WO2014030113A2 - Packaging for ivabradine hydrochloride - Google Patents

Packaging for ivabradine hydrochloride Download PDF

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Publication number
WO2014030113A2
WO2014030113A2 PCT/IB2013/056733 IB2013056733W WO2014030113A2 WO 2014030113 A2 WO2014030113 A2 WO 2014030113A2 IB 2013056733 W IB2013056733 W IB 2013056733W WO 2014030113 A2 WO2014030113 A2 WO 2014030113A2
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WO
WIPO (PCT)
Prior art keywords
bag
vacuum
sealed
vacuum sealed
pack according
Prior art date
Application number
PCT/IB2013/056733
Other languages
French (fr)
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WO2014030113A3 (en
Inventor
Venkat Raman JAYARAMAN
Sanjiv Tomer
Piyush Rana
Kamlesh Kanzariya
Sudhir Shah
Original Assignee
Alembic Pharmaceuticals Limited
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Publication date
Application filed by Alembic Pharmaceuticals Limited filed Critical Alembic Pharmaceuticals Limited
Publication of WO2014030113A2 publication Critical patent/WO2014030113A2/en
Publication of WO2014030113A3 publication Critical patent/WO2014030113A3/en

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Classifications

    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
    • B65D81/24—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants

Definitions

  • the present invention relates to a multiple packing and vacuum sealed pack comprising Ivabradine Hydrochloride.
  • Ivabradine hydrochloride of formula I has very valuable pharmacological and therapeutic properties, and is useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7,8-dimethoxy-3- ⁇ 3- ⁇ N-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-N-
  • Ivabradine with a pharmaceutically acceptable acid have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
  • Ivabradine hydrochloride is first disclosed in U.S. Patent No. 5,296,482.
  • the compound stability is one of the most important criteria by most of the regulatory agencies. Therefore one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life.
  • the compound transformations can occur also in the different solid state, because of changes in humidity or temperature or oxidative degradation conditions.
  • Ivabradine Hydrochloride solids are usually packed into various kinds of packing under normal conditions according to the prior art. These packing generally use LDPE, HDPE, plastic bags. Plastic bags find widespread use in the prior art.
  • Ivabradine Hydrochloride is known to occur in various crystalline forms as well as amorphous forms. However, Ivabradine Hydrochloride can be susceptible to oxidation, heat, light, moisture, low pH, and change to other crystalline forms. Impurities generated upon degradation of active substances can reduce the therapeutic effects of an active substance and unnecessarily burden the body with degradation products. For examples, oxidative degradation of Ivabradine Hydrochloride can lead to impurities such as which are unwanted.
  • Ivabradine Hydrochloride During our research on Ivabradine Hydrochloride it was observed that this class of compounds is not stable during stability tastings. Long term stability was performed at 25°C and 60% RH and 30°C and 65% RH. Accelerated stability was performed at 40°C and 75% RH. The Ivabradine hydrochloride has a tendency to change its polymorph and it appears that some different polymorph by-products are produced with time. The stability under nitrogen is known for Ivabradine Hydrochloride from the European Pharmacopoeia and the US Pharmacopoeia. It was observed that these conditions are not sufficient for Ivabradine Hydrochloride. In order to overcome this problem it was found that the packaging of Ivabradine Hydrochloride should be done in special conditions
  • In one aspect of the present invention provides a packaging system for Ivabradine Hydrochloride so as to enhance their stability. This can be provided by multiple packing and applying a vacuum, which provides additional benefits. Vacuum packed systems require a minimum of space (as compared to inflated bags produced by introduction of inert gases). Vacuum packaged systems are less prone to leakage and any leakage can be easily detected.
  • In another aspect of the present invention provides a method of stabilizing Ivabradine Hydrochloride using a multiple sealed pack comprising Ivabradine Hydrochloride and optionally pharmaceutically acceptable carrier or excipient.
  • a method of stabilizing Ivabradine Hydrochloride using a vacuum sealed pack comprising Ivabradine Hydrochloride and optionally pharmaceutically acceptable carrier or excipient.
  • a vacuum sealed pack wherein the pack comprises three layers.
  • a vacuum sealed pack wherein the innermost layer is a special plastic bag of (HM, HDPE) high molecular high-density poly ethylene comprises moisture absorber and vacuum sealed using heat induction.
  • HM high molecular high-density poly ethylene
  • the Middle layer is a special plastic bag of (HM, HDPE) high molecular high-density poly ethylene or Triple Laminate Sunlight Barrier (TLSB) bag comprises moisture absorber and vacuum sealed using heat induction.
  • HM, HDPE high molecular high-density poly ethylene
  • TLSB Triple Laminate Sunlight Barrier
  • the Outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra barrier (QLUB) bag comprises moisture absorber and vacuum sealed using heat induction.
  • QLUB quad laminate ultra barrier
  • the moisture absorber is selected from the group consisting of canister desiccant, desiccant, activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth.
  • the rigid container is non-airtight/air-tight plastic/metal drums, HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) drum.
  • an improved packing condition for Ivabradine Hydrochloride comprises layers as
  • Middle Triple Laminate Sunlight Barrier (TLSB) bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed.
  • TLSB Triple Laminate Sunlight Barrier
  • QLUB quad laminate ultra barrier
  • the packaging material for package system refer to the substances (e.g., glass, Polyethylene (PE), bi-axially oriented polypropylene (BOPP), PET (polyethylene terpthalate), oriented polyamide (OPA), aluminum foil, resin, metal) used to manufacture a packaging component.
  • substances e.g., glass, Polyethylene (PE), bi-axially oriented polypropylene (BOPP), PET (polyethylene terpthalate), oriented polyamide (OPA), aluminum foil, resin, metal
  • desiccant is a hygroscopic substance that induces or sustains a state of dryness (desiccation) in its local vicinity in a moderately well-sealed container.
  • desiccants Commonly encountered pre-packaged desiccants are solids, and work through absorption or adsorption of water, or a combination of the two.
  • Desiccants for specialized purposes may be in forms other than solid, and may work through other principles, such as chemical bonding of water molecules.
  • Pre-packaged desiccant is most commonly used to remove excessive humidity that would normally degrade or even destroy products sensitive to moisture.
  • Some commonly used desiccants are: silica gel, activated charcoal, calcium sulfate, calcium chloride, montmorillonite clay, and molecular sieves.
  • Silica gel is often used in musical instrument cases. A specific usage of a desiccant would be in insulated windows where it is placed inside the spacer between the air space and window edge. This prevents moisture condensation between the panes
  • the desiccant includes activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth.
  • the particular moisture-retaining materials used will depend upon the humidity level of the environment, for example, in a very low- humidity environment, a moisture-carrying material such as a hydrogel that partially binds water may be preferred.
  • the desiccant can be supplied in the form of a sachet, cartridge or canister.
  • a preferred form is a canister of silica gel, such as SorBitTM (commercially supplied by Sud-Chemie Corporation).
  • Multisorb provides variety of desiccant under trade name of Natrasorb M, Natrasorb S, Natrasorb C, and Hi-dry, which comprise diatomaceous earth, silica gel, calcium oxide and molecular sieve, respectively.
  • the size and number of desiccant can depend on the amount of residual moisture after vacuum has been applied, hence would mainly depend on package system such as HDPE bottle or permeable/impermeable bags.
  • the desiccant may be in the form of packet, sachet, strips or canisters.
  • the packet, sachet, strips or canisters may additionally comprise a moisture-indicating card.
  • the packaging material for package system could comprise air as well as moisture- impermeable material so that vacuum created during packaging is maintained throughout the shelf life of the drug. It can be chosen from Polyethylene (PE), bi-axially oriented polypropylene (BOPP), PET (polyethylene terpthalate), oriented polyamide (OPA), aluminum foil, or a blend of these polymers or a laminated structure of these polymers. Possible structures of the laminate are PET/aluminum foil/PE, or OPA/PET/PE, or Triple Laminate Sunlight Barrier (TLSB) or quad laminate ultra barrier (QLUB) bag and various other permutations and combinations are possible. The laminate structure would primarily depend on moisture/light or gas barrier required by the drug or the composition.
  • polyethylene-based resin there can be enlisted but are not limited to linear low density polyethylene (LLDPE), high density polyethylene (HDPE), low density polyethylene (LDPE), High Molecular High Density Polyethyene (HMHDPE) polypropylene, acrylonitrile, polyamide, polyvinylidinefluoride (PVDF), ethylene acrylic acid, ethylene/methacrylic acid (E/MAA) copolymer, polypropylene lacquer, polyacetal and copolymers thereof.
  • LLDPE linear low density polyethylene
  • HDPE high density polyethylene
  • LDPE low density polyethylene
  • HMHDPE High Molecular High Density Polyethyene
  • PVDF polyvinylidinefluoride
  • E/MAA ethylene acrylic acid
  • E/MAA ethylene/methacrylic acid
  • the rigid container as used herein include non-airtight/air-tight plastic/metal drums, corrugated shipper or fiberboard drum for drug packaging and HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) bottle for composition packaging.
  • HDPE high density polyethylene
  • PP polypropylene
  • LDPE low density polyethylene
  • PET PET
  • PVC polyvinyl chloride
  • the pack comprises three layers.
  • HM high molecular high- density poly ethylene bag
  • moisture absorber and vacuum sealed using heat induction.
  • the Middle layer is a Triple Laminate Sunlight Barrier (TLSB) bag comprises moisture absorber and vacuum sealed using heat induction.
  • TLSB Triple Laminate Sunlight Barrier
  • In another embodiment of the present invention is to provide a vacuum sealed pack wherein the Outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra barrier (QLUB) bag comprises moisture absorber and vacuum sealed using heat induction.
  • QLUB quad laminate ultra barrier
  • the moisture absorber is selected from the group consisting of canister desiccant, desiccant, activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth.
  • In another embodiment of the present invention is to provide a vacuum sealed pack wherein the bag is put in rigid container.
  • the rigid container is non-airtight/air- tight plastic/metal drums, HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) drum.
  • HDPE high density polyethylene
  • PP polypropylene
  • LDPE low density polyethylene
  • PET PET
  • PVC polyvinyl chloride
  • Middle Triple Laminate Sunlight Barrier (TLSB) bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed.
  • TLSB Triple Laminate Sunlight Barrier
  • QLUB quad laminate ultra barrier
  • HMHDPE bag vaccumised and heat sealed.
  • TLSB bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed.
  • Ivabradine Hydrochloride drug substance was packaged for long term use or transporting according to various packaging options as described below:
  • Ivabradine Hydrochloride was packaged in a HMHDPE bag and vacuum was applied the bag was heat sealed. This bag was put into a TSLB bag along with canister desiccant and vacuum was applied to TSLB bag and heat sealed. The sealed TSLB bag was packaged into a QLUB bag along with canister desiccant and vacuum was applied to the QLUB bag and heat sealed. The sealed QLUB bag then packed in HDPE drum.
  • TLSB bag having canister desiccant, nitrogen gas purged with
  • PACKAGING MODE Middle bag vacuum and heat sealed.
  • TLSB bag having canister desiccant, nitrogen gas purged
  • PACKAGING MODE Middle bag with vacuum and heat sealed.
  • TLSB bag having canister desiccant, nitrogen gas purged with vacuum
  • TLSB bag having canister desiccant, nitrogen gas purged with vacuum

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Abstract

The present invention relates to a multiple packing and vacuum sealed pack comprising Ivabradine hydrochloride.

Description

TITLE- PACKAGING FOR IVABRADINE HYDROCHLORIDE
FIELD OF THE INVENTION
The present invention relates to a multiple packing and vacuum sealed pack comprising Ivabradine Hydrochloride.
BACKGROUND OF THE INVENTION
Ivabradine hydrochloride of formula I, has very valuable pharmacological and therapeutic properties, and is useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7,8-dimethoxy-3- {3- {N-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-N-
(methyl)amino)propyl)-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride.
Figure imgf000002_0001
Formula - 1
Ivabradine with a pharmaceutically acceptable acid have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure. Ivabradine hydrochloride is first disclosed in U.S. Patent No. 5,296,482.
The compound stability is one of the most important criteria by most of the regulatory agencies. Therefore one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life. The compound transformations can occur also in the different solid state, because of changes in humidity or temperature or oxidative degradation conditions.
The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations, if the process conditions are not opportunistically controlled. Consequently, a stable Ivabradine hydrochloride would be a significant contribution to the art.
The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations, if the process conditions are not opportunistically controlled. Consequently, a stable Ivabradine Hydrochloride would be a significant contribution to the art.
Ivabradine Hydrochloride solids are usually packed into various kinds of packing under normal conditions according to the prior art. These packing generally use LDPE, HDPE, plastic bags. Plastic bags find widespread use in the prior art.
Ivabradine Hydrochloride is known to occur in various crystalline forms as well as amorphous forms. However, Ivabradine Hydrochloride can be susceptible to oxidation, heat, light, moisture, low pH, and change to other crystalline forms. Impurities generated upon degradation of active substances can reduce the therapeutic effects of an active substance and unnecessarily burden the body with degradation products. For examples, oxidative degradation of Ivabradine Hydrochloride can lead to impurities such as which are unwanted.
There have been various attempts to stabilize the Ivabradine Hydrochloride.
During our research on Ivabradine Hydrochloride it was observed that this class of compounds is not stable during stability tastings. Long term stability was performed at 25°C and 60% RH and 30°C and 65% RH. Accelerated stability was performed at 40°C and 75% RH. The Ivabradine hydrochloride has a tendency to change its polymorph and it appears that some different polymorph by-products are produced with time. The stability under nitrogen is known for Ivabradine Hydrochloride from the European Pharmacopoeia and the US Pharmacopoeia. It was observed that these conditions are not sufficient for Ivabradine Hydrochloride. In order to overcome this problem it was found that the packaging of Ivabradine Hydrochloride should be done in special conditions
OBJECT OF THE INVENTION:
Therefore, it is an object of the invention to provide packaging system for Ivabradine Hydrochloride so as to enhance their stability.
SUMMARY OF THE INVENTION
In one aspect of the present invention provides a packaging system for Ivabradine Hydrochloride so as to enhance their stability. This can be provided by multiple packing and applying a vacuum, which provides additional benefits. Vacuum packed systems require a minimum of space (as compared to inflated bags produced by introduction of inert gases). Vacuum packaged systems are less prone to leakage and any leakage can be easily detected.
In another aspect of the present invention provides a method of stabilizing Ivabradine Hydrochloride using a multiple sealed pack comprising Ivabradine Hydrochloride and optionally pharmaceutically acceptable carrier or excipient.
In another aspect of the present invention provides a method of stabilizing Ivabradine Hydrochloride using a vacuum sealed pack comprising Ivabradine Hydrochloride and optionally pharmaceutically acceptable carrier or excipient. In another aspect of the present invention provides a vacuum sealed pack wherein the pack comprises three layers.
In another aspect of the present invention provides a vacuum sealed pack wherein the innermost layer is a special plastic bag of (HM, HDPE) high molecular high-density poly ethylene comprises moisture absorber and vacuum sealed using heat induction.
In another aspect of the present invention provides a vacuum sealed pack wherein the Middle layer is a special plastic bag of (HM, HDPE) high molecular high-density poly ethylene or Triple Laminate Sunlight Barrier (TLSB) bag comprises moisture absorber and vacuum sealed using heat induction.
In another aspect of the present invention provides a vacuum sealed pack wherein the Outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra barrier (QLUB) bag comprises moisture absorber and vacuum sealed using heat induction.
In another aspect of the present invention provides a vacuum sealed pack wherein the moisture absorber is selected from the group consisting of canister desiccant, desiccant, activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth.
In another aspect of the present invention provides a vacuum sealed pack wherein the bag is put in rigid container.
In another aspect of the present invention provides a vacuum sealed pack wherein the rigid container is non-airtight/air-tight plastic/metal drums, HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) drum. In another aspect of the present invention provides an improved packing condition for Ivabradine Hydrochloride comprises layers as
a. Innermost: HMHDPE bag vaccumised and heat sealed.
b. Middle: Triple Laminate Sunlight Barrier (TLSB) bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed. c. Outermost: quad laminate ultra barrier (QLUB) bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed, then packed in HDPE drum.
DETAILED DESCRIPTION OF THE INVENTION
The packaging material for package system refer to the substances (e.g., glass, Polyethylene (PE), bi-axially oriented polypropylene (BOPP), PET (polyethylene terpthalate), oriented polyamide (OPA), aluminum foil, resin, metal) used to manufacture a packaging component.
The term "desiccant" is a hygroscopic substance that induces or sustains a state of dryness (desiccation) in its local vicinity in a moderately well-sealed container. Commonly encountered pre-packaged desiccants are solids, and work through absorption or adsorption of water, or a combination of the two. Desiccants for specialized purposes may be in forms other than solid, and may work through other principles, such as chemical bonding of water molecules.
Pre-packaged desiccant is most commonly used to remove excessive humidity that would normally degrade or even destroy products sensitive to moisture. Some commonly used desiccants are: silica gel, activated charcoal, calcium sulfate, calcium chloride, montmorillonite clay, and molecular sieves. Silica gel is often used in musical instrument cases. A specific usage of a desiccant would be in insulated windows where it is placed inside the spacer between the air space and window edge. This prevents moisture condensation between the panes
The desiccant includes activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth. The particular moisture-retaining materials used will depend upon the humidity level of the environment, for example, in a very low- humidity environment, a moisture-carrying material such as a hydrogel that partially binds water may be preferred. The desiccant can be supplied in the form of a sachet, cartridge or canister. A preferred form is a canister of silica gel, such as SorBit™ (commercially supplied by Sud-Chemie Corporation). Multisorb provides variety of desiccant under trade name of Natrasorb M, Natrasorb S, Natrasorb C, and Hi-dry, which comprise diatomaceous earth, silica gel, calcium oxide and molecular sieve, respectively.
The size and number of desiccant can depend on the amount of residual moisture after vacuum has been applied, hence would mainly depend on package system such as HDPE bottle or permeable/impermeable bags. The desiccant may be in the form of packet, sachet, strips or canisters. The packet, sachet, strips or canisters may additionally comprise a moisture-indicating card.
The packaging material for package system could comprise air as well as moisture- impermeable material so that vacuum created during packaging is maintained throughout the shelf life of the drug. It can be chosen from Polyethylene (PE), bi-axially oriented polypropylene (BOPP), PET (polyethylene terpthalate), oriented polyamide (OPA), aluminum foil, or a blend of these polymers or a laminated structure of these polymers. Possible structures of the laminate are PET/aluminum foil/PE, or OPA/PET/PE, or Triple Laminate Sunlight Barrier (TLSB) or quad laminate ultra barrier (QLUB) bag and various other permutations and combinations are possible. The laminate structure would primarily depend on moisture/light or gas barrier required by the drug or the composition. As the polyethylene-based resin, there can be enlisted but are not limited to linear low density polyethylene (LLDPE), high density polyethylene (HDPE), low density polyethylene (LDPE), High Molecular High Density Polyethyene (HMHDPE) polypropylene, acrylonitrile, polyamide, polyvinylidinefluoride (PVDF), ethylene acrylic acid, ethylene/methacrylic acid (E/MAA) copolymer, polypropylene lacquer, polyacetal and copolymers thereof.
The rigid container as used herein include non-airtight/air-tight plastic/metal drums, corrugated shipper or fiberboard drum for drug packaging and HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) bottle for composition packaging.
In one of the embodiment of the present invention is to provide a vacuum sealed pack wherein the pack comprises three layers.
In another embodiment of the present invention is to provide a vacuum sealed pack wherein the innermost layer is a special plastic bag of (HM, HDPE) high molecular high- density poly ethylene bag comprises moisture absorber and vacuum sealed using heat induction.
In another embodiment of the present invention is to provide a vacuum sealed pack wherein the Middle layer is a Triple Laminate Sunlight Barrier (TLSB) bag comprises moisture absorber and vacuum sealed using heat induction.
In another embodiment of the present invention is to provide a vacuum sealed pack wherein the Outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra barrier (QLUB) bag comprises moisture absorber and vacuum sealed using heat induction.
In another embodiment of the present invention is to provide a vacuum sealed pack wherein the moisture absorber is selected from the group consisting of canister desiccant, desiccant, activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth.
In another embodiment of the present invention is to provide a vacuum sealed pack wherein the bag is put in rigid container.
In another embodiment of the present invention is to provide a vacuum sealed pack wherein the rigid container is non-airtight/air- tight plastic/metal drums, HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) drum.
In another embodiment of the present invention is to provide an improved packing condition for Ivabradine Hydrochloride API comprises layers as
a. Innermost: HMHDPE bag vaccumised and heat sealed.
b. Middle: Triple Laminate Sunlight Barrier (TLSB) bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed. c. Outermost: quad laminate ultra barrier (QLUB) bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed, then packed in HDPE drum.
Packaging conditions
To avoid degradation during stability, following is the recommended packing condition for Ivabradine Hydrochloride:
Innermost: HMHDPE bag vaccumised and heat sealed.
Middle: TLSB bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed.
Outermost: QLUB bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed, then packed in HDPE drum.
Material should be packed at 25°C+/-2°C 35%+/-5% RH Example
Ivabradine Hydrochloride drug substance was packaged for long term use or transporting according to various packaging options as described below:
Ivabradine Hydrochloride was packaged in a HMHDPE bag and vacuum was applied the bag was heat sealed. This bag was put into a TSLB bag along with canister desiccant and vacuum was applied to TSLB bag and heat sealed. The sealed TSLB bag was packaged into a QLUB bag along with canister desiccant and vacuum was applied to the QLUB bag and heat sealed. The sealed QLUB bag then packed in HDPE drum.
IVABRADINE HC1 INDICATIVE STABILITY SUMMRY DATA, BEFORE VALIDATION
STABILITY
Batch No CG-3180/IV/1753/36
Packing details:
Inner bag LDPE bag vaccumised and heat sealed
Middle bag HMHDPE bag under nitrogen gas purged and heat sealed.
Triple laminated aluminium bag having desicant, under nitrogen gas purged and
Outer bag
heat sealed, then packed in HDPE drum.
Test Initial 7 days 15 days 30 days 45 days
40°C & 40°C & 40°C & 40°C & 75%RH 75%RH 75%RH 75%RH
XRD Complies Complies Complies Complies Not complies
Delta-d Delta-d Delta-d Delta-d
Date of
7/12/2011 13/12/201 1 21/12/2011 5/1/2012 24/01/12 analysis IVABRADINE HCl INDICATIVE STABILITY SUMMRY DATA, BEFORE VALIDATION
STABILITY
Batch No CG-3180/IV/1688/23
Packing details:
Inner bag LDPE bag vaccumised and heat sealed
Middle bag HMHDPE bag under nitrogen gas purged and heat sealed.
Triple laminated aluminium bag having desicant, under nitrogen gas purged and
Outer bag
heat sealed, then packed in HDPE drum.
Test Initial 1 Month
30°C & 65%RH 40°C & 75%RH
Description White powder White powder White powder
% Purity by HPLC 99.93% 99.96% 99.96%
Water (W/W) (Limit :
7.76 5.29 3.56
6-9)
XRD Complies Does not comply Does not comply
Form Delta Delta + Delta-d Delta-d form
Date of analysis 20/05/2011 16/06/2011 16/06/2011
LONG TERM STABILITY DATA
Product Ivabradine
Name : hydrochloride
IVAB- Temperature Stability Protocol No.: ADL/ST-12/002
Batch No. 003/IV/1846/12 2°C-8°C
Purpose Manufacturing Month
of Type of Long January- 12
stability: New Product study : Term
Length of Data presented : 12 month
study: 12 months
Inner bag HMHDPE bag vaccumized and heat sealed.
TLSB bag having canister desiccant, nitrogen gas purged with
PACKAGING MODE: Middle bag vacuum and heat sealed.
QLUB bag having canister desiccant, nitrogen gas purged with
Outer bag vacuum and heat sealed, then packed in HDPE drum.
Sr. No. Test Specification Stability Study for the Month
Initial 3 month 6 month 9 month 12 month
White to off White White White White White
1 Description
white powder. powder powder powder powder powder
Water by KF Not more than
2 0.47 0.57 0.79 0.82 0.9 (% w/w) 2.0
Hydroxy Not more than
ND ND ND ND ND
analogue 0.15
Acetyl Not more than
ND ND ND ND ND
analogue 0.15
Dehydro Not more than
ND ND ND ND ND
analogue 0.15
Any other Not more than
0.04 0.04 0.04 0.04 0.04 impurity 0.10
Total Not more than
0.12 0.1 0.11 0.10 0.10 impurities 0.50
Assay (By
HPLC, % w/w)
4 98.0 to 102.0 98.8 100.5 99.7 100.5 100.2 (On anhydrous
basis)
5 XRD ** Complies Complies Complies Complies Complies LONG TERM STABILITY DATA
Product Ivabradine
Name : hydrochloride
Stability Protocol
Batch IVAB- Temperature ADL/ST- 12/002
No.:
No. 003/IV/1846/13 2°C-8°C
Purpose Manufacturing
of Type of study Long January- 12
Month :
stability: New Product Term
Length Data presented : 12 month
of study: 12 months
Inner bag HMHDPE bag vaccumized and heat sealed.
TLSB bag having canister desiccant, nitrogen gas purged
PACKAGING MODE: Middle bag with vacuum and heat sealed.
QLUB bag having canister desiccant, nitrogen gas purged
Outer bag with vacuum and heat sealed, then packed in HDPE drum.
Sr. No. Test Specification Stability Study for the Month
Initial 3 month 6 month 9 month 12 month
White to off White White White White White
1 Description
white powder. powder powder powder powder powder
Water by F Not more than
2 0.47 0.65 0.58 0.51 0.58
(% w/w) 2.0
Hydroxy Not more than
ND ND ND ND ND
analogue 0.15
Acetyl Not more than
ND ND ND ND ND
analogue 0.15
Dehydro Not more than
ND ND ND ND ND
analogue 0.15
Any other Not more than
0.04 0.05 0.05 0.04 0.04 impurity 0.10
Total Not more than
0.13 0.12 0.12 0.10 0.12 impurities 0.50
Assay (By
HPLC, % w/w)
4 98.0 to 102.0 99.9 99.2 99.4 99.8 100.2 (On anhydrous
basis)
5 XRD ** Complies Complies Complies Complies Complies ACCELARATED STABILITY DATA
IV AB- Temperature 25°C± 2°C & 60% ± Stability Protocol
Batch No. ADL/ST-12/002
003/IV/1846/12 5% RH No.:
Purpose of Type of study Accelarated Manufacturing
New Product January- 12 stability: Condition Month :
Length of
12 months Data presented : 6 month study:
Inner bag HMHDPE bag vaccumized and heat sealed.
TLSB bag having canister desiccant, nitrogen gas purged with vacuum
Middle bag
PACKAGING MODE: and heat sealed.
QLUB bag having canister desiccant, nitrogen gas purged with vacuum
Outer bag
and heat sealed, then packed in HDPE drum.
Sr. No. Test Specification Stability Study for the Month
Initial 1 month 2 month 3 month 4 month 6 month
White to off White White White White White White
1 Description
white powder. powder powder powder powder powder powder
Water by KF Not more than
2 0.47 0.51 0.57 0.72 0.71 0.57
(% w/w) 2.0
Hydroxy
Not more than
analogue ND ND ND ND ND ND
0.15
Acetyl Not more than
ND ND ND ND ND ND
analogue 0.15
3 Dehydro Not more than
ND ND ND ND ND ND
analogue 0.15
Any other Not more than
0.04 0.05 0.05 0.05 0.05 0.05 impurity 0.10
Total Not more than
0.12 0.12 0.14 0.11 0.14 0.12 impurities 0.50
Assay (By
HPLC, % w/w)
4 98.0 to 102.0 98.8 99.5 99.4 98.9 99.4 99.7 (On anhydrous
basis)
5 XRD ** Complies Complies Complies Complies Complies Complies
STABILITY DATA FOR INFORMATION
Product Name Ivabradine hydrochloride
Batch IVAB- 30°C± 2°C & 65% ± Stability Protocol
Temperature ADL/ST-12/002 No. 003/IV/1846/12 5% RH No.:
Purpose
Type of Manufacturing of New Product For information January- 12
study : Month :
stability:
Length
6 months Data presented : 6 month of study:
Inner bag HMHDPE bag vaccumized and heat sealed.
TLSB bag having canister desiccant, nitrogen gas purged with vacuum
PACKAGING MODE: Middle bag
and heat sealed.
QLUB bag having canister desiccant, nitrogen gas purged with vacuum
Outer bag
and heat sealed, then packed in FiDPE drum.
Sr. No. Test Specification Stability Study for the Month
Initial 1 Month 2 month 3 month 4 month 6 month
White to off
White White White White White White
1 Description white
powder powder powder Powder Powder Powder powder.
Water by KF Not more
2 0.47 0.49 0.55 0.98 0.66 0.64 (% w/w) than 2.0
Hydroxy Not more
ND ND ND ND ND ND
analogue than 0.15
Acetyl Not more
ND ND ND ND ND ND
analogue than 0.15
Dehydro Not more
ND ND ND ND ND ND
analogue than 0.15
Any other Not more
0.04 0.04 0.05 0.05 0.05 0.05 impurity than 0.10
Total Not more
0.12 0.10 0.11 0.12 0.1 0.12 impurities than 0.50
Assay (By
HPLC, % w/w)
4 98.0 to 102.0 98.8 98.9 99.3 99.7 99.2 99.7 (On anhydrous
basis)
5 XRD ** Complies Complies Complies complies Complies Complies
ND = Not Detected, NMT = Not More Than, BDL = Below Disregard Limit, NA = Not
Applicable, BLD = Below detection limit
** [l) The XRD diffracto gram of test sample should match with 2theta values at 9.1, 17.2, 20.9, 23.9 ± 0.2°. 2) No peak should be observed in the XRD diffractogram of the test sample 2theta value at 7.7 + 0.2° 3) Limit of Alpha form of Ivabradine HCL should be below detection level]

Claims

We Claim,
1. A vacuum sealed pack comprising Ivabradine Hydrochloride wherein the Ivabradine Hydrochloride is packaged in oxygen and moisture impermeable package.
2. A vacuum sealed pack according to claim 1 wherein the pack comprises three layers.
3. A vacuum sealed pack according to claim 2 wherein the Innermost layer comprises the (HM, HDPE) high molecular high-density poly ethylene which is vacuum sealed and sealed using heat induction.
4. A vacuum sealed pack according to claim 2 wherein the Middle layer is a Triple Laminate Sunlight Barrier (TLSB) bag comprises moisture absorber and nitrogen gas purged and sealed using heat induction.
5. A vacuum sealed pack according to claim 2 wherein the Outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra barrier (QLUB) bag comprises moisture absorber and nitrogen gas purged and sealed using heat induction.
6. A vacuum sealed pack according to claim 4 and 5 wherein the moisture absorber is selected from the group consisting of canister desiccant , desiccant, activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth.
7. A vacuum sealed pack according to claim 4 wherein the bag is put in rigid container.
8. A vacuum sealed pack according to claim 7 wherein the rigid container is non- airtight/air-tight plastic/metal drums, HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) drum.
9. An improved packing condition for Ivabradine Hydrochloride comprises layers as a. Innermost: HMHDPE bag vaccumised and heat sealed.
b. Middle: Triple Laminate Sunlight Barrier (TLSB) bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed.
c. Outermost: quad laminate ultra barrier (QLUB) bag having canister desiccant, nitrogen gas purged with vacuum and heat sealed, then packed in HDPE drum.
PCT/IB2013/056733 2012-08-21 2013-08-19 Packaging for ivabradine hydrochloride WO2014030113A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2418MU2012 2012-08-21
IN2418/MUM/2012 2012-08-21

Publications (2)

Publication Number Publication Date
WO2014030113A2 true WO2014030113A2 (en) 2014-02-27
WO2014030113A3 WO2014030113A3 (en) 2014-05-08

Family

ID=50150440

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Country Link
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015120920A1 (en) * 2014-02-14 2015-08-20 Synthon B.V. Pharmaceutical composition comprising ivabradine hydrochloride polymorph iv

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5983604A (en) * 1991-12-18 1999-11-16 3M Innovative Properties Company Method of using a multilayered barrier structure
EP1594762A1 (en) * 2003-02-19 2005-11-16 Teva Pharmaceutical Industries Limited Methods of stabilizing azithromycin during storage by packaging in a gas impermeable container
CN2897869Y (en) * 2006-01-17 2007-05-09 卢秀莲 Packing bag
US20090071855A1 (en) * 2007-09-14 2009-03-19 Bahuguna Sumit Packaging for amorphous statins and compositions thereof
CN201296459Y (en) * 2008-07-21 2009-08-26 南京泽朗医药科技有限公司 Vacuumized packaging bag with anti-oxidation function

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5983604A (en) * 1991-12-18 1999-11-16 3M Innovative Properties Company Method of using a multilayered barrier structure
EP1594762A1 (en) * 2003-02-19 2005-11-16 Teva Pharmaceutical Industries Limited Methods of stabilizing azithromycin during storage by packaging in a gas impermeable container
CN2897869Y (en) * 2006-01-17 2007-05-09 卢秀莲 Packing bag
US20090071855A1 (en) * 2007-09-14 2009-03-19 Bahuguna Sumit Packaging for amorphous statins and compositions thereof
CN201296459Y (en) * 2008-07-21 2009-08-26 南京泽朗医药科技有限公司 Vacuumized packaging bag with anti-oxidation function

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015120920A1 (en) * 2014-02-14 2015-08-20 Synthon B.V. Pharmaceutical composition comprising ivabradine hydrochloride polymorph iv

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