Method for the preparation of vortioxetine pharmaceutical compositions with low amounts of nitrosamine impurities

Abstract

The present invention relates to a method for the preparation of pharmaceutical compositions comprising vortioxetine or pharmaceutically acceptable salts thereof containing low amounts of nitrosamine impurities, even after long term storage.

Description

[0001] METHOD FOR THE PREPARATION OF VORTIOXETINE PHARMACEUTICAL COMPOSITIONS WITH LOW AMOUNTS OF NITROSAMINE IMPURITIES

[0002] Field of the invention

[0003] The present invention relates to a method for the preparation of pharmaceutical compositions comprising vortioxetine or pharmaceutically acceptable salts thereof containing low amounts of nitrosamine impurities, even after long term storage.

[0004] Background of the invention

[0005] International patent applications including WO 03 / 029232 and WO 2007 / 144005 disclose the compound l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts thereof. The International Non-proprietary Name (INN) for l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine is vortioxetine, and the structure is:

[0006] Vortioxetine is an antagonist on the 5-HT3, 5-HT7 and 5-HTID receptors, an agonist on the 5-HTIA receptor and a partial agonist on the 5-HTIB receptor and an inhibitor of the serotonin transporter. Additionally, vortioxetine has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain. These activities are all considered to be of clinical relevance and potentially involved in the mechanism of action of the compound [JMed.Chem., 54, 3206- 3221, 2011; Eur. Neuropshycopharmacol., 18(suppl 4), S321, 2008; Eur.

[0007] Neuropshycopharmacol., 21(suppl 4), S407-408, 2011; Int. J. Psychiatry Clin Pract. 5, 47, 2012], The pharmacological profile gives reason to believe that vortioxetine may have a pro- cognitive effect. This notion seems to be supported by clinical evidence where vortioxetine has been shown to have a direct beneficial effect on cognition independent of its antidepressive effects [Int. Clin. Psychopharm., 27, 215-227, 2012; Int J neurophy chopharm 17, 1557-1567, 2014; Neuropsychopharm 40, 2025-2037, 2015], In 2013 FDA and EMA, approved vortioxetine for the treatment of major depressive disorder / major depressive episode as the first of a number of regulatory authorities throughout the World under the trade name Brintellix™ or Trintellix™ (United States, Canada and Japan).

[0008] Vortioxetine has been approved and marketed as film coated tablets containing 5, 10, 15 and 20 mg vortioxetine as the HBr salt and as an oral drop solution comprising 20 mg / ml vortioxetine as the DL lactate salt.

[0009] N-Nitroso compounds (NOC) are chemical compounds classified as probable human carcinogens, and which are referred to as ‘cohort of concern’ (International Council for Harmonisation (ICH) Harmonised Guideline M7(R2)). It is well established that nitrosamines are formed from the reaction of nitrosable compounds, for example secondary or tertiary amines, with nitrosating agents which are obtained from e.g. nitrite (NO2 ) or nitrous acid (HNO2). For nitrosation to occur it is generally believed that nitrite is firstly converted to nitrous acid under acidic conditions. Nitrous acid is then converted to an active nitrosating species, for example nitrous anhydride (N2O3). The nitrosating species may subsequently cause nitrosation of a nitrosable compound, for example a secondary amine R2NH, to form an N-nitroso compound, for example R2N-N=0 (a nitrosamine). (S. Mirvish, Toxicol. Appl. Pharmacol. (1975), 31. 325-51)

[0010] Recently the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have reported the detection of nitrosamine impurities in higher than acceptable levels in various drug products, for example sartans, ranitidine, nizatidine and metformine. Due to the findings of nitrosamine impurities in higher than acceptable levels in some drug products, there is a regulatory request for appropriate control strategies to limit the presence of nitrosamine impurities in human medicines. Thus, EMA has recently issued an Acceptable Intake (Al) level for N-nitroso-vortioxetine (Formula II) of 400 ng / day which results in a limit of 20 ppm N-nitroso-vortioxetine relative to the weight of vortioxetine free base in the pharmaceutical formulation, calculated on a maximum daily intake of 20 mg vortioxetine free base.

[0011] Several risk factors have been identified which can lead to the presence of nitrosamine impurities in final drug products. The risk factors can be related to the manufacture of the active substance, for example by use of nitrosating agents in the presence of reagents containing secondary or tertiary amines in the different steps of the manufacturing process, or from the use of starting materials which are contaminated with nitrosamines or nitrosating agents. Alternatively, formation of nitrosamine impurities from the active pharmaceutical ingredient (API) may occur during formulation or storage of the final drug product if nitrite impurities are present in the final drug product. (Control of Nitrosamine Impurities in Human Drugs, FDA, February 2021).

[0012] WO2024 / 153274 discloses a pharmaceutical composition containing vortioxetine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition further contains ascorbic acid, ascorbic acid acting as a kinetic competitor of vortioxetine in the reaction with nitrosating agents.

[0013] Thus, there is a need for providing methods for the preparation of pharmaceutical compositions comprising vortioxetine or pharmaceutically acceptable salts thereof, which contain low amounts of N-nitroso-vortioxetine (the compound of Formula II), such as less than 20 ppm N-nitroso-vortioxetine relative to the weight of vortioxetine free base in the pharmaceutical composition, even after long periods of storage.

[0014] Summary of the invention

[0015] The present invention provides a method for reducing the amount of a nitrosamine impurity in a pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof, the method comprising the step of preparing said pharmaceutical composition, wherein the content of nitrite in said pharmaceutical composition is 3 ppm or less, such as 2.8 ppm or less, relative to the content to vortioxetine as a free base.

[0016] Detailed description of the invention

[0017] The present inventors have found that a pharmaceutical composition comprising vortioxetine or pharmaceutically acceptable salts thereof, and having a content of N-nitroso- vortioxetine of 20 ppm or less relative to the weight of vortioxetine free base in the pharmaceutical composition upon long-term storage, can be obtained by reducing the initial total content of nitrite in the pharmaceutical composition (i.e. in the final drug product) to a level of about 3 ppm or less, such as 2.8 ppm or less, relative to the weight of vortioxetine free base in the pharmaceutical composition. Thus, the inventors have found that the content of N-nitroso-vortioxetine in a pharmaceutical composition comprising vortioxetine or pharmaceutically acceptable salts thereof, can be controlled even without addition of agents which suppress the formation of N-nitroso-vortioxetine, such as ascorbic acid or citric acid (i.e. nitrite scavengers).

[0018] In the present context, the unit ‘ppm’ (parts-per-million) indicates a mass fraction (weight / weight fraction), such as for example ‘microgram per gram’ or ‘nanogram per milligram’.

[0019] In the present context, the measurement of nitrite content (ppm) in the pharmaceutically compositions or excipients, is calculated based on the molecular weight of the ion NCh'.

[0020] The inventors have found that a vortioxetine pharmaceutical composition having a content of nitrite of 3 ppm or less, such as 2.8 ppm or less, relative to the amount of vortioxetine free base can be prepared by utilizing excipients which each have a low content of nitrite for the preparation of said vortioxetine pharmaceutical composition.

[0021] The content of nitrite in a vortioxetine pharmaceutical composition (a final drug product) can be controlled by first determining the content of nitrite in one or more of the excipients which are to be utilized in the preparation of the vortioxetine pharmaceutical composition; and second, if the content of nitrite in the excipient(s) meet a pre-set specification, continuing to prepare the vortioxetine pharmaceutical composition.

[0022] The pre-set specification of nitrite in each excipient varies depending on the amount of the excipient and the amount of vortioxetine or a pharmaceutically acceptable salt thereof to be used in the preparation of the vortioxetine pharmaceutical composition. The total amount of nitrite in the final drug product as calculated from the pre-set levels of nitrite in each excipient should be below 3 ppm, such as below 2.8 ppm relative to the content to vortioxetine as a free base.

[0023] The content of nitrite in excipients can be determined either by the manufacturer or supplier of the excipients, for example by disclosure in a data sheet for the excipient, or it can be determined by nitrite analysis prior to the preparation of the vortioxetine pharmaceutical composition. Accordingly, the invention provides a method for reducing the amount of a nitrosamine impurity in a pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, the method comprising the step of a) determining the content of nitrite in one or more of the pharmaceutically acceptable excipient(s) and b) if said excipient(s) meet pre-set specifications for the content of nitrite, then continuing to prepare the pharmaceutical composition, wherein the content of nitrite in said pharmaceutical composition is 2.8 ppm or less, relative to the content to vortioxetine as a free base.

[0024] The content of nitrite in pharmaceutical compositions comprising vortioxetine or pharmaceutically acceptable salts thereof (vortioxetine pharmaceutical composition) can furthermore be controlled by preparing said vortioxetine pharmaceutical composition, followed by measurement of the nitrite content in the final vortioxetine pharmaceutical composition. If said pharmaceutical composition has a nitrite content of more than 2.8 ppm, such as 3ppm or more, relative to the content of vortioxetine as a free base, said pharmaceutical composition can be discarded.

[0025] Therefore, in an embodiment, the invention provides a method for reducing the amount of a nitrosamine impurity in a pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, the method further comprising the step of c) measuring the content of nitrite in said pharmaceutical composition, and d) discarding said pharmaceutical composition if the content of nitrite in said pharmaceutical composition is more than 2.8 ppm, such as more than 3 ppm, relative to the content to vortioxetine as a free base.

[0026] The present invention furthermore relates to the pharmaceutical composition which is prepared according to the methods of the invention.

[0027] The content of nitrite in the vortioxetine pharmaceutical composition may be measured 1 - 24 hours after the preparation of the pharmaceutical composition, or 1 - 6 days after the preparation of the pharmaceutical composition, or 1 - 4 weeks after the preparation of the pharmaceutical composition, or prior to the pharmaceutical composition being subjected to stability testing conditions.

[0028] As stated above, EMA has recently issued an Acceptable Intake (Al) level for N-nitroso-vortioxetine (Formula II) of 400 ng / day which results in a limit of 20 ppm N- nitroso-vortioxetine relative to the weight of vortioxetine free base in the pharmaceutical formulation, calculated on the maximum daily intake of 20 mg vortioxetine free base. The content of nitrosamine impurity, such as N-nitroso-vortioxetine, in the vortioxetine pharmaceutical compositions prepared according to the present invention, may be determined both shortly after the preparation of the pharmaceutical composition, such as for example 1 - 24 hours after the preparation of the pharmaceutical composition, or 1 - 6 days after the preparation of the pharmaceutical composition, or 1 - 4 weeks after the preparation of the pharmaceutical composition, and additionally upon storage of the pharmaceutical composition under stability testing condition. In the present context, stability testing conditions may be storage at room temperature (RT) at ambient humidity, or at 40 °C at 75% relative humidity (40 °C / 75% RH), or at 25 °C at 60% relative humidity (25 °C / 60% RH). The compounds may be stored under stability testing conditions for 1 months, 2 months, 3 months, 4 months, 5 months, 6 months or 7 months, 12 months, 18 months or up to 24 months. In the present context, ‘ambient humidity’ indicates any humidity between 30% and 75 % RH.

[0029] During the stability testing period the vortioxetine pharmaceutical composition may be analyzed for its content of nitrosamine impurities, more specifically for the content of N-nitroso-vortioxetine after 1 month, such as after 2 months, 3 months, 4 months, 5 months, 6 months or 7 months, or after 12 months. The content of N-nitroso-vortioxetine can be determined as ppm (weight / weight ratio) relative to the content of vortioxetine as a free base in the pharmaceutical composition.

[0030] Pharmaceutical Compositions

[0031] The pharmaceutical compositions which are prepared according to the method of the present invention may be formulated with pharmaceutically acceptable excipients in accordance with conventional techniques such as those disclosed in Remington, The Science and Practice of Pharmacy, 22thedition (2013), Edited by Allen, Loyd V., Jr.

[0032] Pharmaceutical compositions which are prepared according to the present invention may be for oral administration; and include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups as well as powders and granules to be dissolved or suspended in an appropriate liquid.

[0033] Solid oral dosage forms may be presented as discrete units (e.g. tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient, and preferably one or more suitable excipients. Where appropriate, the solid dosage forms may be prepared with coatings such as enteric coatings, or they may be formulated so as to provide modified release of the active ingredient such as delayed or extended release according to methods well known in the art.

[0034] In the present context, “excipient” or “pharmaceutically acceptable excipient” refers to pharmaceutical excipients including, but not limited to, fillers, antiadherents, binders, coatings, colours, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.

[0035] Examples of excipients suitable for solid oral formulation include, but are not limited to, microcrystalline cellulose, hydroxypropylcellulose, corn starch, starch glycolate, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatine, pectin, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Similarly, the solid formulation may include excipients for delayed or extended-release formulations known in the art, such as glyceryl monostearate or hypromellose.

[0036] If solid material is used for oral administration, the formulation may for example be prepared by mixing the active ingredient with intra-granulate excipients followed by wet granulation, mixing of extra-granular excipients and subsequently compressing the mixture in a conventional tableting machine, followed by coating of the compressed cores; or the formulation may for example be placed in a hard capsule e.g. in powder, pellet or mini tablet form.

[0037] Liquid oral dosage forms may be presented as for example elixirs, syrups, oral drops or a liquid filled capsule. Liquid oral dosage forms may also be presented as powders for a solution or suspension in an aqueous or non-aqueous liquid.

[0038] Examples of excipients suitable for liquid oral formulation include, but are not limited to, ethanol, propylene glycol, glycerol, hydroxypropylbetadex, poly ethylengly cols, poloxamers, sorbitol, poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palm oil, and water.

[0039] Liquid oral dosage forms may for example be prepared by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

[0040] Further excipients may be used in solid and liquid oral formulations, such as colourings, flavourings and preservatives etc. Methods of analysis

[0041] In the present context the term ‘nitrite’ is intended to indicate the ion NCU; or salts thereof such as inorganic salts, for example sodium nitrite or potassium nitrite. The term ‘nitrite’ may also comprise nitrite-equivalents, i.e., reagents or compounds which may decompose or transform into nitrite, such as for example alkyl nitrite. The content of nitrite in the above mentioned pharmaceutically compositions or excipients can be detected by a method utilizing the Griess reaction, wherein nitrite forms an azo dye with for example sulfanilamide and N-(l-naphthyl)ethylenediamine, and wherein said azo dye is quantified using HPLC / UV detection (High performance Liquid Chromatography Ultraviolet detection). In the present context, the measurement of the nitrite content (ppm) in the pharmaceutically compositions or excipients, is based on the molecular weight of the ion NCU.

[0042] The term ‘nitrosamine’ is intended to indicate a compound of the general formula RIR2N-N=0. The compound of Formula II, N-nitroso-vortiox etine, is an example of a nitrosamine. Nitrosamines can be analyzed by LCMS (Liquid Chromatography-Mass Spectrometry), such as by UHPLC-MS (Ultra-High performance Liquid Chromatography - Mass Spectrometry).

[0043] Embodiments of the invention

[0044] In an embodiment, the invention provides a method for reducing the amount of a nitrosamine impurity in a pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the content of nitrite in said pharmaceutical composition is 3 ppm or less, such as 2.9 ppm, such as 2.8 ppm, such as 2.7 ppm, such as 2.6 ppm, such as 2.5 ppm, such as 2.4 ppm, such as 2.3, such as 2.2 ppm, such as 2.1 ppm, such as 2.0 ppm, such as 1.9 ppm, such as 1.8 ppm, such as 1.7 ppm, such as 1.6 ppm, such as 1.5 ppm, such as 1.4 ppm, such as 1.3 ppm, such as 1.2 ppm, such as 1.1 ppm, such as 1.0 ppm, or less, relative to the content to vortioxetine as a free base.

[0045] The content of nitrite in the vortioxetine pharmaceutical composition prepared according to the method of the invention can be measured at the timepoint TO; wherein TO is 1 - 24 hours, such as 1 day, such as 2 days, such as 3 days, such as 4 days, such as 5 days, such as 6 days, such as 7 days, such as 2 weeks, such as 3 weeks, such as 4 weeks, such as 1 month, such as 2 months, such as 3 months, such as 4 months, such as 5 month, such as 6 months after the preparation of the pharmaceutical composition (the final drug product). In an embodiment the content of nitrite is measured at timepoint 0 (TO) wherein is TO is defined as the time point when the pharmaceutical composition is subjected to stability storage conditions.

[0046] In an embodiment, the vortioxetine pharmaceutical composition prepared according to the present invention is a pharmaceutical composition for oral administration. In a more preferred embodiment said pharmaceutical composition is a film-coated oral tablet comprising vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients; wherein the content of nitrite in said film-coated oral tablet is 3 ppm or less, such as 2.8 ppm or less, relative to the content of vortioxetine as a free base.

[0047] In an embodiment, the vortioxetine pharmaceutical composition prepared according to the present invention is an oral drop composition comprising vortioxetine lactate in an amount corresponding to 20 mg / mL vortioxetine free base, and one or more pharmaceutically acceptable excipients; wherein the content of nitrite in said oral drop composition is 3 ppm or less, such as 2.8 ppm or less, relative to the content of vortioxetine as a free base.

[0048] In an embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet comprising vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients; and wherein said film-coated tablet has a total weight of 150 mg, such as 151 mg, such as 152 mg, such as 153 mg, such as 154 mg, such as 155 mg, such as 156 mg, such as 157 mg, such as 158 mg, such as 159 mg, such as 160 mg; and wherein the content of nitrite at TO in said film-coated oral tablet is 0.4 ppm or less, such as 0.37 ppm, such as 0.36 ppm, such as 0.35 ppm, such as 0.30 ppm, such as 0.28 ppm, such as 0.27 ppm, such as 0.26 ppm such as 0.25 ppm, such as 0.20 ppm, such as 0.18 ppm, such as 0.17 ppm, such as 0.16 ppm, such as 0.15 ppm, such as 0.10 ppm, such as 0.09 ppm, such as 0.08 ppm, such as 0.05 ppm or less, relative to the weight of the film-coated oral tablet.

[0049] In an embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet comprising vortioxetine hydrobromide in an amount corresponding to 20 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients; and wherein said film-coated tablet has a total weight of 150 mg to 160 mg; and wherein the content of nitrite at TO in said film-coated oral tablet is 0.36 ppm or less, relative to the weight of the film-coated oral tablet. In an embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet comprising vortioxetine hydrobromide in an amount corresponding to 15 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients; and wherein said film-coated tablet has a total weight of 150 mg to 160 mg; and wherein the content of nitrite at TO in said film-coated oral tablet is 0.27 ppm or less, relative to the weight of the film-coated oral tablet.

[0050] In an embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet comprising vortioxetine hydrobromide in an amount corresponding to 10 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients; and wherein said film-coated tablet has a total weight of 150 mg to 160 mg; and wherein the content of nitrite at TO in said film-coated oral tablet is 0.17 ppm or less, relative to the weight of the film-coated oral tablet.

[0051] In an embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet comprising vortioxetine hydrobromide in an amount corresponding to 5 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients; and wherein said film-coated tablet has a total weight of 150 mg to 160 mg; and wherein the content of nitrite at TO in said film-coated oral tablet is 0.09 ppm or less, relative to the weight of the film-coated oral tablet.

[0052] In a preferred embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet, and wherein the tablet core of said film- coated tablet comprises vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base and the excipients mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate (type A) and magnesium stearate.

[0053] In a yet a preferred embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet, and wherein the tablet core of said film-coated tablet comprises vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base and the excipients mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate (type A), magnesium stearate, and wherein the film-coating of said film-coated tablet comprises hypromellose, titanium dioxide (E171), Macrogol 400, iron oxide (E172). In yet a preferred embodiment the tablet core of said film-coated tablet has a weight of 150 mg, and the filmcoating of said film-coated tablet has a weight of 6 mg. In an embodiment the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet, and wherein the tablet core of said film-coated tablet comprises vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base; wherein the film-coating of said film-coated tablet comprises hypromellose, titanium dioxide (E171) or Ca2Co3, Macrogol 400, iron oxide (El 72).

[0054] An embodiment the invention provides a method for reducing the amount of a nitrosamine impurity in a pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, the method comprising the step of a) determining the content of nitrite in one or more of the pharmaceutically acceptable excipients and b) if said excipient(s) meet pre-set specifications for the content of nitrite, then continue to preparing the pharmaceutical composition.

[0055] In an embodiment of the invention, the pre-set specification for the content of nitrite in each of the one or more excipients is 2.0 ppm or less, such as 1.0 ppm, such as 0.5 ppm, such as 0.4 ppm, such as 0.3 ppm, such as 0.2 ppm, such as 0.1 ppm or less.

[0056] In an embodiment of the invention, the pre-set specification for the content of nitrite in the excipient microcrystalline cellulose (MCC) is 0.5 ppm (weight / weight) or less, such as 0.4 ppm, such as 0.3 ppm, such as 0.2 ppm, such as 0.1 ppm or less. In a preferred embodiment the content of nitrite in MCC is 0.2 ppm or less, such as 0.1 ppm or less.

[0057] In an embodiment of the invention, the pre-set specification for the content of nitrite in the excipient Magnesium stearate is 2.5 ppm or less, such as 2.2 ppm, such as 2.1 ppm, such as 2.0 ppm , such as 1.9 ppm, such as 1.8 ppm, such as 1.7 ppm, such as 1,6 ppm, such as 1.5 ppm, such as 1.4 ppm, such as 1.3 ppm, such as 1.2 ppm, such as 1.1 ppm, such as 1.0 ppm, such as 0.9 ppm, such as 0.8 ppm, such as 0.7 ppm, such as 0.6 ppm, such as 0.5 ppm, such as 0.4 ppm, such as 0.3 ppm, such as 0.2 ppm, such as 0.1 ppm or less. In a preferred embodiment the content of nitrite in magnesium stearate is 2.0 ppm or less, such as 1.0 ppm or less.

[0058] In an embodiment of the invention, the pre-set specification for the content of nitrite in the excipient mannitol is 0.1 ppm or less, such as 0.09 ppm, such as 0.08 ppm, such as 0.07 ppm, such as 0.06 ppm, such as 0.05 ppm, such as 0.04 ppm, such as 0.03 ppm, such as 0.02 ppm, such as 0.01 ppm or less. In a preferred embodiment the content of nitrite in mannitol is 0.04 ppm or less, such as 0.02 ppm or less.

[0059] In an embodiment of the invention, the pre-set specification for the content of nitrite in the excipient hydroxypropyl cellulose is 2.0 ppm or less, such as 1.9 ppm, such as 1.8 ppm, such as 1.7 ppm, such as 1,6 ppm, such as 1.5 ppm, such as 1.4 ppm, such as 1.3 ppm, such as 1.2 ppm, such as 1.1 ppm, such as 1.0 ppm, such as 0.9 ppm, such as 0.8 ppm, such as 0.7 ppm, such as 0.6 ppm, such as 0.5 ppm, such as 0.4 ppm, such as 0.3 ppm, such as 0.2 ppm, such as 0.1 ppm or less. In a preferred embodiment the content of nitrite in hydroxypropyl cellulose is 0.5 ppm or less.

[0060] In an embodiment of the invention, the pre-set specification for the content of nitrite in the excipient sodium starch glucolate is 2.0 ppm or less, such as 1.9 ppm, such as 1.8 ppm, such as 1.7 ppm, such as 1,6 ppm, such as 1.5 ppm, such as 1.4 ppm, such as 1.3 ppm, such as 1.2 ppm, such as 1.1 ppm, such as 1.0 ppm, such as 0.9 ppm, such as 0.8 ppm, such as 0.7 ppm, such as 0.6 ppm, such as 0.5 ppm, such as 0.4 ppm, such as 0.3 ppm, such as 0.2 ppm, such as 0.1 ppm or less. In a preferred embodiment the content of nitrite in sodium starch glucolate is 0.5 ppm or less.

[0061] In a preferred embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet, wherein the content of nitrite in said film- coated oral tablet is 3 ppm or less, such as 2.8 ppm or less relative to the content to vortioxetine as a free base; and wherein said film-coated tablet comprises vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients, wherein said pharmaceutically acceptable excipients comprises microcrystalline cellulose having a content of nitrite of 0.2 ppm or less, such as 0.1 ppm or less.

[0062] In a preferred embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet, wherein the content of nitrite in said film- coated oral tablet is 3 ppm or less, such as 2.8 ppm or less relative to the content to vortioxetine as a free base; and wherein said film-coated tablet comprises vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients, wherein said pharmaceutically acceptable excipients comprises magnesium stearate and wherein the content of nitrite in said magnesium stearate is 2.0 ppm or less, such as 1.0 ppm or less, 0.5 ppm or less.

[0063] In a preferred embodiment, the pharmaceutical composition prepared according to the present invention is a film-coated oral tablet, wherein the content of nitrite in said film- coated oral tablet is 3 ppm or less, such as 2.8 ppm or less relative to the content to vortioxetine as a free base; and wherein said film-coated tablet comprises vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients, wherein said pharmaceutically acceptable excipients comprises mannitol and wherein the content of nitrite in said mannitol is 0.04 ppm or less, such as 0.02 ppm or less or less.

[0064] In an embodiment the method of the invention provides a pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the content of nitrosamine impurity, such as for example the compound of formula II (N-nitroso vortioxetine), in said pharmaceutical composition is 20 ppm or less, such as 19 ppm, such as 18 ppm, such as 17 ppm, such as 16 ppm, such as 15 ppm, such as 14 ppm, such as 13 ppm, such as 12 ppm, such as 11 ppm, such as 10 ppm, such as 9 ppm, such as 8 ppm, such as 7 ppm, such as 6 ppm, such as 5 ppm, such as 4 ppm, such as 3 ppm, such as 2 ppm, such as 1 ppm or less, relative to the content to vortioxetine as a free base.

[0065] In an embodiment the method of the invention provides a pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the content of N-nitroso vortioxetine in said pharmaceutical composition is 20 ppm or less, such as 19 ppm, such as 18 ppm, such as 17 ppm, such as 16 ppm, such as 15 ppm, such as 14 ppm, such as 13 ppm, such as 12 ppm, such as 11 ppm, such as 10 ppm, such as 9 ppm, such as 8 ppm, such as 7 ppm, such as 6 ppm, such as 5 ppm, such as 4 ppm, such as 3 ppm, such as 2 ppm, such as 1 ppm or less, relative to the content to vortioxetine as a free base, when said pharmaceutical composition is stored at approximately 40 °C and approximately 75% relative humidity for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or 7 months; and / or at 25 °C and approximately 60% relative humidity for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 12 months, 18 months or 24 months; and / or at 25 °C and ambient humidity for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 12 months, 18 months or 24 months. In an embodiment the method of the invention provides a film-coated tablet comprising vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients, wherein the content of nitrosamine impurity, such as for example the compound of formula II (N-nitroso vortioxetine) in said film-coated tablet is 20 ppm or less relative to the content to vortioxetine as a free base.

[0066] In an embodiment the method of the invention provides an oral drop pharmaceutical composition comprising vortioxetine lactate in an amount corresponding to 20 mg / mL vortioxetine free base, and one or more pharmaceutically acceptable excipients, wherein the content of nitrosamine impurity, such as for example the compound of formula II (N-nitroso vortioxetine) in said oral drop composition is 20 ppm or less relative to the content to vortioxetine as a free base.

[0067] In an embodiment the method of the invention provides a film-coated oral tablet comprising vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base, and one or more pharmaceutically acceptable excipients, wherein the content of the compound of formula II (N-nitroso vortioxetine) in said film- coated oral tablet is 20 ppm or less relative to the content to vortioxetine as a free base when said pharmaceutical composition is stored at approximately 40 °C and approximately 75% relative humidity for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months or 9 months; and / or at 25 °C and approximately 60% relative humidity for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 12 months, 18 months or 24 months; and / or at 25 °C and ambient humidity for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 12 months, 18 months or 24 months; and / or at 30 °C and approximately 75% relative humidity for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 12 months, 18 months or 24 months.

[0068] Experimental

[0069] Example 1

[0070] Tablet A (Reference tablet) and Tablet B (Tablet prepared according to the method of the present invention) were prepared utilizing two different microcrystalline celluloses. Microcrystalline cellulose utilized for Tablet A contained more than 0.5 ppm nitrite.

[0071] Microcrystalline cellulose utilized for Tablet B contained less than 0.1 ppm nitrite. Granulation and drying of intra-granular blend

[0072] Vortioxetine hydrobromide was mixed with intra-granulate excipients (mannitol, microcrystalline cellulose, and hydroxypropyl cellulose) followed by liquid addition and wet massing. The granulated batch was wet screened using a Cone-mill followed by tray drying and dry screening.

[0073] Blending of intragranular blend granules with extra-granular excipients

[0074] The intra-granular blend was then further blended with microcrystalline cellulose and Sodium starch glycolate and Magnesium Stearate.

[0075] Tableting

[0076] The final powder blend was compressed into tablets and coated using the coating suspension.

[0077] Table 1: Composition of Vortioxetine Hydrobromide Film-coated Tablet, Tablet A (reference tablet) and Tablet B (prepared according to the method of the present invention)

[0078] Example 2

[0079] Accelerated stress stability study of 5 mg tablets manufactured using two different microcrystalline celluloses were undertaken. The nitrite level of the two batches of tablets were measured according to Method 1, and subsequently the tablets were stored at 40°C / 75%RH in Duma HDPE bottles. N-Nitroso Vortioxetine (Compound II) was analyzed according to Method 2 at different time points until the increase had leveled off.

[0080] Table 2: Content of N-Nitroso Vortioxetine (Compound of formula II) in tablets A and B upon storage of the tablets at 40°C / 75%RH; and initial nitrite level in the tablets prior to storage at 40°C / 75%RH. The nitrite levels of tablets were analyzed prior to the stability study.

[0081] Example 2 shows, that the content of nitrite in Tablet B (prepared according to the method of the invention) as determined prior to tablet storage at 40°C / 75%RH was 1.3 ppm relative to the weight of vortioxetine as a free base (i.e. below 2.8 ppm relative to the weight of vortioxetine as a free base); and that the content of N-nitroso vortioxetine (compound II) in Tablet B is kept below 20 ppm relative to the content of vortioxetine free base upon storage at 40°C / 75%RH for 7.5 months. Example 2 shows, that the content of nitrite in Tablet A (Reference tablet, not prepared according to the method of the invention) as determined prior to tablet storage at 40°C / 75%RH was 4.4 ppm relative to the weight of vortioxetine as a free base (i.e. above 2.8 ppm relative to the weight of vortioxetine as a free baseband that the content of N-nitroso vortioxetine (compound II) in Tablet A is above 20 ppm relative to the content of vortioxetine free base upon storage at 40°C / 75%RH for 3,5 - 7.5 months.

[0082] Example 3

[0083] Tablets C, D, E, F (prepared according to the method of the present invention) were prepared utilizing microcrystalline cellulose containing less than 0.1 ppm nitrite, mannitol containing less than 0.02 ppm nitrite, and magnesium stearate containing 2 ppm nitrite.

[0084] Preparation of Tablets C, D, E, F:

[0085] Granulation and drying of intra-granular blend

[0086] Vortioxetine hydrobromide was granulated with intra-granulate excipients (mannitol, microcrystalline cellulose, and hydroxypropyl cellulose) using fluidisation spray granulation.

[0087] Blending of intragranular blend granules with extra-granular excipients

[0088] The intra-granular blend was then further blended with microcrystalline cellulose and Sodium starch glycolate and Magnesium Stearate.

[0089] Tableting

[0090] The final powder blend was compressed into tablets and coated using the coating suspension.

[0091] Table 3: Composition of Vortioxetine Hydrobromide Film-coated Tablets (prepared according to the method of the present invention)

[0092] Example 4 Accelerated stress stability study of Tablets C, D, E and F were undertaken. The tablets were stored at 25°C / 60% RH, 30°C / 75% RH and 40°C / 75%RH in Duma HDPE bottles. N-Nitroso Vortioxetine (Compound II) was analyzed according to Method 3 at different time points until the increase had leveled off. Table 4: Nitrite level in tablets C, D, E and F prior to storage at 25°C / 60% RH, 30°C / 75% RH and 40°C / 75%RH.

[0093] Table 5 Tablet C (5 mg Vortioxetine)

[0094] Measurement of N-nitrosovortioxetine in ppm relative to vortioxetine in Tablets C

[0095] Table 6

[0096] Tablet D (10 mg Vortioxetine) Measurement of N-nitrosovortioxetine in ppm relative to vortioxetine in Tablet D Table 7

[0097] Tablet E (15 mg Vortioxetine)

[0098] Measurement of N-nitrosovortioxetine in ppm relative to vortioxetine in Tablets E

[0099] Table 8

[0100] Tablet F (20 mg Vortioxetine)

[0101] Measurement of N-nitrosovortioxetine in ppm relative to vortioxetine in Tablets F

[0102] Example 4 shows, that the content of nitrite in Tablets C, D, E and F (prepared according to the method of the invention) as determined prior to tablet storage was less than 1.5 ppm relative to the weight of vortioxetine as a free base (i.e. below 2.8 ppm relative to the weight of vortioxetine as a free base); and that the content of N-nitroso vortioxetine (compound II) in Tablets C, D, E and F is kept below 20 ppm relative to the content of vortioxetine free base upon storage at 25°C / 60% RH, 30°C / 75% RH and 40°C / 75%RH for up to 9 months.

[0103] Method 1 Analytical method for determining nitrite content.

[0104] An aqueous extract of the sample was reacted under acidic conditions with sulfanilamide and N-(l-naphthyl)ethylenediamine. Suitable nitrite standards were reacted in the same way. Solutions were analyzed by HPLC, using a C18 50 * 2.1 mm, particle size 1.7 pm column with a water / methanol (0.1% formic acid) gradient 10-95% organic over 10 minutes. Column temperature 40 °C, flow 0.5 mL / min, 10 pL injected, UV-VIS detection at 520 nm.

[0105] Method 2 Analytical method for determining N-nitroso Vortioxetine content.

[0106] N-nitroso Vortioxetine in the samples was determined using an Agilent 1290 Infinity II UHPLC equipped with an Agilent Triple Quadrupole mass spectrometer. Column: Zorbax Eclipse Plus C18, 100 mm x 2.1 mm, 1.8. Mobile phase A: 0.1% Formic acid; Mobile phase B: Acetonitrile + 0.1% formic acid. Gradient: time: 0-0.1-4.0-6.0-6.1-8.0 min; Mobile phase A, %: 5-5-95-95-5-5. Detection: MRM 328.1-298.1

[0107] Method 3 Analytical method for determining N-nitroso Vortioxetine content.

[0108] N-nitroso Vortioxetine in the samples was determined using a UPLC system with column oven, degasser and single quadrupole MS detector. Column: Zorbax Eclipse Plus Cl 8, 50 mm x 2.1 mm, 1.8 micrometer. Mobile phase A: 0.1% Formic acid; Mobile phase B: Acetonitrile + 0.1% formic acid. Gradient: time: 0 - 8 - 8.1 - 12 min; Mobile phase A, %: 60 - 5 - 60 - 60. Detection: MS positive ion m / z = 328.00

Claims

CLAIMS1. A method for reducing the amount of a nitrosamine impurity in a pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, the method comprising the step of a) determining the content of nitrite in one or more of said pharmaceutically acceptable excipient(s) and b) if said excipient(s) meet pre-set specifications for the content of nitrite, then continue to preparing the pharmaceutical composition; and wherein the content of nitrite in said pharmaceutical composition is 2.8 ppm or less, relative to the content to vortioxetine as a free base.

2. The method according to claim 1, further comprising the step of c) measuring the content of nitrite in said pharmaceutical composition, and d) discarding said pharmaceutical composition if the content of nitrite in said pharmaceutical composition is more than 2.8 ppm, relative to the content to vortioxetine as a free base.

3. The method according to any one of claims 1-2; wherein the content of nitrite in the pharmaceutical composition as calculated from the pre-set specifications of each the excipients is 2.8 ppm or less, relative to the content to vortioxetine as a free base.

4. The method according to any one of claims 1-3; wherein in step c) the content of nitrite in the pharmaceutical composition is measured at TO, wherein TO is 0 - 6 days after the preparation of said pharmaceutical composition.

5. The method according to any one of claims 1-4; wherein the pharmaceutical composition comprises vortioxetine hydrobromide.

6. The method according to any one of claims 1-5; wherein the pharmaceutical composition is a film-coated oral tablet comprising vortioxetine hydrobromide in an amount corresponding to 5 mg or 10 mg or 15 mg or 20 mg vortioxetine free base.

7. The method according to any one of claims 1-6; wherein the pharmaceutical composition comprises the excipients mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate and magnesium stearate.

8. The method according to claim 7; wherein the pre-set specifications for the content of nitrite in microcrystalline cellulose is 0.2 ppm or less.

9. The method according to claims 7-8; wherein the pre-set specifications for the content of nitrite in microcrystalline cellulose is 0.1 ppm or less.

10. The method according to claim 7; wherein the pre-set specifications for the content of nitrite in magnesium stearate is 2.0 ppm or less.

11. The method according to claim 7; wherein the pre-set specifications for the content of nitrite in mannitol is 0.04 ppm or less.

12. The method according to any one of claims 1-4; wherein the pharmaceutical composition is an oral drop composition comprising vortioxetine lactate in an amount corresponding to 20 mg / mL vortioxetine free base.

13. The method according to any one of claims 1 - 12, wherein the content of N-nitroso vortioxetine in the pharmaceutical composition is 20 ppm or less relative to the content to vortioxetine as a free base upon storage of the pharmaceutical composition for 6 months at 40 °C and 75% relative humidity.

14. A pharmaceutical composition prepared according to any one of claims 1 - 13.

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