Production Of Active Pharmaceutical Ingredients Research Articles

Recent Advances in the Synthesis of Sulfonamides Intermediates

AbstractSulfonamides are one of the most important synthons in drug synthesis, which can increase the water solubility of drugs and regulate their metabolism in vivo. According to statistics, nearly 30% of sulfur-containing drugs on the market contain sulfonamide groups, including omeprazole, hydrochlorothiazide, and other best-selling drugs. Synthesis of sulfonamide is therefore a very important part of new drug development and active pharmaceutical ingredient manufacturing. In this review, we will focus on the recent 5-year advances in the field of synthetic research and structural modification of sulfonamide-containing drugs and their intermediates. The synthesis strategies, including S−N construction, C−N cross-coupling, N−H functionalization, and C−H sulfonamidation, are discussed, hoping to provide new ideas for the researchers to prepare sulfonamides in a green and efficient way.

Research and development investment of Chinese chemical pharmaceutical companies under the national pooled procurement: a retrospective panel data analysis, 2013–2022

ObjectiveTo generate evidence about changes in the research and development (R&D) investment of Chinese chemical pharmaceutical companies before and after the implementation of the national pooled procurement, to respond to...

Environmental impacts of drug products: The effect of the selection of production sites in the supply chain

The environmental impact of drug products is largely determined by activities beyond the direct control of pharmaceutical companies, such as outsourced production of pharmaceutical building blocks. Therefore, this study evaluates the environmental impacts of a prostate cancer drug packaged in one blister (declared unit), thereby analysing the whole value chain to gain insight into 1) the main contributors to the impact of drug product production and 2) the effect of the geographical location of production of solvents and pharmaceuticals. The carbon and resource footprints of the entire life cycle of the drug product are determined, using the IPCC GWP 100 and the Cumulative Exergy Extraction from the Natural Environment methods, respectively. Unlike many other studies, the impacts of building blocks, called intermediate pharmaceutical ingredients (IPIs), are modelled based on primary data, literature and similar processes. The carbon footprint per declared unit equals 34 kg CO2-eq, of which IPIs and active pharmaceutical ingredient (API) production account for 96 %. The resource footprint is 647 MJex/declared unit, with IPI and API production accounting for 93 %. The main impact contributors of these processes are solvents and electricity consumption. Four alternative scenarios for IPI and API production are developed to evaluate the geographical influence of different production locations of solvents and pharmaceuticals between Europe and China. European production of solvents and pharmaceuticals appears to have the lowest carbon and resource footprint. In contrast, Chinese production of solvents and pharmaceuticals increases the carbon footprint by 49 %, while the resource footprint increases by only 4 %, although the natural resource consumption shifts from abiotic renewable resources and nuclear energy to fossil fuels. The high contribution of IPI production and the influence of geography of the supply chain highlight the need for accurate data from external suppliers to fairly estimate the environmental footprint of drug products.

Sustainable medicines development and use: Challenges and opportunities in the sustainable production of active pharmaceutical ingredients.

Sustainable medicines development and use: Challenges and opportunities in the sustainable production of active pharmaceutical ingredients.

Carbon footprint of oral medicines using hybrid life cycle assessment

BackgroundHealthcare represents 3–8% of a country's carbon footprint, and medicines are estimated to represent 20–55% of healthcare's carbon footprint. Unfortunately, only scarce and partial medicine life cycle assessments (LCAs) are reported due to the limited availability of needed data to perform them. MethodsWe describe a method to estimate the cradle-to-pharmacy gate LCA of all oral medicines from the French pharmacopeia (n = 12,316 medicines) that includes the entire medicine-related carbon footprint, encompassing active pharmaceutical ingredient (API), excipients and packaging production, transport, medicine manufacturing, and associated corporate emissions using a hybrid LCA/environmentally extended input-output model. The uncertainty surrounding this estimation is modeled using bootstrap. FindingsAlthough the API carbon footprint is correlated with synthesis yield, its number of steps, presence of chiral center(s), and process mass intensity, the API carbon footprint is better predicted by its wholesale cost. Corporate emissions (34.5%), API production (28.5%), and medicine manufacturing (25.5%) are the most impactful contributors to medicine carbon footprints, while medicine packaging (5.3%), transport (3.6%), and excipients (2.7%) are less significant. Variations from one medicine to another are substantial. The mean carbon footprint of a medicine box is 8.47 kgCO2eq/box (median 1.46 kgCO2eq, 95% CI 0.34–73.98). Medicines' carbon footprint is correlated with their price but not linearly, as low-cost medicines have significantly higher emission factors of 0.2–0.3 kgCO2/€ versus 0.05–0.1 kgCO2/€ for high-cost drugs. Orphan and innovative medicines tend to have higher carbon footprints. InterpretationMedicine carbon footprints are highly variable. This database allows for a better understanding of the carbon footprint associated with medicines, in order to better eco-design care pathways.

A near-complete assembly of the Houttuynia cordata genome provides insights into the regulatory mechanism of flavonoid biosynthesis in Yuxingcao

Houttuynia cordata, also known as Yuxingcao in Chinese, is a perennial herb in the Saururaceae family. It is highly regarded for its medicinal properties, particularly in treating respiratory infections and inflammatory conditions, as well as boosting the human immune system. However, a lack of genomic information has hindered research on the functional genomics and potential improvements of H. cordata. In this study, we present a near-complete assembly of H. cordata genome and investigate the biosynthetic pathway of flavonoids, specifically quercetin, using genomics, transcriptomics, and metabolomics analyses. The genome of H. cordata diverged from that of Saururus chinensis around 33.4 million years ago; it consists of 2.24 Gb with 76 chromosomes (4n = 76) and has undergone three whole-genome duplication (WGD) events. These WGDs played a crucial role in shaping the H. cordata genome and influencing the gene families associated with its medicinal properties. Through metabolomics and transcriptomics analyses, we identified key genes involved in the β-oxidation process for biosynthesis of houttuynin, one of the volatile oils responsible for the plant’s fishy smell. In addition, using the reference genome, we identified genes involved in flavonoid biosynthesis, particularly quercetin metabolism, in H. cordata. This discovery has important implications for understanding the regulatory mechanisms that underlie production of active pharmaceutical ingredients in traditional Chinese medicine. Overall, the high-quality genome assembly of H. cordata serves as a valuable resource for future functional genomics research and provides a solid foundation for genetic improvement of H. cordata for the benefit of human health.

A green Heck reaction protocol towards trisubstituted alkenes, versatile pharmaceutical intermediates.

The Heck reaction is widely employed to build a variety of biologically relevant scaffolds and has been successfully implemented in the production of active pharmaceutical ingredients (APIs). Typically, the reaction with terminal alkenes gives high yields and stereoselectivity toward the trans-substituted alkenes product, and many green variants of the original protocol have been developed for such substrates. However, these methodologies may not be applied with the same efficiency to reactions with challenging substrates, such as internal olefins, providing trisubstituted alkenes. In the present work, we have implemented a Heck reaction protocol under green conditions to access trisubstituted alkenes as final products or key intermediates of pharmaceutical interest. A set of preliminary experiments performed on a model reaction led to selecting a simple and green setup based on a design of experiments (DoE) study. In such a way, the best experimental conditions (catalyst loading, equivalents of alkene, base and tetraalkylammonium salt, composition, and amount of solvent) have been identified. Then, a second set of experiments were performed, bringing the reaction to completion and considering additional factors. The protocol thus defined involves using EtOH as the solvent, microwave (mw) irradiation to achieve short reaction times, and the supported catalyst Pd EnCat®40, which affords an easier recovery and reuse. These conditions were tested on different aryl bromides and internal olefines to evaluate the substrate scope. Furthermore, with the aim to limit as much as possible the production of waste, a simple isomerization procedure was developed to convert the isomeric byproducts into the desired conjugated E alkene, which is also the thermodynamically favoured product. The approach herein disclosed represents a green, efficient, and easy-to-use handle towards different trisubstituted alkenes via the Heck reaction.

Catalytic Dehydration of Biomass-Derived Feedstocks to Obtain 5-Hydroxymethylfurfural and Furfural

Biomass-produced furanics, furfural and 5-hydroxymethylfurfural (5-HMF), are considered as vital platform chemicals used in the production of active pharmaceutical ingredients (APIs), commodity goods, and fuels. The primary challenge associated with their production pertains to the high cost involved in scaling up to industrial levels. Consequently, it is essential to explore more cost-effective options that yield efficient end products. In this study, the use of Lewis and Brønsted acids such as HCl and AlCl3 enhances the isomerization of glucose through catalytic dehydration into 5-HMF. It was observed that employing moderate reaction conditions increased the yield of 5-HMF to 44.94 % and 50.60 % respectively, with changes in HCl concentration and AlCl3 mass loading. The suitable conditions to achieve the highest yield of 5-HMF were 100 μL of HCl, 0.75 g of AlCl3, reaction temperature 150 °C, and reaction time 4 h. In the second experiment, corncob was converted into furfural in the presence of 20 % H2SO4, in combination with NaCl as a promoter. The optimal conditions under which a yield of 44.77 % was achieved were as follows: 50 mL of 20 % H2SO4, reaction temperature 140 °C, 0.5 g of NaCl, 5 g of corncob, and reaction time 160 min. Furthermore, a proposed reaction mechanism was outlined to elucidate the pathway for the production of the aforementioned platform chemicals.

Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced 13C and 15N Solid-State NMR Spectroscopy.

Crystallization is a widely used purification technique in the manufacture of active pharmaceutical ingredients (APIs) and precursor molecules. However, when impurities and desired compounds have similar molecular structures, separation by crystallization may become challenging. In such cases, some impurities may form crystalline solid solutions with the desired product during recrystallization. Understanding the molecular structure of these recrystallized solid solutions is crucial to devise methods for effective purification. Unfortunately, there are limited analytical techniques that provide insights into the molecular structure or spatial distribution of impurities that are incorporated within recrystallized products. In this study, we investigated model solid solutions formed by recrystallizing salicylic acid (SA) in the presence of anthranilic acid (AA). These two molecules are known to form crystalline solid solutions due to their similar molecular structures. To overcome challenges associated with the long 1H longitudinal relaxation times (T1(1H)) of SA and AA, we employed dynamic nuclear polarization (DNP) and 15N isotope enrichment to enable solid-state NMR experiments. Results of solid-state NMR experiments and DFT calculations revealed that SA and AA are homogeneously alloyed as a solid solution. Heteronuclear correlation (HETCOR) experiments and plane-wave DFT structural models provide further evidence of the molecular-level interactions between SA and AA. This research provides valuable insights into the molecular structure of recrystallized solid solutions, contributing to the development of effective purification strategies and an understanding of the physicochemical properties of solid solutions.

Quality by Design Considerations for Drop-on-Demand Point-of-Care Pharmaceutical Manufacturing of Precision Medicine.

Distributed and point-of-care (POC) manufacturing facilities enable an agile pharmaceutical production paradigm that can respond to localized needs, providing personalized and precision medicine. These capabilities are critical for narrow therapeutic index drugs and pediatric or geriatric dosing, among other specialized needs. Advanced additive manufacturing, three-dimensional (3D) printing, and drop-on-demand (DoD) dispensing technologies have begun to expand into pharmaceutical production. We employed a quality by design (QbD) approach to identify critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs) of a POC pharmaceutical manufacturing paradigm. This theoretical framework encompasses the production of active pharmaceutical ingredient (API) "inks" at a centralized facility, which are distributed to POC sites for DoD dispensing into/onto delivery vehicles (e.g., orodispersible films, capsules, single liquid dose vials). Focusing on the POC dispensing/dosing processes, QbD considerations and cause-and-effect analyses identified the dispensed API quantity and solid-state form (CQAs), as well as the nozzle diameter, system pressure channel, and number of drops dispensed (CPPs) for detailed investigation. Final assay quantification and content uniformity CQAs were measured from demonstrative levothyroxine sodium single-dose liquid vials of glycerin/water, meeting the standard acceptance values. Each POC facility is unlikely to maintain full quality control laboratory capabilities, requiring the development of appropriate atline or inline methods to ensure quality control. We developed control strategies, including atline ultraviolet-visible (UV-vis) verification of the API ink prior to dispensing, inline drop counting during dispensing, intermediate atline-dispensed volume checks, and offline batch confirmation by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following production.

Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane‐Based Technologies

AbstractContinuous crystallization of pharmaceuticals has been in the center of attention during the past two decades, with a more focus on the large‐scale production of active pharmaceutical ingredients. The increasing demand for pharmaceuticals requires high‐throughput production of drug crystals with different solubilities, stabilities, shapes, habits, polymorphs, and size distributions. With numerous advantages including low cost, ease of scale‐up, and superior control over polymorph and size distribution of drug crystals, antisolvent crystallization is one of the most promising crystallization methods recently attempted. However, it fails to deliver the required characteristic where the crystal systems tend to grow and for the preparation of metastable polymorphs. This review focuses on the most recent efforts to tackle these drawbacks by coupling antisolvent crystallization with cooling, supercritical‐assisted, microfluidics‐assisted, and membrane‐assisted crystallization. This systematic review aims to provide a concise summary of each coupled antisolvent technique and their positive and negative aspects. This review can be used as a guideline for pharmacist, biologists, and chemists, who are interested in the crystal engineering of pharmaceuticals to pave the way for further developments in this field.

A Novel CFD Model of SMX Static Mixer Used in Advanced Continuous Manufacturing of Active Pharmaceutical Ingredients (API)

A Novel CFD Model of SMX Static Mixer Used in Advanced Continuous Manufacturing of Active Pharmaceutical Ingredients (API)

Bottom-up production of injectable itraconazole suspensions using membrane technology

Bottom-up production of active pharmaceutical ingredient (API) crystal suspensions offers advantages in surface property control and operational ease over top-down methods. However, downstream separation and concentration pose challenges. This proof-of-concept study explores membrane diafiltration as a comprehensive solution for downstream processing of API crystal suspensions produced via anti-solvent crystallization. It involves switching the residual solvent (N-methyl-2-pyrrolidone, NMP) with water, adjusting the excipient (d-α-Tocopherol polyethylene glycol 1000 succinate, TPGS) quantity, and enhancing API loading (solid concentration) in itraconazole crystal suspensions. NMP concentration was decreased from 9 wt% to below 0.05 wt% (in compliance with European Medicine Agency guidelines), while the TPGS concentration was decreased from 0.475 wt% to 0.07 wt%. This reduced the TPGS-to-itraconazole ratio from 1:2 to less than 1:50 and raised the itraconazole loading from 1 wt% to 35.6 wt%. Importantly, these changes did not adversely affect the itraconazole crystal stability in suspension. This study presents membrane diafiltration as a one-step solution to address downstream challenges in bottom-up API crystal suspension production. These findings contribute to optimizing pharmaceutical manufacturing processes and hold promise for advancing the development of long-acting API crystal suspensions via bottom-up production techniques at a commercial scale.

A continuous flow approach for the desulfurative bromination of sulfides

The preparation of alkyl bromides is a pivotal transformation in organic chemistry. The wide range of applications that bromides have as building blocks render this class of compounds a privileged motif widely used in the manufacture of active pharmaceutical ingredients. Traditionally prepared from the deoxygenation of alcohols, alkyl bromides have been recently obtained from sulfides in high yields, a transformation we have named desulfurative bromination. In order to improve the efficiency of this transformation, we report herein the investigation and optimisation of a continuous flow strategy. The influence of the flow rate; role of the brominating agent; and substrate scope have been studied delivering an in-flow protocol to access multigram quantities of these valuable intermediates.

Evaluation of a Novel LC-MS/MS Based Analytical Method for the Risk Assessment of Nitrosamines in Pharmaceutical Products and Packaging Materials

The detection of nitrosamine impurities, particularly small dialkyl types, which are frequently known to be potent mutagenic carcinogens, in some Sartan group active pharmaceutical ingredients (APIs) and finished drug products caused global regulatory organizations to have concerns. Accordingly, Registration Holders/Applicants, API manufacturers, and their raw material suppliers are required to check the presence of nitrosamines in their products and carry out risk assessments using the quality risk management principles specified in the ICH Q9 guide. In this context, a new LC-MS/MS method has been developed and validated for the simultaneous determination of NDMA, NDEA, NMBA, NDIPA, NEIPA, NDBA, and MeNP nitrosamine compounds in API and finished products as well as in primary packaging materials, one of the risk sources. This validated method was applied to check the nitrosamine content may occur from canister, blister, printed aluminum foil, nasal spray, and eye drop packaging materials as part of the Extractables & Leachables studies arising from interactions between the product and the primary packaging. For the determination and quality control of nitrosamines in sartan group pharmaceutical products and packaging materials, the developed LC-MS/MS analytical method offers highly reliable, fast, high accuracy, good sensitivity and simultaneous detection even at low concentrations.

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

AbstractThe pharmaceutical industry has traditionally employed batch processing as a means of synthesizing active pharmaceutical ingredients (APIs) on a commercial scale. Batch manufacturing enables API synthesis in large quantities in order to meet regulations. Yet, this strategy remains cumbersome, is labor‐intensive, and creates complex logistical networks. In recent decades, batch API processing has gradually eroded American economic competitiveness and has led to the offshoring of API manufacturing from the United States. Today it is estimated that +80% of APIs are manufactured overseas.[1] Meanwhile, disruptions from the Coronavirus Disease (SARS‐CoV‐2) have exacerbated weaknesses in the global supply chain, culminating with widespread shortages of critical life‐saving drugs.[2] These shortages have emphasized the importance of reshoring drug manufacturing to the U.S. and fostered a regulatory landscape that seeks advanced methods of API manufacturing in order to bolster America's supply chain resiliency.[3] Recently, increased attention has been directed towards continuous drug manufacturing to enable nonstop API production within modular stand‐alone flow systems. Continuous manufacturing (CM) facilitates modular automation, offers new avenues towards process intensification, and even enables in‐line analytical monitoring from raw materials to packaged products. This strategy offers better conversion, increased safety, reduced waste, and overall cost savings versus traditional batch‐style processing. The rise of advanced API manufacturing, coupled with the current regulatory landscape, offers a rare window of opportunity to convert traditional batch pharmaceutical processes into continuous, streamlined production systems to on‐shore API manufacturing and eliminate drug shortages. This review will outline the current state‐of‐the‐art in the CM of APIs and will highlight the translation of chemistry and unit operations from batch processes to modular CM systems.

Towards continuous flow manufacturing of active pharmaceutical ingredients in Africa: a perspective

Building start-of-the-art, sustainable and competitive local API manufacturing in Africa using continuous flow technology.

Multiphasic Continuous‐Flow Reactors for Handling Gaseous Reagents in Organic Synthesis: Enhancing Efficiency and Safety in Chemical Processes

AbstractThe use of reactive gaseous reagents for the production of active pharmaceutical ingredients (APIs) remains a scientific challenge due to safety and efficiency limitations. The implementation of continuous‐flow reactors has resulted in rapid development of gas‐handling technology because of several advantages such as increased interfacial area, improved mass‐ and heat transfer, and seamless scale‐up. This technology enables shorter and more atom‐economic synthesis routes for the production of pharmaceutical compounds. Herein, we provide an overview of literature from 2016 onwards in the development of gas‐handling continuous‐flow technology as well as the use of gases in functionalization of APIs.

Multiphasic Continuous-Flow Reactors for Handling Gaseous Reagents in Organic Synthesis: Enhancing Efficiency and Safety in Chemical Processes.

The use of reactive gaseous reagents for the production of active pharmaceutical ingredients (APIs) remains a scientific challenge due to safety and efficiency limitations. The implementation of continuous-flow reactors has resulted in rapid development of gas-handling technology because of several advantages such as increased interfacial area, improved mass- and heat transfer, and seamless scale-up. This technology enables shorter and more atom-economic synthesis routes for the production of pharmaceutical compounds. Herein, we provide an overview of literature from 2016 onwards in the development of gas-handling continuous-flow technology as well as the use of gases in functionalization of APIs.

Problem and Prospect of Pharmaceuticals Industry of Bangladesh amid LDC Graduation

Aims: The paper aims to identify the prospects and challenges of the pharmaceutical sector of Bangladesh after graduation and explores potential areas of market and product diversification. Addressing the upcoming graduation challenges, the paper sheds light on trade-related challenges of pharmaceutical industry and digs out a way forward. Study Design: The study is conducted using primary data from the Key Informant Interview (KII) and secondary data from different publications and sources. A qualitative survey tool is used for assessing the view of stakeholders and graduation challenges for pharmaceutical sector. Methodology: The study uses qualitative tools to evaluate the area of market and product diversification of the pharmaceutical industry and finally uses the Autoregressive Integrated Moving Average (ARIMA) model to forecast export figure from 2023 to 2032 and what interventions need to be taken to reach the expected level of growth amid LDC graduation. Results: The pharmaceutical industry will confront significant hurdles in terms of value addition, TRIPS-waiver erosion, patent payments, and license fees for producing pharmaceuticals product and medicine after graduation. Moreover, the industry faces difficulties due to excessive reliance on Active Pharmaceutical Ingredient (API) imports, limited diversified products, lack of Research and Development (R&D) and lab testing facilities, lack of infrastructure in the API park, dearth of bioequivalence test facilities, and patentable molecules in the post-graduation era. Recommendation: Bangladesh needs to accentuate API production, R&D, reverse engineering, and technical know-how as well as make a functional API Park, develop a curriculum to have experts in synthesis chemistry, and establish an accredited bioequivalence study center to secure patentable molecules and API.