Abstract:
The invention relates to the novel compound mometasone furoate monohydrate, process for its preparation and pharmaceutical compositions containing said compound.

Description:
This is a continuation of application Ser. No. 07/984,573, filed Mar. 5, 1993, which is a 371 of PCT/US91/06249, filed Sep. 6, 1991, which is a continuation of application Ser. No. 07/580,239, filed Sep. 10, 1990, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates to a novel composition of matter, 9α, 21-dichloro-16α-methyl-1,4-pregnadiens-11β, 17α-diol-3,20-dione-17-(2′-furoate) monohydrate, also designated mometasone furoate monohydrate, process for its preparation, and pharmaceutical preparation thereof. 
     Mometasone furoate is known to be useful in the treatment of inflammatory conditions. The compound is prepared by procedures disclosed in U.S. Pat. No. 4,472,393, which patent is hereby incorporated by reference. 
     When aqueous pharmaceutical compositions, e.g. suspensions, containing anhydrous mometasone furoate were subjected to stability testing by rotating for four weeks at room temperature and 35° C., formation of a crystalline material which is different from the anhydrous mometasone furoate crystal was observed in suspension. Experiments were designed to determine the nature of the crystalline material. It was postulated that formulation of mometasone furoate compositions with the stable crystalline form would reduce the probability of crystal growth during long term storage of the suspension leading to a more stable product. 
     SUMMARY OF THE INVENTION 
     The present invention provides mometasone furoate monohydrate of formula I                           
     a process for preparing said compound by crystallization from a saturated aqueous water miscible organic solution. The present invention also provides aqueous stable pharmaceutical compositions of mometasone furoate monohydrate. 
    
    
     BRIEF DESCRIPTION OF THE FIGURES 
     FIG.  1 : Infrared spectrum of crystalline mometasone furoate monohydrate 
     FIG.  2 : X-ray diffraction pattern of crystalline mometasone furoate monohydrate 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The composition of matter of the present invention, mometasone furoate monohydrate has the following characteristics. 
     
       
         
               
               
             
           
               
                   
               
             
             
               
                 Molecular formula 
                 C 27 H 30 Cl 2 O 6 H 2 O 
               
               
                 Formula weight 
                 539.46 
               
               
                 Elemental Analysis (theory) 
                 C = 60.11%, H = 5.98%; Cl = 13.16% 
               
               
                 (found) 
                 C = 59.99%; H = 5.56%; Cl = 13.17% 
               
               
                 Water Analysis (% H 2 O) 
                 3.34% 
               
               
                 (theory) 
               
               
                 (found) 
                 3.31, 3.47 
               
               
                   
               
             
          
         
       
     
     The crystalline mometasone furoate monohydrate exhibits an x-ray crystallographic powder diffraction pattern having essentially the values as shown in Table I. 
     
       
         
               
               
               
             
           
               
                 TABLE I 
               
               
                   
               
               
                 Angle of 
                 Spacing 
                   
               
               
                 2θ 
                 d 
                 Relative Intensity 
               
               
                 (degrees) 
                 (Å) 
                 I/I 
               
               
                   
               
             
             
               
                 7.795 
                 11.3324 
                 100 
               
               
                 11.595 
                 7.6256 
                 6 
               
               
                 12.035 
                 7.3478 
                 3 
               
               
                 12.925 
                 6.8437 
                 11 
               
               
                 14.070 
                 6.2893 
                 22 
               
               
                 14.580 
                 6.0704 
                 5 
               
               
                 14.985 
                 5.9072 
                 12 
               
               
                 15.225 
                 5.8146 
                 33 
               
               
                 15.635 
                 5.6631 
                 96 
               
               
                 16.710 
                 5.3011 
                 15 
               
               
                 17.515 
                 5.0592 
                 14 
               
               
                 18.735 
                 4.7324 
                 12 
               
               
                 20.175 
                 4.3978 
                 13 
               
               
                 20.355 
                 4.3593 
                 6 
               
               
                 20.520 
                 4.3246 
                 4 
               
               
                 21.600 
                 4.1108 
                 5 
               
               
                 21.985 
                 4.0396 
                 22 
               
               
                 22.420 
                 3.9622 
                 8 
               
               
                 22.895 
                 3.8811 
                 7 
               
               
                 23.245 
                 3.8234 
                 14 
               
               
                 23.550 
                 3.7746 
                 13 
               
               
                 24.245 
                 3.6680 
                 4 
               
               
                 24.795 
                 3.5878 
                 11 
               
               
                 24.900 
                 3.5729 
                 5 
               
               
                 25.800 
                 3.4503 
                 5 
               
               
                 25.985 
                 3.4262 
                 3 
               
               
                 26.775 
                 3.3268 
                 84 
               
               
                 27.170 
                 3.2794 
                 10 
               
               
                 27.305 
                 3.2635 
                 9 
               
               
                 27.710 
                 3.2167 
                 5 
               
               
                 28.385 
                 3.1417 
                 7 
               
               
                 29.165 
                 3.0594 
                 1 
               
               
                 29.425 
                 3.0330 
                 2 
               
               
                 29.725 
                 3.0030 
                 2 
               
               
                 30.095 
                 2.9670 
                 7 
               
               
                 30.255 
                 2.9516 
                 3 
               
               
                 30.490 
                 2.9294 
                 10 
               
               
                 30.725 
                 2.9075 
                 6 
               
               
                 31.115 
                 2.8720 
                 3 
               
               
                 31.595 
                 2.8294 
                 47 
               
               
                 32.135 
                 2.7831 
                 6 
               
               
                 32.985 
                 2.7133 
                 7 
               
               
                 33.400 
                 2.6805 
                 2 
               
               
                 33.820 
                 2.6482 
                 2 
               
               
                 34.060 
                 2.6301 
                 8 
               
               
                 34.625 
                 2.5885 
                 4 
               
               
                 34.795 
                 2.5762 
                 2 
               
               
                 35.315 
                 2.5394 
                 1 
               
               
                 36.780 
                 2.4416 
                 21 
               
               
                 37.295 
                 2.4090 
                 2 
               
               
                   
               
             
          
         
       
     
     Single crystal data of mometasone furoate monohydrate exhibits the following values as shown in Table II. 
     
       
         
               
             
               
               
               
             
           
               
                 TABLE II 
               
             
             
               
                   
               
               
                 Crystallographic Data   a     
               
             
          
           
               
                   
                 Crystal system 
                 triclinic 
               
               
                   
                 Space group 
                   P 1(C 1   1 )-No.1 
               
               
                   
                   
               
               
                   
                   a (Å) 
                  8.481(1) 
               
               
                   
                   b (Å) 
                  11.816(2) 
               
               
                   
                   c (Å) 
                  7.323(1) 
               
               
                   
                 α(°) 
                  95.00(1) 
               
               
                   
                 β(°) 
                 110.66(1) 
               
               
                   
                 γ(°) 
                  73.27(1) 
               
               
                   
                   V (Å 3 ) 
                 657.5(3) 
               
               
                   
                   D calcd.(g cm −3 ) 
                  1.362 
               
               
                   
                   
               
               
                   
                     a   An Enraf-Nonius CAD-4 diffractometer (Cu- K α radiation, incident-beam graphite monochromator) was used for all measurements, Intensity data were corrected for the usual Lorentz and polarization effects; an empirical absorption correction was also applied.  
               
             
          
         
       
     
     The crystal structure was solved by direct methods (RANTAN). Approximate non-hydrogen atom positions were derived from an E-map. Hydrogen atoms were located in a series of difference Fourier syntheses evaluated following several rounds of full-matrix least-squares adjustment of non-hydrogen atom positional and anisotropic temperature factor parameters. Hydrogen atom positional and isotropic thermal parameters were included as variables in the later least-squares iterations which also involved refinement of an extinction correction. Crystallographic calculations were performed on PDP11/44 and MicroVAX computers by use of the Enfra-Nonius Structure Determination Package (SDP). For all structure-factor calculations, neutral atom scattering factors and their anomalous dispersion corrections were taken from  International Tables for X-Ray Crystallography , vol. IV, The Knynock Press, Birmingham, England, 1974. 
     Mometasone furoate monohydrate can be prepared by forming a saturated homogeneous solution of anhydrous mometasone furoate in a mixture of water and a water miscible organic solvent. The saturated solution is prepared by dissolving the mometasone furoate in a water miscible organic solvent at the temperature of about 85° C. Hot water, about 85° C., is added dropwise with agitation. After removing the solution from the steam bath, the reaction is stirred for about one hour and then allowed to stand undisturbed overnight while cooling to room temperature. The solution is stirred while adding additional water at room temperature and the solution becomes cloudy and a white precipitate forms. The reaction is allowed to stir for a time, the preciptitate collected by filtration and the product dried to constant weight. 
     Organic solvents that can be employed in the process of this invention must be miscible with water and one in which mometasone furoate is soluble. Examples of water miscible organic solvents include alcohols, such as, ethanol, isopropanol, and the like; ketones, such as acetone, and the like; ethers, such as dioxane, and the like; esters such as ethyl acetate, and the like. The preferred solvents are acetone and isopropanol. 
     In another aspect, the present invention provides pharmaceutical compositions comprising mometasone furoate monohydrate of formula I in an inert pharmaceutically acceptable carrier or diluent. 
     The pharmaceutical compositions according to the invention can be prepared by combining mometasone furoate. monohydrate with any suitable inert pharmaceutical carrier or diluent and administered orally, parentally or topically in a variety of formulations. 
     Of particular interest are aqueous suspension compositions of mometasone furoate monohydrate, e.g. for nasal administration. The aqueous suspensions of the invention may contain from 0.1 to 10.0 mg of mometasone furoate monohydrate per gram of suspension. 
     The aqueous suspension compositions according to the present invention may contain, inter alia, auxiliaries and/or more of the excipients, such as: suspending agents, e.g. microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl-methyl cellulose; humectants, e.g. glycerin and propylene glycol; acids, bases or buffer substances for adjusting the pH, e.g. citric acid, sodium citrate, phosphoric acid, sodium phosphate e.g. citrate and phosphate buffers; surfactants, e.g. Polysorbate 80; and antimicrobial preservatives, e.g. benzalkonium chloride, phenylethyl alcohol and potassium sorbate. 
     The following examples illustrate the present invention and the best made of practicing the process of the invention. It will be apparent to those skilled in the art that modifications thereof may be practical without departing from the purpose and intent of this disclosure. 
     GENERAL EXPERIMENTAL 
     Infrared absorption spectra were taken as Nujol Mull on a Nicolet FT-Infrared spectrometer Model No. 5DXB. X-ray crystallograph powder diffraction patterns were taken on a Philips X-ray diffractometer Model APD-3720 equipped with a radiation source: copper Kα. Decomposition temperatures were measured on a Dupont differential scanning calorimeter, Model No. 990. 
     Moisture content of the crystalline mometasone furoate monohydrate was determined by titration with Karl Fisher reagent. 
     EXAMPLE 1 
     Place 4.5 liters of ethyl alcohol into a suitable vessel equipped with an appropriate agitator and closure. Dissolve 27 g of mometasone furoate anhydrous powder into the ethanol with stirring. Filter the saturated solution and slowly add purified water about 1.5 liters, at a flow rate of approximately 50 ml/minute while stirring at moderate speed. When the solvent mixture reaches a ratio of 1:3 (water:ethanol), the addition of water is stopped and stirring of the reaction mixture is continued for approximately 2 hours to facilitate seeding. Resume addition of water, about 7.5 liters at a rate of approximately 50 ml/minute, until a ratio of 2:1 (water:ethanol) is achieved. Continue stirring to complete crystallization. The crystals are collected by filtration and dried in a vacuum desiccator at room temperature to afford 24.83 g of mometasone furoate monohydrate having an infrared spectrum and X-ray diffraction graph substantially the same as that in FIGS. 1 and 2. 
     EXAMPLE 2 
     Place 24.3 liters of 2-propanol into a suitable container. Dissolve 340 grams of anhydrous mometasone furoate in the 2-propanol by heating the mixture (steam bath) to 85° C. with stirring. After the furoate has dissolved, add dropwise with stirring over 15 minutes 1950 ml of hot (85° C.) water. The hot solution is removed from the steam bath and the solution is stirred for 1 hour. The solution is allowed to cool to room temperature overnight without stirring. The remainder of water, about 24 liters is added with stirring; the solution becomes cloudy and a white precipitate begins to form. The reaction is stirred for one hour, following addition of the water. The white precipitate is collected by filtration, washed with 2 liters of water and air dried overnight. The solid is dried in a draft oven at 50° C. to constant weight. Mometasone furoate monohydrate, 316.5 g, weight yield 90%, is obtained having an infrared spectrum and X-ray diffraction graph substantially the same as that in FIGS. 1 and 2. 
     EXAMPLE 3 
     An aqueous nasal suspension of mometasone furoate monohydrate is prepared from the following: 
     
       
         
               
               
               
             
           
               
                   
               
               
                   
                 Concentration 
                 Representative Batch 
               
               
                 Ingredients 
                 mg/g 
                 g/12 kg 
               
               
                   
               
             
             
               
                 Mometasone furoate 
                 0.5 
                 6.0 
               
               
                 monohydrate 
               
               
                 Avicel RC 591* 
                 20.0 
                 240.0 
               
               
                 Glycerin 
                 21.0 
                 252.0 
               
               
                 Citric Acid 
                 2.0 
                 24.0 
               
               
                 Sodium citrate 
                 2.8 
                 33.6 
               
               
                 Polysorbate 80** 
                 0.1 
                 1.2 
               
               
                 Benzalkonium chloride 
                 0.2 
                 2.4 
               
               
                 Phenylethyl alcohol 
                 2.5 
                 30.0 
               
               
                 Purified water q.s. ad 
                 1.0 g 
                 12.0 kg 
               
               
                   
               
               
                 *Avicel RC-591-is a trademark of FMC for a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose.  
               
               
                 **Polysorbate 80 is a tradename for a mixture of an oleate ester of sorbitol and its anhydride copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydride.  
               
             
          
         
       
     
     After dispersing the Avicel RC 591 in 6 kg of purified water, the glycerin is added thereto. The citric acid and sodium citrate is dissolved in 240 ml of water, said solution is added to the Avicel-glycerin dispersion with mixing. In a separate vessel, Polysorbate 80 is dissolved in approximately 400 ml of purified water with stirring. The mometasone furoate monohydrate is dispersed in the aqueous Polysorbate 80 solution and; said slurry is then added with stirring to the Avicel-glycerin citric acid mixture. After dissolving benzalkonuim chloride and phenylethyl alcohol in purified water, said solution is added to the suspension mixture with stirring. The suspension is brought to 12 kg with purified water with mixing. The final pH of the suspension is 4.5±0.5. 
     EXAMPLE 4 
     The following compositions were prepared without the suspending agent, Avicel RC-591 to prevent interference in X-ray diffraction studies: 
     
       
         
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Concentration 
               
               
                   
                 mg/g 
               
             
          
           
               
                   
                 Ingredients 
                 4A 
                 4B 
                 4C 
               
               
                   
                   
               
               
                   
                 Mometasone Furoate 
                 0.5 
                 0.5 
                 0.5 
               
               
                   
                 Monohydrate Micronized 
               
               
                   
                 Citric Acid Monohydrate 
                 2.0 
                 2.0 
                 2.0 
               
               
                   
                 Sodium Citrate Dihydrate 
                 2.8 
                 — 
                 2.8 
               
               
                   
                 Sodium Phosphate Dibasic 
                 — 
                 4.0 
                 — 
               
               
                   
                 Polysorbate 80 
                 0.1 
                 0.1 
                 0.1 
               
               
                   
                 Benzalkonium Chloride 
                 0.2 
                 0.2 
                 0.2 
               
               
                   
                 Phenylethyl Alcohol 
                 2.5 
                 — 
                 — 
               
               
                   
                 Potassium Sorbate 
                 — 
                 3.4 
                 — 
               
               
                   
                 Propylene Glycol 
                 — 
                 — 
                 100.0 
               
               
                   
                 Glycerin 
                 21.0 
                 21.0 
                 21.0 
               
               
                   
                 Water Purified USP q.s. ad 
                 1.0 g 
                 1.0 g 
                 1.0 g 
               
               
                   
                   
               
             
          
         
       
     
     These compositions were prepared according to the procedure described in Example 3. 
     The three compositions 4A, 4B and 4C were rotated for five (5) days at 35° C. and a additional four (4) weeks at room temperature to assess crystal form stability. The crystals were isolated from the suspension and X-ray diffraction patterns determined. The results indicated that the crystals collected from each of the three compositions are in the form of mometasone furoate monohydrate. 
     EXAMPLE 5 
     The following compositions were prepared and tested to determine thermal stability of said compositions. 
     
       
         
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Concentration 
               
               
                   
                 mg/g 
               
             
          
           
               
                   
                 Ingredients 
                 5A 
                 5B 
                 5C 
               
               
                   
                   
               
               
                   
                 Mometasone Furoate 
                 0.5 
                 0.5 
                 0.5 
               
               
                   
                 Monohydrate Micronized 
               
               
                   
                 Citric Acid Monohydrate 
                 2.0 
                 2.0 
                 2.0 
               
               
                   
                 Sodium Citrate Dihydrate 
                 2.8 
                 — 
                 2.8 
               
               
                   
                 Sodium Phosphate Dibasic 
                 — 
                 4.0 
                 — 
               
               
                   
                 Polysorbate 80 
                 0.1 
                 0.1 
                 0.1 
               
               
                   
                 Benzalkonium Chloride 
                 0.2 
                 0.2 
                 0.2 
               
               
                   
                 Phenylethyl Alcohol 
                 — 
                 2.5 
                 — 
               
               
                   
                 Potassium Sorbate 
                 — 
                 — 
                 3.4 
               
               
                   
                 Propylene Glycol 
                 100.0 
                 — 
                 — 
               
               
                   
                 Glycerin 
                 21.0 
                 21.0 
                 21.0 
               
               
                   
                 Avicel RC-591 
                 20.0 
                 20.0 
                 20.0 
               
               
                   
                 Water Purified USP q.s. ad 
                 1.0 g 
                 1.0 g 
                 1.0 g 
               
               
                   
                   
               
             
          
         
       
     
     The compositions were prepared according to the procedure described in Example 3. 
     The compositions were thermally cycled between 4° C. (24 hours), and 30° C. (24 hours) for a period of one month. Microscopic analyses revealed no detectable mometasone furoate monohydrate crystal growth under these conditions.