A method for reduction of nitrosamine in pharmaceutical preparations and systems thereof

Abstract

The invention provides a method for reduction of nitrosamine during synthesis of a pharmaceutical preparation The method includes obtaining an ionized air through an ionizer arrangement, exposing a mixture of pharmaceutical ingredients to the ionized air during atleast one step of synthesis and additionally repeating the step of exposure at least one more time. The exposure of the pharmaceutical ingredients to the ionized air reduces nitrosamine content of the pharmaceutical preparation. The reduction in nitrosamine content is upto a limit lower than the maximum permissible limit of nitrosamine in a particular pharmaceutical preparation.

Description

[0001] A METHOD FOR REDUCTION OF NITROSAMINE IN PHARMACEUTICAL PREPARATIONS AND SYSTEMS THEREOF

[0002] FIELD OF INVENTION

[0003] The invention generally relates to the field of pharmaceutical preparations and more specifically, embodiments of the invention relate to a method for reduction of nitrosamine in pharmaceutical preparations.

[0004] BACKGROUND

[0005] In the last 5 years, there have been numerous drug recalls and drug rejections throughout the pharma industry because of the discovery of a new impurity called nitrosamines and more broadly as Nitroso-drug-substance-related-impurity (NDSRI). Nitrosamines describes a class of compounds having a chemical structure of a nitroso group bonded to an amine (RiN(- R2)-N=O). NDSRIS are a category of nitrosamines that are structurally similar to the active pharmaceutical ingredient (API) in drug products. Nitrosamine impurities are known to be mutagenic and carcinogenic. Nitrosamines in pharmaceutical products may arise from APIs, manufacturing processes, direct and indirect cross-contamination from solvents and equipment, and chemical degradation during storage. Global regulatory authorities have established guidelines for manufacturers of APIs and drug products to follow to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical preparations. However, despite following the guidelines, nitrosamine impurities are making their way into the pharmaceutical preparations. Various works has proposed reduction of nitrosamine in pharmaceutical preparations.

[0006] US 2022 / 0079894 A1 proposes reducing nitrosamine impurities in pharmaceuticals by use of a desiccant as moisture absorption agent when the pharmaceutical is being stored in a sealed container.

[0007] WO2023275413A2 discloses use of nitrite anion scavenger agent including ascorbic acid, sodium ascorbate, caffeic acid, ferulic acid and ammonium chloride for reducing nitrosamine impurity in varenicline.

[0008] IN2021 11059970A discloses preparation of stable pharmaceutical composition with nitrosamine impurity below FDA acceptable limit using an antioxidant and storing the pharmaceutical composition at 40° C / 75% RH in a container with an oxygen scavenger.

[0009] WO2021259396A3 discloses addition of a pharmaceutically acceptable acid particularly tartaric acid to the pharmaceutical composition to reduce the generation of nitrosamine impurity. Although there are methods like addition of antioxidants and other stabilizing agents employed for controlling nitrosamine impurity, still there has been several instances where medicines has been recalled due to presence of nitrosamine.

[0010] Hence, there is a need for a method for reducing nitrosamine impurities in pharmaceutical preparations which looks beyond the use of chemicals and stabilizers. BRIEF DESCRIPTION OF DRAWINGS

[0011] So that the manner in which the recited features of the invention can be understood in detail, some of the embodiments are illustrated in the appended drawings. It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.

[0012] FIG.1 shows an arrangement for reducing nitrosamine in pharmaceutical preparations during air jet milling, according to an embodimentof the invention.

[0013] FIG.1 a shows an arrangement for reducing nitrosamine in pharmaceutical preparations during air jet milling, according to another embodimentof the invention.

[0014] FIG.2 shows an arrangement for reducing nitrosamine in pharmaceutical preparations during fluid bed drying, according to an embodimentof the invention.

[0015] SUMMARYOF THE INVENTION

[0016] One aspect of the invention provides a method for reduction of nitrosamine during synthesis of a pharmaceutical preparation. The method includes obtaining an ionized air through an ionizer arrangement, exposing a mixture of pharmaceutical ingredients to the ionized air during atleast one step of synthesis and additionally repeating the step of exposure at least one more time. The exposure of the pharmaceutical ingredients to the ionized air reduces nitrosamine content of the pharmaceutical preparation. The reduction in nitrosamine content is upto a limit lower than the maximum permissible limit of nitrosamine in a particular pharmaceutical preparation.

[0017] DETAILED DESCRIPTION OF THE INVENTION

[0018] The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting of the invention. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, the use of the terms a, an, etc. does not denote a limitation of quantity, but rather denotes the presence of at least one of the referenced item. It will be further understood that the terms “comprises” and / or “comprising,” or “includes” and / or “including” when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof . Unless otherwise defined, all terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0019] The term ‘nitrosamine’ refers to organic compounds with the chemical structure R2N-N=O, where R is usually an alkyl group. Nitrosamines have a nitroso group (NO+) bonded to a deprotonated amine.

[0020] The term ‘nitroso-drug-substance-related-impurity’ refers to a category of nitrosamines that are structurally similar to the active pharmaceutical ingredient (API) in drug products.

[0021] Terms like ‘Nitrosamine’, ‘nitrosamine impurity’ and ‘nitroso- drug-substance-related-impurity’ are used interchangeably in the description.

[0022] Various embodiments of the invention provide a method for reduction of nitrosamine in pharmaceutical preparations during manufacturing. Nitrosamine, which is carcinogenic in nature, can arise in pharmaceutical products from raw materials, manufacturing processes, direct and indirect cross - contamination from solvents and equipment, and chemical degradation during storage. It is an established fact that very high static charges are generated during various medicine manufacturing including but not limited to fluid bed drying, air jet milling, sifting. High static charge generation is attributed to lack of moisture in the hot air and the continuous friction between powder particles. The invention is based on the principle of neutralization of static charges that are generated during various manufacturing steps. Generation of static charges result in the formation of carcinogenic nitrosamine impurity in the pharmaceutical preparations through the means of two phenomena: i). Electrostatic adsorption: The most important precursor for the formation of nitrosamines is the availability of nitrite ions. The static charge on the powder causes adsorption of the nitrite ions that are available in the air used in these processes on the powder particles. ii). Generation of nitrite ions due to electrostatic discharge : Production of nitric oxide is a well known phenomena occurring during lightning strike. The nitric oxide thus produced combines with atmospheric oxygen to form nitrogen dioxide and also the entire group of oxides of nitrogen, denoted as NOx. Similar high voltage arcs and sparks are frequently seen inside a fluid bed dryer or air jet mill, during operation, caused by the discharge of the accumulated static charge on the powder particles.

[0023] Pharmaceutical ingredients having a nitrogen containing functional group undergo nitrosation in presence of nitrite ions to form nitrosamine. Removal of static charges by passing air that is ionized i.e. containing positive and negative ions during pharmaceutical manufacturing cause dissociation of adsorbed nitrite ions from the surface of the powder particles. Ionized air also prevents the accumulation of static charges on the surface of the powder particles, and thus avoids the subsequent electrostatic discharge, thereby reducing the frequency of occurrence of high voltage arcs and sparks.

[0024] Various embodiments of the invention provide a method for reduction of nitrosamine during synthesis of a pharmaceutical preparation through use of ionized air. The method includes obtaining an ionized air through an ionizer arrangement, exposing a mixture of pharmaceutical ingredients to the ionized air during atleast one step of synthesis and additionally repeating the step of exposure at least one more time. The exposure of the pharmaceutical ingredients to the ionized air reduces nitrosamine content of the pharmaceutical preparation. The most common source of nitrosamine contamination in a pharmaceutical preparation is through contaminated pharmaceutical ingredient. The pharmaceutical ingredient includes but is not limited to active pharmaceutical ingredient, non-active pharmaceutical ingredient, excipients, preservatives and dyes. Apart from pharmaceutical ingredient, the contamination also happen through nitrosamine contaminated solvents and water. Suitable measures are taken to prevent the contamination at these levels by strictly monitoring the quality of pharmaceutical ingredients, solvents and water used for synthesis of pharmaceutical preparation. The pharmaceutical ingredient selected should be free of nitrosamine or should be below the threshold value. In one embodiment of the invention, the pharmaceutical ingredients that are free of nitrosamine impurities are selected. A mixture of selected pharmaceutical ingredients is exposed to ionized air. The ionized air is obtained through an ionizer arrangement. The ionizer arrangement has atleast one ionizer arranged on an air supply line. For obtaining ionized air from the ionizer arrangement, atleast one ionizer is arranged radially or linearly or curvilinearly or perpendicularly on the air supply line. The ionizer emits positive charged ions and negative charged ions into the air supply line. The air supply line provides hot air or pneumatic air to the atleast one synthesis step and include but is not limited to the drying of the mixture of pharmaceutical ingredients, milling of the mixture of pharmaceutical ingredients and pelletizing of mixture of pharmaceutical ingredients. In one embodiment of the invention, for obtaining the ionized air, an ionizer is arranged perpendicularly to air supply line of the air jet miller. In another embodiment of the invention, a plurality of bar ionizer are arranged radially on an inner surface of the air supply line of the fluid bed dryer.

[0025] The pharmaceutical preparation is then passed through various steps of synthesis for obtaining a pharmaceutical preparation. The steps of synthesis include but are not limited to milling of pharmaceutical ingredients or alternatively granulation of pharmaceutical ingredients, blending of pharmaceutical ingredients, drying of pharmaceutical ingredients, pelletizing and packaging of pharmaceutical ingredients.

[0026] In one embodiment of the invention, milling of the mixture of the pharmaceutical ingredients is achieved by air jet milling. Air jet milling is a process wherein the size of a pharmaceutical ingredient is reduced to micrometer. For milling, the powder particles of pharmaceutical ingredients are fed in a milling chamber; compressed air is fed into the milling chamber thro ugh special nozzles and is accelerated strongly to entrain the powder particles. In the process, the powder particles repeatedly collide with each other and with the walls of the milling chamber and are thus reduced in size. Static charges are developed on the powder particles due to colliding of the particles with each other and with the walls of the milling chamber. The static charge on the powder particles of the pharmaceutical ingredients causes the adsorption of available nitrite ions (from the air used in these processes) on the powder particles. The pharmaceutical ingredient having N containing functional group undergoes nitrosation reaction in presence of the nitrite ions and form nitrosamine or NDSRI. The pharmaceutical ingredient having N containing functional group include but are not limited to amines, amides, azides, carbamates, amidine, amine oxides, azo, diazo carbodiimides, enamines, hydrazines, hydrazones, imides, imines and nitrates. Further, the nitrite ions are also formed during the high voltage arc or spark observed in the milling chamber of the air jet mill. The high voltage arcs and sparks occur due to the discharge of the build-up static charges. During these electrostatic discharges, the normally inert nitrogen gas becomes reactive with oxygen to form nitrite ions (denoted as NO2-) and oxides of nitrogen (denoted as NOx), these nitrite ions are the most important precursor for formation of nitrosamine.

[0027] The static charges that are developed during the air jet milling are neutralized by exposing the mixture of pharmaceutical ingredients to the ionized air. In one embodiment of the invention, the ionized air is obtained by passing positive charged ions and negative charged ions into an air supply line that is connected to the milling chamber. The positive charged ions and negative charged ions are provided to the air supply line by means of an AC ion emitter or a DC ion emitter or other such ion emitters known in the art. In one embodiment of the invention, an AC ion emitter is used. In one embodiment of the invention, the AC ion emitter is attached to the air supply line through an ionizer arrangement 100 such that the positive ions and the negative ions emitted by the ion emitter combine with the air being supplied to the milling chamber of the air jet mill (Fig .1 ). In one embodiment of the invention, the ionizer arrangement 100 includes a horizontal tubular element 101 and a vertical tubular element 103; the vertical tubular element 103 is substantially perpendicularto the horizontal tubular element 101 and joins the horizontal tubular element 101 to form a T. The AC ion emitter (not shown) is held inside the vertical tubular element 103 and on supply of voltage, emits positive charged ions and negative charged ions into the horizontal tubular element 101 . In one embodiment of the invention, the ionizer arrangement 100 is connected to an air supply line 105 that supplies ionized air to the milling chamber 107 of the air jet mill through a material feed line(Fig. 1 ). In another embodiment of the invention, the ionizer arrangement 100 is additionally connected to a grind air supply line 109 and to a collection bin 1 1 1 of the air jet mill (Fig.1 a). Exposing the pharmaceutical ingredients in the milling chamber to the ionized air neutralizes the static charges generated during the synthesis of the pharmaceutical preparation. Neutralization of static charges enables dissociation of nitrite ions adsorbed on the surface of the particles of pharmaceutical preparations and also prevents the discharge of accumulated static charges as high voltage arc discharge. The prevention of high voltage arc discharge inhibits the formation of nitrite ions required for the nitrosation reaction leading to formation of nitrosamines.

[0028] In one embodiment of the invention, milling of the pharmaceutical ingredients is followed by drying of the mixture of the pharmaceutical ingredients. In one embodiment of the invention, drying of the mixture of the pharmaceutical ingredients is achieved by fluid bed drying. Fluid bed drying is a process by which powder particles are fluidized and dried. In a fluidization process, hot air is introduced at high pressure through a perforated bed of moist powder particles. The wet powder particles are lifted from the bottom and suspended in a stream of air (fluidized state). As the hot air passes between the powder particles, it takes the excess moisture from the powder particles thus drying them. Heat transfer is accomplished by direct contact between the wet powder particles and hot gases. Static charge is generated in a fluid bed dryer due to rubbing of the powder particles with each other and with the walls of the dryer. The static charge on the powder particles of the pharmaceutical ingredients causes the adsorption of available nitrite ions (from the air used in these processes) on the powder particles. The pharmaceutical ingredient having N containing functional group undergoes nitrosation reaction in presence of the nitrite ions and form nitrosamine or NDSRI. The pharmaceutical ingredient having N containing functional group include but are not limited to amines, amides, azides, carbamates, amidine, amine oxides, azo, diazo carbodiimides, enamines, hydrazines, hydrazones, imides, imines and nitrates. Further, the nitrite ions are also formed during the high voltage arc or spark observed in the dryer. The high voltage arcs and sparks occur due to the discharge of the build-up static charges. During these electrostatic discharges, the normally inert nitrogen gas becomes reactive with oxygen to form nitrite ions (denoted as NO2-) and oxides of nitrogen (denoted as NOx), these nitrite ions are the most important precursor for formation of nitrosamine. The static charges that are developed during the fluid bed drying are neutralized by exposing the mixture of pharmaceutical ingredients to the ionized air. In one embodiment of the invention, the ionized air is obtained by passing positive charged ions and negative charged ions into an air supply line that is connected to the fluid bed dryer. The hot air can be ionized by using bar ionizers, rod ionizers, nozzle ionizers, duct ionizers or other such ionizers emitting bipolar ions. In one embodiment of the invention, an ionizer arrangement is used for ionizing the air in the air supply line. In one embodiment of the invention, the ionizer arrangement 201 includes a hollow cylinder having an inner surface 203 with slotted projections formed radially at equal intervals along the axis of the hollow cylinder and an outer surface 205 having a bar ionizer 207 mounted on each of the slotted projections (Fig 2). The bar ionizers 207 emit positive charged ions and negative charged ions into the hollow cylinder. The ionizer arrangement 201 is attached to the air supply line 209 of the fluid bed dryer 211 such that the bipolar ions emitted by the bar ionizers are carried by the air to the fluid bed dryer for neutralizing the static charges generated during drying. Exposing the pharmaceutical ingredients in the drying chamber to the ionized air neutralizes the static charges generated during the synthesis of the pharmaceutical preparation. Neutralization of static charges enables dissociation of nitrite ions adsorbed on the surface of the particles of pharmaceutical preparations and also prevents the discharge of accumulated static charges as high voltage arc discharge. The prevention of high voltage arc discharge inhibits the formation of nitrite ions required for the nitrosation reaction leading to formation of nitrosamines.

[0029] Subsequent to the exposure of the pharmaceutical ingredients to the ionized air at various synthesis steps, the pharmaceutical ingredients are analyzed for the nitrosamine / NDSRI content. In one example of the invention, about 40 active pharmaceutical ingredients (API) are analyzed for the NDSRI content after exposing the API’s to the ionized air. The NDSRI content of the API’s without exposure to the ionized air and after exposing to the ionized air is shown in table 1 .

[0030] Table 1 . NDSRI content of the active pharmaceutical ingredients before and after exposure to the ionized air

[0031]

[0032] The values are observations taken from independent batches

[0033] A significant decrease in the nitrosamine content in all the API’s is observed when the API’s are exposed to the ionized air at atleast one synthesis step as compared to the API’s that are not exposed to the ionized air. Exposing of the pharmaceutical ingredient to ionized air reduced the nitrosamine content of the API’s belowthe maximum permissible limit of the API.

[0034] The invention thus provides a method for reducing nitrosamine content of pharmaceutical preparations by exposing the mixture of pharmaceutical ingredients to ionized air at various synthesis steps. Exposure of the pharmaceutical ingredients to the ionized air reduces the nitrosamine content of the pharmaceutical preparation to levels significantly below the maximum permissible limit of nitrosamine in a particular pharmaceutical preparation.

[0035] The foregoing description of the invention has been set merely to illustrate the invention and is not intended to be limiting. Since modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occurto person skilled in the art, the invention should be construed to include everything within the scope of the appended claims and equivalents thereof.

Claims

We Claim:1 . A method for reduction of nitrosamine during synthesis of a pharmaceutical preparation, the method comprising: obtaining an ionized air through an ionizer arrangement; exposing a mixture of pharmaceutical ingredients to the ionized air during atleast one step of synthesis; and additionally repeating the step of exposure at least one more time wherein the exposure reduces the nitrosamine content of the pharmaceutical preparation.

2. The method as claimed in claim 1 , wherein one of the pharmaceutical ingredients in the mixture has a nitrogen containing functional group.

3. The method as claimed in claim 1 , wherein nitrogen containing functional group is selected from a group comprising of amines, amides, azides, carbamates, amidine, amine oxides, azo, diazo carbodiimides, enamines, hydrazines, hydrazones, imides, imines and nitrates.

4. The method as claimed in claim 1 , wherein the reduction in nitrosamine content is upto a limit lower than the maximum permissible limit of nitrosamine in a particular pharmaceutical preparation.

5. The method as claimed in claim 1 , wherein the pharmaceutical ingredient include active pharmaceuticalingredient, non-active pharmaceutical ingredient, excipients, dyes, preservatives, flavouring agents, solvents and water.

6. The method as claimed in claim 1 , wherein the pharmaceutical ingredient selected is free of nitrosamine impurity.

7. The method as claimed in claim 1 , wherein the ionized air is the air containing positive charged ions and negative charged ions.

8. The method as claimed in claim 1 , wherein the ionizer arrangement have atleast one ionizer arranged radially or linearly or curvilinearly or perpendicularly on an air supply line for discharging positive charged ions and negative charged ions into the air supply line, wherein the ionizer is selected from a group comprising of a bar air ionizer, a single pin AC ion emitter, a multi-pin ion emitter, a duct type ionizer, an air tube output type ionizer and a fan output type ionizer.

9. The method as claimed in claim 1 , wherein the ionized air containing the positive charged ions and the negative charged ions neutralize the static charges generated during the synthesis of pharmaceutical preparation.

10. The method as claimed in claim 1 , wherein the neutralization of static charges enables dissociation of nitrite ions adsorbed on the surface of the particles of pharmaceutical preparations.1 1 . The method as claimed in claim 1 , wherein the neutralization of static charges prevent the discharge of accumulated static charges as high voltage arc discharge wherein prevention of high voltage arc discharge inhibits the formation of nitrite ions required for the nitrosation reaction leading to formation of nitrosamines.

12. The method as claimed in claim 1 , wherein atleast one step of synthesis include passing the mixture of pharmaceutical ingredients to fluid bed drying and / or air jet milling and / or sifting and / or pelletizing.

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