AP828A - Process and crystal forms of 2-methyl-thieno-benzodiazepine. - Google Patents
Process and crystal forms of 2-methyl-thieno-benzodiazepine. Download PDFInfo
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- AP828A AP828A APAP/P/1997/001065A AP9701065A AP828A AP 828 A AP828 A AP 828A AP 9701065 A AP9701065 A AP 9701065A AP 828 A AP828 A AP 828A
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- Prior art keywords
- olanzapine
- polymorph
- active ingredient
- methyl
- ray powder
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract
A stable pharmaceutical olanzapine polymorph, having a typic X-ray powder diffraction pattern
Description
FROCESS AND CRYSTAL FORMS OF 2-METHYL-THIENOBENZODIAZEPINE . This invention relates to a novel form of 2-methyl4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (hereinafter referred co by its generic name olanzapine), more specifically to a novel crystalline form of that compound and to pharmaceutical formulations containing that novel form as an active ingredient.
A novel crystal form of olanzapine has now been synthesized and characterized which possesses distinct advantages over the previously known form, that is the material produced using the methods described in U.S. Patent No. 5,229,382 (hereinafter referred to as “the '382 patent), and which is clearly distinguishable therefrom by x-ray powder diffractometry. The first form of olanzapine (hereinafter referred to as Form I), as prepared by the procedures described in the '382 patent, has been found to be metastable and not well suited for commercial use in pharmaceutical formulations. However, in accordance with the present invention, a newly discovered second polymorph of olanzapine, which will be designated hereinafter as Form II, has been found to be obtainable in highly pure form, that is free from Form I and contamination by solvates such as water or acetonitrile, is stable, pharmaceutically elegant, and therefore well adapted for commercial use in pharmaceutical formulations .such as tablets.
Olanzapine has shown great promise in the treatment of psychotic patients and is currently being evaluated for that purpose. Unfortunately/ olanzapine prepared using the methods described in the ‘382 patent typically exhibits a color which is undesirable for commercial pharmaceutical use, especially since the color was found to change over time on exposure to air. Even carbon treatment of the olanzapine prepared using the methods described in the '382 patent does not remove all of the undesired color. Such a pharmaceutical which changes color over time could be particularly
AP/P/ 9 7 / 0 1 0 6 5
AP Ο Ο Ο 8 2 8
-2troublesome for psychotic patients if a dosage form, such as a tablet, were to be chosen where color changes were apparent. Therefore, greater purity and freedom from color change are- desirable. The novel polymorph of this invention provides precisely the longed for pharmaceutically elegant and desirable properties needed for a drug to be administered to psychotic patients, and has satisfactory color stability and is substantially free of undesired solvating agents such as water and acetonitrile.
The present invention provides Form II olanzapine polymorph having a typical x-ray powder diffraction pattern uh & as represented by the following interplanar spacings:
V?·d
10.2689
8.577
7.4721
7.125
6.1459
6.071
5.4849
5.2181
5.1251
4.9874
4.7665 • 4.7158 4.4787 4.3307 4.2294 4.141 3.9873
AP/P/ 9 7 / 0 1 0 6 5
AP Ο Ο Ο 8 2 8
-3d
3.7206
3.5645
3.5366
3.3828
3.2516
3.134
3.0848
3.0638
3.0111
2.8739
2.8102
2.7217
2.6432
2.6007
A typical example of an· x-ray diffraction pattern for Form II is as follows wherein d represents the interplanar spacing and I/Ii represents the typical relative intensities:
d | I/Il |
10.2689 | 100.00 |
8.577 | 7.96 |
7.4721 | 1.41 |
7.125 | 6.50 |
6.1459 | 3.12 |
6.071 | 5.12 |
5.4849 | 0.52 |
5.2181 | 6.86 |
5.1251 | 2.47 |
4.9874 | 7.41 |
4.7665 | 4.03 |
4.7158 | 6.80 |
4.4787 | 14.72 |
4.3307 | 1.48 |
AP/P/ 9 7 / 0 1 0 6 5
APO00828
d | I/l! |
4.2294 | 23.19 |
4.141 | 11.28 |
3.9873 | 9.01 |
3.7206 | 14.04- |
3.5645 | 2.27 |
3.5366 | 4.85 |
3.3828 | 3.47 |
3.2516 | 1.25 |
3.134 | 0.81 |
3.0848 | 0.45 |
3.0638 | 1.34 |
3.0111 | 3.51 |
2.8739 | 0.79 |
2.8102 | 1.47 |
2.7217 | 0.20 |
2.6432 | 1.26 |
2.6007 | 0.77 |
The x-ray diffraction patterns set out herein were obtained using a Siemens D5000 x-ray powder diffractometer having a copper Ka radiation source of wavelength, λ=1·54ΐΑ.
The invention further provides the Form II ; polymorph in substantially pure form.
The present invention also provides a pharmaceutical formulation, such as a tablet, comprising Form II as an active ingredient, associated with one or more 10 pharmaceutical acceptable excipients. In another embodiment of the invention,' there is proyided a method for using Form II for treating a psychotic condition, mild anxiety, gastrointestinal conditions and for providing pharmaceutical formulations for use in such methods.
The polymorph obtainable by the process taught in the '382 patent will be designated as Form I and has a typical x-ray powder diffraction pattern substantially as
AP/P/ 9 7 / 0 1 0 6 5
ΑΡ ΰ ύ Ο 8 2 8
-5follows, obtained using a Siemens D5000 x-ray powder diffractometer, wherein d represents the interplanar spacing:
d
9.9463
8.5579
8.2445
6.8862
6.3787
6.2439
5.5895
5.3055
4.9815
4.8333
4.7255
4.6286
4.533
4.4624
4.2915
4.2346
4.0855
3.8254
3.7489
3.6983
3.5817
3.5064
3.3392
3.2806
3.2138 '3.1118
3.0507
2.948
2.8172
2.7589
2.6597
2.6336
2.5956
AP/P/ 97/0 1 065
ΑΡ ο ο Ο 8 2 8
-6Α typical example of an x-ray diffraction pattern for Form I is as follows wherein d represents the interplanar spacing and Ι/Ιχ represents the d
9.9463
8.5579
8.2445
6.8862
6.3787
6.2439
5.5895
5.3055
4.9815
4.8333
4.7255
4.6286
4.533 4.4624 4.2915 4.2346 4.0855 3.8254 3.7489 3.6983 3.5817 3.5064 3.3392 3.2806 3.2138 3.1118 3.0507
2.948 2.8172 2.7589 2.6597 2.6336 2.5956 typical relative intensities: I/Il
100.00
15.18
1.96
14.73
4.25
5.21
1.10
0.95
6.14
68.37
21.88
3.82
17.83 . 5.02
9.19
18.88
17.29
6.49
10.64
14.65 3.04 9.23 4.67 1.96 2.52 4.81 1.96 2.40 2.89 2.27 1.86 1.10 1.73
AP/P/ 97/01065
£.;3
APO 0 0 8 2 8
-7The x-ray powder diffraction patterns herein were obtained with a copper Kaof wavelength λ = 1.541A. The interplanar spacings in the column marked d are in Angstroms. The typical relative intensities are in the column marked I/Iq/' .
The novel form of olanzapine provided by this invention is rather difficult to prepare in substantially pure form. However, in accordance with the invention, it has been discovered that when olanzapine of reasonably high purity, that is of technical grade (that is olanzapine containing less than about 5% undesired related substances and preferably less than about 1% undesired related substances and see Example 1), is dissolved in ethyl acetate under anhydrous conditions, Form II can be crystallized out of the solution so formed in substantially pure form, that is free from the undesired polymorph or solvates such as water or acetonitrile. Anhydrous conditions refer to less than one percent water present in the ethyl acetate.
In preparing Form II according to the invention, the technical grade olanzapine can be dissolved in the ethyl acetate by agitation such as stirring and the like. Crystallization from the resulting solution can be by any conventional process including seeding, chilling, scratching the glass of the reaction vessel, and other such common techniques .
As used herein substantially pure refers to Form II associated with less than about 5% Form I, preferably less than about 2% Form I, and more preferably less than about 1% Form I. Further, substantially pure Form II will contain less than about 0.5% related substances, wherein related substances refers to undesired chemical impurities or residual solvent or water. In particular, substantially pure Form II should contain less than about 0.05% content of acetonitrile, more preferably, less than about 0.005% content of acetonitrile. Additionally, the polymorph of the invention should contain less than 0.5% of associated water.
AP/P/ 9 7 / 0 1 0 6 5
APO 0 0 8 2 8
-8Advantageously, the novel polymorph of the invention will be free from solvates, for instance existing as the anhydrate.
Pharmaceutical formulations containing Form II 5 should contain less than about 10% Form I, more preferably less than about 5% Form I polymorph.
Olanzapine has useful central nervous system activity. This activity has been demonstrated using wellestablished procedures, for example, as described in the '382 patent. Form II provided by the present invention appears to have the same profile of receptor activity and has the same therapeutic uses as olanzapine described in the '382 patent. Therefore, Form II is useful for the treatment of schizophrenia, schizophreniform disorders, psychosis, mild anxiety states, and functional bowel disorders.
Form II is effective over a wide dosage range, the actual dose administered being dependent on the condition being treated. For example, in the treatment of adult humans, dosages of from about 0.25 to 50 mg, preferably from 1 to 30 mg, and most preferably 1 to 20 mg per day may be used. A once a day dosage is normally sufficient, although divided doses may be administered.
For treatment of central nervous system disorders, a dose range of from 1 to 30 mg, preferably 2.5 to 20 mg per day is suitable.
Form II will normally be administered orally and, for this purpose, it is' usually employed in the form of a pharmaceutical formulation.
Accordingly, pharmaceutical formulations 30 comprising Form II as active ingredient, associated with a pharmaceutically acceptable carrier may be prepared. In making the compositions of the invention conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
AP/P/ 9 7 / 0 1 0 6 5
'Ο'
AP Ο Ο Ο 8 2 8
-9When the carrier serves as a diluent, it may be solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. The active ingredient can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxy-benzoate, talc, magnesium stearate or mineral oil. The compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient. For example, one such preferred quick release formulation is described in U.S. Patent Nos. 5,079,018, 5,039,540, 4,305,502, 4,758,598, and 4,371,516, hereby incorporated by reference.
Depending on the method of administration, the compositions for the treatment of central nervous system conditions may be formulated as tablets, capsules, gel or suspension for transdermal delivery, suspensions or elixirs for oral use or suppositories. Preferably the compositions are formulated in a unit dosage form, each dosage containing from 0.25 to 100 mg, more usually 1 to 30 mg, of the active ingredient. When a sustained release formulation is desired, the unit dosage form may contain from 0.25 to 200 mg of the active ingredient. A preferred formulation of the invention·is a capsule or tablet comprising 0.25 to 75 mg or 1 to 30 mg of active ingredient together with a pharmaceutically acceptable carrier therefor.
The starting materials for the present invention can be prepared by a variety of procedures well known to those of ordinary skill in the art. The material to be employed as starting materials in the process of this invention can be prepared by the general procedure taught by Chakrabarti in U.S. Patent No 5,229,382 (’382), herein incorporated by reference in its entirety.
AP/P/ 9 7 / 0 1 0 6 5
AP ο Ο Ο 8 2 8
-10The following examples are provided for purposes of illustration and are not to be construed as limiting the scope of the claimed invention.
Compound characterization methods include, for example, x-ray powder pattern analysis, thermogravimetric analysis (TGA), differential scanning calorimetery (DSC), titrametric analysis for water, and H^-NMR analysis for solvent content.
Example 1
Technical Grade olanzapine : -J
Intermediate 1
In a suitable three neck flask the following was added:
Dimethylsulfoxide (analytical): 6 volumes
Intermediate 1 : 75 g
N-Methylpiperazine (reagent) : 6 equivalents
Intermediate 1 can be prepared using methods known to the skilled artisan'. For example, the preparation of the Intermediate 1 is taught in the '382 patent.
A sub-surface nitrogen sparge line was added to remove the ammonia formed during the reaction. The reaction was heated to 12.0°C and maintained at that temperature throughout the duration of the reaction. The reactions were followed by HPLC until < 5% of the intermediate 1 was left unreacted.
AP/P/ 9 7 / 0 1 0 6 5
AP Ο Ο Ο 8 2 8
-IlAfter the reaction was complete, the mixture was allowed to cool slowly to 20°C (about 2 hours). The reaction mixture was then transferred to an appropriate three-neck round bottom flask and water bath. To this solution with agitation was added 10 volumes reagent grade methanol and the reaction was stirred at 20°C for 30 minutes. Three volumes of water was added slowly over about 30 minutes. The reaction slurrv was cooled to zero to 5°C and stirred for 3 0 minutes. The product was filtered and the wet cake was washed with chilled methanol. The wet cake was dried in vacuo at 45°C overnight. The product was identified as technical olanzapine.
tp Yield: 76.7%; Potency: 98.1%
Example 2
Form II
A 270 g sample of technical grade 2-methyl-4-(4methyl-l-piperazinyl)-10H-thieno[2,3-b)[1,5) benzodiazepine was suspended in anhydrous ethyl acetate (2.7 L) . The mixture was heated to 76°C and maintained at 76°C for 30 minutes. The mixture was allowed to cool to 25°C. The resulting product was isolated using vacuum filtration. The product was identified as Form II using x-ray powder analysis .
Yield: 197 g.
The process described above for preparing Form II provides a pharmaceutically elegant product having potency > 97%, total related substances < 0.5% and an isolated yield of > 73%.
AP/P/ 9 7 / 0 1 0 6 5
EXAMPLE 3 Tablet Formulation
A tablet formulation was made by granulating the active with appropriate diluent, lubricant, disintegrant and binder and compressing
AP Ο Ο Ο 8 2 8
Form II olanzapine | .10.0 | mg |
Magnesium stearate | '0.9 | mg |
Microcrystalline cellulose | 75.0 | mg |
Povidone | 15-.0 | mg |
Starch, directly | 204.1 | mg |
compressible |
Example 4 Tablet Formulation
A portion of hydroxypropyl cellulose was dissolved in purified water to form a solution for granulation. The remaining hydroxypropyl cellulose (total of 4.0% w/w final tablet weight), which was an extra fine grade, was combined with the Form II (1.18% w/w), lactose (79.32% w/w) and a portion of crospovidone (5% w/w) in a high shear granulator. All ingredients were security sieved prior to addition and dry blended in the granulator. This mixture was then granulated with the hydroxypropyl cellulose solution in the high shear granulator. The granulation was wet sized using standard methods. The wet granulation was then dried in a fluidized bed dryer and sized. The material was then added to a tumble bin mixer.
The outside powders consisting of microcrystal*line cellulose (granular) (10% w/w), magnesium stearate (0.5% w/w) , and the remainder of the crospovidone were added to the sized granulation. The mixture was blended and compressed with the appropriate tooling on tablet compression equipment.
AP/P/ 9 7 / 0 1 0 6 5
Subcoatincr:
Hydroxypropyl methylcellulose (1.5% w/w) was mixed with purified water to form a solution. Core tablets were divided into approximately equal sections and spray coated with the hydroxypropyl methylcellulose solution . The operation was performed in a perforated coating pan.
APO 0 0 8 2 8
-13Coatinc? of Core Tablets:
Color Mixture White (hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide) was mixed with purified water to form the coating suspension. Subcoated tablets were divided into approximately equal sections and spray coated with the coating suspension described above. The operation was performed in a perforated coating pan.
The coated tablets were lightly dusted with carnauba wax and imprinted with appropriate identification.
Claims (9)
- Claims ί,ϊ·..1. Form II olanzapine polymorph having a typical x-ray powder diffraction pattern as represented by the following5 interplanar spacings:a (A)10.2689 8.577 7.4721 7.125 6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.56453.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739AP/F/ 9 7 / 0 1 0 6 5AP Ο Ο Ο 8 2 8-15d (A)
- 2.81022.72172.64322.60072. Form II as claimed in Claim 1 which is substantially pure.5
- 3. Form II as claimed in Claim 2 which contains less than about 5% Form I as hereinbefore defined.
- 4. Form II as claimed in Claim 3 which contains less than about 2% content of Form I as hereinbefore defined.10
- 5. Form II as claimed in any one of Claims 1 to 4 which is solvate free.
- 6. Form II as claimed in any one of Claims 1 to 5 15 which is anhydrous.
- 7. A pharmaceutical formulation comprising as an active ingredient Form II as claimed in any one of Claims 1 to 6-¾ associated with one or more pharmaceutically acceptable carriers, excipients, or diluents therefor.
- 8. A pharmaceutical formulation as claimed in Claim 7 which is a tablet.
- 9. A process for preparing Form II comprising slurrying technical grade olanzapine in ethyl acetate under anhydrous conditions and crystallizing Form II from the solution so formed.AP/P/ 9 7 / 0 1 0 6 5-Ιδιο. Form II olanzapine polymorph for use in treating a condition selected from the group consisting of psychosis, schizophrenia, a schizophrenic form disorder, mild anxiety, a gastrointestinal disorder, and acute mania.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40956695A | 1995-03-24 | 1995-03-24 | |
PCT/US1996/003917 WO1996030375A1 (en) | 1995-03-24 | 1996-03-22 | Process and crystal forms of 2-methyl-thieno-benzodiazepine |
Publications (2)
Publication Number | Publication Date |
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AP9701065A0 AP9701065A0 (en) | 1997-10-31 |
AP828A true AP828A (en) | 2000-04-28 |
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Application Number | Title | Priority Date | Filing Date |
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APAP/P/1997/001065A AP828A (en) | 1995-03-24 | 1996-03-22 | Process and crystal forms of 2-methyl-thieno-benzodiazepine. |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EG23659A (en) * | 1995-03-24 | 2007-03-26 | Lilly Co Eli | Process and crystal forms of methyl-thieno-benzodiazepine |
CA2232559A1 (en) * | 1995-09-29 | 1997-04-03 | Charles Merritt Beasley Jr. | Method for treating a tic disorder |
UA57727C2 (en) * | 1996-03-11 | 2003-07-15 | Елі Ліллі Енд Компані | Method for treating excessive aggression |
EP0904083A4 (en) * | 1996-03-25 | 2002-05-22 | Lilly Co Eli | Anesthetic method |
PL329221A1 (en) * | 1996-03-25 | 1999-03-15 | Lilly Co Eli | Method of relieving hemicrania pains |
AU725556B2 (en) * | 1996-03-25 | 2000-10-12 | Eli Lilly And Company | Method for treating pain |
AU721338B2 (en) * | 1996-03-25 | 2000-06-29 | Eli Lilly And Company | Method for treating pain |
CZ299247B6 (en) * | 1996-09-23 | 2008-05-28 | Eli Lilly And Company | Dihydrate D olanzapine |
ZA978515B (en) * | 1996-09-23 | 1999-03-23 | Lilly Co Eli | Intermediates and process for preparing olanzapine |
DK1155696T3 (en) * | 1997-04-15 | 2004-07-12 | Lilly Co Eli | Use of olanzapine in the manufacture of a drug for neuroprotection |
WO1998046596A1 (en) * | 1997-04-15 | 1998-10-22 | Eli Lilly And Company | Method for providing neuro-protective effects |
US20030022889A1 (en) * | 1997-04-15 | 2003-01-30 | Bymaster Franklin P. | Method for providing neuro-protective effects |
ZA982917B (en) * | 1997-04-15 | 1999-10-06 | Lilly Co Eli | Method for treating cerebral focal stroke. |
USRE43932E1 (en) | 1997-07-18 | 2013-01-15 | Novartis Ag | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
US6617321B2 (en) | 1997-09-30 | 2003-09-09 | Eli Lilly And Company | 2-methyl-thieno-benzodiazepine formulation |
NZ510208A (en) * | 1998-09-30 | 2003-04-29 | Lilly Co Eli | Olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) pamoate salt |
FR2802101B1 (en) | 1999-12-10 | 2003-02-28 | Aventis Pharma Sa | COMBINATION OF CYMEMAZINE AND AN ATYPICAL NEUROLEPTIC |
US7022698B2 (en) | 1999-12-28 | 2006-04-04 | U & I Pharmaceuticals, Ltd. | Pharmaceutical compositions containing new polymorphic forms of olanzapine and uses thereof |
US6348458B1 (en) | 1999-12-28 | 2002-02-19 | U & I Pharmaceuticals Ltd. | Polymorphic forms of olanzapine |
AU779452B2 (en) * | 1999-12-28 | 2005-01-27 | Cipla Limited | New polymorphic forms of olanzapine |
CA2420987A1 (en) * | 2000-08-31 | 2002-03-07 | Dr. Reddy's Laboratories Ltd. | Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine |
AU2001282913A1 (en) * | 2000-09-08 | 2002-03-22 | Eli Lilly And Company | A method of treating weight gain associated with atypical antipsychotic use |
US6740753B2 (en) | 2001-01-04 | 2004-05-25 | Geneva Pharmaceuticals, Inc. | Olanzapine crystal modification |
CA2464306A1 (en) * | 2001-10-29 | 2003-05-08 | Dr. Reddy's Laboratories Ltd. | Olanzapine dihydrate-ii a process for its preparation and use thereof |
CA2471341C (en) | 2001-12-24 | 2012-01-24 | Sun Pharmaceutical Industries Limited | Crystalline form i of 2-methyl-4-(4-methyl-1-piperazinyl) 10h thieno [2,3-b][1,5]benzodiazepine |
US7790905B2 (en) * | 2002-02-15 | 2010-09-07 | Mcneil-Ppc, Inc. | Pharmaceutical propylene glycol solvate compositions |
US7927613B2 (en) * | 2002-02-15 | 2011-04-19 | University Of South Florida | Pharmaceutical co-crystal compositions |
US20100311701A1 (en) * | 2002-02-15 | 2010-12-09 | Transform Pharmaceuticals, Inc | Pharmaceutical Co-Crystal Compositions |
WO2004089313A2 (en) * | 2003-04-01 | 2004-10-21 | Transform Pharmaceuticals, Inc. | Novel olanzapine forms and related methods of treatment |
EP2316468A1 (en) | 2002-02-22 | 2011-05-04 | Shire LLC | Delivery system and methods for protecting and administering dextroamphetamine |
EP1494998A2 (en) | 2002-03-01 | 2005-01-12 | University Of South Florida | Multiple-component solid phases containing at least one active pharmaceutical ingredient |
PL196814B1 (en) * | 2002-05-17 | 2008-02-29 | Inst Farmaceutyczny | Method of obtaining polymorphous form of i olansapine |
AU2003237305A1 (en) * | 2002-05-31 | 2003-12-19 | Geneva Pharmaceuticals, Inc. | Process of preparation of olanzapine form i |
CA2489984A1 (en) * | 2002-06-21 | 2003-12-31 | Transform Pharmaceuticals, Inc. | Pharmaceutical compositions with improved dissolution |
SI21270A (en) * | 2002-07-15 | 2004-02-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Crystal forms of olanzapine and procedures for their preparation |
PL202856B1 (en) * | 2002-12-20 | 2009-07-31 | Adamed Spo & Lstrok Ka Z Ogran | Method of obtaining pharmaceutically pure polymorphic form of I olanzapine |
US7323459B2 (en) | 2002-12-24 | 2008-01-29 | Teva Pharmaceutical Industries Ltd. | Crystal forms, methods for their preparation and method for preparation of olanzapine |
US8183290B2 (en) * | 2002-12-30 | 2012-05-22 | Mcneil-Ppc, Inc. | Pharmaceutically acceptable propylene glycol solvate of naproxen |
EP1507774A1 (en) * | 2003-03-12 | 2005-02-23 | Biogal Gyogyszergyar Rt. | Processes for preparation of polymorphic forms of desloratadine |
US20060135547A1 (en) * | 2003-03-12 | 2006-06-22 | Toth Zoltan G | Stable pharmaceutical compositions of desloratadine and processes for preparation of polymorphic forms of desloratadine |
GB0314149D0 (en) * | 2003-06-18 | 2003-07-23 | Generics Uk Ltd | Novel amorphous forms |
GB0326148D0 (en) | 2003-11-10 | 2003-12-17 | Lilly Co Eli | Morpholine derivatives |
CA2546200A1 (en) * | 2003-11-18 | 2005-06-02 | 3M Innovative Properties Company | Olanzapine containing transdermal drug delivery compositions |
US7425627B2 (en) * | 2003-12-22 | 2008-09-16 | Teva Pharmaceutical Industries Ltd. | Methods of synthesizing olanzapine |
US20050272720A1 (en) * | 2004-01-27 | 2005-12-08 | Rolf Keltjens | Process for making olanzapine Form I |
DE602005027308D1 (en) | 2004-01-27 | 2011-05-19 | Synthon Bv | STABLE SALT OF OLANZAPIN |
ES2253091B1 (en) | 2004-07-27 | 2007-02-01 | Inke, S.A. | MIXED SOLVATO OF OLANZAPINE, PROCEDURE FOR OBTAINING AND PROCEDURE OF OBTAINING THE FORM I OF OLANZAPINE FROM THE SAME. |
WO2006027800A1 (en) * | 2004-09-06 | 2006-03-16 | Shasun Chemicals And Drugs Limited | A novel process for preparation of a pharmaceutically pure polymorphic form 1 of olanzapine |
BRPI0518187A (en) * | 2004-11-16 | 2008-11-04 | Elan Pharma Int Ltd | injectable nanoparticulate olanzapine formulations |
EP1838716B1 (en) | 2005-01-05 | 2011-06-01 | Eli Lilly And Company | Olanzapine pamoate dihydrate |
CZ200563A3 (en) * | 2005-02-02 | 2006-10-11 | Zentiva, A. S. | Therapeutical composition containing olanzapin as active component and process for its preparation |
US20100174066A1 (en) * | 2005-03-21 | 2010-07-08 | Venkataraman Sundaram | Process for preparing crystalline form i of olanzapine |
US20070021605A1 (en) * | 2005-07-20 | 2007-01-25 | Rolf Keltjens | Process and composition for making olanzapine form i |
WO2007020080A1 (en) * | 2005-08-17 | 2007-02-22 | Synthon B.V. | A process for making olanzapine form i |
GB0522474D0 (en) * | 2005-11-03 | 2005-12-14 | Actavis Group | A pharmaceutical formulation |
HUP0501046A2 (en) * | 2005-11-11 | 2007-08-28 | Egis Gyogyszergyar Nyilvanosan | Process for the preparation of olanzapine |
US8721202B2 (en) | 2005-12-08 | 2014-05-13 | Ncr Corporation | Two-sided thermal print switch |
US8367580B2 (en) | 2006-03-07 | 2013-02-05 | Ncr Corporation | Dual-sided thermal security features |
US8222184B2 (en) | 2006-03-07 | 2012-07-17 | Ncr Corporation | UV and thermal guard |
ES2279715B1 (en) | 2005-12-26 | 2008-06-01 | Laboratorios Lesvi, S.L. | ORAL FORMULATION OF OLANZAPINE. |
US7834176B2 (en) | 2006-01-26 | 2010-11-16 | Sandoz Ag | Polymorph E of Olanzapine and preparation of anhydrous non-solvated crystalline polymorphic Form I of 2-methyl-4(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine (Olanzapine Form I) from the polymorphic Olanzapine Form E |
US20070293479A1 (en) * | 2006-05-18 | 2007-12-20 | Osinga Niels J | Olanzapine pharmaceutical composition |
CL2007002807A1 (en) * | 2006-09-29 | 2008-04-11 | Synthon Bv | PHARMACEUTICAL COMPOSITION IN SOLID STATE THAT INCLUDES OLANZAPINE OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME AND LACTOSE ANHYDRA; ORAL PHARMACEUTICAL TABLET; PROCEDURE FOR PREPARATION OF SUCH TABLET, USEFUL IN THE TREATMENT OF SKI |
US7718649B1 (en) | 2006-11-10 | 2010-05-18 | Pisgah Labs, Inc. | Physical states of a pharmaceutical drug substance |
US8039461B1 (en) | 2006-11-10 | 2011-10-18 | Pisgah Laboratories, Inc. | Physical states of a pharmaceutical drug substance |
PL381564A1 (en) | 2007-01-22 | 2008-08-04 | Koźluk Tomasz Nobilus Ent | The manner of production of basically clean variety of polymorphic olanzapine |
CA2591644A1 (en) * | 2007-06-14 | 2008-12-14 | Apotex Pharmachem Inc. | Novel processes to form-i of olanzapine |
US9056488B2 (en) | 2007-07-12 | 2015-06-16 | Ncr Corporation | Two-side thermal printer |
US8883863B1 (en) | 2008-04-03 | 2014-11-11 | Pisgah Laboratories, Inc. | Safety of psuedoephedrine drug products |
CN101735239B (en) * | 2008-11-06 | 2011-08-31 | 齐鲁制药有限公司 | Preparation method of anhydrous olanzapine crystal form II |
EP2292624A1 (en) | 2009-07-20 | 2011-03-09 | LEK Pharmaceuticals d.d. | Process for the purification of olanzapine |
HUE041981T2 (en) | 2010-08-23 | 2019-06-28 | Alkermes Pharma Ireland Ltd | Methods for treating antipsychotic-induced weight gain |
CN102093386B (en) * | 2011-01-05 | 2016-06-01 | 浙江华海药业股份有限公司 | A kind of method preparing Zyprexa crystal form II |
WO2012153347A2 (en) | 2011-05-04 | 2012-11-15 | Zentiva K.S. | Oral pharmaceutical composition of olanzapine form 1 |
PL2888284T3 (en) | 2012-08-21 | 2023-02-27 | Janssen Pharmaceutica Nv | Antibodies to risperidone haptens and use thereof |
PT2887952T (en) * | 2012-08-21 | 2019-08-30 | Janssen Pharmaceutica Nv | Antibodies to olanzapine haptens and use thereof |
EP2888590B1 (en) | 2012-08-21 | 2020-07-08 | Janssen Pharmaceutica NV | Antibodies to olanzapine and use thereof |
EP2919788A4 (en) | 2012-11-14 | 2016-05-25 | Univ Johns Hopkins | Methods and compositions for treating schizophrenia |
CN103848847B (en) * | 2012-12-04 | 2018-02-06 | 广东东阳光药业有限公司 | A kind of method that improvement prepares Olanzapine and its crystal formation II |
JP6008734B2 (en) * | 2012-12-20 | 2016-10-19 | 株式会社トクヤマ | Olanzapine type II crystal production method |
CN103145731B (en) * | 2013-02-26 | 2014-02-19 | 江苏豪森药业股份有限公司 | Olanzapine crystal form as well as preparation method and application thereof |
WO2023139531A1 (en) | 2022-01-20 | 2023-07-27 | Teva Pharmaceuticals International Gmbh | Olanzapine, compositions thereof and methods of use thereof |
US20240238308A1 (en) | 2023-01-10 | 2024-07-18 | Medincell Sa | Olanzapine compositions and methods of use |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5229382A (en) * | 1990-04-25 | 1993-07-20 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4115568A (en) * | 1974-11-26 | 1978-09-19 | Lilly Industries Limited | Thieno[3,2-b]-[1,5]benzodiazepines |
GB1548022A (en) | 1976-10-06 | 1979-07-04 | Wyeth John & Brother Ltd | Pharmaceutial dosage forms |
CA1097233A (en) | 1977-07-20 | 1981-03-10 | George K. E. Gregory | Packages |
US4237279A (en) * | 1979-07-27 | 1980-12-02 | Eli Lilly And Company | Crystalline 3-hydroxycephalosporin solvates |
IE53696B1 (en) | 1981-12-02 | 1989-01-18 | Wyeth John & Brother Ltd | Solid shaped articles |
US5039540A (en) | 1989-08-14 | 1991-08-13 | Neophore Technologies, Inc. | Freeze dry composition and method for oral administration of drugs, biologicals, nutrients and foodstuffs |
US5079018A (en) | 1989-08-14 | 1992-01-07 | Neophore Technologies, Inc. | Freeze dry composition and method for oral administration of drugs, biologicals, nutrients and foodstuffs |
GB9009229D0 (en) * | 1990-04-25 | 1990-06-20 | Lilly Industries Ltd | Pharmaceutical compounds |
PT582368E (en) * | 1992-05-29 | 2001-05-31 | Lilly Co Eli | TIENOBENZODIAZEPINE DERIVATIVES FOR THE TREATMENT OF CNS DISEASES |
US5439888A (en) * | 1994-03-04 | 1995-08-08 | Eli Lilly And Company | Antithrombotic agents |
US5457101A (en) * | 1994-06-03 | 1995-10-10 | Eli Lilly And Company | Thieno[1,5]benzoidiazepine use |
EG23659A (en) * | 1995-03-24 | 2007-03-26 | Lilly Co Eli | Process and crystal forms of methyl-thieno-benzodiazepine |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5229382A (en) * | 1990-04-25 | 1993-07-20 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
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