WO2024165666A1

WO2024165666A1 - Method of reducing the amount of n-nitrosamine impurities

Info

Publication number: WO2024165666A1
Application number: PCT/EP2024/053170
Authority: WO
Inventors: Pawel STASIAK; Filip Šembera; Pavel Šebek; Igor Čerňa; Michal Douša; Petr Gibala; František BARTÁČEK; Jaroslav Říha; Stanislav KALÁŠEK; Jakub Heřt; Josef Černý; Tomáš JIRKAL; Anna KLUK; Ewa BARTOSIŃSKA; Jaroslava Svobodová; Michaela SYROVÁTKOVÁ; Filip SOUČEK; Jakub JIREŠ; Dita SPÁLOVSKÁ; Petr Koukal
Original assignee: Zentiva K.S.
Priority date: 2023-02-09
Filing date: 2024-02-08
Publication date: 2024-08-15
Also published as: GB202301853D0

Abstract

A method for reducing the amount of nitrosating agents and/or N-Nitrosamine impurities in a pharmaceutically acceptable excipient, the method comprising a pre-treatment step of mixing one or more pharmaceutically acceptable excipients with at least one reducing agent.

Description

METHOD OF REDUCING THE AMOUNT OF N-NITROSAMINE IMPURITIES Field of the Invention The present invention relates to a method for reducing the amount of nitrosating agents and/or N-Nitrosamine impurities in pharmaceutically acceptable excipients. Background N-Nitrosamines are organic compounds with the chemical structure R2N-N=O, where R is usually an alkyl group. They feature a nitroso group (NO⁺) bonded to a deprotonated amine. N-Nitrosamines have been found to be mutagenic and potentially carcinogenic in humans. The carcinogenic potential of N-Nitrosamines has been found to be dependent on multiple factors: ^ the ability of the N-nitrosamine to be metabolically activated by α-hydroxylation which leads to formation of diazonium ions; ^ the metabolic competence and capacity of the tissue to form diazonium ions; ^ the nature and stability of the diazonium ion and the related DNA-adducts formed; ^ the capacity, velocity and accuracy of the different cellular repair mechanisms responsible for the repair of the different DNA-adducts in tissues. The carcinogenic nature of N-Nitrosamines means that exposure to them, even in small amounts, may have a significant risk to humans. Accordingly, acceptable daily limits of N- Nitrosamines such as N-nitroso-dimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) have been set at 96 ng/day and 26.5 ng/day respectively. Recently, N-nitrosamine impurities have been detected in medicinal products for humans. Regulators first became aware of the presence of N-nitrosamines in medicinal products in 2018, with reports of N-nitroso-dimethylamine (NDMA) being detected in the angiotensin II receptor blocker valsartan. A subsequent EU review of all valsartan medicines was triggered by the European Medicines Agency (EMA) and was later extended to all sartans and other angiotensin receptor blockers. A separate review was also started for ranitidine medicines. This was followed by an EU-wide examination of the risk of N-nitrosamines being present in all medicines intended for humans. The EU-reviews identified a number of root causes leading to the presence of N- nitrosamines in medicines, all of which have in common the reaction of a nitrosable compound, such as a secondary or tertiary amine, with a nitrosating agent. Frequently, the nitrosating agent was found to be a nitrite or nitrate salt reacting under acidic or neutral conditions during manufacture of the active pharmaceutical ingredient (API). It has been found that contaminated reagents or solvents may also comprise nitrosating agents. Nitrosating agents can also be found in many commonly used excipients at parts per million levels. Sodium starch glycolate, croscarmellose sodium, pre-gelatinized starch, polyvinylpyrrolidone (PVP), cross polyvinylpyrrolidone (cPVP), and lactose are just some examples of the excipients that could carry trace levels of nitrate or nitrite impurities. By way of example, reactions of residual amine impurities with nitrosating sources in excipients or primary packaging are postulated to have contributed to NDMA contamination in metformin medicines. Furthermore, degradation of the API itself may lead to N-nitrosamine impurities. It is evident from these root causes that N-nitrosamine formation may occur at any stage of the manufacturing process of a medicinal product and it highlights the urgent need to find ways of reducing their formation. Improved testing methods enable the detection of even trace amounts of impurities in drug products and allow the levels of N-nitrosamines to be carefully monitored. However, whilst monitoring the amount of N-nitrosamines in a final drug product prevents non-compliant drug products entering the market, it does not represent an efficient way to deliver compliant drug products. As such, there remains a need to effectively reduce the formation of N-nitrosamine impurities during the manufacture of a drug product. A common approach has been to adapt synthesis routes to exclude nitrosable compounds and nitrosating agents that could react to form N-nitrosamines. However, changing the synthesis route of active ingredients may require the selection of alternative solvents and starting materials containing primary, secondary and tertiary amines or quaternary ammonium salts. This may result in more complex and expensive synthesis routes. Accordingly, there remains a need for methods that reduce or prevent the formation of N-nitrosamine impurities in active pharmaceutical ingredients and final drug products but require minimal changes to the existing synthetic routes and/or manufacturing processes. Detailed Description The present invention relates to a method for reducing the amount of nitrosating agents and/or N-Nitrosamine impurities in pharmaceutically acceptable excipients. The method may comprise a pre-treatment step of mixing one or more pharmaceutically acceptable excipients with at least one reducing agent. Preferably, the present invention relates to a method for reducing the amount of nitrosating agents in pharmaceutically acceptable excipients. The pre-treatment step of mixing one or more pharmaceutically acceptable excipients with at least one reducing agent has been shown to reduce the amount of N-Nitrosamine impurities in a finished dosage form by directly reducing the levels of nitrosating agents prior to the pharmaceutically acceptable excipients being mixed with one or more active pharmaceutical ingredients. The reaction rate quantifies the relationship between the reactants in a chemical reaction. The method of the present invention limits the chemical reaction to only two reactant species meaning that any nitrosating agents present in the pharmaceutically acceptable excipients do not have to compete with other reactants when interacting with the reducing agent. This results in the concentration of the nitrosating agent decreasing proportionately with the concentration of the reducing agent. The combined effect of reduced competition and increased kinetics results in a significantly lower amount of N-nitrosamine impurities in the finished dosage form. This is particularly pronounced in medicinal products because the pharmaceutical excipients are usually present in the finished dosage form in much larger quantities than the active pharmaceutical ingredient. Furthermore, the method of the present invention advantageously negates the need to adapt synthesis routes and perform additional purification steps in order to reduce the amount of N-nitrosamine impurities. As used herein the term “active pharmaceutical ingredient” refers to the substance (or combination of substances) that is the biologically active component of a drug product. As used herein the term “or salt thereof” refers to any crystalline or amorphous salt of the active pharmaceutical agent, prepared from bases or acids including inorganic or organic bases and inorganic and organic acids. As used herein the term “pharmaceutically acceptable salt” refers to any non-toxic salt, prepared from bases or acids including inorganic or organic bases and inorganic and organic acids, suitable for use in human drug products. The active pharmaceutical ingredient or salt thereof used in any aspect of the present invention may be any biologically active component of a drug product. Preferably the salt is a pharmaceutically acceptable salt (e.g. any pharmaceutically acceptable salt known in the art, e.g. hydrochloride or sulphate). As used herein, the term “finished dosage form” indicates any combination of an active pharmaceutical ingredient with other components for the purpose of producing a drug product in a form to be administered to a patient. Preferably, the finished dosage form is a solid dosage form, such as a tablet, capsule, powder or topical formulation. In some embodiments of the present invention, the mixing of one or more pharmaceutically acceptable excipients with at least one reducing agent may be selected from the group consisting of dry homogenisation, co-sifting, compaction, high-shear, fluid-bed granulation, hot-melt extrusion, and spray drying. In a further embodiment, the mixing may be by spray drying. In some further embodiments of the present invention, the spray drying may comprise the steps of spraying the composition comprising one or more pharmaceutically acceptable excipients with a reducing solution comprising a solvent and at least one reducing agent; and removing the solvent. Advantageously, it has been found that spraying the composition comprising one or more pharmaceutically acceptable excipients results in enhanced mixing of the reducing agent and nitrosating agents which improves the reaction efficiency between the nitrosating agents and the reducing agents. In certain embodiments of the present invention, the spraying duration may be selected from 1 minute to 10 minutes, from 1.5 minutes to 9.5 minutes, from 2 minutes to 9 minutes, from 2.5 minutes to 8.5 minutes, from 3 minutes to 8 minutes, from 3.5 minutes to 7.5 minutes, from 4 minutes to 7 minutes, from 4.5 minutes to 6.5 minutes, from 5 minutes to 6 minutes. In other embodiments of the present invention, the spraying duration may be selected from at least 1 minute, at least 1.5 minutes, at least 2 minutes, at least 2.5 minutes, at least 3 minutes, at least 3.5 minutes, at least 4 minutes, at least 4.5 minutes, at least 5 minutes, at least 5.5 minutes, at least 6 minutes, at least 6.5 minutes, at least 7 minutes, at least 7.5 minutes, at least 8 minutes, at least 8.5 minutes, at least 9 minutes, at least 9.5 minutes, or at least 10 minutes. In other embodiments of the present invention, the spraying duration may be selected from no more than 1 minute, no more than 1.5 minutes, no more than 2 minutes, no more than 2.5 minutes, no more than 3 minutes, no more than 3.5 minutes, no more than 4 minutes, no more than 4.5 minutes, no more than 5 minutes, no more than 5.5 minutes, no more than 6 minutes, no more than 6.5 minutes, no more than 7 minutes, no more than 7.5 minutes, no more than 8 minutes, no more than 8.5 minutes, no more than 9 minutes, no more than 9.5 minutes, or no more than 10 minutes. In some embodiments of the present invention, the solvent removal step may comprise heat drying, vacuum drying and/or lyophilisation. As used herein, the term “heat drying” a process for the removal of moisture present in a substance based on moisture evaporation by heating. The heat for evaporation may be transferred by convective heat transfer or, in alternative embodiments, may be transferred by radiation and/or high frequency currents. As used herein, the term “vacuum drying” indicates a process in which the moisture present in a substance may be removed by means of creating a vacuum to decrease the pressure below the vapour pressure of the solvent, causing it to boil. As used herein, the term “lyophilisation” indicates a process in which a solvent may be removed from a product after it is frozen and placed under vacuum, allowing the ice to change directly from solid to vapour without passing through a liquid phase. In certain embodiments of the present invention, the heat drying duration may be from 5 minutes to 30 minutes, from 10 minutes to 25 minutes, from 15 minutes to 20 minutes. In other embodiments of the present invention, the heat drying duration may be at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes. In other embodiments of the present invention, the heat drying duration may be no more than 5 minutes, no more than 10 minutes, no more than 15 minutes, no more than 20 minutes, no more than 25 minutes, or no more than 30 minutes. In other embodiments of the present invention, the vacuum drying duration may be up to 3 hours. Surprisingly, it has been found that the time of drying may influence the performance of the pre-treatment step, for example a longer drying time may result in lower amounts of nitrosating agents remaining in the pharmaceutically acceptable excipients. In certain embodiments of the present invention, the heat drying temperature may be from 25 ºC to 70 ºC, from 35 ºC to 65 ºC, from 40 ºC to 60 ºC, or from 45 ºC to 55 ºC. In other embodiments of the present invention the heat drying temperature may be at least 25 ºC, at least 30 ºC, at least 35 ºC, at least 40 ºC, at least 45 ºC, at least 50 ºC, at least 55 ºC, at least 60 ºC, at least 65 ºC, or at least 70 ºC. In other embodiments of the present invention, the heat drying temperature may be no more than 25 ºC, no more than 30 ºC, no more than 35 ºC, no more than 40 ºC, no more than 45 ºC, no more than 50 ºC, no more than 55 ºC, no more than 60 ºC, no more than 65 ºC, or no more than 70 ºC. In certain embodiments of the present invention, the drying pressure may be from 50 mbar to 1000 mbar, from 100 mbar to 950 mbar, from 150 mbar to 900 mbar, from 200 mbar to 850 mbar, from 250 mbar to 800 mbar, from 300 mbar to 750 mbar, from 350 mbar to 700 mbar, from 400 mbar to 650 mbar, from 450 mbar to 600 bar, or from 500 mbar to 550 mbar. In other embodiments of the present invention, the drying pressure may be at least 50, at least 100 mbar, at least 150 mbar, at least 200 mbar, at least 250 mbar, at least 300 mbar, at least 350 mbar, at least 400 mbar, at least 450 mbar, at least 500 mbar, at least 550 mbar, at least 600 mbar, at least 650 mbar, at least 700 mbar, at least 750 mbar, at least 800 mbar, at least 850 mbar, at least 900 mbar, at least 950 mbar, or at least 1000 mbar. In other embodiments of the present invention, the drying pressure may be no more than 50, no more than 100 mbar, no more than 150 mbar, no more than 200 mbar, no more than 250 mbar, no more than 300 mbar, no more than 350 mbar, no more than 400 mbar, no more than 450 mbar, no more than 500 mbar, no more than 550 mbar, no more than 600 mbar, no more than 650 mbar, no more than 700 mbar, no more than 750 mbar, no more than 800 mbar, no more than 850 mbar, no ore than 900 mbar, no more than 950 mbar, or no more than 1000 mbar. In some embodiments of the present invention, the reducing agent may be selected from at least one of sodium sulphite, sodium metabisulphite, sodium bisulphite, sodium thiobisulphate, acetone sodium bisulphite, dithiothreitol, monothioglycerol, sodium formaldehyde sulfoxylate, alpha-tocopherol, ascorbic acid, citric acid, sodium iodide, acetylcysteine, trans-ferrulic acid, sodium phosphite dibasic pentahydrate, glucosamine HCl, catechin hydrate, L-cystine, maltol, pyridoxine, ammonium ferrous sulphate hexahydrate, propyl paraben, tris(2,4-di-tert-butylphenyl) phosphite, glutathione, propyl gallate, rutin, L-(+)-tartaric acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), histidine, methionine, glyceraldehyde, pyridoxine HCl, L-malic acid, dihydrolipoic acid, or a combination thereof. In further embodiments of the present invention, the reducing agent may be selected from at least one of dithiothreitol, monothioglycerol, sodium formaldehyde sulfoxylate, alpha- tocopherol, ascorbic acid, sodium iodide, acetylcysteine, trans-ferrulic acid, sodium phosphite dibasic pentahydrate, glucosamine HCl, catechin hydrate, L-cystine, maltol, pyridoxine, ammonium ferrous sulphate hexahydrate, propyl paraben, tri(2,4-di-tert-butylphenyl) phosphite, glutathione, propyl gallate, rutin, L-(+)-tartaric acid, methionine, glyceraldehyde, pyridoxine HCl, L-malic acid, dihydrolipoic acid, or a combination thereof. In other embodiments of the present invention, the reducing agent may be selected from at least one of ascorbic acid, acetylcysteine, L-cysteine hydrochloride monohydrate, dithiothreitol, sodium phosphite dibasic pentahydrate, or a combination thereof. In a further embodiment of the present invention, the reducing agent may be acetylcysteine. In a yet further embodiment, the reducing agent may be ascorbic agent. In another embodiment of the present invention, the reducing agent is not selected from sodium metabisulphite, sodium bisulphite, sodium thiobisulphate and acetone sodium bisulphite. Surprisingly, it has been found that in the method according to the present invention the ability of certain reducing agents to limit the amount of N-Nitrosamine impurities in a finished dosage form is markedly improved when they are applied in a pre-treatment step to the pharmaceutically acceptable excipients compared to when they are added as part of the finished dosage form. In a further embodiment of the present invention, the ratio of the total weight of the reducing agent versus the total weight of the pharmaceutically acceptable excipients may be selected from 0.01% to 5%, from 0.02% to 4.5%, from 0.03% to 4%, from 0.04% to 3.5%, from 0.05% to 3%, from 0.06% to 2.5%, from 0.07% to 2%, from 0.08% to 1.5%, from 0.09% to 1%, or from 0.1% to 0.5%. According to other embodiments of the present invention, the ratio of the total weight of the reducing agent versus the total weight of the pharmaceutically acceptable excipients may be selected from at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.5%, at least 1%, at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, or at least 5%. In another embodiment the ratio of the total weight of the reducing agent versus the total weight of the pharmaceutically acceptable excipients is 0.5%. According to other embodiments of the present invention, the ratio of the total weight of the reducing agent versus the total weight of the pharmaceutically acceptable excipients may be selected from no more than 0.01%, no more than 0.02%, no more than 0.03%, no more than 0.04%, no more than 0.05%, no more than 0.06%, no more than 0.07%, no more than 0.08%, no more than 0.09%, no more than 0.1%, no more than 0.5%, no more than 1%, no more than 1.5%, no more than 2%, no more than 2.5%, no ore than 3%, no more than 3.5%, no more than 4%, no more than 4.5%, or no more than 5%. In another embodiment the ratio of the total weight of the reducing agent versus the total weight of the pharmaceutically acceptable excipients is 0.5%. In certain embodiments of the present invention, the concentration of reducing agent in the reducing solution may be selected from 0.1% to 10%, from 0.15% to 9.5%, from 0.2% to 9%, from 0.25% to 8.5%, from 0.3% to 8%, from 0.35% to 7.5%, from 0.4% to 7%, from 0.45% to 6.5%, from 0.5% to 6%, from 0.55% to 5.5%, from 0.6% to 5%, from 0.65% to 4.5%, from 0.7% to 4%, from 0.75% to 3.5%, from 0.8% to 3%, from 0.85% to 2.5%, from 0.9% to 2%, or from 0.95% to 1.5%. In other embodiments of the present invention, the concentration of reducing agent in the reducing solution may be selected from at least 0.1%, at least 0.15%, at least 0.2%, at least 0.25%, at least 0.3%, at least 0.35%, at least 0.4%, at least 0.45%, at least 0.5%, at least 0.55%, at least 0.6%, at least 0.65%, at least 0.7%, at least 0.75%, at least 0.8%, at least 0.85%, at least 0.9%, at least 0.95%, at least 1.0%, at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5%, at least 5.5%, at least 6%, at least 6.5%, at least 7%, at least 7.5%, at least 8%, at least 8.5%, at least 9%, at least 9.5%, or at least 10%. In other embodiments of the present invention, the concentration of reducing agent in the reducing solution may be selected from no more than 0.1%, no more than 0.15%, no more than 0.2%, no more than 0.25%, no more than 0.3%, no more than 0.35%, no more than 0.4%, no more than 0.45%, no more than 0.5%, no more than 0.55%, no more than 0.6%, no more than 0.65%, no more than 0.7%, no more than 0.75%, no more than 0.8%, no more than 0.85%, no more than 0.9%, no more than 0.95%, no more than 1.0%, no more than 1.5%, no more than 2%, no more than 2.5%, no more than 3%, no more than 3.5%, no more than 4%, no more than 4.5%, no more than 5%, no more than 5.5%, no more than 6%, no more than 6.5%, no more than 7%, no more than 7.5%, no more than 8%, no more than 8.5%, no more than 9%, no more than 9.5%, or no more than 10%. In another embodiment of the present invention the concentration of reducing agent in the reducing solution is 2%. According to other embodiments of the present invention, the solvent used in the reducing solution may be aqueous, organic, or a combination thereof. In some embodiments, the organic solvent may be selected from the group consisting of ethanol, methanol, isopropanol or a combination thereof. The method of the present invention may further comprise the use of excipients that are substantially free of nitrate and/or nitrite impurities, and preferably free of nitrate and/or nitrite impurities. The nitrate and/or nitrite impurities may be present in an amount of less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.1% by weight based on the total weight of the excipients. The nitrate and/or nitrite impurities may be present in an amount of less than 50 ppm (e.g. less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm or less than 1 ppm). The method of the present invention may further comprise the use of excipients that are substantially free of nitrite impurities, and preferably free of nitrite impurities. The nitrite impurities may be present in an amount of less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.1% by weight based on the total weight of the excipients. The nitrite impurities may be present in an amount of less than 50 ppm (e.g. less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm or less than 1 ppm). The method of the present invention may further comprise a step of combining the one or more pre-treated pharmaceutically acceptable excipients with an active pharmaceutical ingredient or pharmaceutically acceptable salt thereof. Advantageously, the method of the present invention may be implemented early in the manufacturing process, including at the site of excipient production. The present invention also relates to a method for reducing the amount of N-Nitrosamine impurities in a finished dosage form comprising mixing the pre-treated pharmaceutically acceptable excipients with an active pharmaceutical ingredient or pharmaceutically acceptable salt thereof. In further embodiments of the present invention, the active pharmaceutical ingredient or acceptable salt thereof may be a secondary amine or a tertiary amine. In another embodiment of the present invention the secondary amine or a tertiary amine may be selected from the group consisting of ramipril, bisoprolol, cinacalcet, desloratadine, trimetazidine, perindopril, duloxetine and pramipexol. The active pharmaceutical ingredient may be substantially free of nitrate and/or nitrite impurities, and preferably free of nitrate and/or nitrite impurities. The nitrate and/or nitrite impurities may be present in an amount of less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.1% by weight based on the total weight of the active pharmaceutical ingredient. The nitrate and/or nitrite impurities may be present in an amount of less than 50 ppm (e.g. less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm or less than 1 ppm). In certain embodiments, the active pharmaceutical ingredient may be substantially free of, preferably free of N-Nitrosamine impurities. The present invention may also relate to a method for reducing the amount of N- Nitrosamine impurities in a finished dosage form, the method comprising a step of mixing one or more reducing agents with at least one active ingredient. Alternatively, the present invention may relate to a method for reducing the amount of N-Nitrosamine impurities in a finished dosage form, wherein the method may comprise a step of mixing one or more reducing agents with a mixture of at least one pharmaceutically acceptable excipient and at least one active ingredient. The mixing step may be selected from the group consisting of dry homogenisation, co-sifting, compaction, high-shear, fluid-bed granulation, hot-melt extrusion, and spray drying. The present invention may also relate to a method for reducing the amount of N- Nitrosamine impurities in a finished dosage form, the method comprising mixing an active pharmaceutical ingredient or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are substantially free of, preferably free of nitrate and/or nitrite impurities. The nitrate and/or nitrite impurities may be present in an amount of less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.1% by weight based on the total weight of the excipients. The nitrate and/or nitrite impurities may be present in an amount of less than 50 ppm (e.g. less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm or less than 1 ppm). The present invention may also relate to a method for reducing the amount of N- Nitrosamine impurities in a finished dosage form, the method comprising mixing an active pharmaceutical ingredient or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are substantially free of, preferably free of nitrite impurities. The nitrite impurities may be present in an amount of less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.1% by weight based on the total weight of the excipients. The nitrite impurities may be present in an amount of less than 50 ppm (e.g. less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm or less than 1 ppm).A further aspect of the present invention relates to a pharmaceutical composition comprising an active pharmaceutical ingredient or salt thereof, one or more pharmaceutically acceptable excipients, and one or more pH modifying agents. Such compositions may reduce the amount of nitrosable compounds (e.g. amines) in the active pharmaceutical ingredient and/or reduce the conversion of nitrosable compounds into nitrosamines. The one or more pharmaceutically acceptable excipients may be substantially free of, preferably free of nitrite impurities. As used herein the term “pH modifying agent” is an agent that is capable of modifying the pH of the composition to achieve a desired pH. Thus the pH modifying agent is capable of achieving a pH range ranging from acidic to alkaline, preferably the pH is from 7 to 12, e.g. pH from 7 to 11, pH from 7 to 10 or pH from 8 to 9. The pH modifying agent may be selected from a group consisting of an acid, base, or buffer. Preferably the pH modifying agent is a base, for example a carbonate or hydrogen carbonate salt of an alkali or alkaline earth metal. The pH modifying agent may be selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium hydrogen carbonate, potassium carbonate, magnesium oxide, wollastonite (CaSiO3) or meglumine. The pH modifying agent may be present in an amount from 0.1 to 5 wt%, 0.2 to 4 wt%, 0.3 to 3 wt%, 0.4 to 2 wt% or 0.5 to 1 wt% of the pharmaceutical composition. The composition may comprise less than 50 ppm of peroxide impurities (e.g. hydrogen peroxide) and less than 50 ppm of an amine impurity (e.g. a primary, secondary, or tertiary amine or quaternary ammonium salt). The amine impurity may be dimethylamine. The composition may comprise less than 45 ppm, less than 40 ppm, less than 35 ppm, less than 30 ppm, less than 25 ppm, less than 20 ppm, less than 15 ppm, less than 10 ppm, less than 5 ppm, less than 1 ppm of an amine impurity. The composition may comprise less than 45 ppm, less than 40 ppm, less than 35 ppm, less than 30 ppm, less than 25 ppm, less than 20 ppm, less than 15 ppm, less than 10 ppm, less than 5 ppm, less than 1 ppm of peroxide impurities. As used herein the term “amine impurity” refers to any primary, secondary or tertiary amine or quaternary ammonium salt capable of being nitrosated by a nitrosating agent to form a nitrosamine. It will be appreciated that amine impurities may have been introduced into the active pharmaceutical ingredient and/or pharmaceutical composition at any stage during the manufacturing process, for example in the reactants and solvents used or formed through the degradation of the active pharmaceutical ingredient or salt thereof. It will be further appreciated that one or more different amine impurities (e.g. primary, secondary, or tertiary amines or quaternary ammonium salts) may be present in a pharmaceutical composition according to the present invention. Thus the pharmaceutical composition may comprise one or more amine impurities or a combination thereof. Such amine impurities may include, but are not limited to, dimethylamine (DMA), diethylamine (DEA), triethylamine (TEA), diisopropylethylamine (DIPEA), dibutylamine (DBA), tributylamine (TBA) and N-methyl-4-aminobutyric acid (MBA). As mentioned above, the formation of nitrosamine impurities may occur when a nitrosable compound (e.g. an amine impurity or ammonia) reacts with a nitrosating agent. One such way nitrosating agents may be introduced into a pharmaceutical composition is by the oxidation of amine and/or ammonia impurities by oxidizing agents, for example atmospheric oxygen or peroxide impurities present in the composition. As used herein the term “peroxide impurities” refers to any residual peroxide, for example hydrogen peroxide, present in a substance (e.g. an excipient) or in a pharmaceutical composition. Peroxide impurities may be introduced into a pharmaceutical composition through the presence of excipients, for example povidone, crospovidone or polysorbate. Peroxide impurities may react with amine and/or ammonia impurities in a pharmaceutical composition to form nitrosating agents. Additionally, peroxide impurities present in excipients may also react with the active pharmaceutical ingredient or salt thereof to form nitrosating agents. In drug products the presence of excipients such as binders, disintegrants or solubilsers (including those containing peroxide impurities) is necessary to, for example, facilitate disintegration of tablets, bind together the dry ingredients or help solubilize the active pharmaceutical ingredient. The active pharmaceutical ingredient or a salt thereof may be a secondary amine or a tertiary amine. In another embodiment of the present invention the secondary amine or a tertiary amine may be selected from the group consisting of ramipril, bisoprolol, cinacalcet, desloratadine, trimetazidine perindopril, duloxetine and pramipexol. The active pharmaceutical ingredient is preferably selected from the group consisting of desloratadine, perindopril erbumine, perindopril arginine and bisoprolol. In a further embodiment of the present invention, the ratio of the total weight of the pH modifying agent versus the total weight of the pharmaceutically acceptable excipients may be selected from 0.01% to 5%, from 0.02% to 4.5%, from 0.03% to 4%, from 0.04% to 3.5%, from 0.05% to 3%, from 0.06% to 2.5%, from 0.07% to 2%, from 0.08% to 1.5%, from 0.09% to 1%, or from 0.1% to 0.5%. According to other embodiments of the present invention, the ratio of the total weight of the pH modifying agent versus the total weight of the pharmaceutically acceptable excipients may be selected from at least 0.01%, at least 0.02%, at least 0.03%, at least 0.04%, at least 0.05%, at least 0.06%, at least 0.07%, at least 0.08%, at least 0.09%, at least 0.1%, at least 0.5%, at least 1%, at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, or at least 5%. In another embodiment the ratio of the total weight of the pH modifying agent versus the total weight of the pharmaceutically acceptable excipients is 0.5%. According to other embodiments of the present invention, the ratio of the total weight of the pH modifying agent versus the total weight of the pharmaceutically acceptable excipients may be selected from no more than 0.01%, no more than 0.02%, no more than 0.03%, no more than 0.04%, no more than 0.05%, no more than 0.06%, no more than 0.07%, no more than 0.08%, no more than 0.09%, no more than 0.1%, no more than 0.5%, no more than 1%, no more than 1.5%, no more than 2%, no more than 2.5%, no more than 3%, no more than 3.5%, no more than 4%, no more than 4.5%, or no more than 5%. In another embodiment the ratio of the total weight of the pH modifying agent versus the total weight of the pharmaceutically acceptable excipients is 0.5%. The present invention is now described in more detail by, but is not limited to, the following Examples. Example 1: Reducing agent screening tests For the purpose of the screening test, a formulation composition was prepared containing: ^ 1.0 mg of Ramipril (active pharmaceutical ingredient); ^ 0.5 mg of a reducing agent; ^ 50 mg of starch; and ^ 50 mg of cellulose microcrystalline. The components of the formulation were mixed through direct mixing, and triple homogenization was applied. The tablets were manufactured using a bench-top single punch tablet press and packed into glass vials. Nitroso-ramipril content was measured at 40°C, 60% RH with sampling at T0, T = 7 days and T = 14 days. The results are presented in Table 1 below. Table 1 Nitroso-ramipril content in ppm API (tablets) Reducing agent T0 T7 T14 (40°C, 60% RH) (40°C, 60% RH) Ramipril Sodium metabisulphite 0.9 0.7 0.9 Ramipril Sodium bisulphite 1.1 1 1.3 Ramipril Sodium thiobisulphate 1.4 2.5 2.7 Ramipril Acetone sodium bisulphite 2.1 3.1 3.0 Ramipril Dithiothreitol 6.8 25.6 26.2 Ramipril Monothioglycerol 10% in 6.7 29.8 31.5 PVP Ramipril Monothioglycerol 16.9 41.3 54.1 Ramipril Sodium formaldehyde 11.6 75.8 85.2 sulfoxylate Ramipril Alpha-tocopherol 12.8 96.5 149.2 Ramipril Ascorbic acid 5.7 127.3 248.6 Ramipril Sodium iodide 14.9 157.1 no data Ramipril Acetylcysteine 7.2 159.8 no data Ramipril Trans-ferrulic acid 10.1 174.6 266.1 Ramipril Sodium phosphite dibasic 11.4 203.8 269.8 pentahydrate Ramipril Glucosamine HCl 10 206.6 334.8 Ramipril Catechin hydrate 15.1 224.5 no data Ramipril L-cysteine*HCl*H₂O, 50% in 3.6 225.3 266.8 PVP Ramipril L-cysteine hydrochloride 57.1 233.9 251.8 monohydrate Ramipril Maltol 9.6 260.8 344.1 Ramipril Pyridoxine free base 13.9 262.2 no data Ramipril Ammonium ferrous sulphate 8.9 279.2 341.2 hexahydrate Ramipril Propyl paraben 10.4 285.8 452.5 Ramipril Tris(2,4-di-tert-butylphenyl) 11.9 287.4 382.3 phosphite Ramipril Glutathione 16.2 288.5 375.7 Ramipril Propyl gallate 12.5 289.3 392.6 Ramipril Rutin 16.5 313.5 no data Ramipril L-(+)-tartaric acid 15.2 330.3 423.1 Ramipril Methionine 13.7 355.0 393.7 Ramipril Glyceraldehyde 12.4 360.5 395.0 Ramipril Pyridoxine HCl 17.8 404.4 no data Ramipril L-malic acid 16.2 510.5 561.5 Ramipril Dihydrolipoic acid 25.1 726.4 738.8 Ramipril No reducing agent – 10.4 279.7 355.1 reference Whilst some reducing agents displayed low-levels of nitroso-ramipril after 14-days, a number of known reducing agents performed very poorly. Example 2: Sodium metabisulphite, sodium bisulphite, and ascorbic acid comparative test Sodium metabisulphite, sodium bisulphite, and ascorbic acid were tested with the active pharmaceutical ingredients ramipril, bisoprolol fumarate and pramipexole dihydrochloride. Dry mixing as described in Example 1 and wet granulation were used to prepare the formulations. The results are presented in Tables 2a-c below. Table 2a Ramipril API + Dry mixing process, Nitroso-ramipril Wet granulation process, Nitroso-ramipril reducing agent content in ppm content in ppm T0 T7 T14 T0 T7 T14 (40°C, 60% RH) (40°C, 60% RH) (40°C, 60% RH) (40°C, 60% RH) Sodium 0.9 0.7 0.9 1.5 1.9 2.3 metabisulphite Sodium bisulphite 1.1 1.0 1.3 1.1 1.5 2.0 Ascorbic acid 5,7 127.3 248.6 4.2 6.3 13.3 No reducing agent 10.4 279.7 355.1 11.1 12.3 14.3 – reference Table 2b Bisoprolol Dry mixing process, Nitroso-bisoprolol Wet granulation process, Nitroso-bisoprolol fumarate API + content in ppm content in ppm reducing agent T0 T7 T14 T0 T7 T14 (40°C, 60% RH) (40°C, 60% RH) (40°C, 60% RH) (40°C, 60% RH) Sodium 0.2 1.0 0.7 0.3 0.7 0.5 metabisulphite Sodium bisulphite 0.9 1.9 0.8 0.2 0.5 0.2 Ascorbic acid 0.5 3.2 11.2 0.9 2.5 3.1 No reducing agent 0.5 6.7 16.8 3.8 34.7 78.6 – reference Table 2c Pramipexole Dry mixing process, Nitroso-pramipexole Wet granulation process, Nitroso- dihydrochloride content in ppm pramipexole content in ppm API + reducing T0 T7 T14 T0 T7 T14 agent (40°C, 60% RH) (40°C, 60% RH) (40°C, 60% RH) (40°C, 60% RH) Sodium 0.1 0.1 0.1 0.1 0.1 0.2 metabisulphite Sodium bisulphite 0.4 0.1 0.4 0.5 0.1 0.2 Ascorbic acid 1.3 5.4 12.4 0.1 0.1 0.3 No reducing agent 5.7 21.5 29.3 0.4 1.3 1.4 – reference The test showed ascorbic acid to be the least effective of the reducing agents, when compared to sodium metabisulphite and sodium bisulphite, which showed effective nitroso reduction regardless of the active pharmaceutical ingredient and the process used for formulation preparation. Example 3: Pre-treatment of excipients prior to tabletting Example 3 was designed to investigate the effectiveness of pre-treating excipient with a reducing agent prior to tabletting. A mixture of starch and microcrystalline cellulose 1:1 w/w was used as an example of mixture of pharmaceutically acceptable excipients. Aqueous reducing solutions comprising 2% reducing agents were prepared. The mixture of excipients was pre-treated with the reducing solutions in either a fluid-bed dryer or a high-shear granulator. The pre-treatment step consisted in spraying the excipient mixture with the reducing solution followed by a drying step. The drying step lasted from 5 to 30 minutes. In selected cases vacuum drying was applied for 3 hours. In addition, an untreated mixture of pharmaceutically acceptable excipients was prepared for comparison. Both the treated and untreated mixtures of excipients were combined with approximately 1% w/w of the active pharmaceutical ingredient ramipril, and tabletted. The total concentration of the reducing agent in the final formulation was 0.5% w/w. Nitroso-ramipril content was measured at T0, T = 7 days and, in selected cases at T = 14 days. The results are presented in Table 3 below. Table 3 Nitroso-ramipril content in ppm API (tablets) Reducing agent T0 T7 T14 (40°C, 60% RH) (40°C, 60% RH) Ramipril Sodium bisulphite 0.8 8.4 6.0 Ramipril Ascorbic acid 2.8 3.5 5.1 Ramipril Sodium/Potassium 1.7 3.7 6.4 borohydride Ramipril Acetylcysteine 1.4 4.8 6.7 Ramipril L-cysteine hydrochloride 3.6 13.5 86.8 monohydrate Ramipril Dithiothreitol 2.6 17.9 22.0 Ramipril Sodium phosphite dibasic 1.0 19.4 21.9 pentahydrate Ramipril FeCl₂ in water 13.4 24.3 43.4 Ramipril L-cysteine hydrochloride 5 no data 114.4 monohydrate HCl, pH 3 Ramipril Glucosamine HCl 2.5 107 210.8 Ramipril Ammonium chloride in water 6.8 142.5 no data Ramipril Dimethylammonium chloride 437.8 763.3 843.4 Ramipril Chitosan hydrochloride pH 3 113.7 no data 331.8 Ramipril Ammonium chloride pH 3 164.1 no data 572.4 Ramipril Dimethylamine 1.1 1.9 3.4 Ramipril No reducing agent – 10.4 279.7 355.1 reference A comparison of the nitroso-ramipril content observed at T0, T = 7 and T = 14 days in the tablets prepared by the direct mixing of excipients, reducing agent and active ingredient in Example 1 and the use of pre-treated excipients in Example 3 is provided in Table 4 below. Table 4 Ramipril API + Direct mixing, Nitroso-ramipril content in Pre-treatment, Nitroso-pramipexole content reducing agent ppm in ppm T0 T7 T14 T0 T7 T14 (40°C, 60% RH) (40°C, 60% RH) (40°C, 60% RH) (40°C, 60% RH) Sodium bisulphite 1.1 1 1.3 0.8 8.4 6.0 Ascorbic acid 5.7 127.3 248.6 2.8 3.5 5.1 Acetylcysteine 7.2 159.8 no data 1.4 4.8 6.7 L-cysteine 57.1 233.9 251.8 3.6 13.5 86.8 hydrochloride monohydrate Dithiothreitol 7.2 72.6 95 2.6 17.9 22.0 Sodium phosphite 11.4 203.8 269.8 1.0 19.4 21.9 dibasic pentahydrate Glucosamine HCl 10 206.6 334.8 2.5 107 210.8 The comparison shows that reducing agents performed remarkably better when the pre-treatment step was applied. Example 4: Combination of nitrite-free excipients and pre-treatment (cinacalcet) Example 4 was designed to investigate the effectiveness of the combination of the use of nitrite- free excipients and pre-treatment of these excipients with a reducing agent prior to tabletting. Compositions of the batches comprising cinacalcet are presented in Table 5 below. Compared to Reference Composition 1, Example Compositions 1 to 3 comprise nitrite-free pregelatinized starch, nitrite-free Crospovidone type A and SuperTab 14SD. The nitrite-free pregelatinized starch, nitrite-free Crospovidone type A and SuperTab 14SD were also pre-treated by fluid bed granulation with 0.5% sodium bisulphite, 0.5% ascorbic acid or 0.5% L-cysteine. Table 5 Strength 90 mg Reference Example Example Example Composition 1 Composition 1 Composition 2 Composition 3 Cinacalcet HCl 99.15 99.15 99.15 99.15 Starch pregelatinized, 108.00 - - - standard Starch pregelatinized, nitrite- - 108.00 108.00 108.00 free Silica colloidal, anhydrous 5.40 5.40 5.40 5.40 Crospovidone type A, 21.60 - - - standard Crospovidone type A, nitrite- - 21.60 21.60 21.60 free Copovidone K-28 37.80 37.80 37.80 37.80 Prosolv SMCC HD 90 54.00 54.00 54.00 54.00 StarLac 211.35 - - - SuperTab 14SD (Lactose - 208.65 208.65 208.65 monohydrate spray dried) Magnesium stearate 2.70 2.70 2.70 2.70 Sodium bisulphite - 2.70 - - Ascorbic acid micronized - - 2.70 - L-cysteine HCl - - - 2.70 540.00 540.00 540.00 540.00 The nitroso-cinacalcet content for Reference Composition 1, and Example Compositions 1 to 3 were measured at T0, T = 7 days and T = 14 days. The results are presented in Table 6 below. Table 6 Nitroso-cinacalcet content in ppm Composition T0 T7 T14 (40°C, 75% RH) (40°C, 75% RH) Reference Composition 1 3.30 4.27 4.78 Example Composition 1 0.49 0.42 0.45 Example Composition 2 0.42 0.40 0.42 Example Composition 3 0.44 0.36 0.40 Example 5: Direct mixing of reducing agent and nitrite-free excipients (cinacalcet) Example 5 was designed to investigate the effectiveness of adding a reducing agent by directly mixing with cinacalcet and nitrite-free excipients, without a pre-treatment step. Compositions of the batches comprising cinacalcet are presented in Table 7 below. Example Compositions 4 to 6 comprise nitrite-free pregelatinized starch, nitrite-free Crospovidone type A and SuperTab 14SD. 0.5% sodium bisulphite, 0.5% ascorbic acid or 0.5% L-cysteine was also added to the composition. Table 7 Strength 90 mg Example Example Example Composition 4 Composition 5 Composition 6 Cinacalcet HCl 99.15 99.15 99.15 Starch pregelatinized, nitrite- 108.00 108.00 108.00 free Silica colloidal, anhydrous 5.40 5.40 5.40 Crospovidone type A, nitrite- 21.60 21.60 21.60 free Copovidone K-28 37.80 37.80 37.80 Prosolv SMCC HD 90 54.00 54.00 54.00 SuperTab 14SD (Lactose 208.65 208.65 208.65 monohydrate spray dried) Magnesium stearate 2.70 2.70 2.70 Sodium bisulphite 2.70 - - Ascorbic acid micronized - 2.70 - L-cysteine HCl - - 2.70 540.00 540.00 540.00 The nitroso-cinacalcet content for Example Compositions 4 to 6 were measured at T0, T = 7 days and T = 14 days. The results are presented in Table 8 below. Table 8 Nitroso-cinacalcet content in ppm Composition T0 T7 T14 (40°C, 75% RH) (40°C, 75% RH) Example Composition 4 0.46 0.51 0.64 Example Composition 5 0.37 0.31 0.34 Example Composition 6 0.62 0.69 0.92 Example 6: Combination of nitrite-free excipients and pre-treatment (desloratadine) Example 6 was designed to investigate the effectiveness of the combination of the use of nitrite- free excipients and pre-treatment of these excipients with a reducing agent prior to tabletting. Compositions of the batches comprising desloratadine are presented in Table 9 below. Compared to Reference Composition 2, Example Compositions 7 and 8 comprise nitrite-free microcrystalline cellulose. The nitrite-free microcrystalline cellulose was also pre-treated by fluid bed granulation with 0.5% ascorbic acid or 0.5% L-cysteine. Table 9 Reference Example Example Composition 2 Composition 7 Composition 8 Desloratadine 5.00 5.00 5.00 Maize Starch, pregelatinized 15.00 15.00 15.00 Cellulose microcrystalline 63.00 - - Cellulose microcrystalline, - 62.50 62.50 nitrite-free Ascorbic acid micronized - 0.50 L-cysteine hydrochloride - 0.50 Lactose anhydrous 10.00 10.00 10.00 Hypromellose 5.00 5.00 5.00 Hydrogenated vegetable oil 1.00 1.00 1.00 Silica colloidal, anhydrous 1.00 1.00 1.00 The nitroso-desloratadine content for Reference Composition 2, and Example Compositions 7 and 8 were measured at T0, T = 7 days and T = 14 days. The results are presented in Table 10 below. Table 10 Nitroso-desloratadine content in ppm Composition T0 T7 T14 (40°C, 75% RH) (40°C, 75% RH) Reference Composition 2 4.17 10.32 13.54 Example Composition 7 1.50 1.92 1.88 Example Composition 8 0.97 1.23 0.60 Example 7: Direct mixing of reducing agent and nitrite-free excipients (desloratadine) Example 7 was designed to investigate the effectiveness of adding a reducing agent by directly mixing with desloratadine and nitrite-free excipients, without a pre-treatment step. Compositions of the batches comprising desloratadine are presented in Table 11 below. Compositions 9 and 10 comprise nitrite-free microcrystalline cellulose. 0.5% ascorbic acid or 0.5% L-cysteine was also added to the composition. Table 11 Example Composition 9 Example Composition 10 Desloratadine 5.00 5.00 Maize Starch, 15.00 15.00 pregelatinized Cellulose microcrystalline, 62.50 62.50 nitrite-free Ascorbic acid micronized 0.50 - L-cysteine hydrochloride - 0.50 Lactose anhydrous 10.00 10.00 Hypromellose 5.00 5.00 Hydrogenated vegetable 1.00 1.00 oil Silica colloidal, anhydrous 1.00 1.00 The nitroso-desloratadine content for Example Compositions 9 and 10 were measured at T0, T = 7 days and T = 14 days. The results are presented in Table 12 below. Table 12 Nitroso-desloratadine content in ppm Composition T0 T7 T14 (40°C, 75% RH) (40°C, 75% RH) Example Composition 9 1.71 3.22 4.99 Example Composition 10 1.74 3.08 3.63 Example 8: Direct mixing of reducing agent (trimetazidine) Example 8 was designed to investigate the effectiveness of adding a reducing agent by directly mixing with compositions comprising trimetazidine. The composition of tablets comprising trimetazidine is presented in Table 13 below. As the reducing agent, 0.5% ascorbic acid (Example Composition 11), mixture of 0.5% ascorbic and 0.5% citric acid (Example Composition 12), 0.5% sodium sulfite (Example Composition 13) or 0.5% L-cysteine (Example Composition 14) was used. Table 13 Composition mg/tbl %/tbl Trimetazidine dihydrochloride 35.00 13.06 Excipients mannitol pearlitol 160C 100.00 – 97.40 37.31 – 36.34 Reducing agent 0 – 2.6 0 – 1.0 maize starch 51.50 19.22 hypromellose (K15M premium) 50.00 18.66 povidone K30 9.00 3.36 talc 6.30 2.35 silica, colloidal anhydrous 4.20 1.57 hydrogenated vegetable oil 1.40 0.52 magnesium stearate 2.60 0.97 Core weight 260.00 97.01 Film coating aqua Polish D PINK: 8.00 2.99 Tablet weight 268.00 100.00 In the composition above (Table 13), excipients comprising low nitrite content were used. More specifically, maize starch was identified as the most problematic excipient regarding nitrite content and therefore, nitrite-free maize starch was used. The nitroso-trimetazidine content for Reference Composition 3 (corresponding to the composition in Table 13 but without any reducing agent) and Example Compositions 11 to 14 were measured at T0, T = 7 days and T = 14 days. The results are presented in Table 14 below. Table 14 Nitroso-trimetazidine content in ppm Composition Reducing agent T0 T7 T14 (40°C, 75% RH) (40°C, 75% RH) Reference Composition 3 - 2.88 3.45 3.03 Example Composition 11 Ascorbic acid 1.55 1.80 1.63 Example Composition 12 Ascorbic acid and citric acid 1.20 1.28 1.11 Example Composition 13 Sodium sulphite 0.67 0.69 0.70 Example Composition 14 L-cysteine HCl 1.25 1.44 1.37 Example 9: Addition of reducing agent (pramipexole) Example 9 was designed to investigate the effectiveness of adding various reducing agents to compositions comprising pramipexole. The composition comprising pramipexole is presented in Table 15 below. Table 15 Composition 1 tbl [mg] %/tbl Pramipexole dihydrochloride monohydate 1.5 0.7 mannitol pearlitol 50C 114.9 54.7 maize starch 50.4 24.0 Hydroxypropyl cellulose (Klucel LF) 8.4 4.0 maize starch low moisture (5%) 29.4 14.0 magnesium stearate 3.0 1.4 silica, colloidal anhydrous 2.4 1.1 total 210.0 100 1% of several reducing agents were added as w/w percentage increase to the above composition and were tested in the stress conditions 60°C, 20% RH for 7 days in an open flask. These were compared with the standard composition as provided in Table 15. The nitroso-pramipexole content was measured at T0 and T = 7 days. The results are presented in Table 16a below. Table 16a Nitroso-pramipexole content in ppm API (tablets) Reducing agent T0 T7 (60°C, 20% RH) Pramipexole Standard composition (Table 15) 0.4 14.6 Pramipexole 1% Butylated hydroxytoluene (BHT) 0.6 10.4 Pramipexole 1% Butylated hydroxyanisole (BHA) 0.3 5.5 Pramipexole 1% ascorbic acid <0.2 0.46 Pramipexole 1% ascorbic acid and 1% citric acid <0.2 0.33 Pramipexole 1% tocopherol 0.3 10.6 Pramipexole 1% histidine 0.6 13.0 Pramipexole 1% histidine and 1% citric acid 0.3 11.6 Pramipexole 1% sulphite 1.0 3.6 Pramipexole 1% ascorbic acid and 1% tocopherol <0.2 0.81 Pramipexole 1% Na2S2O5 0.4 1.0 From the results above, ascorbic acid was identified as an effective reducing agent, and therefore further experiments were conducted with different concentrations of ascorbic acid. The nitroso- pramipexole content for each composition was then measured at T0, T = 7 days (60°C, 20% RH) and T = 7 days (60°C, 75% RH) and compared with the standard composition as provided in Table 15. The results are presented in Table 16b below. Table 16b Nitroso-pramipexole content in ppm API (tablets) Reducing agent T0 T7 T7 (60°C, 20% RH) (60°C, 75% RH) Pramipexole Standard composition (Table 15) 1.5 14.9 14.4 Pramipexole 0.1% ascorbic acid 0.4 1.6 1.6 Pramipexole 0.3% ascorbic acid 0.2 0.6 2.4 Pramipexole 0.4% ascorbic acid 0.2 0.4 1.8 Pramipexole 0.5% ascorbic acid 0.2 0.4 1.3 Pramipexole 0.7% ascorbic acid 0.2 0.3 0.3 Pramipexole 1.0% ascorbic acid 0.2 0.2 0.2 Pramipexole 2.5% ascorbic acid 0.2 0.1 0.1 Pramipexole 5.0% ascorbic acid 0.2 0.1 0.1 Based on the results in Table 16b, the composition comprising 0.7% ascorbic acid kept the nitroso-pramipexole formation to below 1 ppm whilst having the lowest amount of reducing agent. Tabel 16c provides the optimized compositions comprising pramipexole. Table 16c Composition 1 tbl [mg] %/tbl Pramipexole dihydrochloride monohydate 1.5 0.7 mannitol pearlitol 50C 114.9 54.3 maize starch 50.4 23.8 Hydroxypropyl cellulose 8.4 4.0 maize starch low moisture 29.4 13.9 magnesium stearate 3.0 1.4 silica, colloidal anhydrous 2.4 1.1 Ascorbic acid 1.5 0.7 total 211.5 100.0 Composition 1 tbl [mg] %/tbl Pramipexole dihydrochloride monohydate 0.13 0.12 mannitol pearlitol 50C 58.07 54.91 maize starch 25.20 23.83 Hydroxypropyl cellulose 4.20 3.97 maize starch low moisture 14.70 13.90 magnesium stearate 1.20 1.13 silica, colloidal anhydrous 1.50 1.42 Ascorbic acid 0.76 0.7 total 105.76 100.00 Example 10: Addition of reducing agent (perindopril erbumine) Example 10 was designed to investigate the effectiveness of adding Na2S2O5 to compositions comprising perindopril erbumine. Two commercially available reference products (Priamlo and Lopridam) were tested with and without the addition of Na2S2O5. Priamlo is a combination tablet comprising perindopril erbumine and amlodipine besylate. Lopridam is a combination tablet comprising perindopril erbumine, indapamide and amlodipine besylate. The nitroso-perindopril content was measured at T0, T = 14 days, T = 45 days and T = 90 days. The results are presented in Table 17 below. Table 17 Nitroso-perindopril content in ppm Reducing agent T0 T14 T45 T90 (40°C, 75% RH) (40°C, 75% RH) (40°C, 75% RH) Priamlo - 0.5 4.1 10.2 20.3 (Reference) Priamlo (addition 0.5% Na₂S₂O₅ 0.6 1.6 2.6 6.6 of reducing agent) Lopridam - 0.6 7.1 26.5 44.7 (Reference) Lopridam (addition 0.5% Na₂S₂O₅ 0.6 1.6 5.1 8.2 of reducing agent) Example 11: Direct mixing of reducing agent and nitrite-free excipient (perindopril arginine) Example 11 was designed to investigate the effectiveness of adding a reducing agent by directly mixing with perindopril arginine and nitrite-free excipient. A composition comprising perindopril arginine, low-nitrite pregelatinized starch (0.03 ppm of nitrites) and Na2S2O5 (Example Composition 15) was tested against a reference composition comprising perindopril arginine, pregelatinized starch (0.36 ppm of nitrites) and no reducing agent (Reference Composition 4). The nitroso-perindopril content for Example Composition 15 and Reference Composition 4 were measured at T0, T = 14 days, T = 45 days and T = 90 days. The results are presented in Table 18 below. Table 18 Nitroso-perindopril content in ppm Reducing agent T0 T14 T45 T90 (40°C, 75% RH) (40°C, 75% RH) (40°C, 75% RH) Reference - 0.3 3.2 17.4 25.5 Composition 4 Example 0.5% Na₂S₂O₅ 0.9 1.7 3.0 2.4 Composition 15 Example 12: Addition of reducing agent (duloxetine) Example 12 was designed to investigate the effectiveness of adding a reducing agent to compositions comprising duloxetine. As the reducing agent, ascorbic acid (Example Composition 16) or sodium metabisulphite (Example Composition 17) was used and compared against Reference Composition 5 (no reducing agent). The nitroso-duloxetine content was measured at T0, T = 1 month, T = 2.5 months at 40°C, 75% RH and at T = 2.5 months at 30°C, 65% RH. The results are presented in Table 19 below. Table 19 Nitroso-duloxetine content in ppm Reducing agent T0 T 1 month T 2.5 months T 2.5 months (40°C, 75% RH) (40°C, 75% RH) (30°C, 65% RH) Reference - 0.46 1.32 1.67 1.11 Composition 5 Example Ascorbic acid 0.44 0.78 0.77 0.69 Composition 16 Example Sodium 0.46 0.63 0.59 0.57 Composition 17 metabisulphate Final dosage forms comprising duloxetine may be in the form of enteric coated pellets consisting of three layers – active (AL), insulation (IL) and enteric (EL) in a capsule. In certain embodiments, compositions comprising duloxetine may comprise the reducing agent (e.g. ascorbic acid or sodium metabisulphite) in the insulation layer. Example 13: Use of nitrite-free excipients (cinacalcet) Example 13 was designed to investigate the effectiveness of the use of nitrite-free excipients in reducing the amount of nitrosamine impurities. Compositions comprising cinacalcet using nitrite-free starch pregelatinized and nitrite-free crospovidone type A are presented in Table 20 below. Table 20 Strength 90 mg Example Composition 18 Example Composition 19 Cinacalcet HCl 99.15 99.15 Starch pregelatinized, nitrite-free 108.00 108.00 Silica colloidal, anhydrous 5.40 5.40 Crospovidone type A, nitrite-free 21.60 21.60 Copovidone K-28 37.80 37.80 Prosolv SMCC HD 90 54.00 54.00 StarLac - 211.35 SuperTab 14SD (Lactose monohydrate spray dried) 211.35 - Magnesium stearate 2.70 2.70 540.00 540.00 The nitroso-cinacalcet content for Example Composition 18 was measured at T0, T = 7 days and T = 14 days. The results are presented in Table 21 below. Table 21 Nitroso-cinacalcet content in ppm Composition T0 T7 T14 (40°C, 75% RH) (40°C, 75% RH) Example Composition 18 0.40 0.35 0.37 Example 14: Use of nitrite-free excipients (desloratadine) Example 14 was designed to investigate the effectiveness of the use of nitrite-free excipients in reducing the amount of nitrosamine impurities. Compositions comprising desloratadine using nitrite-free maize starch pregelatinized, and/or nitrite-free cellulose microcrystalline are presented in Table 22 below. Table 22 Example Example Composition 20 Composition 21 Manufacturing method DC DC Desloratadine 5.00 5.00 Maize Starch, pregelatinized 15.00 - Maize Starch, pregelatinized, nitrite-free - 15.00 Cellulose microcrystalline, 63.00 63.00 nitrite-free Lactose anhydrous 10.00 10.00 Hypromellose 5.00 5.00 Hydrogenated vegetable oil 1.00 1.00 Silica colloidal, anhydrous 1.00 1.00 The nitroso-desloratadine content for Example Compositions 20 and 21 were measured at T0, T = 7 days and T = 14 days. The results are presented in Table 23 below. Table 23 Nitroso-desloratadine content in ppm Composition T0 T7 T14 (40°C, 75% RH) (40°C, 75% RH) Example Composition 20 1.91 3.69 5.06 Example Composition 21 0.91 1.21 1.49 Example 15: Use of nitrite-free excipients (ramipril) Example 15 was designed to investigate the effectiveness of the use of nitrite-free excipients in reducing the amount of nitrosamine impurities. A composition comprising ramipril using nitrite-free cellulose microcrystalline (Example Composition 22) was compared against Reference Composition 6 containing standard cellulose microcrystalline. The two compositions are presented in Table 24 below. Table 24 Reference Example Composition 6 Composition 22 1 tbl. (mg) 1 tbl. (mg) Ramipril 1.250 1.250 Silica, colloidal anhydrous 0.006 0.006 Hypromellose 0.221 0.221 Cellulose, microcrystalline 53.403 - Cellulose, microcrystalline (nitrite-free) - 53.403 Starch, pregelatinized 44.00 44.00 Sodium stearyl fumarate 1.000 1.000 Iron oxide red 0.050 0.050 Iron oxide yellow 0.070 0.070 The nitroso-ramipril content for Reference Composition 6 and Example Composition 22 were measured at T0 and T = 1 month. The results are presented in Table 25 below. Table 25 Nitroso-ramipril content in ppm Composition T0 T = 1 month T = 3 months T = 6 months (40°C, 75% RH) (40°C, 75% RH) (40°C, 75% RH) Reference Composition 6 1.3 86.8 119.4 141.8 Example Composition 22 1.5 67.6 99.6 109.5 Compositions comprising ramipril using nitrite-free starch and/or nitrite-free microcrystalline cellulose are presented in Tables 26a to 26c below. Table 26a 1.25 2.5 5 10 strength strength strength strength (mg) (mg) (mg) (mg) Ramipril API 1.250 2.500 5.000 10.000 d e_{b .} _d ⁿ ⁱ _a _u ^r ^l _g Hypromellose 2910/5 (type Methocel Binder 0.221 0.441 0.882 1.765 F E5) Pregel Starch (Starch 1500) Binder/Disintegrant 49.529 48.459 46.568 48.985 . Microcrystalline cellulose PH 102 Filler/Diluent 48.750 48.000 47.000 39.000 n_a ^r _g (low nitrite) a^r _t x Sodium stearyl fumarate Lubricant 0.250 0.500 0.500 0.250 E Ferric oxide yellow Coloring agent 0.100 0.000 0.000 Ferric oxide red Coloring agent 0.000 0.050 0.000 Sum (mg) 100.000 100.000 100.000 100.000 Table 26b 1.25 2.5 5 10 strength strength strength strength (mg) (mg) (mg) (mg) Ramipril API 1.250 2.500 5.000 10.000 d e_{b .} _d ⁿ ⁱ _a _u ^r ^l _g Hypromellose 2910/5 (type Methocel Binder 0.221 0.441 0.882 1.765 F E5) Pregel Starch (Starch 1500) (low Binder/Disintegrant 49.529 48.459 46.568 48.985 . nitrite) n_a ^r _g Microcrystalline cellulose PH 102 Filler/Diluent 48.750 48.000 47.000 39.000 a_rt Sodium stearyl fumarate Lubricant 0.250 0.500 0.500 0.250 x _E Ferric oxide yellow Coloring agent 0.100 0.000 0.000 Ferric oxide red Coloring agent 0.000 0.050 0.000 Sum (mg) 100.000 100.000 100.000 100.000 Table 26c 1.25 2.5 5 10 strength strength strength strength (mg) (mg) (mg) (mg) Ramipril API 1.250 2.500 5.000 10.000 d e_{b .} _d ⁿ ⁱ _a _u ^r ^l _g Hypromellose 2910/5 (type Methocel Binder 0.221 0.441 0.882 1.765 F E5) Pregel Starch (Starch 1500) (low Binder/Disintegrant 49.529 48.459 46.568 48.985 nitrite) . n_a Microcrystalline cellulose PH 102 Filler/Diluent 48.750 48.000 47.000 39.000 r_g a_r (low nitrite) t x _E Sodium stearyl fumarate Lubricant 0.250 0.500 0.500 0.250 Ferric oxide yellow Coloring agent 0.100 0.000 0.000 Ferric oxide red Coloring agent 0.000 0.050 0.000 Sum (mg) 100.000 100.000 100.000 100.000 Example 16: Use of nitrite-free excipients (duloxetine) Representative compositions comprising duloxetine are presented in Table 27 below. Table 27 20 mg 30 mg 40 mg 60 mg Composition Composition Composition Composition 1cps. (mg) % 1cps. (mg) % 1cps. (mg) % 1cps. (mg) % Duloxetine hydrochloride 22.450 20.42 33.680 20.42 44.900 20.42 67.350 20.42 Sugar spheres 25.000 22.74 37.500 22.74 50.000 22.74 75.000 22.74 Transparent coating premix 3.200 2.91 4.800 2.91 6.400 2.91 9.600 2.91 Hypromellose 8.170 7.43 12.260 7.43 16.340 7.43 24.510 7.43 Sucrose 8.170 7.43 12.260 7.43 16.340 7.43 24.510 7.43 Talc 13.370 12.16 20.050 12.16 26.730 12.16 40.100 12.16 Hypromellose acetate succinate 24.540 22.32 36.810 22.32 49.080 22.32 73.620 22.32 Triethyl citrate 4.920 4.48 7.380 4.48 9.850 4.48 14.769 4.48 Scavenger 0.114 0.10 0.171 0.10 0.228 0.10 0.342 0.10 Sum 109.934 100.000 164.911 100.000 219.868 100.000 329.801 100.000 Nitrite-free excipients may be used in the compositions comprising duloxetine in order to mitigate the formation of nitrosamine impurities, and in particular, nitroso-duloxetine. In preferred embodiments, the duloxetine used in the composition may be substantially free of, preferably free of amine impurities, and in particular, nitroso-duloxetine. Example 17: Use of pH modifier (desloratadine) Example 17 was designed to investigate the effectiveness of the use of pH modifiers in reducing the formation of nitrosamine impurities. Compositions comprising desloratadine are presented in Table 28 below. Example Composition 23 comprises sodium bicarbonate as the pH modifier and was made by direct compression method. Example Composition 24 comprises sodium bicarbonate as the pH modifier and was made by fluid bed granulation method. Table 28 Example Example Composition 23 Composition 24 Desloratadine 5.00 5.00 Maize Starch, pregelatinized 15.00 15.00 Cellulose microcrystalline, 62.50 62.50 nitrite-free Sodium bicarbonate 0.50 0.50 Lactose anhydrous 10.00 10.00 Hypromellose 5.00 5.00 Hydrogenated vegetable oil 1.00 1.00 Silica colloidal, anhydrous 1.00 1.00 The nitroso-desloratadine content for Example Compositions 23 and 24 were measured at T0, T = 7 days and T = 14 days. The results are presented in Table 29 below. Table 29 Nitroso-desloratadine content in ppm Composition T0 T7 T14 (40°C, 75% RH) (40°C, 75% RH) Example Composition 23 1.81 3.58 4.87 Example Composition 24 1.65 1.47 1.83 Example 18: Use of pH modifier (perindopril erbumine) Example 18 was designed to investigate the effectiveness of adding a pH modifier (K2CO3) to compositions comprising perindopril erbumine. Two commercially available reference products (Priamlo and Lopridam) were tested. Priamlo is a combination tablet comprising perindopril erbumine and amlodipine besylate. Lopridam is a combination tablet comprising perindopril erbumine, indapamide and amlodipine besylate. The nitroso-perindopril content was measured at T0, T = 14 days, T = 45 days and T = 90 days. The results are presented in Table 30 below. Table 30 pH Nitroso-perindopril content in ppm pH modifying tbl T0 T14 T45 T90 agent (40°C, 75% RH) (40°C, 75% RH) (40°C, 75% RH) Priamlo 0.19% K₂CO₃ 7.4 0.6 0.8 0.9 1.3 Priamlo 0.34% K₂CO₃ 7.8 0.5 0.8 1.0 1.1 Priamlo 0.58% K2CO3 8.3 0.5 0.8 0.8 0.9 Priamlo 0.89% K2CO3 8.8 0.5 0.7 0.8 0.9 Priamlo 2.90% K₂CO₃ 9.8 0.5 0.6 0.6 0.6 Lopridam 0.19% K₂CO₃ 7.5 0.5 0.7 0.9 0.9 Lopridam 0.34% K₂CO₃ 7.9 0.5 0.7 1.0 0.8 Lopridam 0.58% K2CO3 8.4 0.5 0.7 0.8 0.8 Lopridam 0.89% K₂CO₃ 8.9 0.5 0.7 0.8 0.8 Lopridam 2.90% K₂CO₃ 9.8 0.5 0.5 0.6 0.6 Example 19: Use of pH modifier (perindopril arginine) Example 19 was designed to investigate the effectiveness of adding a pH modifier (K2CO3) to compositions comprising perindopril arginine. The nitroso-perindopril content was measured at T0, T = 14 days, T = 45 days and T = 90 days. The results are presented in Table 31 below. Table 31 pH Nitroso-perindopril content in ppm pH modifying tbl T0 T14 T45 T90 agent (40°C, 75% RH) (40°C, 75% RH) (40°C, 75% RH) perindopril 0.03% K₂CO₃ 7.7 0.3 0.8 7.7 21.7 arginine perindopril 0.13% K₂CO₃ 8.3 0.3 0.5 2.3 17.7 arginine perindopril 0.47% K₂CO₃ 9.1 0.3 0.4 0.9 1.9 arginine Example 20: Use of pH modifier and low-nitrite excipients (perindopril arginine) Example 20 was designed to investigate the effectiveness of using low nitrite pregelatinized starch together with a pH modifier (K2CO3) to compositions comprising perindopril arginine. The compositions set out in Table 32 below contained 0.03 ppm of nitrites in the pregelatinized starch compared to 0.36 ppm in the pregelatinized starch used in compositions set out in Table 31. The nitroso-perindopril content was measured at T0, T = 14 days, T = 45 days and T = 90 days. The results are presented in Table 32 below. Table 32 pH Nitroso-perindopril content in ppm pH modifying tbl T0 T14 T45 T90 agent (40°C, 75% RH) (40°C, 75% RH) (40°C, 75% RH) perindopril 0.13% K₂CO₃ 8.2 0.2 0.5 2.0 27.7 arginine perindopril 0.75%/0.5% 8.2 0.6 0.9 0.7 1.0 arginine K₂CO₃/Na₂S₂O₅ perindopril 0.47% K2CO3 9.0 0.2 0.3 0.8 3.9 arginine Example 21: Use of pH modifier (bisoprolol) Example 21 was designed to investigate the effectiveness of the use of pH modifiers in reducing the formation of nitrosamine impurities, and in particular nitroso-bisoprolol. A composition comprising bisoprolol is presented in Table 33 below. Table 33 Composition Quantity (mg) Bisoprolol 1.25 Cellulose microcrystalline 64.98 Starch, pregelatinized 12.19 Crospovidone 2.68 Silica, colloidal anhydrous 2.19 Magnesium stearate 1.71 pH modifier 1.70 The nitroso-bisoprolol content for compositions comprising various pH modifiers were measured at T0 and T = 7 days. These were compared against compositions containing no pH modifiers. The results are presented in Table 34 below. Table 34 Nitroso-bisoprolol content in ppm pH modifier pH T0 T7 (60°C, 50% RH) N_{o (standard cellulose, microcrystalline) 7.8} ^{1.3 66.8} No (low-nitrite cellulose, microcrystalline) 7.6 <0.1 39.1 2% w/w of NaHCO3 8.3 0.4 26.0 2% w/w of Na₂CO₃ 10.2 0.3 0.8 2% w/w of MgO 10.6 0.2 14.9 2% w/w of CaSiO3 8.5 0.7 47.8 The nitroso-bisoprolol content for compositions comprising various pH modifiers were measured at T = 1 month and T = 3 months. The results are presented in Table 35 below. Table 35 Nitroso-bisoprolol content in ppm pH modifier T = 1 month T = 3 months (40°C, 75% RH) (40°C, 75% RH) W_{ithout pH modifier} ^{21.5 28.7} 2% w/w of NaHCO3 15.5 18.9 0.095% w/w of Na2CO3 16.2 Not measured 0.24% w/w of Na₂CO₃ 6.0 12.2 1.0% w/w of Na₂CO₃ 2.5 4.4 2% w/w of Na2CO3 1.3 2.5 2% w/w of MgO 2.8 Not measured 0.12% w/w of K₂CO₃ 4.0 13.7 0.31% w/w of K2CO3 3.5 7.5 0.5% w/w of K2CO3 0.6 4.0 2% w/w of K₂CO₃ 0.4 Not measured 2% w/w meglumine 0.9 1.7

Claims

CLAIMS 1. A method for reducing the amount of nitrosating agents and/or N-Nitrosamine impurities in a pharmaceutically acceptable excipient, the method comprising a pre-treatment step of mixing one or more pharmaceutically acceptable excipients with at least one reducing agent.

2. The method according to claim 1, wherein the mixing is selected from the group consisting of dry homogenisation, co-sifting, compaction, high-shear, fluid-bed granulation, hot-melt extrusion, and spray drying.

3. The method according to claim 2, wherein the spray drying comprises the steps of: a) spraying the composition comprising one or more pharmaceutically acceptable excipients with a reducing solution comprising a solvent and at least one reducing agent; and b) removing the solvent.

4. The method according to claim 3, wherein the spraying duration is less than 1 minute, less than 1.5 minutes, less than 2 minutes, less than 2.5 minutes, less than 3 minutes, less than 3.5 minutes, less than 4 minutes, less than 4.5 minutes, less than 5 minutes, less than 5.5 minutes, less than 6 minutes, less than 6.5 minutes, less than 7 minutes, less than 7.5 minutes, less than 8 minutes, less than 8.5 minutes, less than 9 minutes, less than 9.5 minutes, or less than 10 minutes.

5. The method according to claims 3 and 4, wherein the solvent removal step b) comprises heat drying, vacuum drying and/or lyophilisation.

6. The method according to claim 5, wherein the heat drying duration is less than 5 minutes, less than 10 minutes, less than 15 minutes, less than 20 minutes, less than 25 minutes, or less than 30 minutes.

7. The method according to claims 5 and 6, wherein the heat drying temperature is from 25 ºC to 70 ºC, from 35 ºC to 65 ºC, from 40 ºC to 60 ºC, or from 45 ºC to 55 ºC.

8. The method according to claims 5 to 7, wherein the drying pressure is from 50 mbar to 1000 mbar, from 100 mbar to 950 mbar, from 150 mbar to 900 mbar, from 200 mbar to 850 mbar, from 250 mbar to 800 mbar, from 300 mbar to 750 mbar, from 350 mbar to 700 mbar, from 400 mbar to 650 mbar, from 450 mbar to 600 bar, or from 500 mbar to 550 mbar.

9. The method according to any preceding claim, wherein the reducing agent is selected from at least one of ascorbic acid, acetylcysteine, L-cysteine hydrochloride monohydrate, dithiothreitol, sodium phosphite dibasic pentahydrate, or a combination thereof.

10. The method according to any preceding claim, wherein the ratio of the total weight of the reducing agent versus the total weight of the pharmaceutically acceptable excipients is selected from 0.01% to 5%, from 0.02% to 4.5%, from 0.03% to 4%, from 0.04% to 3.5%, from 0.05% to 3%, from 0.06% to 2.5%, from 0.07% to 2%, from 0.08% to 1.5%, from 0.09% to 1%, or from 0.1% to 0.5%.

11. The method according to claims 3 to 10, wherein the concentration of reducing agent in the reducing solution is selected from 0.1% to 10%, from 0.15% to 9.5%, from 0.2% to 9%, from 0.25% to 8.5%, from 0.3% to 8%, from 0.35% to 7.5%, from 0.4% to 7%, from 0.45% to 6.5%, from 0.5% to 6%, from 0.55% to 5.5%, from 0.6% to 5%, from 0.65% to 4.5%, from 0.7% to 4%, from 0.75% to 3.5%, from 0.8% to 3%, from 0.85% to 2.5%, from 0.9% to 2%, or from 0.95% to 1.5% 12. The method according to claims 3 to 11, wherein the solvent is aqueous, organic, or a combination thereof. 13. The method according to claim 12, wherein the organic solvent is selected from the group consisting of ethanol, methanol, isopropanol or a combination thereof. 14. The method according to any preceding claim, further comprising a step of combining the one or more pre-treated pharmaceutically acceptable excipients with an active pharmaceutical ingredient or pharmaceutically acceptable salt thereof. 15. A method for reducing the amount of N-Nitrosamine impurities in a finished dosage form, the method comprising mixing the pre-treated pharmaceutically acceptable excipients obtained by the method of claims 1 to 13 with an active pharmaceutical ingredient or pharmaceutically acceptable salt thereof. 16. The method according to claims 14 and 15, wherein the active pharmaceutical ingredient or pharmaceutically acceptable salt thereof is a secondary amine or a tertiary amine. 17. A method for reducing the amount of N-Nitrosamine impurities in a finished dosage form, the method comprising a step of mixing one or more reducing agents with at least one active ingredient, or with a mixture of at least one pharmaceutically acceptable excipient and at least one active ingredient, wherein the mixing step is selected from the group consisting of dry homogenisation, co-sifting, compaction, high-shear, fluid-bed granulation, hot-melt extrusion, and spray drying.