An adsorption composition for reduction of nitrosamine impurities in pharmaceutical products
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- JAIN MANISH
- Filing Date
- 2026-01-23
- Publication Date
- 2026-08-06
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Abstract
Description
[0001] AN ADSORPTION COMPOSITION FOR REDUCTION OF NITROSAMINE IMPURITIES IN PHARMACEUTICAE PRODUCTS FIELD OF THE INVENTION:
[0002] The present invention relates to an adsorption composition for reduction of nitrosamine impurities, and more particularly to an adsorption composition for reduction of nitrosamines, such as NDMA (N-Nitrosodimethylamine) and NDEA (N-Nitrosodiethylamine), along with moisture control in pharmaceutical products.
[0003] BACKGROUND OF THE INVENTION:
[0004] Pharmaceutical products are often found to contain undesirable impurities, including nitrosamine impurities. These nitrosamines are generated in drug products through various routes, including synthesis, storage, or transportation. These compounds typically arise when secondary or tertiary amines react with nitrous acid under acidic or oxidative conditions. Additionally, raw materials, excipients, additives, or packaging components may contribute to nitrosamine contamination. The presence of N-nitroso compounds, especially N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-Nitrosodipropylamine (NDPA), and others, has raised global safety concerns due to their genotoxic and mutagenic effects, with even trace amounts posing significant risks for DNA damage and cancer.
[0005] Moreover, the nitrosamine impurity crisis has indeed caused significant disruptions in the pharmaceutical industry. Regulatory authorities, such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), responded with recalls of widely used medications, including valsartan (July 2018),irbesartan (October 2018), losartan (November 2018), ranitidine (2019), nizatidine (2020), and later metformin. These recalls, aimed at protecting public health, have led to shortages of essential drugs, particularly those used to treat chronic conditions such as hypertension, diabetes, and gastrointestinal disorders disrupting the treatment for millions of patients and complicating clinical trials and drug development timelines.
[0006] In response, regulatory bodies have set specific acceptable daily intake limits for various nitrosamine impurities, such as 96 ng / day for NMDA and 26.5 ng / day for a range of other nitrosamines, to control and mitigate the risks associated with these impurities. By establishing these limits, regulators aim to ensure patient safety while minimising disruptions to the supply chain. However, for many patients, particularly those with chronic conditions who rely on medications like metformin or ranitidine, there remains a pressing need for the effective detection, prevention, and removal of nitrosamine impurities from affected drugs to ensure the continued availability of safe and effective medications.
[0007] To mitigate nitrosamine risk, API and formulation manufacturers are advised to assess nitrosamine risk and develop reformulation strategies to prevent impurity formation. This includes API manufacturers, who are required to adopt a meticulous approach when selecting catalysts, reagents, and solvents for the multi-step synthesis process. During multi-step API synthesis, incorporating additional purification steps leads to the elimination of nitrosamine formation. Factors like pH, moisture content, particle size distribution, material characteristics, storage conditions, and elastomeric components are also to be considered. Manufacturersare also required to monitor storage conditions and select excipients cautiously, considering the nitrite levels. Furthermore, to mitigate nitrosamine impurities, reformulation strategies must be designed, including the inclusion of antioxidants like ascorbic acid and a-tocopherol and the use of alkaline excipients such as sodium carbonate. However, these approaches often necessitate the exclusion of amine- or ammonium-containing reagents and solvents, resulting in more complex, time-consuming, and expensive routes.
[0008] Furthermore, these existing strategies primarily focus on controlling or preventing nitrosamine formation during manufacturing by limiting nitrite levels, adding antioxidants, and modifying synthetic pathways. However, these preventive measures neither address the removal or reduction of nitrosamine impurities once formed nor provide practical post-production remediation options. Additionally, current strategies for managing nitrosamine impurities often lack industrial reproducibility and operational simplicity, relying on loose adsorbents, powders, or desiccant sachets that causes dust generation, handling difficulties, non-uniform exposure, and inconsistent performance.
[0009] The Chinese Patent Application CN113117084A to Tang Chunlei et al. discloses a pharmaceutical preparation that uses a precursor substance that breaks down into N-nitrosamine genotoxic components during the manufacturing and storage of active pharmaceutical ingredients or preparations. To prevent or reduce the formation of N-nitrosamine genotoxic substances, a suitable antioxidant is included.The PCT Application WO2024069649A1 to Vaibhavi Shah and others discloses a pharmaceutical composition that contains an amine and at least one excipient in a medicinal ingredient, with a nitrite content of no more than 2 ppm and a nitrosamine impurity content of no more than 18.5 ppm.
[0010] The above-discussed references clearly indicate that the existing art teaches control of nitrosamine impurities at the stage of manufacturing pharmaceutical compositions. However, these approaches address prevention rather than removal of nitrosamines once formed and often lack industrial reproducibility or broad applicability across drug formulations.
[0011] Thus, there is a need for a chemical composition capable of efficiently reducing nitrosamine impurities in pharmaceutical products, including those formed during manufacturing, storage, or transport. There is a further need for a robust, integrated solid-state system that minimizes dust generation and handling difficulties, concurrently reduces nitrosamine impurities and controls moisture across a broad range of pharmaceutical products and active pharmaceutical ingredients (APIs).
[0012] SUMMARY OF THE INVENTION:
[0013] The present invention discloses an adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products includes at least one porous adsorbent material that adsorbs nitrosamine impurities and / or nitrosamine precursors, at least onemoisture-regulator material that controls local humidity and suppresses nitrosamine formation, and a binding agent that forms a matrix that imparts structural integrity and forms a solid-state article. Further, the adsorption composition reduces nitrosamine impurities formed during manufacturing, storage, or transport of pharmaceutical products without physical contact with the pharmaceutical product.
[0014] In the present invention, the porous adsorbent material is activated carbon, the moisture-regulator material is silica gel, and the pharmaceutically acceptable binding agent is selected from polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), starch derivatives, or combinations thereof, wherein the activated carbon is in an amount of 50 to 70% w / w, silica gel is in an amount of 20 to 40% w / w, and a pharmaceutically acceptable binding agent is in an amount of 5 to 10% w / w.
[0015] Additionally, the adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products is in the form of a solid-state articles such as a tablet, pellet, or similar solid dosage form. The solid-state article possesses a hardness in the range of 50 to 100 N and a friability of less than 0.5%, thereby minimizing dust formation during handling and transport. Moreover, the present invention composition reduces nitrosamine impurities by at least 50% under accelerated stability conditions and by up to 80% or 90% under optimal conditions and adsorbs nitrosamine impurities and / or their precursors, particularly N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA), that are formed during manufacturing, storage, and transport of pharmaceutical products.Further, the adsorption composition for reducing nitrosamine impurities is co-packaged with a pharmaceutical product within primary, secondary, or tertiary packaging and is positioned inside the package without physical contact with the pharmaceutical product.
[0016] In another embodiment of the present invention, a process of preparing a tablet for an adsorption composition is described. The process includes a first phase for the preparation of an activated carbon powder mixture and a second phase for the final preparation and packaging of activated carbon tablets.
[0017] The first phase of preparation of activated carbon powder mixture includes the following steps: a first step of grinding activated carbon granules, a second step of sieving the ground activated carbon, a third step of mixing the sieved activated carbon with silica gel and a binding agent, and a fourth step of drying the resulting mixture. In the first step, 35 kg of activated carbon granules are ground into a powder using a pulveriser. In the second step, the powder obtained from the first step is sieved through an 18-mesh size to obtain uniformly sized activated carbon particles. In the third step, the activated carbon powder obtained from the second step is mixed with 60 kg of silica gel powder in a twin-screw blender with the gradual addition of 5 kg of polyvinyl alcohol dissolved in 10 litres of water for at least 30 minutes. In the fourth step, the resulting mixture obtained from the third step is dried at 110 °C for 2 hours.
[0018] The second phase of activated carbon tablet preparation includes the following steps: a first step of tablet compression, a second step of drying the compressed tablets, and a third step of packaging the dried tablets. In the first step,the dried powder obtained from the first phase is compressed into tablets of the desired size and shape using a tablet press machine. In the second step, the tablets of required dimensions obtained from the first step are dried at 120 °C for 3 hours. In the third step, the final dried tablets obtained from the second step are packaged in aluminium bags for further use.
[0019] DETAILED DESCRIPTION OF THE INVENTION:
[0020] References in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, characteristic, or function described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment.
[0021] References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.
[0022] The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously, many modifications and variations are possible in light of the above teaching.
[0023] The present invention relates to a solid-state chemical composition for the reduction of nitrosamine impurities and, more specifically, to the reduction ofnitrosamines, such as NDMA (N-Nitrosodimethylamine) and NDEA (N-Nitrosodiethylamine), formed in pharmaceutical products during manufacturing, storage, and transport. Nitrosamines, such as NDMA and NDEA, are classified as potent carcinogens and are frequently detected as impurities in pharmaceutical products.
[0024] The adsorption composition includes activated carbon as an adsorbent, silica gel as a moisture regulator, and polyvinyl alcohol (PVA) as a binder, in a precisely optimized ratio to form a solid dosage form such as tablets and the like, to provide dual functionality of nitrosamine adsorption and moisture control, two critical and interrelated factors influencing nitrosamine formation and stability. The high surface area of activated carbon (500-1500 m2 / g) allows it to adsorb harmful impurities like nitrosamines, while the moisture-absorbing properties of silica gel regulate the local humidity, thereby suppressing nitrosation reactions and enhancing the adsorption efficiency. PVA acts as a binder to ensure mechanical strength, low friability, and structural uniformity.
[0025] Together with increased shelf life, this combination helps reduce nitrosamine contamination and improves the stability of pharmaceutical drug products over time. The adsorption composition is suitable for use as a co-packaged tablet or as a standalone nitrosamine adsorbent, providing an integrated, user-friendly, and robust solid-state system that enhances drug product stability, minimizes impurity formation, and extends the shelf life through a defined, reproducible, and dust-free manufacturing process.In general aspect of the present invention, an adsorption composition is provided in the form of a solid-state tablet comprising activated carbon in an amount of about 50-70% w / w, silica gel in an amount of about 20-40% w / w, and a binding agent comprising polyvinyl alcohol (PVA) in an amount of about 5-10% w / w, prepared in accordance with process (100) as described herein. The tablet is subjected to a dual-stage drying process at temperatures of about 110 °C and 120 °C to activate adsorption surfaces and impart mechanical stability, and is copackaged with a pharmaceutical product within primary, secondary, or tertiary packaging without physical contact with the pharmaceutical product, thereby enabling vapour-phase adsorption of nitrosamine impurities while simultaneously controlling moisture during storage.
[0026] Now, a preferred adsorption composition for the reduction of the nitrosamine impurities formed in pharmaceutical products in accordance with the present invention is described.
[0027] In accordance with the present invention, the adsorption composition for reduction of nitrosamine impurities and moisture control in pharmaceutical products includes the following ingredients:
[0028] 1. at least one porous adsorbent material 50 - 70 w / w %, 2. at least one moisture-regulating material 20 - 40 w / w %, and 3. a binding agent 5 - 10 w / w %.
[0029] In accordance with this preferred embodiment, the porous adsorbent material includes activated carbon to adsorb nitrosamine impurities such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). Themoisture-regulating material includes silica gel. The binding agent is selected from polyvinyl alcohol (PVA) or the like, that forms a binding matrix that imparts structural integrity and facilitates the formation of a solid-state article, such as a tablet, pellet, or other similar solid dosage forms.
[0030] In an alternate embodiment, the binding agent is selected from hydroxypropyl methylcellulose (HPMC) or starch derivatives or the like. It is to be noted that the binding agent is selected depending on the disintegration profile, compatibility with drugs, and regulatory preferences, ensuring that the binder used does not significantly mask the surface area of activated carbon or silica gel. In accordance with another embodiment, a process (100) of preparing an activated carbon tablet with varying proportions of silica gel containing a binder (herein after referred to as “process 100”) is described. The process (100) of preparing an activated carbon tablet includes a first phase (101) of activated carbon powder mixture preparation and a second phase (201) of activated carbon tablet preparation. The first phase (101) of activated carbon powder mixture preparation includes a set of steps carried out for the preparation of activated carbon powder mixture. The second phase (201) of activated carbon tablet preparation includes a set of steps carried out for the final preparation and packaging of the activated carbon tablets.
[0031] The first phase (101) of activated carbon powder mixture preparation includes the set of steps carried out for the preparation of activated carbon powder mixture. A first step (110) includes grinding of activated carbon granules; a second step (120) includes sieving of the ground activated carbon; a third step (130) includes mixing the sieved activated carbon with silica gel and a binding agent; anda fourth step (140) includes drying of the resulting activated carbon powder mixture.
[0032] In accordance with process (100) of the present invention, the first phase (101) of activated carbon powder mixture preparation includes the following steps:
[0033] a. a first step (110) of grinding activated carbon granules; b. a second step (120) of sieving the ground activated carbon;
[0034] c. a third step (130) of mixing the sieved activated carbon with silica gel and a binding agent; and
[0035] d. a fourth step (140) of drying the resulting mixture.
[0036] The first step (110) of grinding activated carbon granules includes grinding a predefined quantity of activated carbon granules into a powder by using a pulveriser.
[0037] The second step (120) of sieving the ground activated carbon includes sieving the resulting powder prepared in the first step (110) through a predefined mesh size to obtain uniformly sized activated carbon particles.
[0038] The third step (130) of mixing the sieved activated carbon with silica gel and a binding agent includes mixing of activated carbon powder prepared in the second step (120) with the required predefined quantity of silica gel powder thoroughly in a twin-screw blender with the gradual addition of the required predefined quantity of PVA solution for a predefined time.
[0039] The fourth step (140) of drying the resulting mixture includes drying the mixture prepared in the third step (130) in a hot air oven at a predefined temperature for a predefined time.In accordance with the present invention, in the first step (110) the predefined quantity of activated carbon granules is 35 kg. In the second step (120), the predefined mesh size is 18. In the third step (130), the predefined quantity of silica gel is 60 kg, the predefined quantity of PVA is 5kg in 10 litres of water, and the predefined time is at least 30 minutes. In the fourth step (140), the predefined temperature is 110°C and the predefined time is 2 hours.
[0040] The second phase (201) of activated carbon tablet preparation includes the set of steps carried out for the final preparation and packaging of activated carbon tablets. A first step (210) includes tablet compression; a second step (220) includes drying the compressed tablets; and a third step (230) includes packaging the dried tablets.
[0041] In accordance with process (100) of the present invention, the second phase (201) of activated carbon tablet preparation includes the following steps:
[0042] a. a first step (210) of tablet compression;
[0043] b. a second step (220) of drying the compressed tablets; and c. a third step (230) of packaging the dried tablets.
[0044] The first step (210) of tablet compression includes compressing the dried powder obtained from the first phase (101) into tablets of desired size and shape using a tablet press machine.
[0045] The second step (220) of drying the compressed tablets includes drying of tablets of required dimensions obtained from the first step (210) at a predefined temperature for a predefined time.The third step (230) of packaging the dried tablets includes packaging of the final dried tablets obtained from the second step (220) into aluminium bags for further usage.
[0046] In accordance with the present invention, in the second step (220), the predefined temperature is 120°C and the predefined time is 3 hours.
[0047] The second step (220) of the drying process is critical for activating the adsorbents and stabilizing the tablet structure. The dual-stage drying carried out in the fourth step (140) of the first phase (101) at 110°C and in the second step (220) of the second phase (201) at 120°C effectively removes the residual moisture from the silica gel and the PVA binder without causing thermal degradation. This dualstage drying process restores porosity by generating a high-energy, dry surface on activated carbon and silica gel, maintains structural integrity by preventing pore collapse, and cures the PVA binder to form a strong, stable matrix that enhances tablet hardness and mechanical strength.
[0048] Additionally, the tablets obtained in the second step (220) have optimal mechanical properties having hardness of approximately 50 - 100 N to withstand handling and transport, and very low friability that is <0.5% to minimize dust formation, and structural stability throughout the drug’s shelf life and ensures the tablets remain intact and physically stable, preventing contact with pharmaceutical products while maintaining a high surface area for vapor-phase adsorption.
[0049] Further, for reducing NDMA and NDEA impurities in pharmaceutical formulations, this activated carbon tablet-containing silica gel is co-packaged with drug products or used as a standalone nitrosamine adsorbent.In accordance with this one embodiment, the tablet is co-packaged with a pharmaceutical product within a primary, secondary, or tertiary packaging and positioned within the packaging without physical contact with the pharmaceutical product, thereby providing an integrated, user-friendly, and robust solid-state system that enhances drug product stability, minimizes impurity formation, and extends shelf life through a defined, reproducible, and dust-free manufacturing process.
[0050] In one embodiment, the adsorption composition is spatially separated from the pharmaceutical product within the packaging such that the adsorption composition is positioned at a predefined distance from the pharmaceutical dosage form, without direct physical contact, thereby preventing any physical interaction while allowing effective impurity mitigation.
[0051] The reduction of nitrosamine impurities is achieved predominantly through vapour-phase adsorption, wherein volatile and semi-volatile nitrosamine molecules and / or their precursors migrate through the headspace of the packaging and are selectively adsorbed by the activated carbon surface.
[0052] EXAMPLES:
[0053] Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
[0054] Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing thedisclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.
[0055] Example 1: An experimental demonstration using activated carbon tablets for evaluation of the reduction of NDMA and NDEA.
[0056] Experimental Details:
[0057] 1. Materials and Methods
[0058] i. Activated Carbon Tablets Composition:
[0059] a. activated carbon: 50-70% (w / w),
[0060] b. silica gel: 20-40% (w / w), and
[0061] c. binder (e.g., PVA): 5-10% (w / w).
[0062] ii. Pharmaceutical Products Tested
[0063] a. Valsartan tablets
[0064] b. Metformin tablets
[0065] iii. Storage Conditions:
[0066] a. Temperature: 40 °C.
[0067] b. Relative Humidity (RH): 75%.
[0068] c. Duration: 3 months.iv. Experimental Setup:
[0069] a. Control Samples: Pharmaceutical products stored without activated carbon tablets.
[0070] b. Test Samples: Pharmaceutical products stored with activated carbon tablets containing varying silica gel proportions. Replicates: All experiments were conducted in triplicate to ensure statistical reliability.
[0071] v. Evaluation Parameters:
[0072] a. NDMA and NDEA Levels: Monitored at intervals of 0, 1, 2, and 3 months.
[0073] b. Drug Potency: Measured using HPLC to assess active pharmaceutical ingredient (API) stability.
[0074] c. Water Activity: Analyzed using a water activity meter to evaluate silica gel Aw (water activity).
[0075] vi. Instrumentation:
[0076] a. Gas Chromatography- Mass Spectrometry (GC-MS) for NDMA / NDEA detection.
[0077] b. Liquid Chromatography- Mass Spectrometry (LC-MS) for validation.c. Water activity meter to monitor silica gel’s water activity values.
[0078] vii. Instrumentation Validation:
[0079] a. GC-MS provided precise quantification of NDMA and
[0080] 5 NDEA with a detection limit of 1 ng / g.
[0081] b. LC-MS validation confirmed GC-MS results with a
[0082] correlation coefficient of 0.98.
[0083] viii. Results:
[0084] Table 1 below shows the NDMA and NDEA reduction using activated
[0085] 10 carbon tablets as per the experimental study:
[0086]
[0087] Table 1: NDMA and NDEA reduction using activated carbon tablets
[0088] Table 2 below shows the shelf-life improvement as per the experimental study:
[0089] <
[0090]
[0091] Table 2: Study demonstrating shelf-life improvement
[0092] Table 3 below shows the moisture content analysis of silica gel:
[0093]
[0094] Table 3: Moisture content analysis of silica gelTable 4 below shows the time-dependent data of comparative reduction studies for the control and test samples showing reduction of NDMA and NDEA impurities under accelerated storage conditions (40°C / 75% RH).
[0095]
[0096] ix. Observation:Employing silica gel-containing activated carbon tablets is a novel and efficient method of reducing nitrosamine levels and improving the shelf life of pharmaceutical products. The experimental findings confirm the effectiveness of the same, as the results shown below:
[0097] a. Effective reduction of nitrosamines: Table 1 indicates a significant reduction in NDMA and NDEA levels up to 96.9% in the S3 formulation containing activated carbon (AC) and 40% silica gel (SG). The observed reduction exceeds that expected from a simple additive contribution between the two components, indicating a synergistic interaction between AC and SG. In this synergistic system, SG suppresses the formation of new nitrosamines, while AC effectively adsorbs both pre-existing and newly generated nitrosamine molecules.
[0098] Further, Table 1 demonstrates a kinetic study, showing a time-dependent reduction in nitrosamine levels. For sample S3, NDMA concentrations decreased from 96 ng / g to 12 ng / g after one month and further to 3 ng / g after three months. This indicates rapid initial adsorption, followed by a sustained suppression effect, thereby effectively controlling nitrosamine impurities throughout the accelerated storage period.Furthermore, a clear correlation between higher SG content and improved performance was observed in Table 1, with SI (20% SG) showing an 87.5% reduction, compared to S3 (40% SG), which achieved a 96.9% reduction. This suggested that the AC-SG combination was more effective than AC alone, particularly under high-humidity conditions, where SG contributes to maintaining adsorption efficiency and preventing further nitrosamine formation.
[0099] b. Improved shelf life: Table 2 indicates drug potency was preserved even under high-temperature and high-humidity conditions, with minimal or zero degradation with enhanced stability.
[0100] c. Moisture absorption capacity of silica gel: Table 3 indicates maximum absorption capacity of silica gel was observed with 40% w / w.
[0101] d. Comparative Reduction Studies data: Table 4 indicates the comparative reduction studies data for NDMA and NDEA impurities under accelerated stability conditions (40°C / 75% RH).
[0102] Table 4 compares:
[0103] (i) Control samples, consisting of pharmaceutical products stored without the present invention composition, and(ii) Test samples, consisting of the same products stored with the present invention’s compositions.
[0104] The results show that the control samples exhibited a progressive increase in nitrosamine levels, consistent with the continued in situ formation of these impurities under stressed storage conditions. In contrast, the test samples containing the present composition demonstrated a marked and time-dependent reduction in both NDMA and NDEA levels. These findings indicate that the composition of the present invention provides a sustained reduction of key nitrosamine impurities, confirming its effectiveness in mitigating nitrosamine formation during accelerated stability studies.
[0105] x. Findings:
[0106] Now the findings of the above experiment are discussed. The optimized composition of the activated carbon tablet, comprising 50-70% Activated Carbon (AC), 20-40% Silica Gel (SG), and 5- 10% Polyvinyl Alcohol (PVA), shows a deliberate balance between adsorption efficiency and mechanical stability. Activated carbon serves as the primary adsorbent, and its large surface area effectively captures NDMA and NDEA impurities, ensuring sufficientadsorption capacity without compromising tablet cohesion. This reduces nitrosamine concentrations in the surrounding environment.
[0107] Silica gel acts as a moisture absorber, disrupting the chemical pathways responsible for nitrosamine formation. By establishing a low-humidity microenvironment, silica gel suppresses nitrosamine generation and enhances activated carbon performance by preventing pore blockage. The resulting combination synergistically improves adsorption capacity, and this optimized ratio ensures superior nitrosamine reduction performance while maintaining the physical robustness necessary for co-packaging with pharmaceutical products
[0108] xi. Inference:
[0109] 1. Samples with higher silica gel content (40%) exhibited greater reductions in NDMA and NDEA levels.
[0110] 2. The combination of activated carbon and silica gel maintained drug potency and prevented nitrosamine formation even under accelerated storage conditions.
[0111] Advantageously, the adsorption composition of the present invention significantly enhances the adsorption of harmful impurities and leads to a reduction of nitrosamine impurities such as NDMA and NDEA, thereby ensuring enhanced drug stability, safety, and overall product quality throughout storage. The silica gelcontaining activated carbon tablets provide a novel, workable, cost-effective and scalable solution to reduce nitrosamine impurities and improve the shelf life ofpharmaceuticals. Experimental results validate the efficacy of this formulation, providing a strong scientific foundation for regulatory compliance in accordance with FDA and EMA nitrosamine impurity guidelines, thus facilitating industry adoption.
[0112] Furthermore, the tablet form provides several quantitative and qualitative advantages over conventional powder sachets, including superior handling, reduced contamination risk, controlled sorption kinetics, and minimal drug-excipient interaction. In addition, while composed of low-cost materials such as silica gel and activated carbon, the tablet configuration simplifies the packaging, enhances line efficiency, and reduces overall operational costs, including the risk of expensive product recalls related to nitrosamine contamination. Collectively, these advantages establish the present invention as a highly effective, economical, and industrially viable solution for ensuring long-term pharmaceutical quality and compliance.
[0113] The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art, to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
[0114] It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the scope of the present invention.
Claims
Claims:
1. An adsorption composition for reducing nitrosamino impurities and controlling moisture in pharmaceutical products, comprising:a. at least one porous adsorbent material adsorbing nitrosamino impurities and / or nitrosamino precursors;b. at least one moisture-regulating material controlling local humidity and suppressing nitrosamino formation; andc. a binding agent forming a matrix that imparts structural integrity and forms a solid-state article,wherein the adsorption composition reducing nitrosamino impurities formed during manufacturing, storage, or transport of pharmaceutical products without physical contact with the pharmaceutical product.
2. The adsorption composition for reducing nitrosamino impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the porous adsorbent material including activated carbon.
3. The adsorption composition for reducing nitrosamino impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the moisture-regulating material including silica gel.
4. The adsorption composition for reducing nitrosamino impurities and controlling moisture in pharmaceutical products as claimed in claim 1,wherein the pharmaceutically acceptable binding agent being selected from polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), starch derivatives, or combinations thereof.
5. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the composition including activated carbon in an amount of 50 to 70% w / w; silica gel in an amount of 20 to 40% w / w; and a pharmaceutically acceptable binding agent in an amount of 5 to 10% w / w.
6. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the solid-state article in the form of a tablet, pellet, or other similar solid dosage form.
7. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products as claimed in claim 1, the solid-state article has a hardness in the range of 50 to 100 N, and a friability of less than 0.5%, thereby minimising dust formation during handling and transport.
8. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the composition reducing nitrosamine impurities by at least 50% under accelerated stability conditions.
9. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the composition reducing nitrosamine impurities by at least 80% under accelerated stability conditions.
10. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the composition reducing nitrosamine impurities by at least 90% under accelerated stability conditions.
11. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the said composition adsorbing nitrosamine impurities and / or their precursors, particularly N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA), in pharmaceutical products formed during manufacturing, storage, and transport.
12. The adsorption composition for reducing nitrosamine impurities and controlling moisture in pharmaceutical products as claimed in claim 1, wherein the composition being co-packaged with a pharmaceutical product within primary, secondary, or tertiary packaging and being positioned within the packaging without physical contact with the pharmaceutical product.
13. A process (100) of preparing a tablet for adsorption composition as claimed in claim 6, wherein the process (100) including a first phase (101) for the preparation of an activated carbon powder mixture and a second phase (201) for the final preparation and packaging of activated carbon tablets.
14. The process (100) of preparing a tablet for adsorption composition as claimed in claim 13, wherein the first phase (101) of preparation of activated carbon powder mixture including the following steps:a. a first step (110) of grinding activated carbon granules;b. a second step (120) of sieving the ground activated carbon;c. a third step (130) of mixing the sieved activated carbon with silica gel and a binding agent; andd. a fourth step (140) of drying the resulting mixture.
15. The process (100) of preparing a tablet for adsorption composition as claimed in claim 14, wherein in the first step (110) including grinding 35 kgof activated carbon granules into a powder using a pulveriser; the second step (120) including sieving the powder obtained from the first step (110) through an 18-mesh size to obtain uniformly sized activated carbon particles; the third step (130) including mixing the activated carbon powder obtained from the second step (120) with 60 kg of silica gel powder in a twin-screw blender with gradual addition of 5 kg of polyvinyl alcohol dissolved in 10 litres of water for at least 30 minutes; and the fourth step (140) including drying the resulting mixture obtained from the third step (130) at 110 °C for 2 hours.
16. The process (100) of preparing a tablet for adsorption composition as claimed in claim 13, wherein the second phase (201) of activated carbon tablet preparation including the following steps:a. a first step (210) of tablet compression;b. a second step (220) of drying the compressed tablets; and c. a third step (230) of packaging the dried tablets.
17. The process (100) of preparing a tablet for adsorption composition as claimed in claim 16, wherein in the first step (210), the dried powder obtained from the first phase (101) being compressed into tablets of desired size and shape using a tablet press machine; in the second step (220), tablets of required dimensions obtained from the first step (210) being dried at 120°C for 3 hours; and in the third step (230) the final dried tablets obtainedfrom the second step (220) being packaged into aluminium bags for further usage.