FORM 2
THE PATENTS ACT, 1970
(39 OI7 1970)
&
THE PATENTS RULES. 2QQ3
PROVISIONAL SPECIFICATION
(See section 10: rule i3)
STABLE OLANZAPINE TABLETS AND THE PROCESS FOR ITS
PREPARATION


GENEPHARM INDIA PRIVATE LIMITED
A company incorporated under the laws of India having their office at
Read. Off.: IB. Old Post Street, Kolkata-70000!
The following specification describes the nature of this invention

STABLE OLANZAPINE TABLETS AND THE PROCESS FOR ITS
PREPARATION
The present invention relates to stable olanzapine tablets and the process for its preparation; wherein the said tablets are stable to color, chemical degradation and polymorphic changes. The chemical name of olanzapine is 2-methyl-4-(4-methyl-l-piperazinyl)-l0H-thieno[2,3-6] [ I5]benzodiazcpine. Olanzapine is an antagonist of dopamine at D-I and D-2 receptors and. in addition, it has antimuscarinic anticholinergic properties and antagonist actives at 5KT-2 receptor sites, with antagonist activity at noradrenergic a- receptors. The compound is useful in treating psychotic conditions such as schizophrenia, acute mania and mild anxiety states.
BACKGROUND OF THE INVENTION
European Patent Number 454436B1, assigned to M/S Eli Liily. discloses pharmaceutical composition of olanzapine using conventional techniques. The active ingredient can be mixed with a carrier such as lactose, dextrose, sucrose, sorbitol, mannkol, starches, gum acacia, calcium phosphate, alignates, tragacanth, gelatin, syrup, methyl cellulose, microcrysta'lline cellulose, methyl and propyl- hydroxy benzoate, povidone, talc, aluminum stearate, magnesium stearate or mineral oil and converted to a suitable pharmaceutical composition.
Formulations of coated olanzapine are exemplified in European Patent Number 733367 Bl assigned to M/S Eli Lilly. Olanzapine being moisture sensitive and metastable in nature, the patentees have observed that coating olanzapine with a polymer prevents the undesired discoloration. Further, the patentees believe that dry blend direct compression or dry granulated process for preparing solid oral formulation may create poor dose uniformity.
Coated formulations of olanzapine are also prepared in European Patent application 1231903 assigned to M/S Biochemie and PCT publication 2005009407.
The formulation presently on the market is coated in order to assure protection of the active substance from moisture and light.
Coated and uncoated formulation of olanzapine are known in the art as techniques like wet granulaton are not suitable due to problems of stability.
'■L

Direct compression (DC) is widely used for moderate dose active (API) as a process of choice. It involves simple mixing of active with other excipients followed by compression to tablets. However, the tablets produced by DC may possess problems of poor content uniformity. Tasie masking and chemical eompatability are often compromised as active is present as primary particles and completely exposed to saliva of oral cavity and all excipients of tablet.
Lyoplfilised tablets e.g. Zyprexa Velotab are produced by a complex, time intensive and costly process involving freeze drying of suspension of drug/ excipients in preformed blister. This requires dedicated facility to carry out this operation.
Coating of active with tastemasking polymers is also conventionally used to improve taste and stability characteristics of API, however it is a critical and lengthy process and the taste masked granules often provide grittiness, roughness and poor content uniformity problems
We have surprisingly found stable olanzapine tablets and the process of its preparation using compaction as the key operation. This process overcomes all the limitations highlighted with
■conventional methods.
OBJECT OF THE INVENTION
The object of the invention is to provide stable olanzapine tablets. The tablets of the present invention are without any coating. The tablets are stable to color, chemicai degradation and polymorphic changes for at least 3 months at 40°C / 75% relative humidity in open vials. Also provided herewith is a simple process for the preparation of stable olanzapine tablets.
The advantages of the process of the present invention are
I. Compaction of olanzapine with one or more relatively protective excipient (e.g. calcium carbonate, microcrystalline cellulose ) can protect olanzapine from direct contact with relatively incompatible but crucial excipients like aspartame and crospovidone
2. Taste masking can be achieved by compaction with saliva insoluble fillers which have good solubility or swellability in GIT fluids
3. Due to the formation of granules prior to tablet compression the content uniformity segregation problems, slicking or compressibility problems are reduced considerably.

4. Color changes and color variations between tablets are avoided
5. Less polymorphic changes as the operation is free of solvent or heat.
6. The process can be carried out with conventional infrastructure hence economically viable.
SUMMARY OF THE INVENTION
Stable olanzapine tablets comprising compacted blend of olanzapine and at least one pharmaceutical excipient; mixed with extragranular blend of diluent(s), disintegrant(s), lubricants) and sweeteners); wherein the said tablets are stable to color, chemical degradation and polymorphic changes for atleast 3 months at 40°C / 75% relative humidity in open vials,
DESCRIPTION OF THE INVENTION
According to the present invention there is provided stable olanzapine tablets without any undesirable discoloration or poor dose uniformity and the process of its preparation. The tablets of the present invention can be prepared by a simple process such as compaction of granules with olanzapine with at least one pharmaceutical excipient.
The stable olanzapine tablets prepared according to one embodiment of the present invention are stable to color, chemical degradation and polymorphic changes for atleast 3 months at 40°C / 75% relative humidity in open vials.
The term "stable" as used herein is intended to encompass stability with respect to color, chemical degradation and polymorphic changes.
The formulations of the present invention may contain anhydrous forms of olanzapine, which are disclosed e.g. in European Patent Number 733635 Bl, therein designated as Form I and Form II; in United States Patent Number 6,348,458, therein designated as Form III. Form IV, Form V: in United States Patent Number 2002/086993 Al, therein designated as form X. Also useful are hydrates of olanzapine which are disclosed e.g. in European Patent Number 0831098 Bl, therein designated as forms B. D. E; in PCT publication Number 02/1S39QA, therein designated as monohydrate I and dihydrate I.

According to another embodiment of the present invention is provided a process for the preparation of stable olanzapine tablets. The process comprises compaction, miling, mixing and compression.
Olanzapine tablets prepared by process comprising compacting olanzapine with atleast one pharmaceutical excipient, milling and mixing with extragranular blend of pharmaceutical excipienis selected from diluent, lubricant, disintegrant, sweetener and the like; are stable to color, chemical degradation and polymorphic changes for atleast 3 months at 40°C / 75% relative humidity in open vials*
Compaction of olanzapine and at least one pharmaceutical excipient is a key step in the process of the present invention.
Olanzapine is effective over a wide dosage range, the actual dose administered depending on the condition treated. For example, in the treatment of adult humans, dosages of from 0.25 to 50 mg per day may be used. A once-daily dosage is normally sufficient, although divided doses may be administered. Preferred tablets of the invention thus comprises 0.25 to 50 mg of olanzapine The preferred weight of the tablets is 50 to 1000 mg.
The pharmaceutical excipient may be selected from directly compressible calcium carbonate, dibasic calcium phosphate, microcrystalline cellulose, tribasic calcium phosphate, starches, celluloses and the like. The ratio of olanzapine (o phannaceutical excipient may be in the range of 1: i to 1:10 .
Calcium carbonate when included in orally- administered solid pharmaceutical products, such as tablets, the tablets readily disintegrates in the mouth, and thus eliminates the need for swallowing the tablets in order to release the active pharmaceutical ingredient. It accelerates rapid disintegration of the tablets when the tablets contacts water and is used in conjunction with a super disintegrant.
The compacts of olanzapine and at least one pharmaceutical excipient obtained on compaction may be subjected to milling. Granules obtained may have an average diameter of less than 600 microns.

The granules obtained are then mixed with extragranular blend comprising pharmaceutical excipients such as diluent(s), lubricant(s), disintegrant(s), binders) flavoring agent(s). coloring agent(s), stabilizer(s), surfactant(s), glidant(s), plasticizci^s), prcscrvativc(s) and swcctcncrts). The pharmaceutical excipient must be compatible with olanzapine.
The amounts of excipients used in the formulation are for the diluent from 20 to 90 %, for the disintegrant up to 15 %, for the binder from 5 to 20 %, for the lubricant from 0.25 to 5 %, for the sweetener from 0.1 to 3 %.
Diluents may be selected from inorganic diluents such as calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate; celluloses such as microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, ethyl cellulose, starches, saccharides and sugar alcohols such as dextrates, dextrose,fructosejactitol,lactose anhydrous, lactose monohydrate, lactose diliydrate, lactose trihydrate, mannitol sorbitol, starch, prege latinized starch ,sucrose,talc,xyIitol,maltose maltodextrin,maltitol.
Binders may be selected from acacia, alginic acid, carbomer,carboxymethylcellulose calcium, carbomethyicellulose sodium,microcrystalline ceiiuiose.powdcred cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl ccllulos, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,methylcellulose,ploydextrose, polyethtylene oxide,povidone,sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl celiulose,glucose, sorbitol.
Suitable fillers are preferably selected from atleast one of starch derivatives.such as corn starch, potato starch or rice starch.Polysaccharides such as dextrins, maltodextrins. dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol.
Disintegrants may be selected from alginic acid, carbon dioxide, carbonxymethylcellulose calcium carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose. methylcellulose, polacrilin potassium , poloxamer. povidone, sodium alginate, sodium glycine

carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose.
Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.
Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyi fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, and glyceryl behenate.
Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cvclamate and salts thereof; saccharin and salts thereof; and aspartame.
Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavour and peppermint flavour.
The mixture obtained on mixing granules comprising olanzapine with at least one pharmaceutical excipient with extragranular blend is then compressed into tablets using conventional compression techniques known to a person skilled in the art.
Tablets of the present invention may be soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, effervescent tablet, chewable tablet, water dispersible tablet and orodispersible tablet.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.

EXAMPLES
Example 1

Ingredients mg/tab
Intruaranular
Olanzapine Form I 20
Calcium Carbonate Directly Compressible 78
Mg Stearate 2
Extrasranular
Crospovidone 15
Aspartame 5
Lactose spray dried 376.75
Mg Stearate 3.25
Average weight 500
Analytical data (a) HPLC analysis

I
NAME RESULT S
Zero time 2 months
40°C/75%RH
open vial 3 months
40°C/75%RH
open vial
opl 0,01% N.O. N.D.
N-oxide* 0.03% 0.35% 0.31%
op2 0:04% 0.04% 0,04%
op4* 0.02% 0.29% 0.30%
Total unknown 0J0% 0,07% 0.07%
Total impurities 0:20% 0:75% 0.72%
* op4 is 2-methyl-IOH-thieno[2.3-b][l,5]benzodiazepine-4-one
* N-Oxidc is 2-methyl-4-(4-meth>l-4-oxido-]-pipera7.in\[)-l0H-thieno[2.j- b]
[l.5]bcnzodiazepine

(b) Visual inspection of 3 months 40 C / 75% relative humidity open vial samples indicates no change in color.
(c ) XRD analysis of 3 months 40"C / 75% relative humidity open vial samples indicates retention of Form I.
Examples 2,3 & 4

Ingredients mg/tab
Intragranular
Olanzapine Form I 20
Calcium Carbonate Directly Compressible or Microcrystalline Cellulose or Oibasic calcium phosphate 78.5
Mg Stearate 1.5
Extra granular
Lactose SD 340
Microcrystalline Cellulose 50
Aspartame 5
Mg stearate 5
Average weight 500
Example 5 : Test for content uniformity (as per PhEur §2.9.40]
The acceptance values for Olanzapine pilot 1, 5/10/15/20mg tablets

mg AV<15
5 6,8
10 6.2
15 6.6
20 8,6

We Claim:
1. Stable olanzapine tablets comprising compacted biend of olanzapine and at least one pharmaceutical excipient; mixed with extragranular blend of diluent(s), disintegrant(s). Iubricant(s) and sweetener(s); wherein the said tablets are stable to color, chemical degradation and polymorphic changes for atleast 3 months at 40 C / 75% relative humidity in open vials.
2. Stable olanzapine tablets as claimed in claim 1 wherein the tablets are not coated.
3. Stable olanzapine tablets as claimed in claim I wherein pharmaceutical excipient is selected from directly compressible calcium carbonate, dibasic calcium phosphate, microcrystalline tribasic calcium phosphate, celluloses , cellulose based polymers and starches.
4. Stable olanzapine tablets as claimed in claim 1 wherein the extragranular blend comprises diluent(s), lubricant(s), disintegrant(s) and sweetener(s).
5. Stable olanzapine tablets as claimed in claim 1 wherein chemical degradation impurity is <0.5%byHPLC.
6. A process for the preparation of stable olanzapine tablets comprising compacting blend of olanzapine and at least one pharmaceutical excipient, miiiing compacts to granules, mixing granules with extragranular blend and compressing into tablets.
7. A process as claimed in claim 6 wherein the said tablets are stable to color, chemical and degradation polymorphic changes for atleast 3 months at 40° C / 75% relative humidity in open vials.
8. A process as claimed in claim 6 wherein the tablets are not coated.
9. A process as claimed in claim 6 wherein the pharmaceutical excipient is selected from directly compressible calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, celluloses cellulose based polymers and starches.
10. A process as claimed in claim 6 wherein the extragranular blend comprises diluem(s), lubricant(s), disintegrant(s) and sweeteners).
11. A process as claimed in claim 6 wherein chemical degradation impurity is <0.5% by HPLC.
12. Stable olanzapine tablets comprising compacted blend of olanzapine, pharmaceutical excipient selected from directly compressible calcium carbonate or microcrystalline cellulose or dibasic calcium phosphate; mixed with extragranular blend of lactose, magnesium stearate, crospovidone or microcrystalline cellulose and aspartame, wherein

the said tablets are stable to color, chemical & degradation polymorphic changes for atleast 3 months at 40° C / 75% relative humidity in open vials.
13. Stable olanzapine tablets as claimed in claim 11 wherein the tablets are not coated
14. Stable olanzapine tablets as claimed in claim 11 wherein chemical degradation impurity is <0.5% by HPLC.
15. A process for the preparation of stable olanzapine tablets comprising compacting blend of olanzapine, directly compressible calcium carbonate or microcrystalline cellulose or dibasic calcium phosphate; milling the compacts to granules; mixing the granules with extragranular blend comprising lactose, magnesium stearate, crospovidone or microcrystalline cellulose and aspartame; and compressing into tablets.
16. A process as claimed in claim 15 wherein the said tablets are stable to color, chemical & degradation polymorphic changes for atleast 3 months at 40° C / 75% relative humidity in open vials.
17. A process for preparing stable olanzapine tablets as claimed in claim 15 wherein the tablets are not coated.
18. A process as claimed in claim 15 wherein chemical degradation impurity is <0.5% by HPLC.