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.