USOO6547997 B1 (12) United States Patent (10) Patent No.: US 6,547,997 B1 Breitenbach et al. (45) Date of Patent: Apr. 15, 2003

(54) METHOD FOR PRODUCING SOLVENT. (58) Field of Search ...... 264/85, 102,349; FREE NONCRYSTALLINE BIOLOGICALLY 424/489 ACTIVE SUBSTANCES (56) References Cited (75) Inventors: Jörg Breitenbach, Mannheim (DE); U.S. PATENT DOCUMENTS Ulrich Reinhold, Speyer (DE); Jirgen a Zeidler, Mutterstadt (DE); Jörg 4,578.455 A 3/1986 Pipper et al. Rosenberg, Ellerstadt (DE) 5,667,807 A * 9/1997 Hurner et al...... 424/455 5,789,436 A 8/1998 Kato et al...... 514/443 (73) Assignee: Abbot Laboratories, Abbott Park, IL 5,811,547 A 9/1998 Nakamichi et al. (US) 6,260,995 B1 * 7/2001 Schuchardt ...... 366/300 FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 5. s: 3.E. U.S.C. 154(b) by 0 days. EP 665 009 8/1995 (21) Appl. No.: 09/554.215 EP 813 904 12/1997 WO 95/O1321 1/1995 (22) PCT Filed: Nov. 9, 1998 WO 97/18839 5/1997 (86) PCT No.: PCT/EP98/07141 * cited by examiner S371 (c)(1), Primary Examiner Mark Eashoo (2), (4) Date: May 11, 2000 (74) Attorney, Agent, or Firm-Keil & Weinkauf (87) PCT Pub. No.: WO99/27891 (57) ABSTRACT PCT Pub. Date:Jun. 10, 1999 Solvent-free noncrystalline bioactive Substances are pre pared from the corresponding crystalline bioactive Sub (30) Foreign Application Priority Data stances in an extruder by melting the Substances in the extruder under reduced pressure and in the absence of Nov. 28, 1997 (DE) ...... 197 52.895 auxiliaries, cooling and comminuting. (51) Int. Cl...... B29C 47/00 (52) U.S. Cl...... 264/85; 264/102; 264/349 12 Claims, No Drawings US 6,547.997 B1 1 2 METHOD FOR PRODUCING SOLVENT Sep raconazole, clindamycin, cephalosporins, FREE NONCRYSTALLINE BIOLOGICALLY chloramphenicol, erythromycin, 5-fluorouracil, ACTIVE SUBSTANCES etoposide, flucytosine, ganciclovir, griseofulvin, gyrase inhibitors, isoniazid, lincosamides, mebendazole, The present invention relates to a process for preparing mefloquine, metronidazole, nitroimidazoles, Solvent-free noncrystalline bioactive Substances from the novobiocin, platinum compounds, polymyxin B, corresponding Solvent-containing crystalline Substances in praziquantel, pyrimethamine, rifamipicin, Saquinavir, an extruder. Streptomycin, Sulfonamides, tetracy cline S, It is frequently possible for one and the same chemical Substance to form Solids based on different order states. This trimethoprim, Vancomycin, Zidovudine, Situation is referred to as polymorphism and can likewise be antipyretics, analgesics, antiinflammatory agents, influenced by the novel process. The various crystallo paracetamol, ibuprofen, ketoprofen, oxaprozin, acetyl graphic forms also include pseudopolymorphic forms. These Salicylic acid, morphine, propoxyphene, phenylbuta are ones in which not only the relevant Substance but also ZOne, foreign Substances are involved in the Structure due to antibiotics rifampicin, griseofulvin, chloramphenicol, formation of mixed crystals, Solvates or hydrates. Mixed 15 cycloSerine, erythromycin, penicillins Such as penicil crystals are crystals composed of two or more chemical lin G, Streptomycin, tetracycline, Substances, and the components involved together form a antiepileptics hydantoins, carbamazepine; Specific crystallographic Structure. Solvates and hydrates are to be regarded as Special cases in which one of the compo antituSSives and antiasthmatics diphenhydramine; nents of the mixture is a Solvent, with hydrates being formed antirheumatics chloroquine, indomethacin, gold with water. compounds, phenylbutaZone, oxyphenbutaZone, peni Hydrates are particularly important. Because of the Strict cillamine; Structural conditions, they have a Stoichiometric structure hypnotics barbiturates, phenobarbital, Zolpidem, and often show significantly poorer dissolving behavior than dioxopiperidines, ureides, the anhydrous forms, because the water of crystallization is 25 insecticides aldrin, dieldrin, chlorophenotane, hexachlo able to Saturate additional Secondary Valencies in the rocyclohexane, molecular assemblage. The latter are unable in Some circumstances, for Steric reasons, to undergo Saturation in herbicides Vinclozolin, strobilurins; the anhydrous form. This means that forms containing water psychopharmaceuticals, neuroleptics pera Zine, of crystallization often have greater thermodynamic Stabil promazine, Sulpiride, thioridazine, chlorpromazine ity. meprobamate, triflupromazine, melperone, clozapine, Many bioactive Substances contain Solvents as a result of risperidone, reserpine; the process for their preparation. tranquilizers, However, it is often difficult to remove Such solvents, antidepressants imipramine, paroxetine, Viloxazine, especially Solvents bound in the crystal, by conventional 35 moclobemide, processes Such as heating or freeze drying. psychotonics, It is to this extent of interest to provide a proceSS for psychomimetics, converting bioactive Substances into a Solvent-free form in diuretics potassium can renoate, loop diuretics, a simple manner. furosemide, hydrochlorothiazide, Spironolactone, It is also known that the bioavailability of Substances is 40 thiazides, triamterene; frequently leSS good in their crystalline form than in the hormones androgens, antiandrogens, geStagens, corresponding amorphous form. glucocorticoids, oestrogens, cortisol, dexamethasone, EP-A 0 665 009 discloses a process in which active prednisolone, testosterone, Adiuretin, oxytocin, Substances are converted in a twin Screw extruder from one Somatropin, insulin; morphological State into another. However, this does not 45 disclose the use of reduced pressure, nor does the proceSS immunosuppresants ciclosporin; indicate how to proceed with active Substances which con bronchodilators; tain water of crystallization or Solvents. muscle relaxants, tranquilizers carisoprodol, tetrazepam, It is an object of the present invention to provide a diazepam, chlordiazepoxide; process for preparing Solvent-free noncrystalline, ie. 50 enzymes lipase, phytase, amorphous, bioactive Substances from the corresponding gout remedies allopurinol, colchicine; Solvent-containing crystalline bioactive Substances. anticoagulants coumarins, We have found that this object is achieved by a process antiepileptics phenytoin, phenobarbital, primidone, Valp for preparing noncrystalline bioactive Substances, which roic acid, carbamazepine; comprises melting the crystalline Solvent-containing Sub 55 stances in an extruder in the absence of auxiliaries, the antihistamines chlorphenoxamine, dimenhydrinate; preSSure being reduced in one Zone of the extruder. antimimetics, It is possible according to the invention to employ for this antihypertensives, antiarrhythmics lidocaine, purpose not only pharmaceutical active Substances but also procainamide, quinidine, calcium antagonists, glycerol a large number of bioactive Substances which, by their 60 trinitrate, iSo Sorbide dinitrate, iSo Sorbide nature, have Solvent bound in their crystal lattice or else are 5-mononitrate, pentaerythrityl tetranitrate, nifedipine, merely moistened with a Solvent. diltiazem, felodipine, Verapamil, reserpine, minoxidil, The novel process is Suitable, for example, for formu captopril, enalapril, lisinopril; lating the following Substances or their physiologically Sympathomimetics norfenefrine, Oxedrine, midodrine, acceptable Salts 65 phenylephrine, isoprenaline, Salbutamol, clenbuterol, antiinfectives aciclovir, aminoglycosides, amphotericin ephedrine, tyramine, B blockerS Such as alprenolol, B, azole antimycotics, clotrimazole, itraconazole, metoprolol, bisoprolol, US 6,547.997 B1 3 4 antidiabetics biguanides, Sulfonylureas, carbutamide, However, the extrusion can also according to the invention tolbutamide, glibenclamide, metformin, acarbose, tro take place from the open extruder. There is then a fall in glitaZone; preSSure in the last Section. iron preparations, Depending on the Viscosity of the melt and the Screw geometry, the operating preSSure in the extruder Zones which Vitamins vitamin C, B, A, D, folic acid; are located upstream of the Zone equipped for reducing the ACE inhibitors captopril, ramipril, enalapril; preSSure, Such as extruder channel, can be from 1 to 500 bar. anabolics, Pressures from 3 to 60 bar are preferred. iodine compounds, It is preferred according to the invention for the pressure X-ray contrast agents, in the last Segment or Section (Zone of the extruder) before the die or the end of the extruder channel to be from 10 to CNS-active compounds; 600 mbar, preferably 30-400 mbar, particularly preferably antiparkinson agents bipe ride n, ben Zatropine, 50-100 mbar. The solvent is stripped out of the melt in this amantadine, opioid analgesics, barbiturates, reduced-pressure Segment. The result is an amorphous mass benzodiazepines, disulfiram, lithium Salts, 15 which can be converted into a powder by cooling in another theophylline, Valproate, neuroleptics, Segment and the use of Shear forces which can be cytostatics, introduced, for example, via particular Screw configurations. antispasmolytics, It is thus possible also to discharge the melt and then cool it vasodilators naftidrofuryl, pentoxifylline. and Subsequently grind it. It is also possible to employ mixtures of bioactive Sub Such powders of bioactive substances are suitable for stances. Amorphous Solids have, like liquids, a high dissolv pharmaceutical and cosmetic preparations, but also for use ing capacity for mixing partners. It is therefore possible for in the food, feed and Veterinary Sectors. one bioactive Substance to dissolve another in the melt. This The bioactive substance is particularly preferably in the may lead to mixing diagrams with eutectics. Depending on form of an amorphous powder. the position of the melting curves, one or other Substance 25 Unambiguous assessment of the State of a powdered may be present as crystals at the Same time as the amorphous material is possible only with the aid of X-ray fine-structure first Substance. investigation. The investigation methods are based on the Preferred Substances are those mentioned in the list or fact that interference effects occur when X-ray light is those which contain organic Solvents and/or water from a passed through an ordered material. Phase transformations, crystallization process. This also applies to Vitamins. ie. changes in the State of the material as a function of Preferred active substances for the novel process are temperature, can be observed with the aid of thermal ana amiloride HC1.2H2O, amoxicillin.3H2O, ampicillin.3H2O, lytical methods Such as differential thermal analysis and atropine Sulfate. 1H2O, benzylpenicillin benzathine.1H2O, differential Scanning calorimetry. They provide important calcium folinate.5H2O, carbidopa.1H2O, cefepime.1H2O, indications of the possible behavior of an active Substance cefixime.3H2O, ceftazidime.5H2O, cephaclor. 1H, O, 35 during processing. cephalexin. 1H2O, quinidine Sulfate.4H2O, quinine The Screw geometry in the extruder heating Zone in which sulfate.2H2O, clindamycin HC1. HO, codeine the mixing and melting take place can be chosen to be phosphate./2H2O, cyclophosphamide.1H2O, dihydralazine closely intermeshing, intermeshing or nonintermeshing, sulfate. 2% H2O, do Xy cycline. 1 H2O, with closely intermeshing Screw geometry being preferred. doxycycline.'/3CHOH./2HO, iron(II) gluconate.2H2O, 40 The Screws may rotate in the Same direction or, preferably, iron(II) sulfate. 1H2O, flucloxacillin sodium.1H2O, in opposite directions. In the mixing and melting region, G-strophanthin.8HO, ipratropium bromide. 1H, O, besides conveying elements there are preferably mixing and lidocaine HC1.1 HO, lincomycin HC1.1 HO, kneading elements arranged on the Screws. Conveying ele loracarbef.1H2O, mepacrine 2HC1.2H2O, metamizole ments are Single- and multi-flight Screw elements which sodium.1H2O, methyldopa.1%HO, mino cycline 45 differ in pitch. Mixing elements are gear-like toothed disk HC 1.2H2O, morphine sulfate.5H2O, sodium elements or backward-conveying elements provided with ibuprofenate.2H2O, sodium picosulfate. 1H, O, perforations, it being possible for Some of the perforations to oxyphenbutazone.1H2O, pyritinol 2HC1.1H2O, Sultamicillin extend as far as the Screw root or take up at least half of the tosilate.2HO, theophylline ethylenediamine.2HO or vin helical radius. Kneading elements are bicuspid or tricuspid blastine sulfate.1HO or mixtures thereof. 50 disks, with the elements always having a plurality of disks The amount of Solvent in these cases may vary within a which differ in width and have a defined angle of offset to wide range. Thus, active Substances used in pharmacy are one another. The jacket of the cooling Zone is cooled with known with low solvent contents<1% by weight. However, liquid coolant. The temperature in the conveying Zone of the in the chemical Synthesis of the active Substances, despite cooling Zone is preferably-adjusted to be 5-30 Celsius drying, the bioactive Substance may become moist So that 55 below the Softening point of the composition to be cooled. solvent contents of more than 10% by weight are found. It is possible for the temperature to be reduced over the The novel bioactive Substances are prepared using shear entire cooling Zone in the direction of flow by up to 150 forces and with input of thermal energy. The mixing pref Celsius below the Softening point, depending on the Soft erably takes place in a single Screw or multiScrew extruder, ening point of the composition. It may also be advisable for particularly preferably a twin Screw extruder. A melt of the 60 Shock cooling to take place in the mixing region of the bioactive Substance is produced by thermal energy input. cooling Zone and to cool the jacket to temperatures in the This normally takes place by heating the extruder casing to range from -10° Celsius to +10 Celsius. 35-350° C. The process temperature depends on the melting The detailed Screw geometry also depends on the melting point of the Substance or mixture of Substances. point of the Substances to be processed. The molten bioactive Substance or the mixture of molten 65 It is possible with the aid of the novel process to prepare bioactive substances is conveyed by the movement of the compositions with particle sizes in the range from 0.0001 to screw toward the extruder outlet, which is preferably a die. 50 mm diameter. Depending on the choice of the screw US 6,547.997 B1 S 6 diameter, of the mixing and kneading elements and of the Example 2 Speeds of rotation of the Screw, the resulting particles have sizes in the range 10-50 mm, 1-3 mm, 0.3-1 mm, 0.1-0.3 Sodium ibuprofenate obtained from a crystallization pro mm, 0.03-0.1 mm or 0.001-0.03 mm. The particle sizes are cess and containing 2% by weight of water and 2% by preferably 0.001-10 mm, particularly preferably 0.005-3 weight of methanol was processed as in Example 1. An mm. The particle sizes adjusted in the Specific case depend amorphous Solvent-free powder was obtained. in particular on the area of use required. The particulate preparations show good uniformity in the particle size We claim: distribution so that they can be processed further without 1. A process for preparing a Solvent-free noncrystalline other Screening processes. bioactive Substance from the corresponding Solvent The compositions according to the invention can be containing bioactive Substance crystals in an extruder, processed to tablets, Suppositories, granules, instant wherein the Solvent-containing Substance crystals are melted granules, pellets, implants, floating tablets or be used to fill in the extruder under reduced pressure, the pressure being capsules. reduced in one Zone of the extruder, and wherein the 15 Substance crystals are employed free of auxiliary Substances. PREPARATION EXAMPLES 2. A process as claimed in claim 1, which is carried out The extrudates were prepared using a corotating, inter under inert gas. meshing twin-screw extruder (ZSK 30 from Werner & 3. A process as claimed in claim 2, wherein the inert gas Pfleiderer, Stuttgart, Germany) consisting of 8 Separate is nitrogen. chamber-like Zones which could be heated and cooled. 4. A proceSS as claimed in claim 1, wherein the Solvent is These Zones are referred to hereinafter as "Zone 1”, “Zone integrated into the crystal lattice of the bioactive Substance. 2', etc., with the Starting material entering at Zone 1 and 5. A proceSS as claimed in claim 4, wherein the Solvent is emerging at Zone 8. Zone 1 was cooled with water Water. (outflowing water at 30° Celsius). Throughout the test, Zone 6. A proceSS as claimed in claim 4, wherein the Solvent is 2 was operated at 200 Celsius and Zones 3 and 4 at 210 25 an organic Solvent. Celsius. Zone 4 contained an attachment for reducing the 7. A process as claimed in claim 1, wherein more than one pressure to 150 millibar. Zones 5, 6, 7 and 8 were cooled bioactive Substance is employed. with water, the resulting outflowing water being at 40 8. The process of claim 1, wherein the reduced pressure Celsius, 30 Celsius, 25 Celsius and 20° Celsius, respec is from 10 to 600 mbar. tively. 9. The process of claim 8, wherein the solvent-containing substance crystals are melted at from 35 to 350° C. Example 1 10. The process of claim 1, wherein the reduced pressure is from 30 to 400 mbar. Preparation of an Amorphous Sodium Ibuprofenate 35 11. The process of claim 1, wherein the reduced pressure 1700 g of sodium ibuprofenate dihydrate were fed per is from 50 to 100 mbar. hour through belt weigh feeders equipped with Screws 12. The process of claim 1, wherein the solvent rotating at 36 revolutions per minute into Zone 1 of this containing Substance crystals are melted at from 35 to 350 extruder. The extruder was operated for 10 hours. The C. ibuprofenate was then in the form of an amorphous anhy drous mass.