Elucidation and visualization of solid-state transformation and mixing in a pharmaceutical mini hot melt extrusion process using in-line Raman spectroscopy

Abstract

Mixing of raw materials (drug + polymer) in the investigated mini pharma melt extruder is achieved by using co-rotating conical twin screws and an internal recirculation channel. In-line Raman spectroscopy was implemented in the barrels, allowing monitoring of the melt during processing. The aim of this study was twofold: to investigate (I) the influence of key process parameters (screw speed -barrel temperature) upon the product solid-state transformation during processing of a sustained release formulation in recirculation mode; (II) the influence of process parameters (screw speed -barrel temperature -recirculation time) upon mixing of a crystalline drug (tracer) in an amorphous polymer carrier by means of residence time distribution (RTD) measurements. The results indicated a faster mixing endpoint with increasing screw speed. Processing a high drug load formulation above the drug melting temperature resulted in the production of amorphous drug whereas processing below the drug melting point produced solid dispersions with partially amorphous/crystalline drug.Furthermore, increasing the screw speed resulted in lower drug crystallinity of the solid dispersion. RTD measurements elucidated the improved mixing capacity when using the recirculation channel. In-line Raman spectroscopy has shown to be an adequate PAT-tool for product solid-state monitoring and elucidation of the mixing behavior during processing in a mini extruder.

Exploring the Complexity of Processing-Induced Dehydration during Hot Melt Extrusion Using In-Line Raman Spectroscopy

“…A Raman Dynisco probe (Kaiser optical systems, Ann Arbor, MI, USA) was installed facing the screws at the bottom of the barrel (position 2) in a splittable barrel, using the setup previously reported [19]. The probe was connected via a fiber optical cable to the RxN2 Raman spectrometer (Kaiser optical systems, Ann Arbor, MI, USA), equipped with a CCD detector.…”

“…Combining in-line Raman spectroscopy and Principal Component Analysis (PCA), it is possible to determine the effects of process parameters on the crystalline-to-amorphous transformation rate of a drug in a melt extrusion process, as shown in a recent study, where the amorphization of metoprolol in Eudragit ® RSPO was monitored as a function of screw speed [19]. Recently, a combination of Raman spectroscopy and Multivariate Curve Resolution (MCR) was found to be able to estimate the percentage of crystalline and molten polymer in a semi-crystalline polymer sample [20].…”

Multivariate Calibration for the Development of Vibrational Spectroscopic Methods

“…Scatter effects are common for all spectroscopic techniques and the phenomenon appears mostly because of the physical variabilities between samples or path-length variations. Two of those pre-processing concepts are standard normal variate (SNV) and multiplicative scatter correction (MSC) which also normalize the baseline shifts of different samples [4,5]. The second set of pre-processing methods has the capacity to reduce or remove the noise by smoothing and differentiating the spectral values.…”

“…Considering the pharmaceutical domain, these methods have been extensively applied to quantify active pharmaceutical ingredients, excipients, or physical properties either as offline method for intermediate/final product characterization [1] or as real-time-monitoring methods implemented within blending [2], granulation [3], extrusion [4], tableting [5], coating [6], or freeze-drying processes [7].…”

A Visualization of Flow Patterns of Viscoelastic Fluid Partially Filled in a Co‐Rotating Nontwin Screw Extruder

“…Dimer et al also used PEPT to follow the trajectory of an individual particle and some preliminary discussions were made . In recent years, some other on‐line measurement techniques, such as near infrared (NIR), far infrared (FIR), ultrasonic tomography, and nucleation magnet resonance (NMR) imaging, have also been introduced to examine the residence time distribution and particle distributions during the extrusion process by twin screw extruders . How to balance spatial and temporal resolutions during imaging for these noninvasive visualization investigations is a key point for future studies.…”