Synthesis and Characterization of Genotoxic and Process Impurities of Active Pharmaceutical Ingredients (APIs)

Abstract

Active Pharmaceutical Ingredients (APIs) are biologically active substances responsible for medication's therapeutic efficacy and safety. They are the backbone of the pharmaceutical industry, and their assurance and effectiveness are critical to the health and well-being of the public. As such, strict quality control standards and regulatory guidelines are in place to validate the assurance and effectiveness of APIs. Developing new and innovative APIs is a critical research domain in the therapeutic industry, as it can revolutionize the treatment of a wide range of diseases and health conditions. The discovery of new APIs requires significant investment in research and development, and the process can take many years due to the rigorous testing necessary to ensure their safety and efficacy. Impurities formed during the bulk manufacturing of drugs present in APIs can significantly affect drug formulations' assurance, excellence, and effectiveness. The formation pathways of impurities play a vital role in understanding their properties and designing appropriate measures to control them. Impurities can arise due to various factors, including the raw materials used in producing, storing, and transporting the final product. So, it is essential to detect the primary origin of impurities and control their formation to ensure the assurance of the final product. This research focuses on two APIs, Rufinamide and Lidocaine, subject to strict regulatory guidelines. Impurities in these APIs are known to be a significant concern, and their synthesis and characterization are essential to understanding their properties and effects. Rufinamide is a type of medication that belongs to the antiepileptic drug class and is primarily used to treat seizures that are linked with Lennox-Gastaut syndrome. This neurological disorder is characterized by multiple types of seizures that start in early childhood and are usually difficult to manage with conventional treatments. Rufinamide stabilizes the brain's electrical activity and reduces the frequency and intensity of seizures. A total of 9 impurities of Rufinamide were synthesized using a green and cost-effective 1,3-dipolar cycloaddition approach with benzyl bromide derivatives methodology, optimizing reaction conditions, solvents, and catalysts to enhance efficiency and yield. This study also investigated the hydrolysis process to convert a cycloadduct product to Rufinamide under different conditions, emphasizing the critical role of specific solvents and catalyst concentrations for successful hydrolysis. The research provides a sustainable route for Rufinamide production. The maximum yield of most of the products was obtained between 90 and 97% by the stoichiometry of the reactions. Lidocaine, being an amino amide, is a well-known drug that is utilized for several numbing purposes. Through systemic intravenous injection, lidocaine becomes more extensive in many situations of acute and chronic pain, such as visceral pain, labor pains, postoperative pain, neuropathic pain, postherpetic neuralgia, hyperalgesia, visceral pain, and centralized pains. A total of 13 impurities of Lidocaine were synthesized through a cost-effective green methodology with high yields, utilizing palladium over carbon as a reducing agent and less hazardous inorganic salts to create an eco-friendly and safer process. The synthesized compounds exhibit potential biomedical applications, including inducing cancer cell death or protective autophagy. The maximum yield of most of the products was obtained between 90 and 97% by the stoichiometry of the reactions. The research also discusses the synthesis of impurities in Rufinamide and Lidocaine, highlighting their academic and industrial relevance across various scientific disciplines. Efficient synthetic protocols for these impurities open new avenues for innovation and drug discovery in the pharmaceutical industry. The optimization process for synthesizing Rufinamide without isolating it as a single intermediate has significantly reduced cycle time, saving time and cost while maintaining high product quality. Monitoring lidocaine levels is crucial to prevent toxicity, with healthcare professionals needing to understand its toxicity and effective management strategies, especially in high-risk scenarios involving intravenous lidocaine infusions. These impurities were formed through various pathways, including oxidation, dealkylation, and nitration. It found that the impurities could be controlled by optimizing the synthesis process and using appropriate storage conditions. For example, these are formed due to oxidation, which could be controlled by using antioxidants during synthesis and storing the final product in a dark and cool environment. The synthesized impurities and their formation pathways are identified and characterized using NMR and MS spectroscopy. The results contribute to the ongoing efforts to improve pharmaceutical quality control and regulatory compliance, ultimately benefiting public health and ensuring the effectiveness of these critical medications. It is essential to understand the formation pathways of impurities and design appropriate measures to control them. Advanced analytical techniques in this study have provided valuable information that will help pharmaceutical companies improve product integrity. Lastly, APIs are critical to the pharmaceutical industry, and their safety and effectiveness are paramount to the health and well-being of the public. Impurities in API can reduce the integrity, assurance, and effectiveness of the drug. So, excipient and product quality rely on understanding impurities formation pathways. The application of state-of-the-art analytical procedures in this research has presented essential information that pharmaceutical companies' success depends on to guarantee the integrity and success of their products. At large, the public is the beneficiary, and the effectiveness of medications is not compromised. Considering the impurities pivots, they acquire greater relevance in polymer chemistry, biological chemistry, and materials science, characterized by unique features. The implication of azole and amide-type groups into polymers could substantiate the advent of materials with predesigned and distinctive qualities. Along with azole as the basic building block, such compounds can serve multiple purposes as molecular probes for investigating biomolecular connections and biological processes in this subject. The fact that they can be used to study a particular biomolecule's structural and functional features comes from the ability to interact with biomolecules and proteins directly. For example, introducing these contaminations can cause the user to interact with biomolecules and proteins directly from materials with higher conductivity, mechanical strength, and thermal stability. In addition, a fusion of these impurities contributes to the resistance of polymers to such factors as heating, moisture, and UV rays from the sun inside the material.