Composition containing ranitidine with low iron content

Abstract

This invention relates to compositions containing ranitidine or a pharmaceutically acceptable salt thereof with a low iron content. The invention also relates to compositions having a low iron content that does not complex with a chelating agent and / or having a low iron content that partially or completely complexes with a chelating agent and / or having a low iron content that complexes with chelating agents other than ranitidine and / or having a low complex content forming between ranitidine and iron. The invention further relates to methods for preparing said compositions. The invention also relates to a second pharmaceutical use of said compositions.

Description

Technical Field

[0001] This invention relates to compositions containing ranitidine or a pharmaceutically acceptable salt thereof with a low iron content. The invention also relates to compositions having a low iron content that does not complex with a chelating agent and / or having a low iron content that partially or completely complexes with a chelating agent and / or having a low iron content that complexes with chelating agents other than ranitidine and / or having a low complex content forming between ranitidine and iron. The invention further relates to methods for preparing said compositions. The invention also relates to a second pharmaceutical use of said compositions. Background Technology

[0002] Recently, due to concerns about levels of the contaminant N-nitrosodimethylamine (NDMA), most drug regulatory agencies worldwide, particularly the Food and Drug Administration, have decided to recall ranitidine compositions from the market. The levels of this contaminant, NDMA, increase with time and temperature. Based on animal studies, NDMA has been classified as a possible human carcinogen.

[0003] Among the many root causes of NDMA contamination in commercial ranitidine compositions, the inventors have unexpectedly discovered that NDMA contamination is due to the presence of iron in the said ranitidine compositions.

[0004] Unbound by theory, the inventors believe that the formation of NDMA in ranitidine compositions in the presence of iron is generated by the mechanism shown in the following scheme.

[0005]

[0006] Iron contamination can originate from processing (e.g., from equipment used to produce ranitidine and ranitidine compositions), transportation, or even be naturally present in the raw materials used to produce ranitidine and ranitidine compositions.

[0007] The inventors also unexpectedly discovered an alternative method for reducing the iron content in compositions containing ranitidine and thus the NMDA content in these compositions, even after storage, according to the stability test defined in European guideline CPMP / ICH / 2736 / 99. Summary of the Invention

[0008] The first object of the present invention relates to a composition containing ranitidine or one of its pharmaceutically acceptable salts, said composition comprising, by weight, less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb of iron relative to the total dry weight of the composition.

[0009] A second object of the present invention relates to a composition containing one of ranitidine or a pharmaceutically acceptable salt thereof, the composition comprising:

[0010] - Less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb of iron in a non-complexing form relative to the total dry weight of the composition, and / or

[0011] - Relative to the total dry weight of the composition, by weight, less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb of iron, which exists in a complexed form with the chelating agent, and / or

[0012] - Relative to the total dry weight of the composition, by weight, less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb of iron, which exists in a complexed form with a chelating agent other than ranitidine, and / or

[0013] - A complex formed between ranitidine and iron substances, with a weight of less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb, relative to the total dry weight of the composition.

[0014] Another object of the present invention relates to a method for preparing the aforementioned defined composition, wherein the composition does not come into contact with iron.

[0015] The compositions described above can be manufactured, at least in part, in stainless steel-free equipment, glass equipment, glass production line equipment, equipment coated with inactive polymers or copolymers (such as copolymers of ethylene and trifluorochloroethylene) and polytetrafluoroethylene, and / or equipment coated with enamel.

[0016] The present invention also relates to a method for preparing the aforementioned composition, the method comprising at least one step selected from the following: a step of complexing at least a portion or all of the iron substance with a chelating agent, a step of removing at least a portion or all of the complex formed between the chelating agent and the iron substance, and a step of removing at least a portion or all of the iron substance.

[0017] Another object of the present invention relates to the use of the compositions defined above for the prevention and / or treatment of duodenal ulcers, gastric or stomach ulcers, heartburn, indigestion due to acid reflux (such as gastroesophageal reflux), weak stomach, dermatitis, and Zollinger-Ellison syndrome. Detailed Implementation

[0018] Ranitidine is (E)-1N'-[2-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfonyl]ethyl]-1N-methyl-2-nitroethylene-1,1-diamine.

[0019] "Ranitidine, HCl" in this article can be understood as ranitidine hydrochloride.

[0020] In this article, “ppb” is understood as one part per billion of weight.

[0021] In this article, “ppm” is understood as parts per million by weight.

[0022] In this article, "RH" is understood as relative humidity.

[0023] “K SP "In this paper, it is understood as the solubility product constant."

[0024] The term "purification step" should be understood herein as any physical separation of the iron substance or the complex formed between the chelating agent and the iron substance from a composition containing ranitidine or its salts. Examples of purification steps include, but are not limited to, filtration, centrifugation, evaporation, liquid-liquid extraction, crystallization, grinding, absorption, chromatography, melting, distillation, sublimation, electrolysis, dissolution, precipitation, magnetic separation, and combinations thereof.

[0025] In this article, “NDMA” can be understood as nitrosodimethylamine.

[0026] "At least once" can be understood in this document as once or more, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 times, more preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times, and even more preferably 1, 2, 3, 4 or 5 times.

[0027] This invention relates to compositions containing ranitidine or one of its pharmaceutically acceptable salts, said compositions comprising less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb, relative to the total dry weight of the composition. For example, the iron content relative to the total dry weight of the composition may include between 50 ppb and 900 ppb, preferably between 100 ppb and 600 ppb, and more preferably between 200 ppb and 300 ppb.

[0028] The present invention also relates to a product containing ranitidine or a pharmaceutically acceptable salt thereof, comprising, by weight, less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb of iron relative to the total dry weight of ranitidine or a pharmaceutically acceptable salt thereof. For example, the iron content may be between 50 ppb and 900 ppb, preferably between 100 ppb and 600 ppb, and even more preferably between 200 ppb and 300 ppb.

[0029] The iron content can be measured using techniques known to those skilled in the art. These techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).

[0030] In a particular embodiment, the composition comprises, by weight, less than 320 ppb, preferably less than 160 ppb, more preferably less than 80 ppb, and even more preferably less than 17 ppb of N-nitrosodimethylamine (NDMA) relative to the total dry weight of ranitidine or a pharmaceutically acceptable salt thereof.

[0031] In a particular embodiment, the composition comprises, by weight, less than 320 ppb, preferably less than 160 ppb, more preferably less than 80 ppb, and even more preferably less than 17 ppb of N-nitrosodimethylamine (NDMA) relative to the total dry weight of ranitidine or a pharmaceutically acceptable salt thereof, wherein the NDMA content is determined according to the stability test as defined in European guideline CPMP / ICH / 2736 / 99. Preferably, the stability test is an accelerated stability test as defined in CPMP / ICH / 2736 / 99, i.e., stored at 40°C ± 2°C / 75%RH ± 5%RH (relative humidity) for 6 months.

[0032] In another specific embodiment, the composition comprises, by weight, less than 320 ppb, preferably less than 160 ppb, more preferably less than 80 ppb, and even more preferably less than 17 ppb of N-nitrosodimethylamine (NDMA) relative to the total dry weight of ranitidine or a pharmaceutically acceptable salt thereof, the NDMA content being measured after exposure to 70°C for up to 5 days. The NDMA content, as previously described, can also be measured after exposure to forced conditions (i.e., temperatures above or equal to about 70°C for 22 days). For example, these exposures can be performed at 75% RH.

[0033] NDMA content can be measured using techniques known to those skilled in the art. Examples of such techniques include, but are not limited to, gas chromatography-mass spectrometry (GC-MS), GC-MS / MS, liquid chromatography-mass spectrometry (LC-MS, and especially HPLC-MS) and LC-MS / MS (and especially HPLC-MS / MS), preferably liquid chromatography-mass spectrometry (LC-MS) and LC-MS / MS.

[0034] The present invention also relates to compositions containing one of ranitidine or a pharmaceutically acceptable salt thereof, comprising:

[0035] - Relative to the total dry weight of the composition, by weight, less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb of iron substances existing in a non-complexed form with the chelating agent.

[0036] - Relative to the total dry weight of the composition, by weight, less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb of iron, which exists in a complexed form with the chelating agent, and / or

[0037] - Relative to the total dry weight of the composition, by weight, less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb of iron, which exists in a complexed form with a chelating agent other than ranitidine, and / or

[0038] - A complex formed between ranitidine and iron substances, with a weight of less than 1 ppm, preferably less than 900 ppb, more preferably less than 600 ppb, and even more preferably less than 300 ppb, relative to the total dry weight of the composition.

[0039] For example, the content of iron that does not exist in a complexed form with the chelating agent, relative to the total dry weight of the composition, can be between 50 ppb and 900 ppb, preferably between 100 ppb and 100 ppb, and more preferably between 200 ppb and 300 ppb.

[0040] For example, the content of iron in a complexed form, either partially or completely with the chelating agent, relative to the total dry weight of the composition, can be between 50 ppb and 900 ppb, preferably between 100 ppb and 600 ppb, and more preferably between 200 ppb and 300 ppb.

[0041] For example, the content of iron in complex form with chelating agents other than ranitidine, relative to the total dry weight of the composition, can be between 50 ppb and 900 ppb, preferably between 100 ppb and 600 ppb, and more preferably between 200 ppb and 300 ppb.

[0042] For example, the content of the complex formed between ranitidine and iron, relative to the total dry weight of the composition, may include between 50 ppb and 900 ppb, preferably between 100 ppb and 600 ppb, and more preferably between 200 ppb and 300 ppb.

[0043] The content of iron that does not exist in a complexed form with the chelating agent can be measured using techniques well known to those skilled in the art. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).

[0044] The content of iron, whether partially or completely in a complexed form, can be measured using techniques well known to those skilled in the art. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).

[0045] The content of iron in complexed form with chelating agents other than ranitidine can be measured using techniques well known to those skilled in the art. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).

[0046] The content of the complex formed between ranitidine and iron can be measured using techniques well known to those skilled in the art. Examples of such techniques include, but are not limited to, inductively coupled plasma mass spectrometry (ICP-MS).

[0047] Pharmaceutically acceptable salts of ranitidine, as mentioned above, can be ranitidine hydrochloride, bismuth ranitidine citrate, and mixtures thereof.

[0048] The iron substances mentioned above can be metallic iron (iron(0)), iron(II) and iron(III) and mixtures thereof, preferably metallic iron (iron(0)), iron oxide, such as iron oxide(II) and iron oxide(III), iron chloride, such as iron chloride(II) and iron chloride(III) and mixtures thereof.

[0049] Preferably, the compositions defined above comply with pharmacopoeias, particularly the United States Pharmacopeia or the European Pharmacopoeia.

[0050] The compositions described above may also contain one or more excipients.

[0051] The composition described above may consist of ranitidine or a pharmaceutically acceptable salt thereof with an iron substance, the amount of which is as described above.

[0052] The composition described above may consist essentially of ranitidine or a pharmaceutically acceptable salt thereof with an iron substance, the amount of which is as described above.

[0053] The composition described above may also consist of ranitidine or a pharmaceutically acceptable salt thereof with an iron substance in the amount described above and one or more excipients.

[0054] The compositions described above may also consist essentially of ranitidine or a pharmaceutically acceptable salt thereof, with an iron substance in the amounts described above, and one or more excipients.

[0055] Ranitidine can be in the form of powder, compacted powder or solution.

[0056] The compositions described above may be pharmaceutical compositions.

[0057] The present invention also relates to a method for preparing the aforementioned composition.

[0058] In one particular embodiment, the composition does not come into contact with iron during the preparation process.

[0059] The compositions described above can be manufactured, at least in part, in stainless steel-free equipment, glass equipment, glass production line equipment, equipment coated with inactive polymers or copolymers (such as copolymers of ethylene and trifluorochloroethylene) and polytetrafluoroethylene, and / or equipment coated with enamel.

[0060] The term "inactive polymer" refers to an inert polymer, which is a polymer that does not leave metallic residues such as ferrous substances at high temperatures and is resistant to thermal corrosive environments such as hydrochloric acid and ethanol. Therefore, inactive polymers ensure the permanence and continuity of the protective polymer film bonded to the metal of a device (such as stainless steel). Examples of inactive polymers include, but are not limited to, copolymers of ethylene and trifluorochloroethylene, polytetrafluoroethylene, and mixtures thereof.

[0061] Examples of copolymers of ethylene and trifluorochloroethylene include, but are not limited to, those commercially available from Solvay.

[0062] The preparation method of the composition as described above may include at least one step selected from the following: a step of complexing at least a portion or all of the iron with a chelating agent, a step of removing at least a portion or all of the complex formed between the chelating agent and the iron, and a step of removing at least a portion or all of the iron.

[0063] In particular, the step selected from the steps of complexing at least some or all of the iron with a chelating agent, removing at least some or all of the complex formed between the chelating agent and the iron, and removing at least some or all of the iron includes:

[0064] - Distillation steps of methylthiomethyl (MTM) compounds such as 1-methylamino-1-methylthio-2-nitroethylene, and / or

[0065] - A complexation step using N,N-dialkyl-dithiocarbamates (such as N,N-dimethyl-dithiocarbamate, N,N-diethyl-dithiocarbamate and / or N,N-dibutyl-dithiocarbamate), ethylenediaminetetraacetic acid (EDTA), and / or cysteine, optionally followed by a purification step, and / or

[0066] - A complexation step is performed using a resin or silica grafted with N,N-dialkyl-dithiocarbamates (such as N,N-dimethyl-dithiocarbamate, N,N-diethyl-dithiocarbamate and / or N,N-dibutyl-dithiocarbamate), ethylenediaminetetraacetic acid (EDTA), and / or cysteine, optionally followed by a purification step, and / or

[0067] - A complexation step using a resin or silica with carbon-linked functional groups capped by functional groups, wherein the functional groups are iron chelating agents, optionally followed by a purification step, and / or

[0068] - Adsorption steps using zeolite, activated carbon, silica, or silica-activated carbon composites, and / or

[0069] - Separation steps using a magnetic separator.

[0070] These steps can be combined and / or repeated if necessary.

[0071] The aforementioned iron chelating agent may be selected from dithiocarbamate groups, thiol groups, dimethoxytriphenylmethyl (DMT) groups, amino groups, (aminomethyl)phosphonic acid (AMPA) groups, cysteine ​​groups, propyl diethanolamine (DEAM) groups, diamine groups, dodecane-tetraacetic acid (DOTA) groups, imidazole groups, triaminotetraacetic acid (TaAcOH) groups, sodium triaminotetraacetic acid (TAACONa) groups, thiourea groups, p-toluenesulfonic acid (methylbenzenesulfonic acid) groups, triamine groups, and mixtures thereof.

[0072] The silicon dioxide with functional group-terminated carbon links can be produced by SiliCycle under the trademark name... Iron removers, such as Cysteine ​​(Si-Cys) is the equivalent of cysteine, an amino acid bonded to silicon dioxide.

[0073] The complex formed between the iron and the chelating agent can be present in the final composition or can be removed from the composition by purification steps such as filtration. In cases where the chelation of the iron deactivates the iron, i.e., once the iron is complexed, it no longer participates in the redox reaction, the complex formed between the iron and the chelating agent can be present in the final composition.

[0074] Preferably, the complex formed between the iron and the chelating agent is removed from the composition by a purification step such as a filtration step.

[0075] Methylthiomethyl (MTM) compounds, such as 1-methylamino-1-methylthio-2-nitroethylene, are known to have high thermal stability (they do not decompose before 190 °C). Therefore, iron can be separated from ranitidine by using MTM compounds, such as 1-methylamino-1-methylthio-2-nitroethylene, during distillation. The distillation step can be carried out under reduced pressure, particularly in the millibar range.

[0076] Due to the difference in solubility between ranitidine and the complexes formed between chelating agents such as N,N-dialkyl-dithiocarbamate, EDTA, or cysteine ​​and iron substances, the complexes can be easily separated from solid compositions containing ranitidine by purification steps such as filtration.

[0077] For example, the complexes formed between N,N-dialkyl-dithiocarbamates and iron compounds have low solubility in water, and therefore, unlike ranitidine, they have high pK values. SP (equals log(K) SP Therefore, the complex formed between N,N-dialkyl-dithiocarbamate and iron can be readily separated from compositions containing ranitidine through purification steps such as filtration.

[0078] Similarly, due to the solubility of the complex formed between EDTA and iron, the complex can be readily separated from compositions containing ranitidine by purification steps such as filtration.

[0079] Cysteine ​​is an iron chelating agent. The inventors have discovered that cysteine, when present in excess as a reagent in the synthesis of ranitidine, can act as an iron chelating agent. Therefore, cysteine ​​can be added during the manufacture of ranitidine, or a crude adduct of cysteine ​​and methylthiomethyl (MTM) (particularly 2-(((5-(((dimethylamino)methyl)furan-2-yl)methyl)thio)ethylamine, also known as the fluoxetine impurity (cystofur) or cystofer) can be used. Using cysteine ​​as a chelating agent avoids the use of additional chemical entities in this method and is therefore advantageous. Therefore, cysteine ​​is the preferred iron chelating agent.

[0080] An example of a step involving the adsorption of iron by using activated carbon, silica, or a silica-activated carbon composite is described in Heavy Metals Removal Using Activated Carbon, Silica and Silica Activated Carbon Composite, Mona Karnib et al., Energy Procedia 50 (2014) 113-120. Zeolite, activated carbon, silica, or silica-activated carbon composites can be used in purification processes, such as filtering homogeneous phases containing ranitidine from solvents such as ethyl acetate.

[0081] Due to the ferromagnetism of the complexes formed between ranitidine and some or all of the iron substances, such as iron(O) and iron(III), and the ferromagnetism of some or all of the iron substances, such as iron(O) and iron(III), such compounds can be captured by using a magnetic field, particularly by using a magnetic separator. Magnetic separation equipment for capturing iron substances can include ceramics, neodymium iron boron (NdFeB), praseodymium, and / or neodymium.

[0082] Methods for removing at least some or all of the iron may also include the following steps:

[0083] a) The dissolution step of ranitidine in a solvent such as water, followed by a purification step, such as a purification step by reverse osmosis or a filtration step such as ultrafiltration.

[0084] b) Optionally, a recrystallization step using a solvent, such as an alcohol-based solvent and preferably methanol, ethanol and / or isopropanol.

[0085] Step a) may be repeated at least once before step b). Steps a) and b) may be repeated at least once.

[0086] The methods described above can be used in combination. High temperature, high humidity, and oxygen affect the degradation rate of ranitidine. Furthermore, low pH also affects the degradation rate of ranitidine. In addition, ranitidine exhibits lower chemical activity in heterogeneous solid phases compared to homogeneous aqueous phases.

[0087] Therefore, the compositions described above can be manufactured and / or stored in an atmosphere with low oxygen content, preferably the compositions are prepared and / or stored in an inert atmosphere using an inert gas such as nitrogen, argon and mixtures thereof.

[0088] The compositions described above can also be manufactured and / or stored at low temperatures.

[0089] The compositions described above can also be manufactured and / or stored at lower relative humidity.

[0090] The compositions described above can also be manufactured and / or stored in a manner with low water and ethanol content.

[0091] The compositions described above can also be prepared and / or stored at low pH.

[0092] The compositions described above can also be stored in solid form.

[0093] Ranitidine is known to be used for the prevention and / or treatment of duodenal ulcers, gastric or stomach ulcers, heartburn, indigestion caused by acid reflux (such as gastroesophageal reflux), weak stomach, dermatitis, and E. syndrome.

[0094] Therefore, another object of the present invention relates to compositions defined above for the prevention and / or treatment of duodenal ulcers, gastric or stomach ulcers, heartburn, indigestion caused by acid reflux (such as gastroesophageal reflux), weak stomach, dermatitis, and E. syndrome. Attached Figure Description

[0095] Figure 1 The NDMA content is indicated by the ranitidine sample after storage at 40°C for 7, 15, and 30 days.

[0096] Example

[0097] Example 1: Iron Spike

[0098] The purpose of this experiment is to demonstrate that the presence of iron in commercially available compositions containing ranitidine (not according to the present invention) leads to the degradation of ranitidine into NDMA.

[0099] Solution: The test is described in Table 1 below.

[0100] Table 1

[0101]

[0102] The ranitidine hydrochloride used in these tests is a representative industrial sample of ranitidine hydrochloride with an iron content of approximately 1500 ppb (1.5 ppm) (not according to the present invention).

[0103] To ensure complete homogenization, the mixture is ground in a mortar.

[0104] The NDMA content was measured using the GC-MC measurement method.

[0105] result:

[0106] The results are listed in Table 1.

[0107] As shown in Table 1:

[0108] The presence of iron promoted the formation of NDMA in the tested ranitidine-HCl compositions.

[0109] - Due to the strong interaction such as iron / oxygen further activating the NDMA formation process, exposure of the ranitidine, HCl test composition to oxygen promotes NDMA formation. Conversely, in a nitrogen atmosphere, even with iron spikes, the NDMA formation process is strongly slowed down, but not canceled. Therefore, in the presence of iron in the ranitidine composition, oxygen is a very important factor for NDMA formation. In fact, nitrosylated N2O substances (dimerized in N2O4) are present with oxygen, not with nitrogen, where only the precursor NO, known to be less reactive in nitrosation reactions, is present. Iron (iron O, II, III) is more chemically active in heterogeneous solid phases than in homogeneous aqueous phases (not shown). This is because the pH of the solid form is higher than that of the dissolved form in water.

[0110] The presence of a mixture of iron substances is more reactive than that of a stainless steel sheet (not shown). In fact, there is a known synergistic effect between the ethylene-nitro cleavage to aldehyde and the reaction of nitro oxygen with Nef, in which iron (0) contains a small amount of iron (III) to initiate the reduction cycle, thereby initiating the cleavage cycle.

[0111] Low-temperature testing will also demonstrate the importance of the temperature factor. In fact, it has been previously observed that NDMA formation is more significant at 70°C (in the ppm range) and less significant at 40°C (in the ppb range) (not shown), which justifies using a temperature of 70°C to allow for the quantization of NDMA using a GC-MS system compatible with quantization in the ppb range.

[0112] in conclusion:

[0113] It was confirmed that ranitidine and HCl degrade to NDMA in the presence of iron and oxygen. This phenomenon can be amplified in an aqueous phase because low pH promotes the degradation reaction (not shown).

[0114] Therefore, ranitidine and HCl with low iron content as defined in this invention are obtained, so that after storage under the conditions defined in CPMP / ICH / 2736 / 99 (stability test at 40°C and 75% RH for 6 months), ranitidine and HCl can be guaranteed to have low NDMA content.

[0115] Example 2: Formation Mechanism of NDMA

[0116] As previously mentioned, the inventors have unexpectedly discovered that the formation of NDMA in the ranitidine composition is due to the presence of iron in the ranitidine composition, and the mechanism of NDMA formation can be explained by the following scheme.

[0117]

[0118] HPLC-MS and HPLC-MS / MS analyses have been performed, demonstrating the above-mentioned NDMA formation mechanism in the presence of iron in the ranitidine composition.

[0119] In particular, HPLC-MS / MS analysis showed that the key intermediate contained an enol aldehyde moiety, which was obtained after the nitrite moiety was cleaved by iron and participated in the formation of NDMA (results not shown).

[0120] This discovery demonstrates that NDMA formation is due to the presence of iron and involves the following steps: the cleavage of ranitidine with iron, accompanied by the formation of mineral nitrites, and the formation of NDMA. The formation of NDMA is accelerated when the temperature increases.

[0121] Example 3: Correlation between iron content and NDMA formation

[0122] Ranitidine samples containing the amounts of iron shown in Table 2 were prepared.

[0123] The NDMA content in ranitidine samples was measured by HPLC-MS after storage at 40°C for 1, 2, 7, 15 and 30 days.

[0124] The total iron content in the ranitidine sample was measured by ICP-MS.

[0125] The results are listed in Table 2 and Figure 1 .

[0126] Table 2

[0127]

[0128] These results demonstrate the correlation between iron content and NDMA formation.

Claims

1. A composition containing ranitidine or one of its pharmaceutically acceptable salts, said composition comprising, by weight, less than 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron relative to the total dry weight of said composition.

2. A composition containing ranitidine or one of its pharmaceutically acceptable salts, comprising: - Relative to the total dry weight of the composition, by weight, less than 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron substances not present in a complexed form with the chelating agent, and / or - Relative to the total dry weight of the composition, by weight, less than 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron, which are partially or completely complexed with the chelating agent, and / or - Relative to the total dry weight of the composition, by weight, less than 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron, present in a complexed form with a chelating agent other than ranitidine, and / or - A complex formed between ranitidine and iron substances, by weight, less than 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb relative to the total dry weight of the composition.

3. The composition according to claim 1 or 2, wherein, After exposure to 70°C for 5 days, the composition comprises, by weight, less than 320 ppb, less than 160 ppb, less than 80 ppb, or less than 17 ppb of N-nitrosodimethylamine relative to the total dry weight of ranitidine or a pharmaceutically acceptable salt thereof.

4. The composition of claim 1 or 2, wherein, The pharmaceutically acceptable salt of ranitidine is ranitidine hydrochloride.

5. The composition of claim 1 or 2, wherein, The iron substance is metallic iron, iron(II) and iron(III) and mixtures thereof.

6. The composition according to claim 1 or 2, wherein the composition is a pharmaceutical composition.

7. A process for the preparation of a composition according to any one of claims 1 to 6, wherein, The composition does not come into contact with iron.

8. A process for the preparation of a composition according to claim 1 or 2, wherein, The composition is manufactured, at least in part, in equipment without stainless steel, glass equipment, glass production line equipment, equipment coated with inactive polymers or copolymers, or copolymers of ethylene and trifluorochloroethylene, and polytetrafluoroethylene, and / or equipment coated with enamel.

9. A method for preparing the composition according to claim 1 or 2, comprising at least one step selected from the following: a step of complexing at least a portion or all of the iron substance with a chelating agent, a step of removing at least a portion or all of the complex formed between the chelating agent and the iron substance, and a step of removing at least a portion or all of the iron substance.

10. The method of claim 9, wherein, The at least one step selected from the steps of complexing at least some or all of the iron with a chelating agent, removing at least some or all of the complex formed between the chelating agent and the iron, and removing at least some or all of the iron includes: - Distillation steps of methylthiomethyl compounds, and / or - A complexation step using N,N-dialkyl-dithiocarbamate, ethylenediaminetetraacetic acid, and / or cysteine, optionally followed by a purification step, and / or - A complexation step using resins or silica grafted with N,N-dialkyl-dithiocarbamate, ethylenediaminetetraacetic acid, and / or cysteine, optionally followed by a purification step, and / or - A complexation step using a resin or silica with carbon-linked functional groups capped by functional groups, wherein the functional groups are iron chelating agents, optionally followed by a purification step, and / or - Adsorption steps using zeolite, activated carbon, silica, or silica-activated carbon composites, and / or - Separation steps using a magnetic separator.

11. The method of claim 10, wherein, The functional groups of the iron chelating agent are selected from dithiocarbamate groups, thiol groups, dimethoxytriphenylmethyl groups, amino groups, (aminomethyl)phosphonic acid groups, cysteine ​​groups, propyldiethanolamine groups, diamine groups, dodecane-tetraacetic acid groups, imidazole groups, triaminotetraacetic acid groups, sodium triaminotetraacetic acid groups, thiourea groups, p-toluenesulfonic acid groups, triamine groups, and mixtures thereof.

12. The method of claim 10, wherein, The silica used with functional group-terminated carbon linkers is an iron scavenger commercialized by SiliCycle under the trademark SiliaMetS®.

13. The composition according to claim 1 or 2, for the prevention and / or treatment of duodenal ulcers, gastric or stomach ulcers, heartburn, indigestion caused by acid reflux.

14. The composition according to claim 13, wherein the composition is used for the prevention and / or treatment of acid reflux, wherein, Acid reflux is caused by gastroesophageal reflux, weak stomach, dermatitis, or E. coli syndrome.

15. The composition containing ranitidine or a pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising less than 1 ppm of iron relative to the total dry weight of the composition.

16. The composition containing ranitidine or a pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising less than 900 ppb of iron relative to the total dry weight of the composition.

17. The composition containing ranitidine or a pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising less than 600 ppb of iron relative to the total dry weight of the composition.

18. The composition containing ranitidine or a pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising less than 300 ppb of iron relative to the total dry weight of the composition.

19. The composition of claim 5, wherein, The iron substance is metallic iron, ferrous oxide, ferric oxide, ferrous chloride, ferric chloride, and mixtures thereof.

20. The method of claim 10, wherein, The methylthiomethyl compound is selected from 1-methylamino-1-methylthio-2-nitroethylene; and / or The N,N-dialkyl-dithiocarbamate is selected from N,N-dimethyl-dithiocarbamate, N,N-diethyl-dithiocarbamate and / or N,N-dibutyl-dithiocarbamate.

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