WO2013093934A1 - Process for preparation of decitabine injection - Google Patents
Process for preparation of decitabine injection Download PDFInfo
- Publication number
- WO2013093934A1 WO2013093934A1 PCT/IN2012/000598 IN2012000598W WO2013093934A1 WO 2013093934 A1 WO2013093934 A1 WO 2013093934A1 IN 2012000598 W IN2012000598 W IN 2012000598W WO 2013093934 A1 WO2013093934 A1 WO 2013093934A1
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- WIPO (PCT)
- Prior art keywords
- decitabine
- impurity
- vial
- lyophilized
- compressed air
- Prior art date
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- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 title claims abstract description 72
- 229960003603 decitabine Drugs 0.000 title claims abstract description 71
- 238000002347 injection Methods 0.000 title claims abstract description 35
- 239000007924 injection Substances 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 239000012535 impurity Substances 0.000 claims abstract description 56
- 239000000203 mixture Substances 0.000 claims abstract description 36
- 238000004108 freeze drying Methods 0.000 claims description 21
- 238000012792 lyophilization process Methods 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000008364 bulk solution Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000012495 forced degradation study Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 229940111688 monobasic potassium phosphate Drugs 0.000 description 3
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000006198 deformylation Effects 0.000 description 2
- 238000006344 deformylation reaction Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229940083608 sodium hydroxide Drugs 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- 101100437175 Aspergillus niger (strain ATCC 1015 / CBS 113.46 / FGSC A1144 / LSHB Ac4 / NCTC 3858a / NRRL 328 / USDA 3528.7) azaC gene Proteins 0.000 description 1
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 1
- SQSPRWMERUQXNE-UHFFFAOYSA-N Guanylurea Chemical class NC(=N)NC(N)=O SQSPRWMERUQXNE-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- OQSJWQNOMXRCEL-UHFFFAOYSA-N methyl 4-methylbenzoate Chemical group [CH2]C1=CC=C(C(=O)OC)C=C1 OQSJWQNOMXRCEL-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
- 239000012808 vapor phase Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- This invention relates to an improved process to obtain a stable lyophilized Decitabine composition by allowing compressed air in lyophilizer for conversion of impurity to Decitabine.
- Decitabine 5-aza-2'-deoxycytidine
- One of the major challenges with Decitabine is its chemical instability. It is well-known that Decitabine and related nucleoside analogues decompose within few hours at physiological temperature and pH. Decitabine is degraded via hydrolytic opening of the triazine ring, deformylation, and anomerization. This result in reduced drug concentration and the degradation products may have pharmacological and toxic properties independent of the Decitabine. Hydrolytic ring-opening in Decitabine occurs at C-6 position in aqueous solutions under acidic conditions; its glycosidic bond is labile, releasing the free base azaC and deoxyribose.
- vial to vial variation in amount of impurity present in the lyophilized composition there is vial to vial variation in amount of impurity present in the lyophilized composition.
- the inventors of the present invention have found out that by making a few incremental changes in the lyophilization process, a stable lyophilized Decitabine composition is obtained. Further, the process according to the present invention also minimizes vial to vial variation of impurity in lyophilized Decitabine injection composition.
- the main object of the present invention is to prepare lyophilized Decitabine injection composition having reduced levels of impurity. Another object of the present invention is to minimize vial to vial variation of impurity in lyophilized Decitabine injection composition.
- Another object of the present invention is to minimize vial to vial variation of impurity at RRT 0.7 in lyophilized Decitabine injection composition.
- Another object of the invention is to use compressed air in the lyophilizer after lyophilization process for the preparation of lyophilized Decitabine injection composition in order to convert impurity back to Decitabine.
- the invention relates to process to obtain stable lyophilized Decitabine injection composition having reduced amount of impurity by allowing compressed air in lyophilizer for 1-24 hour after lyophilization cycle. During this time, the impurity formed during the bulk manufacturing process is reversed back to Decitabine.
- the invention relates to the process for the preparation of lyophilized Decitabine injection composition wherein vial to vial variation of impurity is at minimum in the said lyophilized injection composition.
- Lyophilization or freeze-drying is a process in which water is removed from a product after it is frozen and placed in a surrounding with vacuum, which allows the frozen water to sublimate directly from a solid to a vapor phase, without passing through a liquid phase.
- the lyophilization process consists of three separate, unique, and interdependent processes; a freezing phase, a primary drying phase (sublimation), and a secondary drying phase (desorption).
- the vacuum is usually broken with an inert gas, such as nitrogen, before the product is stoppered.
- Lyophilization is sometimes employed to formulate injectable pharmaceuticals that exhibit poor active ingredient stability in aqueous solutions. It is common practice to sparge inert gas such as nitrogen during formulation of injectable preparation in order to minimize the degradation of active constituents.
- impurity in lyophilized Decitabine composition are divided into characterized / known impurity and unknown impurity; wherein known impurity is methyl-4-methyl benzoate, a anomer and mono ester impurity.
- compressed air refers to compressed air or atmospheric air or a synthetic mixture of 21 % oxygen and 79% nitrogen.
- DacogenTM which contains 50 mg Decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 1 1 .6 mg sodium hydroxide.
- the amount of impurity present in Decitabine bulk solution is gradually increased as time passes during the manufacture of bulk solution. Also there is variation in amount of impurity present in vial to vial when lyophilized Decitabine injection is prepared according to conventional preparation methods known i.e. either using nitrogen sparging or without using nitrogen sparging.
- inventors of the present invention designed a novel process for the preparation of Decitabine injection using compressed air in the lyophilizer.
- vacuum is broken with compressed air and compressed air is allowed in lyophilizer for about 1 -24 hour, preferably for about 10-24 hours more preferably 18-24 hours.
- lyophilized Decitabine injection composition is prepared without using inert gas during bulk manufacturing process.
- the vacuum was broken with compressed air after lyophilization cycle was completed and the vials were kept as such without stoppering in lyophilizer for 18- 24 hours in presence of compressed air for conversion of impurity into Decitabine.
- the present invention provides a stable lyophilized Decitabine injection composition, wherein the impurity does not exceed 0.2% w/w in the said composition.
- the present invention provides an improved process for the preparation of stable lyophilized Decitabine injection composition comprising impurity not exceeding 0.2% w/w; wherein the improvisation of lyophilization comprises the step of allowing compressed air in the lyophilizer for a time period of 1 to 24 hours after the completion of lyophilization cycle. More specifically, once the lyophilization process is completed, vacuum is broken with compressed air and compressed air is allowed in lyophilizer for about 1-24 hour, preferably for about 10-24 hours more preferably 18-24 hours.
- the present invention provides a stable lyophilized Decitabine injection composition, wherein variation of impurity at RRT 0.7 from vial to vial in the said stable lyophilized Decitabine injection is not more than 0.1% w/w.
- the present invention provides an improved process for the preparation of stable lyophilized Decitabine injection composition wherein variation of impurity at RRT 0.7 from vial to vial in the said stable lyophilized Decitabine injection is not more than 0.1% w/w; wherein the improvisation of lyophilization comprises the step of allowing compressed air in the lyophilizer for a time period of 1 to 24 hours, after the completion of lyophilization cycle.
- Example 1 More specifically, once the lyophilization process is completed, vacuum is broken with compressed air and compressed air is allowed in lyophilizer for about 1 - 24 hour, preferably for about 10-24 hours more preferably 18-24 hours.
- Example 1 Example 1:
- Example 2 Lyophilized Decitabine injection composition prepared according to the present invention
- the headspace of the vials were taken and confirmed that the headspace is approximately 20% - 21%.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to process for the preparation of stable lyophilized Decitabine injection composition having reduced amount of impurity. Also present invention relates a process for minimizing the vial to vial variation of impurity.
Description
FIELD OF THE INVENTION
This invention relates to an improved process to obtain a stable lyophilized Decitabine composition by allowing compressed air in lyophilizer for conversion of impurity to Decitabine.
BACKGROUND OF THE INVENTION Decitabine, 5-aza-2'-deoxycytidine, is an antagonist of its related natural nucleoside, deoxycytidine. One of the major challenges with Decitabine is its chemical instability. It is well-known that Decitabine and related nucleoside analogues decompose within few hours at physiological temperature and pH. Decitabine is degraded via hydrolytic opening of the triazine ring, deformylation, and anomerization. This result in reduced drug concentration and the degradation products may have pharmacological and toxic properties independent of the Decitabine. Hydrolytic ring-opening in Decitabine occurs at C-6 position in aqueous solutions under acidic conditions; its glycosidic bond is labile, releasing the free base azaC and deoxyribose.
Scheme for Decitabine decomposition in aqueous solution
II III
Decitabine (I) is in equilibrium with its ring-open-formylated derivative (II), which undergoes irreversible deformylation and formation of the guanylurea derivative (III). Decitabine, which is chemically unstable in aqueous solution, is commonly supplied as a sterile lyophilized powder for injection. In order to prepare lyophilized composition, bulk solution containing Decitabine is prepared and thereafter the solution is lyophilized in vials. However, it is observed by the inventors of the present invention that when lyophilized Decitabine injection is prepared by using normal lyophilization technique or by using nitrogen gas during lyophilization process, the amount of impurity present in the lyophilized product are high. Further, there is vial to vial variation in amount of impurity present in the lyophilized composition. To overcome the above mentioned problems associated with lyophilized Decitabine injection composition, the inventors of the present invention have found out that by making a few incremental changes in the lyophilization process, a stable lyophilized Decitabine composition is obtained. Further, the process according to the present invention also minimizes vial to vial variation of impurity in lyophilized Decitabine injection composition.
OBJECTS OF THE INVENTION The main object of the present invention is to prepare lyophilized Decitabine injection composition having reduced levels of impurity.
Another object of the present invention is to minimize vial to vial variation of impurity in lyophilized Decitabine injection composition.
Another object of the present invention is to minimize vial to vial variation of impurity at RRT 0.7 in lyophilized Decitabine injection composition.
Another object of the invention is to use compressed air in the lyophilizer after lyophilization process for the preparation of lyophilized Decitabine injection composition in order to convert impurity back to Decitabine.
SUMMARY OF THE INVENTION
The invention relates to process to obtain stable lyophilized Decitabine injection composition having reduced amount of impurity by allowing compressed air in lyophilizer for 1-24 hour after lyophilization cycle. During this time, the impurity formed during the bulk manufacturing process is reversed back to Decitabine.
Further the invention relates to the process for the preparation of lyophilized Decitabine injection composition wherein vial to vial variation of impurity is at minimum in the said lyophilized injection composition.
DETAILED DESCRIPTION
Lyophilization or freeze-drying is a process in which water is removed from a product after it is frozen and placed in a surrounding with vacuum, which allows the frozen water to sublimate directly from a solid to a vapor phase, without passing
through a liquid phase. The lyophilization process consists of three separate, unique, and interdependent processes; a freezing phase, a primary drying phase (sublimation), and a secondary drying phase (desorption). After the freeze-drying process is complete, the vacuum is usually broken with an inert gas, such as nitrogen, before the product is stoppered.
Lyophilization is sometimes employed to formulate injectable pharmaceuticals that exhibit poor active ingredient stability in aqueous solutions. It is common practice to sparge inert gas such as nitrogen during formulation of injectable preparation in order to minimize the degradation of active constituents.
It is observed by the inventors of the present inventors, that when lyophilized Decitabine injection composition is prepared by using normal lyophilization technique or by using nitrogen gas during lyophilization process, the amount of impurity present in the lyophilized injection is high. Also, there is vial to vial variation in amount of impurity present, compared to lyophilized injection prepared according to present invention i.e. allowing compressed air for about 18-24 hours in the lyophilizer after lyophilization cycle is complete. Allowing of compressed air in the lyophilizer after completion of lyophilization cycle helps reduce the impurity levels in the lyophilized product.
Presently, impurity in lyophilized Decitabine composition are divided into characterized / known impurity and unknown impurity; wherein known impurity is methyl-4-methyl benzoate, a anomer and mono ester impurity.
Single major unknown impurity is impurity at RRT 0.7; which when determined using HPLC equipped with DAD Detector (Make: Agilent 1 100 series or equivalent) using Zorbax RX-SIL (250 x 4.6 mm) column and acetonitrile: water (19: 1 ) as
mobile phase with 1.0 mL/min flow rate having sample temperature 2-8°C, having relative retention time of 0.7 with respect to Decitabine which is having retention time of about 12 min in described conditions. Two isomeric forms of Decitabine are established as a anomer and β anomer; wherein a anomer is an inactive form and β anomer is the active form of Decitabine. In aqueous solution, Decitabine gets converted from β anomer to a anomer.
As used herein, the term "compressed air" refers to compressed air or atmospheric air or a synthetic mixture of 21 % oxygen and 79% nitrogen.
Currently, Decitabine is available as Dacogen™, which contains 50 mg Decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 1 1 .6 mg sodium hydroxide.
The amount of impurity present in Decitabine bulk solution is gradually increased as time passes during the manufacture of bulk solution. Also there is variation in amount of impurity present in vial to vial when lyophilized Decitabine injection is prepared according to conventional preparation methods known i.e. either using nitrogen sparging or without using nitrogen sparging.
It is found by the inventors that when vials having high amount of impurity were allowed to remain open, then the amount of impurity is decreased significantly. Below mentioned data suggests that when vials having high levels of impurity are exposed to air, then it would significantly reduce the levels of impurity.
Time intervals Level of Impurity at RRT 0.7
Initial 2.5%
After 17 Hrs 0.04%
After 22 Hrs Not Detected
Based on above observations, inventors of the present invention designed a novel process for the preparation of Decitabine injection using compressed air in the lyophilizer.
The presence of oxygen / environmental air is useful for fast, complete and uniform conversion of impurity to Decitabine once water is removed during lyophilization.
According to present invention, once the lyophilization process is completed, vacuum is broken with compressed air and compressed air is allowed in lyophilizer for about 1 -24 hour, preferably for about 10-24 hours more preferably 18-24 hours.
According to one embodiment of the present invention, lyophilized Decitabine injection composition is prepared without using inert gas during bulk manufacturing process. The vacuum was broken with compressed air after lyophilization cycle was completed and the vials were kept as such without stoppering in lyophilizer for 18- 24 hours in presence of compressed air for conversion of impurity into Decitabine. After exposing vials to air for 18-24 hours at room temperature in lyophilizer, the vials were stoppered and unloaded. The headspace of the vials were taken and confirmed that the headspace is approximately 20% - 21%.
Further, according to another embodiment, the present invention provides a stable lyophilized Decitabine injection composition, wherein the impurity does not exceed 0.2% w/w in the said composition.
Also, according to another embodiment, the present invention provides an improved process for the preparation of stable lyophilized Decitabine injection composition comprising impurity not exceeding 0.2% w/w; wherein the improvisation of lyophilization comprises the step of allowing compressed air in the lyophilizer for a time period of 1 to 24 hours after the completion of lyophilization cycle. More specifically, once the lyophilization process is completed, vacuum is broken with compressed air and compressed air is allowed in lyophilizer for about 1-24 hour, preferably for about 10-24 hours more preferably 18-24 hours. Further, according to another embodiment, the present invention provides a stable lyophilized Decitabine injection composition, wherein variation of impurity at RRT 0.7 from vial to vial in the said stable lyophilized Decitabine injection is not more than 0.1% w/w. Further, according to another embodiment, the present invention provides an improved process for the preparation of stable lyophilized Decitabine injection composition wherein variation of impurity at RRT 0.7 from vial to vial in the said stable lyophilized Decitabine injection is not more than 0.1% w/w; wherein the improvisation of lyophilization comprises the step of allowing compressed air in the lyophilizer for a time period of 1 to 24 hours, after the completion of lyophilization cycle. More specifically, once the lyophilization process is completed, vacuum is broken with compressed air and compressed air is allowed in lyophilizer for about 1 - 24 hour, preferably for about 10-24 hours more preferably 18-24 hours. In the following section embodiments are described by a way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of present invention. Several variants of these examples would be evident to present person ordinarily skilled in the art.
Example 1:
Lyophilized Decitabine injection composition
a) Bulk solution preparation
* Removed during lyophilization Process for preparation:
1. Prepare bulk solution comprising Decitabine, monobasic potassium phosphate and sodium hydroxide in water for injection.
Stability studies for the above disclosed bulk solution is described in Table 1
Table 1: Stability Data of Decitabine for Injection Bulk solution
From table 1, it is observed that during preparation of bulk solution of Decitabine, impurity is steadily increased in solution as time progresses.
b) Lyophilization of the Decitabine bulk solution using nitrogen sparging
Bulk solution prepared above is further lyophilized using nitrogen sparging during process and head space of the vial. Table 2: Stability data of Bulk Solution and Lyophilized product (FP) produced from the same Bulk Solution
From table 2, it is observed that when Decitabine bulk solution was lyophilized using nitrogen sparging during process and in headspace of the vial, impurity is reverted back to Decitabine during lyophilization.
However, during scale-up of lyophilized process, it is observed that there is vial to vial variation of impurity, which gives a clue that the conversion of impurity into Decitabine is not uniform during / after the lyophilization cycle. (See Table 3)
Table 3- Vial to vial variation of impurity after lyophilization
* ND - Not detected
c) Forced degradation study
Forced degradation study for Decitabine formulation was carried out under various conditions such as normal, water hydrolysis, acidic conditions, basic conditions and in presence of oxidising agent such as KM 04. Objective of performing forced degradation study was to understand the vial to vial variation of impurity.
For normal conditions Decitabine powder is used as sample, for water hydrolysis solution of Decitabine in water is prepared, for acidic conditions 5.0mL 0.05M HCL is added to solution of Decitabine in water, for basic conditions 2.0mL 0.05M NaOH is added to solution of Decitabine in water, for oxidising conditions 1 mL 0.01 M NO4 is added to solution of Decitabine in water.
Results obtained are described in table below:
Table 4- Result of forced degradation study
Example 2: Lyophilized Decitabine injection composition prepared according to the present invention
Composition of Decitabine Bulk solution
* Removed during lyophilization
Process for preparation:
1. Prepare bulk solution comprising Decitabine, monobasic potassium phosphate and sodium hydroxide in water for injection with or without using any gas during manufacturing process.
2. Prepared bulk solution is subjected to lyophilization process using compressed air.
3. Vacuum was broken with compressed air after cycle was over and the vials were kept as such without stoppering in lyophilizer for 18-24 hours in presence of air.
4. After exposing vials to compressed air for 1 8-24 hours at room temperature in lyophilizer, the vials were stoppered and unloaded.
5. The headspace of the vials were taken and confirmed that the headspace is approximately 20% - 21%.
Analytical results of product obtained by present example:
Table 5 - Stability data of Lyophilized product (FP)
40 ± 2°C, 75 ± 5 % RH
25 ± 2°C, 60 ± 5 % RH (Upright
Conditions Initial (Upright)
1M 2M 3M 6M 3M 6M 9M 12V
Description White lyophilized cake
Assay 98.4% 98.9% 99.9% 99.7% 97.3% 99.7% 99.3% 101.91% 100.
Chromatographic Purity
Methyl 4- methyl 0.02% ND ND ND ND ND ND ND 0.02 benzoate
Mono ester
0.02% 0.01% 0.02% 0.03% BQL 0.03% BQL BQL BQI impurity
a anomer 0.04% 0.03% 0.03% 0.01 % BQL 0.04 BQL BQL BQI
Single
unknown
0.06% 0.01% 0.02% 0.01% BQL 0.02% ND BQL ND impurity at
RRT 0.7
Total
0.10% 0.05% 0.07% 0.05% BQL 0.10% BQL BQL 0.02 impurity
BQL - Below the levels of quantification M - month
ND - Not detected
From the stability data according to table 5, it can be inferred that the lyophilized 5 product obtained with respect to the process for preparation according to the present invention are stable and have reduced impurity levels.
Table 6 - Vial to vial variation of impurity after using compressed air
ND - Not detected
10
According to the data of table 6 for vial to vial variation of impurity with regards to lyophilized product obtained according to the present invention, it can be inferred that vial to vial variation of impurity is reduced and is uniform as compared to the lyophilized product obtained with conventional lyophilization process.
Claims
we ciaim,
1) An improved process to reduce impurity in Iyophilized Decitabine injection composition, wherein the improvisation comprises the step of
- allowing compressed air in lyophilizer after the completion of lyophilization cycle for a time period of 1 to 24 hours.
2) The improved process according to claim 1, wherein the impurity is impuritjy at RRT 0.7.
3) The improved process according to claim 2, wherein the impurity at RRT 0.7 does not exceed 0.2% w/w in the said stable Iyophilized Decitabine injection composition.
4) The improved process according to claim 1 , wherein variation of impurity at RRT 0.7 from vial to vial in the said stable Iyophilized Decitabine injection composition is reduced as compared to Iyophilized Decitabine injection composition obtained with respect to conventional lyophilization process.
5) The improved process according to claim 4, wherein variation of impurity at RRT 0.7 from vial to vial in the said stable Iyophilized Decitabine injection composition is not more than 0.1% w/w.
6) The improved process according to claim 1 , wherein the time period for allowing compressed air in lyophilizer is preferably between 10 to 24 hours.
7) The improved process according to claim 6, wherein the time period for allowing compressed air in lyophilizer is more preferably between 18 to 24 hours.
8) A stable Iyophilized Decitabine injection composition, wherein the impurity at RRT 0.7 does not exceed 0.2% w/w in the said composition.
9) A stable lyophilized Decitabine injection composition as obtained by the improvised lyophilization process as described here within the description
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2550MU2011 | 2011-09-09 | ||
| IN2550/MUM/2011 | 2011-09-09 |
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| Publication Number | Publication Date |
|---|---|
| WO2013093934A1 true WO2013093934A1 (en) | 2013-06-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2012/000598 WO2013093934A1 (en) | 2011-09-09 | 2012-09-07 | Process for preparation of decitabine injection |
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| Country | Link |
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| WO (1) | WO2013093934A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101637458A (en) * | 2009-08-19 | 2010-02-03 | 北京满格医药科技有限公司 | Preparation method of stable decitabine freeze-dried preparation |
| US20110042247A1 (en) * | 2009-06-25 | 2011-02-24 | Chandrasekhar Kocherlakota | Formulations of azacitidine and its derivatives |
-
2012
- 2012-09-07 WO PCT/IN2012/000598 patent/WO2013093934A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110042247A1 (en) * | 2009-06-25 | 2011-02-24 | Chandrasekhar Kocherlakota | Formulations of azacitidine and its derivatives |
| CN101637458A (en) * | 2009-08-19 | 2010-02-03 | 北京满格医药科技有限公司 | Preparation method of stable decitabine freeze-dried preparation |
Non-Patent Citations (1)
| Title |
|---|
| ANONYMOUS: "Remington, The science and practice of pharmacy", 2006, LIPPINCOTT WILLIAMS&WILKINS, USA, XP002698089 * |
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