Method for inducing crystalline state transition in medicinal substance

• US 5,811,547 A
• Filed: 06/09/1995
• Issued: 09/22/1998
• Est. Priority Date: 10/14/1992
• Status: Expired due to Fees

• Current Assignee: Nippon Shinyaku Company Limited
• Original Assignee: Nippon Shinyaku Company Limited
• Inventors: Oka, Masaaki, Izumi, Shougo, Nakamichi, Kouichi
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): WONG, KING
• Application Number:
  US08/416,815
• Time in Patent Office: 1,201 Days
• Field of Search: 548/500, 564/45, 564/213, 540/589
• US Class Current: 540/589
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51

Abstract

This invention has for its object to provide a method of inducing a transition in crystalline state of a crystallizable medicinal substance with great ease and improved efficiency and uniformity on a high production scale. According to the invention, an extruder is used for inducing a transition from one crystalline state (Δ) to another crystalline state in a crystallizable medicinal substance.

Claims

1. A method for inducing a transition from a first crystalline state to a second crystalline state in a crystallizable medicinal substance, said method comprising the steps of:

a) feeding said substance, in the first crystalline state, into extruder means having at least two separate temperature zones, maintained at differing temperatures, with a first of said zones being maintained in a temperature range sufficient to melt the medicinal substance in the first crystalline state but below a decomposition temperature thereof, and with the second of said temperature zones being maintained in a temperature range below that of the first zone and at a level whereby the second crystalline state of the material is induced;

b) melting the substance in the first crystalline state in said first zone and continuously moving the melted substance from the first zone to the second zone;

c) inducing the second crystalline state in the crystallizable substance in said second zone; and

d) extruding the substance, in said second crystalline state, from the extruder means.

2. The method of claim 1, wherein said extruder means comprises a single screw extruder, wherein a screw member effects the continuous moving of the medicinal substance from the first zone to the second zone, and wherein said extruder means further comprises a die, having at least one orifice through which the medicinal substance in the second crystalline state is extruded from the extruder means, and wherein the extruder means further comprises means for inducing the second crystalline state of the medicinal substance in said second zone to provide said inducing of the second crystalline state in the medicinal substance.

3. The method of claim 1, wherein said extruder means comprises a twin screw extruder, wherein intermeshed twin screw members effect the continuous moving of the medicinal substance from the first zone to the second zone, and wherein said extruder means further comprises a die, having at least one orifice through which the medicinal substance in the second crystalline state is extruded from the extruder means, and wherein the extruder means further comprises means for inducing the second crystalline state of the medicinal substance in said second zone to provide said inducing of the second crystalline state in the medicinal substance.

4. The method of claim 3, wherein said first crystalline state is a metastable crystalline state or an amorphous solid state and said second crystalline state is a stable crystalline state.

5. The method of claim 3, wherein said first crystalline state is a stable crystalline state or an amorphous solid state and said second crystalline state is a metastable crystalline state.

6. The method of claim 3, wherein said first crystalline state is a stable or metastable crystalline state and said second crystalline state is an amorphous solid state.

7. The method of claim 3, wherein said first crystalline state is a heterogeneous crystalline state and said second crystalline state is a homogeneous crystalline state.

8. The method of claim 3, wherein the medicinal substance is selected from the group consisting of general anesthetics;

hipnotic/sedatives/antianxiety drugs;

antiepileptics;

antipyretic/analgesic/antiinflammatory agents;

analeptic/antihypnotic agents;

antiparkinsonian drugs;

psychotropic/neurotropic drugs;

CNS drugs;

local anesthetics;

skeletal muscle relaxants;

autonomic drugs;

antispasmodics;

antivertigo drugs;

sense organ drugs;

cardiotonics;

antiarrhythmic drugs;

diuretics;

antihypertensive drugs;

vasoconstrictors;

vasodilators;

cardiovascular drugs;

respiratory stimulants;

antitussives;

expectorants;

brochodilators;

antidiarrheal drugs/drugs for controlling intestinal function;

peptic ulcer remedies;

stomachics/digestants;

laxatives/clysters;

cholagogues;

gastrointestinal drugs;

thyroid/parathyroid hormone drugs;

anabolic steroid drugs;

corticoid drugs;

male hormone drugs;

estrogen/progestin drugs;

hormone drugs other than thyroid/parathyroid hormone drugs, anabolic steroid drugs, corticoid drugs, male hormone drugs, and estrogen/progestin drugs;

urinary tract drugs;

oxytocics;

vitamins;

hemostatics;

anticoagulants;

liver disease remedies;

antidotes;

arthrifuges;

antidiabetics;

metabolism drugs;

antitumor drugs;

antiallergic agents;

antibiotics;

sulfa drugs;

antituberculosis drugs;

antileprotics;

synthetic antimicrobial agents;

antiviral agents;

chemotherapeutic drugs;

anthelmintics; and

narcotics.

9. The method of claim 8, wherein said general anesthetics are selected from the group consisting of ketamine hydrochloride, thiamylal sodium, thiopental sodium, droperidol, said hipnotic/sedatives/antianxiety drugs are selected from the group consisting of amobarbital, alprazolam, estazolam, flurazepam hydrochloride, rilmazafone hydrochloride, oxazepam, oxazolam, cloxazolam, clotiazepam, clorazepate dipotassium, chlordiazepoxide, chlormezanone, diazepam, secobarbital sodium, zopiclone, triazolam, triclofos sodium, nitrazepam, nimetazepam, barbital, haloxazolam, phenobarbital, prazepam, fludiazepam, flutazolam, flutoprazepam, flunitrazepam, flurazepam, brotizolam, bromazepam, bromovalerylurea, hexobarbital, perlapine, pnetobarbiturate, midazolam, mexazolan:

, medazepam, ethyl loflazepate, lorazepam, lormetazepam, said antiepileptics are selected from the group consisting of acetylpheneturide, ethosuximide, ethotoin, carbamazepine, clonazepam, sultiame, zonisamide, trimethadione, sodium valproate, phenytoin sodium, primidone, metharbital, said antipyretic/analgesic/antiinflammatory agents are selected from the group consisting of aspirin, aspirin DL-lysine, aspirin aluminum, acetaminophen, acemetacin, alclofenac, alminoprofen, amfenac sodium, isopropylantipyrine, ibuprofen, indomethacin, indomethacin farnesil, ethenzamide, epirizole, emorfazone, tiaramide hydrochloride, tinoridine hydrochloride, tramadol hydrochloride, buprenorphine hydrochloride, benzydamine hydrochloride, oxaprozin, clofezone, ketophenylbutazone, ketoprofen, sasapyrine, salicylamide, choline salicylate, sodium salicylate, Saridon, diclofenac sodium, diflunisal, eptazocine hydrobromide, butorphanol tartrate, sulindac, sulpyrine, tiaprofenic acid, tenoxicam, tolfenamic acid, tolmetin sodium, nabumetone, naproxen, Neo vitacain, Neurotropin, bitoxin, piroxicam, phenacetin, phenylacetylglycine, phenylbutazone, fenoprofen calcium, fenbufen, bucolome, pranoprofen, flufenamic acid, flufenamic acid aluminium, flurbiprofen, flurbiprofenaxetil, floctafenine, pentazocine, proglumetacin maleate, migrenin, dimetotiazine mesilate, metiazinic acid, mefenamic acid, loxoprofen sodium, lobenzarit disodium, said analeptic/antihypnotic agents are selected from the group consisting of methamphetamine hydrochloride, bemegride, said antiparkinsonian drugs are selected from the group consisting of amantadine hydrochloride, trihexyphenidyl hydrochloride, piroheptine hydrochloride, mazaticol hydrochloride, methixene hydrochloride, droxidopa, biperiden, bromocriptine mesilate, levodopa, said psychotropic/neurotropic drugs are selected from the group consisting of amoxapine, etizolam, amitriptyline hydrochloride, imipramine hydrochloride, clocapramine dihydrochloride, clomipramine hydrochloride, safrazine hydrochloride, sultopride hydrochloride, thioridazine hydrochloride, desipramine hydrochloride, dosulepin hydrochloride, trazodone hydrochloride, triflupromazine hydrochloride, nortriptyline hydrochloride, hydroxyzine hydrochloride, pipamperone hydrochloride, pipradorol hydrochloride, maprotiline hydrochloride, mianserin hydrochloride, methylphenidate hydrochloride, mosapramine hydrochloride, moperone hydrochloride, lofepramine hydrochloride, oxypertine, carpipramine, clotiapine, chlorprothixene, chlorpromazine, thioproperazine dimethansulfonate, spiperone, sulpiride, zotepine, tiotixene, timiperone, haloperidol decanoate, nemonapride, hydroxyzine pamoate, haloperidol, pimozide, fluphenazine, prochlorperazine, propericyazine, bromazepam, bromperidol, pemoline, perphenazine, cetiprin maleate, trifluoperazine maleate, trimipramine maleate, reserpine, levomepromazine, said CNS drugs are selected from the group consisting of idebenone, amantadine hydrochloride, indeloxazine hydrochloride, cyproheptadine hydrochloride, tiapride hydrochloride, bifemelane hydrochloride, meclofenoxate hydrochloride, lefetamine hydrochloride, τ

-amino-β

-hydroxybutyric acid, citicoline, protirelin tartrate, baclofen, propentofylline, calcium hopantenate, mazindol, said local anesthetics are selected from the group consisting of ethyl aminobenzoate, oxybuprocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, p-butylaminobenzoyldiethyl aminoethanol hydrochloride, bupivacaine hydrochloride, procaine hydrochloride, propitocaine hydrochloride, mepivacaine hydrochloride, oxethazaine, ethyl p-piperidinoacetyl aminobenzoate, lidocaine hydrochloride, said skeletal muscle relaxants are selected from the group consisting of alcuronium chloride, suxamethonium chloride, tubocurarine chloride, chlorphenesin carbamate, chlorzoxazone, chlormezanone, pancuronium bromide, vecuronium bromide, dantrolene sodium, phenprobamate, pridinol mesylate, methocarbamol, said autonomic drugs are selected from the group consisting of acetylcholine chloride, ambenonium chloride, carpronium chloride, trospium chloride, bethanechol chloride, oxyphencyclimine hydrochloride, dicycloverin hydrochloride, tolazoline hydrochloride, distigmine bromide, valethamate bromide, pyridostigmine bromide, prifinium bromide, propantheline bromide, mepenzolate bromide, tofisopam, aclatonium napadisilate, neostigmine, oxapium iodide, diphenylpiperidinomethyldioxolane iodide, said antispasmodics are selected from the group consisting of afloqualone, etomidoline, isoxsuprine hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, tolperisone hydrochloride, papaverine hydrochloride, piperidolate hydrochloride, bromoethyl pipethanate, scopolamine hydrobromide, timepidium bromide, valethamate bromide, butylscopolamine bromide, atropine methobromide, anisotropine methobromide, benactyzium methobromide, baclofen, flopropione, metyrapone, N-methyl-scopolamine methyl sulfate, atropine sulfate, said antivertigo drugs are selected from the group consisting of isoprenaline hydrochloride, difenidol hydrochloride, meclizine hydrochloride, dimenhydrinate, thiethylperazine, promethazine theoclate and, betahistine mesylate, said sense organ drugs are selected from the group consisting of oxymetazoline hydrochloride, tetrizoline, said cardiotonics are selected from the group consisting of 2-aminoethanesulfonic acid, aminophylline, caffeine-sodium benzoate, etilefrine hydrochloride, ephedrine hydrochloride, dopamine hydrochloride, dobutamine hydrochloride, bucumolol hydrochloride, choline theophylline, diisobutylaminobenzoyloxypropyl theophylline, digitoxin, digoxin, diprophylline, metaraminol bitartrate, deslanoside, denopamine, trans-π

-oxocamphor, bucladesine sodium, proxyphylline, proscillaridin, besnalinone, metildigoxin, ubidecarenone, lanatoside C, said antiarrhythmic drugs are selected from the group consisting of ajmaline, atenolol, acebutolol hydrochloride, aprindine hydrochloride, alprenolol hydrochloride, arotinolol hydrochloride, indenolol hydrochloride, oxprenolol hydrochloride, carteolol hydrochloride, pyrudicainide hydrochloride, bufetolol hydrochloride, bupranolol hydrochloride, procainamide hydrochloride, propafenone hydrochloride, propranolol hydrochloride, befunolol hydrochloride, verapamil hydrochloride, mexiletine hydrochloride, cibenzoline succinate, flecainide acetate, disopyramide, metoprolol tartrate, nadolol, pindolol, bisoprolol fumarate, timolol maleate, quinidine sulfate, said diuretics are selected from the group consisting of acetazolamide, azosemide, isosorbide, etacrynic acid, ethiazide, potassium canrenoate, quinethazone, clofenamide, chlorthalidone, cyclopenthiazide, spironolactone, theosalicin, triamterene, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, piretanide, bumetanide, furosemide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide, metolazone, mefruside, said antihypertensive drugs are selected from the group consisting of alacepril, alseroxylon, indapamide, urapidil, amosulalol hydrochloride, carteolol hydrochloride, guanfacine hydrochloride, clonidine hydrochloride, diltiazem hydrochloride, celiprolol hydrochloride, tilisolol hydrochloride, terazosin hydrochloride, delapril hydrochloride, todralazine hydrochloride, nicardipine hydrochloride, hydralazine hydrochloride, bunazosin hydrochloride, bunitrolol hydrochloride, prazosin hydrochloride, manidipine hydrochloride, labetalol hydrochloride, dimethylaminoethyl reserpilinate dihydrochloride, cadralazine, captopril, trimetaphan camsilate, guanabenz acetate, hexamethonium bromide, metoprolol tartrate, silazapuril, syrosingopine, tripamide, nadolol, nipradilol, nilvadipine, budralazine, enalapril maleate, dihydroergotoxine mesylate, doxazosin mesylate, phentolamine mesilate, meticrane, methyldopa, Rauwopur, ricinopuril, guanethidine sulfate, betanidine, sulfate, penbutolol sulfate, rescinnamine, reserpine, 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate, said vasoconstrictors are selected from the group consisting of norfenefrine hydrochloride, phenylephrine hydrochloride, midodrine hydrochloride, methoxamine hydrochloride, dihydroergotamine mesylate, said vasodilators are selected from the group consisting of inositol hexanicotinate, efloxate, isoxsuprine hydrochloride, etafenone hydrochloride, oxyfedrine hydrochloride, carbocromen hydrochloride, dilazep dihydrochloride, trimetazidine hydrochloride, valnidipine hydrochloride, venidipine hydrochloride, verapamil hydrochloride, nicametate citrate, cyclandelate, pentaerythrityl tetranitrate, dipyridamole, isosorbide dinitrate, trapidil, nicorandil, nisoldipine, nitrendipine, nifedipine, hepronicate, bamethan sulfate, τ

-oryzanol, clinofibrate, clofibrate, aluminium clofibrate, colestyramine, symvastatin, simfibrate, soysterol, dextran sulfate sodium, nicomol, niceritrol, pravastatin sodium, probucol, bezafibrate, polyenephos phatidylcholine, melinamide, ethyl linoleate, said cardiovascular drugs are selected from the group consisting of argatroban, alprostadil, ibudilast, flunarizine hydrochloride, meclofenoxate hydrochloride, moxisylyte hydrochloride, sodium ozagrel, citicoline, ifenprodil tartrate, cinnarizine, cytochrome C, tocopherol nicotinate, nicergoline, pyridinol carbamate, vinpocetine, nizofenone fumarate, brovincamine fumarate, bencyclane fumarate, pentoxifylline, calcium polystyrene sulfonate, sodium polystyrene sulfonate, cinepazide maleate, lisuride maleate, dihydroergotamine nesylate, amezinium methyl sulfate, limaprost α

-cyclodextrin clathrate, said respiratory stimulants are selected from the group consisting of dimefline hydrochloride, doxapram hydrochrolide, naloxone hydrochloride, lobeline hydrochloride, dimorpholamine, levallorphan tartrate, flumazenil, said antitussives are selected from the group consisting of asdrin, clofedanol hydrochloride, clobutinol hydrochloride, fominoben hydrochloride, methylephedrine hydrochloride, isoaminile citrate, oxeladin citrate, pentoxyverine citrate, Chlophedrin S, chloperastine, dextromethorphan hydrochloride, oxeladin tannate, dl-methylephedrine hydrochloride, dl-methylephedrine, noscapine, dimemorfan phosphate, benproperine phosphate, said expectorants are selected from the group consisting of N-Acetyl-L-cysteine, ambroxol hydrochloride, L-cysteine ethyl ester hydrochloride, bromhexine hydrochloride, carbocisteine, eprazinone hydrochloride, guaifenesin, tipepidine hibenzate, codeine phosphate, dihydrocodeine phosphate, said brochodilators are selected from the group consisting of epinephrine hydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride, tulobuterol hydrochloride, trimetoguinol hydrochloride, pirbuterol hydrochloride, procaterol hydrochloride, methoxyphenamine hydrochloride, sodium cromoglycate, diprophylline, fenoterol hydrobromide, theophylline, formoterol fumarate, isoproterenol sulfate, orciprenaline sulfate, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, said antidiarrheal drugs/drugs for controlling intestinal function are selected from the group consisting of berberine chloride, leperamide hydrochloride, dimethicone, bismuth subgallate, berberine tannate, lactomin, berberine sulfate, said peptic ulcer remedies are consisting of the group consisting of aceglutamide aluminium, sodium alginate, aldioxa, L-glutamine, cetraxate hydrochloride, pirenzepine hydrochloride, ranitidine hydrochloride, roxatidine acetate hydrochloride, omeprazole, ornoprostil, chlophyllin S, gefarnate, Kolantyl, cimetidine, sucralfate, sulpiride, secretin, sofalcone, teprenone, troxipide, nizatidine, famotidine, plaunotol, proglumide, bergenin, irsogladine maleate, methylmethionine sulfonium chloride, clebopride malate, levamipil, said stomachics/digestants are consisting of the group consisting of carnitine chloride, said laxatives/clysters are consisting of the group consisting of bisoxatin acetate, sodium picosulfate, bisacodyl, lactulose, said cholagogues are consisting of the group consisting of anetholtrithion, ursodesoxycholic acid, osalmid, chenodeoxycholic acid, dehydrocholic acid, trepibutone, hymecromone, said gastrointestinal drugs are consisting of the group consisting of granisetron hydrochloride, cisapride, triamcinolone acetonide, tricaprilin, domperidone, fenipentol, trimebutine maleate, metoclopramide, said thyroid/parathyroid hormone drugs are consisting of the group consisting of thiamazole, propylthiouracil, liothyronine sodium, levothyroxine sodium, said anabolic steroid drugs are consisting of the group consisting of ethylnandrol, oxymetholone, nandrolone cyclohexane propionate, bolandiol dipropionate, stanozolol, nandrolone decanoate, nandrolone phenylpropionate, furazabol, nandrolone furylpropionate, mestanolone, metenolone, said corticoid drugs are consisting of the group consisting of epinephrine, hydrocortisone sodium succinate, prednisolone sodium succinate, cortisone acetate, dexamethasone acetate, triamcinolone diacetate, paramethasone acetate, halopredone acetate, hydrocortisone acetate, fludrocortisone acetate, prednisolone acetate, methylprednisolone acetate, dexamethasone, triamcinolone, norepinephrine, dexamethasone palmitate, hydrocortisone, prednisolone butylacetate, prasterone sodium sulfate, prednisolone, beclometasone dipropionate, betamethasone, dexamethasone sodium metasulfobenzoate, methylprednisolone, dexamethasone sodium phosphate, hydrocortisone sodium phosphate, prednisolone sodium phosphate, betamethasone sodium phosphate, said male hormone drugs are consisting of the group consisting of testosterone enanthate, fluoxymesterone, testosterone propionate, dromostanolone propionate, methyltestosterone, said estrogen/progestin drugs are consisting of the group consisting of allylestrenol, estradiol benzoate, estriol benzoyldiacetate, estriol, ethinylestradiol, gestonorone caproate, hydroxyprogesteron caproate, estradiol valerate, chlormadinone acetate, medroxyprogestero ne acetate, dydrogesterone, estradiol dipropionate, dimethisterone, norethisterone, pregnanediol, progesterone, estriol tripropionate, fosfestrol, mestranol, said hormone drugs other than thyroid/parathyroid hormone drugs, anabolic steroid drugs, corticoid drugs, male hormone drugs, and estrogen/progestin drugs are consisting of the group consisting of epitiostanol, oxendolone, clomifene citrate, glucagon, gemeprost, octreotide acetate, goserelin acetate, gonadorelin acetate, cyproterone acetate, buserelin acetate, leuprolerin acetate, cyclofenil, dinoprost, dinoprost tromethamine, dinoprostone, danazol, trilostane, mitotane, mepitiostane, said urinary tract drugs are consisting of the group consisting of oxybutynin hydrochloride, flavoxate hydrochloride, Paraprost, hexamine, said oxytocics are consisting of the group consisting of ergometrine maleate, methylergometrine maleate, sparteine sulfate, said vitamins are consisting of the group consisting of alfacalcidol, etretinate, ergocalciferol, calcitriol, retinol acetate, dihydrotachysterol, retinol palmitate, cetotiamine hydrochloride, thiamine hydrochloride, cocarboxylase, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, bisibuthiamine, bisbutytiamine, bisbentiamine, fursultiamine, prosultiamine, benfotiamine, pyridoxine hydrochloride, cobamamide, hydroxocobalamin acetate, cyanocobalamin, nicotinic acid, nicotinamide, pantethine, mecobalamin, folic acid, riboflavin butyrate, riboflavin, pyridoxamine phosphate, pyridoxal phosphate, riboflavin sodium phosphate, ascorbic acid, tocopherol calcium succinate, tocopherol acetate, phytonadione, menatetrenone, biotin, said hemostatics are consisting of the group consisting of sodium alginate, ethamsylate, carbazochrome, carbazochrome sodium sulfonate, tranexamic acid, thrombin, adrenochrome monoaminoguanidine methanesulfonate, said anticoagulants are consisting of the group consisting of dipyridamole, dalteparin sodium, heparin calcium, heparin sodium, warfarin potassium, said liver disease remedies are consisting of the group consisting of 2-Aminoethanesulfonic acid, glucuronolactone, glucuronamide, sodium glucuronate, cianidanol, diisopropylamine dichloroacetate, thioctic acid, thioctic acid amide, tiopronin, protoporphyrin disodium, malotilate, said antidotes are consisting of the group consisting of calcium disodium edetate, glutathione, penicillamine, deferoxamine mesilate, pralidoxime iodide, said arthrifuges are consisting of the group consisting of allopurinol, colchicine, sulfinpyrazone, probenecid, benzbromarone, said antidiabetics are consisting of the group consisting of acetohexamide, buformine hydrochloride, metformin hydrochloride, gliclazide, glyclopyramide, glybuzole, glibenclamide, glymidine sodium, chlorpropamide, tolazamide, tolbutamide, said metabolism drugs are consisting of the group consisting of azathioprine, adenosine triphosphate disodium, aprotinin, ipriflavone, urinastatin, disodium etidronate, epalrestat, elcatonin, L-cysteine, levocarnitine chloride, sapropterin hydrochloride, calcitonin, arginine glutamate, sodium glutamate, sodium chondroitin sulfate, ciclosporin, sodium hyaluronate, mizoribine, gabexate mesilate, camostat mesilate, nafamostat mesilate, lactulose, said antitumor drugs are consisting of the group consisting of aceglatone, ifosfamide, ubenimex, enocitabine, procarbazine hydrochloride, mitoxantrone hydrochloride, nitrogen mustard N-oxide hydrochloride, nimustine hydrochloride, carboquone, carboplatin, carmofur, tamoxifen citrate, cyclophosphamide, cisplatin, cytarabine, sizofiran, dacarbazine, thiotepa, thioinosine, tegafur, improsulfan tosilate, doxifluridine, hydroxycarbamide, fluorouracil, busulfan, mitobronitol, melphalan, methotrexate, mercaptopurine, ranimustine, estramustine sodium phosphate, lentinan, said antiallergic agents are consisting of the group consisting of amlexanox, azelastine hydrochloride, isothipendyl hydrochloride, iproheptine hydrochloride, ozagrel hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, cyproheptadine hydrochloride, triprolidine hydrochloride, promethazine hydrochloride, homochlorcyclizine hydrochloride, oxatomide, glycyrrhizin, sodium cromoglycate, alimemazine tartrate, tazanolast, diphenhydramine tannate, diphenylpyraline teoclate, terfenadine, tranilast, pemirolast potassium, clemastine fumarate, chlorpheniramine maleate, dimethindene maleate, mequitazine, said antibiotics are consisting of the group consisting of aspoxicillin, aztreonam, acetylkitasamycin, amoxicillin, ampicillin, erythromycin estolate, spectinomycin hydrochloride, oxytetracycline hydrochloride, cefotiam dihydrochloride, cefotiam hexetil hydrochloride, cefmenoxime hydrochloride, tetracycline hydrochloride, demethylchlortetracycline hydrochloride, doxycycline hydrochloride, vancomycin hydrochloride, pivmecillinam hydrochloride, minocycline hydrochloride, lincomycin hydrochloride, carindacillin sodium, carumonam sodium, clarithromycin, griseofulvin, clindamycin, cloxacillin sodium, chloramphenicol, chloram phenicol sodium succinate, colistin sodium methanesulfonate, cycloserine, midecamycin acetate ciclacillin, cefazolin sodium, cefatrizine propylene glycol, cefapirin sodium, cefamandole sodium, cefalexin, cefalotin sodium, cefaloridine, cefixime, cefodizime sodium, cefotaxime sodium, cefdinir, cefuzonam sodium, ceftazidime, ceftizoxime sodium, ceftezole sodium, ceftriaxone sodium, cefsulodin sodium, cefminox sodium, cefradine, cefroxadine, cefuroxime axetil, cefuroxime sodium, tetracycline, sultamicillin tosilate, chloramphenicol palmitate, pheneticillin potassium, phenoxymethylpenic illin potassium, flucloxacillin sodium, josamycin propionate, flucloxacillin sodium, benzylpenicillin potassium, benzylpenicillin benzathine, fosfomycin, midecamycin, rifampicin, capreomycin sulfate, sisomicin sulfate, paromomycin sulfate, loxythromycin, said sulfa drugs are consisting of the group consisting of acetylsulfamethoxazol, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfamethopyrazine, sulfamonomethoxine, sulfisoxazole, sulfisomidine, said antituberculosis drugs are consisting of the group consisting of Isoniazid, isoniazid sodium glucuronate, isoniazid sodium methansulfonate, ethionamide, ethambutol hydrochloride, pyrazinamide, said antileprotics are consisting of the group consisting of sodium glucosulfone, diaphenylsulfone, thiazosulfone, said synthetic antimicrobial agents are consisting of the group consisting of enoxacin, thiamphenicol glycinate hydrochloride, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, ofloxacin, cinoxacin, thiamphenicol, tosfloxacin tosylate, nalidixic acid, norfloxacin, pipemidic acid trihydrate, 6-fluoro-1-methyl-7- 4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylpiperazinyl!-4-oxo-4H 1,3!-thiazeto 3,2-a!quinoline-3-carboxylic acid, said antiviral agents are consisting of the group consisting of aciclovir, ganciclovir, zidanocin, vidarabine, said chemotherapeutic drugs are consisting of the group consisting of inosine pranobex, nalidixic acid, fluconazole, flucytosine, miconazole, said anthelmintics are consisting of the group consisting of kainic acid, diethylcarbamazine citrate, santonin, bithionol, praziquantel, piperazine phosphate, and said narcotics are selected from the group consisting of ethylmorphine hydrochloride, cocaine hydrochloride, morphine hydrochloride, oximetebanol, fentanyl citrate, morphine sulfate, codeine phosphate, dihydrocodeine phosphate.

10. The method of claim 9, wherein said medicinal substance is selected from the group consisting of indomethacin, bromovalerylurea, chloramphenicol palmitate, and carbamazepine.

11. The method of claim 3, wherein the means for inducing the second crystalline state comprises the intermeshing of the twin screw members whereby there is a high energy physical output in shearing and blending the medicinal substance.

12. The method of claim 11, wherein said means for inducing the second crystalline state members further includes at least one kneading paddle, extending between said twin screws such that the medicinal substance is compounded thereby to facilitate effecting the inducing of the second crystalline state.