form II. Therein lies another novelty of this invention.  
         [0022]     Surprisingly, the present inventors found that Olanzapie dihyd can be dried to obtain Olna form 1, with low organic impurities. The starting material for the present invention (technical grade of Olanzapine) can be prepared by a variety of procedures well known to those of ordinary skill in the art. The material to be employed as starting materials in the process of this invention can be prepared by general procedure as disclosed by Chakrabati in U.S. Pat. No. 5,299,382.  
         [0023]     The novel dihydrate Form C of Olanzapine, as obtained in step (iii), is clearly distinguishable by powder x-ray crystallography, infrared spectroscopy, and differential scanning calorimetry. A typical x-ray power diffraction pattern is shown in  FIG. 1 .  
         [0024]     Powder X-ray diffraction patterns were measured on a Shimadzu XDD1 diffractometer with Cu Kα radiation, 2-theta range 2 to 60 degree and recorded diffraction angle 2-theta, interplanar spacings d and relative intensity I/I 0  (scan speed 0.02 deg/sec, step 0.02 deg/sec, slit 1-1-0.3 mm). A typical powder X-ray diffraction pattern for this noval Olanzapine dihydrate C is given in the table 1.  
                                           TABLE 1                           XRD data for Olanzapine Dihydrate-C            2 Theta (deg)   D (A)   I/I 1                      8.88   9.95002   100       9.16   9.64649   12       12.6   7.01951   3       14.32   6.18002   11       14.48   6.11209   10       14.94   5.92492   2       16.28   5.44014   5       16.92   5.23577   2       18.42   4.81265   50       18.8   4.71622   13       19.54   4.53925   20       19.92   4.45351   11       20.34   4.36249   7       20.44   4.34137   4       20.76   4.27517   4       21.06   4.21494   3       22.02   4.0333   4       22.62   3.92766   9       22.96   3.87026   12       23.22   3.82751   15       23.58   3.76988   9       23.96   3.71094   19       24.16   3.68068   6       24.3   3.65979   4       24.4   3.64501   3       24.84   3.58143   6       25.42   3.50102   15       27.86   3.19969   2       28.38   3.14223   3       28.82   3.09525   2.       29.78   2.99762   2       29.9   2.98587   2       30.24   2.95306   4       30.34   2.94356   2       31.24   2.86078   3       31.54   2.83425   2       32.64   2.7412   2       33.86   2.64517   2       38.18   2.35522   2       40.58   2.22129   3       40.70   2.21502   2                  
 
         [0025]     Further characterization of Olanzapine dihydrate C by infrared spectroscopy and differential scanning calorimetry is provided in  FIG. 2  and  FIG. 3  respectively.  
         [0026]     The infrared (FT-IR) spectra were obtained in a KBR disk using a perkin Elmer FT-IR spectrometer spectrum one at resolution 4 cm −1  from 4000 to 400 cm −1 . A typical FT-IR spectra of the novel Olanzapine dihydrate C showed absorptions at the following wave numbers (cm −1 ): 3412, 3240, 3063, 2933, 2845, 2807, 1589, 1561, 1468, 1457, 1411, 1367, 1342, 1282, 1266, 1221, 1200, 1178, 1148, 1120, 1074, 1048, 1005, 971, 944, 929, 846, 818, 781, 756, 670, 509.  
         [0027]     The differential scanning calorimetry was run on Perkin Elmer DSC 7 at a scanning rate of 10° C./min. A typical differential scanning calorimetry of this novel Olanzapine dihydrate C showed endotherm at 88.5° C. due to water loss and a endotherm at 183.4° C. with imbedded exotherm due to crystal rearrangement and another endotherm at 198.0° C.  
         [0028]     It is to be noted that treatment of crude Olanzapine Form I with water substantially reduces the content of methylene chloride in the final product. Preferably, Olanzapine Form I contains less than 200 ppm of methlylene chloride; more preferably less than 100 ppm of methlylene chloride; and, most preferably, less than 50 ppm of methlylene chloride. Comparatively, when Olanzapine Form I is ordinarily crystallized from methylene chloride the level of residual methylene chloride in the final product may levels of around 500 ppm, and more likely above 600 ppm.  
         [0029]     The treatment of crude Olanzapine Form I with water allows for rejection of impurity C as the impurity is water-soluble. Preferably the impurity C is less than 0.1% in the final product.  
         [0030]     The Olanzapine dihydrate C, made by the present invention, can be administered in oral formulations to a patient suffering from following symptoms/conditions: anxiety disorders selected from the group consisting of psychoactive substance disorder, organic anxiety disorder, obsessive compulsive disorder, post traumatic stress disorder, generalized anxiety disorder, and anxiety disorder NOS, or pathologic psychological conditions wherein delusions, disorganized behavior, or anxiety are a consistent manifestation of the pathologic condition comprising administering an affective amount of the Olanzapine Dihydrate C as described previously.  
         [0031]     Conventional pharmaceutical formulations for this novel Olanzapine dihydrate C can be prepared using conventional methods such as wet granulation. A formulation will contain known diluents/excipients/acceptable carriers. A typical formulation can be made by known methods and comprise of the Olanzapine dihydrate C, mixed with lactose, starch, talc or magnesium stearate using known methods. Especially preferred are formulations with polymer coatings on the formulation. Such coatings can be selected from hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, poly vinyl pyrrolidone, metacrylate polymers or similar polymers known to those skilled in the art of formulation.  
       EXAMPLES  
       [0032]     The following examples are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. The polymorphic form of finally prepared crystalline olanzapine may be determined by infrared (IR) spectroscopy and X-ray powder diffraction analysis.  
       Example 1  
     Preparation of Crude Olanzapine Form I  
       [0033]     Crude Olanzapine (30.0 g) is added into dichloromethane (180 ml). The reaction mixture is refluxed at 35-40° C. for a period of 15-20 min. When complete dissolution occurs, activated carbon (1.20 g) is added and the reaction mixture is then refluxed at 35-40° C. for 15 min. The solution is then filtered through hy-flo bed and the bed is washed with dichloromethane (30 ml). The filtrate is then slowly cooled to 0-5° C. and then maintained at 0-5° C. for 5 h to complete the crystallization. The content is then filtered, washed with chilled (0-5°) dichloromethane (30 ml) and dried at 70° C.-75° C. under vacuum for 12 hours (Yield 14 g) to give Olanzapine Form I. Dichloromethane content 620 ppm. Impurity C is 0.2% w/w.  
       Example 2  
     Preparation of Olanzapine Dihydrate C  
       [0034]     Olanzapine Form—I (10 g) is suspended in water (30 ml) and stirred at 30 to 35° C. over a period of 30 minutes. The slurry is then filtered and washed with water (50 ml) and suck dried. The product obtained is dried at 30 to 35° C. for 24 hrs (Yield: 9.5 g). The moisture content of the product is 10.2%.  
         [0035]     The product is examined by powder x-ray crystallography, infrared spectroscopy and differential scanning calorimetry to identify the crystal form (FIGS.  1  to  3 ). The product is examined by powder x-ray crystallography, infrared spectroscopy and differential scanning calorimetry to identify the crystal form (FIGS.  1  to  3 ).  
       Example 3  
     Preparation of Form I of Olanzapine  
       [0036]     The Olanzapine Dihydrate C (10 g) is dried at 60° C. to 70° C. under vacuum for 3 to 4 hours (Yield: 8.5 g) to obtain substantially pure Olanzapine Form I. The moisture content of the product is 0.2% and dichloromethane is 112 ppm. Impurity C content is 0.08% w/w. Thus it is clear that producing Olanzapine Form I by following the process as invented by the present applicant [eg. 3] results in lesser DCM content as well as lower impurity C levels.