Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology
<b>Objectives:</b> Hot-melt extrusion (HME) offers a solvent-free, scalable approach for manufacturing pharmaceutical co-crystals (CCs), aligning with the industry’s shift to continuous manufacturing (CM). However, challenges like undefined yield optimization, insufficient risk managemen...
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| Format: | Article |
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MDPI AG
2025-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/17/5/568 |
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| author | Lianghao Huang Wen Ni Yaru Jia Minqing Zhu Tiantian Yang Mingchao Yu Jiaxiang Zhang |
| author_facet | Lianghao Huang Wen Ni Yaru Jia Minqing Zhu Tiantian Yang Mingchao Yu Jiaxiang Zhang |
| author_sort | Lianghao Huang |
| collection | DOAJ |
| description | <b>Objectives:</b> Hot-melt extrusion (HME) offers a solvent-free, scalable approach for manufacturing pharmaceutical co-crystals (CCs), aligning with the industry’s shift to continuous manufacturing (CM). However, challenges like undefined yield optimization, insufficient risk management, and limited process analytical technology (PAT) integration hinder its industrial application. This study aimed to develop a proof-of-concept HME platform for CCs, assess process risks, and evaluate PAT-enabled monitoring to facilitate robust production. <b>Methods:</b> Using carbamazepine (CBZ) and nicotinamide (NIC) as model compounds, an HME platform compatible with PAT tools was established. A systematic risk assessment identified five key risk domains: materials, machinery, measurement, methods, and other factors. A Box–Behnken design of experiments (DoE) evaluated the impact of screw speed, temperature, and mixing sections on CC quality. Near-infrared (NIR) spectroscopy monitored CBZ-NIC co-crystal formation in real time during HME process. <b>Results:</b> DoE revealed temperature and number of mixing sections significantly influenced particle size (D<sub>50</sub>: 2.0–4.0 μm), while screw speed affected efficiency. NIR spectroscopy detected a unique CC absorption peak at 5008.3 cm⁻¹, enabling real-time structural monitoring with high accuracy (R² = 0.9999). Risk assessment highlighted material attributes, process parameters, and equipment design as critical factors affecting CC formation. All experimental batches yielded ≥ 94% pure CCs with no residual starting materials, demonstrating process reproducibility and robustness. <b>Conclusions:</b> Overall, this work successfully established a continuous hot-melt extrusion (HME) process for manufacturing CBZ-NIC co-crystals, offering critical insights into material, equipment, and process parameters while implementing robust in-line NIR monitoring for real-time quality control. Additionally, this work provides interpretable insights and serves as a basis for future machine learning (ML)-driven studies. |
| format | Article |
| id | doaj-art-b3fb0502a30f4815a1dedff89f18ac97 |
| institution | DOAJ |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-b3fb0502a30f4815a1dedff89f18ac972025-08-20T03:14:35ZengMDPI AGPharmaceutics1999-49232025-04-0117556810.3390/pharmaceutics17050568Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion TechnologyLianghao Huang0Wen Ni1Yaru Jia2Minqing Zhu3Tiantian Yang4Mingchao Yu5Jiaxiang Zhang6Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaMaterial Characterization, Thermo Fisher Scientific, Shanghai 201203, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China<b>Objectives:</b> Hot-melt extrusion (HME) offers a solvent-free, scalable approach for manufacturing pharmaceutical co-crystals (CCs), aligning with the industry’s shift to continuous manufacturing (CM). However, challenges like undefined yield optimization, insufficient risk management, and limited process analytical technology (PAT) integration hinder its industrial application. This study aimed to develop a proof-of-concept HME platform for CCs, assess process risks, and evaluate PAT-enabled monitoring to facilitate robust production. <b>Methods:</b> Using carbamazepine (CBZ) and nicotinamide (NIC) as model compounds, an HME platform compatible with PAT tools was established. A systematic risk assessment identified five key risk domains: materials, machinery, measurement, methods, and other factors. A Box–Behnken design of experiments (DoE) evaluated the impact of screw speed, temperature, and mixing sections on CC quality. Near-infrared (NIR) spectroscopy monitored CBZ-NIC co-crystal formation in real time during HME process. <b>Results:</b> DoE revealed temperature and number of mixing sections significantly influenced particle size (D<sub>50</sub>: 2.0–4.0 μm), while screw speed affected efficiency. NIR spectroscopy detected a unique CC absorption peak at 5008.3 cm⁻¹, enabling real-time structural monitoring with high accuracy (R² = 0.9999). Risk assessment highlighted material attributes, process parameters, and equipment design as critical factors affecting CC formation. All experimental batches yielded ≥ 94% pure CCs with no residual starting materials, demonstrating process reproducibility and robustness. <b>Conclusions:</b> Overall, this work successfully established a continuous hot-melt extrusion (HME) process for manufacturing CBZ-NIC co-crystals, offering critical insights into material, equipment, and process parameters while implementing robust in-line NIR monitoring for real-time quality control. Additionally, this work provides interpretable insights and serves as a basis for future machine learning (ML)-driven studies.https://www.mdpi.com/1999-4923/17/5/568hot-melt extrusionco-crystalcontinuous manufacturingprocess analytical technology toolsrisk assessmentBox–Behnken design |
| spellingShingle | Lianghao Huang Wen Ni Yaru Jia Minqing Zhu Tiantian Yang Mingchao Yu Jiaxiang Zhang Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology Pharmaceutics hot-melt extrusion co-crystal continuous manufacturing process analytical technology tools risk assessment Box–Behnken design |
| title | Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology |
| title_full | Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology |
| title_fullStr | Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology |
| title_full_unstemmed | Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology |
| title_short | Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology |
| title_sort | process development for the continuous manufacturing of carbamazepine nicotinamide co crystals utilizing hot melt extrusion technology |
| topic | hot-melt extrusion co-crystal continuous manufacturing process analytical technology tools risk assessment Box–Behnken design |
| url | https://www.mdpi.com/1999-4923/17/5/568 |
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