DESC:FIELD OF THE INVENTION
The present invention relates to a packaging system for pharmaceutical products comprising an absorbent. Furthermore, invention is also related to a process for purification of pharmaceutical products, wherein process optionally comprises treating with an antioxidant.
BACKGROUND OF THE INVENTION
It has been recognized that drugs products are prone to contamination with undesired impurities either originating from manufacturing process or from degradation due to inappropriate storage or packaging conditions. These impurities may be carcinogenic, mutagenic and teratogenic in nature or may impart undesirable physical attributes, such as foul odour, to drug products making them unfit for human consumption. Therefore, health agencies like USFDA and EMEA have stringent regulatory requirements for acceptable limit of undesired impurities in drug products.
Much effort has been directed to control the content of such impurities in drugs during manufacturing or storage, still, there is a need for an efficient system for drug eliminating or minimizing nitrosamine impurities in compliance with stringent regulatory requirements. Nitrosation to form nitrosamine impurities can occur either during manufacturing process or during storage. Accordingly there is a need to control the genotoxic impurities such as nitrosoamines.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a packaging system for pharmaceutical products comprising an absorbent.
In one aspect, the present invention provides a packaging system for pharmaceutical products comprising an absorbent, wherein absorbent contains an oxygen absorber.
In one aspect, the present invention provides a packaging system for pharmaceutical products comprising an absorbent, wherein absorbent contains an oxygen absorber and optionally a desiccant.
In one aspect, the present invention provides a process for purification of pharmaceutical products, wherein process optionally comprises treating pharmaceutical products with an antioxidant in a suitable solvent.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a packaging system for drug products comprising an absorbent.
In one embodiment, the present invention provides a packaging system for pharmaceutical products comprising an absorbent, wherein absorbent contains an oxygen absorber.
In one aspect, the present invention provides a packaging system for pharmaceutical products comprising an absorbent, wherein absorbent contains an oxygen absorber and optionally a desiccant.
The term “pharmaceutical products” as used herein refers to active pharmaceutical ingredient (drug substance) or any pharmaceutical formulation (drug product) which includes, but not limited to, tablets, coated tablets, layered tablets, granules, powders, microparticles, capsules which may be hard gelatin or soft gelatin, caplets, sachets, pellets, spheroids, mini-tablets, beads, microcapsules and pills.
The term “oxygen absorber” as used herein refers to any oxygen absorbing agent that absorbs and remove oxygen from all components of the system.
Suitable materials for oxygen absorbers include metal-based substances that remove oxygen by reacting with it by chemical bonding, generally forming a metal oxide component. Metal-based substances include, but not limited to, elemental iron as well as iron oxide, iron hydroxide, iron carbide and the like. Other metals for use as oxygen absorbers include, but not limited to, nickel, tin, copper and zinc. Metal-based oxygen absorbers are typically in the form of a powder to increase surface area. Additional materials for oxygen absorbers include, but not limited to, low molecular weight organic compounds such as ascorbic acid, sodium ascorbate, catechol and phenol, activated carbon and polymeric materials incorporating a resin and a catalyst. In some embodiments of the pharmaceutical packaging system, the oxygen absorber is a metal-based oxygen absorber. In certain instances of the pharmaceutical packaging system, the oxygen absorber is an iron-based oxygen absorber.
Oxygen absorbents which can be used in the present invention include, but not limited to, iron and glucose oxidase. A salt may be used as an electrolyte for oxidation of the iron. The iron may be hydrogen-reduced iron, electrolytically reduced iron, or chemically reduced iron. Although iron is preferred as the metallic oxygen absorbing agent, it will be appreciated that other metals may be used. These are, by way of example and not limitation, aluminum, copper, zinc, titanium, magnesium, and tin. Also, other elements which can be used in elemental or partially oxidized form are sodium, manganese, iodine, sulfur, and phosphorus.
The electrolytic salt may be sodium chloride or any other suitable food compatible salt including, but not limited to, sodium sulfate, potassium chloride, ammonium chloride, ammonium sulfate, calcium chloride, sodium phosphate, calcium phosphate, and magnesium chloride.
The term “desiccant” as used herein refers to any drying agent that removes moisture from the air. Desiccants include, but are not limited to, silica gel, clay desiccants, calcium sulfate, calcium chloride, calcium oxide, zeolite, activated alumina, activated charcoal and combinations thereof. However, other vapor or moisture absorbing mechanisms are not beyond the scope of the present invention. Other vapor or moisture absorbing materials include, but not limited to, desiccants made from inorganic materials such a zeolites and aluminas. Other exemplary moisture absorbing materials include, but are not limited to, alumina, bauxite, anhydrous calcium sulphate, water-absorbing clay, activated bentonite clay, a molecular sieve, or other like materials.
The desiccant should be present in an amount sufficient to absorb any residual moisture inside the package. Moreover, the desiccant should be present in an amount sufficient to absorb any moisture that possibly ingresses from the external environment.
Preferably the desiccant is selected from the group consisting of silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activated bentonite clay, water-absorbing clay, molecular sieve and any mixtures thereof.
In one embodiment, the present invention provides a packaging system for pharmaceutical products comprising an absorbent, wherein absorbent contains an oxygen absorber and optionally a desiccant, wherein the oxygen absorber is selected from the group consisting of elemental iron, iron oxide, iron hydroxide, iron carbide, nickel, tin, copper, zinc, aluminum, titanium, magnesium, elemental or partially oxidized form are sodium, manganese, iodine, sulfur, and phosphorus, ascorbic acid, sodium ascorbate, catechol, phenol, iron oxidase, glucose oxidase, sodium sulfate, potassium chloride, ammonium chloride, ammonium sulfate, calcium chloride, sodium phosphate, calcium phosphate, magnesium chloride, and combinations thereof, and the desiccant is selected from the group consisting of silica gel, clay desiccants, calcium sulfate, calcium chloride, calcium oxide, zeolite, activated alumina, activated charcoal, and combinations thereof.
In one embodiment, the present invention provides a packaging system for pharmaceutical products comprising an absorbent, wherein absorbent is in the form of a sachet, pouch, capsule, strip, patch, cartridge, etc. In some embodiments, the absorbent is in the form of a sachet.
In one embodiment, the present invention provides a process for purification of pharmaceutical products, wherein process optionally comprises treating with an antioxidant. The term pharmaceutical products described herein includes both drug substances as well drug products.
In one embodiment, the present invention provides a process for purification of drug substances, wherein process optionally comprises treating the drug substances with an antioxidant in a suitable solvent, followed by isolating the drug substance and packaging the drug substance according to packaging system as described herein.
In one embodiment, the present invention provides a process for purification of pharmaceutical products, ,wherein process optionally comprises adding a small amount of an antioxidant such as, but not limited to, citric acid, ascorbic acid, triphenylphosphine, 2,6-di-tert-butyl-4-methylphenol (BHT), butylated hydroxyanisole, a mixture of 2-tert-butylhydroxy anisole and 3-tert-butylhydroxy anisole (BHA), ethyl gallate (EtG) and propyl gallate (PrG) during crystallization or isolation of the product from a solvent. In one embodiment, antioxidant is added in catalytic amount such that it does not interfere the reaction progress.
In one embodiment, process for purification of pharmaceutical products as described herein includes any method known in art such as crystallization/recrystallization involving single solvent, mixture of solvents or solvent-anti solvent technique; reprecipitation; slurring in a solvent mixture of solvents; or of pharmaceutical products comprising recrystallization, slurrying in solvent, solvent anti-solvent, conversion into salt form and reconversion into corresponding unsalted form or vice-versa by treating with suitable acid and suitable base.
In one embodiment of present invention, the packaging system and the purification process according to present invention provides pharmaceutical products with desired quality and enhanced storage stability.
The term "desired quality and enhanced storage stability" as described herein refers to low levels of N-nitroso impurities in pharmaceutical products when exposed to specified temperature and humidity conditions for specified amount of time.
In another embodiment, the packaging system provided herein capable of maintaining the nitrosamine impurity within the acceptable level as specified by regulatory authorities, in the absence of such a packaging system the said impurity might increase over a period of time. The term “regulatory authorities” as described herein include but not limited to EMEA, ICH, US-FDA, PMDA, TGA and the like. The term “acceptable level as specified by regulatory authorities” is the minimum level acceptable by the various regulatory authorities. The packaging system described herein is suitable for both long term as well as accelerated stability conditions as specified in the regulatory guidelines.
The pharmaceutical products as described herein exhibits enhanced storage stability and low levels of N-nitroso impurities for a shelf-life.
The term “suitable acid” as used herein refers to inorganic acids such as, but not limited to, hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid or organic acids such as, but not limited to, acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2-methylpropionic acid, 1,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, N-glycolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy-2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl) phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid, 10-undecenoic acid.
The term “suitable base” as used herein refers to inorganic bases such as but not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium hydride, sodium hydride, potassium hydride, sodamide; n-butyl lithium; lithium diisopropylamide, or organic bases such as but not limited to methylamine, ethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, cyclohexylamine.
The term “suitable solvent” as used herein refers to any inert solvent which does not take part in the reaction, selected from the group comprising of, but not limited to, alcohols, amides, amines, esters, ethers, halogenated solvents, hydrocarbon solvents, ketone, nitriles, nitro and inorganic solvents, wherein alcohols are selected from the methanol, ethanol, propanol, isopropanol, cyclopropanol, butanol,, isobutanol, tertiary butanol, benzyl alcohol, Ethylene glycol, Propylene glycol; amides are selected from formamide, dimethylacetamide, dimethylformamide, N-Methyl-2-pyrrolidone; amines are selected from Piperidine, Pyridine, diethylenetriamine, ethylenediamine, tributylamine; esters are selected from ethyl acetate, methyl acetate, ethyl acetoacetate, propyl acetate, butyl acetate, isobutyl acetate; ethers are selected from diisopropyl ether, di-tert-butyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane; halogenated solvents are selected from dichloromethane, dichloroethane, chloroform, chlorobenzene; aliphatic hydrocarbon solvents are selected from heptane, hexane, aromatic hydrocarbon solvents are selected form toluene, cycloheptane, cyclohexane, cyclohexene, cyclooctane, cyclopentane; ketones are selected from acetone, butanone, ethyl isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone; nitriles are selected from acetonitrile, proprionitrile, or benzonitrile; nitro are selected from nitrobenzene, nitroethane, nitromethane; inorganic solvents are selected from ammonia, water, sulfuric acid.
Accordingly, the drug substance purified by the method given according to the invention and stored under the condition described herein complies the regulatory requirement with respect to genotoxic impurities as prescribed by various regulatory bodies like ICH, USFDA, PMDA, EMCA, TGA etc. throughout their stability period both under normal condition or under accelerated condition.
In one embodiment of present invention, the packaging system and the purification process according to present invention can be used for pharmaceutical products selected from group comprising of, but not limited to, Acalabrutinib, Adapalene, Afatinib, Agomelatine, Alogliptin, Amantadine, Apixaban, Apremilast, Aripiprazole, Asenapine, Atomoxetine, Axitinib, Azacitidine, Azilsartan, Azithromycin, Bempedoic acid, Bimatoprost, Binimetinib, Bosentan, Bosutinib, Brexpiprazole, Brivaracetam, Bupivacaine, Bupropion, Cabozantinib, Canagliflozin, Candesartan, Carfilzomib, Celecoxib, Cilostazol, Clevidipine, Dabigatran etexilate, Dapagliflozin, Dapsone, Darifenacin, Darolutamide, Dasatinib, Deferasirox, Dexlansoprazole, Donepezil, Dorzolamide, Dronedarone, Duloxetine, Empagliflozin, Enzalutamide, Erlotinib, Erythromycin, Etoricoxib, Famotidine, Febuxostat, Felodipine, Fenocholin, Fenofibrate, Fenofibric acid, Ferumoxytel, Fesoterodine, Fingolimod, Fluoxetine, Fluphenazine, Fulvestrant, Gefitinib, Hydrochlorothiazide, Ibrutinib, Illoperidone, Infigratinib, Irbesartan, Iron sucrose, Ivabradine, Ivacaftor , Ivosidenib, Ketorolac, Lacosamide, Lamotrigine, Larotrectinib, Leflunomide, Lenalidomide, Lercanidipine, Linagliptin, Linezolid, Losartan, Lurasidone, Macitentan, Memantine, Methomyl, Methotrexate, Metolazone, Metoprolol, Mexiletine, Minodronic acid, Modafinil, Nelarabine, Niraparib, Nisoldipine, Nisoxetine, Nitrofurantoin, Obeticholic acid, O-desmethyl venlafaxine, Olaparib, Olmesartan, Oseltamivir, Osimertinib, Palbociclib, Pinaverium bromide, Pirfenidone, Ponatinib, Pramipaxole, Prasugrel, Pregabalin, Prucalopride, Quetiapine, Rabeprazol, Ribociclib, Rifaximin, Riociguat, Rivaroxaban, Rivastigmine, Roflumilast, Ropinirole, Roxithromycin, Ruxolitinib, Sacubitril, Selexipag, Sertraline, Silodosin, Solifenacin, Sorafenib, Suvorexant, Tadalafil, Tegaserod, Telmisartan, Temazepam, Tepotinib, Teriflunomide, Ticagrelor, Tivozanib, Topiramate, Trametinib, Valsartan, Vardenafil, Venetoclax, Venlafaxine, Vilazodone, Vildagliptin, Viloxazine, Vortioxetine, Warfarin, Zolmitriptan, 2-chlorophenylisocyanate, 2-isocyanate ethyl methacryate
In one embodiment of present invention, the packaging system and the purification process according to present invention can be used for pharmaceutical products selected from group comprising of , but not limited to, Adapalene, Erythromycin, Pemetrexed, Triamcinolone acetonide, Abiraterone, Acetaminophen, Acetazolamide, Acitretin, Acyclovir, Albendazole, Alcaftadine, Ambrisentan, Amiodarone, Amitriptyline, Amlodipine, Anidulafungin, Aprepitant, Argatroban, Atorvastatin, Azathieoprine, Azelastine, Baclofen ,Benzoyl peroxide, Bepotastine, Betamethasone, Bexarotene, Bisoprolol ,Bivalirudin, Bortezomib, Brimonidine, Brinzolamide, Bromfenac, Bromocriptin, Budesonide, Bumetanide, Calcipotriene, Calcipotriol, Calcitriol, Carbamazepine, Carbidopa, Carvedilol, Chlordiazepoxide, Chlorpromazine, Chlorthalidone, Ciprofloxacin , Clarithromycin, Clidinium , Clindamycin, Clobazam, Clobetasol, Clobetasol , Clofarabine, Clonazepam, Clopidogrel, Clozapine, Cobicistat, Cyclobenzaprine, Cyclophosphamide, Cyclosporin, Cytarabine, Dantrolene, Daptomycin, Desipramine, Desmopressin, Desonide, Dexamethasone, Dextromethorphan , Diclofenac, Difluprednate, Diltiazem, Dimethyl fumarate, Divalproex, Docetaxel, Docosanol, Doxepin, Doxercalciferol, Doxycycline, Doxylamine, Dronabinol, Droxidopa, Efinaconazole, Emtricitabine, Entacapone, Eslicarbazepine, Esomeprazole, Estradiol, Ethacrynate ,Ezetimibe, Fluorouracil, Fosaprepitant, Galanthamine, Ganciclovir, Gemcitabine, Glipizide, Glycopyrollate, Guanfacine, Hydrocortisone, Ibuprofen, Itraconazole, Ivermactine, Ivermectin, Ketoconazole, Lamotrigene, Lansoprazole, Latanoprost, Ledipasvir, Levodopa, Levothyroxine, Lidocaine, Loteprednol, Medroxyprogesterone, Meloxicam, Mesalamine, Metaxalone, Metformin, Methyl phenidate, Methylprednisolone, Metronidazole, Micafungin, Midodrine, Minocyclin, Molindone, Moxifloxacin, Mupirocin calcium , Nadolol, Nifedipine, Nilotinib, Nimodipine, Nintedanib, Nizatidine, Nystatin, Olanzapine, Olmesartan medoxomil , Olopatadine, Omeprazole, Oseltamavir phosphate, Ospemifien, Oxaliplatin, Oxcarbazapine, Oxcarbazepine, Oxybutynin, Paclitaxel, Palanosetron, Paliperidone, Paliperidone palmitate, Pantoprazole, Paroxetine, Paroxetine, Pazopanib, Penciclovir, Perindopril, Perindropil, Pimecrolimus, Pioglitazone, Piorxicam, Plerixafor , Posaconazole, Prazosin, Prednisolone, Prednisone, Prilocaine, Prilocaine , Progesterone, Propafenone, Propofol, Regadanoson, Rizatriptan, Sildenafil, Simvastatin, Sitagliptin, Sumatriptan, Sunitinib, Tacrolimus, Tamsulosin, Tavaborol, Tazarotene, Tegicyclin, Teicoplanin, Temozolamide, Testosterone, Theophylline, Timolol, Tizanidine, Tobramycin, Tofcitinib, Topiramet, Travoprost, Tretinoin, Trientine, Valganciclovir, Vancomycin, Varenicline, Verapamil, Zileuton, Zoledronic acid.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material like N-acetyl-L-cysteine, SilaMetS thiol to remove metallic impurity, color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C., less than about 80°C., less than about 60°C., less than about 50°C., less than about 30°C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples:
Example-1: Purification of Sertraline HCl
Ethyl acetate was added to solution of sertraline HCl in water and stirred at 10-20°C. To the reaction mixture, solution of sodium hydroxide in water was added gradually till the pH of reaction mixture becomes 9-10. Citric acid (catalytic amount) was added and the reaction mixture was stirred at 15-25°C for 1 hour. After completion of reaction, organic layer was separated by conventional work-up and distilled to obtain sertraline free base as concentrated mass. The obtained concentrated mass was dissolved in acetone, treated with activated charcoal at 25-35°C and filtered through Hyflow to obtain clear filtrate. The filtrate was acidified with Ethylacetate HCl and the reaction mixture was stirred at 20-30°C for 1 hour followed by filtration, washing with acetone and drying to get pure sertraline HCl (complies the genotoxic impurity/nitrosoamine impurity level as specified by regulatory agency). The obtained product was packed with an absorbent sachet containing iron powder and zeolite.

Example-2: Purification of Losartan potassium
To a solution of Losartan potassium in acetone, ascorbic acid (catalytic amount) was added and stirred at 25-30°C for 3 hours. Further, reaction mixture was cooled to 0-5°C and stirred for 2 hours. The solid was filtered, washed with acetone and dried to obtain the title compound. The obtained product was packed with an absorbent sachet containing iron powder and zeolite. (Complies with the genotoxic impurity/ nitrosoamine impurity level as specified by regulatory agency throughout stability period)

Example-3: Purification of Valsartan
A solution of valsartan in ethyl acetate was heated to reflux temperature until complete dissolution was achieved. The reaction mixture was cooled to 25-30°C, BHA (catalytic amount) was added and stirred for 1 hour. n-Heptane was added at 25-30°C and stirred for 2 hours. Further, reaction mixture was cooled to 0-5°C and stirred for 2 hours. The solid was filtered, washed with n-Heptane and dried to obtain the title compound. The obtained product was packed with an absorbent sachet containing iron powder and zeolite. (Complies with the genotoxic impurity/ nitrosoamine impurity level as specified by regulatory agency throughout stability period)

Example-4: Purification of Irbesartan
To a solution of crude Irbesartan in acetone at 25-30°C, BHT (catalytic amount) was added and the reaction mixture was stirred for 3 hours at 25-30°C. The solid was filtered, washed with acetone and dried to obtain the title compound. The obtained product was packed with an absorbent sachet containing iron powder and zeolite. (Complies with the genotoxic impurity/ nitrosoamine impurity level as specified by regulatory agency throughout stability period)

Example-5: Purification of Duloxetine HCl
Ethylacetate (500 ml) was added to solution of crude Duloxetine HCl (100 g) in water (500 ml) and stirred at 10-20°C. To the reaction mixture, solution of sodium hydroxide (15 g) in water (150ml) was added gradually till the pH of reaction mixture becomes 9-10. Ascorbic acid (1.3 g) was added and the reaction mixture was stirred at 15-25°C for 1 hour. After completion of reaction, organic layer was separated by conventional work-up and distilled to obtain Duloxetine free base as concentrated mass. The obtained concentrated mass was dissolved in acetone, treated with activated charcoal at 25-35°C and filtered through Hyflow to obtain clear filtrate. The filtrate was acidified with Ethylacetate HCl and the reaction mixture was stirred at 20-30°C for 1 hour followed by filtration, washing with acetone and drying to get Pure Duloxetine HCl. The obtained product was packed with an absorbent sachet containing iron powder and zeolite. (Complies with the genotoxic impurity level/ nitrosoamine impurity as specified by regulatory agency throughout stability period)

Example-6: Purification of Duloxetine HCl
A solution of duloxetine in methyl ethyl ketone was heated to reflux temperature until complete dissolution was achieved. The reaction mixture was cooled to 25-30°C, Ethyl gallate (catalytic amount) was added and stirred for 1 hour. Further, reaction mixture was cooled to 0-5°C and stirred for 2 hours. The solid was filtered, washed with ethylacetate and dried to obtain the title compound. The obtained product was packed with an absorbent sachet containing iron powder and zeolite. (Complies with the genotoxic impurity leve/ nitrosoamine impurity l as specified by regulatory agency throughout stability period)

Example-7: Purification of Atomoxetine HCl
Ethylacetate was added to solution of crude Atomoxetine HCl in water and stirred at 10-20°C. To the reaction mixture, solution of sodium hydroxide in water was added gradually till the pH of reaction mixture becomes 9-10. Triphenylphosphine (catalytic amount) was added and the reaction mixture was stirred at 15-25°C for 1 hour. After completion of reaction, organic layer was separated by conventional work-up and distilled to obtain Atomoxetine free base as concentrated mass. The obtained concentrated mass was dissolved in acetone, treated with activated charcoal at 25-35°C and filtered through Hyflow to obtain clear filtrate. The filtrate was acidified with Ethylacetate HCl and the reaction mixture was stirred at 20-30°C for 1 hour followed by filtration, washing with acetone and drying to get Pure Atomoxetine HCl. The obtained product was packed with an absorbent sachet containing iron powder and zeolite. (Complies with the genotoxic impurity level/ nitrosoamine impurity as specified by regulatory agency throughout stability period)

Example-8: Purification of Duloxetine HCl
A solution of duloxetine in methyl ethyl ketone was heated to reflux temperature until complete dissolution was achieved. The reaction mixture was cooled to 25-30°C, triphenylphosphine (catalytic amount) was added and stirred for 1 hour. Further, reaction mixture was cooled to 0-5°C and stirred for 2 hours. The solid was filtered, washed with ethyl acetate and dried to obtain the title compound. The obtained product was packed with an absorbent sachet containing iron powder and zeolite. (Complies with the genotoxic impurity level/ nitrosoamine impurity as specified by regulatory agency throughout stability period)

Example-9: Purification of Fluoxetine HCl
Ethylacetate was added to solution of crude fluoxetine HCl in water and stirred at 10-20°C. To the reaction mixture, solution of sodium hydroxide in water was added gradually till the pH of reaction mixture becomes 9-10. Triphenylphosphine (catalytic amount) was added and the reaction mixture was stirred at 15-25°C for 1 hour. After completion of reaction, organic layer was separated by conventional work-up and distilled to obtain fluoxetine free base as concentrated mass. The obtained concentrated mass was dissolved in acetone, treated with activated charcoal at 25-35°C and filtered through Hyflow to obtain clear filtrate. The filtrate was acidified with Ethylacetate HCl and the reaction mixture was stirred at 20-30°C for 1 hour followed by filtration, washing with acetone and drying to get pure fluoxetine HCl. The obtained product was packed with an absorbent sachet containing iron powder and zeolite. (Complies with the genotoxic impurity level/ nitrosoamine impurity as specified by regulatory agency throughout stability period)

,CLAIMS:We claim:
1. A packaging system for a pharmaceutical product comprising an absorbent, wherein absorbent contains an oxygen absorber.
2. The packaging system as claimed in claim- 1, wherein the oxygen absorber is selected from the group consisting of iron, aluminum, copper, zinc, titanium, magnesium, and tin and combinations thereof.
3. The packaging system as claimed in claim- 1 further comprising a desiccant.
4. The packaging system as claimed in claim- 1, wherein the desiccant is selected from the group consisting of zeolite, silica gel, alumina, bauxite, calcium sulphate activated bentonite clay, water-absorbing clay, molecular sieve, calcium chloride, calcium oxide, activated charcoal and combinations thereof.
5. The packaging system as claimed in claim- 1, wherein the pharmaceutical product includes both drug substance and drug product.
6. A process for preparing a pharmaceutical product having acceptable level of N-nitroso impurities in limits as specified by ICH guidelines comprising treating the drug substance with antioxidant in a suitable solvent followed by isolation, wherein the pharmaceutical substance is packed according to packaging system as claimed in claim- 1.
7. The process as claimed in claim- 6, wherein the antioxidant is selected group consisting of citric acid, ascorbic acid, triphenylphosphine, 2,6-di-tert-butyl-4-methylphenol (BHT), butylated hydroxyanisole, a mixture of 2-tert-butylhydroxy anisole and 3-tert-butylhydroxy anisole (BHA), ethyl gallate (EtG) and propyl gallate (PrG).
8. The process as claimed in claim- 6, wherein suitable solvent is selected group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, propyl acetate, heptane, hexane, methanol, ethanol, propanol, isopropanol, butanol,, isobutanol, tertiary butanol, dimethylacetamide, dimethylformamide, N-Methyl-2-pyrrolidone diisopropyl ether, di-tert-butyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, toluene, acetonitrile, nitrobenzene, water.
9. The process as claimed in any of the proceeding claim is suitable in maintaining the N-nitroso impurities in limits as per regulatory guidelines.