Drug Synthesis

The pharmaceutical industry is emerging as a significant industrial sector with tremendous potential for providing innovative drugs to treat life-threatening diseases as well as for providing economical generic alternatives of supreme quality. Hence this sector is not only responsible to provide the much desired boost to the health of the society, especially of the developing countries, but also it is a competitive yet profitable sector from a business perspective. Currently, the primary focus of the pharmaceutical industry is to raise the bar for the quality, safety and efficacy of the drug products that are made available in the global market place. Product quality, price of raw materials [API (active pharmaceutical ingredient) and excipients] and market return competition are vital factors that determine the longevity or existence and profitability of a company in the crowded pharmaceutical market.. Hence these critical factors receive special consideration from drug product manufacturers. Active Pharmaceutical Ingredient (API) is the primary constituent of a pharmaceutical drug product that governs the final cost of the drug product as well as the commercial profit earned by the company. Most of the major generic drug manufacturing companies have their own API manufacturing facility and hence may not prefer to screen independent API suppliers as part of their generic drug development plan to procure additional API. Contradictorily, the generic drug manufacturers who do not synthesize the API themselves are dependent on external and independent API manufacturers for procurement of the API. Such generic drug manufacturing companies have to select suitable API suppliers by adapting a risk aversive approach. This article presents an informed and comprehensive discussion on the primary and alternate API supplier selection processes for generic drug products manufacturing firms. This API supplier selection process can be categorized into several stages which include preliminary assessment, documents review, samples analysis, onsite or offsite audit, results evaluation and final approval or rejection. This API selection process includes the anticipated product specific risk assessment with relation to API characteristics, specifications, analytical results, document review observations and inspection results. A generic drug product manufacturing company can choose an alternative API supplier or change the existing API supplier either during the development phase or after development of the drug product. Generic drug product manufacturing companies should rework on development activities if any API supplier change happens during the development phase. API supplier change or addition of an alternative API supplier has to be followed as per SUPAC guidance for US market and VARIATION filing procedures for European market.

A new N-(phthalazin-5-yl)hydrazonoyl chloride derivative (2) is made accessible from luminol via the Japp-Klingemann reaction. In presence of triethyl amine, compound 2 reacted with N-substituted piperazines and related sec-amine congeners to deliver the respective set of new N-(phthalazin-5-yl)amidrazones (4a-h) in fair yield. The chemical structures of the newly synthesized compounds were confirmed by 1H NMR, 13C NMR and ESI-HRMS spectral data. However, the amidrazones (4a-e) were found to display weak to moderate activity against breast cancer cell line (MCF-7) with MIC50 » 25-100 μM/mL.

Background: Recently, in silico or computer-aided drug design has emerged as a cornerstone on the harbor of modern drug discovery. One of the approaches to treat cancer is the inhibition of tyrosine kinase, which is considered as a key enzyme in the survival of the cancerous cells. Spebrutinib, as a member of the tyrosine kinase inhibitors, has few unwanted side effects due to its off-target bindings. In this work, the GOLD program was employed to predict the bindings and thus the inhibitory activity toward the tyrosine kinase. Methodology: After the design and docking processes, the chemical synthesis of three spebrutinib analogues was achieved. Results: The percent yields of the chemical syntheses were ranged from 81% to 89%.  These analogues were characterized utilizing; FT-IR, DSC, CHN, and 1H NMR. In conclusion, these new spebrutinib analogues were successfully designed, synthesized, and characterized. However, these analogues are potential anticancer agents and biological activity against cancerous and toxicity pattern against normal cells are crucial to affirm the present findings.