EP1641438B1 - Process for the preparation of the amorphous form of a drug - Google Patents

Process for the preparation of the amorphous form of a drug Download PDF

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Publication number
EP1641438B1
EP1641438B1 EP05758626A EP05758626A EP1641438B1 EP 1641438 B1 EP1641438 B1 EP 1641438B1 EP 05758626 A EP05758626 A EP 05758626A EP 05758626 A EP05758626 A EP 05758626A EP 1641438 B1 EP1641438 B1 EP 1641438B1
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European Patent Office
Prior art keywords
solution
less
chamber
mmhg
drying
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EP05758626A
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German (de)
English (en)
French (fr)
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EP1641438A1 (en
Inventor
Szabolcs Szoke
Csaba Szabo
Lorant Gyuricza
Claude Singer
Valerie Niddam-Hildesheim
Greta Sterimbaum
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Teva Pharmaceutical Works PLC
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Teva Pharmaceutical Works PLC
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Priority to EP05758626A priority Critical patent/EP1641438B1/en
Priority to PL05758626T priority patent/PL1641438T3/pl
Priority to SI200531011T priority patent/SI1641438T1/sl
Priority claimed from PCT/US2005/019485 external-priority patent/WO2005117837A1/en
Publication of EP1641438A1 publication Critical patent/EP1641438A1/en
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Publication of EP1641438B1 publication Critical patent/EP1641438B1/en
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    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/041—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum for drying flowable materials, e.g. suspensions, bulk goods, in a continuous operation, e.g. with locks or other air tight arrangements for charging/discharging
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B11/00—Machines or apparatus for drying solid materials or objects with movement which is non-progressive
    • F26B11/12—Machines or apparatus for drying solid materials or objects with movement which is non-progressive in stationary drums or other mainly-closed receptacles with moving stirring devices

Definitions

  • the present invention provides a process for preparation of amorphous form of a drug, i . e ., a pharmaceutical active ingredients (API).
  • a drug i . e ., a pharmaceutical active ingredients (API).
  • Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystalline lattice.
  • Amorphous solids consist of disordered arrangements of molecules and do not possess a distiguishable crystal lattice.
  • Polymorphs of a pharmaceutical solid may have different physical and solid-state chemical (reactivity) properties. These polymorphs differ in internal solid-state structure and, therefore, possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on drug product quality/performance, including stability, dissolution and bioavailability.
  • the most stable polymorphic form of a drug substance is often used in a formulation because it has the lowest potential for conversion from one polymorphic form to another.
  • metastable a form other than the most stable form
  • amorphous forms may be chosen to enhance the bioavailability of the drug product.
  • Amorphous form being a disorganized solid mass, does not need to lose crystal structure before dissolution in the gastric juices, and thus often has greater bioavailability than a crystalline form.
  • lyophilization for example as shown in EP 1 384 721 and WO03/06595 for amorphous mupirocin calcium, is quite expensive process on large scale, and generally has limited capacity. Further, lyophilization with an organic solvent is often dangerous since it possesses a fire hazard.
  • spray drying consists of bringing together a highly dispersed liquid and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. Spray-drying however is often limited to aqueous solutions unless special expensive safety measures are taken. Also in spite of the short contact time, certain undesirable physical and chemical characteristics of the emerging solids are in particular cases unavoidable. The turbulence present in a spray drier as a result of the moving air may alter the product in an undesirable manner. Modifications to the spray drying technique is disclosed in WO 03/063821 and WO 03/063822 .
  • the present invention provides a process for preparing an amorphous form of an active pharmaceutical ingredient comprising: a) providing a chamber having a pressure of less than about 760 mmHg and a temperature of below about 100°C, wherein the chamber has a stirrer and an inlet; b) feeding a solution of the active pharmaceutical ingredient in a solvent having a concentration of more than about 20 m/m%, at a flow rate of about 10 to about 50 cm 3 /hour/inlet to obtain amorphous form as a sponge or a solid; and c) stirring the sponge or solid with the stirrer to obtain an amorphous powder.
  • the present invention provides a process for preparing an amorphous form of an active pharmaceutical ingredient comprising: a) providing a chamber having a pressure of less than about 760 mmHg and a temperature of below about 100°C b) and feeding a solution of the active pharmaceutical ingredient in a solvent having a concentration of more than about 20 m/m%, at a flow rate of about 10 to about 50 cm 3 /hour/inlet, to obtain amorphous form as a sponge or a solid.
  • amorphous refers to a product containing less than 5% crystalline form, preferably less than 3% and more preferably, less than 1%, as measured as area percentage of peaks present in a powder XRD. Presence of amorphous form may be detected by lack of peaks in a powder XRD pattern or lack of a melting point in a DSC thermogram. The area under the peaks in an XRD pattern may be added to obtain total amount of crystalline material. With DSC, presence of endotherms may point to melting of crystalline material.
  • vacuum refers to a reduced pressure of below about 100 mmHg, more preferably below about 50 mmHg, and most preferably below about 30mmHg.
  • reduced pressure refers to a pressure below 760mmHg or 1 atmosphere.
  • amorphous form of a drug including pro-drug
  • a drug including pro-drug
  • the principle is that amorphous solid is formed when the active pharmaceutical ingredient is dried fast by rapid evaporation from a suitable solvent under reduced pressure.
  • the main driving force of the evaporation in the process of the present invention is a combination of temperature/reduced pressure, and not a hot air flow as in spray drying.
  • the authors of Polymorphism in Pharmaceutical Sciences, Drugs and the Pharmaceutical Sciences, Vol. 95 do not list the process of the present invention as one employed to produce amorphous form.
  • the process of the present invention allows for preparing amorphous API on an industrial scale, i . e ., a batch of at least about 500grams, more preferably at least about 1Kg and most preferably at least about 10Kg.
  • the concentration, solvent type, temperature, vacuum, feeding rate are set to such a combination where the API, coming from the inlet, such as a nozzle, precipitates instantly. Otherwise crystalline material can also form.
  • the specific conditions employed are API dependent, however, generally the process may be carried out at a temperature below about 100°C, a reduced pressure and a concentrated solution of the API in a solvent, preferably having a concentration of more than about 20% m/m, and/or concentrated to the point of saturation (solution in equilibrium with a solid solute), and a flow rate of about 10 to about 50 cm 3 /hour/inlet.
  • organic solvents are generally more volatile.
  • Preferred solvents are the easily volatile organic solvents with relatively low boiling point such as C 1 to C 4 alcohol, C 3 to C 7 ketone, C 3 to C 7 ester, C 5 to C 7 straight or cyclic saturated hydrocarbon or C 2 to C 8 ethers, or mixtures thereof.
  • Particularly preferred solvents may be selected from methanol, ethanol, acetone, ethylacetate, heptane, hexane, diethylether methyl isobutylether, or mixtures thereof.
  • Especially preferred solvents are methanol or acetone.
  • Preferably technical grade of these solvents are used containing less than about 20% water, more preferably less than about 2% water by volume.
  • the boiling point of the solvent is preferably below about 100°C, more preferably below about 70°C, under atmospheric pressure at room temperature.
  • the active pharmaceutical ingredient may be in the form of a free base, a free acid, ester or a salt.
  • the solution of the API for drying may be prepared depending on whether the API is a salt or not. For example if the API is an acid, and a salt is desired, the API may be reacted with a base to obtain a solution of the salt (montelukast and NaOH; mupirocin and CaOH). Such reaction may be carried out by suspending or dissolving the API in a solvent, and adding the base. The solution may be filtered if necessary.
  • salts of API that may be used with the present invention include sodium, calcium, potassium, acetate, benzoate, fumarate, maleate, citrate, tartrate, gentisate, methanesulfonate, ethanesulfonate, benzenesulfonate, laurylsulfonate, taurocholate, hydrochloride and hydrobromide salts.
  • the solution may also be of the API in free acid or free base form, e.g. valsartan.
  • a polymer may be added to the solution to increase the solubility of the API.
  • a desirable polymer may be chosen based on criteria such as glass transition temperature and effect on bioavailability. Examples of such polymers include those disclosed in WO03/063822 .
  • a class of polymers is those derived from cellulose.
  • the process of the present invention is carried out optimally with a concentrated solution.
  • the last step of the API isolation process is preferably a concentration in a solvent where the API is dissolved.
  • This concentrated solution with preferably more than about 20 m/m%, more preferably about 20 to about 80 m/m%, more preferably about 60% to about 75%, and/or a solution concentrated to the point of saturation, is fed into a reduced pressure chamber, at a temperature of less than about 100° C , through preferably a sort of nozzles (inlets).
  • the feeding may be carried out by a pump, pressure from another tank, vacuum in the drying chamber or pressure from a syringe device.
  • a chamber may be any reactor, flask, container capable of maintaining the desirable process conditions such as reduced pressure.
  • the solution is added dropwise or continuously to the drying chamber.
  • the speed of the addition of the solution will depend on the solvent used, the viscosity of the mixture, and the height of the chamber. The speed may also vary from one API to another. Rate of flow of the solution, if delivered through a nozzle, is preferably in the range of about 10 to about 50 cm 3 /hour/nozzle (inlet), depending on the concentration, pressure, temperature, properties of the solvent and the API.
  • the drop of solution explodes (like a popcorn kernel popping) instantaneously in the chamber.
  • This solidification is spontaneous, and does not require further actions such as stirring, and occurs as the solution comes out of the nozzle (inlet) into the drying chamber.
  • This instant evaporation allows for obtaining a phase change (solidification) before the solution contacts the bottom of an industrial sized chamber when fed from the top.
  • a small industrial size chamber has a height of about 0.5 to about 1 meter. It is possible to feed the solution from the side or bottom of the chamber as well.
  • the solvent instantly evaporates, while the dissolved API precipitates as a sponge (a solid foam) or even possibly as a solid with certain API.
  • the sponge grows due to continuous feeding and hangs on the syringe/nozzles.
  • the sponge mass reaches a certain mass with mupirocin calcium, it falls down to the bottom of the drying chamber.
  • other API it is possible for the solid to fall as it comes out of the nozzel.
  • Number of inlets for the nozzles in the drying chamber depends on the capacity of vacuum. Vapor removal from the drying chamber can be accelerated by a small leak of an inert gas, preferably nitrogen. Drying equipment preferably contains a stirrer, which is suitable to break the solid, forming a powder.
  • API drying can be continued under reduced pressure, preferably with stirring until the residual solvent concentration reduces to the required FDA level.
  • the solvent level depends on the type of solvent but is preferably no more than about 5000 ppm, more preferably no more than about 4000 ppm, and most preferably no more than about 3000 ppm.
  • the drying of the powder after the stirring is preferably carried out under reduced pressure (below 1 atm), more preferably below about 100mmHg, most preferably below about 50mmHg.
  • the temperature is preferably about 30°C to about 50°C, more preferably about 35°C to about 45°C.
  • the drying is preferably carried out for about 1 hour to about 10 hour.
  • the powder can be discharged from the dryer by conventional way, for example via an outlet of a chamber located at the bottom of the chamber, while the stirrer is rotating.
  • a valve may be opened to discharge the powder, and additional force in addition to gravitational force may be used to accelerate the discharge.
  • the process of the present invention is preferably carried out with a feeding system having a distributor of preferably less than about 3 mm diameter syringe/nozzle, more preferably less than about 2 mm, continuous feeding of API solution, API solution in organic or aqueous solvent, working pressure of preferably less than about 760 mmHg, more preferably less than about 100mmHg, more preferably less than about 50 mmHg, most preferably less than about 20 mmHg, working temperature of less than about 100°C, preferably about 20°C to about 80°C, more preferably about 25°C to about 45°C, optional inert gas flow (such as No), and a drying chamber with stirrer and a discharge device. While drop-wise addition is possible, scaling up is easier with a syringe and continuous feeding.
  • the instrument of the present invention has a place for injection of the API, which is contemplated to be at top or side of a chamber, but may also be at the bottom of the chamber.
  • the left intake of the instrument shown in Figure 1 is closed to allow for vacuum generation.
  • the left intake may be used to feed inert gas so as to create a dry environment.
  • the instrument has an outlet to a vacuum.
  • the instrument may also have a place for applying heat, a discharge place and/or a stirrer.
  • a sample of the solid from the chamber may be taken with various API and tested for quality assurance. For example, if the process results in more than about 5% crystalline material as area percentage XRD, and less than 5% crystallinity is desired, the process may be changed by manipulating the conditions. If highly pure amorphous API is desired, API having more than about 5% crystallinity may be discarded after the process. Any such API having a crystallinity of 5% or more can be recycled in the process. Batches with less than about 5% crystallinity may be chosen. In some instances crystallinity of less than about 3% or less than about 1% may be desired.
  • Presence of amorphous form may be detected by lack of peaks in a powder XRD pattern or lack of a melting point in a DSC thermogram.
  • the area under the peaks in an XRD pattern may be used in order to calculate the obtained crystallinity.
  • API for use with this process include fexofenadine hydrochloride, sertraline hydrochloride, moxifloxacin hydrochloride, losartan potassium, esomeprazole magnesium, clopidogrel hydrogensulfate, repaglinide, benazepril hydrochloride, nelfinavir mesylate, donepezil hydrochloride, torasemide, alendronate sodium, fluvastatin sodium, atorvastatin calcium, simvastatin calcium, telmisartan sodium, nelfinavir mesylate, zolenodrate sodium, rosiglitazone maleate, beta-L-2-deoxythymidine and losartan postassium, valganciclovir hydrochloride, repalglinide, levocetririzine dihydrochloride, donepezil hydrochlor
  • compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transdermally, bucally, or nasally.
  • suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups and suspensions.
  • Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration suitable forms for administration include suppositories with hydrophilic or hydrophobic vehicle.
  • the invention provides suitable transdermal delivery systems known in the art, and for nasal delivery there are provided suitable aerosol delivery systems known in the art.
  • compositions of the present invention contain amorphous form of an active pharmaceutical ingredient prepared by the present invention.
  • the pharmaceutical compositions of the present invention may contain one or more excipients or adjuvants. Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • 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 dextra
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as 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.
  • povidone e.g. Kollidon ® , Plasdone ®
  • pregelatinized starch sodium alginate and starch.
  • 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
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to 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
  • 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 the release of the product from 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 that may be included in the composition of the present invention 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.
  • liquid pharmaceutical compositions of the present invention the active ingredient 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.
  • 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 may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
  • a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, 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 administration 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.
  • the dosage form of the present invention may be 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.
  • compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling 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 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 a 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 subsequently be compressed 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 for 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, however, they are not subjected to a final tableting step.
  • Pseudomonic acid (4.0 kg) was dissolved in 10.0 1 ethanol at 25 - 27 °C.
  • Potassium hydroxide ethanolic solution (448 grams in 2.6 l ethanol) was added to the pseudomonic acid solution.
  • Calcium chloride ethanolic solution (444 grams in 2.6 1 ethanol) was added to the potassium pseudomonate solution.
  • the reaction mixture was stirred at room temperature for an hour.
  • the precipitated potassium chloride was filtered. Part of ethanol was evaporated from the ethanolic calcium pseudomonate solution to reduced volume about 10 1 at 40-50°C.
  • the concentration of solution was 24-35 wt%.
  • Pseudomonic acid (30 grams) was dissolved in 30 cm 3 methanol at 25-27°C.
  • the reaction mixture was seeded with potassium chloride crystals.
  • the reaction mixture was stirred at room temperature for an hour and cooled at 5 °C.
  • the precipitated potassium chloride was filtered. Part of methanol was evaporated from the methanolic calcium pseudomonate solution at 40°C. The final concentration of the solution after evaporation was about 75 wt%.
  • the concentrated solution was introduced-injected into an evacuated (5-20 mbar) and heated (jacket temperature 40°C) 30 liter reactor through 8 nozzles. After feeding, the product was broken by a mechanic stirrer and dried under vacuum (5-20 mbar) at 35 °C for 8 hours. The obtained sponge was milled with a grinder. The final product was dried under vacuum (5-20 mbar) for 2 hours at 50°C. Chemical purity: assay: 97.3%, Mup-II: 0.52%, water content: 1.1%, residual methanol 2440 ppm.
  • the product dried under vacuum (max. 20 mbar) for 2 hours at 40 °C (jacket temperature).
  • the product dried under vacuum (max. 20 mbar) for 6 hours at 35°C (jacket temperature).
  • the final product was dried under vacuum (max. 20 mbar) for 12 hours at 50 - 54 °C.
  • Montelukast sodium salt (1.5 g) and acetone (30 mL) were added to a 100 mL flask equipped with a magnetic stirrer. The solution was stirred at ambient temperature for 1 hour and then filtered under vacuum to remove the insoluble particles. The clear solution was concentrated to half and then transferred to the dropping funnel. The reaction mixture was slowly added dropwise into a 500 mL reactor under vacuum of 1 mm Hg and heated at 45°C. Every drop added immediately evaporated before reaching the sides or bottom of the reactor. After the end of the addition, the mechanical stirrer was switched on to break the foam formed. The reactor was inverted to collect the powder produced.

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  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP05758626A 2004-06-01 2005-06-01 Process for the preparation of the amorphous form of a drug Not-in-force EP1641438B1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP05758626A EP1641438B1 (en) 2004-06-01 2005-06-01 Process for the preparation of the amorphous form of a drug
PL05758626T PL1641438T3 (pl) 2004-06-01 2005-06-01 Sposób wytwarzania amorficznej postaci leku
SI200531011T SI1641438T1 (sl) 2004-06-01 2005-06-01 Postopek za pripravo amorfne oblike zdravila

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US57621604P 2004-06-01 2004-06-01
US58377804P 2004-06-28 2004-06-28
US59970004P 2004-08-05 2004-08-05
EP05758626A EP1641438B1 (en) 2004-06-01 2005-06-01 Process for the preparation of the amorphous form of a drug
PCT/US2005/019485 WO2005117837A1 (en) 2004-06-01 2005-06-01 Process for preparation of amorphous form of a drug

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EP1641438A1 EP1641438A1 (en) 2006-04-05
EP1641438B1 true EP1641438B1 (en) 2010-02-24

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PL (1) PL1641438T3 (pl)
SI (1) SI1641438T1 (pl)

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