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Ep 0665009 A1 Eu^^esP— || | MMMMI 1 1 1 1 1 1|||| 1 1 1||| || J European Patent Office _ _ _ _ _ © Publication number: 0 665 009 A1 Office europeen desj brevets © EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC © Application number: 93922625.4 © Int. CI.6: A61 K 9/00 @ Date of filing: 13.10.93 © International application number: PCT/JP93/01469 © International publication number: WO 94/08561 (28.04.94 94/10) ® Priority: 14.10.92 JP 303085/92 Koga-gun, Shiga 520-32 (JP) @ Date of publication of application: Inventor: IZUMI, Shougo 02.08.95 Bulletin 95/31 3-94, Nlshltsutsujlgaoka Mlyamadal 1-chome Kameoka-shl, © Designated Contracting States: Kyoto 621 (JP) AT BE CH DE DK ES FR GB GR IE IT LI LU MC Inventor: OKA, Masaakl NL PT SE 18-8-207, Hoshlgaoka 1-chome Hlrakata-shl, © Applicant: NIPPON SHINYAKU COMPANY, Osaka 573 (JP) LIMITED 14, Klssholn Nlshlnosho Monguchlcho Mlnaml-ku © Representative: Vogeser, Werner, Dipl.-lng. et Kyoto-shl al Kyoto 601 (JP) Patent- und Rechtsanwalte Hansmann, Vogeser, Dr. Boecker, © Inventor: NAKAMICHI, Koulchl Alber, Dr. Strych, Lledl 13-16, Kltayamadal 1-chome, Albert-Rosshaupter-Strasse 65 Koselcho D-81369 Munchen (DE) © CRYSTALLINE CONDITION DISLOCATING METHOD. © An object of this invention is to provide a meth- od of the crystalline condition of dislocating cry- \A/ < stalline medicine simply, speedily and homoge- 4 ^ 0 at neously, and, moreover, in large quantities at once. A X. X O O x.X o °o This invention is directed to a method using an x x.x O outlet side melting zonex cooling zone. extruder when crystalline medicine in a certain cry- stalline condition (A is dislocated to another cry- >- — >- CO stalline condition (O), i.e., when the dislocation of CO crystalline condition (A->0) is carried out. Fig . Rank Xerox (UK) Business Services (3. 10/3.09/3.3.4) 1 EP 0 665 009 A1 2 TECHNICAL FIELD id state to stable crystals, (2) a crystallizable active substance in stable This invention relates to a method of inducing crystalline state or in amorphous solid state to a transition of crystalline state in a crystallizable metastable crystals, medicinal substance. 5 (3) a crystallizable active substance in stable As used in this specification, the term 'stable crystalline state or in metastable crystalline state crystal' means any crystal that is in ther- to an amorphous solid, or modynamically stable crystalline state and the term (4) a crystallizable active substance in 'metastable crystal' means any crystal that is in heterogenous crystalline state to homogeneous thermodynamically unstable crystalline state. The io crystals. term 'crystalline state' is used referring to any of The inventors of this invention found that the stable crystal, metastable crystal and amorphous above-mentioned object can be accomplished by (noncrystalline) solid. The term 'heterogenous cry- utilizing an extruder which enables a continuous stal' means a crystal not in a singular crystalline processing of the load and have arrived at the state. 75 present invention. The term 'extruder' means any screw extruder 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, ani- At this junction, the mechanism of the main mal meat, fish meat, etc.). part (work processing part) of the extruder is briefly 20 described. Generally the main part of an extruder BACKGROUND ART comprises, as illustrated in Fig. 1, a cylindrical structure called 'barrel', a die which corresponds to The conventional technology for inducing a a delivery port, and a screw. The barrel usually transition of crystalline state in a medicinal sub- comprises a plurality of unit barrels and the screw stance includes recrystallization, heating, freeze- 25 extends through them. The screw is available in drying, pulverizing and so on. various types, namely trapezoidal screw, However, none of these conventional methods trapezoidal cut screw, trapezoidal reverse cut are capable of inducing a transition of crystalline screw, ball screw, kneading paddle, etc., which can state expediently, efficiently, uniformly and on a be used in a desired combination. The load fed to mass scale and, therefore, are not well suited for 30 the extruder is forced by the screw to advance, commercial application. One of the reasons for shorn and blended by the screw within the barrel their incapability is that because these technologies structure and extruded from the orifice or orifices of are invariably batch processes, large-scale equip- the die. Usually, the temperature of each unit barrel ment is required for mass processing but the larger and that of the die can be independently controlled. the equipment, the greater is the temperature gra- 35 The extruder is available in two general types, dient created in the processing load, so that homo- namely a single-screw extruder comprising one geneous crystals cannot be easily obtained. Taking screw and a multi-screw extruder comprising two the recrystallisation process as an example, judi- or more screws. While this invention can be carried cious selection of the recrystallization solvent, de- into practice using either type of extruder, the use tailed analysis of recrystallizing temperature and 40 of a multi-screw extruder, particularly a twin-screw other parameters, and accurate control of recrystal- extruder, is preferred. Compared with a single- lization conditions are essential. In the case of screw version, a twin-screw extruder is more effi- freeze-drying, the protracted processing time is cient in that the plural screws interferring with each also a detracting factor. other precludes follow-up movement of the active 45 substance and, moreover, the intermeshing of the DISCLOSURE OF INVENTION screws provides a high energy output physically, thus assisting in the induction of a transition of The object of this invention is to provide a crystalline state. method of inducing a transition of crystalline state In the practice of this invention, such an ex- in a crystallizable medicinal substance which over- 50 truder as is in routine use by food industry can be comes the disadvantages of the above-mentioned utilized as it is. prior art methods. Specifically, the invention has for The mode of use of the extruder in the practice its object to provide a method of inducing, expedi- of this invention is now described, referring to ently, efficiently, uniformly, continuously and on a specific embodiments. high production scale, a transition of crystalline 55 For example, in this invention, the main part of state, for example: the extruder can be utilized as divided into two (1) from a crystallizable active substance in zones, namely a melting zone and a cooling zone metastable crystalline state or in amorphous sol- as illustrated in Fig. 2. The melting zone is the 2 3 EP 0 665 009 A1 4 zone in which the medicinal substance is melted While the cooling zone temperature is de- and the cooling zone is the zone in which the pendant on the physical properties of the me- medicinal substance melted in said melting zone is dicinal substance, the type end ratings of ex- solidified. truder used, etc., the cooling zone temperature In the practice of this invention, the melting 5 can be set within the rage of ambient tempera- zone can be defined by one or more barrels. If and ture to a temperature below the melting-start when the medicinal material can be successfully temperature of stable crystals of the medicinal melted, even a single barrel can serve as the substance. It is practically useless to employ a melting zone. temperature setting lower than ambient tempera- However, the proper number of barrels defining the 10 ture, while the medicinal substance fails to cry- melting zone is dependent on the melting point of stallize at times when the setting exceeds the the medicinal substance, the crystalline state of melting-start temperature of stable crystals of said substance, the condition of the substance, the the medicinal substance. There are cases in type and ratings of the extruder used, the rotational which a transition to stable crystalline state can speed of the screw (which corresponds to the is be obtained even when the setting is below speed at which the medicinal load travels within the ambient temperature and such cases also fall barrel), screw geometry (which is related to the within the scope of this invention. pulverization of the medicinal substance) and so It is true that the higher the cooling zone on. For the processing of a medicinal substance temperature, the greater is the safety with which having a high melting point, in the case where the 20 a medicinal substance can be crystallized. How- medicinal substance is crystalline or coarse, or for ever, although it depends on physical properties increasing the rotational speed of the screw, the of the medicinal substance, a higher cooling number of barrels constituting the melting zone zone temperature setting may call for an in- may have to be increased. crease in the overall length of the barrel defining In the practice of this invention, the tempera- 25 the cooling zone or a reduction in the rotational ture of the barrel or barrels constituting the melting speed of the screw. In either case, processing zone (hereafter referred to as 'melting zone tem- efficiency tends to be sacrificed. On the other perature') can be set to the meltable temperature hand, it is not recommendable, either, to use an of the medicinal substance. However, the tempera- unnecessarily low cooling zone temperature. If ture setting is preferably equal to the melting point 30 the cooling zone temperature letting is too low, a of the medicinal substance and more preferably the amorphous solid may result or the crystals may melting start temperature.
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