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USOO5811547A United States Patent (19) 11 Patent Number: 5,811,547 Nakamichi et al. (45) Date of Patent: Sep. 22, 1998

54 METHOD FOR INDUCING CRYSTALLINE 56) References Cited STATE TRANSTION IN MEDICINAL SUBSTANCE U.S. PATENT DOCUMENTS 4,129,649 12/1978 Inoue et al...... 424/182 75 Inventors: Kouichi Nakamichi, Shiga; Shougo 5,160,680 11/1992 Serpelloni et al...... 264/126 Izumi, Kyoto; Masaaki Oka, Osaka, 5,256.234 10/1993 Mutaguchi et al...... 156/224.27 all of Japan 5,385,749 1/1995 Serpelloni et al...... 426/658 73 Assignee: Nippon Shinyaju Co., Ltd., Kyoto, FOREIGN PATENT DOCUMENTS Japan O 177 428 10/1985 European Pat. Off.. O 490 768 A1 12/1991 European Pat. Off.. 21 Appl. No.: 416,815 O 580 860A1 4/1992 European Pat. Off.. 22 PCT Filed: Oct. 13, 1993 60-190723 9/1985 Japan . 86 PCT No.: PCT/JP93/01469 OTHER PUBLICATIONS Obandie et al., J. of Applied Polymer Science, vol. 37, pp. S371 Date: Jun. 9, 1995 1713–1726 (1989). S 102(e) Date: Jun. 9, 1995 Journal of Pharamaceutical Sciences, vol. 62, No. 1, Jan. 1973 F.W. Goodhart, et al. “Design and Use of A Laboratory 87 PCT Pub. No.: WO94/08561 Extruder for Pharmaceutical Granulations”, pp. 133-136. PCT Pub. Date: Apr. 28, 1994 Primary Examiner Mukund J. Shah Assistant Examiner K. Wong Related U.S. Application Data Attorney, Agent, or Firm-Graham & James LLP 63 Continuation-in-part of Ser. No. 129,133, Nov. 15, 1993, 57 ABSTRACT Pat. No. 5,456,923. This invention has for its object to provide a method of 30 Foreign Application Priority Data inducing a transition in crystalline State of a crystallizable Japan ...... 4-3O3O85 medicinal Substance with great ease and improved efficiency Oct. 14, 1992 JP and uniformity on a high production Scale. According to the 51) Int. Cl...... C07D 209/32; CO7D 223/24 invention, an extruder is used for inducing a transition from 52 U.S. Cl...... 540/589: 548/500; 564/45; one crystalline State (A) to another crystalline State in a 564/213 crystallizable medicinal Substance. 58 Field of Search ...... 548/500; 564/45, 564/213; 540/589 12 Claims, 5 Drawing Sheets U.S. Patent Sep. 22, 1998 Sheet 1 of 5 5,811,547

inlet side

Outlet side

A inlet side A A 4.

outlet side U.S. Patent Sep. 22, 1998 Sheet 2 of 5 5,811,547

5k

A. U > m

() 49 H

O 49 U H t sA -Wul 4. 20 40 60 Diffraction Angle (26)

Eig - 3

8k A. U > 4.

()

H

O s 49

t ar A

4. 20 40 60 Diffraction Angle (26)

Fig - 4 U.S. Patent Sep. 22, 1998 Sheet 3 of 5 5,811,547

4k A. U > ar

O)

H

O ar

RS H ar A

4. 20 40 60 Diffraction Angle (20) Eig - 5

6K

A. U > m

O) 4. H

O ar U t

Wy ar are usaved are 4. 2O 40 60 Diffraction Angle (26)

Fig - 6 U.S. Patent Sep. 22, 1998 Sheet 4 of 5 5,811,547

2 Ok

4. "to - 60 Diffraction Angle (26) Efig - 7

4. k i

4. 20 40 60 Diffraction Angle (26) Erig - 8 U.S. Patent Sep. 22, 1998 Sheet 5 of 5 5,811,547

3 Ok.

O > g

O)

H

O ar

r A

Diffraction Angle (20) Eig - 9

5 Ok

A. U > ar

H

O ar

A

4. 2O 40 60 Diffraction Angle (26)

Big - - O 5,811,547 1 2 METHOD FOR INDUCING CRYSTALLINE invention has for its object to provide a method of inducing, STATE TRANSTION IN MEDICINAL expediently, efficiently, uniformly, continuously and on a SUBSTANCE high production Scale, a transition of crystalline State, for example: This is a continuation in part application of U.S. Ser. No. 5 (1) from a crystallizable active Substance in metastable 08/129,133, filed Nov. 15, 1993, now U.S. Pat. No. 5,456, crystalline State or in amorphous Solid State to stable 923, issued Oct. 10, 1995, and is a 371 national filing of crystals, PCT/JP93/01469, filed Oct. 13, 1993. (2) a crystallizable active Substance in stable crystalline State or in amorphous Solid State to metastable crystals, TECHNICAL FIELD (3) a crystallizable active Substance in stable crystalline This invention relates to a method of inducing a transition State or in metastable crystalline State to an amorphous Solid, of crystalline State in a crystallizable medicinal Substance. O AS used in this specification, the term stable crystal (4) a crystallizable active Substance in heterogenous crys means any crystal that is in thermodynamically stable crys 15 talline State to homogeneous crystals. talline State and the term metastable crystal means any The inventors of this invention found that the above crystal that is in thermodynamically unstable crystalline mentioned object can be accomplished by utilizing an State. The term 'crystalline State is used referring to any of extruder which enables a continuous processing of the load Stable crystal, metastable crystal and amorphous and have arrived at the present invention. (noncrystalline) Solid. The term heterogenous crystal In the pharmaceutical field, few technologies utilizing an means a crystal not in a singular crystalline State. extruder are known. The term 'extruder means any Screw extruder that is in At this junction, the mechanism of the main part (work broad use chiefly in food industry for the processing of food processing part) of the extruder is briefly described. Gener materials (cereals, proteins, animal meat, fish meat, etc.). ally the main part of an extruder comprises, as illustrated in 25 FIG. 1, a cylindrical structure called “barrel, a die which BACKGROUND ART corresponds to a delivery port, and a Screw. The barrel The conventional technology for inducing a transition of usually comprises a plurality of unit barrels and the Screw crystalline State in a medicinal Substance includes extends through them. The Screw is available in various recrystallization, heating, freeze-drying, pulverizing and So types, namely trapezoidal Screw, trapezoidal cut Screw, O. trapezoidal reverse cut Screw, ball Screw, kneading paddle: However, none of these conventional methods are capable etc., which can be used in a desired combination. The load of inducing a transition of crystalline State expediently, fed to the extruder is forced by the screw to advance, shorn efficiently, uniformly and on a mass Scale and, therefore, are and blended by the screw within the barrel structure and extruded from the orifice or orifices of the die. Usually, the not well Suited for commercial application. One of the 35 reasons for their incapability is that because these technolo temperature of each unit barrel and that of the die can be gies are invariably batch processes, large-scale equipment is independently controlled. required for mass processing but the larger the equipment, The extruder is available in two general types, namely a the greater is the temperature gradient created in the pro Single-Screw extruder comprising one Screw and a multi cessing load, So that homogeneous crystals cannot be easily Screw extruder comprising two or more Screws. While this obtained. Taking the recrystallization process as an example, 40 invention can be carried into practice using either type of judicious Selection of the recrystallization Solvent, detailed extruder, the use of a multi-Screw extruder, particularly a analysis of recrystallizing temperature and other parameters, twin-Screw extruder, is preferred. Compared with a single and accurate control of recrystallization conditions are Screw version, a twin-Screw extruder is more efficient in that essential. In the case of freeze-drying, the protracted pro the plural Screws interferring with each other precludes cessing time is also a detracting factor. 45 follow-up movement of the active Substance and, moreover, the intermeshing of the Screws provides a high energy output The present invention will be clearly seen from the physically, thus assisting in the induction of a transition of following discussion and the drawings in which: crystalline State. BRIEF DESCRIPTION OF THE DRAWINGS In the practice of this invention, Such an extruder as is in 50 routine use by food industry can be utilized as it is. FIG. 1 is a Schematic cross-section view of the main part The mode of use of the extruder in the practice of this of the extruder used to effect the method of the present invention is now described, referring to Specific embodi invention; mentS. FIG. 2, is a Schematic representation of change in crys 55 For example, in this invention, the main part of the talline State of the medical Substance being processed in the extruder can be utilized as divided into two Zones, namely extruder of FIG. 1; a melting Zone and a cooling Zone as illustrated in FIG. 2. FIGS. 3-10 are powder diffraction patterns, with each The melting Zone is the Zone in which the medicinal figure showing comparative diffraction patterns for various Substance is melted and the cooling Zone is the Zone in Substances prior to and after processing in accordance with 60 which the medicinal Substance melted in Said melting Zone the present invention. is solidified. In the practice of this invention, the melting Zone can be DISCLOSURE OF INVENTION defined by one or more barrels. If and when the medicinal The object of this invention is to provide a method of material can be Successfully melted, even a single barrel can inducing a transition of crystalline State in a crystallizable 65 Serve as the melting Zone. However, the proper number of medicinal Substance which overcomes the disadvantages of barrels defining the melting Zone is dependent on the melt the above-mentioned prior art methods. Specifically, the ing point of the medicinal Substance, the crystalline State of 5,811,547 3 4 Said Substance, the condition of the Substance, the type and cooling Zone temperature is preferably Selected in consid ratings of the extruder used, the rotational Speed of the Screw eration of the physical properties of the medicinal Substance, (which corresponds to the speed at which the medicinal load the type and ratings of extruder, melting Zone temperature, travels within the barrel), Screw geometry (which is related and the rotational Speed of the Screw, among other factors. to the pulverization of the medicinal Substance) and So on. The cooling Zone temperature can be preset with the aid For the processing of a medicinal Substance having a high of a melting point measuring instrument equipped with a melting point, in the case where the medicinal Substance is optically microscope (e.g. Mettler's, melting/boiling point crystalline or coarse, or for increasing the rotational Speed of meter Model FP-80 or FP-82HT equipped with a polarizing the Screw, the number of barrels constituting the melting microscope), a differential Scanning calorimeter (DSC) or Zone may have to be increased. the like. Thus, in the case of a melting point measuring In the practice of this invention, the temperature of the instrument equipped with a optically microScope, one may barrel or barrels constituting the melting Zone (hereafter use the method which comprises melting the medicinal referred to as melting Zone temperature) can be set to the Substance on a slide glass, cooling it to find the temperature meltable temperature of the medicinal Substance. However, at which stable crystals are formed and using the particular the temperature Setting is preferably equal to the melting 15 temperature as the cooling Zone temperature. point of the medicinal Substance and more preferably the Where the cooling Zone is defined by a plurality of unit melting Start temperature. If the melting Zone temperature be barrels, the temperature Settings of the respective barrels and too high, the medicinal Substance might decompose. When of the die need not necessarily be identical. However, the the melting Zone is defined by a plurality of barrels, the temperature of the down Stream barrel or the die is prefer temperature of the respective barrels need not necessarily be ably set below the temperature of the upstream barrel. uniform. Reversing this relation will be in conflict with the direction In this invention, the cooling Zone can be constituted of crystallization of the medicinal Substance. moreover, in using the remaining barrels, viz. barrels other than the Such cases, it is not a good practice to Set the temperature of barrels defining the melting Zone, and the die. Depending on each barrel constituting the cooling Zone at an unnecessarily cases, the environment (external Zone) Surrounding the 25 low level relative to the temperature of the immediately extruder may be included in the cooling Zone. Even when preceding barrel (both of the melting Zone and cooling the external Zone is included in the cooling Zone, Since the Zone). If Said temperature Setting is unnecessarily too low molten medicinal Substance is delivered out continuously compared with the temperature of the immediately preced and little by little from the die orifices, there is substantially ing barrel, an amorphous Solid tends to form or heterogenous no concern about the loSS of homogenity due to a tempera crystals may be produced. The System in which the cooling ture gradient. Zone temperature is not uniform is instrumental where The temperature settings of the barrel or barrels and die crystallization of the medicinal Substance is desirably defining the cooling Zone (hereinafter called 'cooling Zone achieved by gradual cooling. temperature) are now explained, taking the transition of When the cooling Zone temperature is Set to ambient various crystalline States as examples. 35 temperature, it is not essential to provide a cooling Zone (1) The procedure for inducing a transition from meta within the barrel structure. When the barrel structure has no Stable crystals to stable crystals, for instance, and the pro cooling Zone, the environment functions as a cooling Zone cedure for inducing a transition from hererogenous crystals and all the barrels and die constitute the melting Zone. to homogeneous crystals: 40 (2) The procedure for inducing a transition from stable While the cooling Zone temperature is dependent on the crystalline State or the like to metastable crystalline State and physical properties of the medicinal Substance, the type and the procedure for inducing a transition from heterogenous ratings of extruder used, etc., the cooling Zone temperature crystalline State to metastable crystalline State: can be set within the range of ambient temperature to a The cooling Zone temperature in these cases can be temperature below the melting-start temperature of Stable 45 established beforehand with the aid of a melting point crystals of the medicinal Substance. It is practically useleSS measuring instrument equipped with a optically microScope to employ a temperature Setting lower than ambient (e.g. Mettler's melting/boiling point meter Model FP-80 or temperature, while the medicinal Substance fails to crystal FP-82HT equipped with a polarizing microscope), a differ lize at times when the Setting exceeds the melting-start ential scanning calorimeter (DSC) or the like. Thus, in the temperature of Stable crystals of the medicinal Substance. 50 case of a melting point measuring instrument equipped with There are cases in which a transition to Stable crystalline a optically microscope, the method can be used which State can be obtained even when the Setting is below ambient comprises melting the medicinal Substance on a slide glass, temperature and Such cases also fall within the Scope of this cooling it to find the temperature at which metastable invention. crystals are formed and using the particular temperature as It is true that the higher the cooling Zone temperature, the 55 the cooling Zone temperature. greater is the Safety with which a medicinal Substance can be Where the cooling Zone is defined by a plurality of crystallized. However, although it depends on physical prop barrels, the temperature Settings of the respective barrels and erties of the medicinal Substance, a higher cooling Zone of the die need not necessarily be identical. However, the temperature Setting may call for an increase in the overall temperature of any downstream barrel or the die is prefer length of the barrel defining the cooling Zone or a reduction 60 ably set below the temperature of the upstream barrel. in the rotational Speed of the Screw. In either case, proceSS Reversing this relation will be in conflict with the direction ing efficiency tends to be Sacrificed. On the other hand, it is of crystallization of the medicinal Substance. Moreover, in not recommendable, either, to use an unnecessarily low Such cases, it is not a good practice to Set the temperature of cooling Zone temperature. If the cooling Zone temperature each barrel constituting the cooling Zone at an unnecessarily Setting is too low, an amorphous Solid may result or the 65 low level relative to the temperature of the immediately crystals may become heterogenous. Therefore, in order to preceding barrel (both of the melting Zone and cooling insure an efficient and Safe working of this invention, the Zone). If Said temperature Setting is unnecessarily too low as 5,811,547 S 6 compared with the temperature of the immediately preced Zone using an appropriate number of unit barrels and Supply ing barrel, an amorphous Solid tends to form or heterogenous the medicinal Substance to Said Zone in the first place. This crystals may be produced. is because the barrel adjacent to the inlet is exposed to the The System in which the cooling Zone temperature is not environment and, hence, not well amenable to temperature uniform is instrumental where crystallization of the medici control. Only one barrel generally Suffices for constituting nal Substance is desirably achieved by gradual cooling. Said feeding Zone and, by nature, its temperature may be When the cooling Zone temperature is Set to ambient equal to ambient temperature. temperature, it is not essential to provide a cooling Zone The rotational speed of the screw can be set within the within the barrel structure. When the barrel structure has no allowable range of the extruder used. Generally Speaking, cooling Zone, the environment functions as a cooling Zone assuming that the kind and shape of medicinal Substance are and all the barrels and die constitute the melting Zone. unchanged, the rotational Speed of the Screw can be (3) The procedure for inducing a transition from Stable increased in the case of an extruder with a greater overall crystalline State or the like to amorphous Solid State and the barrel length as compared with an extruder with a shorter procedure for inducing a transition from heterogeneous overall barrel length. crystalline State to homogeneously amorphous Solid State: 15 The Screw geometry and combination of unit Screws can By nature of an amorphous Solid, the cooling Zone tem be Selected without any particular restriction. The principal perature in these cases is preferably as low as possible. In role of the Screw in this invention is to transport, crush and this invention, although it depends on physical properties of knead the medicinal Substance. Therefore, when the particle the medicinal Substance and the type and ratings of the Size of the feed medicinal Substance is previously set to be extruder used, among other variables, the cooling Zone Such that it can be Smoothly transported by the Screw, it is temperature can be set to a temperature about 70% lower Substantially unnecessary to pay attention to the Screw than the melting-start temperature of the medicinal Sub geometry. stance (e.g. 30°C. where the melting-start temperature of the The orifice configuration of the extrusion die is not medicinal Substance is 100° C. ) or even a still lower particularly restricted and may for example be circular, temperature. It is more preferable that the temperature 25 elliptical, rectangular or hexagonal. When the orifice is setting be not higher than a level about 90% lower than the circular in Section, its diameter can be Selected appropri melting-start temperature of the medicinal Substance. If the ately. For example, the range of 0.5-5 mm (p can be temperature Setting is too high, the Stable or metastable mentioned. crystalline State will avail. Although the desired transition to Whether the desired transition has been achieved or not amorphous Solid State may be achieved at times even when can be verified by means of a optically microscope, a powder the temperature Setting is higher than Said limit, Such cases X-ray diffractometer, a differential Scanning calorimeter also fall within the scope of this invention. The cooling Zone temperature in these cases can be (DSC) or the like. established beforehand with the aid of a melting point AS regards the crystallizable medicinal Substance that can measuring instrument equipped with a optically microscope 35 be used in this invention, there is no particular restriction (e.g. Mettler's melting/boiling point meter Model FP-80 or only if it does not decompose on exposure to the melting FP-82HT equipped with a polarizing microscope), a differ Start temperature. This invention can be applied not only to ential scanning calorimeter (DSC) or the like. Thus, in the medicinal Substances but also to other crystallizable Sub case of a melting point measuring instrument equipped with stances used in the fields of farm chemicals and food. The a optically microscope, the method can be used which 40 following specific crystallizable Substances can be men comprises melting the medicinal Substance on a slide glass, tioned by way of example. cooling it to find the temperature at which an amorphous 1. General anesthetics: Solid is formed and using the temperature as the cooling hydrochloride, Sodium, thiopental Zone temperature. Sodium, . 45 2. Hipnotic//antianxiety : Where the cooling Zone is defined by a plurality of , , , barrels, the temperature Settings of the respective barrels and hydrochloride, hydrochloride, , of the die need not necessarily be identical. However, the , , , cloraZe pate temperature of any downstream barrel or the die is prefer dipotassium, , , , ably set below the temperature of the upstream barrel. 50 Sodium, , , Sodium, Reversing this relation will be in conflict with the direction , , , , of Solidification of the medicinal Substance. , , fluidiazepam, fluta Zolam, When the cooling Zone temperature is Set to ambient , , flurazepam, , temperature, it is not essential to provide a cooling Zone , bromoValerylurea, , , within the barrel structure. When the barrel structure has no 55 pnetobarbiturate, , , , cooling Zone, the environment functions as a cooling Zone , , . and all the barrels and die constitute the melting Zone. 3. Antiepileptics: Feeding of the medicinal Substance into the barrel Struc Acetylphene turide, etho Su Ximide, , ture can be performed by utilizing the feeder with which the , , Sultiame, , extruder is generally provided but there is no limitation on 60 , Sodium , Sodium, the device that can be used only if the medicinal Substance , . may be fed at a constant rate. 4. Antipyretic//antiinflammatory agents: AS examples of Such feeding device, a Screw feeder, a , aspirin DL-, aspirin aluminum, table feeder, a belt-conveyer type quantitative feeder, and an acetaminophen, , , aiminoprofen, electromagnetic feeder can be mentioned. 65 Sodium, isopropylantipyr ine, , Although the medicinal Substance can be directly fed into indomethacin, indomethacin farnesil, ethen Zamide, the melting Zone, it is a good practice to provide a feeding , emorfaZone, tiaramide hydrochloride, tinoridine 5,811,547 7 8 hydrochloride, hydrochloride, , Valethamate bromide, pyridoStigmine bromide, hydrochloride, hydrochloride, , pri?inium bromide, , clofeZone, ketophenylbutaZone, , Sasapyrine, bromide, , aclatonium napadisilate, neostigmine, , Salicylate, , Saridon, , diphenylpiperidinomethyldioxolane iodide. Sodium, , eptazocine hydrobromide, 12. Antispasodics: tartrate, , Sulpyrine, , , etomidoline, hydrochloride, , , Sodium, , hydrochloride, hydrochloride, tolp , Neo Vitacain, Neurotropin, bitoxin, , erisone hydrochloride, hydrochloride, piperidol , phenylacetylglycine, , fenopro ate hydrochloride, bromoethyl pipethanate, fen , , bucolome, , flufenamic hydrobromide, , Valethamate bromide, acid, flufe namic acid , , butylscopolamine bromide, methobromide, flurbiprofenaxetil, , , anisotropine methobromide, benactyzium methobromide, maleate, migrenin, mesilate, metiazinic acid, , , , N-methyl-Scopolamine , Sodium, lobenzarit disodium. methyl Sulfate, atropine Sulfate. 5. Analeptic/antihypnotic agents: 15 13. Antivertigo drugs: hydrochloride, bemegride. hydrochloride, difenidol hydrochloride, 6. Antiparkinsonian drugs: hydrochloride, , , Amanta dine hydrochloride, trihexyphen idyl theoclate and, meSylate. hydrochloride, hydrochloride, 14. Sense organ drugs: hydrochloride, methixene hydrochloride, , hydrochloride, tetrizoline. , mesilate, levodopa. 15. Cardiotonics: 7. Psychotropic/neurotropic drugs: 2-AminoethaneSulfonic acid, , , , hydrochloride, imi Sodium benzoate, etile frine hydrochloride, pramine hydrochloride, dihydrochloride, clo hydrochloride, hydrochloride, mipramine hydrochloride, hydrochloride, Sulto 25 hydrochloride, hydrochloride, choline pride hydrochloride, thiorida Zine hydrochloride, the ophylline, diisobutylaminobenzoyloxypropyl hydrochloride, hydrochloride, traZ , , , , odone hydrochloride, triflu hydrochloride, bitartrate, , , trans-U-OXOcamphor, hydrochloride, hydrochloride, bu cladesline Sodium, , , hydrochloride, pipradorol hydrochloride, besnalinone, , ubidecare none, . hydrochloride, hydrochloride, meth 16. Antiarrhythmic drugs: ylphenidate hydrochloride, hydrochloride, , , hydrochloride, hydrochloride, hydrochloride, hydrochloride, hydrochloride, , , , , hydrochloride, hydrochloride, , dimethanSulfonate, 35 hydrochloride, hydrochloride, pyrudicainide , , , , , halo hydrochloride, hydrochloride, peridol decanoate, , hydroxy Zine pamoate, hydrochloride, hydrochloride, , , , , hydrochloride, hydrochloride, propericyazine, bromazepam, , , hydrochloride, hydrochloride, , cetiprin maleate, maleate, 40 hydrochloride, cibenzoline Succinate, , maleate, , . , tartrate, , , biso 8. CNS drugs: prolol fumarate, maleate, Sulfate. Idebenone, hydrochloride, 17. : hydrochloride, hydrochloride, , , isosorbide, etacrynic acid, hydrochloride, hydrochloride, 45 ethiazide, potassium can re noate, quine thaZone, hydrochloride, hydrochloride, Y-amino-3- , chlorthalidone, cyclope nthiazide, hydroxybutyric acid, , protirelin tartrate, baclofen, , theoSalicin, , , , calcium hopantenate, . , , , 9. Local anesthetics: bu metanide, , benzylhydrochlorothiazide, Ethyl aminobenzoate, oxybuprocaine hydrochloride, 50 penflutizide, , , , dibucaine hydrochloride, hydrochloride, . p-butylaminobenzoyldiethyl aminoethanol hydrochloride, 18. Antihypertensive drugs: hydrochloride, hydrochloride, pro Alacepril, , , , pitocaine hydrochloride, hydrochloride, hydrochloride, carteolol hydrochloride, oxethazaine, ethyl p-piperidinoacetyl aminobenzoate, 55 hydrochloride, hydrochloride, hydrochloride. hydrochloride, hydrochloride, 10. relaxants: hydrochloride, hydrochloride, delapril , , tub hydrochloride, todralazine hydrochloride, o curarine chloride, chlorphene Sin carb amate, hydrochloride, hydralazine hydrochloride, , chlormeZanone, , 60 hydrochloride, hydrochloride, , Sodium, , hydrochloride, hydrochloride, meSylate, . hydrochloride, dimethylaminoethyl reSerpilinate 11. Autonomic drugs: dihydrochloride, cadralazine, captopril, trimetaphan chloride, ambenonium chloride, carpro camsilate, acetate, bromide, nium chloride, , chloride, 65 metoprolol tartrate, SilaZapuril, , tripamide, oxyphen cyclimine hydrochloride, dicycloverin nadolol, nipradillol, , budralazine, enalapril hydrochloride, hydrochloride, distigmine maleate, dihydroergotoxine meSylate, meSylate, 5,811,547 9 10 mesilate, , , Rauwopur, 27. Peptic ulcer remedies: ricinopuril, Sulfate, betanidine, Sulfate, penb aluminium, Sodium alginate, aldioxa, utolol Sulfate, , reserpine, 2,6-dimethyl-4-(2- L-, cetraXate hydrochloride, nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4- hydrochloride, hydrochloride, rozatidine acetate dihydropyridine-3-carboxylate. hydrochloride, , ornoprostil, chlophyllin S, 19. Vasoconstrictors: gefarnate, Kolantyl, , Sucralfate, Sulpiride, Norfene frine hydrochloride, Secretin, Sofalcone, teprenone, troXipide, , hydrochloride, hydrochloride, , plaunotol, , bergenin, hydrochloride, meSylate. maleate, methylmethionine Sulfonium chloride, malate, levamipil. 20. Vasodilators: 28. StomachicS/digestants: InoSitol he Xanicotinate, e floxate, isoXSuprine Carnitine chloride. hydrochloride, hydrochloride, 29. Laxatives/clysters: hydrochloride, hydrochloride, Bisoxatin acetate, Sodium picosulfate, bisacodyl, lactu dihydrochloride, hydrochloride, valnidipine lose. hydrochloride, Venidipine hydrochloride, Verapamil 15 30. Cholagogues: hydrochloride, nicametate citrate, , pentaeryth Anetholtrithion, urSodeSOXycholic acid, OSalmid, cheno rityl tetranitrate, , , , deoxycholic acid, dehydrocholic acid, trepibutone, hymec , , , nife dipline, OOC. hepronicate, Sulfate, Y-ory Zanol, , 31. Gastrointestinal drugs: , , cole Styramine, hydrochloride, , Symvastatin, , Soysterol, dextran Sulfate Sodium, acetonide, tricaprilin, , fenipentol, nicomol, , Sodium, , maleate, . , polyenephosphatidylcholine, melinamide, ethyl 32. Thyroid/ drugs: linoleate. Thiamazole, propylthiouracil, liothyronine Sodium, 21. Cardiovascular drugs: 25 Sodium. , alproStadil, ibu dilast, flunari Zine 33. Anabolic drugs: hydrochloride, meclofenoxate hydrochloride, Ethylnandrol, , cyclohexane hydrochloride, Sodium , citicoline, tartrate, propionate, dipropionate, , nandrolone , cytochrome C, nicotinate, decanoate, nandrolone phenylpropionate, , nan , pyridinol , , nizofenone drolone furylpropionate, , meterolone. fumarate, brovincamine fumarate, fumarate, 34. Corticoid drugs: , calcium polystyrene Sulfonate, Sodium poly Epinephrine, Sodium Succinate, predniso Styrene Sulfonate, maleate, maleate, lone Sodium Succinate, acetate, dihydroergotamine neSylate, ameZinium methyl Sulfate, acetate, , parainethasone acetate, limaprost C.-cyclodextrin clathrate. 35 acetate, hydrocortisone acetate, 22. Respiratory : acetate, acetate, acetate, Dimefline hydrochloride, doxapram hydrochrolide, dexamethasone, triamcinolone, , dexametha hydrochloride, lobe line hydrochloride, Sone palmitate, hydrocortisone, prednisolone butylacetate, dimorpholamine, levallorphan tartrate, flumazenil. Sodium Sulfate, prednisolone, 23. Antitussives: 40 dipropionate, , dexamethasone Sodium As drin, clofed hydrochloride, metasulfobenzoate, methylprednisolone, dexamethasone hydrochloride, hydrochloride, methylephedrine Sodium phosphate, hydrocortisone Sodium phosphate, pred hydrochloride, citrate, citrate, pentox nisolone Sodium phosphate, betamethasone Sodium phos yverine citrate, Chlophedrin S, chloperastine, dextrometho phate. rphan hydrochloride, Oxeladin tannate, dl-methylephedrine 45 35. Male hormone drugs: hydrochloride, dl-methylephedrine, , dimenorfan enanthate, , , beinproperine phosphate. propionate, dromoStanolone propionate, . 24. Expectorants: 36. /progestin drugs: N-Acetyl-L-, ambro;ol hydrochloride, L-cysteine Allyle Stre no l; e Stradiol benzoate, e Striol ethyl ester hydrochloride, brom hexine hydrochloride, 50 benzoyldiacetate, , , gestonorone , hydrochloride, , tipe caproate, hydroxyprogesteron caproate, Valerate, pidine hibenzate, phosphate, phoS acetate, medroxyprogestero ne acetate, phate. , , , 25. Brochodilators: nore thisterone, , , estriol Epinephrine hydrochloride, hydrochloride, 55 tripropionate, , . clorprenaline hydrochloride, hydrochloride, tri 37. Hormone drugs other than 32-36: metoquinol hydrochloride, hydrochloride, pro , , citrate, glucagon, caterol hydrochloride, hydrochloride, , Octreotide acetate, acetate, gonadorelin Sodium cromogly cate, diprophylline, fenote rol acetate, acetate, buSerelin acetate, leuprolerin hydrobromide, theophylline, fumarate, isoprot 60 acetate, , dinoprost, dinoprost tromethamine, erenol Sulfate, Sulfate, Sulfate, terb dinoprostone, , , , . utaline Sulfate, Sulfate. 38. Urinary tract drugs: 26. Antidiarrheal drugS/drugs for controlling intestinal func hydrochloride, hydrochloride, tion: Paraprost, hexamine. chloride, leperamide hydrochloride, 65 39. Oxytocics: dimethicone, bismuth Subgallate, berberine tannate, maleate, male ate, lactomin, berberine Sulfate. Sulfate. 5,811,547 11 12 40. : 50. : , etretinate, , , ASpoxicillin, aztreonam, acetylkitasamycin, , acetate, , retinol palmitate, cetotiamine ampicillin, eStolate, Spectinomycin hydrochloride, hydrochloride, cocarboxylase, thia hydrochloride, oxytetracycline hydrochloride, cefotiam mine nitrate, bisthiamine nitrate, thiamine disulfide, dihydrochloride, cefotiam hexetil hydrochloride, cef bisi buthiamine, bis buty tiamine, bisb entiamine, menoXime hydrochloride, hydrochloride, dem , , benfotiamine, ethylchlortetracycline hydrochloride, doxycycline hydrochloride, cobamamide, acetate, hydrochloride, Vancomycin hydrochloride, pivmecillinam , nicotinic acid, , , hydrochloride, hydrochloride, lincomycin mecobalamin, folic acid, butyrate, riboflavin, phosphate, , riboflavin hydrochloride, carindacillin Sodium, carumonam Sodium, Sodium phosphate, ascorbic acid, tocopherol calcium , , , cloxacillin Succinate, tocopherol acetate, phytonadione, menatetrenone, Sodium, chloramphenicol, chloram phenicol Sodium . Succinate, colistin Sodium methaneSulfonate, , 41. Hemostatics: midecamycin acetate ciclacillin, cefazolin Sodium, cefatriz Sodium alginate, ethamsylate, carbazochrome, carbazo 15 ine propylene glycol, cefapirin Sodium, cefamandole chrome Sodium Sulfonate, traneXamic acid, thrombin, Sodium, cefalexin, cefafotin Sodium, cefaloridine, cefixime, adrenochrome monoaminoguanidine methaneSulfonate. cefodizime Sodium, cefotaxime Sodium, cefdinir, cefuZonam 42. Anticoagulants: Sodium, ceftazidime, ceftizOXime Sodium, cefteZole Sodium, Dipyridamole, dalteparin Sodium, calcium, hep ceftriaXOne Sodium, cefSulodin Sodium, cefminoX Sodium, arin Sodium, warfarin potassium. , cefroXadine, cefuroxime axetil, cefuroxime 43. disease remedies: Sodium, tetracycline, Sultamicillin tosilate, chloramphenicol 2-Aminoethane Sulfonic acid, glucuronolactone, palmitate, pheneticillin potassium, phenoxymethylpenic glucuronamide, Sodium glucuronate, cianidanol, diisopro illin potassium, Sodium, josamycin pylamine dichloroacetate, thioctic acid, thioctic acid amide, propionate, flucloxacillin Sodium, benzylpenicillin tiopronin, protoporphyrin disodium, malotilate. 25 potassium, benzylpenicillin benzathine, fosfomycin, 44. : Calcium disodium edetate, , midecamycin, , capreomycin Sulfate, Sisomicin penicillamine, deferoxamine mesilate, pralidoxime Sulfate, paromomycin Sulfate, loxythromycin. iodide. 51. Sulfa drugs: 45. Arthrifuges: Acetylsulfame thoxazol, Sulfa dimethoxine, Allopurinol, colchicine, , probenecid, ben Sulfamethizole, Sulfamethoxazole, Sulfamethopyrazine, Zbromarone. Sulfamonomethoxine, Sulfisoxazole, Sulfisomidine. 46. Antidiabetics: 52. Antituberculosis drugs: , buformine hydrochloride, , isoniazid Sodium glucuronate, isoniazid Sodium hydrochloride, , , glybuzole, methanSulfonate, ethionamide, ethambutol hydrochloride, , gly midine Sodium, , 35 pyrazinamide. , . 53. Antileprotics: Sodium glucosulfone, diaphenylsulfone, 47. drugs: thiazoSulfone. AZathioprine, disodium, 54. Synthetic antimicrobial agents: aprotinin, ipriflavone, urinastatin, disodium etidronate, Enoxacin, thiamphenicol glycinate hydrochloride, cipro epalrestat, elcatonin, L-cysteine, levocarnitine chloride, 40 floxacin hydrochloride, lomefloxacin hydrochloride, Sapropterin hydrochloride, calcitonin, glutamate, ofloxacin, cinoxacin, thiamphenicol, tosfloxacin tosylate, Sodium glutamate, Sodium , ciclosporin, nalidixic acid, norfloxacin, pipemidic acid trihydrate, Sodium hyaluronate, mizoribine, gabexate mesilate, camo 6-fluoro-1-methyl-7-4-(5-methyl-2-oxo-1,3-dioxolen-4-yl) Stat mesilate, nafamoStat mesilate, lactulose. methyl-piperazinyl)-4-oxo-4H1,3-thia Zeto3,2-a 48. Antitumor drugs: 45 -3-carboxylic acid. Aceglatone, , , enocitabine, procar 55. Antiviral agents: bazine hydrochloride, hydrochloride, Aciclovir, ganciclovir, Zidanocin, Vidarabine. mustard N-oxide hydrochloride, hydrochloride, 56. Chemotherapeutic drugs: , , , citrate, Inosine pranobeX, nalidixic acid, , flucytosine, , , , Sizofiran, 50 . , , thioinosine, , improSulfan 57. : tosilate, , , , , citrate, , , , , , , , phosphate. , , Sodium 58. Narcotics: phosphate, lentinan. 55 hydrochloride, hydrochloride, 49. Antiallergic agents: hydrochloride, Oximetebanol, citrate, Amlexanox, azelartine hydrochloride, morphine Sulfate, codeine phosphate, dihydrocodeine phos hydrochloride, hydrochloride, oZagrel phate. hydrochloride, hydrochloride, diphenhy The usefulness of inducing a transition of the crystalline dramine hydrochloride, cyproheptadine hydrochloride, 60 State of a crystallizable Substance is pointed out below. hydrochloride, promethazine hydrochloride, (1) By inducing a transition from metastable crystalline hydrochloride, o Xatomide, State or the like to Stable crystalline State, the Stability of a , Sodium cromoglycate, tartrate, bulk Substance or a pharmaceutical composition, for taZanolast, tannate, diphenylpyraline instance, can be increased. teoclate, , tranilast, pemirolast potassium, clem 65 (2) By inducing a transition from Stable crystalline State or astine fumarate, chlorpheniramine maleate, dimethindene the like to metastable crystalline State or amorphous Solid maleate, meguitazine. State, the Solubility of a medicinal Substance in the gas 5,811,547 13 14 trointestinal tract can be increased and, hence, its bioavail mm wide was continuously charged with Form ability can be improved or modulated. Y-indomethacin (stable crystals) at a feeding rate of 20 (3) By inducing a transition from crystalline State with a g/min. and using the same Screws as described in Example crystal habit to a different crystalline State, powder proper 1 and the barrel and die temperature settings of barrel 1=25 ties Such as flowability and packing and compression char 5 C., barrel 2=162 C., barrel 3=162 C., barrel 4=162 C., acteristics in the granulation Stage and tablet-machine com barrel 5=20 C., and die=10 C., the load was processed and pression Stage can be improved. extruded at an extrusion Speed of 20 rpm to provide amor Since the method of this invention is not a batch process phous Solid indomethacin. but a continuous process, mass processing is feasible with Small equipment. 1O EXAMPLE 5 Moreover, because it is a continuous process, the quantity A twin-screw extruder (KEX-30S-20; manufactured by of the medicinal Substance actually processed within the Kurimoto, Ltd.) equipped with a die having an orifice equipment at any given time-point is Small So that a biased diameter of 5 mm (p was supplied with Form transition of crystalline State due to a temperature gradient is I-bromoValerylurea (metastable crystals) at a feeding rate of little involved. 15 25 g/min. and using the same Screws as described in BEST MODE FOR CARRYING OUT THE Example 1 and the barrel and die temperature Settings of INVENTION barrel 1=25 C., barrel 2=147 C., barrel 3=147 C., barrel 4=147 C., barrel 5=90° C., and die=50° C., the load was The following examples and test example are intended to processed and extruded at an extrusion Speed of 100 rpm to illustrate this invention in further detail. provide Form II-bromovalerylurea (stable crystals). It should be understood that the numbers assigned to the respective barrels are in the order Starting with the barrel EXAMPLE 6 closest to the feeding Side. An amorphous Solid obtained by melting crystalline 25 chloramphenicol palmitate and quenching the melt at -10 EXAMPLE 1. C. was fed to a twin-screw extruder (KEX-30s-20; manu A twin-screw extruder (KEX-30S-20; manufactured by factured by Kurimoto, Ltd.) equipped with a die having an Kurimoto, Ltd.) equipped with a die having an orifice orifice diameter of 5 mmcp at a feeding rate of 40 g/min. and diameter of 5 mmcp was Supplied with Form C-indomethacin using the same Screws as described in Example 1 and the (metastable crystals) at a feeding rate of 30 g/min., and using barrel and die temperature settings barrel of barrel 1=25 C., screws with a diameter of 32 mm), an effective L/D ratio of barrel 2=100° C., barrel 3=100° C., barrel 4=95 C., barrel 20 and a screw pattern of 16P, 12P, 9.6P, 30 deg, 60 deg,9.6P 5=45 C. and die=45 C., the load was processed and and 8P, and the temperature settings of barrel 1=25 C., extruded at an extrusion speed of 50 rpm to provide Form barrel 2=155° C., barrel 3=155 C., barrel 4=155 C., barrel C-chloramphenicol palmitate (metastable crystals). 5=50° C. and die=40 C., the load was extruded at a speed 35 of 100 rpm to provide Form y-indomethacin (stable EXAMPLE 7 crystals). Form I-carbamazepine (metastable crystals) was fed to a twin-screw extruder (KEX-30S-20; manufactured by EXAMPLE 2 Kurimoto, Ltd.) equipped with a die having an orifice sized A twin-screw extruder (XEX-30S-20; manufactured by 40 2 mm high and 10 mm wide at a feeding rate of 25 g/min. Kurimoto, Ltd.) equipped with a die having an orifice and using the same Screws as described in Example 1 and the diameter of 5 mmqp was continuously charged with a mixture barrel and die temperature settings of barrel 1=25 C., barrel (1:1) of Form C-indomethacin (metastable crystals) and 2=177° C., barrel 3=190° C., barrel 4=190° C., barrel Form y-indomethacin (stable crystals) at a feeding rate of 30 5=190° C. and die=100° C., the load was processed and g/min. and using the same Screws as described in Example 45 extruded at an extrusion speed of 20 rpm to provide Form 1 and the barrel and die temperature settings of barrel 1=25 III-carbamazepine (stable crystals). C., barrel 2=155° C., barrel 3=155° C., barrel 4=155° C., barrel 5=50° C., and die=40 C., the load was processed and EXAMPLE 8 extruded at an extrusion speed of 100 rpm to provide 50 Form II-carbamazepine (metastable crystals) was fed to a homogeneous Form Y-indomethacin (stable crystals). twin-screw extruder (KEX-30S-20; manufactured by Kurimoto, Ltd.) equipped with a die having an orifice sized EXAMPLE 3 2 mm high and 10 mm wide at a feeding rate of 30 g/min. A twin-screw extruder (KEX-30S-20; manufactured by and using the same Screws as described in Example 1 and the Kurimoto, Ltd.) equipped with a die having an orifice 2 mm 55 barrel and die settings of barrel 1=25° C., barrel 2=150° C., high and 10 mm wide was fed with Form C-indomethacin barrel 3=150° C., barrel 4=150° C., barrel 5=150° C. and (metastable crystals) at a feeding rate of 20 g/min. had using die=100° C., the load was processed and extruded at an the same Screws as described in Example 1 and the barrel extrusion speed of 30 rpm to provide Form III and die temperature settings of barrel 1=25 C., barrel carbamazepine (stable crystals). 2=155° C., barrel 3=155° C., barrel 4=155° C. and barrel 60 5=20° C., and die=10 C., the load was processed and Test Example 1 extruded at an extrusion speed of 100 rpm to provide The crystals obtained in Example 1 were milled in a amorphous Solid indomethacin. mortar and the powder X-ray diffraction pattern of a Sample EXAMPLE 4 of the resultant finely divided powder (100 mesh pass) was 65 determined. It was found that, as shown in FIG. 3, the A twin-screw extruder (KEX-30S-20; manufactured by Starting Form C-indomethacin (metestable crystals) had Kurimoto, Ltd.) equipped with an orifice 2 mm high and 10 been converted to Form Y-indomethacin (stable crystals). 5,811,547 15 16 The identification of the powder X-ray diffraction patterns of of the resultant finely divided powder (100 mesh pass) was Form C- and Y-indomethacin samples shown in FIG. 3 was determined. It is apparent from FIG. 9 that Form made according to the report of H. Yamamoto: Chem. Pham. I-carbamazepine (metestable crystals) had been converted to Bull. (Tokyo), 16, 17 (1968). Form III-carbamazepine (stable crystals). Identification of the powder X-ray diffraction patterns of Form Test Example 2 I-carbamazepine and Form III- carbamazepine shown in The crystals obtained in Example 2 were milled in a FIG. 9 was made according to T. Umeda, Yakugaku Zasshi, mortar and the powder X-ray diffraction pattern of a Sample 104, 786 (1984). of the resultant finely divided powder (100 mesh pass) was Test Example 8 determined. It could be confirmed that, as shown in FIG. 4, the diffraction peaks assignable to Form C-indomethacin The crystals obtained in Example 8 were milled in a had disappeared from the diffraction pattern of Form mortar and the powder X-ray diffraction pattern of a Sample C-indomethacin (metastable crystals)-Form Y-indomethacin of the resultant finely divided powder (100 mesh pass) was (stable crystals) mixture, Suggesting the presence of Form determined. It is apparent from FIG. 10 that Form Y-indomethacin alone. Identification of the powder X-ray 15 II-carbamazepine (metestable crystals) had been converted diffraction patterns of Form C-indomethacin and Form to Form III-carbamazepine (stable crystals). Identification of Y-indomethacin shown in FIG. 4 was made according to the the powder X-ray diffraction patterns of Form report of H. Yamamoto, Chem. Pham. Bull. (Tokyo), 16, 17 II-carbamazepine and Form III-carbamazepine was made (1968). according to T. Umeda, Yakugaku Zasshi, 104, 786 (1984). Test Example 3 DETAILED DESCRIPTION OF THE DRAWINGS The Solid obtained in Example 3 was milled in a mortar FIG. 1 is a Schematic cross-section view showing the and the powder X-ray diffraction pattern of a Sample of the main part of a universal extruder, wherein 1, 2 and 3 resultant finely divided powder (100 mesh pass) was deter 25 represent a barrel Structure, a die, and a Screw, respectively. mined. As shown in FIG. 5, no diffraction peaks were FIG. 2 is a schematic view showing one embodiment of observed, indicating that Form a indomethacin (metestable the method of this invention, wherein A represents the crystals) had been converted to an amorphous Solid. crystalline State of a medicinal Substance prior to transition, X represents a molten state of the same Substance, and O Test Example 4 represents the crystalline State of Said Substance after tran The Solid obtained in Example 4 was milled in a mortar Sition and the reference numeral 4 represents the processing and the powder X-ray diffraction pattern of a Sample of the part of the extruder. resultant finely divided powder (100 mesh pass) was deter FIG. 3 shows powder X-ray diffraction patterns. The mined. As shown in FIG. 6, no diffraction peaks were abscissa represents the diffraction angle (20) and the ordi observed, indicating that Form C-indomethacin (stable 35 nate represents the diffraction intensity (CPS). The top view crystals) had been converted to an amorphous Solid. is the powder X-ray diffraction pattern of the Form Y-indomethacin obtained in Example 1. The bottom view is Test Example 5 the powder X-ray diffraction pattern of the Form C-indomethacin prior to the processing according to this The crystals obtained in Example 5 were milled in a 40 invention. mortar and the powder X-ray diffraction pattern of a Sample FIG. 4 shows powder X-ray diffraction patterns. The of the resultant finely divided powder (100 mesh pass) was abscissa represents the diffraction angle (20) and the ordi determined. As shown in FIG. 7, Form I-bromovalerylurea nate represents the diffraction intensity (CPS). The top view (metestable crystal) had been converted to Form is the powder X-ray diffraction pattern of the Form II-bromovalerylurea (stable crystals). Identification of the 45 powder X-ray diffraction patterns of Form Y-indomethacin obtained in Example 2 and the bottom view I-bromovalerylurea and Form II-bromovalerylurea shown in is the powder X-ray diffraction pattern of the Form C- and FIG. 7 was made according to the report of H. Kwada, Y-indomethacin mixture prior to the processing according to Chem. Pharm. Bull., 28, 1351 (1980). this invention. 50 FIG. 5 shows powder X-ray diffraction patterns. The Test Example 6 abscissa represents the diffraction angle (20) and the ordi nate represents the diffraction intensity (CPS). The top view The crystals obtained in Example 6 were milled in a is the powder X-ray diffraction pattern of the amorphous mortar and the powder X-ray diffraction pattern of a Sample solid indomethacin obtained in Example 3. The bottom view of the resultant finely divided powder (100 mesh pass) was 55 is the powder X-ray diffraction pattern of the Form determined. It is clear from FIG. 8 that the amorphous solid C-indomethacin prior to the processing according to this chloramphenicol palmitate had been converted to Form invention. C-chloramphenicol palmitate (metestable crystals). Identifi FIG. 6 shows powder X-ray diffraction patterns. The cation of the powder X-ray diffraction patterns of amor phous Solid chloramphenicol palmitate and Form abscissa represents the diffraction angle (20) and the ordi 60 nate represents the diffraction intensity (CPS). The top view C-chloramphenicol palmitate was made according to T. is the powder X-ray diffraction pattern of the amorphous Tamura, Yakugaku Zasshi, 81, 759 (1961) and Y. Tsuda, solid indomethacin obtained in Example 4. The bottom view Chem. Pharm. Bull., (Tokyo), 28,947 (1980). is the powder X-ray diffraction pattern of the Form Test Example 7 Y-indomethacin prior to the processing according to this 65 invention. The crystals obtained in Example 7 were milled in a FIG. 7 shows powder X-ray diffraction patterns. The mortar and the powder X-ray diffraction pattern of a Sample abscissa represents the diffraction angle (20) and the ordi 5,811,547 17 18 nate represents the diffraction intensity (CPS). The top view wherein Said extruder means further comprises a die, having is the powder X-ray diffraction pattern of the Form at least one orifice through which the medicinal Substance in II-bromovalerylurea obtained in Example 5. The bottom the Second crystalline State is extruded from the extruder view is the powder X-ray diffraction pattern of the Form means, and wherein the extruder means further comprises I-bromoValerylurea prior to the processing according to this 5 means for inducing the Second crystalline State of the invention. medicinal Substance in Said Second Zone to provide Said FIG. 8 shows powder X-ray diffraction patterns. The inducing of the Second crystalline State in the medicinal abscissa represents the diffraction angle (20) and the ordi Substance. nate represents the diffraction intensity (CPS). The top view 4. The method of claim 3, wherein said first crystalline is the powder X-ray diffraction pattern of the Form State is a metastable crystalline State or an amorphous Solid C-chloramphenicol palmitate obtained in Example 6. The State and Said Second crystalline State is a Stable crystalline bottom view is the powder X-ray diffraction pattern of the State. chloramphenicol palmitate (amorphous Solid) prior to the 5. The method of claim 3, wherein said first crystalline processing according to this invention. State is a Stable crystalline State or an amorphous Solid State FIG. 9 shows powder X-ray diffraction patterns. The 15 and Said Second crystalline State is a metastable crystalline abscissa represents the diffraction angle (20) and the ordi State. nate represents the diffraction intensity (CPS). The top view 6. The method of claim 3, wherein said first crystalline is the powder X-ray diffraction pattern of the Form III State is a stable or metastable crystalline State and Said carbamazepine obtained in Example 7. Second crystalline State is an amorphous Solid State. 7. The method of claim 3, wherein said first crystalline The bottom view is the powder X-ray diffraction pattern State is a heterogeneous crystalline State and Said Second of the Form I-carbamazepine prior to the processing accord crystalline State is a homogeneous crystalline State. ing to this invention. 8. The method of claim 3, wherein the medicinal Sub FIG. 10 shows powder X-ray diffraction patterns. The stance is Selected from the group consisting of general abscissa represents the diffraction angle (20) and the ordi 25 anesthetics, hipnotic/sedatives/antianxiety drugs, antiepilep nate represents the diffraction intensity (CPS). The top view tics, antipyretic/analgesic/antiinflammatory agents; is the powder X-ray diffraction pattern of the Form III analeptic/antihypnotic agents, antiparkinsonian drugs, carbamazepine obtained in Example 8. The bottom view is psychotropic/neurotropic drugs, CNS drugs, local anesthet the powder X-ray diffraction pattern of the Form ics, skeletal muscle relaxants, autonomic drugs, antispas II-carbamazepine prior to the processing according to this modics, antivertigo drugs, Sense organ drugs, cardiotonics, invention. antiarrhythmic drugs, diuretics, antihypertensive drugs, We claim: vasoconstrictors, vasodilators, cardiovascular drugs, respi 1. A method for inducing a transition from a first cryS ratory Stimulants, antituSSives, expectorants, brochodilators; talline State to a Second crystalline State in a crystallizable antidiarrheal drugs/drugs for controlling intestinal function; medicinal Substance, Said method comprising the Steps of: 35 peptic ulcer remedies, Stomachics/digestants, laxatives/ a) feeding said Substance, in the first crystalline State, into clysters, cholagogues, gastrointestinal drugs; thyroid/ extruder means having at least two separate tempera parathyroid hormone drugs, drugs, corti ture Zones, maintained at differing temperatures, with a coid drugs; male hormone drugs, estrogen/progestin drugs, first of Said Zones being maintained in a temperature hormone drugs other than thyroid/parathyroid hormone range Sufficient to melt the medicinal Substance in the 40 drugs, anabolic Steroid drugs, corticoid drugs, male hormone first crystalline State but below a decomposition tem drugs, and estrogen/progestin drugs, urinary tract drugs, perature thereof, and with the Second of Said tempera Oxytocics, Vitamins, hemostatics, anticoagulants, liver dis ture Zones being maintained in a temperature range ease remedies, antidotes, arthrifuges, antidiabetics, metabo below that of the first Zone and at a level whereby the lism drugs, antitumor drugs, antiallergic agents, antibiotics, Second crystalline State of the material is induced; 45 Sulfa drugs, antituberculosis drugs, antileprotics, Synthetic b) melting the Substance in the first crystalline State in said antimicrobial agents, antiviral agents, chemotherapeutic first Zone and continuously moving the melted Sub drugs, anthelmintics, and narcotics. stance from the first Zone to the Second Zone; 9. The method of claim 8, wherein said general anesthet c) inducing the Second crystalline State in the crystalliz ics are Selected from the group consisting of ketamine able Substance in Said Second Zone; and 50 hydrochloride, thiamylal Sodium, thiopental Sodium, d) extruding the Substance, in said Second crystalline droperidol, Said hipnotic/sedatives/antianxiety drugs are State, from the extruder means. Selected from the group consisting of amobarbital, 2. The method of claim 1, wherein said extruder means alprazolam, estaZolam, flurazepam hydrochloride, ril comprises a Single Screw extruder, wherein a Screw member maZafone hydrochloride, oxazepam, oxazolam, cloxazolam, effects the continuous moving of the medicinal Substance 55 clotiazepam, dipotassium, chlordiazepoxide, from the first Zone to the Second Zone, and wherein Said chlormeZanone, diazepam, Secobarbital Sodium, Zopiclone, extruder means further comprises a die, having at least one triazolam, triclofoS Sodium, nitrazepam, nimetazepam, orifice through which the medicinal Substance in the Second barbital, haloxazolam, phenobarbital, praZepam, crystalline State is extruded from the extruder means, and fluidiazepam, , flutoprazepam, flunitrazepam, wherein the extruder means further comprises means for 60 flurazepam, brotizolam, bromazepam, bromoValerylurea, inducing the Second crystalline State of the medicinal Sub heXobarbital, perlapine, pnetobarbiturate, midazolam, stance in Said Second Zone to provide Said inducing of the mexaZolan:, medazepam, ethyl loflazepate, lorazepam, Second crystalline State in the medicinal Substance. lormetazepam, Said antiepileptics are Selected from the 3. The method of claim 1, wherein said extruder means group consisting of acetylpheneturide, , comprises a twin Screw extruder, wherein intermeshed twin 65 ethotoin, carb amazepine, clonazepam, Sultiame, Screw members effect the continuous moving of the medici Zonisamide, trimethadione, Sodium valproate, phenytoin nal Substance from the first Zone to the Second Zone, and Sodium, primidone, metharbital, Said antipyretic/analgesic/ 5,811,547 19 20 antiinflammatory agents are Selected from the group con meSylate, methocarbamol, Said autonomic drugs are Selected Sisting of aspirin, aspirin DL-lysine, aspirin aluminum, from the group consisting of acetylcholine chloride, acetaminophen, acemetacin, alclofenac, , ambenonium chloride, carpronium chloride, troSpium amfenac Sodium, iSopropylantipyrine, ibuprofen, chloride, be thanechol chloride, oxyphen cyclimine indomethacin, indomethacin farnesil, ethen Zamide, hydrochloride, dicycloverin hydrochloride, tolazoline epirizole, emorfaZone, tiaramide hydrochloride, tinoridine hydrochloride, distigmine bromide, Valethamate bromide, hydrochloride, tramadol hydrochloride, buprenorphine pyridostigmine bromide, pri?inium bromide, propantheline hydrochloride, benzydamine hydrochloride, oxaprozin, bromide, mepenZolate bromide, tofisopam, aclatonium clofeZone, ketophenylbutaZone, ketoprofen, Sasapyrine, napadisilate, neoStigmine, oxapium iodide, diphenylpiperi Salicylamide, choline Salicylate, Sodium Salicylate, Saridon, dinomethyldioxolane iodide, Said are diclofenac Sodium, diflunisal, eptazocine hydrobromide, Selected from the group consisting of afloqualone, butorphanol tartrate, Sulindac, Sulpyrine, tiaprofenic acid, etomidoline, isoXSuprine hydrochloride, eperisone tenoxicam, tolfenamic acid, tolmetin Sodium, nabumetone, hydrochloride, tiZanidine hydrochloride, naproxen, Neo Vitacain, Neurotropin, bitoxin, piroXicam, hydrochloride, papaverine hydrochloride, phenacetin, phenylacetylglycine, phenylbutaZone, fenopro 15 hydrochloride, bromoethyl pipethanate, Scopolamine fen calcium, fenbufen, bucolome, pranoprofen, flufenamic hydrobromide, timepidium bromide, Valethamate bromide, acid, flufe namic acid aluminium, flurbiprofen, butylscopolamine bromide, atropine methobromide, flurbiprofenaxetil, floctafenine, pentazocine, proglumetacin anisotropine methobromide, benactyzium methobromide, maleate, migrenin, dimetotiazine mesilate, metiazinic acid, baclofen, flopropione, metyrapone, N-methyl-Scopolamine mefenamic acid, loxoprofen Sodium, lobenzarit disodium, methyl Sulfate, atropine Sulfate, Said antivertigo drugs are Said analeptic/antihypnotic agents are Selected from the Selected from the group consisting of isoprenaline group consisting of methamphetamine hydrochloride, hydrochloride, difenidol hydrochloride, meclizine bemegride, Said antiparkinsonian drugs are Selected from the hydrochloride, dimenhydrinate, thiethylperazine, promet group consisting of amantadine hydrochloride, trihex hazine theoclate and, betahistine meSylate, Said Sense organ yphenidyl hydrochloride, piroheptine hydrochloride, maza 25 drugs are Selected from the group consisting of oxymetazo ticol hydrochloride, methixene hydrochloride, droxidopa, line hydrochloride, tetrizoline, Said cardiotonics are Selected bipe riden, bromocriptine mesilate, levodopa, Said from the group consisting of 2-aminoethaneSulfonic acid, psychotropic/neurotropic drugs are Selected from the group aminophylline, caffeine-Sodium benzoate, etillefrine consisting of amoxapine, etizolam, amitriptyline hydrochloride, ephedrine hydrochloride, dopamine hydrochloride, hydrochloride, clocapramine hydrochloride, dobutamine hydrochloride, bucumolol dihydrochloride, hydrochloride, Safrazine hydrochloride, choline theophylline, diisobutylaminoben hydrochloride, hydrochloride, Zoyloxypropyl the ophylline, digitoxin, digoxin, hydrochloride, desipramine hydrochloride, doSulepin diprophylline, metaraminol bit artrate, deslanoside, hydrochloride, hydrochloride, triflu promazine denopamine, trans-U-OXOcamphor, bucladesine Sodium, hydrochloride, nortriptyline hydrochloride, hydroxyzine 35 proxyphylline, proscillaridin, besnalinone, metildigoxin, hydrochloride, pipamperone hydrochloride, pipradorol ubidecarenone, lanatoside C, Said antiarrhythmic drugs are hydrochloride, maprotiline hydrochloride, mianserin Selected from the group consisting of ajmaline, atenolol, hydrochloride, hydrochloride, acebutolol hydrochloride, aprindine hydrochloride, alpre mosapramine hydrochloride, moperone hydrochloride, nolol hydrochloride, arotinolol hydrochloride, indenolol lofepramine hydrochloride, oxypertine, carpipramine, 40 hydrochloride, Oxprenolol hydrochloride, carteolol clotiapine, chlorprothixene, chlorpromazine, thiopropera hydrochloride, pyrudicainide hydrochloride, bufetolol Zine dimethanSulfonate, Spiperone, Sulpiride, Zotepine, hydrochloride, bupranolol hydrochloride, procainamide tiotixene, timiperone, , nemonapride, hydrochloride, propafenone hydrochloride, propranolol hydroxy Zine pamoate, haloperidol, pimozide, fluphenazine, hydrochloride, befunolol hydrochloride, Verapamil prochlorpe razine, prope ricya Zine, bromazepam, 45 hydrochloride, mexiletine hydrochloride, cibenzoline bromperidol, pemoline, perphenazine, cetiprin maleate, tri Succinate, flecainide acetate, disopyramide, metoprolol fluoperazine maleate, trimipramine maleate, reserpine, tartrate, nadolol, pindolol, fumarate, timolol levomepromazine, Said CNS drugs are Selected from the maleate, quinidine Sulfate, Said diuretics are Selected from group consisting of idebenone, amantadine hydrochloride, the group consisting of acetazolamide, azosemide, indeloxazine hydrochloride, cyproheptadine hydrochloride, 50 isosorbide, etacrynic acid, ethiazide, , tiapride hydrochloride, bife melane hydrochloride, quine tha Zone, clofen amide, chlorthalidone, meclofenoxate hydrochloride, lefetamine hydrochloride, , Spironolactone, theoSalicin, triamterene, T-amino-3-hydroxybutyric acid, citicoline, protirelin trichlor me thia Zide, hydrochlor othiazide, tartrate, baclofen, propentofylline, calcium hopantenate, hydroflumethiazide, piretanide, , furosemide, maZindol, Said local anesthetics are Selected from the group 55 benzylhydrochlorothiazide, penflutizide, polythiazide, consisting of ethyl aminobenzoate, oxybuprocaine methyclothiazide, metolaZone, mefruSide, Said antihyperten hydrochloride, dibucaine hydrochloride, tetracaine Sive drugs are Selected from the group consisting of hydrochloride, p-butylaminobenzoyldiethyl aminoethanol alacepril, alseroxylon, indapamide, urapidil, amoSulalol hydrochloride, bupivacaine hydrochloride, procaine hydrochloride, carteolol hydrochloride, guanfacine hydrochloride, propitocaine hydrochloride, mepivacaine 60 hydrochloride, clonidine hydrochloride, diltiazem hydrochloride, oxethazaine, ethyl p-piperidinoacetyl hydrochloride, celiprolol hydrochloride, tilisolol aminobenzoate, lidocaine hydrochloride, Said Skeletal hydrochloride, teraZoSin hydrochloride, delapril muscle relaxants are Selected from the group consisting of hydrochloride, todralazine hydrochloride, nicardipine alcuronium chloride, Suxamethonium chloride, tubocurarine hydrochloride, hydralazine hydrochloride, bunaZosin chloride, , chlorZoxaZone, 65 hydrochloride, bunitrolol hydrochloride, prazosin chlorime Zanone, pancuronium bromide, Vecuronium hydrochloride, manidipine hydrochloride, labetalol bromide, dantrolene Sodium, phenprobamate, pridinol hydrochloride, dimethylaminoethyl reSerpilinate 5,811,547 21 22 dihydrochloride, cadralazine, captopril, trimetaphan lactomin, berberine Sulfate, Said peptic ulcer remedies are camsilate, guanabenz acetate, hexamethonium bromide, consisting of the group consisting of aceglutamide metoprolol tartrate, SilaZapuril, Syrosingopine, tripamide, aluminium, Sodium alginate, aldioxa, L-glutamine, cetraxate nadolol, nipradillol, nilvadipine, budralazine, enalapril hydrochloride, pirenzepine hydrochloride, ranitidine maleate, dihydroergotoxine meSylate, doxazosin meSylate, hydrochloride, hydrochloride, phentolamine mesilate, meticrane, methyldopa, Rauwopur, omeprazole, ornoprostil, chlophyllin S, gefarnate, Kolantyl, ricinopuril, guanethidine Sulfate, betanidine, Sulfate, penb cimetidine, Sucralfate, Sulpiride, Secretin, Sofalcone, utolol Sulfate, rescinnamine, reserpine, 2,6-dimethyl-4-(2- teprenone, troXipide, nizatidine, famotidine, plaunotol, nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4- proglumide, bergenin, irSogladine maleate, methylmethion dihydropyridine-3-carboxylate, Said vasoconstrictors are ine Sulfonium chloride, clebopride malate, levamipil, Said Selected from the group consisting of Stomachics/digestants are consisting of the group consisting hydrochloride, phenylephrine hydrochloride, midodrine of carnitine chloride, Said laxatives/clysters are consisting of hydrochloride, methoxamine hydrochloride, dihydroergota the group consisting of bisoxatin acetate, Sodium mine meSylate, Said vasodilators are Selected from the group picOSulfate, bisacodyl, lactulose, Said cholagogues are con consisting of inositol hexanicotinate, , isOXSuprine 15 Sisting of the group consisting of anetholtrithion, urSodes hydrochloride, etafenone hydrochloride, oxyfedrine Oxycholic acid, OSalmid, , dehydro hydrochloride, carbocromen hydrochloride, dilaZep , trepibutone, , Said gastrointestinal dihydrochloride, trimetazidine hydrochloride, valnidipine drugs are consisting of the group consisting of granisetron hydrochloride, Venidipine hydrochloride, Verapamil hydrochloride, cisapride, , hydrochloride, nicametate citrate, cyclandelate, pentaeryth tricaprilin, domperidone, fenipentol, trimebutine maleate, rityl tetranitrate, dipyridamole, isosorbide dinitrate, trapidil, metoclopramide, Said thyroid/parathyroid hormone drugs nicorandil, niSoldipine, nitrendipine, nife dipline, are consisting of the group consisting of thiamazole, hepronicate, bamethan Sulfate, t-ory Zanol, clinofibrate, propylthiouracil, liothyronine Sodium, levothyroXine clofibrate, aluminium clofibrate, cole Styramine, Sodium, Said anabolic Steroid drugs are consisting of the Symvastatin, Simfibrate, Soysterol, dextran Sulfate Sodium, 25 group consisting of ethylnandrol, oxymetholone, nandrolone nicomol, niceritrol, pravastatin Sodium, probucol, cyclohexane propionate, bolandiol dipropionate, Stanozolol, beZafibrate, polyenephosphatidylcholine, melinamide, ethyl , nandrolone phenylpropionate, linoleate, Said cardiovascular drugs are Selected from the furazabol, nandrolone furylpropionate, meStanolone, group consisting of argatroban, alproStadil, , fluna , Said corticoid drugs are consisting of the group rizine hydrochloride, meclofenoxate hydrochloride, moxi consisting of epinephrine, hydrocortisone Sodium Succinate, Sylyte hydrochloride, Sodium OZagrel, citicoline, ifenprodil prednisolone Sodium Succinate, , dexam tartrate, cinnarizine, cytochrome C, tocopherol nicotinate, ethasone acetate, triamcinolone diacetate, nicergoline, pyridinol carbamate, Vinpocetine, nizofenone acetate, halopredone acetate, hydrocortisone acetate, fluidro fumarate, brovincamine fumarate, bencyclane fumarate, cortisone acetate, prednisolone acetate, methylprednisolone pentoxifylline, calcium polystyrene Sulfonate, Sodium poly 35 acetate, dexamethasone, triamcinolone, norepinephrine, Styrene Sulfonate, cinepazide maleate, lisuride maleate, dexamethasone palmitate, hydrocortisone, prednisolone dihydroergotamine neSylate, ameZinium methyl Sulfate, butylacetate, prasterone Sodium Sulfate, prednisolone, limaprost C.-cyclodextrin clathrate, Said respiratory Stimu beclometaSone dipropionate, betamethasone, dexametha lants are Selected from the group consisting of dimefline Sone Sodium metasulfobenzoate, methylprednisolone, dex hydrochloride, doxapram hydrochrolide, naloxone 40 amethasone Sodium phosphate, hydrocortisone Sodium hydrochloride, hydrochloride, dimorpholamine, phosphate, prednisolone Sodium phosphate, betamethasone levallorphan tartrate, flumazenil, Said antituSSives are Sodium phosphate, Said male hormone drugs are consisting Selected from the group consisting of asdrin, clo?edanol of the group consisting of , hydrochloride, clobutinol hydrochloride, fominoben fluoxymesterone, , dromoStanolone hydrochloride, methylephedrine hydrochloride, isoaminile 45 propionate, methyltestosterone, Said estrogen/progestin citrate, oxeladin citrate, citrate, Chlophedrin drugs are consisting of the group consisting of , S, chloperastine, hydrochloride, OXeladin , estriol benzoyldiacetate, estriol, tannate, d1-methyle phe drine hydrochloride, ethinylestradiol, , hydroxyprogesteron dl-methylephedrine, noScapine, dimenorfan phosphate, caproate, , , medroX phosphate, Said expectorants are Selected from 50 y progestero ne acetate, dydrogesterone, estradiol the group consisting of N-Acetyl-L-cysteine, dipropionate, dimethisterone, , pregnanediol, hydrochloride, L-cysteine ethyl ester hydrochloride, brom progesterone, estriol tripropionate, foSfestrol, mestranol, he Xine hydrochloride, carbo cisteine, epra Zinone Said hormone drugs other than thyroid/parathyroid hormone hydrochloride, guaifenesin, hibenzate, codeine drugs, anabolic Steroid drugs, corticoid drugs, male hormone phosphate, dihydrocodeine phosphate, Said brochodilators 55 drugs, and estrogen/progestin drugs are consisting of the are Selected from the group consisting of epinephrine group consisting of epitioStanol, Oxendolone, clomifene hydrochloride, clenbuterol hydrochloride, clorprenaline citrate, glucagon, gemeprost, Octreotide acetate, goSerelin hydrochloride, tulobuterol hydrochloride, trimetoguinol acetate, gonadorelin acetate, , buSerelin hydrochloride, pirbuterol hydrochloride, procate rol acetate, leuprolerin acetate, cyclofenil, dinoprost, dinoprost hydrochloride, methoxyphenamine hydrochloride, Sodium 60 tromethamine, dinoprostone, danazol, triloStane, mitotane, cromoglycate, diprophylline, hydrobromide, mepitioStane, Said urinary tract drugs are consisting of the theophylline, formoterol fumarate, isoproterenol Sulfate, group consisting of oxybutynin hydrochloride, flavoxate orciprenaline Sulfate, Salbutamol Sulfate, Sulfate, hydrochloride, Paraprost, hexamine, Said oxytocicS are con heXoprenaline Sulfate, Said antidiarrheal drugs/drugs for Sisting of the group consisting of ergometrine maleate, controlling intestinal function are Selected from the group 65 methylergometrine maleate, Sparteine Sulfate, Said Vitamins consisting of berberine chloride, leperamide hydrochloride, are consisting of the group consisting of alfacalcidol, dimethicone, bismuth Subgallate, berberine tannate, etretinate, ergocalciferol, calcitriol, retinol acetate, 5,811,547 23 24 dihydrotachysterol, retinol palmitate, cetotiamine hydrochloride, demethylchlortetracycline hydrochloride, hydrochloride, thiamine hydrochloride, cocarboxylase, thia doxycycline hydrochloride, Vancomycin hydrochloride, piv mine nitrate, bisthiamine nitrate, thiamine disulfide, mecillinam hydrochloride, minocycline hydrochloride, lin bisi buthiamine, bis buty tiamine, bisb entiamine, comycin hydrochloride, carindacillin Sodium, carumonam furSultiamine, proSultiamine, benfotiamine, pyridoxine Sodium, clarithromycin, griseofulvin, clindamycin, cloxacil hydrochloride, cobamamide, hydroxocobalamin acetate, lin Sodium, chloramphenicol, chloram phenicol Sodium cyanocobalamin, nicotinic acid, nicotinamide, pantethine, Succinate, colistin Sodium methaneSulfonate, cycloSerine, mecobalamin, folic acid, riboflavin butyrate, riboflavin, midecamycin acetate ciclacillin, cefazolin Sodium, cefatriz pyridoxamine phosphate, pyridoxal phosphate, riboflavin ine propylene glycol, cefapirin Sodium, cefamandole Sodium phosphate, ascorbic acid, tocopherol calcium Sodium, cefalexin, cefalotin Sodium, cefaloridine, cefixime, Succinate, tocopherol acetate, phytonadione, menatetrenone, cefodizime Sodium, cefotaxime Sodium, cefdinir, cefuZonam biotin, Said hemostatics are consisting of the group consist Sodium, ceftazidime, ceftizOXime Sodium, cefteZole Sodium, ing of Sodium alginate, ethamsylate, carbazochrome, carba ceftriaXOne Sodium, cefSulodin Sodium, cefminoX Sodium, Zochrome Sodium Sulfonate, tranexamic acid, thrombin, cefradine, cefroXadine, cefuroxime axetil, cefuroxime adrenochrome monoaminoguanidine methaneSulfonate, Said 15 Sodium, tetracycline, Sultamicillin tosilate, chloramphenicol anticoagulants are consisting of the group consisting of palmitate, pheneticillin potassium, phenoxymethylpenic dipyridamole, dalteparin Sodium, heparin calcium, heparin illin potassium, flucloxacillin Sodium, josamycin Sodium, warfarin potassium, Said liver disease remedies are propionate, flucloxacillin Sodium, benzylpenicillin consisting of the group consisting of 2-AminoethaneSulfonic potassium, benzylpenicillin benzathine, fosfomycin, acid, glucuronolactone, glucuronamide, Sodium midecamycin, rifampicin, capreomycin Sulfate, Sisomicin glucuronate, cianidanol, diisopropylamine dichloroacetate, Sulfate, paromomycin Sulfate, loxythromycin, Said Sulfa thioctic acid, thioctic acid amide, tiopronin, protoporphyrin drugs are consisting of the group consisting of disodium, malotilate, Said antidotes are consisting of the acetylsulfamethoxazol, Sulfadimethoxine, Sulfamethizole, group consisting of calcium disodium edetate, glutathione, Sulf a methoxazole, Sulfame th opy r a Zine, penicillamine, deferoxamine mesilate, pralidoxime iodide, 25 Sulfamonomethoxine, Sulfisoxazole, Sulfisomidine, Said Said arthrifuges are consisting of the group consisting of antituberculosis drugs are consisting of the group consisting allopurinol, colchicine, Sulfin pyraZone, probe necid, of Isoniazid, isoniazid Sodium glucuronate, isoniazid benzbromarone, Said antidiabetics are consisting of the Sodium methan Sulfonate, ethionamide, ethambu tol group consisting of acetohexamide, buformine hydrochloride, pyrazinamide, Said antileprotics are consist hydrochloride, metformin hydrochloride, gliclaZide, ing of the group consisting of Sodium glucosulfone, glyclopyramide, glybuzole, glibenclamide, glymidine diaphenylsulfone, thiazoSulfone, Said Synthetic antimicro Sodium, chlorpropamide, tolaZamide, tolbutamide, Said bial agents are consisting of the group consisting of metabolism drugs are consisting of the group consisting of enoxacin, thiamphenicol glycinate hydrochloride, ciprof aZathioprine, adenosine triphosphate disodium, aprotinin, loxacin hydrochloride, lomefloxacin hydrochloride, ipriflavone, urinastatin, disodium etidronate, epalrestat, 35 ofloxacin, cinoxacin, thiamphenicol, tosfloxacin tosylate, elcatonin, L-cysteine, leVocarnitine chloride, Sapropterin nalidixic acid, norfloxacin, pipemidic acid trihydrate, hydrochloride, calcitonin, , Sodium 6-fluoro-1-methyl-7-4-(5-methyl-2-oxo-1,3-dioxolen-4-yl) glutamate, Sodium chondroitin Sulfate, ciclosporin, Sodium methylpipe razinyl)-4-oxo-4H1,3-thiaze to 3,2-a hyaluronate, mizoribine, gabeXate mesilate, camoStat quinoline-3-carboxylic acid, Said antiviral agents are con mesilate, nafamoStat mesilate, lactulose, Said antitumor 40 Sisting of the group consisting of aciclovir, ganciclovir, drugs are consisting of the group consisting of aceglatone, Zidanocin, Vidarabine, Said chemotherapeutic drugs are con ifosfamide, ubenime X, eno citabine, Sisting of the group consisting of inosine pranobeX, nalidixic hydrochloride, mitoxantrone hydrochloride, nitrogen mus acid, fluconazole, flucytosine, miconazole, Said anthelm tard N-oxide hydrochloride, nimustine hydrochloride, intics are consisting of the group consisting of kainic acid, carboquone, carboplatin, carmofur, tamoxifen citrate, 45 diethylcarb amazine citrate, Santonin, bithionol, cyclophosphamide, cisplatin, cytarabine, Sizofiran, praziquantel, piperazine phosphate, and Said narcotics are dacarbazine, thiotepa, thioinosine, tegafur, improSulfan Selected from the group consisting of ethylmorphine tosilate, doxifluridine, hydroxycarbamide, fluorouracil, hydrochloride, cocaine hydrochloride, morphine buSulfan, mitobronitol, melphalan, methotrexate, hydrochloride, Oximetebanol, fentanyl citrate, morphine mercaptopurine, ranimustine, estramustine Sodium 50 Sulfate, codeine phosphate, dihydrocodeine phosphate. phosphate, lentinan, Said antiallergic agents are consisting of 10. The method of claim 9, wherein said medicinal the group consisting of amle XanoX, a Zelastine Substance is Selected from the group consisting of hydrochloride, isothipendyl hydrochloride, iproheptine indomethacin, bromoValery lurea, chloramphenicol hydrochloride, OZagrel hydrochloride, diphenylpyraline palmitate, and carbamazepine. hydrochloride, diphenhydramine hydrochloride, cyprohep 55 11. The method of claim 3, wherein the means for tadine hydrochloride, triprolidine hydrochloride, promet inducing the Second crystalline State comprises the inter hazine hydrochloride, homochlorcyclizine hydrochloride, meshing of the twin Screw members whereby there is a high , glycyrrhizin, Sodium cromoglycate, alime energy physical output in Shearing and blending the medici mazine tartrate, taZanolast, diphenhydramine tannate, diphe nal Substance. nylpyraline teoclate, terfenadine, tranilast, pemirolast 60 12. The method of claim 11, wherein said means for potassium, fumarate, chlorpheniramine maleate, inducing the Second crystalline State members further dimethindene maleate, meduitazine, Said antibiotics are con includes at least one kneading paddle, extending between Sisting of the group consisting of aspoxicillin, aztreonam, Said twin ScrewS Such that the medicinal Substance is com acetylkitasamycin, amoxicillin, amplicillin, erythromycin pounded thereby to facilitate effecting the inducing of the eStolate, Spectinomycin hydrochloride, Oxytetracycline 65 Second crystalline State. hydrochloride, cefotiam dihydrochloride, cefotiam hexetil hydrochloride, cefimenoXime hydrochloride, tetracycline k k k k k