CA2091360C - Mometasone furoate monohydrate, process for making same and pharmaceutical compositions - Google Patents
Mometasone furoate monohydrate, process for making same and pharmaceutical compositionsInfo
- Publication number
- CA2091360C CA2091360C CA002091360A CA2091360A CA2091360C CA 2091360 C CA2091360 C CA 2091360C CA 002091360 A CA002091360 A CA 002091360A CA 2091360 A CA2091360 A CA 2091360A CA 2091360 C CA2091360 C CA 2091360C
- Authority
- CA
- Canada
- Prior art keywords
- alpha
- monohydrate
- furoate
- mometasone furoate
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The invention relates to the novel compound mometasone furoate monohydate, process for its preparation and pharma-ceutical compositions containing said compound.
Description
MOMETASONE FUROATE MONOHYDRATE, PROCESS FOR
MAKING SAME AND PHARMACEUTICAL COMPOSITIONS
BACKGROUND QF THE INV~NTION
The present invention relates to a novel composition of matter, 9a,21-dichloro-16a-methyl-l,d~-pregnadiene~ ,17c~-diol-3,20-dione-17-(2'-furoate) monohydrate, also designated mometasone furoate monohydrate, process for its preparation, and pharmaceutical preparation thereof.
Mometasone f uroate is known to be usef ul in the treatment of inf lammatory conditions . The compound is prepared by procedures disclosed in U . S . Patent No.
4, 472, 393 .
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 35C, 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 oduct.
WO 92/0436~ 2 ~ 9 ~3 6 PCI'/US91/06249 ~
MAKING SAME AND PHARMACEUTICAL COMPOSITIONS
BACKGROUND QF THE INV~NTION
The present invention relates to a novel composition of matter, 9a,21-dichloro-16a-methyl-l,d~-pregnadiene~ ,17c~-diol-3,20-dione-17-(2'-furoate) monohydrate, also designated mometasone furoate monohydrate, process for its preparation, and pharmaceutical preparation thereof.
Mometasone f uroate is known to be usef ul in the treatment of inf lammatory conditions . The compound is prepared by procedures disclosed in U . S . Patent No.
4, 472, 393 .
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 35C, 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 oduct.
WO 92/0436~ 2 ~ 9 ~3 6 PCI'/US91/06249 ~
- 2-SUMMARY OF THF INVEI~ITION
The present invention provides ~ dsone furoate monohydrate of formula I
5 tltH;~yO ~ ~o HO ~ O~
.-~`
o sl~J H20 a process for pltlpdlill9 said compound by ~.,;s~ from a saturated aqueous water miscible organic solution. The present invention also provides aqueous stable phd""aceutical 15 compositions of l,lG",~Idsone furoate ",~nG~"~ldl~.
DESCRIPTION OF THF FIGURFC
Flgure 1: Infrared spectrum of crystalline mometasone furoate monohydrate igure 2: X-ray diffraction pattern of crystalline mometasone furoate monohydrate DET~Il Fn DESCRIPTION OF THF INVFIHITION
The c~",~osilio~ of matter of the present invention""G",eldsone furoate monGl,~d,d~e has the following characteristics.
= ~ -. ,~
.
~) 92/0436~; 2 0 9 ~3 6 0 PCI`/US91/06249 Molecular formula C27H30C1206H20 Formula weight 539.46 Elemental Analysis (theory) C-60.11%, H=5.98%; Cls13.16%
(found) C=59.99%; H=5.56%; Cl=13.17%
5 Water Analysis (% H20) (theory) 3.34%
(found) 3.31, 3.47 The crystalline mometasone furoate monohydrate exhibits an x-ray crystallographic powder diffraction pattern 10 having essentially the values as shown in Table 1.
W092/04365 2agl36 PCI/US91/06249 TABLE I
. ~ .
5Angle of Spacing Relativs Intensity 2~ d l/l ~de~rees) ~A) 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 1 8.735 4.7324 12 20. 1 75 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 1 0 27.305 3.2635 9 2~91360 ~ 92/04365 ` - PCI/US91/06249 .
Angle of Spacing Relative Intensity 2~ d lll (de~rees) (A~
27.710 3.2167 5 28.385 3.1417 7 29.165 3.0594 29.425 3.0330 2 29.725 3.0030 2 30.095 2.9670 7 30.255 2.951 6 3 30.490 2.9294 1 0 1 5 30.725 2.9075 6 31.115 2.8720 3 31.595 2.8294 47 32.135 2.7831 6 32.985 2.71 33 7 33.400 2.6805 2 33.820 2.6482 2 34.060 2.6301 34.625 2.5885 4 34.795 2.5762 2 35.31 5 2.5394 36.780 2.441 6 2 1 37.295 2.4090 2 Single crystal data of mometasone furoate 30 monohydrate exhibits the following values as shown in Table Il.
WO 92/04365 2 0 9 1 3 6 0 PCI-/US91/06249~
TABLE ll Cryst~llo~r~hic Data~l Crystal system t r i c I i n i c Space group e1 (C1 ) - No. 1 ~(A) 8.481 (1 ) h(A) 11.81 6(2) C(A) 7.323(1) rJ~( ) 95.00(1 ) 13(-) 1 1 0.66(1 ) r(-) 73.27(1 ) V(A3) 657.5(3) ~calcd~(g cm -3) 1 362 ~lAn Enraf-Nonius CAD-4 diffractometer (Cu-~
radiation, incident-beam graphite monochromator) was used 20 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). App~u~ al~ non-hydrogen atom positions were 25 derived from an F-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 30 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 35 structure-factor calculations, neutral atom scattering factors -.. _ . . . . _ _ _ . . .
92/04365 2 ~ 9 1 3 6 0 PCriUS91/06249 . .
and their anomalous dispersion corrections were taken from Internationr~l Tables f~LX-Ray Crys~llo~rr~phy. vol. IV, The Knynock Press, Bi~ lylldllll England, 1974.
~1D."~dsone furoate monohydrate can be prepared 5 by forming a saturated homogeneous solution of anhydrous mometasone furoate in a mixture of water and a water miscible organic soivent. The saturated solution is prepared by dissolving the mo",~dsol~e furoate in a water miscible organic solvent at the temperature of about 85C. Hot water, 10 about 85C, 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 15 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 20 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, i~oprupal~ol, and the like; ketones, such as acetone, and the like; ethers, such as dioxane, and ths like; esters such as ethyl 25 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 30 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 W092/~1 ~ og~3~ ~ ~ PCI/US91/~06249 ~
diluent and ad",i"i:,ldr~d orally, parentatly or topically in a variety of formulations.
Of particular interest are aqueous suspension co",posilions of mometasone furoate monohydrate, e.g. for 5 nasal adl, ,;sL,dlion. The aqueous suspensions of the invention may contain from 0.1 to 10.0m~ of l,,Gl,,dLdsone furoate monohydrate per gram of suspension.
The aqueous suspension compositions according to the present invention may contain, inter alia, auxiliaries 10 and/or more of the excipients, such as: suspending agents, e.~.
microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl-methyl cellulose; h~",e~,ld"l:" e.g. glycerin and propylene glycol; acids, bases or buffer substances for adjusting the pH, e.g. citric acid, sodium citrate, phosphoric 1~ 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 20 invention and the best made of practicing the process of the invention. It will be apparent to those skilled in the art that "10di~icdlions thereof may be practical without departing from the purpose and intent of this disclosure.
General E~periment~l Infrared absorption spectra were taken as Nujol~
ull on a Nicolet FT-lnfrared spectrometer Model No. 5DX~ X-ray crystallograph powder diffraction patterns were taken on 30 a Philips X-ray diffractometer Model APD-3720 equipped with a rddiation source: copper Ko~ . Dec~""po~ilioi1 temperatures were measured on a Dupont differential scanning calorimeter, Model No. 990.
Moisture content of the crystalline ,),ul"e~dso"e furoate ~"~no~,ydldle was d~l~r",;"ed by titration with Karl Fisher reagent.
2~gl360 ~D 92/04365 PCI/US91/06249 g F~AMPLE 1 Place 4.5 liters of ethyl alcohol into a suitable vessel equipped with an app,~prid~ agitator and closure.
Dissolve 279 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 app,uAi,,,dL~ly 5û ml/minute while stirring at moderate speed.
When the solvent mixture reaches a ratio of 1:3 10 (water:ethanol), the addition of water is stopped and stirring of the reaction mixture is continued for appr~,Ai",dt~ly 2 hours to facilitate seeding. Resume addition of water, about 7.5 liters at a rate of app,uxi,,,dl~ly 50 ml/minute, until a ratio of 2:1 (wa~r~ l,allol) is achieved. Continue stirring to complete 15 crystallization. The crystals are collected by filtration and dried in a vacuum de~;ccAt~r at room temperature to afford 24.839 of ",o",eldsûne furoate monohydrate having an infrared spectrum and X-ray diffraction graph substantially the same as that in Figures 1 and 2.
Place 24.3 liters of 2-propanol into a suitable container. Dissolve 34û grams of anhydrous ",o",~as~ne 25 furoate in the 2-propanol by heating the mixture (steam bath) to 85C with stirring. After the furoate has dissolved, add dropwise with stirring over 15 minutes 1950 ml of hot (85C) water. The hot solution is removed from the steam bath and the solution is stirred for 1 hour. The solution is allowed to 30 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, : .. _ _ . _ . .. . _ . . . .. . . . .. . . . _ _ .
WO 92/0436!; 2 0 9 13 6 PCI-/US91/06249 ~
- 1 0 -, washed with 2 liters of water and air dried overni~ht. The solid is dried in a draft oven at 50C to constant weight.
Mol"~Ldsone furoate monohydrate, 316.55, weight yield 90%, is obtained having an infrared spectrum and X-ray clirr-a.;Lion 5 graph substantially the same as that in Figures 1 and 2.
An aqueous nasal suspension of mometasone 10 furoate monohydrate is prepared from the following:
Concentration ReDresent~tive Batch In~redients mglg 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 9 12.0 kg ~Avicel RC-591-is a l,ddei"alk of FMC for a mixture of microcrystalline cellulose and sodium carboxymethyl 1 5 cellulose.
~Polysorbate 80 is a tradename for a mixture of an oleate ester of sorbitol and its anhydride copolymerized with aprjruki",alely 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 slycerin 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 Poiysorbate 80 is dissolved in approximately 400 ml of purified water with stirring. The 5 ",~",~daone 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 10 mixture with stirring. The suspension is brought to 12 kg with purified water with mixing. The final pH of the suspension is 4.5 i 0-5-The following co",posilions were prepared withoutthe suspendi"g agent Avicel RC-591 to prevent i"Le~ rence in X-ray diffraction studies:
Concentration In~redients mQ~g ~ 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 Pllo~,hd~ 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 9 1.0 9 1.0 9 =
2 0 9 1 ~ PCr/USsl/0624s ~
These c~",posilions were prepared according to the procedure des~ ed in Example;3.
The three co",poaili~ns 4A 4B and 4C were 5 rotated for five (5) days at 35C and a ad.litional 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 10 are in the form of ",o",t:Ldsone furoate monohydrate.
The following c~l"~osilions were prepared and 15 tested to determine thermal stability of said compositions.
Concentration In~redients mg~
~ ~ 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 9 1.0 9 1.0 9 2091~6~
6~ Pcr/ussl/0624s The .,ul"~osiLi~ns were prepared according to the procedure described in Example 3.
The compositions were thermally cycled between 5 4C (24 hours) and 30C (24 hours) for a period of one month.
Microscopic analyses revealed no detectable mometasone furoate monohydrate crystal growth under these conditions.
The present invention provides ~ dsone furoate monohydrate of formula I
5 tltH;~yO ~ ~o HO ~ O~
.-~`
o sl~J H20 a process for pltlpdlill9 said compound by ~.,;s~ from a saturated aqueous water miscible organic solution. The present invention also provides aqueous stable phd""aceutical 15 compositions of l,lG",~Idsone furoate ",~nG~"~ldl~.
DESCRIPTION OF THF FIGURFC
Flgure 1: Infrared spectrum of crystalline mometasone furoate monohydrate igure 2: X-ray diffraction pattern of crystalline mometasone furoate monohydrate DET~Il Fn DESCRIPTION OF THF INVFIHITION
The c~",~osilio~ of matter of the present invention""G",eldsone furoate monGl,~d,d~e has the following characteristics.
= ~ -. ,~
.
~) 92/0436~; 2 0 9 ~3 6 0 PCI`/US91/06249 Molecular formula C27H30C1206H20 Formula weight 539.46 Elemental Analysis (theory) C-60.11%, H=5.98%; Cls13.16%
(found) C=59.99%; H=5.56%; Cl=13.17%
5 Water Analysis (% H20) (theory) 3.34%
(found) 3.31, 3.47 The crystalline mometasone furoate monohydrate exhibits an x-ray crystallographic powder diffraction pattern 10 having essentially the values as shown in Table 1.
W092/04365 2agl36 PCI/US91/06249 TABLE I
. ~ .
5Angle of Spacing Relativs Intensity 2~ d l/l ~de~rees) ~A) 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 1 8.735 4.7324 12 20. 1 75 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 1 0 27.305 3.2635 9 2~91360 ~ 92/04365 ` - PCI/US91/06249 .
Angle of Spacing Relative Intensity 2~ d lll (de~rees) (A~
27.710 3.2167 5 28.385 3.1417 7 29.165 3.0594 29.425 3.0330 2 29.725 3.0030 2 30.095 2.9670 7 30.255 2.951 6 3 30.490 2.9294 1 0 1 5 30.725 2.9075 6 31.115 2.8720 3 31.595 2.8294 47 32.135 2.7831 6 32.985 2.71 33 7 33.400 2.6805 2 33.820 2.6482 2 34.060 2.6301 34.625 2.5885 4 34.795 2.5762 2 35.31 5 2.5394 36.780 2.441 6 2 1 37.295 2.4090 2 Single crystal data of mometasone furoate 30 monohydrate exhibits the following values as shown in Table Il.
WO 92/04365 2 0 9 1 3 6 0 PCI-/US91/06249~
TABLE ll Cryst~llo~r~hic Data~l Crystal system t r i c I i n i c Space group e1 (C1 ) - No. 1 ~(A) 8.481 (1 ) h(A) 11.81 6(2) C(A) 7.323(1) rJ~( ) 95.00(1 ) 13(-) 1 1 0.66(1 ) r(-) 73.27(1 ) V(A3) 657.5(3) ~calcd~(g cm -3) 1 362 ~lAn Enraf-Nonius CAD-4 diffractometer (Cu-~
radiation, incident-beam graphite monochromator) was used 20 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). App~u~ al~ non-hydrogen atom positions were 25 derived from an F-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 30 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 35 structure-factor calculations, neutral atom scattering factors -.. _ . . . . _ _ _ . . .
92/04365 2 ~ 9 1 3 6 0 PCriUS91/06249 . .
and their anomalous dispersion corrections were taken from Internationr~l Tables f~LX-Ray Crys~llo~rr~phy. vol. IV, The Knynock Press, Bi~ lylldllll England, 1974.
~1D."~dsone furoate monohydrate can be prepared 5 by forming a saturated homogeneous solution of anhydrous mometasone furoate in a mixture of water and a water miscible organic soivent. The saturated solution is prepared by dissolving the mo",~dsol~e furoate in a water miscible organic solvent at the temperature of about 85C. Hot water, 10 about 85C, 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 15 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 20 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, i~oprupal~ol, and the like; ketones, such as acetone, and the like; ethers, such as dioxane, and ths like; esters such as ethyl 25 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 30 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 W092/~1 ~ og~3~ ~ ~ PCI/US91/~06249 ~
diluent and ad",i"i:,ldr~d orally, parentatly or topically in a variety of formulations.
Of particular interest are aqueous suspension co",posilions of mometasone furoate monohydrate, e.g. for 5 nasal adl, ,;sL,dlion. The aqueous suspensions of the invention may contain from 0.1 to 10.0m~ of l,,Gl,,dLdsone furoate monohydrate per gram of suspension.
The aqueous suspension compositions according to the present invention may contain, inter alia, auxiliaries 10 and/or more of the excipients, such as: suspending agents, e.~.
microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl-methyl cellulose; h~",e~,ld"l:" e.g. glycerin and propylene glycol; acids, bases or buffer substances for adjusting the pH, e.g. citric acid, sodium citrate, phosphoric 1~ 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 20 invention and the best made of practicing the process of the invention. It will be apparent to those skilled in the art that "10di~icdlions thereof may be practical without departing from the purpose and intent of this disclosure.
General E~periment~l Infrared absorption spectra were taken as Nujol~
ull on a Nicolet FT-lnfrared spectrometer Model No. 5DX~ X-ray crystallograph powder diffraction patterns were taken on 30 a Philips X-ray diffractometer Model APD-3720 equipped with a rddiation source: copper Ko~ . Dec~""po~ilioi1 temperatures were measured on a Dupont differential scanning calorimeter, Model No. 990.
Moisture content of the crystalline ,),ul"e~dso"e furoate ~"~no~,ydldle was d~l~r",;"ed by titration with Karl Fisher reagent.
2~gl360 ~D 92/04365 PCI/US91/06249 g F~AMPLE 1 Place 4.5 liters of ethyl alcohol into a suitable vessel equipped with an app,~prid~ agitator and closure.
Dissolve 279 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 app,uAi,,,dL~ly 5û ml/minute while stirring at moderate speed.
When the solvent mixture reaches a ratio of 1:3 10 (water:ethanol), the addition of water is stopped and stirring of the reaction mixture is continued for appr~,Ai",dt~ly 2 hours to facilitate seeding. Resume addition of water, about 7.5 liters at a rate of app,uxi,,,dl~ly 50 ml/minute, until a ratio of 2:1 (wa~r~ l,allol) is achieved. Continue stirring to complete 15 crystallization. The crystals are collected by filtration and dried in a vacuum de~;ccAt~r at room temperature to afford 24.839 of ",o",eldsûne furoate monohydrate having an infrared spectrum and X-ray diffraction graph substantially the same as that in Figures 1 and 2.
Place 24.3 liters of 2-propanol into a suitable container. Dissolve 34û grams of anhydrous ",o",~as~ne 25 furoate in the 2-propanol by heating the mixture (steam bath) to 85C with stirring. After the furoate has dissolved, add dropwise with stirring over 15 minutes 1950 ml of hot (85C) water. The hot solution is removed from the steam bath and the solution is stirred for 1 hour. The solution is allowed to 30 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, : .. _ _ . _ . .. . _ . . . .. . . . .. . . . _ _ .
WO 92/0436!; 2 0 9 13 6 PCI-/US91/06249 ~
- 1 0 -, washed with 2 liters of water and air dried overni~ht. The solid is dried in a draft oven at 50C to constant weight.
Mol"~Ldsone furoate monohydrate, 316.55, weight yield 90%, is obtained having an infrared spectrum and X-ray clirr-a.;Lion 5 graph substantially the same as that in Figures 1 and 2.
An aqueous nasal suspension of mometasone 10 furoate monohydrate is prepared from the following:
Concentration ReDresent~tive Batch In~redients mglg 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 9 12.0 kg ~Avicel RC-591-is a l,ddei"alk of FMC for a mixture of microcrystalline cellulose and sodium carboxymethyl 1 5 cellulose.
~Polysorbate 80 is a tradename for a mixture of an oleate ester of sorbitol and its anhydride copolymerized with aprjruki",alely 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 slycerin 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 Poiysorbate 80 is dissolved in approximately 400 ml of purified water with stirring. The 5 ",~",~daone 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 10 mixture with stirring. The suspension is brought to 12 kg with purified water with mixing. The final pH of the suspension is 4.5 i 0-5-The following co",posilions were prepared withoutthe suspendi"g agent Avicel RC-591 to prevent i"Le~ rence in X-ray diffraction studies:
Concentration In~redients mQ~g ~ 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 Pllo~,hd~ 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 9 1.0 9 1.0 9 =
2 0 9 1 ~ PCr/USsl/0624s ~
These c~",posilions were prepared according to the procedure des~ ed in Example;3.
The three co",poaili~ns 4A 4B and 4C were 5 rotated for five (5) days at 35C and a ad.litional 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 10 are in the form of ",o",t:Ldsone furoate monohydrate.
The following c~l"~osilions were prepared and 15 tested to determine thermal stability of said compositions.
Concentration In~redients mg~
~ ~ 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 9 1.0 9 1.0 9 2091~6~
6~ Pcr/ussl/0624s The .,ul"~osiLi~ns were prepared according to the procedure described in Example 3.
The compositions were thermally cycled between 5 4C (24 hours) and 30C (24 hours) for a period of one month.
Microscopic analyses revealed no detectable mometasone furoate monohydrate crystal growth under these conditions.
Claims (6)
1. 9.alpha.,21-dichloro-16.alpha.-methyl-1,4-pregnadiene-11.beta.,17.alpha.-diol-3,20-dione-17-(2'-furoate) monohydrate.
2. A process for preparing 9.alpha.,21 -dichloro-16.alpha.-methyl-1,4-pregnadiene-11.beta.,17.alpha.-diol-3,20-dione-17-(2'-furoate) monohydrate which comprises:
(a) forming a saturated water-miscible organic solvent solution of 9.alpha.,21 -dichloro-16.alpha.-methyl-1,4-pregnadiene-11.beta.,17.alpha.-diol-3,20-dione-17-(2'-furoate);
(b) adding sufficient water to form a solvent mixture ratio of 1:1 (water:organic solvent) and continuing stirring to complete crystallization.
(a) forming a saturated water-miscible organic solvent solution of 9.alpha.,21 -dichloro-16.alpha.-methyl-1,4-pregnadiene-11.beta.,17.alpha.-diol-3,20-dione-17-(2'-furoate);
(b) adding sufficient water to form a solvent mixture ratio of 1:1 (water:organic solvent) and continuing stirring to complete crystallization.
3. The process of claim 2 wherein the organic solvent is selected from the group consisting of ethanol, isopropanol, acetone, dioxane and ethyl acetate.
4. A pharmaceutical composition comprising an antiinflammatory amount of mometasone furoate monohydrate in a pharmaceutically acceptable carrier.
5. The composition of claim 4 having the following ingredients:
Ingredients mg/g Mometasone furoate monohydrate 0.1-10.0 Microcrystalline cellulose and sodium 20.0 carboxymethyl cellulose Glycerin 21.0 Citric acid 2.0 Sodium citrate 2.8 Polysorbate 80 0.1 Benzalkonium chloride 0.2 Phenylethyl alcohol 2.5 Purified water q.s. ad 1.0 g
Ingredients mg/g Mometasone furoate monohydrate 0.1-10.0 Microcrystalline cellulose and sodium 20.0 carboxymethyl cellulose Glycerin 21.0 Citric acid 2.0 Sodium citrate 2.8 Polysorbate 80 0.1 Benzalkonium chloride 0.2 Phenylethyl alcohol 2.5 Purified water q.s. ad 1.0 g
6. The composition of claim 5 comprising 0.5mg of mometasone furoate monohydrate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US58023990A | 1990-09-10 | 1990-09-10 | |
| US580,239 | 1990-09-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2091360A1 CA2091360A1 (en) | 1992-03-11 |
| CA2091360C true CA2091360C (en) | 1997-04-08 |
Family
ID=24320279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002091360A Expired - Lifetime CA2091360C (en) | 1990-09-10 | 1991-09-06 | Mometasone furoate monohydrate, process for making same and pharmaceutical compositions |
Country Status (35)
| Country | Link |
|---|---|
| US (1) | US6180781B1 (en) |
| EP (1) | EP0548114B1 (en) |
| JP (1) | JPH0725789B2 (en) |
| KR (1) | KR960013445B1 (en) |
| CN (1) | CN1030920C (en) |
| AT (1) | ATE113604T1 (en) |
| AU (1) | AU663471B2 (en) |
| BG (1) | BG60755B2 (en) |
| CA (1) | CA2091360C (en) |
| CZ (1) | CZ281318B6 (en) |
| DE (2) | DE69104991T2 (en) |
| DK (1) | DK0548114T5 (en) |
| EE (1) | EE02962B1 (en) |
| ES (1) | ES2065701T3 (en) |
| FI (1) | FI111078B (en) |
| HK (1) | HK185996A (en) |
| HR (1) | HRP920383B1 (en) |
| HU (1) | HU213401B (en) |
| IE (1) | IE67056B1 (en) |
| IL (1) | IL99437A (en) |
| LU (1) | LU90366I2 (en) |
| MX (2) | MX9203396A (en) |
| MY (1) | MY106644A (en) |
| NL (1) | NL980012I2 (en) |
| NO (1) | NO300548B1 (en) |
| NZ (1) | NZ239711A (en) |
| OA (1) | OA09772A (en) |
| PH (1) | PH30443A (en) |
| PL (1) | PL165803B1 (en) |
| PT (1) | PT98905B (en) |
| SI (1) | SI9111497A (en) |
| TW (2) | TW272195B (en) |
| WO (1) | WO1992004365A1 (en) |
| YU (1) | YU48666B (en) |
| ZA (1) | ZA917148B (en) |
Families Citing this family (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69104991T2 (en) * | 1990-09-10 | 1995-04-20 | Schering Corp | MOMETASON FUROATE MONOHYDRATE, METHOD FOR THE PRODUCTION THEREOF AND THE CONTAINING PHARMACEUTICAL COMPOSITIONS. |
| PE44995A1 (en) * | 1994-01-27 | 1995-12-18 | Schering Corp | MOMETASONE FUROATE FOR THE TREATMENT OF LUNG DISEASES AND RESPIRATORY TRACT |
| US5837699A (en) * | 1994-01-27 | 1998-11-17 | Schering Corporation | Use of mometasone furoate for treating upper airway passage diseases |
| US5886200A (en) * | 1996-07-01 | 1999-03-23 | Schering Corporation | Process for the preparation of 17-esters of 9 α, 21-dihalo-pregnane-11 β, 17 α-diol-20-ones |
| US5976573A (en) | 1996-07-03 | 1999-11-02 | Rorer Pharmaceutical Products Inc. | Aqueous-based pharmaceutical composition |
| CN1059476C (en) * | 1996-08-21 | 2000-12-13 | 邓维鹏 | Eletrolytic colouring technology for golden colour aluminium alloy selenide |
| EP1033991B1 (en) * | 1997-10-09 | 2002-04-17 | Schering Corporation | Mometasone furoate suspensions for nebulization |
| US6187765B1 (en) * | 1997-10-09 | 2001-02-13 | Schering Corporation | Mometasone furoate suspensions for nebulization |
| MY133181A (en) * | 1998-09-10 | 2007-10-31 | Schering Corp | Methods and compositions for treating sinusitis, otitis media and other related disorders using antihistamines |
| BR0010708A (en) | 1999-05-04 | 2002-02-19 | Strakan Ltd | Androgenic glycosides and androgenic activity |
| GB0207906D0 (en) * | 2002-04-05 | 2002-05-15 | 3M Innovative Properties Co | Formoterol and mometasone aerosol formulations |
| US7811606B2 (en) | 2003-04-16 | 2010-10-12 | Dey, L.P. | Nasal pharmaceutical formulations and methods of using the same |
| US9808471B2 (en) | 2003-04-16 | 2017-11-07 | Mylan Specialty Lp | Nasal pharmaceutical formulations and methods of using the same |
| US8912174B2 (en) | 2003-04-16 | 2014-12-16 | Mylan Pharmaceuticals Inc. | Formulations and methods for treating rhinosinusitis |
| US7825147B2 (en) * | 2003-08-29 | 2010-11-02 | Ranbaxy Laboratories Limited | Inhibitors of phosphodiesterase type-IV |
| WO2005051931A2 (en) * | 2003-11-26 | 2005-06-09 | Ranbaxy Laboratories Limited | Phosphodiesterase inhibitors |
| US7491725B2 (en) | 2004-02-06 | 2009-02-17 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| US7915286B2 (en) | 2005-09-16 | 2011-03-29 | Ranbaxy Laboratories Limited | Substituted pyrazolo [3,4-b] pyridines as phosphodiesterase inhibitors |
| US20070099883A1 (en) * | 2005-10-07 | 2007-05-03 | Cheryl Lynn Calis | Anhydrous mometasone furoate formulation |
| WO2007045980A1 (en) * | 2005-10-19 | 2007-04-26 | Ranbaxy Laboratories Limited | Compositions of phosphodiesterase type iv inhibitors |
| EP1948164A1 (en) | 2005-10-19 | 2008-07-30 | Ranbaxy Laboratories, Ltd. | Pharmaceutical compositions of muscarinic receptor antagonists |
| CN100389121C (en) * | 2005-12-09 | 2008-05-21 | 天津药业集团有限公司 | The preparation method of mometasone furoate intermediate 21-hydroxyl |
| CN100436473C (en) * | 2005-12-09 | 2008-11-26 | 天津药业集团有限公司 | Mometasone furoate intermediate 21-ester and its preparation method |
| DE102006034883A1 (en) * | 2006-07-25 | 2008-01-31 | Hermal Kurt Herrmann Gmbh & Co. Ohg | Pharmaceutical composition containing mometasone furoate |
| AU2007298549A1 (en) * | 2006-09-22 | 2008-03-27 | Ranbaxy Laboratories Limited | Inhibitors of phosphodiesterase type-IV |
| EP2066661A2 (en) * | 2006-09-22 | 2009-06-10 | Ranbaxy Laboratories Limited | Phosphodiesterase inhibitors |
| EP1958947A1 (en) | 2007-02-15 | 2008-08-20 | Ranbaxy Laboratories Limited | Inhibitors of phosphodiesterase type 4 |
| WO2008111009A1 (en) * | 2007-03-14 | 2008-09-18 | Ranbaxy Laboratories Limited | Pyrazolo [3, 4-b] pyridine derivatives as phosphodiesterase inhibitors |
| HRP20120361T1 (en) * | 2007-03-14 | 2012-05-31 | Ranbaxy Laboratories Limited | PYRAZOLO [3,4-b] PyRIDINE DERIVATIVES AS PHOSPHODIESTERASE INHIBITORS |
| EP2111861A1 (en) | 2008-04-21 | 2009-10-28 | Ranbaxy Laboratories Limited | Compositions of phosphodiesterase type IV inhibitors |
| PL3111926T3 (en) | 2009-05-29 | 2020-06-29 | Pearl Therapeutics, Inc. | Compositions, methods, and systems for delivering two or more active agents to the respiratory system |
| US8815258B2 (en) * | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
| PT105058B (en) | 2010-04-21 | 2013-04-17 | Hovione Farmaciencia S A | PROCESS FOR PROCESSING OF PARTICLES OF PHARMACEUTICAL ACTIVE INGREDIENTS |
| CA2905542C (en) | 2013-03-15 | 2022-05-03 | Pearl Therapeutics, Inc. | Methods and systems for conditioning of particulate crystalline materials |
| CN107266518B (en) * | 2016-04-08 | 2021-03-30 | 天津金耀集团有限公司 | Mometasone furoate crystal form and preparation method thereof |
| CN107260671B (en) * | 2016-04-08 | 2021-03-26 | 天津金耀集团有限公司 | Mometasone furoate suspension nasal spray composition |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CY1359A (en) * | 1981-02-02 | 1987-08-07 | Schering Corp | Aromatic heterocyclic esters of steroids, their preparation and pharmaceutical compositions containing them |
| US4783444A (en) | 1984-09-17 | 1988-11-08 | Schering Corporation | Antiglaucoma compositions and methods |
| US4808610A (en) * | 1986-10-02 | 1989-02-28 | Schering Corporation | Mometasone furoate anti-inflammatory cream composition using hexylene glycol |
| US4775529A (en) * | 1987-05-21 | 1988-10-04 | Schering Corporation | Steroid lotion |
| DE69104991T2 (en) * | 1990-09-10 | 1995-04-20 | Schering Corp | MOMETASON FUROATE MONOHYDRATE, METHOD FOR THE PRODUCTION THEREOF AND THE CONTAINING PHARMACEUTICAL COMPOSITIONS. |
-
1991
- 1991-09-06 DE DE69104991T patent/DE69104991T2/en not_active Expired - Lifetime
- 1991-09-06 CZ CZ93383A patent/CZ281318B6/en not_active IP Right Cessation
- 1991-09-06 ES ES91915453T patent/ES2065701T3/en not_active Expired - Lifetime
- 1991-09-06 EP EP91915453A patent/EP0548114B1/en not_active Expired - Lifetime
- 1991-09-06 KR KR1019930700702A patent/KR960013445B1/en not_active Expired - Lifetime
- 1991-09-06 DK DK91915453.4T patent/DK0548114T5/en active
- 1991-09-06 MX MX9203396A patent/MX9203396A/en unknown
- 1991-09-06 CA CA002091360A patent/CA2091360C/en not_active Expired - Lifetime
- 1991-09-06 DE DE1991604991 patent/DE19875032I2/en active Active
- 1991-09-06 PL PL91298223A patent/PL165803B1/en unknown
- 1991-09-06 JP JP3514768A patent/JPH0725789B2/en not_active Expired - Lifetime
- 1991-09-06 AU AU84974/91A patent/AU663471B2/en not_active Expired
- 1991-09-06 AT AT91915453T patent/ATE113604T1/en active
- 1991-09-06 HU HU9300685A patent/HU213401B/en unknown
- 1991-09-06 IL IL9943791A patent/IL99437A/en not_active IP Right Cessation
- 1991-09-06 WO PCT/US1991/006249 patent/WO1992004365A1/en not_active Ceased
- 1991-09-09 PH PH43072A patent/PH30443A/en unknown
- 1991-09-09 YU YU149791A patent/YU48666B/en unknown
- 1991-09-09 SI SI9111497A patent/SI9111497A/en unknown
- 1991-09-09 ZA ZA917148A patent/ZA917148B/en unknown
- 1991-09-09 MX MX9100990A patent/MX9100990A/en unknown
- 1991-09-09 TW TW083106101A patent/TW272195B/zh not_active IP Right Cessation
- 1991-09-09 PT PT98905A patent/PT98905B/en not_active IP Right Cessation
- 1991-09-09 TW TW080107102A patent/TW229208B/zh not_active IP Right Cessation
- 1991-09-09 NZ NZ239711A patent/NZ239711A/en not_active IP Right Cessation
- 1991-09-09 IE IE315591A patent/IE67056B1/en not_active IP Right Cessation
- 1991-09-09 MY MYPI91001630A patent/MY106644A/en unknown
- 1991-09-10 CN CN91108910A patent/CN1030920C/en not_active Expired - Lifetime
-
1992
- 1992-09-21 HR HRP-1497/91A patent/HRP920383B1/en not_active IP Right Cessation
-
1993
- 1993-02-26 NO NO930693A patent/NO300548B1/en not_active IP Right Cessation
- 1993-03-09 FI FI931031A patent/FI111078B/en not_active IP Right Cessation
- 1993-03-09 OA OA60348A patent/OA09772A/en unknown
-
1994
- 1994-02-24 BG BG098564A patent/BG60755B2/en unknown
- 1994-11-21 EE EE9400388A patent/EE02962B1/en unknown
-
1995
- 1995-04-17 US US08/422,479 patent/US6180781B1/en not_active Expired - Lifetime
-
1996
- 1996-10-03 HK HK185996A patent/HK185996A/en not_active IP Right Cessation
-
1998
- 1998-03-12 NL NL980012C patent/NL980012I2/en unknown
-
1999
- 1999-03-05 LU LU90366C patent/LU90366I2/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2091360C (en) | Mometasone furoate monohydrate, process for making same and pharmaceutical compositions | |
| US6127353A (en) | Mometasone furoate monohydrate, process for making same and pharmaceutical compositions | |
| JPH0714880B2 (en) | Beclomethasone dipropionate physically modified to be suitable for aerosols | |
| EP3327012A1 (en) | Crystalline forms of bilastine and preparation methods thereof | |
| NO163899B (en) | PROCEDURE FOR THE PREPARATION OF DIISOPROPYLETERSOV BECLOMETASON-17,21-DIPROPIONATE. | |
| TWI672302B (en) | New crystalline form of a bcl-2 inhibitor, a process for its preparation and pharmaceutical compositions containing it | |
| KR20150042275A (en) | Pharmaceutical formulations containing 3-(4-cinnamyl-l-piperazinyl) amino derivatives of 3-formylrifamycin sv and 3-formylrifamycin s and a process of their preparation | |
| EP1651661B1 (en) | Process for the preparation of finasteride form i | |
| WO2023137966A1 (en) | New crystal form of delafloxacin meglumine and preparation method therefor | |
| JP2024511296A (en) | Solid form of CYP11A1 inhibitor with structure 4H-pyran-4one | |
| US7208485B2 (en) | Crystalline forms of halobetasol propionate | |
| US2650894A (en) | Riboflavin-monoborate and process for preparation thereof | |
| CN120247881A (en) | A new crystal form of resmetiro and preparation method thereof | |
| GB2410948A (en) | Novel phosphoric acid salt of rosiglitazone | |
| US20240199642A1 (en) | Method for obtaining rifapentine with a new crystalline form | |
| WO2026036854A1 (en) | New crystal form of resmetirom and preparation method therefor | |
| CN116239527A (en) | Milrinon-citric acid monohydrate co-crystal | |
| GB2421240A (en) | Phosphoric acid salt of rosiglitazone | |
| JPH0129199B2 (en) | ||
| WO2004083230A1 (en) | Novel crystalline forms of finasteride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |