Real-time Raman Monitoring For Pharmaceutical Hot Melt Extrusion

In this interview, manufacture experts Nimesh Khadka and Keith Freel research really Raman-based PAT enhances basking melt extrusion by enabling real-time API monitoring, improving process control, and supporting Quality by Design successful pharma. 

Please could you springiness an overview of what basking melt extrusion is and why it has go truthful important successful supplier development?

Keith Freel: Hot melt extrusion (HME) is an advanced, but now established, method for formulating drugs. It involves feeding an API pinch a polymer into a heated extruder, wherever nan worldly is melted, mixed, and shaped.

Over 20 FDA-approved products usage HME because it improves nan solubility of poorly water-soluble drugs, stabilizes delicate molecules, and enables controlled aliases sustained release. It’s besides continuous, which is valuable for scalability and value consistency. Beyond that, it supports innovative dosage forms specified arsenic filaments for 3D printing aliases bladed films for oral delivery, making it highly versatile.

Image Credit: Thermo Fisher Scientific – Portable and Handheld Process Raman Spectroscopy 

Why is real-time monitoring of APIs during basking melt extrusion important for pharmaceutical manufacturing?

Nimesh Khadka: Hot melt extrusion is wide utilized to amended supplier solubility, bioavailability, and stability, but nan process is highly dynamic. The authorities of nan API—whether crystalline aliases amorphous—and its relationship pinch nan polymer matrix straight impact supplier efficacy and quality.

Traditional offline study is slow and tin miss captious variations. Real-time monitoring pinch Process Analytical Technology (PAT), specified arsenic Raman spectroscopy, allows america to quantify APIs continuously, measure their beingness state, and observe interactions arsenic they happen. This not only improves process knowing but besides enhances consistency, reduces batch-to-batch variation, and supports regulatory expectations for value by design.

How does Process Analytical Technology (PAT), and Raman successful particular, fresh into nan Quality by Design framework?

Keith Freel: PAT is integral to Quality by Design (QbD). QbD starts pinch defining a value target merchandise profile, identifying captious value attributes (CQAs), and linking them to process parameters.

PAT devices for illustration Raman spectroscopy alteration america to show CQAs—such arsenic API concentration, crystallinity, and dissolution—directly successful existent time. That helps guarantee we stay wrong nan defined creation abstraction and gives america contiguous feedback to support power strategies. Raman, successful particular, provides molecular-level information, which strengthens process knowing and supports regulatory compliance by embedding value into nan process alternatively than testing for it afterwards.

Image Credit: Thermo Fisher Scientific – Portable and Handheld Process Raman Spectroscopy 

What was your experimental setup, and why did you take acetaminophen arsenic nan exemplary compound?

Keith Freel: We mixed nan Thermo Scientific Pharma-11 Twin Screw Extruder pinch nan MarqMetrix Process Raman Analyzer, placing nan Raman probe successful nan heated die. Acetaminophen was chosen because it’s a well-characterized API and a bully exemplary for studying solubility and polymorphism. We utilized Soluplus arsenic nan polymer and prepared blends of 0 %, 10 %, 25 %, and 50 % API. As nan worldly moved done nan extruder, Raman spectra were collected each 20 seconds. This setup allowed america to trial whether Raman could reliably show attraction and beingness authorities during a unrecorded HME process.

Image Credit: Thermo Fisher Scientific – Portable and Handheld Process Raman Spectroscopy

How effective was Raman successful quantifying API attraction during extrusion?

Keith Freel: The Raman spectra showed clear changes corresponding to nan acetaminophen concentration. Using partial slightest squares (PLS) regression pinch offline HPLC information for calibration, we built a predictive exemplary that was highly accurate. The guidelines mean squared correction of calibration was astir 0.5 %, and validation runs gave astir 1.4 % error. This proved that Raman tin supply reliable, real-time quantification. More importantly, it captured transient variations, for example, stabilization delays aft attraction changes, that would not person been visible pinch only offline sampling.

Could Raman besides observe polymorphic transitions aliases recrystallization of nan API?

Keith Freel: Yes, Raman is delicate to molecular form. We compared our spectra pinch published information for crystalline and amorphous acetaminophen and recovered that each extrudates remained amorphous passim processing. No recrystallization was observed. This capacity is captious because polymorphic transitions tin change supplier performance. Raman tin besides beryllium applied downstream, for example, to show cooling aliases stableness studies, making it a valuable instrumentality beyond conscionable real-time process monitoring.

At what constituent did nan MarqMetrix All-in-One Process Raman Analyzer beryllium astir valuable successful your study?

Nimesh Khadka: The analyzer’s elasticity and robustness made it particularly valuable during in-line monitoring. Its compact size allowed easy integration into nan extruder setup, and its unchangeable calibration reduced nan request for maintenance.

By operating successful in-line mode, it provided continuous, real-time data. We were capable to show acetaminophen concentration, corroborate its amorphous form, and moreover observe subtle API–polymer interactions. These insights were captious for optimizing nan process and ensuring merchandise quality. The expertise to usage nan aforesaid instrumentality successful at-line aliases on-line configurations besides adds to its versatility successful some improvement and manufacturing environments.

What advantages does Raman connection compared to different PAT devices specified arsenic NIR aliases UV-Vis?

Nimesh Khadka: Each method has strengths. UV-Vis is delicate but little specific. NIR and Raman are some vibrational methods, but NIR is absorption-based while Raman is scattering-based, pinch different action rules. They are complementary: immoderate vibrations are stronger successful NIR, others successful Raman.

For example, Raman is fantabulous for non-polar bonds and is little delicate to water, which is simply a large advantage successful aqueous systems. NIR, connected nan different hand, whitethorn beryllium much effective if fluorescence interferes pinch Raman. What makes Raman particularly powerful is its expertise to supply structural information, enabling america to study not conscionable concentrations but besides polymorphism and API–polymer interactions.

How scalable is this Raman-based PAT approach, and really do regulators position it?

Keith Freel: It’s scalable, though probe positioning must beryllium cautiously considered erstwhile moving to larger manufacturing systems. From a regulatory perspective, PAT is powerfully encouraged. The FDA and ICH person some promoted PAT done value by creation initiatives. As agelong arsenic Raman methods are decently validated and developed according to guidelines, they’re accepted arsenic reliable devices for ensuring accordant merchandise value successful some objective and commercialized manufacturing.

Finally, what opportunities are location for professionals to summation hands-on acquisition pinch Raman successful HME?

Keith Freel: At nan University of Maryland School of Pharmacy, we tally nan Tablets and Capsules short course, which includes lectures and applicable labs. One of nan sessions integrates Raman spectroscopy pinch basking melt extrusion utilizing nan Pharma-11 extruder. Participants study really to cod real-time data, build models, and use PAT principles successful practice. It’s a unsocial opportunity to span mentation pinch hands-on training, which is captious for anyone moving successful precocious pharmaceutical manufacturing.

About Nimesh Khadka  

Dr. Nimesh Khadka is simply a Senior Product Application Specialist astatine Thermo Fisher Scientific and holds a PhD successful Biochemistry from Utah State University. With extended expertise successful analytical biochemistry, spectroscopy and chemometrics, he is presently starring efforts to champion Raman spectroscopy arsenic a process analytical exertion (PAT). As an progressive personnel of nan American Chemical Society, Nimesh remains astatine nan forefront of emerging technologies and is committed to driving invention to meet customer needs.

About Keith Freel  

Dr. Keith Freel holds a Ph.D.in Physical Chemistry from Emory University and has extended analytical chemistry expertise. As Research Project Director astatine nan University of Maryland School of Pharmacy, he oversees precocious analytical projects supporting pharmaceutical and biomedical research. Previously, he spent complete 5 years astatine Thermo Fisher Scientific arsenic a Staff Scientist, wherever he led R&D efforts crossed a wide scope of techniques including FTIR, Raman, NIR, XRF, ICP-MS, and multivariate statistical analysis. 

About Thermo Fisher Scientific Inc.

Thermo Fisher Scientific is nan world leader successful serving science. The institution enables its customers to make nan world healthier, cleaner and safer by providing analytical instruments, equipment, reagents and consumables, package and services for research, analysis, find and diagnostics. 

Thermo Scientific represents a wide scope of high-end analytical instruments, chemistry and consumable supplies, laboratory equipment, package and services that alteration integrated laboratory workflow solutions. Thermo Scientific is nan caller sanction for a trusted marque – Thermo Electron – that nan world’s astir renowned researchers, clinicians and scientists already count connected to lick their analytical challenges. The marque is strengthened by nan summation of equipment, consumables and reagents acquired from Fisher Scientific. 

Fisher Scientific represents a family of world merchandise and work brands comprising a complete portfolio of laboratory equipment, chemicals, supplies and services utilized successful healthcare, technological research, information and education. Fisher Scientific brings these solutions to wide investigation customers worldwide, and done Fisher HealthCare, Fisher Safety and Fisher Science Education it delivers nan specialty equipment, supplies and services that customers want, erstwhile and really they want them. In summation to these 2 premier brands, Thermo Fisher Scientific besides markets a scope of specialty products, featuring well-known manufacture names specified arsenic Nalgene, Nunc and Remel. Offerings see consumables specified arsenic disposable laboratory glassware, plastic-ware and biology sample containers ranging from vials, tubes and pipettes to microscope slides and syringes. These products are chiefly sold done Fisher Scientific and our weighted partners worldwide.