Method for removal of nitrosamine contaminants from pharmaceutical ingredients

Abstract

Disclosed is a method for removal of contaminating nitrosamine compounds from pharmaceutical ingredients. More specifically, this method may be used to remove both small-molecular weight nitrosamines and nitrosamine drug substance-related impurities (NDSRIs) from pharmaceutical ingredients. In an embodiment, the contaminated pharmaceutical ingredient is suspended or dispersed into an appropriate solvent and treated with a defined wavelength and intensity of light for a period of time, followed by recovery of the pharmaceutical ingredient by solvent exchange precipitation, or other method. The method is efficient and cost-effective and applicable to the entire drug synthesis process, from raw ingredients to final active pharmaceutical ingredient, or excipients used in drug product formulations. It provides a standardized approach for combatting the risk of carcinogenic nitrosamine contaminant drugs. In another embodiment a process is disclosed that provides for a streamlined method to tune the reaction conditions of the method to minimize or eliminate any degradation of the pharmaceutical product during nitrosamine removal.

Description

[0001] METHOD FOR REMOVAL OF NITROSAMINE CONTAMINANTS FROM PHARMACEUTICAL INGREDIENTS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claimed priority to U.S. Provisional Patent Application No. 63 / 692,945, filed September 10, 2024, which is hereby incorporated by reference in its entirety.

[0004] FIELD OF INVENTION

[0005] The present disclosure relates to pharmaceutical manufacturing processes, and more particularly to methods using photochemical degradation with defined wavelength light sources for the removal of nitrosamine contaminants from materials used in or generated during the synthesis, formulation or storage of intermediates and active pharmaceutical ingredients.

[0006] BACKGROUND

[0007] Nitrosamines are organic compounds characterized by the chemical structure RIR2N-N=O, where Ri and R2 are typically alkyl or aryl groups. These compounds have been extensively documented in various environmental matrices including water, soil, and numerous consumable products such as cured meats, fish, beer, and tobacco products. Laboratory' studies in animals have demonstrated that nitrosamines exhibit hepatotoxic properties and carcinogenic potential.

[0008] The presence of nitrosamines in pharmaceutical products has emerged as a matter of regulatory concern worldwide. In June 2018, N-nitrosodimethylamine (NDMA) was detected in valsartan, a medication used to treat high blood pressure and heart failure. Subsequently, NDMA and other small dialkyl N-nitrosamine impurities were discovered in additional sartan active pharmaceutical ingredients, as well as in ranitidine, pioglitazone, and metformin. These discoveries led to comprehensive assessments of active pharmaceutical ingredients, drug products, and packaging materials to evaluate the extent and context of nitrosamine contamination risks.

[0009] Nitrosamine drug substance-related impurities (NDSRIs) represent a particular class of nitrosamine contaminants that share structural similarity with the drug substance itself. The formation of NDSRIs can occur when the drug substance contains secondary' amine functionality and manufacturing conditions favor nitrosamine formation. Unlike classical nitrosamines, NDSRIs are structurally diverse, API-dependent impurities formed through complex interactions between nitrites, other reactive species, and amine-containing compounds. Regulatory agencies have developed frameworks for risk assessment of these compounds and established acceptable intake limits.

[0010] Current approaches to address nitrosamine contamination in pharmaceutical manufacturing typically involve modifying synthetic routes to exclude nitrosable compounds and nitrosating agents that can react to form nitrosamines. This approach often requires the exclusion of certain starting materials and solvents, potentially resulting in more complex and expensive synthetic pathways. Additionally, this strategy does not address the use of raw materials that may already contain unacceptable levels of nitrosamines.

[0011] Small molecule nitrosamines and Nitrosamine Drug Substance-Related Impurities (NDSRIs) remain a critical challenge in pharmaceutical development and manufacturing.

[0012] Various methods have been disclosed for reducing nitrosamine levels in pharmaceutical ingredients, including the addition of antioxidants, reducing agents, or radical scavengers, as well as basification, heat treatment, and crystallization techniques. Methods for reducing nitrosamine formation through stabilizing formulations have also been reported.

[0013] Analytical methods for the detection and quantification of nitrosamines in multiple solvent systems have been developed and are widely used, primarily employing liquid chromatography-tandem mass spectrometry (LC-MS / MS) techniques. Multi-analyte methods capable of detecting up to twelve different nitrosamines have been established.

[0014] Water treatment technologies have been developed for nitrosamine removal, including photolysis using ultraviolet radiation in the wavelength range of 200 to 260 nanometers, which breaks the N-N bond of NDMA. However, these methods developed for water treatment applications are not suitable for pharmaceutical ingredient purification due to the potential for degradation of the pharmaceutical compounds themselves and other practical limitations associated with pharmaceutical manufacturing processes.

[0015] SUMMARY

[0016] The summary of this invention, pertaining to these potentially carcinogenic contaminants is provided to introduce concepts that are further described below in the detailed description. The summary is not intended to identify key or essential features of the claimed subject matter, or to be used to aid in limiting the scope of the claimed subject matter.

[0017] In the first aspect, the present disclosure pertains to a method for photochemically removing a contaminating nitrosamine from a pharmaceutical ingredient. It utilizes light at a defined wavelength and intensity to degrade the nitrosamine. In some embodiments, the reaction is performed, without limitation, in solvent in a batch process or in a photochemically flow apparatus under various temperatures or is performed in solid form of the contaminated material. The method may be used to remove small-molecular weight nitrosamines or nitrosamine drug substance-related impurities (NDSRIs) from raw ingredients, intermediates, solvents, active pharmaceutical ingredients or other ingredients found in the drug manufacturing process.

[0018] In some embodiments, the solvent is comprised of a pure substance, or is a mixture of miscible or immiscible solvents, where the pH or ionic composition is adjusted.

[0019] In the second aspect, a spiked-in process is disclosed for tuning the reaction conditions of the photocatalysis in order to define the key parameters for nitrosamine degradation, and for minimizing any degradation of the pharmaceutical ingredient. The process can be done at milliliter scale, wherein the pharmaceutical ingredient is spiked with the nitrosamine contaminant of interest and tested in an iterative series of assays using the photocatalysis method.

[0020] In the third aspect, the treatment of materials using the processes disclosed herein is followed by recrystallizing of the materials, but with lower nitrosamine or NDSRI contamination levels.

[0021] According to an aspect of the present disclosure, a method of removing or reducing to a safe acceptable level a nitrosamine from a pharmaceutical ingredient is provided. The method comprises dissolving or dispersing the pharmaceutical ingredient in a solvent contained in an optically transmissible vessel, and irradiating with a light source of a defined wavelength and intensity for an amount of time sufficient to degrade the nitrosamine with little to no degradation of the pharmaceutical ingredient.

[0022] According to other aspects of the present disclosure, the method may include one or more of the following features. The nitrosamine may be a small molecular weight nitrosamine. The nitrosamine may be N-nitroso-dimethylamine (NDMA), N-nitroso-diethylamine (NDEA), N- nitroso-methylphenylamine (NMPA), N-nitroso-diisopropylamine (NDIPA), N-nitroso- isopropylethylamine (NIPEA), N-nitroso-dibutylamine (NDBA), N-nitroso-N-methyl-4- aminobutyric acid (NMBA), N-nitroso-dipropylamine (NDPA), N-nitroso-morpholine (NMOR), N-methyl-N-nitroso-phenethylamine (NMPEA), N-nitroso-1,2,3,6- tetrahydropyridine (NTHP), N-nitroso-piperidine (NPIP), 4-(methylnitrosamino)-l-(3- pyridyl)-l-(butanone) (NNK), N-nitroso-di ethanolamine (NDELA), N-nitroso-diphenylamine (NDPh), N-nitroso-piperazine, N-nitroso-pyrrolidine (NPYR). l-methyl-4-nitrosopiperazine (MNP), N-nitroso-meglumine, N-nitroso-N-ethyl-benzylamine (NBEA), or 3- ((ethyl(nitroso)amino)methyl)benzenesulfonate. The nitrosamine may be N-nitroso- dimethylamine (NDMA), N-nitroso-diethylamine (NDEA), N-nitroso-diethanolamine (NDELA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-dibutylamine (NDBA), N-nitroso-methylphenylamine (NMPA), N-nitroso-diisopropylamine (NDIPA), or N-Nitroso-ethylisopropylamine (NEIPA). The nitrosamine may be an NDSRI. The NDSRI may be N-nitroso-bumetanide, N-nitroso-duloxetine, N-nitroso-enalapril, N-nitroso- varenicline, N-nitroso-ciprofloxacin, N-nitroso-sitagliptin, N-nitroso-ramipril, N-nitroso- fluoxetine. N-nitroso-valsartan, or N-nitroso-propranolol. The pharmaceutical ingredient may be an active pharmaceutical ingredient, reaction intermediate, raw material or an excipient. The pharmaceutical ingredient may be any pharmaceutical ingredient stable to UV irradiation under conditions wherein the nitrosamine is reduced below acceptable levels. The pharmaceutical ingredient may be any active pharmaceutical ingredient sufficiently stable to UV irradiation under conditions wherein the nitrosamine is reduced below acceptable levels. The active pharmaceutical ingredient may be valsartan, famotidine, losartan, metformin, nizatidine, ranitidine, irbesartan, azithromycin, rifampicin, bumetanide, duloxetine, enalapril, varenicline, ciprofloxacin, sitagliptin, ramipril, fluoxetine valsartan, or propranolol.

[0023] According to another aspect of the present disclosure, a method for avoiding nitrosamine contamination in a pharmaceutical material is provided. The method comprises treating the pharmaceutical material using the method of removing a nitrosamine from a pharmaceutical ingredient as described above.

[0024] According to other aspects of the present disclosure, the method for avoiding nitrosamine contamination may further comprise recrystallizing the pharmaceutical material after treatment.

[0025] According to another aspect of the present disclosure, a method for determining optimal differential degradation conditions for a nitrosamine and a pharmaceutical ingredient using a spiked-in approach procedure is provided. The spiked-in approach procedure comprises generating multiple samples, each sample having a volume of 1 mL to 5 mL and including the pharmaceutical ingredient and a spike of the nitrosamine, each sample having a different solvent composition, different pH, different ionic strength, and / or being exposed to a different wavelength of radiation, reaction time, or temperature. The method further comprises measuring pharmaceutical ingredient loss and nitrosamine loss in each sample after exposure to its corresponding wavelength of radiation, reaction time, and temperature.

[0026] According to other aspects of the present disclosure, the spiked-in method for determining optimal differential degradation conditions may include one or more of the following features. Multifactorial analysis may be performed in a set test system, varying defined wavelength, a panel of solvent, pH, time and temperature. A concentration of the nitrosamine may be in a range of 1 ppm - 200 ppm. A concentration of the pharmaceutical ingredient may be in a range of 0.1 mg / mL - 100 mg / mL.

[0027] According to another aspect of the present disclosure, a system for removing nitrosamines from pharmaceutical ingredients is provided. The system comprises a container containing a composition of matter, the composition of matter comprising a pharmaceutical ingredient dissolved or dispersed in a solvent, an optically transmissible fluid module operably coupled to the container, a pump configured to cause the composition of matter to flow through the optically transmissible fluid module, and a radiation source configured to direct radiation having a defined wavelength and intensity towards the optically transmissible fluid module, the defined wavelength and intensity configured to preferentially degrade a nitrosamine with little to no degradation of the pharmaceutical ingredient.

[0028] According to other aspects of the present disclosure, the system may further comprise one or more processing units configured to control operation of the system. The system may further comprise an analytical device configured to determine a concentration of the pharmaceutical ingredient and / or a nitrosamine within the composition of matter while the composition of matter is within the optically transmissible vessel.

[0029] The foregoing general description of the illustrative embodiments and the following detailed description thereof are merely exemplary aspects of the teachings of this disclosure and are not restrictive.

[0030] BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 is a plot and data table showing NDMA Removal from NDMA-spiked Valsartan by Photocatalysis with UVC Light. Reactions performed at room temperature with UVC light in 95% ethanol for up to 2 hours with quantification by AUC peak analysis.

[0032] Figures 2A and 2B are plots showing NDMA Removal from NDMA-spiked Valsartan in 95% versus 100% Ethanol with UVA light, including Expanded TIC Chromatogram in the 0.1 - 4.8 min NDMA Region (Figure 2A) and Expanded TIC Chromatogram in the 6.0-8.4 min Valsartan Region (Figure 2B).

[0033] Figures 3 A and 3B are plots showing NDMA Removal from NDMA-spiked Valsartan in 95% Ethanol with UVA light at various pH. 3A: Full TIC Chromatogram. 3B: Expanded TIC Chromatogram in the 5.8-8.5 min Valsartan (Upper) and 1.6-5.4 min NDMA Region (Lower).

[0034] Figures 4A and 4B are plots showing NDMA Removal from NDMA-spiked Valsartan in 95% Ethanol with UVV light. 4 A: Full TIC Chromatogram. 4B: Expanded TIC Chromatogram in the 1.6-5.4 min NDMA Region (Upper) and 4.7-9. 1 min Region (Lower).

[0035] Figures 5 A and 5B are plots showing N-nitroso Bumetanide Degradation by Photocatalysis with UVV light. 5 A: Full TIC Chromatogram. 5B: Mass Ion Extraction of the Bumetanide (7.012 min) and N-Nitroso Bumetanide (6.909 min) Peaks.

[0036] Figure 6 is a flowchart relating to a Spike-In Approach to Tune Photocatalysis Reaction for Optimal Differential Degradation, showing the process for preparing a nitrosamine spiked-in pharmaceutical ingredient and determining key parameters of the reaction.

[0037] Figures 7A and 7B are plots showing Bench-Scale Photo Flow-Catalysis of NDMA-Spiked Valsartan with Recovery' by Solvent Exchange Crystallization. Reaction performed at 100 mg / ml valsartan spiked with 150 ppm NDMA in 95% Ethanol with UVA light for 6 hours. 7 A: NDMA LCMS Baseline Region After Photo Flow-Catalysis. 7B: Valsartan LCMS Baseline Region After Photo Flow-Catalysis.

[0038] Figures 8A and 8B are plots showing removal of N-nitroso sitagliptin (NTTP) from a Sitagliptin Phosphate Monohydrate sample. 8A: TIC Chromatogram. 8B: extracted ion counts for NTTP.

[0039] Figure 9 is a plot showing removal of N-nitroso sitagliptin (NTTP) from a Sitagliptin Phosphate Monohydrate sample, and specifically, extracted ion counts for NTTP.

[0040] Figures 10A and 10B are plots showing removal of N-nitroso sitagliptin (NTTP) from a Sitagliptin Phosphate Monohydrate sample. 10A: resulting ion count before precipitation. 10B: extracted ion counts for NTTP.

[0041] DETAILED DESCRIPTION

[0042] Nitrosamines are formed when amines react with nitrosating agents - such as nitrites - typically under acidic conditions. They are widely present in the environment - including air, water, soil, food, and pharmaceuticals. Regulatory concern escalated in 2018 when N- nitrosodimethylamine (NDMA) was detected in various medicines, leading to widespread recalls. Until that time, nitrosamines had not been given much attention - indeed, the FDA released its first guidance document on "‘Control of Nitrosamine Impurities in Human Drugs” in September of 2020. The FDA later released its first guidance document on “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)” in August of 2023.

[0043] As used herein, "nitrosamine" or “small-molecular weight nitrosamine” means an organic compound with the chemical structure RIR2N-N=O, where R1R2 are usually an alkyl or an aryl group or in the case of NDSRI’s a key fragment of the API or the API itself. They feature a nitroso group bonded to a deprotonated amine. These include, but are not limited to 7 compounds identified by the FDA in its 2021 Guidance on Control of Nitrosamine Impurities in Human Drugs, which could potentially be present in drug products: N-nitroso-A-nitroso- dimethylamine (NDMA); N-nitroso-diethylamine (NDEA); N-nitroso-methylphenylamine (NMPA); N-nitroso-diisopropylamine (NDIPA); N-nitroso-isopropylethylamine (NIPEA); N- nitroso-dibutylamine (NDBA); and N-nitroso-N-methyl-4-aminobutyric acid (NMBA).

[0044] This was updated in 2024 by Health Canada’s list of established Acceptable Intake (Al) limits for N-nitrosamine impurities to include: N-nitroso-dipropylamine (NDPA); N-nitroso- morpholine (NMOR); N-methyl-N-nitroso-phenethylamine (NMPEA); N-nitroso- 1,2, 3, 6- tetrahydropyridine (NTHP); N-nitroso-piperidine (NPIP); 4-(methylnitrosamino)-l-(3- pyridyl)-l-(butanone) (NNK); N-nitroso-di ethanolamine (NDELA); N-nitroso-diphenylamine (NDPh); N-nitroso-piperazine; N-nitroso-pyrrolidine (NPYR); 1 -methyl-4-nitrosopiperazine (MNP); N-nitroso-meglumine; N-nitroso-N-ethyl-benzylamine (NBEA); and 3- ((ethyl(nitroso)amino)methyl)benzenesulfonate.

[0045] As used herein. "NDSRI" means a nitrosamine that is a nitrosamine drug substance-related impurity, a class of organic impurities that share structural similarity to the drug substance (having the drug substance or a fragment of the drug substance in the chemical structure). The origin of NDSRI impurities has been ascribed to nitrite impurities present in common excipients at parts-per-million (ppm) levels. Nitrite impurities have been seen in a variety of commonly utilized excipients as well as pharmacopeial-grade water. Lists of NDSRIs and their recommended Acceptable Intake (Al) limits are referenced in regulatory guidances from multiple agencies, are extensive, and non-inclusive. For example, NDSRIs include, e.g., N- Nitroso-Bumetanide (NBMTE); Varenicline NDSRI (NVRLE); N-Nitrosodesipramine (NDSPI); N-Nitrosoatenolol (NNATL); N-nitroso fluoxetine (NFLX); N-nitroso ciprofloxacin (COX-NDSRI); and N-nitroso hydrochlorothiazide (NO-HCTZ).

[0046] As used herein, "pharmaceutical ingredient" means a substance used in the synthesis, purification, formulation or packaging of drug products, and may include raw materials, intermediates, solvents, active pharmaceutical ingredients, excipients, or other substance used in and to the production of the drug product.

[0047] As used herein, “contaminated pharmaceutical ingredient” means a pharmaceutical ingredient containing a nitrosamine or NDSRI, or both.

[0048] As used herein, "solvent" means any substance, usually a liquid, capable of dissolving or dispersing one or more other substances. Polar solvents (e.g. water) favor formation of ions; nonpolar ones (e.g. hydrocarbons) do not. Solvents may be predominantly acidic, predominantly basic, amphoteric (both), or aprotic (neither). Organic compounds used as solvents include, but are not limited to aromatic compounds and other hydrocarbons, alcohols, esters, ethers, ketones, amines, and nitrated and halogenated hydrocarbons.

[0049] As used herein, "light source" means a device whose primary function is to produce visible or near-visible radiant energy for illumination, and may include incandescent sources, luminescent sources, gas discharge sources and light-emitting diodes.

[0050] As used herein, “defined wavelength” means light within a defined range of wavelengths, described by the intensity of light at wavelengths throughout the spectrum range.

[0051] As used herein, "pharmaceutical ingredient" means a substance used in the synthesis, purification, formulation or packaging of drug products, and may include raw materials, intermediates, solvents, active pharmaceutical ingredients, excipients, or other substance used in and to the production of the drug product.

[0052] As used herein, treatments resulting in “little to no degradation” of an API generally refer to treatments where the amount of the API recovered after the treatment is at least 50%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, still more preferably at least 90%, most preferably at least 95% of the amount of the API originally submitted to the treatment. In some instances, the recovery may be at least 96%, at least 97%, at least 98%, or at least 99%.

[0053] As used herein, "optimal differential degradation" means conditions under which degradation of a nitrosamine under specific reaction conditions are optimized for nitrosamine degradation under conditions that minimize degradation of the desired pharmaceutical ingredient(s).

[0054] As used herein, a “photochemical flow apparatus” means a device used in chemical reactions where light initiates or facilitates the reaction in an apparatus that passes the reaction mixture at a defined, controlled rate past a radiant source in a linear or circular path.

[0055] As used herein the term “small molecular weight nitrosamine” (sometimes referred to as “small molecule nitrosamine”) generally refers to nitrosamines having molecular weights between about 70 g / mol to about 500 g / mol, preferably about 70 g / mol to about 400 g / mol, more preferably about 70 g / mol to about 300 g / mol. and most preferably about 74 g / mol to about 250 g / mol.

[0056] As used herein, the “spiked-in approach” to testing and optimizing reaction conditions involves adding a nitrosamine in parts per million to a pharmaceutical ingredient at a defined concentration relative to the pharmaceutical ingredient and measuring the amount of each substituent and any resulting degradants before and during the course of the reaction, using an analytical method capable of detecting the substituents at least down to 1% or less of their starting concentration. The concentrations may vary as desired - in some preferred implementations, the concentrations may be 10-fold or higher concentrations of the pharmaceutical ingredient. In other implementations, the concentrations may be, e.g., 0.01 x - 10 x the concentration of the pharmaceutical ingredient. For example, a low concentration spike may be used to model the presence of a low level of contaminant, which may be influenced by the concentration of the API.

[0057] In June 2018, a potentially carcinogenic nitrosamine impurity. N-nitrosodimethylamine (NDMA), was detected in valsartan, a medication used to treat high blood pressure and heart failure. Soon after, NDMA and further small dialkyl A'-nitrosamine impurities were discovered in other sartan active pharmaceutical ingredients (APIs), and later in stomach acid regulator ranitidine, and diabetes medicines piaglitazone and metformin. Since then, comprehensive assessments have been carried out on APIs, drug products and packaging to understand and evaluate the context and extent of the risk of nitrosamine formation.

[0058] It was discovered subsequently that the drugs themselves could pose a risk if the drug itself is a secondary amine, when chemistry conditions exist during manufacturing to form a nitrosamine derivative of the drug, or NDSRI.

[0059] In September 2019 the FDA in collaboration with regulatory' counterparts around the world issued guidances for acceptable intake limits for nitrosamines based on a risk-assessment of nitrosamines present in approved and marketed drug products, as well as products under review. If drugs contain levels of nitrosamines above the acceptable daily intake limits, FDA recommends these drugs be recalled by the manufacturer as appropriate.

[0060] Overall, a risk has been identified for 17% of chemical drug products. Upon testing, 15% of those (around 2.5% of total products assessed) have, so far, been identified as containing nitrosamines above the corresponding limits.

[0061] In July72023, the EMA and FDA updated their guidance on nitrosamine impurities to include the Carcinogenic Potency Categorization Approach (CPCA) for assigning intake limits in cases where there isn't sufficient mutagenicity data to make a determination of risk. Based on CPCA, the majority of API-derived nitrosamines fall into CPCA potency category 5 and needs to be controlled to a limit of 1500 ng / day, but still recognized as a mutagenic impurity7.

[0062] Nitrosamines are common in air, water, soil and foods, including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of nitrosamines. Nitrosamine impurities may increase the risk of cancer if people are exposed to them above acceptable levels and over long periods of time, but a person taking a drug that contains nitrosamines at-or-below the acceptable daily intake limits even' day for 70 years is not expected to have an increased risk of cancer. Consumers taking over-the-counter medications with potential nitrosamine impurities are also subject to carcinogenic risk.

[0063] When released to soil, NDMA can be highly mobile and will leach into groundwater. In 1998, NDMA was found in a drinking water well in northern California, and subsequently elsewhere, and was also found to be a by-product of certain drinking water treatment processes (e.g.. chloramination, chlorination, ozonation). NDMA contamination of drinking water with NDMA has been of particular concern due to the minute concentrations at which it is harmful, the difficulty in detecting it at these concentrations, and to the difficulty in removing it from drinking water. It does not readily biodegrade, adsorb, or volatilize, and as such, it cannot be removed by activated carbon and travels easily through soils. Membrane filtration is not effective at removing NDMA. Reverse osmosis has removal efficiencies between 25-50%, but is highly variable in practice.

[0064] A common method to treat NDMA in drinking water systems is photolysis by ultraviolet radiation in the wavelength range of 200 to 260 nanometers (nm). which breaks the N-N bond of NDMA, and such methods have been widely studied. Additionally, reverse osmosis removes approximately 50% of NDMA. More complex methods, such as biological treatment, activated sludge, and microfiltration have also been studied and used to remove NDMA or NDMA precursors from wastewater. It has also been observed that decomposition of NDMA in water can occur using nanoscale zero-valent iron in the presence of aluminum and iron salts.

[0065] None of the methods that have been studied or used to remove NDMA from drinking, ground water or wastewater are useful in the removal of NDMA or other bioamines from pharmaceutical ingredients. Irradiation would be an acceptable and scalable approach for nitrosamine removal from pharmaceutical ingredients. However, ultraviolet radiation in the 200-260 nanometer range also degrades most pharmaceutical ingredients, and there is little to no separation the amount of radiation needed in the degradation of the nitrosamine compared to the pharmaceutical ingredients. A fully aqueous solvent system also creates other limitations to a practical method for nitrosamine removal from pharmaceutical ingredients. Other water removal methods that have been investigated would adulterate or degrade the pharmaceutical ingredient, require extensive isolation and / or purification, expensive equipment, or not be scalable for manufacturing.

[0066] A number of approaches have been used in commercial setting to manage nitrosamine contamination, by inspection of ingredients lots for contaminants or trace chemicals that contribute to nitrosamine formation, by avoiding or altering synthetic steps, or by developing methods of storage or formulation to avoid nitrosamine production. Given the analytical work required to monitor these efforts, the various diverse and situational steps that need to be developed and managed through the manufacturing process, the potential for many different nitrosamines to be contaminants to occur, the cost, time and potential manufacturing delays and wastage that can occur, these approaches lack the facility needed in a production environment. A more standardized, predictable, reliable and cost-effective approach applicable in general, consistent manner for pharmaceutical manufacturing is needed.

[0067] The inventors have discovered that the nitroso bonds found in small molecular weight nitrosamines as well as in NDSRIs are more susceptible to certain bands of radiation (e.g., UV irradiation) than the chemical bonds found in a majority of active pharmaceutical ingredients. The inventors have also discovered that reaction conditions influence the differential degradation of the nitrosamine, and that the discrete bands of radiation (e.g., certain UV wavelengths) as well as solvent and other reaction conditions can be adjusted to achieve acceptable removal of the nitrosamine with minimal loss of active pharmaceutical ingredients, and with relatively few exceptions.

[0068] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0069] In a preferred embodiment, a standardized method has been invented that removes or reduces the amount of a nitrosamine in a pharmaceutical ingredient by treating the pharmaceutical ingredient containing the nitrosamine in a non-invasive way using radiant energy of a defined wavelength that provides optimal differential degradation of the nitrosamine.

[0070] In another aspect, the contaminated pharmaceutical ingredient is dissolved or dispersed in a suitable solvent for treatment or is treated as a solid.

[0071] In another aspect, the treatment is carried out in a batch mode in a vessel that will transmit the radiant energy through the vessel wall, or alternatively, the light source is contained within the vessel.

[0072] In another aspect, the radiant energy is derived from any light source that can produce the defined wavelength and intensity required for optimal differential degradation of the nitrosamine.

[0073] Surprisingly, it has been found that the solvent composition, pH, and wavelength of the radiant source, in combination with reaction time and temperature, work together in defining the reaction, and adjustment of each of these parameters to set reaction conditions that result in the optimal differential degradation of a particular pharmaceutical ingredient, and to direct the degradation of the nitrosamine down a desired pathway. In contrast, the photochemical reactions occurring are for the most part independent of the presence of the nitrosamine or pharmaceutical ingredient.

[0074] Nitrosamine contaminants that may be removed using the disclosed methods fall into two primary’ categories: small molecular weight nitrosamines and nitrosamine drug substance- related impurities (NDSRIs).

[0075] Small molecular weight nitrosamines are organic compounds with the chemical structure RIR2N-N=O, where Ri and R2 are usually alkyl or aryl groups. These compounds feature a nitroso group bonded to a deprotonated amine. Small molecular weight nitrosamines generally have molecular weights between about 70 g / mol to about 500 g / mol, in some cases about 70 g / mol to about 400 g / mol, in some cases about 70 g / mol to about 300 g / mol, and in some cases about 74 g / mol to about 250 g / mol.

[0076] Examples of small molecular weight nitrosamines include N-nitroso-dimethylamine (NDMA), N-nitroso-diethylamine (NDEA). N-nitroso-methylphenylamine (NMPA), N- nitroso-diisopropylamine (NDIPA), N-nitroso-isopropylethylamine (NIPEA), N-nitroso- dibutylamine (NDBA), and N-nitroso-N-methyl-4-ammobutyric acid (NMBA). Additional small molecular weight nitrosamines include N-nitroso-dipropylamine (NDPA), N-nitroso- morpholine (NMOR). N-methyl-N-nitroso-phenethylamine (NMPEA), N-nitroso-1,2,3,6- tetrahydropyridine (NTHP), N-nitroso-piperidine (NPIP), 4-(methylnitrosamino)-l-(3- pyridyl)-l -(butanone) (NNK), N-nitroso-diethanolamine (NDELA), N-nitroso-diphenylamine (NDPh), N-nitroso-piperazine, N-nitroso-pyrrolidine (NPYR), l-methyl-4-nitrosopiperazine (MNP), N-nitroso-meglumine, N-nitroso-N-ethyl-benzylamine (NBEA), and 3- ((ethyl(nitroso)amino)methyl)benzenesulfonate.

[0077] NDSRIs represent a class of organic impurities that share structural similarity to the drug substance, having the drug substance or a fragment of the drug substance in the chemical structure. The origin of NDSRI impurities has been ascribed to nitrite impurities present in common excipients at parts-per-million (ppm) levels. Nitrite impurities have been observed in a variety of commonly utilized excipients as well as pharmacopeial-grade water.

[0078] Examples of NDSRIs include N-nitroso-bumetanide, N-nitroso-duloxetine, N-nitroso- enalapril, N-nitroso-varenicline, N-nitroso-ciprofloxacin, N-nitroso-sitagliptin, N-nitroso- ramipril, N-nitroso-fluoxetine. N-nitroso-valsartan, and N-nitroso-propranolol. Each NDSRI contains the parent pharmaceutical compound or a structural fragment thereof combined with a nitroso functional group. Both small molecular weight nitrosamines and NDSRIs are of concern because they are potentially carcinogenic compounds. The presence of these nitrosamine contaminants in pharmaceuticals has led to substantial worldwide regulatory scrutiny because of their health risk. Regulatory agencies have established acceptable intake limits for various nitrosamines based on risk assessments, and pharmaceutical products containing levels of nitrosamines above these acceptable daily intake limits may be subject to recall.

[0079] The disclosed methods may be applied to a wide range of pharmaceutical ingredients used throughout the drug manufacturing process. Pharmaceutical ingredients encompass substances used in the synthesis, purification, formulation, or packaging of drug products. These pharmaceutical ingredients include active pharmaceutical ingredients, reaction intermediates, raw materials, and excipients.

[0080] Active pharmaceutical ingredients represent the biologically active components of pharmaceutical formulations that provide the therapeutic effect. The disclosed photochemical treatment methods have been demonstrated with various active pharmaceutical ingredients, including valsartan. famotidine, losartan, metformin, nizatidine, ranitidine, irbesartan, azithromycin, rifampicin, bumetanide, duloxetine, enalapril, varenicline, ciprofloxacin, sitagliptin, ramipril, fluoxetine, and propranolol. These active pharmaceutical ingredients span multiple therapeutic classes, including antihypertensive agents, antihistamines, antidiabetic medications, antibiotics, and antidepressants.

[0081] Reaction intermediates may also be treated using the disclosed methods. Reaction intermediates are chemical compounds formed during the synthetic pathway to produce the final active pharmaceutical ingredient. These intermediates may accumulate nitrosamine contaminants during synthesis and may benefit from nitrosamine removal before proceeding to subsequent synthetic steps.

[0082] Raw materials used in pharmaceutical manufacturing may be subjected to the disclosed treatment methods. Raw materials include starting materials, reagents, and solvents used in the synthesis of pharmaceutical compounds. These materials may contain nitrosamine contaminants from their manufacturing processes or storage conditions.

[0083] Excipients represent another category of pharmaceutical ingredients that may be treated. Excipients are inactive substances used as carriers or vehicles for active pharmaceutical ingredients in drug formulations. Common excipients include fillers, binders, disintegrants, lubricants, stability enhancing compounds and coating materials. Excipients may contain nitrite impurities at parts-per-million levels, which can contribute to nitrosamine formation.

[0084] The suitability of a pharmaceutical ingredient for treatment depends on the stability of the pharmaceutical ingredient to UV irradiation under conditions that achieve nitrosamine reduction below acceptable levels. Pharmaceutical ingredients that maintain structural integrity and chemical stability during the photochemical treatment process may be successfully treated. The differential degradation approach allows for selective nitrosamine removal while preserving the pharmaceutical ingredient.

[0085] In some cases, pharmaceutical ingredients demonstrate high stability to the treatment conditions. For example, valsartan shows greater than 98% recovery after UVA treatment, with minimal formation of degradation products. Similarly, active pharmaceutical ingredients such as irbesartan, enalapril, ramipril, and propranolol demonstrate high recovery rates exceeding 98% after photochemical treatment with UVV light.

[0086] In some cases, certain pharmaceutical ingredients may show reduced stability under certain treatment conditions. For example, rifampicin shows lower recovery rates with exposure to UVV, with approximately 18.73% recovery after 0.5 hours of treatment and further degradation over extended treatment periods. The stability profile of each pharmaceutical ingredient maybe evaluated using the spiked-in approach to determine appropriate treatment conditions.

[0087] The treatment conditions may be adjusted to accommodate different pharmaceutical ingredients. Solvent composition, pH, wavelength selection, treatment time, and temperature may be modified to achieve differential degradation that removes nitrosamine contaminants while maintaining pharmaceutical ingredient integrity. This flexibility allows the methods to be applied across diverse pharmaceutical ingredient classes with varying chemical structures and stability profiles.

[0088] SOLVENT SYSTEMS

[0089] The photochemical removal method may utilize various solvent compositions to dissolve or disperse the pharmaceutical ingredient containing nitrosamine contaminants. The solvent selection may influence the differential degradation rates between nitrosamines and pharmaceutical ingredients, allowing for selective removal of contaminants while preserving the pharmaceutical ingredient. A variety of solvents and mixtures of solvents may be used.

[0090] Polar solvents may be used in the method, including water and water-miscible organic solvents. Water-miscible solvents may include volatile alcohols such as C1-C4 alcohols. In some cases, methanol or ethanol may serve as the water-miscible solvent. Other w ater-miscible solvents may include acetone or tetrahydrofuran (THF). Nonpolar solvents may also be employed depending on the solubility characteristics of the pharmaceutical ingredient.

[0091] The solvent composition may include at least some water content. In some cases, the solvent composition may be a mixture of a water-miscible organic solvent and water. For example, the solvent composition may be 95% ethanol and 5% water. This ethanol-water mixture may provide enhanced differential degradation compared to pure ethanol systems. The water content may affect the formation of degradation products during the photochemical process.

[0092] The pH of the solvent system may be adjusted to optimize the differential degradation between nitrosamines and pharmaceutical ingredients. In some cases, the solvent pH may be less than 7. The pH may be less than 6 in certain applications. In some cases, the pH may be less than 4. In some cases, the pH may be no more than 3. The pH may be between 1 and 3 for enhanced selectivity. The pH adjustment may be accomplished using acids such as hydrochloric acid or bases such as ammonium hydroxide. Other organic acids and bases that can be used include, but are not limited to: hydroxycarboxylic acids, such as lactic acid, citric acid, malic acid, and tartaric acid; aromatic organic acids, such as benzoid acid, salicylic acid, and p-hydroxybenzoic acid; organofluorine compounds, such as trifluoroacetic acid (TFA); an organosulfuric compound, such as methanesulfonic acid; amines such as ammonia, methylamine, ethylamine, diethylamine (DEA), dimethylamine (DMA), triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, imidazole, tris(hydroxymethyl)aminomethane (Tris / THAM); quaternary ammonium hydroxides such as tetraethylammonium hydroxide (TEAOH), or tetrabutylammonium hydroxide (TBAOH); amidine bases, such as 1,8- Diazabicyclo[5.4.0]undec-7-ene, or l,5-Diazabicyclo[4.3.0]non-5-ene (DBN); or guanidine bases, such as Tetramethylguanidine (TMG).

[0093] Lower pH conditions may reduce the formation of pharmaceutical ingredient degradation products while maintaining effective nitrosamine removal. The acidic conditions may influence the photochemical reaction pathways, directing the degradation toward the nitrosamine contaminants rather than the pharmaceutical ingredient. The pH optimization may be determined through the spiked-in approach procedure for each specific pharmaceutical ingredient and nitrosamine combination.

[0094] The solvent system may be contained in an optically transmissible vessel that allows passage of the defined wavelength radiation. The vessel material may be selected to minimize absorption of the radiation wavelengths used in the photochemical process. Borosilicate glass may serve as the optically transmissible vessel material for many wavelength ranges.

[0095] LIGHT SOURCES AND WAVELENGTH PARAMETERS

[0096] The photochemical removal method may utilize light sources that emit radiation within defined wavelength ranges to achieve selective degradation of nitrosamines while preserving pharmaceutical ingredients. The wavelength selection may influence the differential degradation rates between nitrosamine contaminants and pharmaceutical ingredients.

[0097] The defined wavelength may include one or more wavelengths in the UVA wavelength range, spanning from 320 nm to 395 nm. UVA radiation may provide effective nitrosamine degradation while maintaining stability of many pharmaceutical ingredients. In some cases, the UVA wavelength range may be free of wavelengths in both the UVB wavelength range (280 nm to 320 nm) and UVC wavelength range (200 nm to 280 nm), which may cause more extensive degradation of pharmaceutical ingredients.

[0098] The defined wavelength may include a UVV wavelength range spanning from 395 nm to 455 nm. UVV radiation may provide enhanced selectivity for nitrosamine degradation compared to shorter wavelength UV radiation. In some cases, the UVV wavelength may have an emission peak within 395 nm to 415 nm. The UVV wavelength range may be free of wavelengths in the UVB and UVC ranges. In some cases, the UVV wavelength may be free of wavelengths in the UVA range to further enhance selectivity.

[0099] The visible light range may overlap with the UVV range in the 400 nm to 455 nm region. In some implementations, the defined wavelength may include one or more wavelengths in the visible light range, spanning roughly from 400 nm to 750 nm. Visible light wavelengths may provide gentle photochemical conditions that minimize pharmaceutical ingredient degradation while maintaining nitrosamine removal effectiveness.

[0100] The light source may be at least a 20W light source to provide adequate photon flux for the photochemical degradation process. In some cases, the light source may be a 20W to 70W light source. Higher wattage light sources may reduce the treatment time required for nitrosamine removal. The power specification may be selected based on the volume of material being treated and the desired reaction kinetics.

[0101] The light source intensity may be at least 100 pW / cm2to achieve effective nitrosamine degradation. In some cases, the light source intensity may be at least 10 mW / cm2The intensity may be at least 50 mW / cm2for enhanced reaction rates. In some cases, the intensity may be at least 100 mW / cm2. Higher intensities such as at least 500 mW / cm2may be used for rapid processing. The intensity may be at least 1 W / cm2or at least 5 W / cm2for high-throughput applications. The intensity may reach up to 10 W / cm2while maintaining selectivity for nitrosamine degradation.

[0102] The light source may include electrically controllable sources, such as incandescent sources, luminescent sources (e.g., black fluorescent tubes, compact fluorescent UVA lamps), gas discharge sources (e.g., mercury lamps, xenon arc lamps, metal halide lamps, etc.), or lightemitting diodes), as well as chemical light sources (such as chemiluminescent or photoluminescent dyes or gels that emit UVA when reacting), or phosphorescent light sources that absorb a first wavelength of light and emit a second wavelength of light (upconverting or downconverting phosphors that emit UVA). Light-emitting diodes may provide precise wavelength control and energy efficiency. Gas discharge sources may provide high intensity output for large-scale processing. The light source selection may be based on the specific wavelength requirements and intensity specifications for the pharmaceutical ingredient and nitrosamine combination being treated.

[0103] The wavelength selectivity may enable the nitroso bonds in nitrosamines to be more susceptible to photodegradation than the chemical bonds in pharmaceutical ingredients. Different wavelength ranges may provide varying degrees of selectivity, with longer wavelengths generally providing enhanced selectivity for nitrosamine degradation while preserving pharmaceutical ingredient integrity.

[0104] The photochemical removal method may be carried out using various reaction vessels and equipment configurations designed to facilitate effective light transmission and reaction control. The vessel and equipment selection may influence the efficiency of nitrosamine degradation and the preservation of pharmaceutical ingredients during treatment.

[0105] As will be understood, the scale of the disclosed process may vary based on need, and an appropriate flow-through reactor may be utilized. For example, the process may be utilized at a screening level, such as the spiked-in method, at lab scale, at pilot scale, and / or at manufacturing scale. Each scale may involve different inputs, volumes, and light intensities. For example, the fluid module volume at the screening level may be small (e g., 1 mL to 20 mL or higher), while the fluid module volume at the manufacturing scale may be several orders of magnitude larger (e g., 1 L to 20 L). Further, screening level may involve flow' rates of 1 mL / min - 10 mL / min. lab scale may involve flow rates of 10 mL / min to 200 mL / min. pilot scale may involve flow rates of 200 mL / min to 1000 mL / min, and manufacturing scale may involve How rates of 1000 mL / min to 10,000 mL / min.

[0106] As will be understood, as fluid module volume increases, the fluid module may sometimes increase the optical path length of the light being used to degrade the nitrosamines. With increasing optical path length, the light intensity must necessarily increase as well; therefore, larger volume reactors sometimes need to use a higher intensity light source than smaller volume reactors.

[0107] Regardless of the overall size / scale of the reactor, the underlying technique does not change, merely the specific dimensions or process settings, which can optimized quickly by one skilled in the art. Optically Transmissible Fluid Modules

[0108] The reaction vessels may be constructed from materials that allow transmission of the defined wavelength radiation while maintaining chemical compatibility with the solvent systems and pharmaceutical ingredients. Borosilicate glass may serve as the fluid module material due to its optical transmission properties across UV and visible wavelength ranges. The borosilicate glass construction may provide resistance to thermal stress and chemical attack from various solvent systems.

[0109] The fluid module wall thickness may be selected to balance optical transmission with structural integrity. Thinner walls may provide enhanced light transmission while thicker walls may offer greater mechanical strength for pressurized or high-temperature applications. The fluid module geometry may be configured to maximize the surface area exposed to radiation while maintaining uniform light distribution throughout the reaction mixture.

[0110] Quartz may serve as an alternative fluid module material for applications requiring enhanced UV transmission, particularly in the shorter wavelength ranges. Quartz vessels may provide superior optical clarity and chemical resistance compared to borosilicate glass. The quartz construction may enable transmission of wavelengths down to the UVC range while maintaining structural stability’.

[0111] Batch Reactor Configurations

[0112] Batch reactors may be configured with the light source positioned external to the reaction vessel, with radiation transmitted through the vessel wall. The external light source configuration may allow for easy maintenance and replacement of light sources without disrupting the reaction mixture. The vessel may be positioned at a defined distance from the light source to achieve the desired light intensity at the reaction mixture surface.

[0113] Alternative batch reactor configurations may position the light source within the reaction vessel using a protective housing or immersion well. The internal light source configuration may provide enhanced light utilization efficiency and more uniform radiation distribution throughout the reaction mixture. The protective housing may be constructed from the same optically transmissible materials as the reaction vessel.

[0114] The batch reactor volume may range from milliliter scale for laboratory testing to kilo-liter scale for production applications. Smaller volumes may provide more uniform light distribution while larger volumes may offer enhanced processing throughput. The vessel geometry may be cylindrical, spherical, or rectangular depending on the light source configuration and mixing requirements.

[0115] Flow Cell Systems The treatment may be carried out in a flow cell, in which the contaminated pharmaceutical ingredient may be passed through the path of radiant energy in a flow apparatus. The flow cell configuration may provide continuous processing capability and enhanced control over residence time and light exposure

[0116] The flow cell may be constructed as a tubular reactor with transparent walls that allow, e.g., radial light penetration. The tubular flow cell fluidic module may provide a defined optical path length for consistent light exposure across the flowing reaction mixture, with diameters and lengths that allow for milliliter or kilo-liter reaction volumes. The tube diameter may be selected to balance light penetration depth with flow characteristics, and pressure drop considerations.

[0117] Alternatively, the flow cell fluidic module may be configured as a flat-plate reactor with parallel transparent walls that allow light transmission perpendicular to the flow direction and may allow light transmission from both sides of the plate. The flat-plate configuration may provide uniform light distribution across the flow cross-section while maintaining a defined optical path length. The plate spacing may be adjusted to optimize light penetration and reaction kinetics. The flow cell apparatus configuration and radiant source can be arranged so that the fluidic module may have internal volumes below 5 milliliters for lab scale reactions, between 1 and 20 milliliters for process development scale, and larger volumes of 50 milliliters or above for pilot / production scale, with a capacity of 10,000 kilo-liters per year, or more.

[0118] The flow cell may incorporate a cuboidal cuvette design with defined optical path lengths. A 3.5 mL flow-through quartz cuboidal cuvette with a 10 mm optical path length may serve as the flow cell configuration. The cuboidal geometry may provide uniform light transmission and defined residence time characteristics.

[0119] Flow Apparatus Components

[0120] The flow apparatus may include pumping systems to circulate the reaction mixture through the flow cell. Peristaltic pumps may provide gentle fluid handling that minimizes degradation of sensitive pharmaceutical ingredients. The pump selection may be based on chemical compatibility with the solvent systems and the ability to maintain consistent flow rates.

[0121] The flow rate through the flow cell may be adjustable to control the residence time and extent of nitrosamine degradation. Flow rates may range from 0.5 mL / min to 3.5 mL / min for bench scale or lab scale systems and may flow in a linear direction in one-pass through the fluidic module, or may flow in a circular manner multiple times through the fluidic module depending on the reaction kinetics and desired conversion levels. Higher flow rates may reduce residence time while lower flow rates may increase the extent of reaction per pass. The flow apparatus may include a stirred reaction reservoir that supplies the reaction mixture to the flow cell. The reaction reservoir may be constructed from chemically compatible materials and may include temperature control capabilities. A glass media reaction bottle fitted with appropriate caps and connections may serve as the reaction reservoir.

[0122] Tubing connections between the reaction reservoir and flow cell may be constructed from chemically inert materials such as PTFE or silicone. The tubing selection may consider chemical compatibility, optical properties if light transmission is required, and mechanical flexibility for system assembly.

[0123] Light-Proof Chambers

[0124] The flow cell and light source may be contained within a light-proof chamber to prevent light leakage and enhance safety. The chamber interior surfaces may be coated with reflective materials such as aluminum to maximize light utilization efficiency. The reflective coating may redirect scattered light back toward the reaction mixture, increasing the effective light intensity.

[0125] The light-proof chamber may include access ports for tubing connections and monitoring equipment while maintaining light containment. Ventilation systems may be incorporated to remove heat generated by the light sources and maintain appropriate operating temperatures.

[0126] Temperature Control Systems

[0127] The reaction vessels and flow apparatus may include temperature control systems to maintain optimal reaction conditions. The temperature may be controlled across a large range of temperatures, such as between, e.g., -50°C to 110°C. In some implementations, the temperatures may be controlled to between 0°C and 40°C, with some applications maintaining temperatures between 5°C and 20°C. Cooling systems may be incorporated to remove heat generated by high-intensity light sources.

[0128] Heat exchangers may be integrated into flow systems to maintain consistent temperature throughout the reaction mixture. The heat exchanger design may consider the optical requirements if light transmission through the heat exchange surfaces is needed.

[0129] The photochemical removal method may utilize controlled process parameters to achieve selective degradation of nitrosamines while preserving pharmaceutical ingredients. The reaction conditions may be adjusted to optimize the differential degradation rates between nitrosamine contaminants and pharmaceutical ingredients.

[0130] Temperature Control

[0131] The temperature may be controlled during the photochemical treatment to influence the reaction kinetics and selectivity. The temperature of the sample being irradiated may be maintained between 0°C and 40°C to balance reaction efficiency with pharmaceutical ingredient stability. In some cases, the temperature may be maintained between 5°C and 20°C to minimize pharmaceutical ingredient degradation while maintaining effective nitrosamine removal.

[0132] Higher temperatures may increase the rate of the differential reaction between nitrosamines and pharmaceutical ingredients. The elevated temperatures may accelerate the photochemical degradation process, reducing the treatment time needed for nitrosamine removal. However, higher temperatures may also result in some pharmaceutical ingredient degradation, which may reduce the selectivity of the process.

[0133] Lower temperatures may provide enhanced selectivity by reducing the thermal contribution to pharmaceutical ingredient degradation while maintaining photochemical nitrosamine degradation. The reduced temperature conditions may extend the treatment time needed for complete nitrosamine removal but may preserve pharmaceutical ingredient integrity more effectively.

[0134] Temperature control systems may be integrated into both batch and flow reactor configurations. Cooling systems may remove heat generated by high-intensity light sources to maintain the desired temperature range. Heat exchangers may be incorporated into flow systems to provide consistent temperature control throughout the reaction mixture.

[0135] Reaction Time Parameters

[0136] The amount of time for irradiation may be adjusted based on the specific nitrosamine and pharmaceutical ingredient combination being treated. The treatment time may be sufficient to degrade the nitrosamine to acceptable levels while minimizing damage to the pharmaceutical ingredient. As will be understood, the reaction time may range from seconds to hours depending on various design factors such as the light intensity, wavelength, the fluidic chamber volume, other reaction considerations, and the concentration of the pharmaceutical ingredient and contaminants. As a simple example, a single pass-through system can have a relatively short reaction time, while a recirculating system may have a longer reaction time.

[0137] Shorter treatment times may be achieved using higher light intensities or more selective wavelengths that provide enhanced differential degradation rates. The reduced treatment time may minimize the exposure of pharmaceutical ingredients to potentially degrading conditions while achieving effective nitrosamine removal.

[0138] Longer treatment times may be used with lower light intensities or when treating pharmaceutical ingredients that are particularly sensitive to photodegradation. The extended treatment period may allow for complete nitrosamine removal while maintaining gentle conditions that preserve pharmaceutical ingredient integrity. The reaction time may be monitored through analytical methods that track both nitrosamine degradation and pharmaceutical ingredient stability. Sampling at defined time intervals or continuous monitoring may provide data on the reaction kinetics and allow for optimization of the treatment duration for each specific application.

[0139] Light Intensity and Exposure Parameters

[0140] The light intensity may influence both the reaction rate and the selectivity of nitrosamine degradation. Higher light intensities may accelerate the photochemical process, reducing the treatment time needed for nitrosamine removal. The increased photon flux may provide more efficient utilization of the photochemical reaction pathways that target nitrosamine bonds.

[0141] Lower light intensities may provide enhanced selectivity by reducing the likelihood of pharmaceutical ingredient photodegradation while maintaining effective nitrosamine removal. The reduced intensity conditions may extend the treatment time but may preserve pharmaceutical ingredient quality more effectively.

[0142] The light exposure may be controlled through the combination of intensity and treatment time to achieve the desired level of nitrosamine degradation. The total photon dose delivered to the reaction mixture may be adjusted by varying either parameter while maintaining the differential degradation selectivity.

[0143] Process Parameter Interactions

[0144] The reaction conditions may work together to define the photochemical process and optimize the differential degradation between nitrosamines and pharmaceutical ingredients. The wavelength selection may interact with temperature and reaction time to determine the overall selectivity and efficiency of the treatment.

[0145] Solvent composition may influence how temperature and light intensity affect the reaction kinetics. The pH of the solvent system may interact with wavelength selection to direct the photochemical reactions toward nitrosamine degradation rather than pharmaceutical ingredient degradation.

[0146] The combination of process parameters may be optimized for each specific pharmaceutical ingredient and nitrosamine combination through systematic testing. The parameter optimization may involve adjusting multiple variables simultaneously to achieve the desired balance between nitrosamine removal efficiency and pharmaceutical ingredient preservation.

[0147] Monitoring and Control Systems

[0148] Process monitoring systems may track the reaction conditions throughout the treatment period to maintain consistent performance. Temperature sensors may provide feedback for temperature control systems to maintain the desired thermal conditions. Light intensity meters may monitor the photon flux to ensure consistent exposure conditions.

[0149] Analytical sampling systems may provide real-time or periodic analysis of nitrosamine degradation and pharmaceutical ingredient stability. The analytical data may be used to adjust process parameters during treatment or to optimize conditions for subsequent batches.

[0150] Control systems may automatically adjust process parameters based on monitoring data to maintain optimal reaction conditions. The automated control may provide consistent treatment results and reduce the variability associated with manual process control.

[0151] The photochemical removal method may utilize a spiked-in approach procedure to determine optimal differential degradation conditions for specific combinations of nitrosamines and pharmaceutical ingredients. The spiked-in approach procedure may provide a systematic method for optimizing reaction parameters while minimizing pharmaceutical ingredient degradation during nitrosamine removal.

[0152] Sample Generation and Preparation

[0153] The spiked-in approach procedure may involve generating multiple samples, each sample having a volume of 1-5 mL and including the pharmaceutical ingredient and a spike of the nitrosamine, in a batch reactor in a 20 mL scintillation vial. Each sample may have a different solvent composition, different pH, and / or may be exposed to a different wavelength of radiation, reaction time, or temperature. The sample volume standardization may provide consistent analytical conditions and enable direct comparison of results across different parameter combinations.

[0154] The pharmaceutical ingredient concentration may be maintained within a range of, e g., 0.5 mg / mL to 250 mg / mL across the test samples. The concentration range may accommodate various pharmaceutical ingredients with different solubility characteristics while providing adequate material for analytical detection and quantification. Higher concentrations within the range may provide enhanced analytical precision while lower concentrations may better simulate dilute processing conditions.

[0155] The nitrosamine spike concentration may be maintained within a range of 1 ppm to 200 ppm relative to the pharmaceutical ingredient concentration. The nitrosamine concentration range may simulate realistic contamination levels encountered in pharmaceutical manufacturing while providing adequate analytical signal for quantification. The spike concentration may be selected to be 10-fold or higher than t pical contamination levels to enable precise measurement of degradation kinetics.

[0156] Parameter Variation Matrix

[0157] The spiked-in approach procedure may involve systematic variation of multiple reaction parameters to map the response surface for nitrosamine degradation and pharmaceutical ingredient stability. The parameter matrix may include different solvent compositions ranging from pure organic solvents to aqueous mixtures with varying water content. Solvent pH may be adjusted across acidic, neutral, and basic ranges to evaluate the influence of solution chemistry on differential degradation rates.

[0158] Wavelength parameters may be varied across different UV and visible light ranges, including UVA, UVV. and visible light wavelengths. Each wavelength condition may be tested at different intensities to evaluate the relationship between photon flux and reaction selectivity. The wavelength selection may focus on ranges that provide enhanced differential degradation between nitrosamines and pharmaceutical ingredients.

[0159] Temperature conditions may be varied within the range suitable for pharmaceutical ingredient stability, typically between 0°C and 40°C. The temperature variation may evaluate the thermal contribution to both nitrosamine degradation and pharmaceutical ingredient stability . Reaction time parameters may be varied to establish kinetic profiles for both nitrosamine removal and pharmaceutical ingredient degradation.

[0160] Multifactorial Analysis Implementation

[0161] Multifactorial analysis may be performed in a set test system, varying defined wavelength, a panel of solvents, pH, time and temperature simultaneously. The multifactorial approach may enable evaluation of parameter interactions that influence the differential degradation process. The analysis may identify synergistic or antagonistic effects between different reaction conditions.

[0162] The test system may be designed to evaluate multiple parameter combinations efficiently while maintaining analytical precision. Statistical experimental design methods may be applied to minimize the number of test samples while maximizing the information content of the parameter space evaluation. The multifactorial analysis may include replication of selected conditions to assess experimental variability.

[0163] The parameter combinations may be selected to span the practical operating ranges for each variable while focusing on regions likely to provide enhanced differential degradation. The analysis may include extreme conditions to define the boundaries of acceptable operating parameters for each pharmaceutical ingredient and nitrosamine combination.

[0164] In some implementations, a recommendation engine (running on one or more processing units) may be used to recommend conditions to be tested, to direct the optimization of the process. For example, the recommendation engine could receive information indicating a pharmaceutical active ingredient and one or more nitrosamines, and optionally some or all of the relevant concentrations. Using a trained model, the recommendation engine could output one or more sets of conditions to test that could produce optimal results based on similarities to empirical evidence from previously-performed tests on similar API structures. The recommendation engine may produce different sets of conditions based on different priorities. For example, the output may include a first set of conditions intended to minimize energy costs while ensuring nitrosamines are below a predetermined target level, and a second set of conditions intended to minimize nitrosamine levels, regardless of energy usage.

[0165] Analytical Measurement Procedures

[0166] The spiked-in approach procedure may involve measuring pharmaceutical ingredient loss and nitrosamine loss in each sample after exposure to the corresponding wavelength of radiation, reaction time, and temperature. The analytical measurements may be performed using methods capable of detecting both compounds at concentrations down to 1% or less of the starting concentration.

[0167] Liquid chromatography -tandem mass spectrometry (LC-MS / MS) methods may provide the analytical sensitivity and selectivity needed for accurate quantification of both pharmaceutical ingredients and nitrosamines. The analytical methods may be validated for each pharmaceutical ingredient and nitrosamine combination to ensure accurate measurement of degradation products and remaining parent compounds.

[0168] Sampling may be performed at defined time intervals during the photochemical treatment to establish kinetic profiles for both nitrosamine degradation and pharmaceutical ingredient stability. The time-course data may provide information on reaction rates and enable optimization of treatment duration for each parameter combination.

[0169] Data Analysis and Optimization

[0170] The analytical data from the spiked-in approach procedure may be analyzed to identify conditions that maximize nitrosamine degradation while minimizing pharmaceutical ingredient loss. The optimization may involve calculating differential degradation ratios that quantify the selectivity of each parameter combination.

[0171] Response surface modeling may be applied to the multifactorial data to identify’ optimal operating conditions and predict performance under untested parameter combinations. The modeling may account for parameter interactions and provide guidance for scaling the optimized conditions to larger processing volumes.

[0172] The optimization process may establish acceptance criteria for both nitrosamine removal efficiency and pharmaceutical ingredient recovery. The criteria may be based on regulatory limits for nitrosamine contamination and economic considerations for pharmaceutical ingredient loss during processing.

[0173] Method Validation and Reproducibility

[0174] The spiked-in approach procedure may include validation steps to confirm the reproducibility and accuracy of the optimization results. Replicate testing of selected optimal conditions may verify the consistency of the differential degradation performance. The validation may include testing with different lots of pharmaceutical ingredients to assess the robustness of the optimized conditions.

[0175] Scale-up considerations may be evaluated by comparing the performance of optimized conditions at the 1 mL test scale with larger volume applications. The scale-up evaluation may identify' parameters that require adjustment when transitioning from laboratory optimization to production-scale processing.

[0176] The method validation may include assessment of analytical method performance, including precision, accuracy, and detection limits for both pharmaceutical ingredients and nitrosamines under the various solvent and pH conditions used in the optimization procedure.

[0177] The photochemical removal method may be followed by recovery and purification procedures to isolate the treated pharmaceutical ingredients while removing degraded nitrosamine products and reaction byproducts. The recovery methods may maintain the purity and integrity' of the pharmaceutical ingredients after photochemical treatment.

[0178] Recrystallization Procedures

[0179] Recrystallization may serve as a purification method for recovering pharmaceutical ingredients after photochemical treatment. The recrystallization process may remove degraded nitrosamine products, reaction byproducts, and any residual contaminants while preserving the pharmaceutical ingredient in crystalline form. The recrystallization conditions may be selected based on the solubility characteristics of the pharmaceutical ingredient and the solubility differences between the pharmaceutical ingredient and degradation products.

[0180] The recrystallization process may involve dissolving the treated pharmaceutical ingredient in a suitable solvent at elevated temperature, followed by controlled cooling to promote crystal formation. The solvent selection for recrystallization may differ from the solvent used during photochemical treatment to optimize the purification efficiency. The recrystallization solvent may be chosen to provide high solubility for the pharmaceutical ingredient at elevated temperature and reduced solubility' at lower temperature.

[0181] Temperature control during recrystallization may influence the crystal size, purity, and recovery yield of the pharmaceutical ingredient. Slow cooling rates may promote larger crystal formation and enhanced purity through improved rejection of impurities from the crystal lattice. Rapid cooling may produce smaller cry stals with potentially higher surface area but may result in inclusion of impurities within the crystal structure.

[0182] Solvent Exchange Crystallization

[0183] Solvent exchange crystallization may provide an alternative recovery method that combines solvent removal with recrystallization in a single process step. The solvent exchange process may involve removing the photochemical treatment solvent through evaporation or distillation, followed by redissolving the pharmaceutical ingredient in a different solvent system that promotes crystallization.

[0184] The solvent exchange process may utilize rotary evaporation under vacuum to remove volatile solvents such as ethanol from the treated reaction mixture. The vacuum conditions may enable solvent removal at reduced temperatures, minimizing thermal stress on the pharmaceutical ingredient during recovery. The evaporation conditions may be controlled to prevent overheating or decomposition of the pharmaceutical ingredient.

[0185] After solvent removal, the pharmaceutical ingredient may be redissolved in a crystallization solvent that provides different solubility characteristics compared to the photochemical treatment solvent. The crystallization solvent may be selected to have limited solubility for degraded nitrosamine products and reaction byproducts, enabling their separation from the pharmaceutical ingredient during the crystallization process.

[0186] Crystallization Solvent Selection

[0187] The crystallization solvent may be selected based on the chemical structure and solubility properties of the pharmaceutical ingredient being recovered and may be based on established manufacturing processes of the pharmaceutical ingredient. Organic solvents such as ethyl acetate may provide suitable crystallization conditions for many pharmaceutical ingredients while maintaining limited solubility for nitrosamine degradation products. The solvent polarity may be matched to the pharmaceutical ingredient structure to optimize solubility and crystallization behavior.

[0188] Mixed solvent systems may be employed to fine-tune the crystallization conditions and optimize the recovery yield and purity. The mixed solvent composition may be adjusted to balance the solubility of the pharmaceutical ingredient with the rejection of impurities and degradation products. Water-organic solvent mixtures may provide enhanced selectivity for certain pharmaceutical ingredients.

[0189] The crystallization solvent volume may be optimized to achieve the desired concentration of pharmaceutical ingredient while maintaining practical handling characteristics. Higher solvent volumes may provide enhanced purification through dilution of impurities, while lower volumes may increase the concentration driving force for cry stallization and improve recovery yields.

[0190] Temperature-Controlled Crystallization

[0191] Temperature-controlled crystallization may enhance the purification efficiency and recovery yield of pharmaceutical ingredients after photochemical treatment. The crystallization temperature profile may involve initial dissolution at elevated temperature followed by controlled cooling to promote crystal nucleation and growth. The temperature control may be programmed to optimize crystal quality and minimize impurity incorporation.

[0192] Elevated dissolution temperatures may ensure complete dissolution of the pharmaceutical ingredient while maintaining limited solubility for degradation products and impurities. The dissolution temperature may be selected based on the thermal stability of the pharmaceutical ingredient to prevent decomposition during the recovery process. Temperatures may range from ambient conditions to 70°C depending on the specific pharmaceutical ingredient and solvent system.

[0193] Controlled cooling rates during crystallization may influence the crystal morphology, size distribution, and purity of the recovered pharmaceutical ingredient. Slow cooling rates may promote equilibrium crystal growth with enhanced rejection of impurities from the crystal lattice. The cooling profile may include temperature holds at intermediate temperatures to promote crystal maturation and improve purity.

[0194] Crystal Maturation and Aging

[0195] Crystal maturation processes may be incorporated into the recovery procedure to enhance the purity and stability of the recovered pharmaceutical ingredient. The maturation process may involve maintaining the crystalline suspension at controlled temperature for extended periods to allow crystal growth and impurity rejection. The aging conditions may promote dissolution of smaller, less stable crystals and growth of larger, more thermodynamically stable crystals.

[0196] Stirring during crystal maturation may promote mass transfer and enhance the purification efficiency through improved contact between the cry stals and the surrounding solution. The stirring rate may be controlled to provide adequate mixing without causing crystal breakage or attrition. Gentle agitation may maintain suspension of the crystals while allowing controlled crystal growth.

[0197] The maturation time may be optimized based on the crystallization kinetics of the specific pharmaceutical ingredient and the level of purification needed. Extended maturation periods may provide enhanced purity through continued impurity rejection, while shorter periods may maximize recovery yields by minimizing crystal dissolution losses. Filtration and Washing Procedures

[0198] Filtration procedures may be employed to separate the crystallized pharmaceutical ingredient from the crystallization solution containing dissolved impurities and degradation products. The filtration method may be selected based on the crystal size, solution viscosity, and processing scale requirements. Vacuum filtration may provide enhanced separation efficiency and reduced processing time compared to gravity filtration.

[0199] Filter media selection may consider the crystal size distribution and the need to retain fine crystals while allowing passage of the filtrate containing dissolved impurities. Membrane filters with defined pore sizes may provide precise separation based on particle size. The filter material may be selected for chemical compatibility with the crystallization solvent and pharmaceutical ingredient.

[0200] Washing procedures may be incorporated into the filtration process to remove residual impurities and crystallization solvent from the recovered crystals. The wash solvent may be selected to have limited solubility' for the pharmaceutical ingredient while effectively removing impurities and residual crystallization solvent. Multiple wash steps may be employed to achieve the desired level of punfication.

[0201] Drying and Final Processing

[0202] Drying procedures may remove residual solvents from the recovered pharmaceutical ingredient crystals while maintaining crystal integrity and preventing decomposition. The drying conditions may be selected based on the thermal stability of the pharmaceutical ingredient and the volatility' of the residual solvents. Vacuum drying may enable solvent removal at reduced temperatures to minimize thermal stress.

[0203] Drying temperatures may be controlled to provide effective solvent removal while preventing crystal structure changes or decomposition of the pharmaceutical ingredient. The drying temperature may be maintained below the melting point or decomposition temperature of the pharmaceutical ingredient. Temperature monitoring may' ensure consistent dry ing conditions and prevent overheating.

[0204] Drying time may be optimized to achieve the desired residual solvent levels while minimizing processing time and energy consumption. Extended drying periods may provide more complete solvent removal but may increase the risk of thermal degradation or crystal structure changes. The drying endpoint may be determined through analytical monitoring of residual solvent content.

[0205] Recovery Yield Optimization

[0206] Recovery' yield optimization may involve adjusting the crystallization conditions to maximize the amount of pharmaceutical ingredient recovered while maintaining acceptable purity levels. The yield optimization may consider the solubility characteristics of the pharmaceutical ingredient in the crystallization solvent and the temperature dependence of the solubility.

[0207] Crystallization efficiency may be enhanced through seeding procedures that provide nucleation sites for crystal formation. Seed crystals of the pharmaceutical ingredient may be added to the crystallization solution to promote controlled nucleation and reduce the supersaturation needed for spontaneous crystallization. The seed crystal quantity and addition timing may be optimized to maximize recovery yield.

[0208] Multiple crystallization stages may be employed to maximize recovery yield by processing the mother liquor from the initial crystallization. The secondary crystallization may recover additional pharmaceutical ingredient that remained dissolved after the primary' crystallization step. The combined recovery' from multiple stages may provide enhanced overall yield compared to single-stage crystallization.

[0209] Purity Assessment and Quality Control

[0210] Analytical procedures may be employed to assess the purity and quality of the recovered pharmaceutical ingredient after the recovery and purification process. The analytical methods may quantity' the removal of nitrosamine contaminants and degradation products while confirming the integrity of the pharmaceutical ingredient. Liquid chromatography methods may provide separation and quantification of the pharmaceutical ingredient and potential impurities.

[0211] Mass spectrometry' analysis may confirm the identity' and purity' of the recovered pharmaceutical ingredient while detecting trace levels of nitrosamine contaminants or degradation products. The analytical sensitivity may be sufficient to verify that nitrosamine levels are below regulatory' acceptance limits after the recovery process.

[0212] Physical characterization methods may' assess the crystal properties and stability' of the recovered pharmaceutical ingredient. X-ray diffraction analysis may confirm the crystal structure and polymorphic form of the recovered material. Thermal analysis methods may evaluate the thermal stability and purity of the recovered pharmaceutical ingredient compared to reference standards.

[0213] The photochemical nitrosamine removal process may integrate multiple operational elements to achieve selective degradation of nitrosamine contaminants while preserving pharmaceutical ingredient quality. The integrated process may combine dissolution, irradiation, and recovery operations in a coordinated sequence that optimizes differential degradation rates between nitrosamines and pharmaceutical ingredients.

[0214] Process Initiation and Dissolution

[0215] The integrated process may begin with dissolution or dispersion of the contaminated pharmaceutical ingredient in a selected solvent system. The solvent selection may be based on the solubility' characteristics of both the pharmaceutical ingredient and the nitrosamine contaminants, as yvell as the influence of solvent composition on photochemical reaction pathways. The dissolution process may achieve homogeneous distribution of both the pharmaceutical ingredient and nitrosamine contaminants throughout the reaction medium.

[0216] The solvent system pH may be adjusted during the dissolution stage to establish conditions that favor selective nitrosamine degradation during subsequent irradiation. The pH adjustment may be performed using acids or bases that are compatible with both the pharmaceutical ingredient and the photochemical process. The pH optimization may be based on results from the spiked-in approach procedure for the specific pharmaceutical ingredient and nitrosamine combination being processed.

[0217] Temperature control may be initiated during the dissolution stage to establish thermal conditions that support the subsequent photochemical reactions while maintaining pharmaceutical ingredient stability. The dissolution temperature may be selected to ensure complete dissolution of the pharmaceutical ingredient while preventing thermal degradation or unwanted chemical reactions.

[0218] Irradiation Process Integration

[0219] The irradiation stage may be integrated with the dissolution process through careful control of reaction vessel configuration and light source positioning. The optically transmissible vessel containing the dissolved pharmaceutical ingredient and nitrosamine contaminants may be positioned relative to the light source to achieve uniform light distribution throughout the reaction mixture. The vessel geometry and light source configuration may work together to maximize photon utilization efficiency while maintaining consistent exposure conditions.

[0220] The wavelength selection may interact with the solvent system composition to direct photochemical reactions toward nitrosamine degradation rather than pharmaceutical ingredient degradation. The wavelength-solvent interaction may influence the absorption characteristics of both nitrosamines and pharmaceutical ingredients, enabling selective energy transfer to the nitrosamine bonds while minimizing energy absorption by the pharmaceutical ingredient.

[0221] Light intensity and exposure time parameters may be coordinated to deliver the total photon dose needed for nitrosamine degradation yvhile limiting the exposure of pharmaceutical ingredients to potentially degrading conditions. The intensity -time relationship may be adjusted based on the photochemical kinetics of the specific nitrosamine and the photostability characteristics of the pharmaceutical ingredient.

[0222] Parameter Interaction and Control

[0223] The integrated process may coordinate multiple parameters simultaneously to achieve optimal differential degradation performance. Temperature control during irradiation may influence both the photochemical reaction rates and the thermal stability' of the pharmaceutical ingredient. The temperature-light intensity interaction may be managed to maximize nitrosamine degradation rates while maintaining pharmaceutical ingredient integrity.

[0224] Solvent composition may interact with wavelength selection and temperature control to establish reaction conditions that favor nitrosamine degradation pathways over pharmaceutical ingredient degradation pathways. The solvent-wavelength-temperature interaction may be optimized through systematic evaluation using the spiked-in approach procedure to identify parameter combinations that provide enhanced selectivity7. pH control may be maintained throughout the irradiation process to sustain the chemical environment that supports selective nitrosamine degradation. The pH stability during irradiation may be monitored and adjusted as needed to compensate for any pH changes that may occur due to photochemical reactions or thermal effects.

[0225] Real-Time Process Monitoring

[0226] The integrated process may incorporate analytical monitoring systems that track both nitrosamine degradation and pharmaceutical ingredient stability during the irradiation stage. The monitoring systems may provide real-time or periodic sampling to assess the progress of nitrosamine removal and detect any pharmaceutical ingredient degradation that may occur during treatment.

[0227] The analytical data from process monitoring may be used to adjust irradiation parameters in real-time to optimize the differential degradation performance. The monitoring feedback may enable dynamic control of light intensity, temperature, or other parameters to maintain optimal reaction conditions throughout the treatment period.

[0228] Process monitoring may also provide data for determining the endpoint of the irradiation treatment based on achieving target levels of nitrosamine removal while maintaining acceptable pharmaceutical ingredient recovery. The endpoint determination may be based on analytical detection limits for nitrosamine contaminants and qualify specifications for the pharmaceutical ingredient.

[0229] Transition to Recovery Operations

[0230] The integrated process may coordinate the transition from irradiation to recovery7operations to minimize pharmaceutical ingredient losses and maintain product quality'. The transition may involve controlled cooling of the reaction mixture if elevated temperatures were used during irradiation, or adjustment of solvent composition to prepare for subsequent crystallization or purification steps.

[0231] The reaction mixture composition after irradiation may contain the treated pharmaceutical ingredient, degraded nitrosamine products, and potentially minor amounts of pharmaceutical ingredient degradation products. The composition analysis may guide the selection of recovery methods that effectively separate the pharmaceutical ingredient from degradation products and reaction byproducts.

[0232] Solvent exchange procedures may be integrated into the transition from irradiation to recovery to optimize the conditions for pharmaceutical ingredient crystallization or other purification methods. The solvent exchange may remove photochemical treatment solvents that may interfere with recovery operations while introducing solvents that promote effective purification. Chromatography may also be used to recover the pharmaceutical ingredient.

[0233] Recovery Process Integration

[0234] The recovery operations may be integrated with the photochemical treatment to provide a complete process for nitrosamine removal and pharmaceutical ingredient purification. The recovery methods may be selected based on the chemical properties of the treated pharmaceutical ingredient and the nature of the degradation products formed during photochemical treatment.

[0235] Crystallization procedures may be integrated into the overall process to provide both purification and isolation of the treated pharmaceutical ingredient. The cry stallization conditions may be optimized to reject degraded nitrosamine products and any pharmaceutical ingredient degradation products while maximizing recovery yield of the purified pharmaceutical ingredient.

[0236] The cry stallization solvent selection may consider the solubility7characteristics established during the photochemical treatment stage to ensure compatibility7between the treatment and recovery operations. The solvent systems used in both stages may be coordinated to minimize processing steps and reduce the potential for pharmaceutical ingredient losses during solvent transitions.

[0237] Process Optimization and Scale Considerations

[0238] The integrated process may be optimized through sy stematic evaluation of the interactions between dissolution, irradiation, and recovery operations. The optimization may consider the cumulative effects of all process stages on pharmaceutical ingredient recovery and purity, rather than optimizing individual stages in isolation.

[0239] Scale-up considerations may address how the integration of process operations changes when transitioning from laboratory-scale to production-scale processing. The scale-up may require adjustment of parameter relationships to maintain the same level of integration and performance at larger processing volumes.

[0240] Batch processing integration may coordinate the timing and sequencing of operations to maximize throughput while maintaining product quality. The batch cycle time may be optimized to balance the time needed for each operation with the overall processing efficiency and resource utilization.

[0241] Flow processing integration may coordinate the residence times and flow rates through different process stages to achieve continuous operation with consistent product quality. The flow system integration may require careful matching of processing rates between dissolution, irradiation, and recovery operations to maintain steady-state conditions.

[0242] Quality Assurance Integration

[0243] The integrated process may incorporate quality assurance measures that span all operational stages to ensure consistent performance and product quality. The quality assurance system may include analytical testing at multiple points in the process to verify that each stage is performing as expected and that the overall process is achieving the target nitrosamine removal and pharmaceutical ingredient recovery.

[0244] Process validation procedures may evaluate the integrated performance of all process stages under various operating conditions to establish the operating ranges that provide acceptable product qualify. The validation may include assessment of process robustness and the ability to maintain performance despite normal variations in operating conditions or raw material properties.

[0245] Documentation and record-keeping systems may be integrated across all process stages to provide traceability and support regulatory compliance requirements. The integrated documentation may track the processing conditions, analytical results, and product qualify data throughout the complete process sequence.

[0246] Continuous Improvement Integration

[0247] The integrated process may incorporate feedback mechanisms that use performance data from all process stages to identify' opportunities for improvement. The feedback system may analyze the relationships between processing conditions and final product quality to optimize the integrated performance of the complete process.

[0248] Process development activities may consider the integrated effects of parameter changes across all process stages rather than focusing on individual operations in isolation. The integrated development approach may identify parameter interactions that provide enhanced performance when multiple process stages are considered together.

[0249] Technology transfer procedures may address the integrated nature of the process when implementing the technology at different manufacturing sites or scales. The technology7transfer may include detailed documentation of the parameter interactions and process integration requirements to ensure consistent performance across different implementations.

[0250] SYSTEM CONFIGURATIONS AND APPARATUS

[0251] A photochemical nitrosamine removal system may be configured to combine fluid handling, optical irradiation, and analytical monitoring components to achieve selective degradation of nitrosamine contaminants while preserving pharmaceutical ingredient quality. The system configuration may provide controlled processing conditions and real-time monitoring capabilities for both batch and continuous processing applications.

[0252] Container and Composition Management

[0253] The container may serve as the primary reservoir for the composition of matter comprising the pharmaceutical ingredient dissolved or dispersed in the selected solvent system. The container construction may utilize materials that provide chemical compatibility with the solvent systems and pharmaceutical ingredients while maintaining structural integrity7under the operating conditions. Glass containers may provide chemical inertness and optical transparency for visual monitoring of the composition. Stainless steel containers may offer enhanced durability and temperature control capabilities for larger-scale processing applications.

[0254] The container volume may be selected based on the processing requirements and may range from milliliter volumes for laboratory applications to kilo-liter volumes for production-scale processing. The container geometry may be optimized to facilitate mixing and heat transfer while accommodating the connections needed for fluid transfer to the optically transmissible vessel. The container may include provisions for temperature control through heating or cooling systems integrated into the container walls or through external heat exchangers.

[0255] The composition of matter within the container may be maintained under controlled conditions to preserve the stability of both the pharmaceutical ingredient and the nitrosamine contaminants prior to photochemical treatment. The composition may be protected from light exposure before treatment to prevent premature photodegradation. Inert gas blanketing may be employed to prevent oxidation or other chemical reactions that could affect the composition during storage or processing. Optically Transmissible Vessel Design

[0256] The optically transmissible vessel may be designed to provide optimal light transmission characteristics while maintaining the chemical and mechanical properties needed for the photochemical process. The vessel material selection may consider the wavelength range of the radiation source and the transmission properties of different optical materials. Borosilicate glass may provide suitable transmission characteristics for UVA and visible light wavelengths while offering chemical resistance to various solvent systems.

[0257] Quartz construction may be employed for applications requiring enhanced UV transmission, particularly for shorter wavelength applications in the UVB or UVC ranges. The quartz material may provide superior optical clarity and chemical inertness compared to borosilicate glass, enabling more efficient photon utilization and reduced interference from vessel materials. In some implementations, the optically transmissible vessel may be configured to prevent or restrict UVB or UVC light from interacting with the API.

[0258] The vessel geometry may be optimized to provide uniform light distribution throughout the composition while minimizing optical path length variations that could result in uneven irradiation. Cylindrical vessel configurations may provide radial symmetry for uniform light penetration when used with external light sources. Rectangular or cuboidal vessel geometries may provide defined optical path lengths and uniform light distribution when used with collimated light sources.

[0259] The vessel wall thickness may be selected to balance optical transmission with mechanical strength requirements. Thinner walls may provide enhanced light transmission and reduced optical losses, while thicker walls may offer greater pressure resistance and thermal stabili ty. The wall thickness optimization may consider the operating pressure, temperature, and mechanical stress conditions expected during processing.

[0260] Pump System Integration

[0261] The pump system may be configured to provide controlled fluid circulation between the container and the optically transmissible vessel while maintaining the integrity7of the composition and avoiding contamination. Peristaltic pumps may provide gentle fluid handling that minimizes shear stress on sensitive pharmaceutical ingredients while offering excellent chemical compatibility7through the use of inert tubing materials.

[0262] The pump flow7rate may be adjustable to control the residence time of the composition within the optically transmissible vessel and optimize the extent of photochemical reaction per pass. Variable speed drives may enable precise flow rate control and allow for optimization of the processing conditions based on the specific pharmaceutical ingredient and nitrosamine combination being treated.

[0263] Centrifugal pumps may be employed for higher flow rate applications or when processing larger volumes of composition. The centrifugal pump selection may consider the chemical compatibility of the pump materials with the solvent systems and the ability to maintain consistent flow rates despite variations in system pressure or viscosity'.

[0264] The pump system may include flow measurement and control instrumentation to monitor and maintain the desired circulation rates. Flow meters may provide real-time feedback on the circulation rate and enable automatic adjustment of pump speed to maintain consistent processing conditions. Pressure monitoring may detect blockages or other flow restrictions that could affect the processing performance.

[0265] Radiation Source Configuration

[0266] The radiation source may be positioned relative to the optically transmissible vessel to provide uniform irradiation of the composition while maximizing photon utilization efficiency. External radiation source configurations may position the light source outside the vessel with radiation transmitted through the vessel walls. This configuration may allow for easy maintenance and replacement of radiation sources without disrupting the composition or requiring system shutdown.

[0267] Internal radiation source configurations may position the radiation source within the optically transmissible vessel using protective housings or immersion wells. The internal configuration may provide enhanced light utilization efficiency and more uniform radiation distribution throughout the composition. The protective housing may be constructed from optically transmissible materials that are compatible with the composition and radiation wavelengths.

[0268] The radiation source may include multiple light sources positioned at different locations around the optically transmissible vessel to provide enhanced uniformity of irradiation. The multiple source configuration may reduce shadowing effects and ensure consistent light exposure throughout the composition volume. The individual sources may be controlled independently to optimize the light distribution and intensity profile.

[0269] Light-emitting diode arrays may provide precise wavelength control and energy efficiency compared to traditional light sources. The LED configuration may enable selection of specific wavelength ranges that optimize the differential degradation between nitrosamines and pharmaceutical ingredients. The LED arrays may be arranged to provide uniform light distribution and may include individual control of LED segments for enhanced flexibility.

[0270] Processing Unit Control Systems The processing units may include programmable logic controllers or computer-based control systems that coordinate the operation of all system components. The control system may manage pump operation, radiation source control, temperature regulation, and analytical monitoring to maintain optimal processing conditions throughout the treatment cycle.

[0271] The control system may include user interfaces that allow operators to set processing parameters, monitor system status, and review analytical data. The interface may provide graphical displays of process conditions and trends to facilitate process optimization and troubleshooting. Alarm systems may alert operators to deviations from normal operating conditions or analytical results that indicate process upsets.

[0272] Automated control algorithms may adjust processing parameters in real-time based on analytical feedback to maintain optimal differential degradation performance. The control algorithms may use feedback from analytical monitoring systems to adjust light intensity, flow rate, or other parameters to compensate for variations in composition properties or processing conditions.

[0273] Data logging capabilities may record all processing parameters and analytical results for process documentation and regulatory compliance. The data logging system may provide traceability of processing conditions and enable analysis of process performance trends over time. The recorded data may support process validation activities and continuous improvement initiatives.

[0274] Analytical Device Integration

[0275] The analytical device may be integrated into the system to provide real-time or periodic monitoring of both pharmaceutical ingredient and nitrosamine concentrations during processing. The analytical system may utilize spectroscopic methods such as UV-visible spectroscopy to monitor concentration changes based on the optical absorption characteristics of the compounds.

[0276] Liquid chromatography systems may be integrated to provide separation and quantification of pharmaceutical ingredients and nitrosamines with high specificity and sensitivity. The chromatographic system may include automated sampling capabilities that withdraw small volumes of composition from the optically transmissible vessel for analysis without disrupting the photochemical process.

[0277] Mass spectrometry' detection may be coupled with chromatographic separation to provide enhanced specificity and sensitivity for nitrosamine detection and quantification. The mass spectrometry system may enable detection of nitrosamine degradation products and pharmaceutical ingredient degradation products to assess the selectivity of the photochemical process.

[0278] Flow-through analytical cells may be integrated directly into the circulation system to provide continuous monitoring without the need for discrete sampling. The flow-through configuration may enable real-time tracking of concentration changes and provide immediate feedback for process control adjustments.

[0279] System Integration and Coordination

[0280] The system components may be integrated through coordinated control systems that optimize the interactions between fluid circulation, irradiation, and analytical monitoring. The integration may ensure that changes in one system component are appropriately coordinated with adjustments in other components to maintain optimal processing performance.

[0281] Safety systems may be integrated throughout the apparatus to protect operators and equipment from potential hazards associated with UV radiation, chemical exposure, or equipment malfunctions. Light containment systems may prevent UV exposure to operators while allowing for system operation and maintenance. Emergency shutdown systems may rapidly terminate processing in response to safety alarms or equipment failures.

[0282] The system design may accommodate different processing scales through modular construction that allows for scaling of individual components while maintaining the same level of integration and control. The modular approach may enable customization of system capacity and capabilities based on specific processing requirements.

[0283] Maintenance and cleaning procedures may be integrated into the system design to facilitate routine maintenance and changeover between different pharmaceutical ingredients or processing campaigns. Clean-in-place systems may enable automated cleaning of the circulation system and optically transmissible vessel without requiring disassembly of system components.

[0284] Solid Sample and Suspension Processing

[0285] The photochemical nitrosamine removal method may be applied to solid pharmaceutical ingredients or materials maintained in suspension within the optically transmissible vessel. In some implementations, solid pharmaceutical compounds may be processed while suspended in an appropriate carrier medium that allows for effective light penetration and nitrosamine degradation. The suspension may be maintained through mechanical agitation, ultrasonic mixing, or other suitable means to ensure uniform distribution of the solid material throughout the treatment process and prevent settling that could result in uneven light exposure.

[0286] Example carrier mediums for suspending solid pharmaceutical ingredients may include water, aqueous buffer solutions, organic solvents such as ethanol or methanol, mixed solvent systems comprising water and water-miscible organic solvents, or other pharmaceutically acceptable liquid carriers that provide adequate optical transmission properties while maintaining chemical compatibility with the pharmaceutical ingredient.

[0287] The carrier medium for suspended solid processing may be selected based on its optical transmission properties, chemical compatibility7with the pharmaceutical ingredient, and ability to maintain stable suspension characteristics. Aqueous or organic solvent systems may serve as carrier media, with the selection optimized to provide adequate light transmission while maintaining the integrity of the suspended pharmaceutical ingredient. The carrier medium may also be selected to facilitate subsequent recovery7and purification of the treated pharmaceutical ingredient through filtration, centrifugation, or other separation techniques.

[0288] Testing has demonstrated the effectiveness of this approach with various materials, including ranitidine samples, confirming the method's applicability to suspended solid materials.

[0289] The solid-phase processing may provide advantages in certain applications where dissolution of the pharmaceutical ingredient is not practical or desirable, or where the solid form processing may enhance the selectivity of nitrosamine degradation compared to dissolved systems. The particle size distribution of the suspended solids may7influence the light penetration and reaction kinetics, and may be optimized through milling, sieving, or other particle size control methods to enhance the photochemical treatment effectiveness.

[0290] Al Model and Algorithm System for Reaction Condition Optimization

[0291] The system may incorporate an artificial intelligence model configured to analyze molecular structure data and predict optimal photochemical reaction conditions for nitrosamine removal from pharmaceutical ingredients. The Al model may utilize a curated database comprising reaction data with established controls to generate predictions for preferred reaction parameters based on the structural characteristics of both pharmaceutical ingredients and nitrosamine contaminants.

[0292] The Al model may process various input data types to develop comprehensive predictions for reaction optimization. Molecular structure data may include chemical connectivity information, functional group identification, and three-dimensional conformational data for both pharmaceutical ingredients and nitrosamines. Chemical features such as bond energies, absorption characteristics, and photostability profiles may be incorporated to assess the susceptibility of different molecular bonds to photochemical degradation. Empirical data accumulated across ranges of pharmaceutical ingredients and nitrosamines, including their various combinations, may provide the foundation for pattern recognition and predictive modeling.

[0293] The model development process may involve machine learning algorithms trained on experimental data from the spiked-in approach procedures and larger-scale processing results. The training dataset may include reaction outcomes under various wavelength conditions, solvent compositions, pH levels, temperature ranges, and treatment durations. The Al model may identify correlations between molecular structural features and optimal reaction conditions that achieve selective nitrosamine degradation while preserving pharmaceutical ingredient integrity.

[0294] Validation procedures may incorporate appropriate controls to ensure accuracy and reliability of the Al predictions. Cross-validation techniques may assess the model's ability' to predict reaction outcomes for pharmaceutical ingredient and nitrosamine combinations not included in the training dataset. Control experiments may verify that the Al recommendations produce the expected differential degradation performance when implemented experimentally.

[0295] The Al model training process may utilize superv ised learning approaches where known reaction outcomes are paired with molecular structure and reaction condition data. Feature extraction algorithms may identify key molecular descriptors that correlate with photochemical susceptibility7, including bond dissociation energies, chromophore characteristics, and steric factors. The training process may incorporate iterative refinement as additional experimental data becomes available, enabling continuous improvement of prediction accuracy.

[0296] Model inference may be performed by inputting the molecular structure data for a new pharmaceutical ingredient and nitrosamine combination, along with any constraints on processing conditions such as temperature limitations or solvent compatibility requirements. The trained model may output recommended ranges for wavelength selection, light intensity', treatment duration, solvent composition, and pH conditions that are predicted to achieve optimal differential degradation performance.

[0297] The algorithm output may provide guidance for selecting specific reaction conditions to be tested experimentally through the spiked-in approach procedure. The Al recommendations may prioritize parameter combinations that are predicted to maximize nitrosamine removal while minimizing pharmaceutical ingredient degradation. The algorithm may also identify parameter interactions that may enhance or diminish the selectivity of the photochemical process.

[0298] Condition adjustment procedures may utilize feedback from experimental validation of Al predictions to refine the model recommendations. When experimental results differ from Al predictions, the discrepancies may be analyzed to identity’ additional molecular features or reaction parameters that should be incorporated into the model. The iterative feedback process may enable continuous improvement of the Al model's predictive capabilities and expansion of its applicability to new pharmaceutical ingredient classes.

[0299] The Al system may also incorporate uncertainty quantification to assess the confidence level of its predictions. High-confidence predictions may be implemented directly for process optimization, while low-confidence predictions may be flagged for additional experimental validation. The uncertainty assessment may guide the selection of experimental conditions to test, focusing resources on parameter ranges where the model predictions are most reliable.

[0300] Examples

[0301] The following examples serve to more fully describe the manner of using the abovedescribed invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes. All references cited herein are incorporated by reference in their entirety.

[0302] Example 1. Removal of NDMA from Valsartan with UV Light.

[0303] The FDA method for determination of NDMA in ranitidine (Liquid Chromatography - Tandem Mass Spectrometry (LC-MS / MS) Method for the Determination of NDMA in Ranitidine Drug Substance and Solid Dosage Drug Product 10 / 17 / 2019) was performed using a Sciex ZenoTOF 7600 LCMS System, with NDMA and valsartan standards, individually, and then with a NDMA spiked-in sample of Valsartan (50 ppm NDMA in 0.5 mg / ml Valsartan. The limit of detection (LOD) of NDMA under the analytical condition, quantitating on peak mass ion fragments, was 0.25 ppm, with an NDMA standard curi e showing linearity' through 500 ppm. Valsartan, by this method had a single peak by LC, identified and quantitated by mass ion fragment determination. LOD and linearity were 0.05 ppm and 1000 ppm, respectively.

[0304] A 5 ml spiked-in sample of valsartan was prepared in 95% ethanol (v / v) in a 20 ml borosilicate glass scintillation vial and treated with a 72-watt UVC light (200-280 nm, 253.7 nm max), with aliquots taken over a 2-hour period, followed by LCMS analysis and quantitation by calculation of the AUC of the resulting peaks of NDMA and Valsartan. These reaction conditions resulted in degradation of both NDMA and a majority of Valsartan. Data are shown in FIG. 1.

[0305] Samples of NDMA, valsartan and spiked-in valsartan. prepared and analyzed as above, were treated with 72-watt UVA light (350-410 nm, 384.2 max). In 95% ethanol, NDMA (by itself or spiked-into valsartan) is degraded, with no observable NDMA degradants formed. In 100% ethanol, the NDMA is also degraded, but observable peaks form at the beginning of the reaction, and then plateau. Data are shown in FIG. 2A.

[0306] In the UVA treatment >98% of the valsartan (alone or NDMA spiked) is recovered. However, up to 6 minor valsartan degradant peaks are seen upon expansion of the baseline region of the chromatograms. These form at the beginning of the reaction, and then plateau. In 100% ethanol, these degradant peaks are not seen or are produced at a much lower level. Data are shown in FIG. 2B.

[0307] Degradation of NDMA in NDMA spiked-in valsartan was measured under the UVA-95% ethanol condition, at various pH, by adjustment of the sample with concentrated HC1 or NH4OH. in the range of 3 to 8. NDMA is removed under all pH conditions tested at similar rates. Valsartan remains stable at all pH conditions tested, but the formation of minor valsartan degradant peaks is reduced as the pH of the reaction is lowered. Data are shown in FIGS. 3A and 3B.

[0308] Under optimized conditions in 95% ethanol, using UVV light (20-watt 405 nm LED) , NDMA is removed from NDMA-spiked valsartan within a 2-hour period, with the absence of measurable amounts of valsartan degradants. Data are shown in FIGS. 4A and 4B.

[0309] Example 2. Degradation ofN-nitroso bumetanide with UV light.

[0310] A solution of N-nitroso bumetanide was prepared at 50 ppm in 95% ethanol, and a 2.5 ml sample in a 20 ml borosilicate scintillation vial treated with UVV light (20 watt 405 nm LED). Aliquots were taken at 0, 0.5, 1 and 2 hours and analyzed and quantitated by LCMS. The resulting TIC chromatogram is shown in FIG. 5 A. Peaks were identified by mass ion extraction (FIG. 5B). Under these conditions, N-nitroso bumetanide is removed in the 2-hour treatment period, and the product of the reaction, bumetanide is formed.

[0311] Example 3. Removal of Small Molecular Weight Nitrosamines and NDSRIs from Various Pharmaceutical Ingredients with UVV light.

[0312] Based on insights learned from experiments with various pharmaceutical ingredients and NDMA, a process was conceived that conveniently and efficiently tunes the reactions conditions for photocatalysis among the matrix of interactions that occur. For screening purposes, the 10 / 17 / 19 FDA method for determination of NDMA in ranitidine can be used with some modification, in particular modification of the MS method. Reactions are performed over a standard 2-hour period in borosilicate glass scintillation vials, on 1.5 ml samples (during which NDMA is removed), with sampling at 0, 30, 60 and 120 minutes. NDMA is used as a positive control. This process is shown in the schematic diagram in FIG. 6.

[0313] To establish and demonstrate the versatility of the photochemical method for the removal of nitrosamines from pharmaceutical ingredients, a number of small molecular weight nitrosamines and NDSRIs of different chemical structures and classes were examined for their stability’ to a standardized reaction condition that was optimized for valsartan and NDMA. Data are shown in Table 1. Due to the molecular nature the nitroso bond, it shows an enhanced lability when reaction conditions are tuned, in many cases, independent of the other elements of the bond structure of the nitrosamine or NDSRI, where in the pharmaceutical ingredients tested show a high level of stability' to the treatment, with a few exceptions, for compounds that have comparatively susceptible bonds to the nitrosamine.

[0314] Table 1. Removal of Various Small Molecular Weight Nitrosamines and NDSRIs Measured by the 2 Hour Photocataly sis Test.

[0315] Example 4. Bench-Scale Photo Flow-Catalysis of NDMA-Spiked Valsartan with Recovery by Solvent Exchange Crystallization.

[0316] Based on the results from batch experiments with NDMA-spiked Valsartan, the reaction was scaled-up using a bench-scale flow catalysis reactor. The flow cell was designed using a 3.5mL flow- through CFR quartz cuboidal cuvette with a 10 mm optical path length with quartz connectors with PTFE screw caps, placed immediately adjacent to the light source. The flow cell was placed in a light-proof chamber with internal surfaces coated with aluminum. The flow cell was connected via a peristaltic pump to a glass media reaction bottle fitted with a 2-hole polypropylene cap, with PTFE / silicon tubing. The flow rate range could be adjusted (e.g., from 0.5 mL / min - 3.5 mL / min). The reaction bottle was placed on a standard lab stimng / heat plate, with stirring by a 5 mm glass covered stir bar. The light source for this example was powered by a BIOSHIELDUV® 72W HVAC UV Light System capable of powering two 36-watt 2G11 4-pin bulbs. Light sources used included UVA (36-watt Philips Actinic BL PL-L 36W / 10 / 4P). UVB (36-watt Philips PL-L 36W / 01 / 4P 1CT / 25) or UVC (36- watt Philips TUV PL-L 36Q / 4P 36W 4) bulbs. UV light intensity was measured by a General Tools Digital UVA / B light meter.

[0317] A 25 ml spiked-in sample of valsartan was prepared in 95% ethanol at 100 mg / mL, spiked with 0. 15 mg / mL NDMA (150 ppm).

[0318] The sample, contained in a stirred reaction reservoir, was circulated through the 3.5 ml flow cell irradiated with UVA light, at a rate of 3.5 ml / min.

[0319] The resulting sample was then crystallized by solvent exchange crystallization, by removing the ethanol using rotary7evaporation, under vacuum, and then redissolving the material in 20 ml of EtOAc at 40°C. After allowing the sample to cool overnight at room temperature, the resulting cry stalline material was collected, dried and the amount of recovered material calculated. The LCMS spectrum and concentrations of valsartan and NDMA were determined prior to treatment, at the end of treatment, and following recrystallization.

[0320] At bench-scale and at a valsartan concentration of 100 mg / ml, 150 ppm NDMA was removed from the spiked-in material to undetectable levels, wherein valsartan remained intact, with valsartan degradants at or below 0.1%, if any. Using an unoptimized recrystallization method, the recovery of recry stallized valsartan was around 85%. The resulting TIC chromatogram is shown in FIGS. 7A and 7B.

[0321] Example 5.

[0322] A 10 mL batch of Sitagliptin Phosphate Monohydrate (536 ppm NTTP) was dissolved at 10 mg / mL in a 0.5% formic acid I H2O mixture, then filtered, and treated with a 20W UVV light (405 nm) for 2 hours.

[0323] Samples were tested at time t=0. 0.5, 1, and 2 hours and the percent removal of NTTP was determined via LCMS. At time t=0.5 hours, 20.6% of the NTTP remained (i.e., roughly 80% of the NTTP had been removed in the first half hour). At time t=l hour, 3.12% of the NTTP remained, and at time t=2 hours, the amount of NTTP was below' the limit of detection. The limit of detection had previously been determined to be 0.0078 ppm, so more than 99.9986% of the initial NTTP had been removed in 2 hours of treatment. The resulting TIC chromatogram is shown in FIG, 8A, and the extracted ion counts for NTTP shown in FIG. 8B.

[0324] Example 6.

[0325] A 10 mL batch of Sitagliptin Hydrochloride Monohydrate (19 ppm NTTP) was dissolved at 25 mg / mL in a 0.5% formic acid / H2O mixture, then filtered, and treated with a 20W UVV light (405 nm) for 2 hours in a 3.5 mL flow cell at 1.7 mL / min.

[0326] Samples were tested at time t=0. 0.5, 1, and 2 hours and the percent removal of NTTP was determined via HPLC. At time t=0.5 hours, 13.83% of the NTTP remained (i.e., roughly 80% of the NTTP had been removed in the first half hour). At time t=l hour, 3.02% of the NTTP remained, and at time t=2 hours, the amount of NTTP was below' the limit of detection. The limit of detection had previously been determined to be 0.0078 ppm, so more than 99.96% of the initial NTTP had been removed in 2 hours of treatment. The resulting extracted ion counts for NTTP shown in Fig. is shown in Fig, 9. Example 7.

[0327] A 1 gm sample of Sitagliptin Phosphate Monohydrate (53.6 ppm NTTP) was dissolved at 10 mg / mL in 0.5% formic acid / FLO. fdtered, and then treated with a 20W UVV light for 2.5 hours. NTTP levels were determined by LCMS.

[0328] At time t=0.5 hours, 18.75% of the NTTP remained. At time t=l hours, 3.51% of the NTTP remained. At time t=2 hours, 0.35% of the NTTP remained, and at time t=2.5 hours, 0. 17% of the NTTP remained.

[0329] Following treatment, sitagliptin in the sample was recovered by crystallization using isopropanol. Two volumes of isopropanol were added to the sample with mixing, which was then stirred for 10 minutes at room temperature, and then heated at 70°C for 5 minutes. The sample was allowed to cool at room temperature for 20 minutes, and then cooled to 5°C. After visible formation of crystalline material, the sample was stirred overnight at 5°C. The precipitate was collected by filtration using a 0.22 pm cellulose acetate filter, washed with 7 mL of isopropanol, and dried overnight at 32°C. The recovery was approximately 75%. The resulting material was then analyzed by LCMS, on a 10 mg / mL sample in 0.5% formic acid / FLO. The NTTP level after recrystallization was below the LOD. The resulting ion count before precipitation is shown in Fig, 10 A, and the extracted ion counts for NTTP is shown in Fig. 10B.

[0330] A number of implementations have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other implementations are within the scope of the following claims.

Claims

What is claimed is:

1. A method of removing a nitrosamine from a pharmaceutical ingredient, comprising: dissolving or dispersing the pharmaceutical ingredient in a solvent contained in an optically transmissible vessel, and irradiating with a light source of a defined wavelength and intensity for an amount of time sufficient to degrade the nitrosamine with little to no degradation of the pharmaceutical ingredient.

2. The method of claim 1, wherein the nitrosamine is a small molecular weight nitrosamine.

3. The method of claim 2, wherein the nitrosamine is N-nitroso-dimethylamine (NDMA), N- nitroso-diethylamine (NDEA), N-nitroso-methylphenylamine (NMPA), N-nitroso- diisopropylamine (NDIPA), N-nitroso-isopropylethylamine (NIPEA), N-nitroso-dibutylamine (NDBA). N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-dipropylamine (NDPA). N-nitroso-morpholine (NMOR). N-methyl-N-nitroso-phenethylamine (NMPEA). N- nitroso-l,2,3,6-tetrahydropyridine (NTHP), N-nitroso-piperidine (NPIP), 4- (methylnitrosamino)-l -(3 -pyridyl)- l-(butanone) (NNK), N-nitroso-diethanolamine (NDELA), N-nitroso-diphenylamine (NDPh), N-nitroso-piperazine. N-nitroso-pyrrolidine (NPYR). 1- methyl-4-nitrosopiperazine (MNP), N-nitroso-meglumine, N-nitroso-N-ethyl-benzylamine (NBEA), 3-((ethyl(nitroso)amino)methyl)benzenesulfonate.

4. The method of claim 2, wherein the nitrosamine is N-nitroso-dimethylamine (NDMA), N- nitroso-diethylamine (NDEA), N-nitroso-diethanolamine (NDELA), N-nitroso-N-methyl-4- aminobutyric acid (NMBA), N-nitroso-dibutylamine (NDBA), N-nitroso-methylphenylamine (NMPA), N-nitroso-diisopropylamine (NDIPA), N-Nitroso-ethylisopropylamine (NEIPA).

5. The method of claim 1, wherein the nitrosamine is an NDSRI.

6. The method of claim 5, wherein the NDSRI is N-nitroso-bumetanide, N- nitroso- duloxetine, N-nitroso-enalapril, N-nitroso-varenicline, N-nitroso-ciprofloxacin, N-nitroso- sitagliptin, N- nitroso-ramipril, N- nitroso-fluoxetine, N-nitroso-valsartan, N-nitroso- propranolol.

7. The method of any one of claims 1 to 6, wherein the pharmaceutical ingredient is an active pharmaceutical ingredient, reaction intermediate, raw material or an excipient.

8. The method of claim 7, wherein the pharmaceutical ingredient is any pharmaceutical ingredient stable to UV irradiation under conditions wherein the nitrosamine is reduced below acceptable levels.

9. The method of claim 7, wherein the pharmaceutical ingredient is any active pharmaceutical ingredient stable to UV irradiation under conditions wherein the nitrosamine is reduced below acceptable levels.

10. The method of claim 9, wherein the active pharmaceutical ingredient is valsartan, famotidine, losartan, metformin, nizatidine, ranitidine, irbesartan, azithromycin, rifampicin, bumetanide, duloxetine, enalapril, varenicline, ciprofloxacin, sitagliptin, ramipril, fluoxetine valsartan, propranolol.

11. The method of any one of claims 1 to 10, wherein the defined wavelength is a UVV wavelength.

12. The method of any one of claims 1 to 10, wherein the defined wavelength is a UVA wavelength.

13. The method of claim 1, wherein the pharmaceutical ingredient is an active pharmaceutical ingredient, reaction intermediate, raw material or an excipient.

14. The method of claim 13, wherein the pharmaceutical ingredient is any pharmaceutical ingredient stable to UV irradiation under conditions wherein the nitrosamine is reduced below acceptable levels.

15. The method of claim 13, wherein the pharmaceutical ingredient is any active pharmaceutical ingredient stable to UV irradiation under conditions wherein the nitrosamine is reduced below acceptable levels.

16. The method of claim 15, wherein the active pharmaceutical ingredient is valsartan, famotidine, losartan. metformin, nizatidine, ranitidine, irbesartan. azithromycin, rifampicin, bumetanide, duloxetine, enalapril, varenicline, ciprofloxacin, sitagliptin, ramipril, fluoxetine valsartan, propranolol.

17. The method of claim 1, wherein the defined wavelength is a UVV wavelength.

18. The method of claim 1, wherein the defined wavelength is a UVA wavelength.

19. A method for avoiding nitrosamine contamination in a pharmaceutical material by treating the pharmaceutical material using a method of any one of claims 1 to 12.

20. The method of claim 19, further comprising recrystallizing the pharmaceutical material after treatment.

21. A method for determining optimal differential degradation conditions for a nitrosamine and a pharmaceutical ingredient using a spiked-in approach procedure, wherein the spiked-in approach procedure comprises: generating multiple samples, each sample having a volume of 1 mL to 5 mL and including the pharmaceutical ingredient and a spike of the nitrosamine. each sample having a different solvent composition, different pH, different ionic strength, and / or being exposed to a different wavelength of radiation, reaction time, or temperature; and measuring pharmaceutical ingredient loss and nitrosamine loss in each sample after exposure to its corresponding wavelength of radiation, reaction time, and temperature.

22. The method of claim 21, wherein multifactorial analysis is performed in a set test system, varying defined wavelength, a panel of solvent, pH, time and temperature.

23. The method of claim 21 or 22, wherein a concentration of the nitrosamine is in a range of 1 ppm - 200 ppm.

24. The method of any one of claims 21 to 23, wherein a concentration of the pharmaceutical ingredient is in a range of 0. 1 mg / mL - 10 mg / mL.

25. A system, comprising: a container containing a composition of matter, the composition of matter comprising a pharmaceutical ingredient dissolved or dispersed in a solvent; an optically transmissible fluid module operably coupled to the container; a pump configured to cause the composition of matter to flow through the optically transmissible fluid module; and a radiation source configured to direct radiation having a defined wavelength and intensity towards the optically transmissible fluid module, the defined wavelength and intensity configured to preferentially degrade a nitrosamine with little to no degradation of the pharmaceutical ingredient.

26. The system of claim 25, further comprising one or more processing units configured to control operation of the system.

27. The system of claim 25 or 26, further comprising an analytical device configured to determine a concentration of the pharmaceutical ingredient and / or a nitrosamine within the composition of matter while the composition of matter is within the optically transmissible fluid module.

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