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Home , Bucladesine, Dimetotiazine, Efloxate, Iproheptine, Menatetrenone, Nipradilol

Europäisches Patentamt

(19) European Patent Office Office européen des brevets (11) EP 0 665 009 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int. Cl.7: A61K 9/00, A61K 9/14 of the grant of the patent: 16.02.2000 Bulletin 2000/07 (86) International application number: PCT/JP93/01469 (21) Application number: 93922625.4 (87) International publication number: (22) Date of filing: 13.10.1993 WO 94/08561 (28.04.1994 Gazette 1994/10)

(54) CRYSTALLINE CONDITION DISLOCATING METHOD VERFAHREN ZUR VERSCHIEBUNG EINES KRISTALLZUSTANDES PROCEDE DE DISLOCATION D'UN ETAT CRISTALLIN

(84) Designated Contracting States: (74) Representative: AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL Vogeser, Werner, Dipl.-Ing. et al PT SE Patent- und Rechtsanwälte Hansmann, Vogeser, Dr. Boecker, (30) Priority: 14.10.1992 JP 30308592 Alber, Dr. Strych, Liedl Albert-Rosshaupter-Strasse 65 (43) Date of publication of application: 81369 München (DE) 02.08.1995 Bulletin 1995/31 (56) References cited: (73) Proprietor: EP-A- 0 177 428 EP-A- 0 490 768 NIPPON SHINYAKU COMPANY, LIMITED EP-A- 0 580 860 JP-A- 51 139 613 Minami-ku Kyoto-shi Kyoto 601 (JP) JP-A- 60 190 723

(72) Inventors: • Journal of Pharmaceutical Sciences, Vol. 62, No. • NAKAMICHI, Kouichi 1, (January 1973), F.W. GOODHART et al., Koga-gun, Shiga 520-32 (JP) "Design and Use of a Laboratory Extruder for • IZUMI, Shougo Pharmaceutical Granulations", p. 133-136. Kameoka-shi, Kyoto 621 (JP) • OKA, Masaaki Hirakata-shi, Osaka 573 (JP)

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 665 009 B1 Printed by Xerox (UK) Business Services 2.16.7/3.6 12EP 0 665 009 B1

Description (1) from a crystallizable active substance in metast- able crystalline state or in amorphous solid state to TECHNICAL FIELD stable crystals, (2) a crystallizable active substance in stable crys- [0001] This invention relates to a method of inducing 5talline state or in amorphous solid state to metasta- a transition of crystalline state in a crystallizable medic- ble crystals, inal substance. (3) a crystallizable active substance in stable crys- [0002] As used in this specification, the term 'stable talline state or in metastable crystalline state to an crystal' means any crystal that is in thermodynamically amorphous solid, or stable crystalline state and the term 'metastable crystal' 10 (4) a crystallizable active substance in heteroge- means any crystal that is in thermodynamically unstable nous crystalline state to homogeneous crystals. crystalline state. The term 'crystalline state' is used referring to any of stable crystal, metastable crystal and [0007] The inventors of this invention found that the amorphous (noncrystalline) solid. The term 'heteroge- above-mentioned object can be accomplished by utiliz- nous crystal' means a crystal not in a singular crystal- 15 ing an extruder which enables a continuous processing line state. of the load and have arrived at the present invention. [0003] The term 'extruder' means any screw extruder [0008] In the pharmaceutical field, few technologies that is in broad use chiefly in food industry for the utilizing an extruder are known. processing of food materials (cereals, proteins, animal [0009] At this junction, the mechanism of the main meat, fish meat, etc.). 20 part (work processing part) of the extruder is briefly described. Generally the main part of an extruder com- BACKGROUND ART prises, as illustrated in Fig. 1, a cylindrical structure called 'barrel', a die which corresponds to a delivery [0004] The conventional technology for inducing a port, and a screw. The barrel usually comprises a plural- transition of crystalline state in a medicinal substance 25 ity of unit barrels and the screw extends through them. includes recrystallization, heating, freeze-drying, pul- The screw is available in various types, namely trape- verizing and so on. Document EP-A-0580860 (docu- zoidal screw, trapezoidal cut screw, trapezoidal reverse ment according to Article 54(3) EPC) discloses the use cut screw, ball screw, kneading paddle, etc., which can of an extruder for the production of solid dispersions. be used in a desired combination. The load fed to the [0005] However, none of these conventional methods 30 extruder is forced by the screw to advance, shorn and are capable of inducing a transition of crystalline state blended by the screw within the barrel structure and expediently, efficiently, uniformly and on a mass scale extruded from the orifice or orifices of the die. Usually, and, therefore, are not well suited for commercial appli- the temperature of each unit barrel and that of the die cation. One of the reasons for their incapability is that can be independently controlled. because these technologies are invariably batch proc- 35 [0010] The extruder is available in two general types, esses, large-scale equipment is required for mass namely a single-screw extruder comprising one screw processing but the larger the equipment, the greater is and a multi-screw extruder comprising two or more the temperature gradient created in the processing screws. While this invention can be carried into practice load, so that homogeneous crystals cannot be easily using either type of extruder, the use of a multi-screw obtained. Taking the recrystallization process as an 40 extruder, particularly a twin-screw extruder, is preferred. example, judicious selection of the recrystallization sol- Compared with a single-screw version, a twin-screw vent, detailed analysis of recrystallizing temperature extruder is more efficient in that the plural screws inter- and other parameters, and accurate control of recrystal- ferring with each other precludes follow-up movement of lization conditions are essential. In the case of freeze- the active substance and, moreover, the intermeshing drying, the protracted processing time is also a detract- 45 of the screws provides a high energy output physically, ing factor. thus assisting in the induction of a transition of crystal- line state. DISCLOSURE OF INVENTION [0011] In the practice of this invention, such an extruder as is in routine use by food industry can be uti- [0006] The object of this invention is to provide a 50 lized as it is. method of inducing a transition of crystalline state in a [0012] The mode of use of the extruder in the practice crystallizable medicinal substance which overcomes of this invention is now described, referring to specific the disadvantages of the above-mentioned prior art embodiments. methods. Specifically, the invention has for its object to [0013] For example, in this invention, the main part of provide a method of inducing, expediently, efficiently, 55 the extruder can be utilized as divided into two zones, uniformly, continuously and on a high production scale, namely a melting zone and a cooling zone as illustrated a transition of crystalline state, for example: in Fig. 2. The melting zone is the zone in which the medicinal substance is melted and the cooling zone is

2 34EP 0 665 009 B1 the zone in which the medicinal substance melted in ambient temperature, while the medicinal sub- said melting zone is solidified. stance fails to crystallize at times when the setting [0014] In the practice of this invention, the melting exceeds the melting-start temperature of stable zone can be defined by one or more barrels. If and when crystals of the medicinal substance. There are the medicinal material can be successfully melted, even 5cases in which a transition to stable crystalline state a single barrel can serve as the melting zone. However, can be obtained even when the setting is below the proper number of barrels defining the melting zone ambient temperature and such cases also fall is dependent on the melting point of the medicinal sub- within the scope of this invention. stance, the crystalline state of said substance, the con- It is true that the higher the cooling zone tem- dition of the substance, the type and ratings of the 10 perature, the greater is the safety with which a extruder used, the rotational speed of the screw (which medicinal substance can be crystallized. However, corresponds to the speed at which the medicinal load although it depends on physical properties of the travels within the barrel), screw geometry (which is medicinal substance, a higher cooling zone temper- related to the pulverization of the medicinal substance) ature setting may call for an increase in the overall and so on. For the processing of a medicinal substance 15 length of the barrel defining the cooling zone or a having a high melting point, in the case where the reduction in the rotational speed of the screw. In medicinal substance is crystalline or coarse, or for either case, processing efficiency tends to be sacri- increasing the rotational speed of the screw, the number ficed. On the other hand, it is not recommendable, of barrels constituting the melting zone may have to be either, to use an unnecessarily low cooling zone increased. 20 temperature. If the cooling zone temperature set- [0015] In the practice of this invention, the tempera- ting is too low, an amorphous solid may result or the ture of the barrel or barrels constituting the melting zone crystals may become heterogenous. Therefore, in (hereafter referred to as 'melting zone temperature') can order to insure an efficient and safe working of this be set to the meltable temperature of the medicinal sub- invention, the cooling zone temperature is prefera- stance. However, the temperature setting is preferably 25 bly selected in considera tion of the physical proper- equal to the melting point of the medicinal substance ties of the medicinal substance, the type and and more preferably the melting start temperature. If the ratings of extruder, melting zone temperature, and melting zone temperature be too high, the medicinal the rotational speed of the screw, among other fac- substance might decompose. When the melting zone is tors. defined by a plurality of barrels, the temperature of the 30 The cooling zone temperature can be preset respective barrels need not necessarily be uniform. with the aid of a melting point measuring instrument [0016] In this invention, the cooling zone can be con- equipped with a opticaly microscope (e.g. Mettler's stituted using the remaining barrels, viz, barrels other melting/boiling point meter Model FP-80 or FP- than the barrels defining the melting zone, and the die. 82HT equipped with a polarizing microscope), a dif- Depending on cases, the environment (external zone) 35 ferential scanning calorimeter (DSC) or the like. surrounding the extruder may be included in the cooling Thus, in the case of a melting point measuring zone. Even when the external zone is included in the instrument equipped with a opticaly microscope, cooling zone, since the molten medicinal substance is one may use the method which comprises melting delivered out continuously and little by little from the die the medicinal substance on a slide glass, cooling it orifices, there is substantially no concern about the loss 40 to find the temperature at which stable crystals are of homogenity due to a temperature gradient. formed and using the particular temperature as the [0017] The temperature settings of the barrel or bar- cooling zone temperature. rels and die defining the cooling zone (hereinafter called Where the cooling zone is defined by a plurality 'cooling zone temperature') are now explained, taking of unit barrels, the temperature settings of the the transition of various crystalline states as examples. 45 respective barrels and of the die need not neces- sarily be identical. However, the temperature of the (1) The procedure for inducing a transition from down stream barrel or the die is preferably set metastable crystals to stable crystals, for instance, below the temperature of the upstream barrel. and the procedure for inducing a transition from Reversing this relation will be in conflict with the heterogenous crystals to homogeneous crystals: 50 direction of crystallization of the medicinal sub- While the cooling zone temperature is depend- stance. Moreover, in such cases, it is not a good ent on the physical properties of the medicinal sub- practice to set the temperature of each barrel con- stance, the type and ratings of extruder used, etc., stituting the cooling zone at an unnecessarily low the cooling zone temperature can be set within the level relative to the temperature of the immediately range of ambient temperature to a temperature 55 preceding barrel (both of the melting zone and cool- below the melting-start temperature of stable crys- ing zone). If said temperature setting is unneces- tals of the medicinal substance. It is practically use- sarily too low compared with the temperature of the less to employ a temperature setting lower than immediately preceding barrel, an amorphous solid

3 56EP 0 665 009 B1 tends to form or heterogenous crystals may be pro- ble crystalline state or the like to amorphous solid duced. The system in which the cooling zone tem- state and the procedure for inducing a transition perature is not uniform is instrumental where from heterogeneous crystalline state to homogene- crystallization of the medicinal substance is desira- ously amorphous solid state: bly achieved by gradual cooling. 5By nature of an amorphous solid, the cooling When the cooling zone temperature is set to zone temperature in these cases is preferably as ambient temperature, it is not essential to provide a low as possible. In this invention, although it cooling zone within the barrel structure. When the depends on physical properties of the medicinal barrel structure has no cooling zone, the environ- substance and the type and ratings of the extruder ment functions as a cooling zone and all the barrels 10 used, among other variables, the cooling zone tem- and die constitute the melting zone. perature can be set to a temperature about 70% (2) The procedure for inducing a transition from sta- lower than the melting-start temperature of the ble crystalline state or the like to metastable crystal- medicinal substance (e.g. 30°C where the melting- line state and the procedure for inducing a start temperature of the medicinal substance is transition from heterogenous crystalline state to 15 100°C ) or even a still lower temperature. It is more metastable crystalline state: preferable that the temperature setting be not The cooling zone temperature in these cases higher than a level about 90% lower than the melt- can be established beforehand with the aid of a ing-start temperature of the medicinal substance. If melting point measuring instrument equipped with the temperature setting is too high, the stable or a opticaly microscope (e.g. Mettler's melting/boiling 20 metastable crystalline state will avail. Although the point meter Model FP-80 or FP-82HT equipped desired transition to amorphous solid state may be with a polarizing microscope), a differential scan- achieved at times even when the temperature set- ning calorimeter (DSC) or the like. Thus, in the case ting is higher than said limit, such cases also fall of a melting point measuring instrument equipped within the scope of this invention. with a opticaly microscope, the method can be used 25 The cooling zone temperature in these cases which comprises melting the medicinal substance can be established beforehand with the aid of a on a slide glass, cooling it to find the temperature at melting point measuring instrument equipped with which metastable crystals are formed and using the a opticaly microscope (e.g. Mettler's melting/boiling particular temperature as the cooling zone temper- point meter Model FP-80 or FP-82HT equipped ature. 30 with a polarizing microscope), a differential scan- Where the cooling zone is defined by a plurality ning calorimeter (DSC) or the like. Thus, in the case of barrels, the temperature settings of the respec- of a melting point measuring instrument equipped tive barrels and of the die need not necessarily be with a opticaly microscope, the method can be used identical. However, the temperature of any down- which comprises melting the medicinal substance stream barrel or the die is preferably set below the 35 on a slide glass, cooling it to find the temperature at temperature of the upstream barrel. Reversing this which an amorphous solid is formed and using the relation will be in conflict with the direction of crys- temperature as the cooling zone temperature. tallization of the medicinal substance. Moreover, in Where the cooling zone is defined by a plurality such cases, it is not a good practice to set the tem- of barrels, the temperature settings of the respec- perature of each barrel constituting the cooling 40 tive barrels and of the die need not necessarily be zone at an unnecessarily low level relative to the identical. However, the temperature of any down- temperature of the immediately preceding barrel stream barrel or the die is preferably set below the (both of the melting zone and cooling zone). If said temperature of the upstream barrel. Reversing this temperature setting is unnecessarily too low as relation will be in conflict with the direction of solidi- compared with the temperature of the immediately 45 fication of the medicinal substance. preceding barrel, an amorphous solid tends to form When the cooling zone temperature is set to or heterogenous crystals may be produced. ambient temperature, it is not essential to provide a The system in which the cooling zone tempera- cooling zone within the barrel structure. When the ture is not uniform is instrumental where crystalliza- barrel structure has no cooling zone, the environ- tion of the medicinal substance is desirably 50 ment functions as a cooling zone and all the barrels achieved by gradual cooling. and die constitute the melting zone. When the cooling zone temperature is set to Feeding of the medicinal substance into the ambient temperature, it is not essential to provide a barrel structure can be performed by utilizing the cooling zone within the barrel structure. When the feeder with which the extruder is generally provided barrel structure has no cooling zone, the environ- 55 but there is no limitation on the device that can be ment functions as a cooling zone and all the barrels used only if the medicinal substance may be fed at and die constitute the melting zone. a constant rate. (3) The procedure for inducing a transition from sta- As examples of such feeding device, a screw

4 78EP 0 665 009 B1

feeder, a table feeder, a belt-conveyer type quanti- oxazepam, oxazolam, cloxazolam, clotiazepam, tative feeder, and an electromagnetic feeder can be dipotassium, chlordiazepoxide, chlo- mentioned. rmezanone, , secobarbital sodium, zopi- Although the medicinal substance can be clone, triazolam, triclofos sodium, , directly fed into the melting zone, it is a good prac- 5nimetazepam, barbital, haloxazolam, phenobarbi- tice to provide a feeding zone using an appropriate tal, prazepam, fludiazepam, flutazolam, fluto- number of unit barrels and supply the medicinal prazepam, flunitrazepam, flurazepam, brotizolam, substance to said zone in the first place. This is bromazepam, bromovalerylurea, hexobarbital, per- because the barrel adjacent to the inlet is exposed lapine, pnetobarbiturate, , mexazolam, to the environment and, hence, not well amenable 10 medazepam, ethyl loflazepate, , to temperature control. Only one barrel generally lormetazepam. suffices for constituting said feeding zone and, by 3. Antiepileptics: nature, its temperature may be equal to ambient Acetylpheneturide, , , temperature. , , sultiame, zonisa- The rotational speed of the screw can be set 15 mide, , sodium , within the allowable range of the extruder used. sodium, , . Generally speaking, assuming that the kind and 4. Antipyretic//antiinflammatory agents: shape of medicinal substance are unchanged, the , aspirin DL-, aspirin aluminum, rotational speed of the screw can be increased in acetaminophen, , , almino- the case of an extruder with a greater overall barrel 20 profen, sodium, isopropylantipyr ine, ibu- length as compared with an extruder with a shorter profen, indomethacin, indomethacin farnesil, overall barrel length. , epirizole, emorfazone, tiaramide The screw geometry and combination of unit hydrochloride, tinoridine hydrochloride, screws can be selected without any particular hydrochloride, buprenorphine hydrochloride, ben- restriction. The principal role of the screw in this 25 zydamine hydrochloride, , clofezone, invention is to transport, crush and knead the ketophenylbutazone, , sasapyrine, sali- medicinal substance. Therefore, when the particle cylamide, choline salicylate, , size of the feed medicinal substance is previously Saridon, sodium, diflunisal, eptazocine set to be such that it can be smoothly transported hydrobromide, tartrate, , by the screw, it is substantially unnecessary to pay 30 sulpyrine, , , tolfenamic attention to the screw geometry. acid, sodium, , , Neo The orifice configuration of the extrusion die is vitacain, Neurotropin, bitoxin, , phenace- not particularly restricted and may for example be tin, phenylacetylglycine, , fenopro- circular, elliptical, rectangular or hexagonal. When fen calcium, , bucolome, , the orifice is circular in section, its diameter can be 35 flufenamic acid, flufenamic acid aluminium, flurbi- selected appropriately. For example, the range of profen, flurbiprofenaxetil, floctafenine, , 0.5 - 5 mm ì can be mentioned. maleate, migrenin, dimetotiazine Whether the desired transition has been mesilate, metiazinic acid, , loxopro- achieved or not can be verified by means of a opti- fen sodium, lobenzarit disodium. caly microscope, a powder X-ray diffractometer, a 40 5. Analeptic/antihypnotic agents: differential scanning calorimeter (DSC) or the like. hydrochloride, bemegride. 6. Antiparkinsonian : [0018] As regards the crystallizable medicinal sub- hydrochloride, trihexyphenidyl stance that can be used in this invention, there is no hydrochloride, piroheptine hydrochloride, mazaticol particular restriction only if it does not decompose on 45 hydrochloride, methixene hydrochloride, , exposure to the melting-start temperature. This inven- biperiden, mesilate, levodopa. tion can be applied not only to medicinal substances but 7. Psychotropic/neurotropic drugs: also to other crystallizable substances used in the fields , etizolam, hydrochlo- of farm chemicals and food. The following specific crys- ride, hydrochloride, dihy- tallizable substances can be mentioned by way of 50 drochloride, hydrochloride, safrazine example. hydrochloride, sultopride hydrochloride, thiori- dazine hydrochloride, hydrochloride, 1. General anesthetics: hydrochloride, hydrochloride, hydrochloride, thiamylal sodium, thi- triflupromazine hydrochloride, hydro- opental sodium, droperidol. 55 chloride, hydrochloride, 2. Hipnotic/sedatives/antianxiety drugs: hydrochloride, pipradorol hydrochloride, Amobarbital, alprazolam, estazolam, flu- hydrochloride, hydrochloride, methylphe- razepam hydrochloride, rilmazafone hydrochloride, nidate hydrochloride, hydrochloride,

5 91EP 0 665 009 B1 0 moperone hydrochloride, hydrochlo- chloride, hydrochloride, , ride, oxypertine, , , chlorpro- thiethylperazine, theoclate and, beta- thixene, , thioproperazine histine mesylate. dimethansulfonate, , sulpiride, , 14. Sense organ drugs: , timiperone, decanoate, 5Oxymetazoline hydrochloride, tetrizoline. , hydroxyzine pamoate, haloperidol, 15. Cardiotonics: , fluphenazine, , properi- 2-Aminoethanesulfonic acid, , cyazine, bromazepam, bromperidol, pemoline, per- -sodium benzoate, hydrochloride, phenazine, cetiprin maleate, trifluoperazine hydrochloride, hydrochloride, maleate, maleate, reserpine, levome- 10 hydrochloride, hydrochlo- . ride, choline , diisobutylaminobenzoy- 8. CNS drugs: loxypropyl theophylline, digitoxin, digoxin, Idebenone, amantadine hydrochloride, indel- , bitartrate, deslanoside, oxazine hydrochloride, hydrochlo- , trans-π-oxocamphor, bucladesine ride, tiapride hydrochloride, 15 sodium, , proscillaridin, besnalinone, hydrochloride, meclofenoxate hydrochloride, lefeta- metildigoxin, ubidecarenone, lanatoside C. mine hydrochloride, γ-amino-β-hydroxybutyric acid, 16. Antiarrhythmic drugs: citicoline, protirelin tartrate, baclofen, propentofyl- Ajmaline, , hydrochloride, line, calcium hopantenate, mazindol. aprindine hydrochloride, hydrochloride, 9. Local anesthetics: 20 hydrochloride, hydrochloride, Ethyl aminobenzoate, oxybuprocaine hydro- hydrochloride, hydrochloride, chloride, dibucaine hydrochloride, tetracaine hydro- pyrudicainide hydrochloride, hydrochlo- chloride, p-butylaminobenzoyldiethyl aminoethanol ride, hydrochloride, procainamide hydrochloride, bupivacaine hydrochloride, procaine hydrochloride, hydrochloride, pro- hydrochloride, propitocaine hydrochloride, mepi- 25 pranolol hydrochloride, hydrochloride, vacaine hydrochloride, oxethazaine, ethyl p-piperid- hydrochloride, mexiletine hydrochloride, inoacetyl aminobenzoate, lidocaine hydrochloride. cibenzoline succinate, flecainide acetate, disopyra- 10. Skeletal muscle relaxants: mide, tartrate, , , bisopro- Alcuronium chloride, suxamethonium chloride, lol fumarate, maleate, sulfate. tubocurarine chloride, chlorphenesin carbamate, 30 17. Diuretics: chlorzoxazone, chlormezanone, pancuronium bro- , azosemide, isosorbide, mide, vecuronium , dantrolene sodium, etacrynic acid, ethiazide, potassium canrenoate, phenprobamate, pridinol mesylate, methocar- quinethazone, clofenamide, chlorthalidone, bamol. cyclopenthiazide, spironolactone, theosalicin, tri- 11. Autonomic drugs: 35 amterene, trichlormethiazide, hydrochlorothiazide, Acetylcholine chloride, ambenonium chloride, hydroflumethiazide, piretanide, bumetanide, furo- carpronium chloride, trospium chloride, bethane- semide, benzylhydrochlorothiazide, penflutizide, chol chloride, hydrochloride, polythiazide, methyclothiazide, metolazone, mefru- dicycloverin hydrochloride, hydrochlo- side. ride, distigmine bromide, valethamate bromide, 40 18. Antihypertensive drugs: pyridostigmine bromide, prifinium bromide, propan- Alacepril, alseroxylon, indapamide, , theline bromide, bromide, tofisopam, hydrochloride, carteolol hydrochloride, aclatonium napadisilate, neostigmine, oxapium hydrochloride, hydrochloride, iodide, diphenylpiperidinomethyldioxolane iodide. diltiazem hydrochloride, hydrochloride, 12. Antispasmodics: 45 hydrochloride, hydrochloride, del- Afloqualone, etomidoline, hydro- april hydrochloride, todralazine hydrochloride, nica- chloride, eperisone hydrochloride, hydro- rdipine hydrochloride, hydralazine hydrochloride, chloride, tolperisone hydrochloride, hydrochloride, hydrochloride, hydrochloride, hydrochloride, bromoe- hydrochloride, manidipine hydrochloride, thyl pipethanate, hydrobromide, time- 50 hydrochloride, dimethylaminoethyl reser- pidium bromide, valethamate bromide, pilinate dihydrochloride, cadralazine, , tri- butylscopolamine bromide, methobromide, metaphan camsilate, acetate, anisotropine methobromide, benactyzium metho- hexamethonium bromide, metoprolol tartrate, sila- bromide, baclofen, flopropione, metyrapone, N- zapuril, syrosingopine, tripamide, nadolol, methyl-scopolamine methyl sulfate, atropine sul- 55 , nilvadipine, budralazine, enalapril fate. maleate, dihydroergotoxine mesylate, 13. Antivertigo drugs: mesylate, mesilate, meticrane, meth- hydrochloride, difenidol hydro- yldopa, Rauwopur, ricinopuril, sulfate,

6 11 EP 0 665 009 B1 12 betanidine, sulfate, sulfate, rescin- chloride, clorprenaline hydrochloride, namine, reserpine, 2,6-dimethyl-4-(2-nitrophenyl)- hydrochloride, trimetoquinol hydrochloride, pir- 5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihy- buterol hydrochloride, hydrochloride, dropyridine-3-carboxylate. hydrochloride, sodium cromo- 19. Vasoconstrictors: 5 glycate, diprophylline, hydrobromide, the- hydrochloride, ophylline, fumarate, isoproterenol hydrochloride, hydrochloride, methox- sulfate, sulfate, sulfate, amine hydrochloride, mesylate. sulfate, sulfate. 20. Vasodilators: 26. Antidiarrheal drugs/drugs for controlling intesti- Inositol hexanicotinate, efloxate, isoxsuprine 10 nal function: hydrochloride, hydrochloride, chloride, leperamide hydrochloride, hydrochloride, hydrochloride, dimethicone, bismuth subgallate, berberine tan- dihydrochloride, trimetazidine hydrochloride, valn- nate, lactomin, berberine sulfate. idipine hydrochloride, venidipine hydrochloride, ver- 27. Peptic ulcer remedies: apamil hydrochloride, nicametate citrate, 15 Aceglutamide aluminium, sodium alginate, cyclandelate, pentaerythrityl tetranitrate, dipyrida- aldioxa, L-glutamine, cetraxate hydrochloride, mole, , , , nisol- pirenzepine hydrochloride, hydrochloride, dipine, nitrendipine, , hepronicate, hydrochloride, omeprazole, bamethan sulfate, γ-oryzanol, clinofibrate, clofi- ornoprostil, chlophyllin S, gefarnate, Kolantyl, cime- brate, aluminium clofibrate, colestyramine, symvas- 20 tidine, sucralfate, sulpiride, secretin, sofalcone, tatin, simfibrate, soysterol, dextran sulfate sodium, teprenone, troxipide, , , plauno- nicomol, niceritrol, pravastatin sodium, probucol, tol, proglumide, bergenin, maleate, bezafibrate, polyenephos phatidylcholine, melina- methylmethionine sulfonium chloride, mide, ethyl linoleate. malate, levamipil. 21. Cardiovascular drugs: 25 28. Stomachics/digestants: , alprostadil, , flunarizine Carnitine chloride. hydrochloride, meclofenoxate hydrochloride, moxi- 29. Laxatives/clysters: sylyte hydrochloride, sodium , citicoline, Bisoxatin acetate, sodium picosulfate, bisa- tartrate, , cytochrome C, toco- codyl, lactulose. pherol nicotinate, , pyridinol carbamate, 30 30. Cholagogues: , nizofenone fumarate, brovincamine Anetholtrithion, ursodesoxycholic acid, fumarate, bencyclane fumarate, , cal- osalmid, chenodeoxycholic acid, dehydrocholic cium polystyrene sulfonate, sodium polystyrene acid, trepibutone, hymecromone. sulfonate, cinepazide maleate, maleate, 31. Gastrointestinal drugs: dihydroergotamine nesylate, amezinium methyl sul- 35 hydrochloride, , triamci- fate, limaprost α-cyclodextrin clathrate. nolone acetonide, tricaprilin, , fenipen- 22. Respiratory stimulants: tol, maleate, . Dimefline hydrochloride, doxapram hydro- 32. Thyroid/parathyroid hormone drugs: chrolide, hydrochloride, lobeline hydro- Thiamazole, propylthiouracil, liothyronine chloride, dimorpholamine, levallorphan tartrate, 40 sodium, levothyroxine sodium. flumazenil. 33. Anabolic steroid drugs: 23. Antitussives: Ethylnandrol, oxymetholone, nandrolone Asdrin, hydrochloride, cyclohexane propionate, bolandiol dipropionate, hydrochloride, hydrochloride, methyl- stanozolol, nandrolone decanoate, nandrolone ephedrine hydrochloride, citrate, oxela- 45 phenylpropionate, furazabol, nandrolone furylpropi- din citrate, pentoxyverine citrate, Chlophedrin S, onate, mestanolone, metenolone. chloperastine, hydrochloride, 34. Corticoid drugs: tannate, dl-methylephedrine hydrochlo- Epinephrine, hydrocortisone sodium succinate, ride, dl-methylephedrine, , sodium succinate, cortisone acetate, phosphate, phosphate. 50 acetate, diacetate, 24. Expectorants: paramethasone acetate, halopredone acetate, N-Acetyl-L-, hydrochloride, hydrocortisone acetate, fludrocortisone acetate, L-cysteine ethyl ester hydrochloride, prednisolone acetate, methylprednisolone acetate, hydrochloride, , hydro- dexamethasone, triamcinolone, , chloride, , hibenzate, 55 dexamethasone palmitate, hydrocortisone, pred- phosphate, phosphate. nisolone butylacetate, sodium sulfate, 25. Brochodilators: prednisolone, dipropionate, betam- Epinephrine hydrochloride, hydro- ethasone, dexamethasone sodium metasulfoben-

7 13 EP 0 665 009 B1 14 zoate, methylprednisolone, dexamethasone octic acid amide, tiopronin, protoporphyrin diso- sodium phosphate, hydrocortisone sodium phos- dium, malotilate. phate, prednisolone sodium phosphate, betameth- 44. : asone sodium phosphate. Calcium disodium edetate, glutathione, peni- 35. Male hormone drugs: 5 cillamine, deferoxamine mesilate, pralidoxime Testosterone enanthate, fluoxymesterone, tes- iodide. tosterone propionate, dromostanolone propionate, 45. Arthrifuges: methyltestosterone. Allopurinol, colchicine, sulfinpyrazone, 36. Estrogen/progestin drugs: probenecid, benzbromarone. Allylestrenol, estradiol benzoate, estriol ben- 10 46. Antidiabetics: zoyldiacetate, estriol, ethinylestradiol, gestonorone Acetohexamide, buformine hydrochloride, met- caproate, hydroxyprogesteron caproate, estradiol formin hydrochloride, gliclazide, glyclopyramide, valerate, chlormadinone acetate, medroxyproges- glybuzole, glibenclamide, glymidine sodium, chlo- tero ne acetate, dydrogesterone, estradiol dipropi- rpropamide, tolazamide, tolbutamide. onate, dimethisterone, norethisterone, 15 47. drugs: pregnanediol, , estriol tripropionate, Azathioprine, adenosine triphosphate diso- fosfestrol, mestranol. dium, aprotinin, ipriflavone, urinastatin, disodium 37. Hormone drugs other than 32-36: etidronate, epalrestat, elcatonin, L-cysteine, levo- Epitiostanol, oxendolone, clomifene citrate, glu- carnitine chloride, sapropterin hydrochloride, calci- cagon, , octreotide acetate, goserelin 20 tonin, glutamate, sodium glutamate, acetate, gonadorelin acetate, cyproterone acetate, sodium chondroitin sulfate, ciclosporin, sodium buserelin acetate, leuprolerin acetate, cyclofenil, hyaluronate, mizoribine, gabexate mesilate, camo- dinoprost, dinoprost tromethamine, dinoprostone, stat mesilate, nafamostat mesilate, lactulose. danazol, trilostane, mitotane, mepitiostane. 48. Antitumor drugs: 38. Urinary tract drugs: 25 Aceglatone, ifosfamide, ubenimex, enocitab- Oxybutynin hydrochloride, flavoxate hydrochlo- ine, procarbazine hydrochloride, mitoxantrone ride, Paraprost, hexamine. hydrochloride, nitrogen mustard N-oxide hydrochlo- 39. Oxytocics: ride, nimustine hydrochloride, carboquone, carbopl- maleate, atin, carmofur, tamoxifen citrate, maleate, sparteine sulfate. 30 cyclophosphamide, cisplatin, cytarabine, sizofiran, 40. : dacarbazine, thiotepa, thioinosine, tegafur, impro- , etretinate, , , sulfan tosilate, doxifluridine, hydroxycarbamide, acetate, , retinol palmi- fluorouracil, busulfan, mitobronitol, melphalan, tate, cetotiamine hydrochloride, hydro- methotrexate, mercaptopurine, ranimustine, estra- chloride, cocarboxylase, thiamine , 35 mustine sodium phosphate, lentinan. bisthiamine nitrate, thiamine disulfide, bisibuthia- 49. Antiallergic agents: mine, bisbutytiamine, bisbentiamine, , Amlexanox, hydrochloride, isothi- , benfotiamine, hydrochlo- pendyl hydrochloride, hydrochloride, ride, cobamamide, acetate, ozagrel hydrochloride, hydrochlo- , nicotinic acid, , 40 ride, hydrochloride, cyprohepta- , mecobalamin, folic acid, riboflavin dine hydrochloride, hydrochloride, butyrate, riboflavin, phosphate, pyri- promethazine hydrochloride, doxal phosphate, riboflavin sodium phosphate, hydrochloride, , glycyrrhizin, sodium cro- ascorbic acid, calcium succinate, toco- moglycate, tartrate, tazanolast, pherol acetate, phytonadione, menatetrenone, 45 diphenhydramine tannate, diphenylpyraline teo- . clate, , tranilast, pemirolast potassium, 41. Hemostatics: fumarate, chlorpheniramine maleate, sodium alginate, ethamsylate, carbazochrome, dimethindene maleate, . carbazochrome sodium sulfonate, tranexamic acid, 50. : thrombin, adrenochrome monoaminoguanidine 50 Aspoxicillin, aztreonam, acetylkitasamycin, methanesulfonate. amoxicillin, ampicillin, erythromycin estolate, spec- 42. Anticoagulants: tinomycin hydrochloride, oxytetracycline hydrochlo- , dalteparin sodium, heparin cal- ride, cefotiam dihydrochloride, cefotiam hexetil cium, heparin sodium, warfarin potassium. hydrochloride, cefmenoxime hydrochloride, tetracy- 43. disease remedies: 55 cline hydrochloride, demethylchlortetracycline 2-Aminoethanesulfonic acid, glucuronolactone, hydrochlorine, doxycycline hydrochloride, vanco- glucuronamide, sodium glucuronate, cianidanol, mycin hydrochloride, pivmecillinam hydrochloride, diisopropylamine dichloroacetate, thioctic acid, thi- minocycline hydrochloride, lincomycin hydrochlo-

8 15 EP 0 665 009 B1 16

ride, carindacillin sodium, carumonam sodium, out below. clarithromycin, griseofulvin, clindamycin, cloxacillin sodium, chloramphenicol, chloram phenicol sodium (1) By inducing a transition from metastable crystal- succinate, colistin sodium methanesulfonate, cyclo- line state or the like to stable crystalline state, the serine, midecamycin acetate ciclacillin, cefazolin 5 stability of a bulk substance or a pharmaceutical sodium, cefatrizine propylene glycol, cefapirin composition, for instance, can be increased. sodium, cefamandole sodium, cefalexin, cefalotin (2) By inducing a transition from stable crystalline sodium, cefaloridine, cefixime, cefodizime sodium, state or the like to metastable crystalline state or cefotaxime sodium, cefdinir, cefuzonam sodium, amorphous solid state, the solubility of a medicinal ceftazidime, ceftizoxime sodium, ceftezole sodium, 10 substance in the gastrointestinal tract can be ceftriaxone sodium, cefsulodin sodium, cefminox increased and, hence, its can be sodium, cefradine, cefroxadine, cefuroxime axetil, improved or modulated. cefuroxime sodium, tetracycline, sultamicillin tosi- (3) By inducing a transition from crystalline state late, chloramphenicol palmitate, pheneticillin potas- with a crystal habit to a different crystalline state, sium, phenoxymethylpenic illin potassium, 15 powder properties such as flowability and packing flucloxacillin sodium, josamycin propionate, flu- and compression characteristics in the granulation cloxacillin sodium, benzylpenicillin potassium, ben- stage and tablet-machine compression stage can zylpenicillin benzathine, fosfomycin, midecamycin, be improved. rifampicin, capreomycin sulfate, sisomicin sulfate, paromomycin sulfate, loxythromycin. 20 [0020] Since the method of this invention is not a 51. Sulfa drugs: batch process but a continuous process, mass process- Acetylsulfamethoxazol, sulfadimethoxine, sul- ing is feasible with small equipment. famethizole, sulfamethoxazole, sulfamethopyra- [0021] Moreover, because it is a continuous process, zine, sulfamonomethoxine, sulfisoxazole, the quantity of the medicinal substance actually proc- sulfisomidine. 25 essed within the equipment at any given time-point is 52. Antituberculosis drugs: small so that a biased transition of crystalline state due , isoniazid sodium glucuronate, isoni- to a temperature gradient is little involved. azid sodium methansulfonate, ethionamide, etham- butol hydrochloride, pyrazinamide. BEST MODE FOR CARRYING OUT THE INVENTION 53. Antileprotics: 30 Sodium glucosulfone, diaphenylsulfone, thiazo- [0022] The following examples and test example are sulfone. intended to illustrate this invention in further detail. 54. Synthetic antimicrobial agents: [0023] It should be understood that the numbers Enoxacin, thiamphenicol glycinate hydrochlo- assigned to the respective barrels are in the order start- ride, ciprofloxacin hydrochloride, lomefloxacin 35 ing with the barrel closest to the feeding side. hydrochloride, ofloxacin, cinoxacin, thiamphenicol, tosfloxacin tosylate, nalidixic acid, norfloxacin, pipe- Example 1 midic acid trihydrate, 6-fluoro-1-methyl-7-[4-(5- methyl-2-oxo-1,3-dioxolen-4-yl)methyl-piperazinyl]- [0024] A twin-screw extruder (KEX-30S-20; manufac- 4-oxo-4H[1,3]-thiazeto[3,2-a]quinoline-3-carboxy- 40 tured by Kurimoto, Ltd.) equipped with a die having an lic acid. orifice diameter of 5 mmì was supplied with Form α- 55. Antiviral agents: indomethacin (metastable crystals) at a feeding rate of Aciclovir, ganciclovir, zidanocin, vidarabine. 30 g/min., and using screws with a diameter of 32 56. Chemotherapeutic drugs: mmì, an effective L/D ratio of 20 and a screw pattern of Inosine pranobex, nalidixic acid, fluconazole, 45 16P, 12P, 9.6P, 30deg, 60deg, 9.6P and 8P, and the tem- flucytosine, miconazole. perature settings of barrel 1 = 25°C , barrel 2 = 155°C, 57. Anthelmintics: barrel 3 = 155°C, barrel 4 = 155°C, barrel 5 = 50°C and Kainic acid, diethylcarbamazine citrate, san- die = 40°C, the load was extruded at a speed of 100 rpm tonin, bithionol, praziquantel, phos- to provide Form γ-indomethacin (stable crystals). phate. 50 58. Narcotics: Example 2 hydrochloride, hydro- chloride, morphine hydrochloride, oximetebanol, [0025] A twin-screw extruder (KEX-30S-20; manufac- fentanyl citrate, morphine sulfate, codeine phos- tured by Kurimoto, Ltd.) equipped with a die having an phate, dihydrocodeine phosphate. 55 orifice diameter of 5 mmì was continuously charged with a mixture (1:1) of Form α-indomethacin (metasta- [0019] The usefulness of inducing a transition of the ble crystals) and Form γ-indomethacin (stable crystals) crystalline state of a crystallizable substance is pointed at a feeding rate of 30 g/min. and using the same

9 17 EP 0 665 009 B1 18 screws as described in Example 1 and the barrel and 100°C, barrel 3 = 100°C, barrel 4 = 95°C, barrel 5 = die temperature settings of barrel 1 = 25°C, barrel 2 = 45°C and die = 45°C, the load was processed and 155°C, barrel 3 = 155°C, barrel 4 = 155°C, barrel 5 = extruded at an extrusion speed of 50 rpm to provide 50°C, and die = 40°C, the load was processed and Form α-chloramphenicol palmitate (metastable crys- extruded at an extrusion speed of 100 rpm to provide 5 tals). homogeneous Form γ-indomethacin (stable crystals). Example 7 Example 3 [0030] Form I-carbamazepine (metastable crystals) [0026] A twin-screw extruder (KEX-30S-20; manufac- 10 was fed to a twin-screw extruder (KEX-30S-20; manu- tured by Kurimoto, Ltd.) equipped with a die having an factured by Kurimoto, Ltd.) equipped with a die having orifice 2 mm high and 10 mm wide was fed with Form α- an orifice sized 2 mm high and 10 mm wide at a feeding indomethacin (metastable crystals) at a feeding rate of rate of 25 g/min. and using the same screws as 20 g/min. and using the same screws as described in described in Example 1 and the barrel and die temper- Example 1 and the barrel and die temperature settings 15 ature settings of barrel 1 = 25 °C, barrel 2 = 177°C, bar- of barrel 1 = 25°C, barrel 2 = 155°C, barrel 3 = 155°C, rel 3 = 190°C, barrel 4 = 190°C, barrel 5 = 190°C and die barrel 4 = 155°C and barrel 5 = 20°C, and die = 10°C, = 100°C, the load was processed and extruded at an the load was processed and extruded at an extrusion extrusion speed of 20 rpm to provide Form III-car- speed of 100 rpm to provide amorphous solid indometh- bamazepine (stable crystals). acin. 20 Example 8 Example 4 [0031] Form II-carbamazepine (metastable crystals) [0027] A twin-screw extruder (KEX-30S-20; manufac- was fed to a twin-screw extruder (KEX-30S-20; manu- tured by Kurimoto, Ltd.) equipped with an orifice 2 mm 25 factured by Kurimoto, Ltd.) equipped with a die having high and 10 mm wide was continuously charged with an orifice sized 2 mm high and 10 mm wide at a feeding Form γ-indomethacin (stable crystals) at a feeding rate rate of 30 g/min. and using the same screws as of 20 g/min. and using the same screws as described in described in Example 1 and the barrel and die settings Example 1 and the barrel and die temperature settings of barrel 1 = 25°C, barrel 2 = 150°C, barrel 3 = 150°C, of barrel 1 = 25°C, barrel 2 = 162°C, barrel 3 = 162°C, 30 barrel 4 = 150°C, barrel 5 = 150°C and die = 100°C, the barrel 4 = 162°C, barrel 5 = 20°C ,and die 10°C, the load load was processed and extruded at an extrusion speed was processed and extruded at an extrusion speed of of 30 rpm to provide Form III-carbamazepine (stable 20 rpm to provide amorphous solid indomethacin. crystals).

Example 5 35 Test Example 1

[0028] A twin-screw extruder (KEX-30S-20; manufac- [0032] The crystals obtained in Example 1 were milled tured by Kurimoto, Ltd.) equipped with a die having an in a mortar and the powder X-ray diffraction pattern of a orifice diameter of 5 mmì was supplied with Form I- sample of the resultant finely divided powder (100 mesh bromovalerylurea (metastable crystals) at a feeding rate 40 pass) was determined. It was found that, as shown in of 25 g/min. and using the same screws as described in Fig. 3, the starting Form α-indomethacin (metestable Example 1 and the barrel and die temperature settings crystals) had been converted to Form γ-indomethacin of barrel 1 = 25 °C, barrel 2 = 147°C, barrel 3 = 147°C, (stable crystals). The identification of the powder X-ray barrel 4 = 147°C, barrel 5 = 90°C, and die = 50°C, the diffraction patterns of Form α - and γ -indomethacin load was processed and extruded at an extrusion speed 45 samples shown in Fig. 3 was made according to the of 100 rpm to provide Form II-bromovalerylurea (stable report of H. Yamamoto: Chem. Pham. Bull. (Tokyo) , 16, crystals). 17 (1968).

Example 6 Test Example 2 50 [0029] An amorphous solid obtained by melting crys- [0033] The crystals obtained in Example 2 were milled talline chloramphenicol palmitate and quenching the in a mortar and the powder X-ray diffraction pattern of a melt at -10°C was fed to a twin-screw extruder (KEX- sample of the resultant finely divided powder (100 mesh 30S-20; manufactured by Kurimoto, Ltd.) equipped with pass) was determined. It could be confirmed that, as a die having an orifice diameter of 5 mmì at a feeding 55 shown in Fig. 4, the diffraction peaks assignable to rate of 40 g/min. and using the same screws as Form α-indomethacin had disappeared from the diffrac- described in Example 1 and the barrel and die temper- tion pattern of Form α-indomethacin (metastable crys- ature settings barrel of barrel 1 = 25°C, barrel 2 = tals)-Form γ-indomethacin (stable crystals) mixture,

10 19 EP 0 665 009 B1 20 suggesting the presence of Form γ-indomethacin alone. sample of the resultant finely divided powder (100 mesh Identification of the powder X-ray diffraction patterns of pass) was determined. It is apparent from Fig. 9 that Form α-indomethacin and Form γ-indomethacin shown Form I-carbamazepine (metestable crystals) had been in Fig. 4 was made according to the report of H. converted to Form III-carbamazepine (stable crystals). Yamamoto, Chem. Pham. Bull. (Tokyo), 16, 17 (1968). 5 Identification of the powder X-ray diffraction patterns of Form I-carbamazepine and Form III- carbamazepine Test Example 3 shown in Fig. 9 was made according to T. Umeda, Yaku- gaku Zasshi, 104, 786 (1984). [0034] The solid obtained in Example 3 was milled in a mortar and the powder X-ray diffraction pattern of a 10 Test Example 8 sample of the resultant finely divided powder (100 mesh pass) was determined. As shown in Fig. 5, no diffraction [0039] The crystals obtained in Example 8 were milled peaks were observed, indicating that Form α-indometh- in a mortar and the powder X-ray diffraction pattern of a acin (metestable crystals) had been converted to an sample of the resultant finely divided powder (100 mesh amorphous solid. 15 pass) was determined. It is apparent from Fig. 10 that Form II-carbamazepine (metestable crystals) had been Test Example 4 converted to Form III-carbamazepine (stable crystals). Identification of the powder X-ray diffraction patterns of [0035] The solid obtained in Example 4 was milled in Form II-carbamazepine and Form III-carbamazepine a mortar and the powder X-ray diffraction pattern of a 20 was made according to T. Umeda, Yakugaku Zasshi, sample of the resultant finely divided powder (100 mesh 104, 786 (1984). pass) was determined. As shown in Fig. 6, no diffraction peaks were observed, indicating that Form γ-indometh- BRIEF DESCRIPTION OF THE DRAWINGS acin (stable crystals) had been converted to an amor- phous solid. 25 [0040]

Test Example 5 Fig. 1 is a schematic cross-section view showing the main part of a universal extruder, wherein 1, 2 [0036] The crystals obtained in Example 5 were milled and 3 represent a barrel structure, a die, and a in a mortar and the powder X-ray diffraction pattern of a 30 screw, respectively. sample of the resultant finely divided powder (100 mesh Fig. 2 is a schematic view showing one embodi- pass) was determined. As shown in Fig. 7, Form I-bro- ment of the method of this invention, wherein ) rep- movalerylurea (metestable crystal) had been converted resents the crystalline state of a medicinal to Form II-bromovalerylurea (stable crystals). substance prior to transition, X represents a molten Identification of the powder X-ray diffraction patterns of 35 state of the same substance, and w represents Form I-bromovalerylurea and Form II-bromovalerylurea the crystalline state of said substance after transi- shown in Fig. 7 was made according to the report of H. tion and the reference numeral 4 represents the Kwada, Chem. Pharm. Bull., 28, 1351 (1980). processing part of the extruder. Fig. 3 shows powder X-ray diffraction patterns. Test Example 6 40 The abscissa represents the diffraction angle (2θ) and the ordinate represents the diffraction intensity [0037] The crystals obtained in Example 6 were milled (CPS). The top view is the powder X-ray diffraction in a mortar and the powder X-ray diffraction pattern of a pattern of the Form γ-indomethacin obtained in sample of the resultant finely divided powder (100 mesh Example 1. The bottom view is the powder X-ray pass) was determined. It is clear from Fig. 8 that the 45 diffraction pattern of the Form α-indomethacin prior amorphous solid chloramphenicol palmitate had been to the processing according to this invention. converted to Form α-chloramphenicol palmitate Fig. 4 shows powder X-ray diffraction patterns. (metestable crystals). Identification, of the powder X-ray The abscissa represents the diffraction angle (2θ) diffraction patterns of amorphous solid chloramphenicol and the ordinate represents the diffraction intensity palmitate and Form α-chloramphenicol palmitate was 50 (CPS). The top view is the powder X-ray diffraction made according to T. Tamura, Yakugaku Zasshi, 81, 759 pattern of the Form γ-indomethacin obtained in (1961) and Y. Tsuda, Chem. Pharm. Bull., (Tokyo), 28, Example 2 and the bottom view is the powder X-ray 947 (1980). diffraction pattern of the Form α- and γ-indometh- acin mixture prior to the processing according to Test Example 7 55 this invention. Fig. 5 shows powder X-ray diffraction patterns. [0038] The crystals obtained in Example 7 were milled The abscissa represents the diffraction angle (2θ) in a mortar and the powder X-ray diffraction pattern of a and the ordinate represents the diffraction intensity

11 21 EP 0 665 009 B1 22

(CPS). The top view is the powder X-ray diffraction crystalline state in a crystallizable medicinal sub- pattern of the amorphous solid indomethacin stance characterized in that an extruder is used to obtained in Example 3. The bottom view is the pow- induce said transition. der X-ray diffraction pattern of the Form α- indomethacin prior to the processing according to 5 3. A method of inducing a transition from stable crys- this invention. talline state or amorphous solid state to metastable Fig. 6 shows powder X-ray diffraction patterns. crystalline state in a crystallizable medicinal sub- The abscissa represents the diffraction angle (2θ) stance characterized in that an extruder is used to and the ordinate represents the diffraction intensity induce said transition. (CPS). The top view is the powder X-ray diffraction 10 pattern of the amorphous solid indomethacin 4. A method of inducing a transition from stable crys- obtained in Example 4. The bottom view is the pow- talline state or metastable crystalline state to amor- der X-ray diffraction pattern of the Form γ- phous solid state in a crystallizable medicinal indomethacin prior to the processing according to substance characterized in that an extruder is used this invention. 15 to induce said transition. Fig. 7 shows powder X-ray diffraction patterns. The abscissa represents the diffraction angle (2θ) 5. A method of inducing a transition from heteroge- and the ordinate represents the diffraction intensity nous crystalline state to homogeneous crystalline (CPS). The top view is the powder X-ray diffraction state in a crystallizable medicinal substance char- pattern of the Form II-bromovalerylurea obtained in 20 acterized in that an extruder is used to induce said Example 5. The bottom view is the powder X-ray transition. diffraction pattern of the Form I-bromovalerylurea prior to the processing according to this invention. Patentansprüche Fig. 8 shows powder X-ray diffraction patterns. The abscissa represents the diffraction angle (2θ) 25 1. Verfahren zum Induzieren eines Übergangs von and the ordinate represents the diffraction intensity einem kristallinen Zustand zu einem anderen kri- (CPS). The top view is the powder X-ray diffraction stallinen Zustand in einer kristallisierbaren medizi- pattern of the Form α-chloramphenicol palmitate nischen Substanz, obtained in Example 6. The bottom view is the pow- dadurch gekennzeichnet, daß der X-ray diffraction pattern of the chloramphenicol 30 ein Extruder verwendet wird, um diesen Übergang palmitate (amorphous solid) prior to the processing zu induzieren. according to this invention. Fig. 9 shows powder X-ray diffraction patterns. 2. Verfahren zum Induzieren eines Übergangs von The abscissa represents the diffraction angle (2θ) einem metastabilen kristallinen Zustand oder amor- and the ordinate represents the diffraction intensity 35 phen Festzustand zum stabilen kristallinen Zustand (CPS). The top view is the powder X-ray diffraction in einer kristallisierbaren medizinischen Substanz, pattern of the Form III-carbamazepine obtained in dadurch gekennzeichnet, daß Example 7. The bottom view is the powder X-ray ein Extruder verwendet wird, um diesen Übergang diffraction pattern of the Form I-carbamazepine zu induzieren. prior to the processing according to this invention. 40 Fig. 10 shows powder X-ray diffraction patterns. 3. Verfahren zum Induzieren eines Übergangs vom The abscissa represents the diffraction angle (2θ) stabilen kristallinen Zustand oder amorphen Fest- and the ordinate represents the diffraction intensity zustand zum metastabilen kristallinen Festzustand (CPS). The top view is the powder X-ray diffraction in einer kristallisierbaren medizinischen Substanz, pattern of the Form III-carbamazepine obtained in 45 dadurch gekennzeichnet, daß Example 8. The bottom view is the powder X-ray ein Extruder verwendet wird, um diesen Übergang diffraction pattern of the Form II-carbamazepine zu induzieren. prior to the processing according to this invention. 4. Verfahren zum Induzieren eines Übergangs vom Claims 50 stabilen kristallinen Zustand oder metastabilen kri- stallinen Zustand zum amorphen Festzustand in 1. A method of inducing a transition from one crystal- einer kristallisierbaren medizinischen Substanz, line state to another crystalline state in a crystalliz- dadurch gekennzeichnet, daß able medicinal substance characterized in that an das ein Extruder verwendet wird, um diesen Über- extruder is used to induce said transition. 55 gang zu induzieren.

2. A method of inducing a transition from metastable 5. Verfahren zum Induzieren eines Übergangs vom crystalline state or amorphous solid state to stable heterogenen kristallinen Zustand zum homogenen

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kristallinen Zustand in einer kristallisierbaren medi- zinischen Substanz, dadurch gekennzeichnet, daß ein Extruder verwendet wird, um diesen Übergang zu induzieren. 5

Revendications

1. Procédé pour induire une transition d'un état cristal- lin à un autre état cristallin dans une substance 10 médicinale cristallisable, caractérisé en ce qu'on utilise une extrudeuse pour induire ladite transition.

2. Procédé pour induire une transition d'un état cristal- lin métastable ou d'un état solide amorphe à un état 15 cristallin stable dans une substance médicinale cristallisable, caractérisé en ce qu'on utilise une extrudeuse pour induire ladite transition.

3. Procédé pour induire une transition d'un état cristal- 20 lin stable ou d'un état solide amorphe à un état cris- tallin métastable dans une substance médicinale cristallisable, caractérisé en ce qu'on utilise une extrudeuse pour induire ladite transition. 25 4. Procédé pour induire une transition d'un état cristal- lin stable ou d'un état cristallin métastable à un état solide amorphe dans une substance médicinale cristallisable, caractérisé en ce qu'on utilise une extrudeuse pour induire ladite transition. 30

5. Procédé pour induire une transition d'un état cristal- lin hétérogène à un état cristallin homogène dans une substance médicinale cristallisable, caractérisé en ce qu'on utilise une extrudeuse pour induire 35 ladite transition.

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