Production Of Active Pharmaceutical Ingredients Research Articles

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.

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.

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.

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.

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.

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.

End-to-End Continuous Small-Scale Drug Substance Manufacturing: From a Continuous In Situ Nucleator to Free-Flowing Crystalline Particles

In the evolving landscape of pharmaceutical manufacturing, a comprehensive continuous production process is being crafted for the small-scale production of active pharmaceutical ingredients. This study focuses on continuous crystallization with separate nucleation and crystal growth units, as well as continuous downstream processing, encompassing filtration, washing, and drying until the formation of free-flowing particles. We introduce a novel continuous nucleator designed based on solubility data and produced via 3D printing, enabling the fast and precise small-scale manufacturing of a nucleator meeting the requirements for nucleation and further growth processes. The nucleator is evaluated with regard to its suitability for continuous long-term operation across various coupled crystallizers. As a practical application example, it is connected to a slug flow crystallizer to enable high-quality continuous crystallization. Additionally, the full integration of downstream processes using a continuous vacuum screw filter to achieve free-flowing product particles is realized. Even under non-optimized process conditions, with the help of the in situ generation of nuclei, free-flowing product particles are successfully obtained. This is particularly useful during drug development when no material is available for seed addition and to quickly obtain products for further characterization.

Peptides as Therapeutic Agents: Challenges and Opportunities in the Green Transition Era.

Peptides are at the cutting edge of contemporary research for new potent, selective, and safe therapeutical agents. Their rise has reshaped the pharmaceutical landscape, providing solutions to challenges that traditional small molecules often cannot address. A wide variety of natural and modified peptides have been obtained and studied, and many others are advancing in clinical trials, covering multiple therapeutic areas. As the demand for peptide-based therapies grows, so does the need for sustainable and environmentally friendly synthesis methods. Traditional peptide synthesis, while effective, often involves environmentally draining processes, generating significant waste and consuming vast resources. The integration of green chemistry offers sustainable alternatives, prioritizing eco-friendly processes, waste reduction, and energy conservation. This review delves into the transformative potential of applying green chemistry principles to peptide synthesis by discussing relevant examples of the application of such approaches to the production of active pharmaceutical ingredients (APIs) with a peptide structure and how these efforts are critical for an effective green transition era in the pharmaceutical field.

Securing the supply of benzathine penicillin: a global perspective on risks and mitigation strategies to prevent future shortages.

Benzathine benzylpenicillin is a globally indispensable medicine. As a long-lasting injectable penicillin, it serves as the primary treatment for syphilis, group A streptococcal infections, rheumatic fever and rheumatic heart disease. A competitive market and low profit margins, compounded by limited visibility of demand, have resulted in a decreased number of active pharmaceutical ingredient (API) manufacturers. By 2016, only three Chinese API manufacturers remained, continuing to supply to the global market today. Recurring global shortages, a consequence of supply and demand imbalances, indicate underlying market risks. Therefore, the need for mitigation strategies is imperative.

A total productive maintenance & reliability framework for an active pharmaceutical ingredient plant utilising design for Lean Six Sigma

This research investigates the requirement for and relationship and implementation of a total productive maintenance (TPM) and Reliability Centred Maintenance (RCM) strategy within an Active Pharmaceutical Ingredient (API) Plant. This research aimed to study the tools and techniques of TPM and Reliability Engineering and then deploy a designed model to an API plant. A case study involving Design for Lean Six Sigma phases of Define, Measure, Analyse, Design, and Verify was utilised to build an API site TPM pilot program. Data was collected using interviews across Company 'X's local and Global Engineering teams. Process runtime, downtime and plant availability metrics were compiled and a new design for Total Productive Maintenance and Reliability was proposed and verified. A maintenance framework was designed to optimally incorporate Total Productive Maintenance, Reliability and Operational Excellence with an emphasis on Overall Equipment Efficiency (OEE) realizing a 33 % reduction in planned maintenance activities, a 70 % reduction in Corrective Maintenance, Cleaning for Maintenance was reduced by 50 %, the pilot maintenance area of the centrifuge has its OEE increased by 20 % and plant availability increased by two hundred and 6 h. This research highlights the importance of Total Productive Maintenance as a key component of an effective maintenance strategy and its potential to transform maintenance practices. Based on this research and results, TPM is recommended to be applied to any API manufacturing organization. A limitation of the study is that it is a single-site case study. The novelty of this research is based upon the emphasis on Reliability Engineering to remove non-value add Maintenance time from the manufacturing schedule. The Total Productive Maintenance & Reliability model designed and implemented in this research is unique in the literature and can be leveraged by engineering professionals and academics to understand the benefits of TPM.

The effects of particle shape, orientation, and Reynolds number on particle-wall collisions

Crystallisation is an important unit operation used in the production of Active Pharmaceutical Ingredients (APIs). Crystallisation is typically carried out using seed crystals in a process called secondary nucleation that allows for greater control of crystal quality attributes. The mechanism of secondary nucleation is still not well understood. Particle attrition is one proposed mechanism. This work examines the conditions under which particle-wall collisions occur. This is done through the simulation of free-moving particles in an impinging jet flow using an immersed-boundary lattice Boltzmann method (IB-LBM) CFD solver. Particle Reynolds numbers from 100 to 400 are examined. Particle shapes with aspect ratios from 1:1 to 8:1 are used to represent the crystal habits of APIs.Particles that start in their low-drag or high-drag orientation maintain this orientation on approach to the target surface. All other intermediate initial orientations examined cause particles to rotate toward and overshoot their high-drag form before adopting their high-drag form in proximity to the target surface. Particles in their low-drag form remain in their initial orientation due to the symmetry of the computational domain. In this orientation, a collision is most likely to occur, and the minimum critical Reynolds number at which a particle-wall collision will occur can be determined. This value is shown to increase with increasing particle frontal length. Pointed or rounded leading edges are shown to improve a particle's ability to pierce the boundary layer adjacent to the target surface and reduce this value. In cases where a Reynolds number of 400 is insufficient to cause a particle-wall collision, the particles’ minimum distances from the target surface are reported. Using the minimum critical Reynolds number values obtained, the approach velocities required for particles to collide with a wall are shown to be larger than the impeller tip speeds typically used during crystallisation operations. This work provides for the first time the conditions under which particle-wall collisions occur for varying shape and orientation, their behaviour on approach, and the associated impact velocities.

The Transfer Pricing Implications of GILTI for Transfer Pricing in the Pharmaceutical Sector

Pharmaceutical multinationals generate substantial profits from their ownership of valuable intangible assets including patents and marketing intangibles. Their production activities are often vertically integrated with the production of active pharmaceutical ingredients occurring in Western Europe with the fill and finish function occurring in India. The transfer pricing challenges have led to numerous litigations where tax authorities have accused multinationals of shifting profits to tax havens. This article discusses the transfer pricing issues in litigations involving Canada, India and the United States, noting how the applications of market-based approaches versus profits-based approaches lead to very different results.

SeDeM as a Tool to Validate Drug Substance Manufacturing Processes and Assess Scalability and Suitability for Direct Compression: Supplier Screening.

During the development of an oral solid form of a drug substance, a thorough understanding of the critical material attributes is necessary, as the physical properties of the active pharmaceutical ingredient (API) can profoundly influence the drug product's manufacturability, critical quality attributes, and bioavailability. The objective of this study was to validate the manufacturing process of the drug Linezolid from three different sources at both the pilot and industrial scale and to identify differences in critical material attributes between the API manufacturers. Furthermore, the scalability factor between the pilot and industrial scale and the suitability of a process for direct compression were also evaluated. In the present study, the different sources of API were characterized by SeDeM methodology, particle size distribution, and scanning electron microscopy determinations. The statistical analysis revealed that no statistically significant differences were found for any of the parameters under study for the same API source analyzed on both scales. On the other hand, for most of the parameters evaluated, statistical differences were observed between the different sources. It was concluded that SeDeM was able to successfully validate the API manufacturing process, assess scalability, and distinguish between sources. Therefore, it could be highly valuable in the formulation phase to select the best API source.

Enantioselective Transformations in the Synthesis of Therapeutic Agents.

The proportion of approved chiral drugs and drug candidates under medical studies has surged dramatically over the past two decades. As a consequence, the efficient synthesis of enantiopure pharmaceuticals or their synthetic intermediates poses a profound challenge to medicinal and process chemists. The significant advancement in asymmetric catalysis has provided an effective and reliable solution to this challenge. The successful application of transition metal catalysis, organocatalysis, and biocatalysis to the medicinal and pharmaceutical industries has promoted drug discovery by efficient and precise preparation of enantio-enriched therapeutic agents, and facilitated the industrial production of active pharmaceutical ingredient in an economic and environmentally friendly fashion. The present review summarizes the most recent applications (2008-2022) of asymmetric catalysis in the pharmaceutical industry ranging from process scales to pilot and industrial levels. It also showcases the latest achievements and trends in the asymmetric synthesis of therapeutic agents with state of the art technologies of asymmetric catalysis.