Abstract:
The invention relates to a crystalline polymorph of a pharmaceutically acceptable salt of an optically active anti-fungal imidazole compound of formula (III), the pharmaceutical and agricultural compositions containing such polymorph, its use in the treatment or prevention of skin or mucous membrane infections caused by fungi or yeasts in humans or pets, and its use in the treatment or prevention of agricultural diseases produced by such infectious agents.

Description:
TECHNICAL FIELD OF THE INVENTION 
       [0001]    The invention relates to antifungal agents, specifically imidazole compounds. More particularly, the invention relates to a crystalline polymorph of a pharmaceutically acceptable salt of an optically active antifungal imidazole compound, the pharmaceutical and agricultural compositions containing such polymorph, its use in the treatment or prevention of skin or mucous membrane infections caused by fungi or yeasts in humans or pets, and its use in the treatment or prevention of agricultural diseases produced by such infectious agents. 
       BACKGROUND OF THE INVENTION 
       [0002]    EP151477B1 discloses imidazole compounds of general formula (I): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein [A], R 1  and R 2  have the meanings therein described, as well as pharmaceutical compositions containing them, and their use for treating fungal infections in humans and animals or for combating crop diseases. Compound (I)—specific when [A]=CH, R 1 =H, R 2 =7-Cl and the CH 2  group is bonded to the benzo[b]thiophene ring at the 3 position—is known as sertaconazole and is widely used in therapeutics as an antifungal agent, preferably in the form of mononitrate salt. 
         [0003]    In turn, EP1474422B1 discloses the R-enantiomer of sertaconazole, i.e., R-(−)-1-[2-(7-chlorobenzo[b]thiophen-3-yl-methoxy)-2-(2,4-dichlorophenyl-ethyl]-1H-imidazole, of formula (II, arasertaconazole): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and its preferred salt, which is the mononitrate, of formula (III, arasertaconazole mononitrate): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    as well as its pharmaceutical and agricultural compositions, and its use in the preparation of pharmaceutical compositions for the treatment of infections caused by fungi and yeasts in humans and animals or agricultural compositions for the treatment of crop diseases produced by such microorganisms. Arasertaconazol mononitrate (III) optionally mixed with pharmaceutically acceptable carriers can be administered to humans or animals by the oral route in the form of tablets, capsules, coated tablets, syrups, solutions, powders, granules, emulsions, oral gels, oral pastes, buccopharingeal solutions, buccopharingeal suspensions, buccopharingeal gels, buccopharingeal pastes, etc., by injection, by rectal route and by vaginal-intrauterine route in the form of ovulum, vaginal tablet, vaginal capsule, medicated vaginal tampon, ointment, cream, gel, foam, solution, emulsion, suspension, pessary, lotion, etc., at daily doses ranging from 50 to 400 mg; and by topical route in the form of cream, lotion, paste, suspension, ointment, emulsion, solution, foam, shampoo, powder, gel, etc., at concentrations ranging from 0.05 to 3%. Also the compound of the invention can be optionally applied in admixture with a diluent or carrier against crop diseases by watering, atomizing, spraying, dusting, or in the form of powder, cream, paste, etc., at the rate of 0.05-10 Kg per hectare of soil. 
         [0004]    EP1474422B1 assigns the compound (III) obtained in Example 4 with a DSC peak at 116.87° C. In the course of our present investigations, it was found out that there was a typing error in the above DSC peak, which should be corrected to read 171.6° C. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0005]      FIGS. 1 and 2  show the Differential Scanning Calorimetry thermograms of compound (III) as polymorph I and polymorph II respectively. The ordinate represents the heat flow expressed in mW. The abscissa indicates the temperature expressed in ° C. 
           [0006]      FIG. 3  shows the X-ray Powder Diffraction curves of compound (III) as polymorph I, polymorph II and solvate with ½ mole of acetone (IV). The intensity, in ordinates, is expressed in cps. The abscissa corresponds to 2θ° angle. 
           [0007]      FIG. 4  shows the IR spectrum of compound (III) as polymorph I, polymorph II and solvate with ½ mole of acetone (IV). 
           [0008]      FIG. 5  shows a zone selected from the IR spectrum of compound (III) as polymorph I, polymorph II and solvate with ½ mole of acetone (IV). 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0009]    The present invention refers to polymorph II of arasertaconazole mononitrate (III), as well as methods for its preparation, its use in pharmacy and agriculture and the pharmaceutical and agricultural compositions comprising the novel polymorph. 
         [0010]    Polymorph II of arasertaconazole mononitrate (III) constitutes the main object of the present application. Polymorph II, in contrast to polymorph I, exhibits the outstanding property that its density is much lower than polymorph I. In fact, polymorph II presents an apparent density of 0.39 g/mL and a compact density of 0.53 g/mL, as compared to polymorph I whose apparent density is 0.78 g/mL and whose compact density is 1.08 g/mL. 
         [0011]    The low density of the novel polymorph shows important advantages in both formulation processes at industrial scale and the proper nature of certain types of topical formulations, as in the case of foams, aerosols and solid powders. The advantages of polymorph II of arasertaconazole mononitrate (III) are described as follows. 
       General Advantages in Formulation Processes 
       [0012]    A low density may help to dissolve or disperse an active ingredient more rapidly and, therefore, may be of interest in some stages of the formulation processes at industrial scale. In addition, surprisingly, polymorph II is more stable at high temperature, thereby polymorph I is preferred when required to operate at high temperatures (higher than 80° C.). 
       Advantages of Some Types of Topical Pharmaceutical Formulations 
     Foams 
       [0013]    Foams have an apparent lower density than creams because air is incorporated. An elemental formulation principle recommends approaching the densities and sizes of the different particles in a slurry or solid emulsion in order to minimize the sedimentation effects over time and thus increase the stability of the final formulation. 
       Aerosols and Sprays 
       [0014]    The apparent low density of aerosols usually involves a low energy fragmentation of the solid, thus facilitating the reduction in smaller particles that are to be atomized or sprayed. 
       Solid Powder 
       [0015]    A large treatment area is available by using a less dense active ingredient. 
         [0016]    Thus, in a first embodiment, the present application provides the novel polymorph II of arasertaconazole mononitrate (III) characterized by presenting:
   (i) a melting point within the range of 170°-172° C.;   (ii) the following crystallographic characteristics:   
 
         [0000]                                                    Wavelength (Å)   0.71069       Crystal system, space group   Orthorhombic, P2 1 2 1 2 1              Unit cell dimensions            A (Å)   9.3550(10)       B (Å)   9.5010(10)       C (Å)   25.3810(10)       Volume (Å 3 )   2255.9(3)       Z, Density (calculated)   4, 1.474 mg/m 3         μ (mm −1 )   0.531       F(000)   1024       Crystal size (mm)   0.1 × 0.2 × 0.2       θ Range   1.60-25.00 degrees       Index ranges   0 ≦ h ≦ 11, 0 ≦ k ≦ 10, 0 ≦ l ≦ 30       Reflections collected/   5610/1976 [R(int) = 0.10]       Independent reflections       Integrity at 2θ   85.5%       Data/parameters   1976/283       Goodness-of-Fit F 2     0.912       Final R indices [I &gt;   R1 = 0.048, wR2 = 0.104       2sigma(I)]                  R indices (all data)   R1 = 0.141, wR2 = 0.136       Absolute structure parameter   −0.11(16)       Largest difference peak and   0.241 and −0.136 e.A −3         hole                    
and
   (iii) the following X-ray diffraction peak intensities and spacing:   
 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 h 
                 k 
                 l 
                 D 
                 I 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 0 
                 1 
                 1 
                 8.8980 
                 74. 
               
               
                 1 
                 0 
                 1 
                 8.7777 
                 40. 
               
               
                 0 
                 1 
                 2 
                 7.6057 
                 280. 
               
               
                 1 
                 1 
                 0 
                 6.6660 
                 14. 
               
               
                 1 
                 1 
                 1 
                 6.4473 
                 183. 
               
               
                 0 
                 0 
                 4 
                 6.3453 
                 85. 
               
               
                 0 
                 1 
                 3 
                 6.3184 
                 40. 
               
               
                 1 
                 0 
                 3 
                 6.2749 
                 10. 
               
               
                 1 
                 1 
                 2 
                 5.9014 
                 58. 
               
               
                 0 
                 1 
                 4 
                 5.2767 
                 100. 
               
               
                 1 
                 0 
                 4 
                 5.2513 
                 28. 
               
               
                 1 
                 1 
                 3 
                 5.2360 
                 636. 
               
               
                 0 
                 2 
                 0 
                 4.7505 
                 41. 
               
               
                 0 
                 2 
                 1 
                 4.6694 
                 16. 
               
               
                 2 
                 0 
                 1 
                 4.6000 
                 66. 
               
               
                 1 
                 1 
                 4 
                 4.5960 
                 225. 
               
               
                 0 
                 1 
                 5 
                 4.4772 
                 83. 
               
               
                 1 
                 0 
                 5 
                 4.4617 
                 160. 
               
               
                 0 
                 2 
                 2 
                 4.4490 
                 382. 
               
               
                 1 
                 2 
                 0 
                 4.2357 
                 21. 
               
               
                 0 
                 0 
                 6 
                 4.2302 
                 89. 
               
               
                 0 
                 2 
                 3 
                 4.1422 
                 312. 
               
               
                 2 
                 1 
                 1 
                 4.1403 
                 21. 
               
               
                 2 
                 0 
                 3 
                 4.0935 
                 18. 
               
               
                 1 
                 1 
                 5 
                 4.0385 
                 175. 
               
               
                 2 
                 1 
                 2 
                 3.9843 
                 44. 
               
               
                 0 
                 1 
                 6 
                 3.8644 
                 23. 
               
               
                 1 
                 0 
                 6 
                 3.8544 
                 171. 
               
               
                 0 
                 2 
                 4 
                 3.8028 
                 107. 
               
               
                 1 
                 2 
                 3 
                 3.7875 
                 45. 
               
               
                 2 
                 0 
                 4 
                 3.7651 
                 315. 
               
               
                 2 
                 1 
                 3 
                 3.7594 
                 176. 
               
               
                 1 
                 1 
                 6 
                 3.5717 
                 47. 
               
               
                 1 
                 2 
                 4 
                 3.5229 
                 31. 
               
               
                 2 
                 1 
                 4 
                 3.5002 
                 128. 
               
               
                 2 
                 0 
                 5 
                 3.4398 
                 34. 
               
               
                 0 
                 1 
                 7 
                 3.3876 
                 1000. 
               
               
                 1 
                 0 
                 7 
                 3.3808 
                 25. 
               
               
                 2 
                 2 
                 1 
                 3.3046 
                 159. 
               
               
                 1 
                 2 
                 5 
                 3.2522 
                 54. 
               
               
                 2 
                 1 
                 5 
                 3.2344 
                 10. 
               
               
                 2 
                 2 
                 2 
                 3.2237 
                 54. 
               
               
                 1 
                 1 
                 7 
                 3.1852 
                 32. 
               
               
                 0 
                 0 
                 8 
                 3.1726 
                 162. 
               
               
                 0 
                 2 
                 6 
                 3.1592 
                 77. 
               
               
                 2 
                 2 
                 3 
                 3.1010 
                 119. 
               
               
                 0 
                 3 
                 2 
                 3.0728 
                 39. 
               
               
                 0 
                 1 
                 8 
                 3.0093 
                 27. 
               
               
                 1 
                 3 
                 0 
                 2.9998 
                 30. 
               
               
                 2 
                 1 
                 6 
                 2.9792 
                 45. 
               
               
                 1 
                 3 
                 1 
                 2.9790 
                 9. 
               
               
                 0 
                 3 
                 3 
                 2.9660 
                 26. 
               
               
                 2 
                 2 
                 4 
                 2.9507 
                 31. 
               
               
                 3 
                 1 
                 1 
                 2.9428 
                 141. 
               
               
                 1 
                 3 
                 2 
                 2.9193 
                 106. 
               
               
                 3 
                 1 
                 2 
                 2.8852 
                 41. 
               
               
                 0 
                 2 
                 7 
                 2.8822 
                 10. 
               
               
                 1 
                 1 
                 8 
                 2.8647 
                 10. 
               
               
                 0 
                 3 
                 4 
                 2.8337 
                 18. 
               
               
                 2 
                 2 
                 5 
                 2.7861 
                 23. 
               
               
                 2 
                 1 
                 7 
                 2.7436 
                 8. 
               
               
                 1 
                 3 
                 4 
                 2.7120 
                 37. 
               
               
                 0 
                 3 
                 5 
                 2.6869 
                 10. 
               
               
                 2 
                 2 
                 6 
                 2.6180 
                 10. 
               
               
                 2 
                 3 
                 1 
                 2.6086 
                 19. 
               
               
                 3 
                 2 
                 0 
                 2.6069 
                 10. 
               
               
                 1 
                 1 
                 9 
                 2.5972 
                 14. 
               
               
                 3 
                 1 
                 5 
                 2.5589 
                 11. 
               
               
                 3 
                 2 
                 2 
                 2.5536 
                 23. 
               
               
                 0 
                 0 
                 10 
                 2.5381 
                 9. 
               
               
                 0 
                 3 
                 6 
                 2.5352 
                 9. 
               
               
                 2 
                 1 
                 8 
                 2.5308 
                 9. 
               
               
                 2 
                 3 
                 3 
                 2.5049 
                 9. 
               
               
                 1 
                 3 
                 6 
                 2.4470 
                 10. 
               
               
                 2 
                 3 
                 4 
                 2.4236 
                 8. 
               
               
                 0 
                 4 
                 1 
                 2.3649 
                 12. 
               
               
                 3 
                 0 
                 7 
                 2.3642 
                 9. 
               
               
                 1 
                 2 
                 9 
                 2.3474 
                 12. 
               
               
                 2 
                 3 
                 5 
                 2.3299 
                 26. 
               
               
                 4 
                 0 
                 1 
                 2.3289 
                 10. 
               
               
                 3 
                 2 
                 5 
                 2.3190 
                 8. 
               
               
                 1 
                 3 
                 7 
                 2.3113 
                 10. 
               
               
                 3 
                 1 
                 7 
                 2.2943 
                 33. 
               
               
                 1 
                 4 
                 1 
                 2.2928 
                 10. 
               
               
                 4 
                 1 
                 1 
                 2.2619 
                 12. 
               
               
                 0 
                 3 
                 8 
                 2.2414 
                 14. 
               
               
                 0 
                 2 
                 10 
                 2.2386 
                 9. 
               
               
                 2 
                 0 
                 10 
                 2.2308 
                 14. 
               
               
                 2 
                 3 
                 6 
                 2.2289 
                 10. 
               
               
                 3 
                 3 
                 0 
                 2.2220 
                 26. 
               
               
                 3 
                 2 
                 6 
                 2.2193 
                 36. 
               
               
                 3 
                 3 
                 1 
                 2.2135 
                 10. 
               
               
                 4 
                 0 
                 4 
                 2.1944 
                 29. 
               
               
                 3 
                 3 
                 2 
                 2.1887 
                 11. 
               
               
                 1 
                 1 
                 11 
                 2.1804 
                 22. 
               
               
                 1 
                 3 
                 8 
                 2.1797 
                 20. 
               
               
                 1 
                 2 
                 10 
                 2.1772 
                 11. 
               
               
                 2 
                 2 
                 9 
                 2.1529 
                 10. 
               
               
                 0 
                 4 
                 5 
                 2.1514 
                 15. 
               
               
                 3 
                 3 
                 3 
                 2.1491 
                 9. 
               
               
                 3 
                 2 
                 7 
                 2.1166 
                 24. 
               
               
                 0 
                 3 
                 9 
                 2.1061 
                 18. 
               
               
                 1 
                 4 
                 5 
                 2.0966 
                 18. 
               
               
                 4 
                 2 
                 1 
                 2.0911 
                 26. 
               
               
                 4 
                 2 
                 2 
                 2.0701 
                 42. 
               
               
                 1 
                 0 
                 12 
                 2.0630 
                 8. 
               
               
                 1 
                 3 
                 9 
                 2.0547 
                 13. 
               
               
                 3 
                 1 
                 9 
                 2.0427 
                 32. 
               
               
                 4 
                 2 
                 3 
                 2.0366 
                 11. 
               
               
                 3 
                 3 
                 5 
                 2.0355 
                 20. 
               
               
                 1 
                 2 
                 11 
                 2.0262 
                 18. 
               
               
                 2 
                 1 
                 11 
                 2.0219 
                 36. 
               
               
                 1 
                 1 
                 12 
                 2.0160 
                 10. 
               
               
                 3 
                 2 
                 8 
                 2.0142 
                 27. 
               
               
                 2 
                 4 
                 4 
                 2.0089 
                 20. 
               
               
                 4 
                 1 
                 6 
                 2.0009 
                 10. 
               
               
                 0 
                 3 
                 10 
                 1.9806 
                 9. 
               
               
                 2 
                 4 
                 5 
                 1.9545 
                 8. 
               
               
                 3 
                 1 
                 10 
                 1.9275 
                 10. 
               
               
                 2 
                 2 
                 11 
                 1.8971 
                 17. 
               
               
                 4 
                 3 
                 1 
                 1.8762 
                 15. 
               
               
                 1 
                 1 
                 13 
                 1.8737 
                 12. 
               
               
                 3 
                 4 
                 2 
                 1.8689 
                 13. 
               
               
                 0 
                 3 
                 11 
                 1.8649 
                 9. 
               
               
                 1 
                 5 
                 2 
                 1.8424 
                 17. 
               
               
                 2 
                 4 
                 7 
                 1.8287 
                 10. 
               
               
                 5 
                 1 
                 2 
                 1.8168 
                 9. 
               
               
                 0 
                 0 
                 14 
                 1.8129 
                 31. 
               
               
                 5 
                 1 
                 3 
                 1.7940 
                 10. 
               
               
                 2 
                 2 
                 12 
                 1.7858 
                 9. 
               
               
                 1 
                 4 
                 9 
                 1.7834 
                 16. 
               
               
                 4 
                 3 
                 5 
                 1.7641 
                 14. 
               
               
                 4 
                 2 
                 8 
                 1.7501 
                 9. 
               
               
                 1 
                 1 
                 14 
                 1.7494 
                 17. 
               
               
                 1 
                 3 
                 12 
                 1.7286 
                 20. 
               
               
                 2 
                 5 
                 3 
                 1.7236 
                 9. 
               
               
                 2 
                 2 
                 13 
                 1.6846 
                 10. 
               
               
                 5 
                 1 
                 6 
                 1.6840 
                 13 
               
               
                 0 
                 1 
                 15 
                 1.6659 
                 12. 
               
               
                 3 
                 5 
                 2 
                 1.6096 
                 8. 
               
               
                 1 
                 6 
                 1 
                 1.5583 
                 9. 
               
               
                   
               
             
          
         
       
     
         [0020]    Moreover, the new polymorph is characterized by presenting a DSC (Differential Scanning Calorimetry) endothermal peak at 171.5° C. 
         [0021]    In another embodiment, the present invention provides a process for the preparation of the new polymorph comprising heating of the solvated form of arasertaconazole mononitrate with ½ mole of acetone, of formula (IV): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0022]    at a temperature of 354.2° K. 
         [0023]    In another embodiment, the present invention provides a process for the preparation of the new polymorph comprising heating of polymorph I at 373° K over a period from 2 to 24 h. 
         [0024]    In another embodiment, the present invention provides a process for the preparation of the new polymorph comprising crystallization of polymorph I or the solvated form of arasertaconazole mononitrate with ½ mole of acetone (IV) in water. 
         [0025]    In another embodiment, the present invention provides the use of the new polymorph for the preparation of pharmaceutical compositions for the treatment or prevention of skin or mucous membrane infections caused by fungi or yeasts in humans or pets. This aspect can also be formulated as a method of treating or preventing skin or mucous membrane infections caused by fungi or yeasts in humans or pets, comprising the administration to said human or pet in need thereof of a therapeutically effective amount of the polymorph as defined in the present invention. 
         [0026]    The term “therapeutically effective amount” refers to the amount of the polymorph of the invention that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the infection. The term “therapeutically effective amount” also refers to the amount of polymorph of the invention that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal or human that is being sought by a researcher, veterinarian, medical, doctor or clinician. 
         [0027]    In another embodiment, the present invention provides the use of the new polymorph for the preparation of agricultural compositions for the treatment or prevention of crop diseases produced by fungi and yeasts. 
         [0028]    In another embodiment, the present invention provides pharmaceutical compositions comprising the new polymorph and pharmaceutically acceptable carriers for the treatment or prevention of skin or mucous membrane infections caused by fungi or yeasts in humans or pets. 
         [0029]    In another embodiment, the present invention provides agricultural compositions comprising the new polymorph and agriculturally acceptable carriers for the treatment or prevention of crop diseases produced by fungi and yeasts. 
       Particular Embodiments of the Invention 
       [0030]    The crystallographic studies of the present invention were carried out in accordance with the following specifications. 
       Instruments 
       [0000]    
       
         Microbalance (Mettler, MT5) 
         Analytical balance (Mettler, AT261) 
         Differential Scanning Calorimeter, DSC (Mettler, DSC820C)
       Calibration and titration of substances (Mettler, ME-119422)   40-μl Al Crucible without pin (Mettler, ME-26763)   
     
         Thermogravimetric analyzer (Mettler-Toledo, TG50/MT5, TA-8000)
       70-μl Al 2 O 3  Crucible with perforated lid   
     
         IR Spectrophotometer (Thermo Nicolet, Nexus) equipped with a DTGS KBr detector. Software: Advanced OMNIC CD, v 6.0a for Nexus, together with all of the necessary accessories needed for the preparation of solid samples that are dispersed in 13 mm KBr tablets. 
         Microscope (Nikon, Eclipse E-600)
       Lens: 4×, 10×, 20× and 40×.   Filter and polarized light analyzer.   Video camera (Sony, SSC-C370P)   Software for Windows (Linkam, LinkSys-310RTVMS,), software for real time video digitalization with calibrated lens.   
     
       
     
       Experimental Conditions 
     Differential Scanning Calorimetry (DSC) 
       [0044]    Sample Preparation 
         [0045]    About 3 mg of the test substances were carefully weighed into the 40-μl aluminum crucible. The lid was perforated and hermetically sealed, the crucible was sealed off, and the lid was equalized. Then, the crucible was placed into the furnace and the experiment started. 
         [0046]    Data Acquisition and Processing Techniques 
         [0047]    The samples were heated from 30 to 200° C. at a rate of 10° C./min under a N 2  stream, the flow rate being 80 mL/min. 
       Thermogravimetry (TG) 
       [0048]    Sample Preparation 
         [0049]    The necessary amounts were carefully weighed for completing ¾ parts of the 70-μl Al 2 O 3  crucible provided with a perforated lid that was hermetically sealed. Then, the crucible was placed into the furnace and the experiment started. 
         [0050]    Data Acquisition and Processing Techniques 
         [0051]    The samples were heated from 30 to 120° C. at a rate of 5° C./min under a N 2  stream, the flow rate being 80 mL/min. Mass loss rate was calculated in relation to baseline by horizontal tangent plot. 
       Infrared Spectroscopy (IR) 
       [0052]    Sample Preparation 
         [0053]    About 1 mg of test substance and 200 mg of potassium bromide were ground in an agate mortar. The ground and homogenized mixture was then transferred to a 13 mm diameter die under a pressure of about 800 MP thus giving a homogenous tablet. The die was withdrawn, the tablet was placed on the tablet holder using a clamp, and the tablet was fitted into the apparatus compartment. Then, spectrum measurement was performed. 
         [0054]    Data Acquisition and Processing Techniques
       Resolution: 4 cm −1      Spectral range (x-frequency): 4000 cm −1  at 400 cm −1      Laser range: 15798.3 cm −1      Final polymorph (y): % Transmittance   Number of spectrum accumulations: 32   Number of historical accumulations: 32   Historical acquisition: automatic mode prior to each spectrum and final suppression.   Apodization: Happ-Genzel   Phase correction: Mertz   Baseline correction: automatic       
 
       Polymorphism Study 
       [0065]    Full observation of spectra showed that the same functional groups are present in both polymorphs while referring to the same molecule. A more detailed comparison of spectra revealed small changes in position and intensity in the bands of the three specific spectral regions that were chosen for comparison by the searching software. The three spectral regions were as follows:
       Region 1: Range from 3175 cm −1  to 3000 cm −1      Region 2: Range from 1360 cm −1  to 1150 cm −1      Region 3: Range from 540 cm −1  to 510 cm −1          
 
       EXAMPLE 1 
     Polymorph I of Arasertaconazole Mononitrate (III) 
       [0069]    A solution of arasertaconazole mononitrate (III), previously prepared according to EP1474422B1 (Example 4) in any of the solvents selected from heptane, methanol, ethanol, toluene, 4-chlorotoluene, acetic acid, ethyl acetate, trichloromethane, or a combination thereof with water (50:50, v/v), was verified to provide by addition of water a crystalline precipitate mostly containing the product under the same crystallographic characteristics as the starting material; however, polymorph I was obtained only in a pure form when mixtures of ethanol/water and ethyl acetate/water were used (Table 1). 
         [0000]    
       
         
               
             
               
               
             
               
             
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Crystal data and structure refinements for polymorph 
               
               
                 I of arasertaconazole mononitrate (III) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Molecular formula 
                 C 20 H 16 Cl 3 N 3 O 4 S 
               
               
                 Molecular weight 
                 500.77 
               
               
                 Wavelength (Å) 
                 0.71069 
               
               
                 Crystal system, space group 
                 Monoclinic, P2 1   
               
             
          
           
               
                 Unit cell dimensions 
               
             
          
           
               
                 A (Å) 
                 9.2710(10) 
               
               
                 B (Å) 
                 9.3160(10) 
               
               
                 C (Å) 
                 13.3360(10) 
               
               
                 β (°) = 
                 103.3380(10) 
               
               
                 Volume (Å 3 ) 
                 1120.74(19) 
               
               
                 Z, Density (calculated) 
                 2, 1.484 mg/m 3   
               
               
                 μ (mm −1 ) 
                 0.534 
               
               
                 F(000) 
                 512 
               
               
                 Crystal size (mm) 
                 0.1 × 0.1 × 0.2 
               
               
                 Θ Range 
                 2.26-31.60 degrees 
               
               
                 Index range 
                 0 ≦ h ≦ 13, 0 ≦ k ≦ 12, −19 ≦ l ≦ 19 
               
               
                 Reflections collected/ 
                 3478/3477 [R(int) = 0.01] 
               
               
                 Independent reflections 
               
               
                 Integrity at 2θ 
                 87.4% 
               
               
                 Data/parameters 
                 3477/353 
               
               
                 Goodness-of-Fit F 2   
                 1.103 
               
               
                 Final R indices [I &gt; 
                 R1 = 0.064, wR2 = 0.153 
               
               
                 2sigma(I)] 
               
               
                 R indices (all data) 
                 R1 = 0.119, wR2 = 0.176 
               
               
                 Absolute structure parameter 
                 −0.02(10) 
               
               
                 Extinction coefficient 
                 0.010(5) 
               
               
                 Largest difference peak and 
                 0.216 and −0.225 e.A −3   
               
               
                 hole 
               
               
                   
               
             
          
         
       
     
       Differential Scanning Calorimetry (DSC) 
       [0070]    The main peak was detected at 171.6° C., i.e., the characteristic melting peak within the range of 170°-172° C.,  FIG. 1 . 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 X-ray diffraction peak intensities and spacing for 
               
               
                 polymorph I of arasertaconazole mononitrate (III) 
               
             
          
           
               
                 h 
                 k 
                 l 
                 D 
                 I 
               
               
                   
               
             
          
           
               
                 1 
                 0 
                 0 
                 9.0209 
                 378. 
               
               
                 0 
                 1 
                 1 
                 7.5677 
                 41. 
               
               
                 1 
                 0 
                 1 
                 6.7163 
                 21. 
               
               
                 0 
                 0 
                 2 
                 6.4881 
                 140. 
               
               
                 1 
                 1 
                 0 
                 6.4806 
                 307. 
               
               
                 1 
                 1 
                 −1 
                 6.2248 
                 57. 
               
               
                 1 
                 0 
                 −2 
                 5.9591 
                 485. 
               
               
                 1 
                 1 
                 1 
                 5.4481 
                 552. 
               
               
                 0 
                 1 
                 2 
                 5.3242 
                 186. 
               
               
                 1 
                 1 
                 −2 
                 5.0199 
                 307. 
               
               
                 1 
                 0 
                 2 
                 4.7713 
                 172. 
               
               
                 2 
                 0 
                 −1 
                 4.6024 
                 12. 
               
               
                 2 
                 0 
                 0 
                 4.5105 
                 796. 
               
               
                 0 
                 2 
                 1 
                 4.3841 
                 56. 
               
               
                 0 
                 0 
                 3 
                 4.3254 
                 76. 
               
               
                 1 
                 0 
                 −3 
                 4.3068 
                 17. 
               
               
                 1 
                 1 
                 2 
                 4.2467 
                 279. 
               
               
                 2 
                 1 
                 −1 
                 4.1263 
                 212. 
               
               
                 1 
                 2 
                 −1 
                 4.0698 
                 73. 
               
               
                 2 
                 1 
                 0 
                 4.0597 
                 280. 
               
               
                 2 
                 0 
                 1 
                 3.9849 
                 188. 
               
               
                 0 
                 1 
                 3 
                 3.9232 
                 303. 
               
               
                 1 
                 1 
                 −3 
                 3.9092 
                 235. 
               
               
                 1 
                 2 
                 1 
                 3.8276 
                 231. 
               
               
                 2 
                 1 
                 −2 
                 3.8162 
                 265. 
               
               
                 0 
                 2 
                 2 
                 3.7838 
                 772. 
               
               
                 1 
                 2 
                 −2 
                 3.6699 
                 177. 
               
               
                 2 
                 1 
                 1 
                 3.6638 
                 136. 
               
               
                 1 
                 0 
                 3 
                 3.5907 
                 1000. 
               
               
                 2 
                 0 
                 −3 
                 3.5589 
                 61. 
               
               
                 2 
                 0 
                 2 
                 3.3581 
                 137. 
               
               
                 1 
                 1 
                 3 
                 3.3504 
                 379. 
               
               
                 1 
                 2 
                 2 
                 3.3330 
                 62. 
               
               
                 1 
                 0 
                 −4 
                 3.3051 
                 479. 
               
               
                 2 
                 2 
                 −1 
                 3.2739 
                 127. 
               
               
                 0 
                 0 
                 4 
                 3.2441 
                 307. 
               
               
                 0 
                 2 
                 3 
                 3.1696 
                 31. 
               
               
                 1 
                 2 
                 −3 
                 3.1622 
                 15. 
               
               
                 2 
                 1 
                 2 
                 3.1592 
                 129. 
               
               
                 1 
                 1 
                 −4 
                 3.1149 
                 191. 
               
               
                 2 
                 2 
                 −2 
                 3.1124 
                 253. 
               
               
                 3 
                 0 
                 −1 
                 3.0903 
                 60. 
               
               
                 0 
                 1 
                 4 
                 3.0636 
                 111. 
               
               
                 0 
                 3 
                 1 
                 3.0201 
                 76. 
               
               
                 3 
                 0 
                 0 
                 3.0070 
                 49. 
               
               
                 3 
                 0 
                 −2 
                 3.0055 
                 44. 
               
               
                 2 
                 0 
                 −4 
                 2.9795 
                 20. 
               
               
                 1 
                 3 
                 0 
                 2.9362 
                 59. 
               
               
                 3 
                 1 
                 −1 
                 2.9332 
                 40. 
               
               
                 1 
                 3 
                 −1 
                 2.9113 
                 56. 
               
               
                 3 
                 1 
                 0 
                 2.8616 
                 12. 
               
               
                 3 
                 1 
                 −2 
                 2.8604 
                 22. 
               
               
                 1 
                 0 
                 4 
                 2.8505 
                 25. 
               
               
                 1 
                 2 
                 3 
                 2.8438 
                 50. 
               
               
                 2 
                 1 
                 −4 
                 2.8379 
                 8. 
               
               
                 2 
                 2 
                 −3 
                 2.8279 
                 55. 
               
               
                 1 
                 3 
                 1 
                 2.8186 
                 90. 
               
               
                 2 
                 0 
                 3 
                 2.8144 
                 37. 
               
               
                 0 
                 3 
                 2 
                 2.8010 
                 65. 
               
               
                 3 
                 0 
                 1 
                 2.7912 
                 16. 
               
               
                 3 
                 0 
                 −3 
                 2.7889 
                 12. 
               
               
                 1 
                 3 
                 −2 
                 2.7539 
                 36. 
               
               
                 1 
                 1 
                 4 
                 2.7257 
                 8. 
               
               
                 2 
                 2 
                 2 
                 2.7240 
                 78. 
               
               
                 2 
                 1 
                 3 
                 2.6941 
                 73. 
               
               
                 3 
                 1 
                 1 
                 2.6737 
                 72. 
               
               
                 3 
                 1 
                 −3 
                 2.6717 
                 63. 
               
               
                 0 
                 2 
                 4 
                 2.6621 
                 13. 
               
               
                 1 
                 3 
                 2 
                 2.6026 
                 30. 
               
               
                 0 
                 0 
                 5 
                 2.5953 
                 10. 
               
               
                 3 
                 2 
                 −1 
                 2.5751 
                 9. 
               
               
                 2 
                 3 
                 −1 
                 2.5742 
                 38. 
               
               
                 2 
                 3 
                 0 
                 2.5578 
                 17. 
               
               
                 3 
                 2 
                 −2 
                 2.5254 
                 51. 
               
               
                 0 
                 3 
                 3 
                 2.5226 
                 24. 
               
               
                 2 
                 0 
                 −5 
                 2.5141 
                 22. 
               
               
                 3 
                 0 
                 −4 
                 2.5132 
                 37. 
               
               
                 0 
                 1 
                 5 
                 2.5001 
                 8. 
               
               
                 2 
                 3 
                 −2 
                 2.4934 
                 25. 
               
               
                 2 
                 3 
                 1 
                 2.4494 
                 44. 
               
               
                 1 
                 2 
                 4 
                 2.4313 
                 11. 
               
               
                 2 
                 1 
                 −5 
                 2.4273 
                 23. 
               
               
                 3 
                 1 
                 −4 
                 2.4265 
                 11. 
               
               
                 3 
                 2 
                 1 
                 2.3942 
                 30. 
               
               
                 3 
                 2 
                 −3 
                 2.3928 
                 18. 
               
               
                 2 
                 0 
                 4 
                 2.3856 
                 32. 
               
               
                 1 
                 3 
                 3 
                 2.3488 
                 15. 
               
               
                 2 
                 3 
                 −3 
                 2.3398 
                 86. 
               
               
                 2 
                 1 
                 4 
                 2.3111 
                 22. 
               
               
                 0 
                 4 
                 1 
                 2.2924 
                 13. 
               
               
                 0 
                 2 
                 5 
                 2.2671 
                 10. 
               
               
                 1 
                 3 
                 −4 
                 2.2631 
                 16. 
               
               
                 4 
                 1 
                 −1 
                 2.2456 
                 18. 
               
               
                 1 
                 4 
                 −1 
                 2.2437 
                 26. 
               
               
                 0 
                 3 
                 4 
                 2.2432 
                 16. 
               
               
                 3 
                 0 
                 3 
                 2.2388 
                 20. 
               
               
                 4 
                 1 
                 −2 
                 2.2341 
                 29. 
               
               
                 4 
                 0 
                 −3 
                 2.2208 
                 19. 
               
               
                 1 
                 4 
                 1 
                 2.2005 
                 13. 
               
               
                 0 
                 4 
                 2 
                 2.1920 
                 37. 
               
               
                 3 
                 3 
                 −1 
                 2.1905 
                 21. 
               
               
                 3 
                 1 
                 3 
                 2.1768 
                 77. 
               
               
                 3 
                 1 
                 −5 
                 2.1746 
                 32. 
               
               
                 0 
                 0 
                 6 
                 2.1627 
                 8. 
               
               
                 1 
                 1 
                 −6 
                 2.1619 
                 45. 
               
               
                 4 
                 1 
                 −3 
                 2.1602 
                 14. 
               
               
                 3 
                 3 
                 −2 
                 2.1597 
                 22. 
               
               
                 2 
                 3 
                 −4 
                 2.1499 
                 11. 
               
               
                 4 
                 0 
                 1 
                 2.1402 
                 25. 
               
               
                 0 
                 1 
                 6 
                 2.1067 
                 17. 
               
               
                 1 
                 3 
                 4 
                 2.0999 
                 10. 
               
               
                 1 
                 4 
                 2 
                 2.0930 
                 21. 
               
               
                 4 
                 0 
                 −4 
                 2.0916 
                 12. 
               
               
                 4 
                 1 
                 1 
                 2.0859 
                 28. 
               
               
                 2 
                 4 
                 −1 
                 2.0781 
                 10. 
               
               
                 3 
                 3 
                 1 
                 2.0759 
                 43. 
               
               
                 3 
                 3 
                 −3 
                 2.0749 
                 32. 
               
               
                 4 
                 2 
                 −1 
                 2.0722 
                 21. 
               
               
                 2 
                 4 
                 0 
                 2.0694 
                 30. 
               
               
                 4 
                 2 
                 −2 
                 2.0632 
                 11. 
               
               
                 1 
                 4 
                 −3 
                 2.0486 
                 15. 
               
               
                 4 
                 1 
                 −4 
                 2.0408 
                 21. 
               
               
                 2 
                 4 
                 −2 
                 2.0349 
                 35. 
               
               
                 4 
                 2 
                 0 
                 2.0298 
                 41. 
               
               
                 1 
                 3 
                 −5 
                 2.0213 
                 9. 
               
               
                 3 
                 2 
                 3 
                 2.0178 
                 25. 
               
               
                 3 
                 2 
                 −5 
                 2.0161 
                 19. 
               
               
                 2 
                 4 
                 1 
                 2.0108 
                 26. 
               
               
                 1 
                 2 
                 −6 
                 2.0059 
                 50. 
               
               
                 2 
                 1 
                 5 
                 2.0058 
                 33. 
               
               
                 4 
                 2 
                 −3 
                 2.0046 
                 8. 
               
               
                 1 
                 0 
                 6 
                 2.0011 
                 22. 
               
               
                 0 
                 3 
                 5 
                 1.9914 
                 23. 
               
               
                 1 
                 1 
                 6 
                 1.9564 
                 23. 
               
               
                 3 
                 3 
                 2 
                 1.9548 
                 24. 
               
               
                 2 
                 2 
                 −6 
                 1.9546 
                 26. 
               
               
                 2 
                 3 
                 −5 
                 1.9540 
                 44. 
               
               
                 2 
                 4 
                 −3 
                 1.9488 
                 29. 
               
               
                 3 
                 1 
                 4 
                 1.9446 
                 13. 
               
               
                 4 
                 0 
                 −5 
                 1.9380 
                 18. 
               
               
                 2 
                 4 
                 2 
                 1.9138 
                 13. 
               
               
                 4 
                 2 
                 −4 
                 1.9081 
                 12. 
               
               
                 1 
                 0 
                 −7 
                 1.9045 
                 15. 
               
               
                 0 
                 4 
                 4 
                 1.8919 
                 9. 
               
               
                 2 
                 3 
                 4 
                 1.8918 
                 14. 
               
               
                 1 
                 3 
                 5 
                 1.8759 
                 36. 
               
               
                 0 
                 0 
                 7 
                 1.8538 
                 26. 
               
               
                 5 
                 0 
                 −1 
                 1.8460 
                 9. 
               
               
                 0 
                 5 
                 1 
                 1.8443 
                 21. 
               
               
                 3 
                 4 
                 0 
                 1.8413 
                 11. 
               
               
                 3 
                 4 
                 −2 
                 1.8410 
                 22. 
               
               
                 1 
                 2 
                 6 
                 1.8386 
                 12. 
               
               
                 2 
                 4 
                 −4 
                 1.8349 
                 17. 
               
               
                 4 
                 2 
                 2 
                 1.8319 
                 17. 
               
               
                 3 
                 2 
                 4 
                 1.8288 
                 13. 
               
               
                 3 
                 2 
                 −6 
                 1.8272 
                 18. 
               
               
                 1 
                 5 
                 0 
                 1.8247 
                 21. 
               
               
                 0 
                 1 
                 7 
                 1.8181 
                 12. 
               
               
                 5 
                 1 
                 −2 
                 1.8165 
                 9. 
               
               
                 4 
                 3 
                 −3 
                 1.8064 
                 10. 
               
               
                 4 
                 1 
                 3 
                 1.7993 
                 10. 
               
               
                 4 
                 2 
                 −5 
                 1.7893 
                 12. 
               
               
                 3 
                 4 
                 1 
                 1.7882 
                 10. 
               
               
                 3 
                 4 
                 −3 
                 1.7876 
                 9. 
               
               
                 5 
                 1 
                 −3 
                 1.7873 
                 25. 
               
               
                 0 
                 3 
                 6 
                 1.7747 
                 30. 
               
               
                 5 
                 1 
                 0 
                 1.7713 
                 27. 
               
               
                 3 
                 0 
                 −7 
                 1.7710 
                 10. 
               
               
                 2 
                 3 
                 −6 
                 1.7696 
                 20. 
               
               
                 2 
                 1 
                 6 
                 1.7629 
                 22. 
               
               
                 3 
                 1 
                 −7 
                 1.7399 
                 13. 
               
               
                 2 
                 2 
                 −7 
                 1.7380 
                 9. 
               
               
                 0 
                 4 
                 5 
                 1.7334 
                 10. 
               
               
                 2 
                 5 
                 −1 
                 1.7270 
                 18. 
               
               
                 2 
                 5 
                 0 
                 1.7221 
                 9. 
               
               
                 5 
                 2 
                 −2 
                 1.7210 
                 10. 
               
               
                 2 
                 3 
                 5 
                 1.7131 
                 10. 
               
               
                 0 
                 5 
                 3 
                 1.7112 
                 17. 
               
               
                 1 
                 1 
                 7 
                 1.7090 
                 18. 
               
               
                 2 
                 4 
                 −5 
                 1.7085 
                 10. 
               
               
                 3 
                 4 
                 −4 
                 1.7083 
                 12. 
               
               
                 1 
                 0 
                 −8 
                 1.6647 
                 12. 
               
               
                 3 
                 2 
                 5 
                 1.6568 
                 9. 
               
               
                 4 
                 1 
                 4 
                 1.6524 
                 22. 
               
               
                 1 
                 1 
                 −8 
                 1.6388 
                 37. 
               
               
                 4 
                 4 
                 −2 
                 1.6369 
                 8. 
               
               
                 4 
                 4 
                 0 
                 1.6201 
                 16. 
               
               
                 5 
                 1 
                 2 
                 1.6182 
                 11. 
               
               
                 4 
                 4 
                 −3 
                 1.6072 
                 19. 
               
               
                 3 
                 5 
                 −1 
                 1.5956 
                 18. 
               
               
                 3 
                 1 
                 6 
                 1.5677 
                 14. 
               
               
                 1 
                 2 
                 −8 
                 1.5676 
                 9. 
               
               
                 2 
                 5 
                 3 
                 1.5536 
                 13. 
               
               
                 0 
                 6 
                 0 
                 1.5527 
                 9. 
               
               
                 2 
                 4 
                 5 
                 1.5405 
                 13. 
               
               
                 3 
                 3 
                 5 
                 1.5396 
                 8. 
               
               
                 3 
                 3 
                 −7 
                 1.5384 
                 9. 
               
               
                 6 
                 1 
                 −2 
                 1.5243 
                 8. 
               
               
                 4 
                 4 
                 2 
                 1.5140 
                 12. 
               
               
                   
               
             
          
         
       
     
       EXAMPLE 2 
     Solvated Form of Arasertaconazole Mononitrate with ½ Mole of Acetone (IV) 
       [0071]    The precipitation or crystallization of polymorph I of sertaconazole mononitrate (III) at a temperature below 333° K in acetone or any mixture (50:50, v/v) of acetone with other solvent, under a high vaporization temperature, such as methanol, ethanol, toluene, 4-chlorotoluene, acetic acid, ethyl acetate, trichloromethane, water, or binary mixture thereof, led to the solvated form of arasertaconazole mononitrate with ½ mole of acetone (IV). Crystallographic data of the obtained product are presented in Tables 3 and 4. 
         [0000]    
       
         
               
             
               
               
             
               
             
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Crystal data and structure refinements for the 
               
               
                 solvated form of arasertaconazole mononitrate 
               
               
                 with ½ mole of acetone (IV) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Molecular formula 
                 C 20 H 16 Cl 3 N 3 O 4 S•0.5 C 3 H 6 O 
               
               
                 Molecular weight 
                 510.67 
               
               
                 Wavelength (Å) 
                 0.71069 
               
               
                 Crystal system, space group 
                 Monoclinic, P2 1   
               
             
          
           
               
                 Unit cell dimensions 
               
             
          
           
               
                 A (Å) 
                 15.3710(10) 
               
               
                 B (Å) 
                 9.7800(10) 
               
               
                 C (Å) 
                 17.5570(10) 
               
               
                 β (°) = 
                 92.7800(10) 
               
               
                 Volume (Å 3 ) 
                 2636.2(4) 
               
               
                 Z, Density (calculated) 
                 4, 1.287 mg/m 3   
               
               
                 μ (mm −1 ) 
                 0.534 
               
               
                 F(000) 
                 512 
               
               
                 Crystal size (mm) 
                 0.1 × 0.1 × 0.2 
               
               
                 θ Range 
                 1.3-28.5 deg. 
               
               
                 Index Range 
                 0 ≦ h ≦ 18, 0 ≦ k ≦ 12, −22 ≦ l ≦ 21 
               
               
                 Reflections collected/ 
                 5644/5033 [R(int) = 0.03] 
               
               
                 Independent reflections 
               
               
                 Integrity at 2θ 
                 87.4% 
               
               
                 Data/parameters 
                 5033/596 
               
               
                 Goodness-of-Fit F 2   
                 1.98 
               
               
                 Final R indices [I &gt; 
                 R1 = 0.1001, wR2 = 0.301 
               
               
                 2sigma(I)] 
               
               
                 Absolute structure parameter 
                 −0.02(10) 
               
               
                 Largest difference peak and 
                 0.38 and −0.47 e.A −3   
               
               
                 hole 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 X-ray diffraction peak intensities and spacing for the solvated form of 
               
               
                 arasertaconazole mononitrate with ½ mole of acetone (IV) 
               
             
          
           
               
                 h 
                 k 
                 l 
                 D 
                 I 
               
               
                   
               
             
          
           
               
                 1 
                 0 
                 0 
                 15.3529 
                 101. 
               
               
                 0 
                 0 
                 2 
                 8.7682 
                 265. 
               
               
                 0 
                 1 
                 1 
                 8.5415 
                 34. 
               
               
                 1 
                 0 
                 −2 
                 7.7781 
                 69. 
               
               
                 1 
                 1 
                 −1 
                 7.5402 
                 81. 
               
               
                 1 
                 0 
                 2 
                 7.4597 
                 76. 
               
               
                 1 
                 1 
                 1 
                 7.3903 
                 150. 
               
               
                 2 
                 0 
                 −1 
                 7.1610 
                 9. 
               
               
                 2 
                 0 
                 1 
                 6.9102 
                 40. 
               
               
                 0 
                 1 
                 2 
                 6.5285 
                 611. 
               
               
                 1 
                 1 
                 −2 
                 6.0876 
                 23. 
               
               
                 2 
                 1 
                 0 
                 6.0385 
                 115. 
               
               
                 1 
                 1 
                 2 
                 5.9313 
                 185. 
               
               
                 0 
                 0 
                 3 
                 5.8454 
                 18. 
               
               
                 2 
                 1 
                 −1 
                 5.7777 
                 187. 
               
               
                 2 
                 1 
                 1 
                 5.6436 
                 129. 
               
               
                 2 
                 0 
                 2 
                 5.6417 
                 170. 
               
               
                 1 
                 0 
                 −3 
                 5.5532 
                 81. 
               
               
                 1 
                 0 
                 3 
                 5.3769 
                 54. 
               
               
                 2 
                 1 
                 −2 
                 5.0643 
                 122. 
               
               
                 0 
                 1 
                 3 
                 5.0175 
                 9. 
               
               
                 3 
                 0 
                 −1 
                 4.9781 
                 30. 
               
               
                 0 
                 2 
                 0 
                 4.8900 
                 62. 
               
               
                 2 
                 1 
                 2 
                 4.8869 
                 111. 
               
               
                 3 
                 0 
                 1 
                 4.8499 
                 57. 
               
               
                 1 
                 1 
                 −3 
                 4.8290 
                 206. 
               
               
                 2 
                 0 
                 −3 
                 4.7633 
                 17. 
               
               
                 1 
                 1 
                 3 
                 4.7117 
                 191. 
               
               
                 0 
                 2 
                 1 
                 4.7103 
                 25. 
               
               
                 1 
                 2 
                 0 
                 4.6594 
                 278. 
               
               
                 2 
                 0 
                 3 
                 4.5456 
                 24. 
               
               
                 3 
                 1 
                 0 
                 4.5344 
                 196. 
               
               
                 1 
                 2 
                 −1 
                 4.5197 
                 25. 
               
               
                 3 
                 0 
                 −2 
                 4.5163 
                 186. 
               
               
                 1 
                 2 
                 1 
                 4.4868 
                 30. 
               
               
                 3 
                 1 
                 −1 
                 4.4364 
                 102. 
               
               
                 3 
                 1 
                 1 
                 4.3450 
                 70. 
               
               
                 3 
                 0 
                 2 
                 4.3294 
                 260. 
               
               
                 2 
                 1 
                 −3 
                 4.2824 
                 111. 
               
               
                 1 
                 0 
                 −4 
                 4.2706 
                 216. 
               
               
                 1 
                 0 
                 4 
                 4.1626 
                 14. 
               
               
                 1 
                 2 
                 −2 
                 4.1398 
                 148. 
               
               
                 2 
                 2 
                 0 
                 4.1243 
                 116. 
               
               
                 3 
                 1 
                 −2 
                 4.1002 
                 30. 
               
               
                 1 
                 2 
                 2 
                 4.0896 
                 224. 
               
               
                 0 
                 1 
                 4 
                 4.0005 
                 84. 
               
               
                 2 
                 2 
                 1 
                 3.9916 
                 229. 
               
               
                 3 
                 1 
                 2 
                 3.9588 
                 895. 
               
               
                 3 
                 0 
                 −3 
                 3.9465 
                 35. 
               
               
                 1 
                 1 
                 −4 
                 3.9138 
                 327. 
               
               
                 2 
                 0 
                 −4 
                 3.8891 
                 16. 
               
               
                 4 
                 0 
                 0 
                 3.8382 
                 44. 
               
               
                 1 
                 1 
                 4 
                 3.8301 
                 110. 
               
               
                 4 
                 0 
                 −1 
                 3.7880 
                 286. 
               
               
                 2 
                 2 
                 −2 
                 3.7701 
                 195. 
               
               
                 0 
                 2 
                 3 
                 3.7507 
                 17. 
               
               
                 2 
                 2 
                 2 
                 3.6951 
                 65. 
               
               
                 1 
                 2 
                 −3 
                 3.6699 
                 30. 
               
               
                 3 
                 1 
                 −3 
                 3.6598 
                 118. 
               
               
                 1 
                 2 
                 3 
                 3.6177 
                 151. 
               
               
                 2 
                 1 
                 −4 
                 3.6138 
                 98. 
               
               
                 4 
                 0 
                 −2 
                 3.5805 
                 1000. 
               
               
                 4 
                 1 
                 0 
                 3.5729 
                 172. 
               
               
                 3 
                 2 
                 0 
                 3.5355 
                 249. 
               
               
                 4 
                 1 
                 −1 
                 3.5323 
                 172. 
               
               
                 3 
                 1 
                 3 
                 3.5105 
                 22. 
               
               
                 0 
                 0 
                 5 
                 3.5073 
                 27. 
               
               
                 3 
                 2 
                 −1 
                 3.4885 
                 12. 
               
               
                 2 
                 1 
                 4 
                 3.4850 
                 26. 
               
               
                 4 
                 1 
                 1 
                 3.4705 
                 43. 
               
               
                 1 
                 0 
                 −5 
                 3.4558 
                 10. 
               
               
                 4 
                 0 
                 2 
                 3.4551 
                 193. 
               
               
                 3 
                 2 
                 1 
                 3.4435 
                 65. 
               
               
                 3 
                 0 
                 −4 
                 3.4122 
                 57. 
               
               
                 2 
                 2 
                 −3 
                 3.4121 
                 12. 
               
               
                 4 
                 1 
                 −2 
                 3.3622 
                 134. 
               
               
                 2 
                 2 
                 3 
                 3.3293 
                 66. 
               
               
                 3 
                 2 
                 −2 
                 3.3177 
                 58. 
               
               
                 0 
                 1 
                 5 
                 3.3014 
                 36. 
               
               
                 0 
                 2 
                 4 
                 3.2643 
                 191. 
               
               
                 1 
                 1 
                 −5 
                 3.2583 
                 13. 
               
               
                 4 
                 1 
                 2 
                 3.2578 
                 97. 
               
               
                 3 
                 0 
                 4 
                 3.2524 
                 9. 
               
               
                 3 
                 2 
                 2 
                 3.2415 
                 30. 
               
               
                 3 
                 1 
                 −4 
                 3.2217 
                 9. 
               
               
                 0 
                 3 
                 1 
                 3.2051 
                 26. 
               
               
                 1 
                 1 
                 5 
                 3.1978 
                 53. 
               
               
                 1 
                 3 
                 0 
                 3.1889 
                 67. 
               
               
                 1 
                 2 
                 4 
                 3.1697 
                 72. 
               
               
                 1 
                 3 
                 −1 
                 3.1430 
                 27. 
               
               
                 4 
                 0 
                 3 
                 3.1393 
                 21. 
               
               
                 2 
                 0 
                 5 
                 3.1332 
                 79. 
               
               
                 1 
                 3 
                 1 
                 3.1319 
                 44. 
               
               
                 4 
                 1 
                 −3 
                 3.1117 
                 31. 
               
               
                 3 
                 1 
                 4 
                 3.0862 
                 18. 
               
               
                 2 
                 1 
                 −5 
                 3.0844 
                 58. 
               
               
                 3 
                 2 
                 −3 
                 3.0711 
                 75. 
               
               
                 5 
                 0 
                 0 
                 3.0706 
                 109. 
               
               
                 5 
                 0 
                 −1 
                 3.0498 
                 12. 
               
               
                 1 
                 3 
                 −2 
                 3.0066 
                 17. 
               
               
                 5 
                 0 
                 1 
                 2.9999 
                 28. 
               
               
                 4 
                 1 
                 3 
                 2.9891 
                 34. 
               
               
                 1 
                 3 
                 2 
                 2.9872 
                 16. 
               
               
                 3 
                 2 
                 3 
                 2.9813 
                 90. 
               
               
                 2 
                 2 
                 4 
                 2.9656 
                 15. 
               
               
                 3 
                 0 
                 −5 
                 2.9608 
                 18. 
               
               
                 5 
                 0 
                 −2 
                 2.9429 
                 47. 
               
               
                 5 
                 1 
                 0 
                 2.9296 
                 14. 
               
               
                 1 
                 0 
                 −6 
                 2.8971 
                 58. 
               
               
                 4 
                 2 
                 −2 
                 2.8889 
                 32. 
               
               
                 5 
                 1 
                 1 
                 2.8681 
                 18. 
               
               
                 2 
                 3 
                 −2 
                 2.8556 
                 17. 
               
               
                 5 
                 0 
                 2 
                 2.8551 
                 9. 
               
               
                 0 
                 2 
                 5 
                 2.8500 
                 11. 
               
               
                 0 
                 3 
                 3 
                 2.8472 
                 12. 
               
               
                 3 
                 1 
                 −5 
                 2.8338 
                 13. 
               
               
                 4 
                 1 
                 −4 
                 2.8330 
                 9. 
               
               
                 2 
                 3 
                 2 
                 2.8226 
                 72. 
               
               
                 1 
                 2 
                 −5 
                 2.8222 
                 15. 
               
               
                 4 
                 2 
                 2 
                 2.8218 
                 24. 
               
               
                 5 
                 1 
                 −2 
                 2.8181 
                 14. 
               
               
                 3 
                 2 
                 −4 
                 2.7983 
                 32. 
               
               
                 1 
                 3 
                 3 
                 2.7876 
                 10. 
               
               
                 1 
                 1 
                 −6 
                 2.7778 
                 19. 
               
               
                 5 
                 0 
                 −3 
                 2.7743 
                 10. 
               
               
                 3 
                 3 
                 0 
                 2.7495 
                 9. 
               
               
                 5 
                 1 
                 2 
                 2.7407 
                 12. 
               
               
                 1 
                 1 
                 6 
                 2.7326 
                 41. 
               
               
                 3 
                 3 
                 −1 
                 2.7272 
                 20. 
               
               
                 4 
                 2 
                 −3 
                 2.7253 
                 9. 
               
               
                 3 
                 1 
                 5 
                 2.7183 
                 15. 
               
               
                 4 
                 1 
                 4 
                 2.7104 
                 10. 
               
               
                 3 
                 2 
                 4 
                 2.7081 
                 16. 
               
               
                 2 
                 2 
                 −5 
                 2.7068 
                 8. 
               
               
                 3 
                 3 
                 1 
                 2.7056 
                 13. 
               
               
                 2 
                 1 
                 −6 
                 2.6710 
                 23. 
               
               
                 3 
                 3 
                 −2 
                 2.6433 
                 69. 
               
               
                 4 
                 2 
                 3 
                 2.6418 
                 12. 
               
               
                 0 
                 3 
                 4 
                 2.6160 
                 25. 
               
               
                 3 
                 3 
                 2 
                 2.6043 
                 21. 
               
               
                 5 
                 2 
                 0 
                 2.6004 
                 12. 
               
               
                 2 
                 1 
                 6 
                 2.5923 
                 20. 
               
               
                 1 
                 3 
                 −4 
                 2.5913 
                 43. 
               
               
                 5 
                 0 
                 −4 
                 2.5744 
                 16. 
               
               
                 5 
                 1 
                 3 
                 2.5718 
                 39. 
               
               
                 1 
                 3 
                 4 
                 2.5666 
                 23. 
               
               
                 3 
                 2 
                 −5 
                 2.5327 
                 49. 
               
               
                 4 
                 2 
                 −4 
                 2.5321 
                 28. 
               
               
                 5 
                 2 
                 −2 
                 2.5215 
                 16. 
               
               
                 2 
                 3 
                 −4 
                 2.4984 
                 8. 
               
               
                 1 
                 0 
                 −7 
                 2.4918 
                 19. 
               
               
                 6 
                 0 
                 −2 
                 2.4890 
                 8. 
               
               
                 6 
                 1 
                 0 
                 2.4755 
                 11. 
               
               
                 6 
                 1 
                 −1 
                 2.4673 
                 11. 
               
               
                 5 
                 2 
                 2 
                 2.4656 
                 39. 
               
               
                 3 
                 3 
                 3 
                 2.4634 
                 9. 
               
               
                 2 
                 3 
                 4 
                 2.4546 
                 10. 
               
               
                 1 
                 0 
                 7 
                 2.4536 
                 11. 
               
               
                 4 
                 1 
                 5 
                 2.4483 
                 8. 
               
               
                 4 
                 2 
                 4 
                 2.4434 
                 9. 
               
               
                 6 
                 1 
                 1 
                 2.4354 
                 16. 
               
               
                 6 
                 0 
                 2 
                 2.4249 
                 14. 
               
               
                 0 
                 4 
                 1 
                 2.4216 
                 16. 
               
               
                 1 
                 4 
                 0 
                 2.4146 
                 13. 
               
               
                 2 
                 2 
                 −6 
                 2.4145 
                 11. 
               
               
                 6 
                 1 
                 −2 
                 2.4121 
                 9. 
               
               
                 4 
                 3 
                 −2 
                 2.4105 
                 12. 
               
               
                 3 
                 1 
                 6 
                 2.4099 
                 28. 
               
               
                 1 
                 4 
                 −1 
                 2.3945 
                 34. 
               
               
                 1 
                 4 
                 1 
                 2.3895 
                 8. 
               
               
                 0 
                 3 
                 5 
                 2.3878 
                 24. 
               
               
                 5 
                 1 
                 4 
                 2.3853 
                 26. 
               
               
                 4 
                 0 
                 −6 
                 2.3816 
                 12. 
               
               
                 2 
                 2 
                 6 
                 2.3559 
                 20. 
               
               
                 2 
                 0 
                 7 
                 2.3482 
                 36. 
               
               
                 1 
                 3 
                 5 
                 2.3477 
                 17. 
               
               
                 2 
                 4 
                 0 
                 2.3297 
                 23. 
               
               
                 1 
                 4 
                 2 
                 2.3234 
                 29. 
               
               
                 6 
                 1 
                 −3 
                 2.3189 
                 24. 
               
               
                 2 
                 4 
                 −1 
                 2.3138 
                 8. 
               
               
                 6 
                 0 
                 3 
                 2.3034 
                 13. 
               
               
                 3 
                 3 
                 4 
                 2.3025 
                 12. 
               
               
                 5 
                 1 
                 −5 
                 2.3014 
                 23. 
               
               
                 3 
                 0 
                 −7 
                 2.2944 
                 32. 
               
               
                 3 
                 2 
                 −6 
                 2.2907 
                 13. 
               
               
                 4 
                 0 
                 6 
                 2.2728 
                 18. 
               
               
                 6 
                 2 
                 0 
                 2.2672 
                 12. 
               
               
                 6 
                 2 
                 −1 
                 2.2609 
                 8. 
               
               
                 2 
                 4 
                 −2 
                 2.2598 
                 18. 
               
               
                 2 
                 3 
                 5 
                 2.2590 
                 18. 
               
               
                 6 
                 0 
                 −4 
                 2.2581 
                 12. 
               
               
                 0 
                 4 
                 3 
                 2.2556 
                 8. 
               
               
                 2 
                 4 
                 2 
                 2.2434 
                 9. 
               
               
                 1 
                 4 
                 −3 
                 2.2377 
                 9. 
               
               
                 3 
                 1 
                 −7 
                 2.2338 
                 19. 
               
               
                 0 
                 2 
                 7 
                 2.2296 
                 14. 
               
               
                 6 
                 2 
                 −2 
                 2.2182 
                 15. 
               
               
                 4 
                 1 
                 6 
                 2.2138 
                 9. 
               
               
                 3 
                 0 
                 7 
                 2.2082 
                 9. 
               
               
                 3 
                 4 
                 0 
                 2.2061 
                 17. 
               
               
                 6 
                 1 
                 −4 
                 2.2002 
                 26. 
               
               
                 5 
                 2 
                 4 
                 2.1973 
                 23. 
               
               
                 7 
                 0 
                 0 
                 2.1933 
                 17. 
               
               
                 0 
                 0 
                 8 
                 2.1920 
                 20. 
               
               
                 0 
                 3 
                 6 
                 2.1762 
                 14. 
               
               
                 6 
                 2 
                 2 
                 2.1725 
                 8. 
               
               
                 5 
                 0 
                 −6 
                 2.1702 
                 22. 
               
               
                 2 
                 2 
                 −7 
                 2.1663 
                 17. 
               
               
                 1 
                 0 
                 8 
                 2.1555 
                 8. 
               
               
                 3 
                 4 
                 −2 
                 2.1501 
                 17. 
               
               
                 5 
                 3 
                 2 
                 2.1479 
                 19. 
               
               
                 4 
                 2 
                 −6 
                 2.1412 
                 36. 
               
               
                 7 
                 1 
                 0 
                 2.1401 
                 22. 
               
               
                 0 
                 1 
                 8 
                 2.1390 
                 19. 
               
               
                 4 
                 3 
                 4 
                 2.1331 
                 21. 
               
               
                 1 
                 1 
                 −8 
                 2.1323 
                 18. 
               
               
                 2 
                 2 
                 7 
                 2.1168 
                 10. 
               
               
                 1 
                 4 
                 4 
                 2.1082 
                 24. 
               
               
                 7 
                 0 
                 2 
                 2.1038 
                 13. 
               
               
                 7 
                 1 
                 −2 
                 2.1021 
                 14. 
               
               
                 2 
                 3 
                 6 
                 2.0741 
                 10. 
               
               
                 2 
                 4 
                 −4 
                 2.0699 
                 15. 
               
               
                 6 
                 1 
                 −5 
                 2.0687 
                 12. 
               
               
                 4 
                 4 
                 0 
                 2.0621 
                 15. 
               
               
                 6 
                 2 
                 −4 
                 2.0501 
                 17. 
               
               
                 5 
                 2 
                 5 
                 2.0490 
                 14. 
               
               
                 2 
                 4 
                 4 
                 2.0448 
                 12. 
               
               
                 5 
                 1 
                 6 
                 2.0228 
                 15. 
               
               
                 0 
                 4 
                 5 
                 2.0057 
                 11. 
               
               
                 7 
                 2 
                 0 
                 2.0012 
                 17. 
               
               
                 4 
                 3 
                 5 
                 1.9981 
                 13. 
               
               
                 1 
                 4 
                 −5 
                 1.9960 
                 24. 
               
               
                 4 
                 4 
                 2 
                 1.9958 
                 15. 
               
               
                 5 
                 0 
                 −7 
                 1.9889 
                 25. 
               
               
                 0 
                 3 
                 7 
                 1.9864 
                 10. 
               
               
                 6 
                 2 
                 4 
                 1.9794 
                 18. 
               
               
                 6 
                 1 
                 5 
                 1.9792 
                 8. 
               
               
                 6 
                 3 
                 −2 
                 1.9783 
                 11. 
               
               
                 1 
                 2 
                 8 
                 1.9723 
                 9. 
               
               
                 4 
                 2 
                 −7 
                 1.9651 
                 8. 
               
               
                 5 
                 3 
                 4 
                 1.9635 
                 16. 
               
               
                 4 
                 4 
                 −3 
                 1.9608 
                 16. 
               
               
                 7 
                 1 
                 −4 
                 1.9601 
                 14. 
               
               
                 3 
                 4 
                 4 
                 1.9544 
                 52. 
               
               
                 4 
                 0 
                 −8 
                 1.9445 
                 9. 
               
               
                 6 
                 2 
                 −5 
                 1.9424 
                 9. 
               
               
                 4 
                 4 
                 3 
                 1.9290 
                 13. 
               
               
                 2 
                 4 
                 5 
                 1.9275 
                 8. 
               
               
                 4 
                 3 
                 −6 
                 1.9231 
                 23. 
               
               
                 8 
                 0 
                 0 
                 1.9191 
                 9. 
               
               
                 5 
                 4 
                 0 
                 1.9127 
                 10. 
               
               
                 0 
                 1 
                 9 
                 1.9109 
                 14. 
               
               
                 0 
                 5 
                 2 
                 1.9091 
                 11. 
               
               
                 1 
                 5 
                 −2 
                 1.8969 
                 18. 
               
               
                 3 
                 2 
                 −8 
                 1.8916 
                 11. 
               
               
                 8 
                 1 
                 0 
                 1.8832 
                 11. 
               
               
                 5 
                 4 
                 −2 
                 1.8806 
                 12. 
               
               
                 7 
                 1 
                 −5 
                 1.8666 
                 13. 
               
               
                 5 
                 1 
                 7 
                 1.8619 
                 10. 
               
               
                 8 
                 1 
                 −2 
                 1.8595 
                 15 
               
               
                 8 
                 0 
                 2 
                 1.8560 
                 11. 
               
               
                 5 
                 3 
                 5 
                 1.8555 
                 9. 
               
               
                 0 
                 5 
                 3 
                 1.8549 
                 17. 
               
               
                 8 
                 0 
                 −3 
                 1.8501 
                 14. 
               
               
                 2 
                 5 
                 2 
                 1.8481 
                 9. 
               
               
                 6 
                 1 
                 6 
                 1.8467 
                 20. 
               
               
                 4 
                 1 
                 8 
                 1.8319 
                 15. 
               
               
                 8 
                 1 
                 2 
                 1.8235 
                 10. 
               
               
                 0 
                 3 
                 8 
                 1.8191 
                 15. 
               
               
                 8 
                 1 
                 −3 
                 1.8179 
                 13. 
               
               
                 7 
                 3 
                 −1 
                 1.8176 
                 16. 
               
               
                 3 
                 5 
                 −2 
                 1.7949 
                 12. 
               
               
                 4 
                 3 
                 −7 
                 1.7925 
                 10. 
               
               
                 8 
                 1 
                 3 
                 1.7681 
                 11. 
               
               
                 6 
                 4 
                 0 
                 1.7677 
                 9. 
               
               
                 8 
                 1 
                 −4 
                 1.7610 
                 15. 
               
               
                 4 
                 5 
                 0 
                 1.7427 
                 12. 
               
               
                 2 
                 5 
                 4 
                 1.7323 
                 11. 
               
               
                 6 
                 3 
                 5 
                 1.7177 
                 10. 
               
               
                 4 
                 5 
                 2 
                 1.7022 
                 9. 
               
               
                 6 
                 4 
                 3 
                 1.6766 
                 11. 
               
               
                 2 
                 5 
                 −5 
                 1.6759 
                 13. 
               
               
                 1 
                 3 
                 −9 
                 1.6702 
                 12. 
               
               
                 9 
                 1 
                 1 
                 1.6653 
                 11. 
               
               
                 3 
                 4 
                 7 
                 1.6388 
                 9. 
               
               
                 9 
                 0 
                 −4 
                 1.6165 
                 12. 
               
               
                 9 
                 2 
                 0 
                 1.6107 
                 8. 
               
               
                 2 
                 5 
                 −6 
                 1.5991 
                 9. 
               
               
                 9 
                 1 
                 4 
                 1.5447 
                 9. 
               
               
                 5 
                 4 
                 −7 
                 1.5429 
                 11. 
               
               
                   
               
             
          
         
       
     
         [0072]    Drying of the product at a temperature of ≦353° K led to polymorph I, whereas at a temperature of &gt;353° K polymorph II was also obtained, its proportion being dependent on the drying time. 
       EXAMPLE 3 
     Polimorph II of Arasertaconazole Mononitrate (III) 
       [0073]    Polymorph II was obtained by heating the solvated form with ½ mole of acetone (IV) at 354.2° K. This value corresponds to the start temperature of Differential Thermal Analysis (DTA) and Thermogravimetry (TG). Polymorph II was also obtained by heating polymorph I at 373° K over a period from 2 to 24 h. DTA, TG or X-Ray Powder Diffraction (XRD) analysis showed this conversion. Similarly, polymorph II as a pure form was obtained by crystallization from polymorph I or from (IV) in water (Tables 5 and 6). 
         [0000]    
       
         
               
             
               
               
             
               
             
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Crystal data and structure refinements for polymorph 
               
               
                 II of arasertaconazole mononitrate (III) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Molecular formula 
                 C 20 H 16 Cl 3 N 3 O 4 S 
               
               
                 Molecular weight 
                 500.77 
               
               
                 Wavelength (Å) 
                 0.71069 
               
               
                 Crystal system, space group 
                 Orthorhombic, P2 1 2 1 2 1   
               
             
          
           
               
                 Unit cell dimensions 
               
             
          
           
               
                 A (Å) 
                 9.3550(10) 
               
               
                 B (Å) 
                 9.5010(10) 
               
               
                 C (Å) 
                 25.3810(10) 
               
               
                 Volume (Å 3 ) 
                 2255.9(3) 
               
               
                 Z, Density (calculated) 
                 4, 1.474 mg/m 3   
               
               
                 μ (mm −1 ) 
                 0.531 
               
               
                 F(000) 
                 1024 
               
               
                 Crystal size (mm) 
                 0.1 × 0.2 × 0.2 
               
               
                 θ Range 
                 1.60-25.00 degrees 
               
               
                 Index ranges 
                 0 ≦ h ≦ 11, 0 ≦ k ≦ 10, 0 ≦ l ≦ 30 
               
               
                 Reflections collected/ 
                 5610/1976 [R(int) = 0.10] 
               
               
                 Independent reflections 
               
               
                 Integrity at 2θ 
                 85.5% 
               
               
                 Data/parameters 
                 1976/283 
               
               
                 Goodness-of-Fit F 2   
                 0.912 
               
               
                 Final R indices [I &gt; 
                 R1 = 0.048, wR2 = 0.104 
               
               
                 2sigma(I)] 
               
               
                 R indices (all data) 
                 R1 = 0.141, wR2 = 0.136 
               
               
                 Absolute structure parameter 
                 −0.11(16) 
               
               
                 Largest difference peak and 
                 0.241 and −0.136 e.A −3   
               
               
                 hole 
               
               
                   
               
             
          
         
       
     
       Differential Scanning Calorimetry (DSC) 
       [0074]    Only an endothermic peak was recorded at 171.5° C., i.e., the characteristic melting peak within the range of 170°-172° C.,  FIG. 2 . 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 X-ray diffraction peak intensities and spacing for 
               
               
                 polymorph II of arasertaconazole mononitrate (III) 
               
             
          
           
               
                 h 
                 k 
                 l 
                 d 
                 I 
               
               
                   
               
             
          
           
               
                 0 
                 1 
                 1 
                 8.8980 
                 74. 
               
               
                 1 
                 0 
                 1 
                 8.7777 
                 40. 
               
               
                 0 
                 1 
                 2 
                 7.6057 
                 280. 
               
               
                 1 
                 1 
                 0 
                 6.6660 
                 14. 
               
               
                 1 
                 1 
                 1 
                 6.4473 
                 183. 
               
               
                 0 
                 0 
                 4 
                 6.3453 
                 85. 
               
               
                 0 
                 1 
                 3 
                 6.3184 
                 40. 
               
               
                 1 
                 0 
                 3 
                 6.2749 
                 10. 
               
               
                 1 
                 1 
                 2 
                 5.9014 
                 58. 
               
               
                 0 
                 1 
                 4 
                 5.2767 
                 100. 
               
               
                 1 
                 0 
                 4 
                 5.2513 
                 28. 
               
               
                 1 
                 1 
                 3 
                 5.2360 
                 636. 
               
               
                 0 
                 2 
                 0 
                 4.7505 
                 41. 
               
               
                 0 
                 2 
                 1 
                 4.6694 
                 16. 
               
               
                 2 
                 0 
                 1 
                 4.6000 
                 66. 
               
               
                 1 
                 1 
                 4 
                 4.5960 
                 225. 
               
               
                 0 
                 1 
                 5 
                 4.4772 
                 83. 
               
               
                 1 
                 0 
                 5 
                 4.4617 
                 160. 
               
               
                 0 
                 2 
                 2 
                 4.4490 
                 382. 
               
               
                 1 
                 2 
                 0 
                 4.2357 
                 21. 
               
               
                 0 
                 0 
                 6 
                 4.2302 
                 89. 
               
               
                 0 
                 2 
                 3 
                 4.1422 
                 312. 
               
               
                 2 
                 1 
                 1 
                 4.1403 
                 21. 
               
               
                 2 
                 0 
                 3 
                 4.0935 
                 18. 
               
               
                 1 
                 1 
                 5 
                 4.0385 
                 175. 
               
               
                 2 
                 1 
                 2 
                 3.9843 
                 44. 
               
               
                 0 
                 1 
                 6 
                 3.8644 
                 23. 
               
               
                 1 
                 0 
                 6 
                 3.8544 
                 171. 
               
               
                 0 
                 2 
                 4 
                 3.8028 
                 107. 
               
               
                 1 
                 2 
                 3 
                 3.7875 
                 45. 
               
               
                 2 
                 0 
                 4 
                 3.7651 
                 315. 
               
               
                 2 
                 1 
                 3 
                 3.7594 
                 176. 
               
               
                 1 
                 1 
                 6 
                 3.5717 
                 47. 
               
               
                 1 
                 2 
                 4 
                 3.5229 
                 31. 
               
               
                 2 
                 1 
                 4 
                 3.5002 
                 128. 
               
               
                 2 
                 0 
                 5 
                 3.4398 
                 34. 
               
               
                 0 
                 1 
                 7 
                 3.3876 
                 1000. 
               
               
                 1 
                 0 
                 7 
                 3.3808 
                 25. 
               
               
                 2 
                 2 
                 1 
                 3.3046 
                 159. 
               
               
                 1 
                 2 
                 5 
                 3.2522 
                 54. 
               
               
                 2 
                 1 
                 5 
                 3.2344 
                 10. 
               
               
                 2 
                 2 
                 2 
                 3.2237 
                 54. 
               
               
                 1 
                 1 
                 7 
                 3.1852 
                 32. 
               
               
                 0 
                 0 
                 8 
                 3.1726 
                 162. 
               
               
                 0 
                 2 
                 6 
                 3.1592 
                 77. 
               
               
                 2 
                 2 
                 3 
                 3.1010 
                 119. 
               
               
                 0 
                 3 
                 2 
                 3.0728 
                 39. 
               
               
                 0 
                 1 
                 8 
                 3.0093 
                 27. 
               
               
                 1 
                 3 
                 0 
                 2.9998 
                 30. 
               
               
                 2 
                 1 
                 6 
                 2.9792 
                 45. 
               
               
                 1 
                 3 
                 1 
                 2.9790 
                 9. 
               
               
                 0 
                 3 
                 3 
                 2.9660 
                 26. 
               
               
                 2 
                 2 
                 4 
                 2.9507 
                 31. 
               
               
                 3 
                 1 
                 1 
                 2.9428 
                 141. 
               
               
                 1 
                 3 
                 2 
                 2.9193 
                 106. 
               
               
                 3 
                 1 
                 2 
                 2.8852 
                 41. 
               
               
                 0 
                 2 
                 7 
                 2.8822 
                 10. 
               
               
                 1 
                 1 
                 8 
                 2.8647 
                 10. 
               
               
                 0 
                 3 
                 4 
                 2.8337 
                 18. 
               
               
                 2 
                 2 
                 5 
                 2.7861 
                 23. 
               
               
                 2 
                 1 
                 7 
                 2.7436 
                 8. 
               
               
                 1 
                 3 
                 4 
                 2.7120 
                 37. 
               
               
                 0 
                 3 
                 5 
                 2.6869 
                 10. 
               
               
                 2 
                 2 
                 6 
                 2.6180 
                 10. 
               
               
                 2 
                 3 
                 1 
                 2.6086 
                 19. 
               
               
                 3 
                 2 
                 0 
                 2.6069 
                 10. 
               
               
                 1 
                 1 
                 9 
                 2.5972 
                 14. 
               
               
                 3 
                 1 
                 5 
                 2.5589 
                 11. 
               
               
                 3 
                 2 
                 2 
                 2.5536 
                 23. 
               
               
                 0 
                 0 
                 10 
                 2.5381 
                 9. 
               
               
                 0 
                 3 
                 6 
                 2.5352 
                 9. 
               
               
                 2 
                 1 
                 8 
                 2.5308 
                 9. 
               
               
                 2 
                 3 
                 3 
                 2.5049 
                 9. 
               
               
                 1 
                 3 
                 6 
                 2.4470 
                 10. 
               
               
                 2 
                 3 
                 4 
                 2.4236 
                 8. 
               
               
                 0 
                 4 
                 1 
                 2.3649 
                 12. 
               
               
                 3 
                 0 
                 7 
                 2.3642 
                 9. 
               
               
                 1 
                 2 
                 9 
                 2.3474 
                 12. 
               
               
                 2 
                 3 
                 5 
                 2.3299 
                 26. 
               
               
                 4 
                 0 
                 1 
                 2.3289 
                 10. 
               
               
                 3 
                 2 
                 5 
                 2.3190 
                 8. 
               
               
                 1 
                 3 
                 7 
                 2.3113 
                 10. 
               
               
                 3 
                 1 
                 7 
                 2.2943 
                 33. 
               
               
                 1 
                 4 
                 1 
                 2.2928 
                 10. 
               
               
                 4 
                 1 
                 1 
                 2.2619 
                 12. 
               
               
                 0 
                 3 
                 8 
                 2.2414 
                 14. 
               
               
                 0 
                 2 
                 10 
                 2.2386 
                 9. 
               
               
                 2 
                 0 
                 10 
                 2.2308 
                 14. 
               
               
                 2 
                 3 
                 6 
                 2.2289 
                 10. 
               
               
                 3 
                 3 
                 0 
                 2.2220 
                 26. 
               
               
                 3 
                 2 
                 6 
                 2.2193 
                 36. 
               
               
                 3 
                 3 
                 1 
                 2.2135 
                 10. 
               
               
                 4 
                 0 
                 4 
                 2.1944 
                 29. 
               
               
                 3 
                 3 
                 2 
                 2.1887 
                 11. 
               
               
                 1 
                 1 
                 11 
                 2.1804 
                 22. 
               
               
                 1 
                 3 
                 8 
                 2.1797 
                 20. 
               
               
                 1 
                 2 
                 10 
                 2.1772 
                 11. 
               
               
                 2 
                 2 
                 9 
                 2.1529 
                 10. 
               
               
                 0 
                 4 
                 5 
                 2.1514 
                 15. 
               
               
                 3 
                 3 
                 3 
                 2.1491 
                 9. 
               
               
                 3 
                 2 
                 7 
                 2.1166 
                 24. 
               
               
                 0 
                 3 
                 9 
                 2.1061 
                 18. 
               
               
                 1 
                 4 
                 5 
                 2.0966 
                 18. 
               
               
                 4 
                 2 
                 1 
                 2.0911 
                 26. 
               
               
                 4 
                 2 
                 2 
                 2.0701 
                 42. 
               
               
                 1 
                 0 
                 12 
                 2.0630 
                 8. 
               
               
                 1 
                 3 
                 9 
                 2.0547 
                 13. 
               
               
                 3 
                 1 
                 9 
                 2.0427 
                 32. 
               
               
                 4 
                 2 
                 3 
                 2.0366 
                 11. 
               
               
                 3 
                 3 
                 5 
                 2.0355 
                 20. 
               
               
                 1 
                 2 
                 11 
                 2.0262 
                 18. 
               
               
                 2 
                 1 
                 11 
                 2.0219 
                 36. 
               
               
                 1 
                 1 
                 12 
                 2.0160 
                 10. 
               
               
                 3 
                 2 
                 8 
                 2.0142 
                 27. 
               
               
                 2 
                 4 
                 4 
                 2.0089 
                 20. 
               
               
                 4 
                 1 
                 6 
                 2.0009 
                 10. 
               
               
                 0 
                 3 
                 10 
                 1.9806 
                 9. 
               
               
                 2 
                 4 
                 5 
                 1.9545 
                 8. 
               
               
                 3 
                 1 
                 10 
                 1.9275 
                 10. 
               
               
                 2 
                 2 
                 11 
                 1.8971 
                 17. 
               
               
                 4 
                 3 
                 1 
                 1.8762 
                 15. 
               
               
                 1 
                 1 
                 13 
                 1.8737 
                 12. 
               
               
                 3 
                 4 
                 2 
                 1.8689 
                 13. 
               
               
                 0 
                 3 
                 11 
                 1.8649 
                 9. 
               
               
                 1 
                 5 
                 2 
                 1.8424 
                 17. 
               
               
                 2 
                 4 
                 7 
                 1.8287 
                 10. 
               
               
                 5 
                 1 
                 2 
                 1.8168 
                 9. 
               
               
                 0 
                 0 
                 14 
                 1.8129 
                 31. 
               
               
                 5 
                 1 
                 3 
                 1.7940 
                 10. 
               
               
                 2 
                 2 
                 12 
                 1.7858 
                 9. 
               
               
                 1 
                 4 
                 9 
                 1.7834 
                 16. 
               
               
                 4 
                 3 
                 5 
                 1.7641 
                 14. 
               
               
                 4 
                 2 
                 8 
                 1.7501 
                 9. 
               
               
                 1 
                 1 
                 14 
                 1.7494 
                 17. 
               
               
                 1 
                 3 
                 12 
                 1.7286 
                 20. 
               
               
                 2 
                 5 
                 3 
                 1.7236 
                 9. 
               
               
                 2 
                 2 
                 13 
                 1.6846 
                 10. 
               
               
                 5 
                 1 
                 6 
                 1.6840 
                 13 
               
               
                 0 
                 1 
                 15 
                 1.6659 
                 12. 
               
               
                 3 
                 5 
                 2 
                 1.6096 
                 8. 
               
               
                 1 
                 6 
                 1 
                 1.5583 
                 9. 
               
               
                   
               
             
          
         
       
     
       Stability 
       [0075]    Polymorph II was stable against humidity and at a temperature below 423° K. Polymorph II remained stable in the course of a 1-month test at ambient temperature or humidity and after 1 day at 25° C./80 RH. No transition from II to I was observed during this 1-month test. The start of endothermic peak temperature occurred at 437.6° K, but the first recorded weight loss began at 449° K from DTA analysis. Polymorph II placed in a furnace at 423° K started decomposition after 2 hours. 
       EXAMPLE 4 
     Determination of Apparent Density and Compacted Density 
       [0076]    The determination of apparent and compacted densities was carried out with a Stampf STAV 2003 volumeter equipped with a 100-mL glass volumetric flask. 
       Procedure 
       [0000]    
       
         (i) The flask was filled with a volume between 50 and 100 mL of test sample. 
         (ii) The volume occupied before the test (mL) was recorded. 
         (iii) 2500 strokes were performed with the volumeter. 
         (iv) The volume occupied after the test (mL) was recorded. 
         (v) The amount of analyzed sample (g) was weighed. 
       
     
       Calculation 
       [0000]    
       
         (i) Apparent density (g/mL)=weight/initial volume 
         (ii) Compacted density (g/mL)=weight/final volume 
       
     
       Results 
       [0084]      
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Apparent density and compacted density of polymorph I 
               
               
                 and polymorph II of arasertaconazole mononitrate (III) 
               
             
          
           
               
                   
                 Polymorph 1 
                 Polymorph II 
               
               
                   
                   
               
             
          
           
               
                   
                 Apparent density (g/mL) 
                 0.78 
                 0.39 
               
               
                   
                 Compacted density (g/mL) 
                 1.08 
                 0.53 
               
               
                   
                   
               
             
          
         
       
     
       EXAMPLE 5 
     1% Cream Formulation (100 g) 
       [0085]      
         [0000]    
       
         
               
               
             
           
               
                   
               
             
             
               
                 Polymorph II of arasertaconazole mononitrate (III) 
                 1.00 g 
               
               
                 Palmitic and stearic acid mono- and diglyceride 
                 6.00 g 
               
               
                 Cetostearyl alcohol with 20 mol of ethylene oxide 
                 1.00 g 
               
               
                 Oleic acid decyl ester 
                 5.00 g 
               
               
                 Undecylenic acid monoethanolamine 
                 2.00 g 
               
               
                 Carbomer 
                 1.00 g 
               
               
                 Triethanolamine 
                 0.60 g 
               
               
                 Methylparaben 
                 0.15 g 
               
               
                 Propylparaben 
                 0.05 g 
               
               
                 Distilled water q.s. to 
                 100.00 g  
               
               
                   
               
             
          
         
       
     
       EXAMPLE 6 
     1% Gel Formulation (100 g) 
       [0086]      
         [0000]    
       
         
               
               
             
           
               
                   
               
             
             
               
                 Polymorph II of arasertaconazole mononitrate (III) 
                 1.00 g 
               
               
                 Propylen glycol 
                 10.00 g  
               
               
                 Carbomer 
                 1.00 g 
               
               
                 Tween 20 
                 0.10 g 
               
               
                 Phenoxyethanol 
                 0.35 g 
               
               
                 EDTA disodium 
                 0.15 g 
               
               
                 Citric acid 
                 0.25 g 
               
               
                 1N Sodium hydroxide 
                 1.50 g 
               
               
                 Triethanolamine 
                 1.55 g 
               
               
                 Distilled water q.s. to 
                 100.00 g