US20060069150A1 - Processes for preparation of crystalline mycophenolate sodium - Google Patents

Processes for preparation of crystalline mycophenolate sodium Download PDF

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Publication number
US20060069150A1
US20060069150A1 US11/186,164 US18616405A US2006069150A1 US 20060069150 A1 US20060069150 A1 US 20060069150A1 US 18616405 A US18616405 A US 18616405A US 2006069150 A1 US2006069150 A1 US 2006069150A1
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Prior art keywords
sodium
solution
mycophenolate
crystalline form
crystalline
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Sandor Molnar
Csaba Szabo
Tivadar Tamas
Janos Hajko
Adrienne Kovacsne-Mezei
Judith Aronhime
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Teva Pharmaceutical Works PLC
Teva Pharmaceuticals USA Inc
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Teva Pharmaceutical Works PLC
Teva Pharmaceuticals USA Inc
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Priority to US11/186,164 priority Critical patent/US20060069150A1/en
Assigned to TEVA GYOGYSZERGYAR RESZVENYTARSASAG reassignment TEVA GYOGYSZERGYAR RESZVENYTARSASAG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARONHIME, JUDITH, HAJKO, JANOS, KOVACSNE-MEZEI, ADRIENNE, MOLNAR, SANDOR, SZABO, CSABA, TAMAS, TIVADAR
Publication of US20060069150A1 publication Critical patent/US20060069150A1/en
Assigned to TEVA GYOGYSZERGYAR ZARTKORUEN MUKODO RESZVENYTARSASAG reassignment TEVA GYOGYSZERGYAR ZARTKORUEN MUKODO RESZVENYTARSASAG CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: TEVA GYOGYSZERGYAR RESZVENYTARSASAG
Assigned to TEVA PHARMACEUTICALS USA, INC. reassignment TEVA PHARMACEUTICALS USA, INC. ASSIGNMENT OF RIGHTS IN BARBADOS Assignors: TEVA GYOGYSZERGYAR RESZVENYTARSASAG
Priority to US12/002,069 priority patent/US20080097096A1/en
Priority to US12/002,049 priority patent/US20080103317A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3

Definitions

  • the present invention relates to the solid state chemistry of mycophenolate sodium.
  • Mycophenolate sodium salt MMS
  • Myfortic® mycophenolate sodium
  • Mycophenolic acid can be formed either as mono- or disodium salt.
  • South African patent No. 6804959 describes the preparation of mono- and disoditim mycophenolate.
  • Monosodium mycophenolate can be isolated after reaction of one molar equivalent of sodium methoxide with mycophenolic acid in a mixture of methanol and chloroform by precipitation with n-pentane. Preparation of the corresponding disodium salt is also described. In this case two molar equivalents of sodium methoxide were added to a solution of mycophenolic acid in 2:1 benzene-chloroform mixture. The evaporated material was crystallized from aqueous acetone.
  • the synthetic route of WO 97/38689 is identical to the one described in South African patent No. 6804959.
  • the compound may be obtained in crystalline form by recrystallization from acetone/ethanol if necessary with water (m.p.189-191° C.).
  • the present invention relates to the solid state physical properties of mycophenolate sodium. These properties may be influenced by controlling the conditions under which mycophenolate sodium is obtained in solid form.
  • Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
  • Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid state form of a compound may also affect its behavior on compaction and its storage stability.
  • polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some polymorphic forms from others.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • a particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state C NMR spectrometry and infrared spectrometry.
  • WO2004/020426 discloses preparation of sodium mycophenolate by reacting mycophenolic acid or its ammonium or dibenzyl-amine salt with a sodium salt of C 2 to C 10 carboxylic acid.
  • Mycophenolic acid is converted to its ammonium salt by reacting with ammonia. This compound is reacted with sodium acetate to obtain the sodium salt of mycophenolic acid.
  • WO 2004/064806 discloses additional polymorphic forms of mycophenolate sodium and acid.
  • South African patent No. 68/4,959 provides an example for preparing monosodium mycophenolate salt (Example 3). Sodium methylate in anhydrous methanol was added to mycophenolic acid in chloroform, then the monosodium salt was precipitated by adding n-pentane and collected by filtration and vacuum dried.
  • Acta Chrystallographica Sect. C, (2000), C56, 432-433 describes another process for producing monosodium mycophenolate.
  • a methanolic solution of the commercially available mycophenolic acid was treated with one equivalent of sodium methanolate. After stirring for 1 hour at room temperature, the solvent was evaporated to dryness in vacuum. The melting point of the product was 463 K (190° C.).
  • Single crystals were grown by evaporation and cooling of a water/ethyl acetate solution from about 323K to room temperature. The crystal structure of the produced sodium mycophenolate measured by single crystal diffractometer is also described.
  • Form M2 is an anhydrous form.
  • Form M2 is characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2 theta ( FIG. 3 ) and FTIR peaks at 1719, 1571, 1317, 1266, 1134 and 927 cm-1 ( FIG. 4 ).
  • Form M2 may be further characterized by XRD peaks at 13.6 and 19.0 ⁇ 0.2 degrees 2 theta.
  • Form M2 may be further characterized by IR peaks at 1194, 1108, 1075, 1034, 971, 875, 826, 794 and 722 cm-1.
  • Form M2 may be further characterized by a DSC curve ( FIG. 43 ).
  • PCT 97/38689 describes sodium mycophenolate salts as known from South African Patent. It also describes the process for obtaining monosodium salt in crystalline form by recrystallization from acetone/ethanol if necessary with water. The melting point provided is 189-191° C.
  • J. Med. Chem. (1996), 39, 1236-1242 describes treating a solution of mycophenolic acid in ethanol with equimolar sodium ethylate at room temperature and stirring for 30 minutes. The solvent was evaporated in vacuum.
  • South African patent No. 68/4,959 provides an example for producing disodium mycophenolate (Example 2).
  • Mycophenolic acid was dissolved in benzene:chloroform 2:1 solvent mixture and sodium methoxide dissolved in anhydrous methanol was added to it. The solution was stirred for 15-20 minutes, evaporated to dryness and redissolved in water. Crystallization was effected by the addition of acetone to the hot water solution and chilling overnight. No physical data was given.
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of:
  • the present invention provides a process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9 ⁇ 0.2 degrees 2-theta comprising the steps of heating a solid mixture of a crystalline mycophenolate sodium (Form M1) characterized by a powder XRD pattern with peaks at 4.7, 6.6, 11.2 and 15.6 ⁇ 0.2 degrees 2-theta and a crystalline mycophenolate sodium (Form M3) characterized by at least one of a powder XRD pattern with peaks at 6.0, 9.3, 15.5, and 18.4 ⁇ 0.2 degrees 2-theta.
  • FIG. 1 is a characteristic X-ray powder diffraction pattern for monosodium mycophenolate form M2.
  • FIG. 2 is a characteristic FT-IR spectrum of monosodium mycophenolate form M2.
  • FIG. 3 is a characteristic DSC curve for monosodium mycophenolate form M2.
  • FIG. 4 is a calculated XRD pattern of a single crystal data of article Acta Crystallographica Sect. C, (2000), C56, 432-434.
  • FIG. 5 is a characteristic X-ray powder diffraction pattern for monosodium mycophenolate form M1.
  • FIG. 6 is a characteristic FT-IR spectrum of monosodium mycophenolate form M1.
  • FIG. 7 is a characteristic DSC curve for monosodium mycophenolate form M1.
  • FIG. 8 is a characteristic X-ray powder diffraction pattern for monosodium mycophenolate form M3.
  • FIG. 9 is a characteristic FT-IR spectrum of monosodium mycophenolate form M3.
  • FIG. 10 is a characteristic DSC curve for monosodium mycophenolate form M3.
  • the present invention provides various processes for preparation of Form M2 of mycophenolate sodium on an industrial scale.
  • Most of the processes developed in the present invention are crystallization or slurry processes, which are suitable for use on an industrial scale (batches of at least 0.5 Kg). Further, crystallization often allows for obtaining a product with higher purity.
  • Form M2 may be prepared by slurry or crystallization from a solution of the sodium salt in a C 3 to C 8 organic ester as solvent, such as ethyl acetate or isobutyl acetate.
  • the solution or slurry may contain charcoal for removal of colored impurities, which charcoal is then removed by filtration.
  • a source of sodium is added to the solution of MPA in the ester.
  • a base in methanol such as about a 30% solution of sodium methoxide in methanol is added portion-wise, preferably at a temperature of about 10 to about 60° C., most preferably at about room temperature.
  • the reaction mixture is preferably stirred for an additional approximately of 1 or 2 hours.
  • the solid material is then preferably dried, preferably at about 40 to about 85° C. in a vacuum oven.
  • a slurry process with such ester is illustrated in example 3.
  • Form M2 may be prepared by crystallization from a C 1 -C 4 alcohol, preferably methanol.
  • a solution of the mycophenolic acid in the alcohol is combined with a base or source of sodium, preferably sodium methoxide.
  • the combining may be carried out portion-wise, or in one step.
  • the resulting reaction mixture may be heated to a temperature of at least about 35° C. to obtain complete dissolution, though the reaction may be carried out without heating.
  • a crystalline form is then crystallized from the solution, preferably by cooling, more preferably by cooling to a temperature of less than about 0° C., most preferably about ⁇ 10° C. to about ⁇ 20° C.
  • the crystals are then recovered and may be dried. Analysis of the dried product showed that it was Form M2. During this process, the reaction mixture is kept for at least about 5 hours during crystallization.
  • an antisolvent is added to the methanol to precipitate Form M2.
  • sodium mycophenolate is dissolved in methanol, preferably at room temperature, then a halogen-free solvent such as a C 3 to C 8 ketone (preferably acetone) or ester (preferably ethyl acetate iso-butyl acetate) or a C 2 to C 8 ether (preferably tetrahydrofuran or t-butyl methyl ether or diisopropyl ether) or a C 2 to C 4 alcohol (preferably isopropanol or isobutanol) is added to the solution.
  • a halogen-free solvent such as a C 3 to C 8 ketone (preferably acetone) or ester (preferably ethyl acetate iso-butyl acetate) or a C 2 to C 8 ether (preferably tetrahydrofuran or t-butyl methyl ether or diisopropyl ether) or
  • a solid then crystallizes from the solution, preferably at room temperature overnight.
  • the solid is then recovered, and preferably dried at room temperature.
  • the product may have to be dried to obtain Form M2. Drying may be carried out at room temperature and/or under atmospheric pressure.
  • Form M2 of sodium mycophenolate may also be obtained when sodium mycophenolate (MPS) is crystallized from ethanol or 1-butanol.
  • the ethanol is preferably absolute ethanol.
  • sodium mycophenolate is dissolved in ethanol or 1-butanol at ambient or elevated temperature, cooled to room temperature and crystallized at this temperature for overnight.
  • the solution may be heated to a temperature of at least about 60° C., such as the reflux temperature of the solvent.
  • the crystals obtained from ethanol may have to be dried to obtain Form M2. Drying may be carried out at room temperature under atmospheric pressure (ambient conditions).
  • mycophenolate sodium Form M2 is prepared by precipitating Form M2 by adding acetone as an antisolvent to a solution of mycophenolate sodium in ethyl lactate.
  • sodium mycophenolate is dissolved in ethyl lactate at elevated temperature, such as about 60° C.
  • the solution is then cooled, preferably to about room temperature, and acetone is added to the solution.
  • the solution is further cooled, preferably to about 0° C. to about 10° C. and allowed to crystallize.
  • the product is then recovered by conventional techniques and may be dried.
  • mycophenolate sodium Form M2 is prepared by precipitating Form M2 by adding 2-propanol as an antisolvent to a solution of mycophenolate sodium in dimethylformide.
  • 2-propanol is combined with a solution of sodium mycophenolate in dimethylformide and allowed to crystallize.
  • the product is then recovered by conventional techniques.
  • the product may have to be dried to obtain Form M2.
  • the crystalline form may be dried at room temperature and/or under atmospheric pressure.
  • Form M2 may also be obtained by crystallization from a C 3 to C 8 ketone, such as acetone.
  • a base and a source of sodium preferably an aqueous solution of sodium hydroxide, is added to a solution of MPA in acetone.
  • examples of other bases include sodium methoxide and sodium ethoxide.
  • the reaction is preferably carried out with stirring.
  • the solid product is then recovered by conventional techniques and may be dried.
  • Another process for preparing crystalline mycophenolate sodium M2 comprises heating a solid mixture of crystalline mycophenolate sodium Form M1 and Form M3.
  • mycophenolate sodium Form M2 is prepared by heating a solid mixture of mycophenolate sodium Forms M1 and M3 in an oven at about 170° C. to obtain Form M2, preferably about 30 minutes, and placing the mixture in a desicator to allow it to cool to room temperature.
  • mycophenolate sodium Form M2 by adding a base and a source of sodium to a solution of mycophenolic acid in a mixture of dichloromethane and methanol.
  • a base and a source of sodium Preferably sodium methoxide in methanol is added to the solution.
  • Crystalline Form M2 obtained with the processes of the present invention preferably contains less than 30%, more preferably less than 20%, more preferably less than 10%, and most preferably less than about 5% of other polymorphic forms by weight.
  • the single particle size for Form M2 is less than about 100 micrometers, as measured by polarizing light microscope of crystal described in the invention.
  • the starting material used for the processes of the present invention may be any crystalline or amorphous form of mycophenolate sodium or acid, including various solvates and hydrates.
  • the processes of the present invention may also be practiced as the last step of prior art processes that synthesize mycophenolate sodium.
  • the base and the source of sodium as used throughout this invention can be different, or they can be the same.
  • sodium methoxide, sodium ethoxide, or sodium hydroxide can be used as both the base and the source of sodium.
  • the preferred base and source of sodium is sodium methoxide.
  • the conditions may also be changed to induce precipitation.
  • a preferred way of inducing precipitation is to reduce the solubility of the solvent.
  • the solubility of the solvent may be reduced, for example, by cooling the solvent or adding an anti-solvent.
  • an anti-solvent is added to a solution to decrease its solubility for a particular compound, thus resulting in precipitation.
  • Another way of accelerating crystallization is by seeding with a crystal of the product or scratching the inner surface of the crystallization vessel with a glass rod.
  • compositions of the present invention contain mycophenolate sodium Form M2.
  • the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes.
  • Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • microcrystalline cellulose e.g. Avicel®
  • microfine cellulose lactose
  • starch pregelitinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • Solid pharmaceutical compositions that are compacted into a dosage Form like a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
  • carbomer e.g. carbopol
  • carboxymethylcellulose sodium, dextrin ethyl cellulose
  • gelatin guar
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®
  • Glidants can be added to improve the flowability of non-compacted solid composition and improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • a dosage Form such as a tablet is made by compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease release of the product Form the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage Form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • hydrochloride Forms and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition according to the present invention may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
  • a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage Form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage Forms include solid dosage Forms like tablets, powders, capsules, suppositories, sachets, troches and losenges as well as liquid syrups, suspensions and elixirs.
  • a dosage Form of the present invention is a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • the active ingredient and excipients may be Formulated into compositions and dosage Forms according to methods known in the art.
  • a composition for tableting or capsule filing may be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder Form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump up into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may then be tableted or other excipients may be added prior to tableting such as a glidant and or lubricant.
  • a tableting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules.
  • the compacted granules may be compressed subsequently into a tablet.
  • a blended composition may be compressed directly into a compacted dosage Form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited to direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular Formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, only they are not subjected to a final tableting step.
  • ARL X-ray powder diffractometer model X'TRA-030, Peltier detector, round standard aluminum sample holder with round zero background quartz plate was used. Scanning parameters: Range: 2-40 deg. 2 ⁇ , continuous Scan, Rate: 3 deg./min. The accuracy of peak positions is defined as ⁇ 0.2 degrees due to experimental differences like instrumentations, sample preparations etc.
  • Heating rate 10° C./min., Number of holes of the crucible: 3
  • the DSC curves of the novel forms of mycophenolate monosodium indicates only endothermic peaks due to dehydration, desolvation and melting.
  • Heating rate 10° C./min.
  • In N 2 stream: flow rate 50 ml/min
  • the particle size of single crystals was observed by a polarizing light Microscope, Type: Zeiss TOPIC-B. Sample preparation was done by dispersing a sample in one drop of mineral oil. The magnification was 200.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080009050A1 (en) * 2006-06-29 2008-01-10 Zdenek Pokluda Regulation of acid metabolite production
US20080254520A1 (en) * 2007-04-11 2008-10-16 Eva Gulyas Method for reducing impurity level in mycophenolic acid fermentation

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080182998A1 (en) * 2007-01-25 2008-07-31 Apotex Fermentation Inc. Novel crystalline mycophenolate sodium polymorph and processes to manufacture same
US20080176937A1 (en) * 2007-01-23 2008-07-24 Apotex Fermentation Inc. Novel crystalline mycophenolate sodium polymorph and processes to manufacture same
CA2729834A1 (en) * 2008-07-09 2010-01-14 Aspreva International Ltd. Formulations for treating eye disorders
US20110166347A1 (en) * 2008-09-10 2011-07-07 Ipca Laboratories Ltd. Process for preparation of mycophenolic acid, its salt and ester derivatives
CN103880800A (zh) * 2010-11-16 2014-06-25 北京京卫信康医药科技发展有限公司 麦考酚酸钠的新晶型及其制备方法
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RU2723255C2 (ru) * 2018-11-14 2020-06-09 Общество с ограниченной ответственностью "Изварино Фарма" Экструдат с микофенолятом натрия для получения пероральной твердой лекарственной формы
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CN114478452B (zh) * 2022-02-22 2024-02-06 广东蓝宝制药有限公司 一种麦考酚钠的制备方法

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452891A (en) * 1980-09-08 1984-06-05 Ajinomoto Company Incorporated Method for production of mycophenolic acid by fermentation
US4748173A (en) * 1987-01-30 1988-05-31 Syntex (U.S.A.) Inc. Heterocyclic aminoalkyl esters of mycophenolic acid and derivatives thereof and pharmaceutical compositions
US4753935A (en) * 1987-01-30 1988-06-28 Syntex (U.S.A.) Inc. Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions
US4861776A (en) * 1987-01-30 1989-08-29 Syntex (U.S.A) Inc. Heterocyclic aminoalkyl esters of mycophenolic acid and derivatives thereof, compositions and use
US5247083A (en) * 1992-07-10 1993-09-21 Syntex (U.S.A.) Inc. Direct esterification of mycophenolic acid
US5455045A (en) * 1993-05-13 1995-10-03 Syntex (U.S.A.) Inc. High dose formulations
US5543408A (en) * 1993-09-15 1996-08-06 Syntex (U.S.A.) Inc. Crystalline anhydrous mycophenolate mofetil and intravenous formulation thereof
US5688529A (en) * 1993-10-01 1997-11-18 Syntex (U.S.A) Inc. Mycophenolate mofetil high dose oral suspensions
US6333198B1 (en) * 1998-06-10 2001-12-25 Glaxo Wellcome, Inc. Compound and its use
US6709846B1 (en) * 1998-12-09 2004-03-23 Biocon India Limited Methods of producing esters of mycophenolate
US20040167130A1 (en) * 2003-02-21 2004-08-26 Kwang-Chung Lee Process for making mycophenolate mofetil by transesterification

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1157099A (en) 1966-09-27 1969-07-02 Ici Ltd Fermentation Process
GB1158387A (en) 1967-06-13 1969-07-16 Ici Ltd Procedure for Isolation of Mycophenolic Acid
ZA684959B (en) 1967-11-22 1969-05-22 Lilly Co Eli Agents and methods for inhibiting the growth of malignant tumor cells in warm-blooded mammals
ID18663A (id) * 1996-04-12 1998-04-30 Novartis Ag Komposisi farmasi berlapis enterik
HUP9903226A2 (en) 1999-09-23 2002-08-28 Gyogyszerki Process for producing mycophenolic acid and derivatives thereof
DE60023187D1 (de) 2000-02-29 2006-02-23 Biocon Ltd Herstellung und reinigung von mycophenolsäure
CZ292123B6 (cs) 2001-06-08 2003-08-13 Ivax Pharmaceuticals S.R.O. Způsob přípravy mykofenolátu mofetilu
GB0124953D0 (en) * 2001-10-17 2001-12-05 Novartis Ag Organic Compounds
EP1532130B1 (en) 2002-08-29 2009-11-04 Biocon Limited Process for the production of an immunosuppressant
GB0301259D0 (en) * 2003-01-20 2003-02-19 Novartis Ag Organic compounds
GB0307553D0 (en) 2003-04-01 2003-05-07 Novartis Ag Organic compounds

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452891A (en) * 1980-09-08 1984-06-05 Ajinomoto Company Incorporated Method for production of mycophenolic acid by fermentation
US4748173A (en) * 1987-01-30 1988-05-31 Syntex (U.S.A.) Inc. Heterocyclic aminoalkyl esters of mycophenolic acid and derivatives thereof and pharmaceutical compositions
US4753935A (en) * 1987-01-30 1988-06-28 Syntex (U.S.A.) Inc. Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions
US4786637A (en) * 1987-01-30 1988-11-22 Syntex (U.S.A.) Inc. Treatment of allograft rejection with mycophenolic acid morpholinoethylester and derivatives thereof
US4808592A (en) * 1987-01-30 1989-02-28 Syntex (U.S.A.) Inc. Method of treating diseases by administering morpholinoethylester of mycophenolic acid and derivatives thereof
US4861776A (en) * 1987-01-30 1989-08-29 Syntex (U.S.A) Inc. Heterocyclic aminoalkyl esters of mycophenolic acid and derivatives thereof, compositions and use
US4868153A (en) * 1987-01-30 1989-09-19 Syntex (U.S.A.) Inc. Treatment of allograft rejection with mycophenolic acid, its morpholinoethylester and derivatives thereof
US4948793A (en) * 1987-01-30 1990-08-14 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with the morpholinoethyl ester of mycophenolic acid, and derivatives thereof
US4952579A (en) * 1987-01-30 1990-08-28 Syntex (U.S.A.) Inc. Method of treating diseases by administering morpholino-ethylester of mycophenolic acid or derivatives thereof
US5247083A (en) * 1992-07-10 1993-09-21 Syntex (U.S.A.) Inc. Direct esterification of mycophenolic acid
US5455045A (en) * 1993-05-13 1995-10-03 Syntex (U.S.A.) Inc. High dose formulations
US5543408A (en) * 1993-09-15 1996-08-06 Syntex (U.S.A.) Inc. Crystalline anhydrous mycophenolate mofetil and intravenous formulation thereof
US5545637A (en) * 1993-09-15 1996-08-13 Syntex (U.S.A.) Inc. Process for preparing pharmaceutical compositions containing crystalline anhydrous mycophenolate mofetil salts
US5688529A (en) * 1993-10-01 1997-11-18 Syntex (U.S.A) Inc. Mycophenolate mofetil high dose oral suspensions
US6333198B1 (en) * 1998-06-10 2001-12-25 Glaxo Wellcome, Inc. Compound and its use
US6709846B1 (en) * 1998-12-09 2004-03-23 Biocon India Limited Methods of producing esters of mycophenolate
US20040167130A1 (en) * 2003-02-21 2004-08-26 Kwang-Chung Lee Process for making mycophenolate mofetil by transesterification

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080009050A1 (en) * 2006-06-29 2008-01-10 Zdenek Pokluda Regulation of acid metabolite production
US20080254520A1 (en) * 2007-04-11 2008-10-16 Eva Gulyas Method for reducing impurity level in mycophenolic acid fermentation

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