In this article, Katharina Paulsen, Ines Ruff, Dirk Leister, Jennifer Ramirez and Robert Heintz from Thermo Fisher Scientific, describe a co-extrusion technique and how Raman imaging microscopy was used to measure the thickness, quality and continuity of the outer shell of the extruded material.
Imaging quality
Hot melt extrusion is a process used to produce a broad range of pharmaceutics. It can be used for oral applications, implants or patches. In oral solid dosage forms it can be either used to increase the bioavailability of poorly soluble active pharmaceutical ingredients (API) in immediate and sustained release formulations or even in combination of different release behaviours.1,2
To produce a combination of different release profiles and/or different drugs in fixed-dose combinations, it can be extruded in a multi-layer system. With co-extrusion, the production of an inner core and an outer shell will be achieved in one single step. The most important parameter is a precise inner core and outer layer to achieve the desired drug content and release. For quality control, we employed Raman imaging microscopy.
The materials and method
Hot melt extrusion:
One extruder was required to produce each layer — inner core and outer layer — for co-extrusion. For the inner core, we used a co-rotating twin-screw extruder with a screw diameter of 16 mm.a For the outer layer a lower throughput is needed, therefore, we used a co-rotating twin-screw extruder with a screw diameter of 11 mm.b
The co-extrusion die was equipped with an insert of 4 mm for the total diameter and the thickness of the outer layer was controlled by the ratio of the mass flow of the inner and the outer phase. For co-extrusion, we arranged the extruders in a 90° position, as shown in Figure 1 — with the outer layer extruder oriented from the left to the right.
Additionally, to ensure we achieved precise feed rates of the inner and the outer phase, we employed two gravimetric MiniTwin powder feeders.c
Figure 1: Set-up of twin-screw extruders for co-extrusion.
Thermo Figure 1
Materials:
The model drug we used for our inner layer was Itraconazold with lactosee and PVP/PVA copolymerf as a carrier. The outer layer consisted of a cationic methacrylate copolymerg without API.
Thermal analysis:
To be able to determine the solid state of the inner core we employed dynamic scanning calorimetry (DSC).h
Raman spectroscopy
To characterise the co-extrudates we used Raman imaging microscopy.i The Raman spectra were collected using a 532 nm laser with 10 mW power and a 10 μm image pixel size and a 10x magnification objective lens. The exposure time was 0.0025 s and the number of scans was 100. Additionally, we collected the reference spectra of the single components.
Results
Determination of the solid state
In theory, the crystalline Itraconazol should be transferred into a solid solution by the hot melt extrusion process to increase the solubility and, consequently, the bioavailability. The result of the DSC measurement in Figure 2 demonstrated only one glass transition of the sample of the inner core, which means that a solid solution was achieved.
Figure 2: DSC scan of the crystalline Itraconazol (green) and the extruded product (blue).
Thermo Figure 2
Quality control measurements of the two layers
Determination of the shell thickness and the quality of the shell was performed using Raman imaging microscopy. Through using chemical imaging, we were able to visualise the thickness of the shell layers more easily, which would be more difficult or impossible with light microscopy. Furthermore, any defects in the layers can be easily determined (Figure 3).
Figure 3: Cross section of a co-extrudate with a clear defect of the outer shell layer.
Thermo Figure 3
This method was also used to determine if there was any migration of the Itraconazol from the inner core to the outer shell, which would be reflected in the Raman spectra obtained from the outer shell. We found no migration.
Impact of extrusion parameters on the co-extrudate
During a stable process the appearance of the co-extrudate was very homogeneous, and the surface was without any defects. The Raman microscopy images given in Figure 4 clearly show that the shell had a very homogeneous thickness, and there was no migration of the Itraconazol into the outer layer.
Figure 4(a-c): Cross section of co-extrudates produced with different process parameters: from a to b the throughput of the inner core is doubled and as a result the thickness of the shell in b is only half the size; from b to c the process temperature of the extruder producing the outer shell was increased by 25 K, and the layer thickness stays the same.
Thermo Figure 4a-c
The total diameter of the strand was defined by the die insert used. By varying feed rates different shell thicknesses were generated. With an increased feed rate for the inner core the outer shell became thinner. By doubling the feed rate of the inner core, the thickness of the outer layer was reduced by half the thickness [Figure 4(a) and (b)].
Different process temperatures and, therefore, different viscosities of the different layers do not have an impact on the layer thickness. In the case of the co-extrudate shown in Figure 4c the process temperature of the extruder for the outer layer was increased 25 K compared to the co-extrudate process in Figure 4b, resulting in no change in outer layer thickness.
Conclusion
Hot melt extrusion can be used to produce multi-layer systems by co-extrusion to produce pharmaceutical dosage forms with different dissolution behaviour for one API or for fixed-dose combinations of different APIs.
The resulting outer shell thickness was very homogenous and can be varied easily by varying the throughput.
Raman microscopy imaging was found to be an ideal tool to determine the shell layer thickness and to visualise any chemical and physical defects of the outer shell.
References:
- Crowley et al., ‘Pharmaceutical applications of Hot melt extrusion’, Drug Development and Industrial Pharmacy, 2007.
- Dierickx et al., ‘Co-extrusion as manufacturing technique for multi-layer mini-matrices with dual drug release’, European Journal of Pharmaceutics and Biopharmaceutics, 2013.
Product/materials list:
- Thermo Scientific Pharma 16 Twin-Screw Extruder, Thermo Fisher Scientific, Karlsruhe, Germany.
- Thermo Scientific Process 11 extruder, Thermo Fisher Scientific, Karlsruhe, Germany.
- Brabender Technology, Duisburg, Germany.
- Itraconazol, BASF, Ludwigshafen, Germany.
- GranuLac, Meggle, Germany.
- Kollidon VA 64, BASF, Ludwigshafen, Germany.
- Eudragit E, Evonik, Darmstadt, Germany.
- DSC 204 F1 Phoenix; Netzsch-Geratebau GmbH, Selb, Germany.
- Thermo Scientific DXRxi Raman Imaging Microscope, Thermo Fisher Scientific, Madison, USA.