Plastic and nonmetallic article shaping or treating: processes – Utilizing special inert gaseous atmosphere or flushing mold...
Reexamination Certificate
2000-05-11
2003-04-15
Eashoo, Mark (Department: 1732)
Plastic and nonmetallic article shaping or treating: processes
Utilizing special inert gaseous atmosphere or flushing mold...
C264S102000, C264S349000
Reexamination Certificate
active
06547997
ABSTRACT:
The present invention relates to a process for preparing solvent-free noncrystalline bioactive substances from the corresponding solvent-containing crystalline substances in an extruder.
It is frequently possible for one and the same chemical substance to form solids based on different order states. This situation is referred to as polymorphism and can likewise be influenced by the novel process. The various crystallographic forms also include pseudopolymorphic forms. These are ones in which not only the relevant substance but also foreign substances are involved in the structure due to formation of mixed crystals, solvates or hydrates. Mixed crystals are crystals composed of two or more chemical substances, and the components involved together form a specific crystallographic structure. Solvates and hydrates are to be regarded as special cases in which one of the components of the mixture is a solvent, with hydrates being formed with water.
Hydrates are particularly important. Because of the strict structural conditions, they have a stoichiometric structure and often show significantly poorer dissolving behavior than the anhydrous forms, because the water of crystallization is able to saturate additional secondary valencies in the molecular assemblage. The latter are unable in some circumstances, for steric reasons, to undergo saturation in the anhydrous form. This means that forms containing water of crystallization often have greater thermodynamic stability.
Many bioactive substances contain solvents as a result of the process for their preparation.
However, it is often difficult to remove such solvents, especially solvents bound in the crystal, by conventional processes such as heating or freeze drying.
It is to this extent of interest to provide a process for converting bioactive substances into a solvent-free form in a simple manner.
It is also known that the bioavailability of substances is frequently less good in their crystalline form than in the corresponding amorphous form.
EP-A 0 665 009 discloses a process in which active substances are converted in a twin screw extruder from one morphological state into another. However, this does not disclose the use of reduced pressure, nor does the process indicate how to proceed with active substances which contain water of crystallization or solvents.
It is an object of the present invention to provide a process for preparing solvent-free noncrystalline, ie. amorphous, bioactive substances from the corresponding solvent-containing crystalline bioactive substances.
We have found that this object is achieved by a process for preparing noncrystalline bioactive substances, which comprises melting the crystalline solvent-containing substances in an extruder in the absence of auxiliaries, the pressure being reduced in one zone of the extruder.
It is possible according to the invention to employ for this purpose not only pharmaceutical active substances but also a large number of bioactive substances which, by their nature, have solvent bound in their crystal lattice or else are merely moistened with a solvent.
The novel process is suitable, for example, for formulating the following substances or their physiologically acceptable salts
antiinfectives aciclovir, aminoglycosides, amphotericin B, azole antimycotics, clotrimazole, itraconazole, sepraconazole, clindamycin, cephalosporins, chloramphenicol, erythromycin, 5-fluorouracil, etoposide, flucytosine, ganciclovir, griseofulvin, gyrase inhibitors, isoniazid, lincosamides, mebendazole, mefloquine, metronidazole, nitroimidazoles, novobiocin, platinum compounds, polymyxin B, praziquantel, pyrimethamine, rifamipicin, saquinavir, streptomycin, sulfonamides, tetracyclines, trimethoprim, vancomycin, zidovudine;
antipyretics, analgesics, antiinflammatory agents, paracetamol, ibuprofen, ketoprofen, oxaprozin, acetylsalicylic acid, morphine, propoxyphene, phenylbutazone;
antibiotics rifampicin, griseofulvin, chloramphenicol, cycloserine, erythromycin, penicillins such as penicillin G, streptomycin, tetracycline;
antiepileptics hydantoins, carbamazepine;
antitussives and antiasthmatics diphenhydramine;
antirheumatics chloroquine, indomethacin, gold compounds, phenylbutazone, oxyphenbutazone, penicillamine;
hypnotics barbiturates, phenobarbital, zolpidem, dioxopiperidines, ureides;
insecticides aldrin, dieldrin, chlorophenotane, hexachlorocyclohexane;
herbicides vinclozolin, strobilurins;
psychopharmaceuticals, neuroleptics perazine, promazine, sulpiride, thioridazine, chlorpromazine meprobamate, triflupromazine, melperone, clozapine, risperidone, reserpine;
tranquillizers;
antidepressants imipramine, paroxetine, viloxazine, moclobemide;
psychotonics;
psychomimetics;
diuretics potassium canrenoate, loop diuretics, furosemide, hydrochlorothiazide, spironolactone, thiazides, triamterene;
hormones androgens, antiandrogens, gestagens, glucocorticoids, oestrogens, cortisol, dexamethasone, prednisolone, testosterone, Adiuretin, oxytocin, somatropin, insulin;
immunosuppresants ciclosporin;
bronchodilators;
muscle relaxants, tranquilizers carisoprodol, tetrazepam, diazepam, chlordiazepoxide;
enzymes lipase, phytase;
gout remedies allopurinol, colchicine;
anticoagulants coumarins;
antiepileptics phenytoin, phenobarbital, primidone, valproic acid, carbamazepine;
antihistamines chlorphenoxamine, dimenhydrinate;
antimimetics;
antihypertensives, antiarrhythmics lidocaine, procainamide, quinidine, calcium antagonists, glycerol trinitrate, isosorbide dinitrate, isosorbide 5-mononitrate, pentaerythrityl tetranitrate, nifedipine, diltiazem, felodipine, verapamil, reserpine, minoxidil, captopril, enalapril, lisinopril;
sympathomimetics norfenefrine, oxedrine, midodrine, phenylephrine, isoprenaline, salbutamol, clenbuterol, ephedrine, tyramine, &bgr; blockers such as alprenolol, metoprolol, bisoprolol;
antidiabetics biguanides, sulfonylureas, carbutamide, tolbutamide, glibenclamide, metformin, acarbose, troglitazone;
iron preparations;
vitamins vitamin C, B, A, D, folic acid;
ACE inhibitors captopril, ramipril, enalapril;
anabolics;
iodine compounds;
X-ray contrast agents;
CNS-active compounds;
antiparkinson agents biperiden, benzatropine, amantadine, opioid analgesics, barbiturates, benzodiazepines, disulfiram, lithium salts, theophylline, valproate, neuroleptics;
cytostatics;
antispasmolytics;
vasodilators naftidrofuryl, pentoxifylline.
It is also possible to employ mixtures of bioactive substances. Amorphous solids have, like liquids, a high dissolving capacity for mixing partners. It is therefore possible for one bioactive substance to dissolve another in the melt. This may lead to mixing diagrams with eutectics. Depending on the position of the melting curves, one or other substance may be present as crystals at the same time as the amorphous first substance.
Preferred substances are those mentioned in the list or those which contain organic solvents and/or water from a crystallization process. This also applies to vitamins.
Preferred active substances for the novel process are amiloride HCl.2H
2
O, amoxicillin.3H
2
O, ampicillin.3H
2
O, atropine sulfate.1H
2
O, benzylpenicillin benzathine.1H
2
O, calcium folinate.5H
2
O, carbidopa.1H
2
O, cefepime.1H
2
O, cefixime.3H
2
O, ceftazidime.5H
2
O, cephaclor.1H
2
O, cephalexin.1H
2
O, quinidine sulfate.4H
2
O, quinine sulfate.2H
2
O, clindamycin HCl.H
2
O, codeine phosphate.½H
2
O, cyclophosphamide.1H
2
O, dihydralazine sulfate.2½H
2
O, doxycycline.1H
2
O, doxycycline.½C
2
H
5
OH.½H
2
O, iron(II) gluconate.2H
2
O, iron(II) sulfate.1H
2
O, flucloxacillin sodium.1H
2
O, G-strophanthin.8H
2
O, ipratropium bromide.1H
2
O, lidocaine HCl.1H
2
O, lincomycin HCl.1H
2
O, loracarbef.1H
2
O, mepacrine 2HCl.2H
2
O, metamizole sodium.1H
2
O, methyldopa.1½H
2
O, minocycline HCl.2H
2
O, morphine sulfate.5H
2
O, sodium ibuprofenate.2H
2
O, sodium picosulfate.1H
2
O, oxyphenbutazone.1H
2
O, pyritinol 2HCl.1H
2
O, sultamicillin tosilate.2H
2
O, theophylline ethylenediamine.2H
2
O or vinblastine sulfate.1H
2
O or mixtures thereof.
The amount of
Breitenbach Jörg
Reinhold Ulrich
Rosenberg Jörg
Zeidler Jürgen
Abbot Laboratories
Eashoo Mark
Keil & Weinkauf
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