WO2024176162A1

WO2024176162A1 - Stable pharmaceutical composition of histamine h2‐receptor antagonist

Info

Publication number: WO2024176162A1
Application number: PCT/IB2024/051717
Authority: WO
Inventors: Abhishek Tyagi; Sant Singh; Abhishek Srivastava; Simrata Bedi; Romi Singh
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2023-02-22
Filing date: 2024-02-22
Publication date: 2024-08-29
Anticipated expiration: 2025-08-22

Abstract

The present disclosure relates to a stable pharmaceutical composition comprising a Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof and a stabilizing amount of at least one alkalizer. The composition provides effective control of the level of nitrosamine drug substance-related impurities (NDSRIs) such as NDMA in the drug product during shelf life of the product.

Description

STABLE PHARMACEUTICAL COMPOSITION OF HISTAMINE H2-

RECEPTOR ANTAGONIST

FIELD OF THE INVENTION

[0001] The present invention relates to a stable pharmaceutical composition comprising a Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof and a stabilizing amount of at least one alkalizer. The composition shows an improved stability with controlled levels of potentially carcinogenic nitrosamine drug substance-related impurities (NDSRIs).

BACKGROUND OF THE INVENTION

[0002] Histamine H2-receptor antagonist are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of stomach acid. H2 antagonists can be used in the treatment of dyspepsia, peptic ulcers and gastroesophageal reflux disease. Various H2 blockers are cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine.

[0003] Among H2 blockers ranitidine was found to have a much better tolerability profile (i.e. fewer adverse drug reactions), longer-lasting action, and ten times the activity of cimetidine. Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H2 receptors found in gastric parietal cells. This results in decreased gastric acid secretion and gastric volume, and reduced hydrogen ion concentration. It is sold under the brand name Zantac* among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger- Ellison syndrome. It can be given by mouth, injection into a muscle, or injection into a vein.

[0004] The recent unexpected finding of nitrosamine impurities, which are probable human carcinogens, in drugs such as angiotensin II receptor blockers (ARBs), H2 blockers such as ranitidine, nizatidine, and biguanides such as metformin, has made clear the need for a risk assessment strategy for potential nitrosamines in any pharmaceutical product at risk for their presence. FDA has been investigating the presence of nitrosamine impurities in certain drug products. Since 2018, several drug products including ARBs, ranitidine, nizatidine, and metformin have been found to contain unacceptable levels of nitrosamines.

[0005] In June 2018, FDA was informed of the presence of an impurity identified as N-nitrosodimethylamine (NDMA) in the ARB valsartan. Through investigation, the Agency determined that numerous lots of valsartan and a few other ARB drug products from different manufacturers contained unacceptable levels of nitrosamines. The drug product manufacturers voluntarily recalled the affected batches of these drug products, which led to a drug shortage in some of the affected products.

[0006] In September 2019, FDA learned that some common heartburn products (ranitidine, commonly known as Zantac, and nizatidine, commonly known as Axid*) contained unacceptable levels of NDMA. FDA recommended that manufacturers voluntarily recall ranitidine and nizatidine products with NDMA levels above what the Agency considers acceptable. Recently, preliminary findings from FDA stability testing raised concerns that NDMA levels in some ranitidine products stored at room temperature can increase with time to unacceptable levels. FDA's preliminary results using accelerated stability testing demonstrated that elevated levels of NDMA were measured in all products after 2 weeks. FDA's testing suggests that NDMA levels increase with storage time. On April 1, 2020, FDA requested that all ranitidine products be withdrawn from the U.S. market.

[0007] N-Nitrosodimethylamine (NDMA) is an organic compound with the formula (CHshNNO which is formed by the combination of dimethyl amine with nitrates. Whilst NDMA is a known common environmental contaminant, nitrosamine such as NDMA are known to be carcinogenic. Chronic ingestion of NDNMA is postulated to cause an increase in liver and other cancers.

[0008] Ranitidine can generate NDMA, classified by the IARC as "probably carcinogenic to humans" (Class 2A carcinogen), as a decomposition product. Also, in August 2019, preliminary results in a random selection and testing by official medicinal control laboratories (OMCLs) of ranitidine API batches and finished products available in the EU showed levels of NDMA in a range that raised concerns according to the principles of ICH-M7. All ranitidine products, including the oral liquid/syrup, was banned by USFDA.

[0009] Therefore, there is a strong need for development of formulations with controlled or minimal content of Nitrosamine Drug Substance Related Impurities (NDSRIs). Various references although have talked about methods to optimize the level of nitrosamine impurities by using approaches. However, there are limited disclosures available that are actually enabled to control the nitrosamine impurities in drug product during storage period.

[0010] The inventors in the present application have evaluated various formulation strategies to mitigate the risk associated by nitrosamine compounds in drug product, and surprisingly arrived at a stable formulation.

SUMMARY OF THE INVENTION

[0011] The present disclosure relates to a stable composition comprising Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof, a stabilizing amount of at least one alkalizer and one or more pharmaceutically acceptable excipient. The composition provides effective control of the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product during shelf life of the product.

[0012] In one aspect, the present invention relates to stable pharmaceutical composition of ranitidine hydrochloride comprising an alkali metal stabilizer and one or more pharmaceutically acceptable excipients.

[0013] In one aspect, the composition according to the present invention comprises of Histamine H2-receptor antagonist with an alkali stabilizer and has controlled level of impurities including the nitrosamine drug substance-related impurities (NDSRIs). In some aspects, the nitrosamine drug substance-related impurity is N- nitrosodimethylamine (NDMA).

[0014] In one aspect the stable pharmaceutical composition according to the present invention comprises a Histamine H2-receptor antagonist, a stabilizing amount of at least one alkalizer and one or more pharmaceutically acceptable excipient, wherein the alkalizer effectively control the formation of nitrosamine drug substance-related impurities (NDSRIs) in the composition, to a level below about 11 ppm, upon storage or acid exposure. Preferably, the Histamine H2-receptor antagonist is ranitidine hydrochloride

[0015] In one aspect, the stable pharmaceutical composition according to the present invention comprises the ratio of a Histamine H2-receptor antagonist and an alkalizer in the composition in the range of 100:0.1 to 100:5.

[0016] In one aspect, the stable pharmaceutical composition according to the present invention the nitrosamine drug substance-related impurity is N- nitrosodimethylamine (NDMA) impurity.

[0017] In one aspect, the stable pharmaceutical composition according to the present invention the alkalizer is selected from alkali metal oxide, pH modifier, nitrite quencher. Preferably, the alkalizer is alkali metal oxide. More preferably, the alkali metal oxide is magnesium oxide

[0018] In one aspect the stable pharmaceutical composition according to the present invention the level of nitrosamine drug substance related impurities (NDSRIs) level is below about 11 ppm upon storage under controlled room temperature condition of 25°C/60% RH for at least 12 months.

[0019] In one aspect the stable pharmaceutical composition according to the present invention comprises ranitidine hydrochloride and magnesium oxide, wherein the magnesium oxide is present in the composition in an amount present in an amount ranging from about 0.1% w/w to about 10% w/w of the composition, wherein the composition is characterized by a level of N- Nitrosodimethylamine (NDMA) impurity below 11 ppm, upon storage at 25°C/60% RH for a period of at least 12 months. More preferably, the amount of magnesium oxide ranges from about 0.1% w/w to about 2% w/w of the composition.

[0020] In one aspect, the stable pharmaceutical composition according to the present invention is characterized by a level of nitrosamine drug substance related impurity below 3 ppm, upon storage at 25°C/60% RH for a period of 12 months.

[0021] In one aspect according to the present invention, the composition is a stable oral dosage form of ranitidine Hydrochloride with controlled levels of N- nitrosodimethylamine (NDMA) impurity. [0022] In another aspect, the present invention also provides method for controlling nitrosamine drug substance-related impurities (NDSRIs) in amine containing drug products.

[0023] In yet another aspect, the present invention provides a method for preparing a stable pharmaceutical composition comprising a Histamine H2-receptor antagonist or a pharmaceutically acceptable salt and at least one alkali metal stabilizer, wherein the alkali metal stabilizer is placed in the composition in a way to effectively control the formation of nitrosamine drug substance-related impurities (NDSRIs) in the composition.

DESCRIPTION OF TH E INVENTION

[0024] As used herein, the word "a" or "plurality" before a noun represents one or more of the particular nouns.

[0025] For the terms "for example" and "such as," and grammatical equivalences thereof, the phrase "and without limitation" is understood to follow unless explicitly stated otherwise. As used herein, the term "about" is meant to account for variations due to experimental error. All measurements reported herein are understood to be modified by the term "about," whether or not the term is explicitly used, unless explicitly stated otherwise. The term "about" as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

[0026] The term "coating" as used herein the description, can be used interchangeably with the term "coat" or "layer" around the core.

[0027] The term "Histamine H2-receptor antagonist" as used herein the description, can be used interchangeably to "HR2as" or "H2 blockers". The most commonly used Histamine H2-receptor antagonist that can be used according to the present invention including but not limited to cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine. Alternatively the disclosure according to present invention can also be used with other amine drugs such as sartans, antidiabetic drugs, antihistamines, and antibiotics; for e.g. the drugs include Amoxicillin, Bendroflumethiazide, Betahistine, Bisoprolol, Bromazepam, Carvedilol, Cetirizine, Desloratadine, Diclofenac, Doxylamine, Duloxetine, Enalapril, Ergometrine, Felodipine, Flecainide, Fluoxetine, Hydrochlorothiazide (HCT), Levofloxacin, Metoprolol, Metformin, Mirabegron, Mirtazapine, Moxifloxacin, Nebivolol, Opipramol, Pergolide, Propranolol, Quetiapine, Ramipril, Roxithromycin, Sertraline, Sotalol, Sumatriptan, Sitagliptin, Valsartan, Varenicline, Metformin, ranitidine, Gliclazide, Sitagliptin, Prucalopride, Clarithromycin, Oxcarbazepine, Sunitinib, Rivaroxaban, Citalopram, Escitalopram, Tamsulosin, Diltiazem, Amlodipine or pharmaceutically acceptable salt thereof, and combination thereof.

[0028] The term "shelf life" as used herein, means the shelf life of the drug product, in its form as a product sold for use by consumers, during which period the product is suitable for use by a patient. The shelf life of the drug product can be greater than 3, 6, 12, 18, or preferably 24 months. The shelf life may be achieved when the product is stored at room temperature at about 25° C, protected from light and moisture.

[0029] The term "dosage form" or "composition" as used herein the description, can be used interchangeably with the term 'pharmaceutical composition' or 'pharmaceutical formulation' or 'pharmaceutical preparation' or 'drug product', wherein the drug product is defined as a composition of H2 blocker drug and one or more pharmaceutical excipients.

[0030] The term "alkalizer" as used in the description, represents the chemical entity responsible for increasing the pH of the composition, and comprises alkali metal stabilizers such as alkali metal oxides, alkali metal salts; pH modifiers; and Nitrite quenchers.

[0031] The present invention provides a stable pharmaceutical composition of an H2 blocker or a pharmaceutically acceptable salt thereof, and at least one alkali metal stabilizer in the composition, wherein the alkali metal stabilizer effectively controls the level of the nitrosamine drug substance-related impurities (NDSRIs) in the composition. In some aspects the nitrosamine drug substance-related impurities (NDSRIs) in the composition is /V-nitrosodimethylamine (NDMA) impurity.

[0032] In some embodiment according to the present invention, the pharmaceutical composition is a stable composition comprising an H2 blocker or a pharmaceutically acceptable salt thereof, with stabilizing amount of one or more alkali metal stabilizer in an amount effective for controlling the level of nitrosamine related impurities in the drug product during shelf life of the product.

[0033] In another embodiment according to the present invention, the alkali metal stabilizer is an alkali metal oxide present in the composition in such a way that it effectively controls the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product.

[0034] In one aspect of the above embodiments, the alkali metal oxide is present in the core of the composition for effective control of the level of nitrosamine drug substance-related impurity in the drug product. In another aspect of the above embodiment, the alkali metal oxide is present in the composition within a coating for effective control of the level of nitrosamine drug substance-related impurity in the drug product.

[0035] The nitrosamine drug substance-related impurities (NDSRIs) in the composition may be formed due to nitrosating reaction between amines (primary, secondary, tertiary, or quaternary amines) of drug and/or excipients present in the drug product, and the applicant surprisingly found that the alkali metal stabilizer in claimed concentration ranges and arrangement play crucial role in controlling nitrosamine drug substance-related impurities (NDSRIs) as well as other impurities simultaneously in the composition below acceptable levels.

[0036] In some embodiment according to present invention, the composition comprises of an amine containing drug and stabilizing amount of at least one alkalizer. In one aspect according to above embodiment, the alkalizer characteristically controls or prevents formation of nitrosamine drug substance- related impurity in the drug product upon storage or acid exposure.

[0037] The term "stable" as used herein, refers to a chemical stability of the composition which means that the level of nitrosamine drug substance related impurity (NDSRIs) in the composition remains below about 11 ppm, preferably below about 10 ppm, below about 9 ppm, below about 8 ppm, below about 7 ppm, below about 6 ppm, below about 5 ppm, below about 4 ppm, below about 3 ppm, below about 2 ppm, or below about 1 ppm, upon storage under the temperature and humidity conditions of 40°C/75% RH for at least 3 months and at controlled room temperature condition of 25°C/60% RH for at least 12 months, 18 months or 24 months.

[0038] The term "stable" as used herein, also refers to physical stability which means that the composition retain its structural integrity and does not rupture in a significant way after exposure to storage conditions which means the composition is stable when stored under the temperature and humidity conditions of 40°C./75% RH and 30°C./75% RH for at least 3 months or at controlled room temperature condition of 25°C/60% RH for at least 12 months, 18 months or 24 months

[0039] According to another embodiment, the disclosed composition comprises of an H2-blocker drug or a pharmaceutically acceptable salt thereof, with one or more alkalizer in an amount effective for controlling the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product, the drug product is coated with a suitable coating. In one aspect, the coating is a film coating. In some aspect, the coating is an aqueous film coating. In one related aspect, the coating is a non-aqueous film coating.

[0040] In some embodiment according to the present invention, the disclosed stable composition comprises amine drug or a pharmaceutically acceptable salt thereof, with one or more alkalizer in an amount effective for controlling the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product and the drug product is coated with an aqueous film coating.

[0041] In one aspect of the above embodiment, the amine drug is ranitidine or a pharmaceutical acceptable salt thereof.

[0042] In another embodiment according to the present invention, the disclosed stable composition comprises amine drug or a pharmaceutically acceptable salt thereof, with one or more alkalizer in an amount effective for controlling the level of nitrosamine drug substance-related impurities (NDSRIs) in the drug product and the drug product is coated with a non-aqueous film coating.

[0043] In one aspect of the above embodiment, the amine drug is ranitidine or a pharmaceutical acceptable salt thereof.

[0044] In another embodiment according to present invention, the disclosed stable dosage form comprises ranitidine or a pharmaceutically acceptable salt thereof with one or more alkalizer for controlling the level of nitrosamine drug substance related impurities (NDSRIs) to a level below about 11 ppm. In one aspect the level of nitrosamine drug substance related impurity (NDSRIs) in the composition remains below about 11 ppm, preferably below about 10 ppm, below about 9 ppm, below about 8 ppm, below about 7 ppm, below about 6 ppm, below about 5 ppm, below about 4 ppm, below about 3 ppm, below about 2 ppm or below about 1 ppm upon storage under the temperature and humidity conditions of 40°C./75% RH or 30°C./75% RH for at least 3 months and at controlled room temperature condition of 25°C/60% RH for at least 12 months, 18 months or 24 months. In one aspect of the above embodiment the nitrosamine drug substance related impurities (NDSRIs) is N- Nitrosodimethylamine (NDMA).

[0045] In one aspect, the level of N- nitrosodimethylamine (NDMA) is below about 11 ppm, preferably below 5 ppm, more preferably below 3 ppm for shelf life period.

[0046] The term "N- nitrosodimethylamine (NDMA)" as used herein the specification, refers to the nitrosamine drug substance related impurities (NDSRIs) associated with ranitidine or its pharmaceutical acceptable salts. Such impurities may be present in active pharmaceutical ingredients or can be formed in the drug product up on storage.

[0047] In yet another embodiment according to present invention the disclosed stable dosage form comprises an H2 blocker drug or a pharmaceutically acceptable salt thereof and at least one alkalizer. In one aspect, the alkalizer is selected from alkali metal oxide, pH modifier, nitrite quencher. In one aspect, the alkali metal oxide is magnesium oxide. In another aspect, the alkalizer is sodium metabisulfite. In yet another aspect the pH modifier is selected from meglumine.

[0048] In one embodiment according to present invention, the disclosed stable dosage form comprises an H2 blocker drug or a pharmaceutically acceptable salt thereof and a combination of two or more alkalizer, in an amount and ratio effective for controlling the Nitrosamine drug substance related impurities (NDSRIs).

[0049] In an aspect of the above embodiment, the H2 blocker drug is ranitidine or a pharmaceutical acceptable salt thereof and the alkalizer is a combination of alkali metal oxide and pH modifier. In one aspect, the composition further comprises alkalizer as alkali metal oxide and an additional antioxidant component. In another aspect, the composition comprises alkalizer as a pH modifier and an additional antioxidant component. In yet another aspect the alkalizer is a combination of alkali metal oxide and pH modifier, with an additional antioxidant component.

[0050] In some embodiment according to present invention, the disclosed stable dosage form comprises a ranitidine or a pharmaceutically acceptable salt thereof and one or more alkalizer, in an amount and ratio effective for controlling the nitrosamine drug substance related impurities (NDSRIs).

[0051] In an aspect, the composition comprises ranitidine hydrochloride and magnesium oxide, wherein the magnesium oxide is present in the composition in an amount effective for controlling the nitrosamine drug substance related impurities (NDSRIs) of ranitidine.

[0052] In some aspect the nitrosamine drug substance related impurities (NDSRIs) of ranitidine is N- Nitrosodimethylamine (NDMA).

[0053] In some aspect, the alkalizer is magnesium oxide and is present in an amount ranging from about 0.1% w/w to about 10% w/w, preferably about 0.1% w/w to about 2% w/w.

[0054] Some exemplary embodiments:

[0055] In one embodiment, the present invention provides a stable pharmaceutical composition comprising of a Histamine H2-receptor antagonist drug or a pharmaceutically acceptable salt thereof and an alkalizer, wherein the composition is characterized by a level of nitrosamine drug substance related impurity below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm.

[0056] In one related aspect of the above embodiment, the alkalizer is selected from an alkali metal stabilizer such as alkali metal oxides, alkali metal salts, pH modifiers and nitrite quencher, or mixture thereof.

[0057] In another related aspect of the above embodiment, the alkalizer is an alkali metal stabilizer selected from magnesium oxide, sodium oxide and potassium oxide or mixture thereof. In one aspect, the alkali metal stabilizer is magnesium oxide.

[0058] In yet another related aspect in the pharmaceutical composition the alkalizer can be selected from sodium sulfites, sodium metabisulfite, sodium bisulfite, or combination thereof. [0059] In one aspect, the alkalizer can be used in combination with an antioxidant selected from ascorbic acid, tocopherol, sodium ascorbate, butylated hydroxy anisole, butylated hydroxyl toluene, and propyl gallate or mixture thereof.

[0060] In some related aspects of the above embodiment in the pharmaceutical composition, the alkalizer is a nitrite quencher selected from ascorbic acid or salt thereof. In one aspect, the nitrite quencher is sodium ascorbate.

[0061] In a further related aspect of the above embodiment in the pharmaceutical composition, the alkalizer is a pH modifier selected from meglumine or salt thereof.

[0062] In some aspects of the above embodiment, the alkalizer is present in the composition in a concentration range of about 0.1% w/w to about 10% w/w of the composition, preferably about 0.1% w/w to about 5% w/w, more preferably about 0.1 to about 3% w/w of the composition. In one aspect, the alkalizer is alkali metal oxide. In one preferred aspect, the alkali metal oxide is magnesium oxide.

[0063] In some aspects of the above embodiments, in the pharmaceutical composition the Histamine H2-receptor antagonist drug is selected from cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine or a pharmaceutically acceptable salt thereof. In one aspect, the Histamine H2-receptor antagonist drug is ranitidine or a pharmaceutically acceptable salt thereof. In another aspect, the Histamine H2-receptor antagonist drug is Nizatidine or a pharmaceutically acceptable salt thereof.

[0064] In some aspects of the above embodiment in the pharmaceutical composition, the nitrosamine drug substance related impurity is N- nitrosodimethylamine (NDMA) impurity.

[0065] In another embodiment the present invention provides a stable pharmaceutical composition of ranitidine comprising ranitidine or a pharmaceutically acceptable salt thereof, at least one alkali metal stabilizer, and one or more pharmaceutically acceptable excipient, wherein the composition is characterized by nitrosamine drug substance-related impurities (NDSRIs) in the composition below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C./60% RH for a period of 24 months.

[0066] In yet another embodiment the present invention provides a stable pharmaceutical composition comprising of ranitidine hydrochloride and magnesium oxide with one or more pharmaceutically acceptable excipients, wherein the composition is characterized by nitrosamine drug substance related impurity as N- Nitrosodimethylamine (NDMA) below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C/60% RH for a period of 24 months.

[0067] In some aspects of the above embodiment, the pharmaceutical composition is further coated with a film coating. In one aspect, the film coating is an aqueous film coating. In another aspect, the film coating is a non-aqueous film coating.

[0068] In some embodiments, the pharmaceutical composition according to present invention comprises Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof and an alkalizer, wherein a ratio of a Histamine H2-receptor antagonist drug or a pharmaceutically acceptable salt thereof and an alkalizer in the composition is 100:0.1 to 100:10, preferably 100:0.1 to 100:5. In one aspect according to the embodiment the presence of Histamine H2-receptor antagonist or a pharmaceutically acceptable salt thereof and an alkalizer in a ratio of 100:0.1 to 100:10 is effective for controlling the level of N- Nitrosodimethylamine (NDMA) impurity below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C/60% RH for a period of 24 months.

[0069] In one embodiment the present invention provides a process for preparing a stable pharmaceutical composition of Histamine H2-receptor antagonist comprising a Histamine H2-receptor antagonist or a pharmaceutically acceptable salt and at least one alkali metal stabilizer, wherein the alkali metal stabilizer is placed in the composition for effective control of the formation of nitrosamine drug substance- related impurities (NDSRIs) in the composition below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C./60% RH for a period of 24 months.

[0070] In some aspect according to above embodiment the process comprises of: a) blending Histamine H2-receptor antagonist and alkali metal stabilizer and sifting with one or more pharmaceutically acceptable excipient to form the core blend; b) lubricating the core blended, followed by compressing into tablets; c) coating the tablet and packing. [0071] In one related aspect of the above embodiment in the process of preparation of said composition, the Histamine H2-receptor antagonist and alkali metal stabilizer are mixed prior to co-sifting with other excipients.

[0072] In one related aspect of the above embodiment, the process according to present invention is carried out under sodium light with low relative humidity condition.

[0073] In some embodiments, the present invention provides a method for controlling N-nitrosodimethylamine in a pharmaceutical composition of an amine drug, wherein the method comprises mixing an amine drug with an alkali metal oxide during preparation of the pharmaceutical composition followed by sifting the mixture with pharmaceutical acceptable excipient. In one related aspect of the embodiment the method characteristically controls the level of the N- Nitrosodimethylamine below 11 ppm, preferably below 5 ppm, more preferably below 3 ppm upon storage at 25°C/60% RH for a period of 24 months.

[0074] In some embodiment according to the present invention, the stable dosage form comprising ranitidine or a pharmaceutically acceptable salt thereof with at least one or more alkalizer, wherein alkalizer is selected from magnesium oxide, meglumine, aluminum oxide, ammonium hydroxide, magaldrate, an alkali metal salt or alkaline earth metal salt, such as sodium bicarbonate, calcium carbonate or sodium citrate, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide. In some aspects of the embodiment, the preferred alkalizer according to the present invention is magnesium oxide. In some aspect of the above embodiment the dosage form is characterized by controlled level of the N-Nitrosodimethylamine below 11 ppm, preferably below 5, more preferably below 3 ppm upon storage at 25°C/60% RH for a period of 24 months.

[0075] The dosage form according to present invention may be present in the form of solid oral dosage form such as tablet, pellet, granule, capsules.

[0076] The dosage form according to present invention comprises one or more pharmaceutically acceptable excipients selected from one or more of fillers, disintegrants, lubricants, glidants, anti-adherents, coating agents, and mixtures thereof. [0077] Suitable diluents are selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium sulphate, calcium carbonate, powdered cellulose, mannitol, sorbitol, xylitol, lactitol, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulphate, and mixtures thereof.

[0078] Suitable binders are selected from the group consisting of cellulose derivatives (for example methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC / Hypromellose), ethylcellulose, hydroxyl ethyl cellulose, L-hydroxy propyl cellulose); polyvinylpyrrolidone (for example povidone, copovidone); starch (for example corn starch, pre-gelatinized starch and hydroxypropyl starch), polymethacrylates (for example Eudragit RS, RL), and mixtures thereof.

[0079] Suitable disintegrants are selected from the group consisting of low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, starch derivatives, and mixtures thereof.

[0080] Suitable lubricants are selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof.

[0081] Suitable glidants or antiadherents are selected from the group consisting of talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate, and mixtures thereof.

[0082] Non-limiting examples of suitable coating gents selected from the group comprising of aqueous and non-aqueous coating agents selected from Hypromellose, polyvinyl acetate, cellulose acetate, ethyl cellulose or combination thereof.

[0083] Additional excipients present in the coating include one or more of film forming polymers, plasticizers, anti-adherents, opacifiers, colorants, pigments, antifoaming agents, and polishing agents.

[0084] Suitable film-forming polymers are selected from the group consisting of hydroxypropylmethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, and methacrylic acid copolymers, e.g., Eudragit*, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, and mixtures thereof. Other suitable film-forming polymers which are known in the art may also be used. Many suitable film coating products which are commercially available, e.g., Opadry*, Colorezy and Opagios* may be used.

[0085] Suitable plasticizers are selected from the group consisting of propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glyceryl monostearate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, diacetylated monoglycerides, cetyl alcohol, and mixtures thereof.

[0086] Suitable opacifiers are selected from the group consisting of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof.

[0087] Suitable coloring agents are selected from FDA approved colorants such as iron oxide, lake of tartrazine, allura red, titanium dioxide, and mixtures thereof.

[0088] Suitable polishing agents are selected from the group consisting of polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (glycerol monostearate and poloxamers), fatty alcohols (stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol), waxes (carnauba wax, candelilla wax and white wax), and mixtures thereof.

[0089] Various solvents that may be employed during the preparation of the dosage form of the present invention are selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, and mixtures thereof.

[0090] The coating may be carried out by using any conventional coating techniques known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.

[0091] The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

[0092] EXAMPLES [0093] Examples 1 and 2:

[0094] Manufacturing Process:

Raw material including excipient and active pharmaceutical ingredient were weighed and dispensed for manufacturing the tablet;

Sifting drug, diluent, disintegrant, alkalizer, glidant, through suitable sieve;

Blending the sifted material followed by adding lubricant and lubricating to formed blend;

Compression of the lubricated blend, followed by coating the compressed tablet as per coating requirement.

During manufacturing relative humidity was kept below about 40% under sodium light.

[0095] Example 3: Formulation with aqueous and non-aqueous coating using different alkalizer:

* Ranitidine Hydrochloride is taken in a weight equivalent to 300 mg of ranitidine base for example A to G and 150 mg of ranitidine base for example H and I respectively.

[0096] Manufacturing process:

1. All the ingredients were weighed.

2. LOD of Microcrystalline Cellulose was checked; (if LOD is not complying to a limit of NMT 3.0 % w/w then dry the Microcrystalline Cellulose in Tray Dryer or Fluidized bed dryer, to get the desired LOD)

3. Ranitidine Hydrochloride, Microcrystalline Cellulose (RQ. 102S) (Dried from step-2), respective alkalizer, Colloidal anhydrous silica and Croscarmellose sodium through were sifted through suitable sieve.

4. The step-3 ingredients were blended in blender for 30 minutes at suitable speed.

5. Magnesium Stearate and Talc were sifted through suitable sieve.

6. Step-4 material were lubricated with the material of step-5 in a blender for suitable time at suitable speed.

7. The lubricated blend was unloaded in double polyethylene lined HDPE container.

8. Then the lubricated blend was compressed using approved tooling for both the strengths.

9. Then the core tablets were stored in double polyethylene lined HDPE container. 10. A 6% w/w dispersion of Opadry white OY-S-58910 prepared in a mixture of Isopropyl

Alcohol and Methylene Chloride (60:40) under stirring to form uniform dispersion. (For aqueous coating separate material were used)

11. Then the core tablets of step 10 were coated with dispersion of step 10 respectively to achieve a target weight buildup of 4.5 ± 0.5% w/w.

12. Followed by packing in suitable packaging.

[0097] Example 4: Stability data of Sample F & G with different percentage of

Sodium metabisulfite

* A I impurity profile specification is in line with Indian Pharmacopoeia drug product monograph, except for NDMA.

[0098] Observation:

• NDMA results was found to be controlled in both the concentration of SMBS i.e. 1% and 10%.

• Significant increase in related substance (impurity) was observed in 10%SMBS as compared to 1%SMBS.

[0099] Example 5: Stability data of Sample A-D and H-H^# with different percentage of Alkalizer:

Sample H^#: Controlled batch with modified API 150 mg, composition same as batch H

[00100] Observation:

Bottle pack is comparatively better than strip pack to control NDMA using at least one alkalizer as shown in above table.

Alu strip samples are having higher percentage of impurities in samples A and B, however the impurity levels were significant controlled in case of sample C & D under accelerate stability condition i.e. 40°C/75%RH conditions, which depicts that magnesium oxide and sodium ascorbate provides a comparatively better NDMA control in case of HDPE over Alu strip packings.

NDMA data for alkali oxide batch at 9M_LT & CRT was also found to be controlled. [00101] Example 6: Formulation approaches with different coating and API strategy:

ample not charged; * Samples not analysed due to failed description

[00102] Batch Description with coating composition and process as provided in above table:

Batch J: Prepared with modified milled API using similar process as in example 3, with a granulation step including Isopropyl alcohol granulation without alkalizer.

Batch K: Prepared with modified coarse API using similar process as in example 3, with 10% ascorbic acid.

Batch L: Prepared with modified coarse API using similar process as in example 3, with alkalizer as 10% sodium metabisulphite.

Batch M: Prepared with modified coarse API using similar process as in example 3, with alkalizer as 5% Sodium Carbonate.

Batch N: Prepared with modified coarse API using similar process as in example 3, without alkalizer.

Batch O: Prepared with modified milled API using similar process as in example 3, with 1.2% Vitamin E.

Batch P: Prepared with modified milled API using similar process as in example 3, with 1.2% Vitamin E.

[00103] Observation: Samples of Batch J to P with different type of API viz., coarse / milled API, different coating composition and alkalizer or stabilizers strategy were evaluated and found to be unstable.

- The sample tablets were brown or yellow colored and were found with cracks, hence found to be undesirable and failing.

Based on experiments it can be considered that PVC/PVDC is not an appropriate pack as tablets failing in description as compared to Alu Strip pack.

Also, the samples which were loaded for stability were unstable and have higher NDMA levels within IM at 40°C/75%RH and 14 days at 60°C.

[00104] Example 7: Stability data of composition of Example 3C with aqueous coating and non-aqueous coating stored in 25x30's Strips

1. With Non-aqueous film coating - at ACC for 6 months and 30°C/75%RH for 12 months

2. With aqueous film coating - at ACC for 6 months and 30°C/75%RH for 12 months

ND: Not detected

BLQ: Below limit of quantification

[00105] Based on the data it was observed that the composition are stable with an NDMA amount of less than llppm when stored for 12 months at 30°C/75%RH and at 40°C/75%RH for 6 months.

Claims

1. A stable pharmaceutical composition comprising, a Histamine H2-receptor antagonist, a stabilizing amount of at least one alkalizer and one or more pharmaceutically acceptable excipient, wherein the alkalizer effectively control the formation of nitrosamine drug substance-related impurities (NDSRIs) in the composition, to a level below about 11 ppm, upon storage or acid exposure.

2. A stable pharmaceutical composition of claim 3, wherein the Histamine H2-receptor antagonist is ranitidine hydrochloride

3. A stable pharmaceutical composition of claim 3, wherein the ratio of a Histamine H2- receptor antagonist and an alkalizer in the composition is in the range of 100:0.1 to 100:5.

4. A stable pharmaceutical composition of claim 3, wherein the nitrosamine drug substance-related impurity is N-nitrosodimethylamine (NDMA) impurity.

5. A stable pharmaceutical composition of claim 3, wherein the alkalizer is selected from alkali metal oxide, pH modifier, nitrite quencher.

6. A stable pharmaceutical composition of claim 7, wherein the alkalizer is alkali metal oxide.

7. A stable pharmaceutical composition of claim 8, wherein the alkali metal oxide is magnesium oxide

8. A stable pharmaceutical composition of claim 7, wherein the alkali metal oxide is present in the core of the composition.

9. A stable pharmaceutical composition of claim 7, wherein the alkali metal oxide is present in the composition within a coating.

10. A stable pharmaceutical composition of claim 11, wherein the coating is an aqueous film coating.

11. A stable pharmaceutical composition of claim 11, the coating is a non-aqueous film coating.

12. A stable pharmaceutical composition of any of the preceding claims, wherein the level of nitrosamine drug substance related impurities (NDSRIs) level is below about 11 ppm upon storage under controlled room temperature condition of 25°C/60% RH for at least 12 months.

13. A stable pharmaceutical composition comprising ranitidine hydrochloride and magnesium oxide, wherein the magnesium oxide is present in the composition in an amount present in an amount ranging from about 0.1% w/w to about 10% w/w of the composition, wherein the composition is characterized by a level of N- Nitrosodimethylamine (NDMA) impurity below 11 ppm, upon storage at 25°C/60% RH for a period of at least 12 months.

14. A stable pharmaceutical composition of claim 17, wherein the amount of magnesium oxide ranges from about 0.1% w/w to about 2% w/w of the composition.

15. A stable pharmaceutical composition of claim 17, wherein the composition is characterized by a level of nitrosamine drug substance related impurity below 3 ppm, upon storage at 25°C./60% RH for a period of 12 months.