Active Pharmaceutical Ingredient Process Research Articles

HOT MELT EXTRUSION IN ENGINEERING OF DRUG COCRYSTALS: A REVIEW

Crystal engineering technique has been widely explored in recent times to bring about changes in crystallinity which aids to achieve various goals such as solubility enhancement, stability and in vivo bioavailability without altering the chemical properties of the drug. Cocrystallisation is one of the crystal engineering approaches where the drug and an inert coformer are linked together by hydrogen bonding forming supramolecular homosynthon or heterosynthon using solvent-based or solvent-free techniques. Processing of active pharmaceutical ingredients with inert water-soluble coformers yields multicomponent crystalline cocrystals with high-performance characteristics and enhanced flow properties. Due to the emerging need of the industry for greener techniques, hot melt extrusion (HME), a continuous and solvent-free process is emerging as a field of interest in the mechanochemical synthesis of various pharmaceutical dosage forms such as solid dispersions, implants, ointments, and cocrystals. The current review emphasizes the role of HME as a cocrystallization technique for drugs to tailor-make their properties and ease of formulation. The distinct feature of HME is phase control during the process of cocrystallization. Furthermore, the selection of appropriate coformers with desirable water-solubility and stability features makes HME amenable to cocrystallization of versatile actives yielding suitable dosage forms. The application of process analytical technology further adds ease of monitoring during HME in cocrystallization approaches. Due to these salient features of HME, it can act as a prospective technique for cocrystallization of versatile drugs thus yielding dosage forms with desirable solubility and stability features.

Process Modeling and Simulation of Tableting-An Agent-Based Simulation Methodology for Direct Compression.

In pharmaceutical manufacturing, the utmost aim is reliably producing high quality products. Simulation approaches allow virtual experiments of processes in the planning phase and the implementation of digital twins in operation. The industrial processing of active pharmaceutical ingredients (APIs) into tablets requires the combination of discrete and continuous sub-processes with complex interdependencies regarding the material structures and characteristics. The API and excipients are mixed, granulated if required, and subsequently tableted. Thereby, the structure as well as the properties of the intermediate and final product are influenced by the raw materials, the parametrized processes and environmental conditions, which are subject to certain fluctuations. In this study, for the first time, an agent-based simulation model is presented, which enables the prediction, tracking, and tracing of resulting structures and properties of the intermediates of an industrial tableting process. Therefore, the methodology for the identification and development of product and process agents in an agent-based simulation is shown. Implemented physical models describe the impact of process parameters on material structures. The tablet production with a pilot scale rotary press is experimentally characterized to provide calibration and validation data. Finally, the simulation results, predicting the final structures, are compared to the experimental data.

New trends in the biocatalytic production of nucleosidic active pharmaceutical ingredients using 2′-deoxyribosyltransferases

Nowadays, pharmaceutical industry demands competitive and eco-friendly processes for active pharmaceutical ingredients (APIs) manufacturing. In this context, enzyme and whole-cell mediated processes offer an efficient, sustainable and cost-effective alternative to the traditional multi-step and environmentally-harmful chemical processes. Particularly, 2′-deoxyribosyltransferases (NDTs) have emerged as a novel synthetic alternative, not only to chemical but also to other enzyme-mediated synthetic processes. This review describes recent findings in the development and scaling up of NDTs as industrial biocatalysts, including the most relevant and recent examples of single enzymatic steps, multienzyme cascades, chemo-enzymatic approaches, and engineered biocatalysts. Finally, to reflect the inventive and innovative steps of NDT-mediated bioprocesses, a detailed analysis of recently granted patents, with specific focus on industrial synthesis of nucleoside-based APIs, is hereunder presented.

A Compact Device for the Integrated Filtration, Drying, and Mechanical Processing of Active Pharmaceutical Ingredients

Recent changes in the pharmaceutical sector call for the development of novel manufacturing approaches to reduce costs and improve control over product quality. In this area, the development of compact, plug-and-play devices that fit in a continuous manufacturing system has gained interest in recent years. Most Nutsche filters offer a versatile solution as compact filtration and drying devices. However, conventional drying processes tend to generate a large amount of lumps, usually requiring further mechanical processing of the isolated drug substance before it can be formulated. In this work, we present a compact, automatable filtration device that takes advantage of a unique impeller design and in situ measurements of the drying heat duty to integrate mechanical processing into the drying step. By preventing the formation of dry lumps during drug substance drying, and breaking needle-like crystals through the developed agitation program, the resulting powder can be directly used for tablet formulation. This device, designed to fit in a compact continuous manufacturing module, has the potential to reduce manufacturing costs and footprint, while allowing for the low-shear mechanical processing of heat-sensitive compounds.

Downstream Processability of Crystal Habit-Modified Active Pharmaceutical Ingredient

Efficient downstream processing of active pharmaceutical ingredients (APIs) can depend strongly on their particulate properties, such as size and shape distributions. Especially in drug products with high API content, needle-like crystal habit of an API may show compromised flowability and tabletability, creating significant processability difficulties on a production scale. However, such a habit can be adapted to the needs of downstream processing. To this end, we modified the needle-like crystal habit of the model API 5-aminosalicylic acid (5-ASA). This study reports processability assessment of six representative crystal habits of 5-ASA (needles, plates, rectangular bars, rhombohedrals, elongated hexagons, and spheroids) in the context of direct compression using ring shear tester, flow rate analyzer, and instrumented tablet press. As expected, needles were very cohesive, had low flow rate (1.0 ± 0.08 mg/s), and low bulk density (0.14 ± 0.01 g/mL) but showed better tabletability, whereas the opposite w...

Sustainability Concept in Decision-Making: Carbon Tax Consideration for Joint Product Mix Decision

Carbon emissions are receiving greater scrutiny in many countries due to international forces to reduce anthropogenic global climate change. Carbon taxation is one of the most common carbon emission regulation policies, and companies must incorporate it into their production and pricing decisions. Activity-based costing (ABC) and the theory of constraints (TOC) have been applied to solve product mix problems; however, a challenging aspect of the product mix problem involves evaluating joint manufactured products, while reducing carbon emissions and environmental pollution to fulfill social responsibility. The aim of this paper is to apply ABC and TOC to analyze green product mix decision-making for joint products using a mathematical programming model and the joint production data of pharmaceutical industry companies for the processing of active pharmaceutical ingredients (APIs) in drugs for medical use. This paper illustrates that the time-driven ABC model leads to optimal joint product mix decisions and performs sensitivity analysis to study how the optimal solution will change with the carbon tax. Our findings provide insight into ‘sustainability decisions’ and are beneficial in terms of environmental management in a competitive pharmaceutical industry.

A Hybrid MPC-PID Control System Design for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

In this work, a hybrid MPC (model predictive control)-PID (proportional-integral-derivative) control system has been designed for the continuous purification and processing framework of active pharmaceutical ingredients (APIs). The specific unit operations associated with the purification and processing of API have been developed from first-principles and connected in a continuous framework in the form of a flowsheet model. These integrated unit operations are highly interactive along with the presence of process delays. Therefore, a hybrid MPC-PID is a promising alternative to achieve the desired control loop performance as mandated by the regulatory authorities. The integrated flowsheet model has been simulated in gPROMSTM (Process System Enterprise, London, UK). This flowsheet model has been linearized in order to design the control scheme. The ability to track the set point and reject disturbances has been evaluated. A comparative study between the performance of the hybrid MPC-PID and a PID-only control scheme has been presented. The results show that an enhanced control loop performance can be obtained under the hybrid control scheme and demonstrate that such a scheme has high potential in improving the efficiency of pharmaceutical manufacturing operations.

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry because of its simplicity and robustness. The designed control system consists of single and cascade (nested) control loops. The control system has been simulated in gPROMSTM (Process System Enterprise). The ability of the control system to track the specified set point changes as well as to reject disturbances has been evaluated. Results demonstrate that the model shows an enhanced performance in the presence of random disturbances under closed-loop control compared to an open-loop operation. The control system is also able to track the set point changes effectively. This proves that closed-loop feedback control can be used in improving pharmaceutical manufacturing operations based on the Quality by Design (QbD) paradigm.

Spherical Crystallization of Glycine from Monodisperse Microfluidic Emulsions

Emulsion-based crystallization to produce spherical crystalline agglomerates (SAs) is an attractive route to control crystal size during downstream processing of active pharmaceutical ingredients (APIs). However, conventional methods of emulsification in stirred vessels pose several problems that limit the utility of emulsion-based crystallization. In this paper, we use capillary microfluidics to generate monodisperse water-in-oil emulsions. Capillary microfluidics, in conjunction with evaporative crystallization on a flat heated surface, enables controllable production of uniformly sized SAs of glycine in the 35–150 μm size range. We report detailed characterization of particle size, size distribution, structure, and polymorphic form. Further, online high-speed stereomicroscopic observations reveal several clearly demarcated stages in the dynamics of glycine crystallization from emulsion droplets. Rapid droplet shrinkage is followed by crystal nucleation within individual droplets. Once a nucleus is form...

ChemInform Abstract: How Do the Fine Chemical, Pharmaceutical and Related Industries Approach Green Chemistry and Sustainability?

AbstractReview: 12 refs.

How do the fine chemical, pharmaceutical, and related industries approach green chemistry and sustainability?

Developing manufacturing processes for active pharmaceutical ingredients and intermediates often involves complex chemistry. All companies now aim to uphold the principles of green chemistry and sustainability as far as possible, but how effective are they in achieving this and how much variation is there from company to company? This perspective discusses the results of a survey carried out with 24 companies, including 11 “big pharma” companies and 6 “other pharma” companies. Companies from outside the pharma sector were also included to give a comparison with other areas of the fine chemical industry. These included two fine chemical manufacturers, one agrochemical manufacturer, and one flavour and fragrance company. The survey covered organisational aspects of green chemistry and sustainability, such as corporate policy and policy implementation, green chemistry and technologies, process metrics, and how the application of green issues changes through the various stages of development and whether there are different standards for low volume and/or high potency compounds.

Normal phase and reverse phase HPLC-UV-MS analysis of process impurities for rapamycin analog ABT-578: Application to active pharmaceutical ingredient process development

ABT-578, an active pharmaceutical ingredient (API), is a semi-synthetic tetrazole derivative of the fermented polyene macrolide rapamycin. Reverse phase (RP)-HPLC-UV-MS and normal phase (NP)-HPLC-UV-MS methods employing an LC/MSD trap with electrospray ionization (ESI) have been developed to track and map all significant impurities from the synthetic process. Trace-level tracking of key impurities occurring at various process points was achieved using complimentary methodologies, including a stability indicating reverse phase HPLC method capable of separating at least 25 starting materials and process-related impurities from the API (YMC-Pack Phenyl column, UV-MS, 210 nm) and a targeted reverse phase HPLC method capable of separating very polar compounds from crude reaction mixtures (Phenomenex Synergi Polar RP column, UV, 265 nm). In addition, a normal phase HPLC method condition with post-column modifier infusion is described for the separation of epimeric impurities, and analysis of aqueous-sensitive reactive species (YMC-Pack SIL column, UV-MS, 278 nm). Process control strategies were established with these combinations of analytical technologies for impurities analyses to enable a rich understanding of the ABT-578 process.

Fast life cycle assessment of synthetic chemistry (FLASC™) tool

Background, Aim and Scope There is a clear need for simple methodology to deliver metrics that may be used to determine and benchmark the ‘greenness’ or relative sustainability of synthetic processes for Active Pharmaceutical Ingredients (APIs). Such methodology and metrics should facilitate more informed and sustainable business choices. This capability is particularly important at an early stage in R&D development activities when route and processes are being selected and detailed environmental data are not available. FLASC™ (Fast Life cycle Assessment of Synthetic Chemistry) is a web-based tool and methodology designed to meet these requirements.

Recent Advances in Developing Chemoenzymatic Processes for Active Pharmaceutical Ingredients

Biocatalysis is becoming a transformational technology for chemical synthesis as a result of recent advances in large-scale DNA sequencing, structural biology, protein expression, high throughput screening, and enzyme evolution technologies. To truly impact chemical synthesis at the industrial scale, enzyme discovery, biocatalyst optimization, process design, and development must be integrated in order to deliver cost-effective and green chemistry solutions for drug manufacture. In this article, some recent applications of biocatalysis in developing chemoenzymatic processes were selected to illustrate the principle of this integrated approach. The emphasis will be directed to those examples where the chemoenzymatic route represents a second-generation process developed to replace the existing chemical one.