Real-time monitoring of multiparticulate coating processes at industrial-scale using ultra-high-resolution optical coherence tomography

Available online 31 March 2025, 125546 In Press, Journal Pre-proof
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Matthias Wolfgang, Johannes Poms, Vanessa Herndler, Ingo Huegel,
Thomas Kipping, Martin Spoerk, Johannes G. Khinast

Abstract

Optical Coherence Tomography (OCT) has been reported as a promising technology for in-line monitoring of pharmaceutical film-coating processes, providing real-time information on actual tablet coating thicknesses and thickness variability, together enabling correlation modeling of the dissolution behavior. However, an increasing interest in the in-line investigation of multiparticulates demands further evolution of the technology and new concepts for process interfacing. To achieve this, we present a novel way to interface OCT to the relevant coating processes using a cutting-edge industry-ready ultra-high-resolution OCT (UHR-OCT) for in-line monitoring. Based on the setup, real-time in-line data of multiparticulate coating processes was acquired, enabling an automated coating thickness evaluation starting at the low micron range. The system was tested with two different core sizes of 250- and 700-µm mean diameter, coated in two different coaters, namely a Glatt MultiLab (2  kg batch size) and a Glatt GPCG PRO 30 (30  kg batch size). Coating thicknesses were successfully measured directly in the process in real-time within a range from 2.5 to 20 µm. Reference measurements based on sprayed coating mass showed excellent agreement between OCT and the reference when agglomeration was neglectable. Additionally, conducted image-based photometry emphasizes the capabilities of UHR-OCT as a powerful technology for multiparticulate coating monitoring. The presented approach was found to be stable, batch size-independent, and translatable to an industrial setup. Moreover, it extends the capabilities of OCT toward a versatile process analytical technology to monitor even the thinnest coatings and small particles used in pharmaceutical coating processes.

https://www.sciencedirect.com/science/article/abs/pii/S0378517325003837

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OSeeT Software

A simple and User Friendly OSeeT software, monitors the growth of the coating thickness and other characteristics throughout the whole process or at-line measurement. Each black spot on the chart corresponds to one thickness evaluation. Individual evaluations can be reviewed clicking on the black spots.

Screenshot of the Results tab in our OSeeT Pharma 1D software at the end of a coating process

Direct vs indirect measurements

 Direct measurements with standard OseeT softwareIndirect measurements with new development software
Typical use casemonitoring of transparent or semi-transparent coatings without scattering pigmentsmonitoring of scattering coatings (containing e.g. TiO₂, Fe₂O₃ etc.), uncoated products investigation, correlation of compression force to dissolution
Coating layersvisible in OseeT imagesnot visible in OseeT images
Calibration and correlationnot necessary – initial results are available right after the first measurementsA model needs to be created to correlate light penetration depth with the desired parameters (coating thickness, compression force, dissolution time)
Evaluationbased on visible interfaces between coating and corebased on penetration depth of light into the sample
Example OCT images

Images fromWolfgang et al., Ascertain a minimum coating thickness for acid protection of enteric coatings by means of optical coherence tomography (2022)Elisabeth Fink, Elen Gartshein, Johannes G. Khinast. Extending the Use of Optical Coherence Tomography to Scattering Coatings Containing Pigments

Comment regarding direct measurement imgs: Imgs are from following time points: 65, 130, 240 min. Include the time points on the images on the HP as on the images of the indirect measurements

Samples measured at 3 different time points of a coating process.
Evaluated area shown in color.

Types of OSeeT systems and probe heads

Depending on the intended application, there are different systems or combinations of OseeT systems and probe heads available.

Base Unit

Use Case

Specification

Image

HW 1.5

Mainly tablets

  • Axial resolution: 4 µm

  • Minimum coating thickness for automatic evaluation: 12 µm

HW 2.0

Samples with layer thicknesses between 12 µm and 150 µm (in certain cases up to 400 µm or more possible)

Suitable dosage forms: tablets, pellets, polymer films, co-extrudates, transdermal patches

  • Axial resolution: 3.7 µm

  • Minimum coating thickness for automatic evaluation: 12 µm

Compared to HW 1.5:

  • Improved image quality

  • Faster acquisition rate

  • Stronger PC components

UHR OCT

Pellets with very thin coating layers starting from about 4.5 µm

(UHR OCT is not recommended for tablets and coatings thicker than about 50 µm)

  • Axial Resolution: 1.5 µm

  • Minimum coating thickness for automatic evaluation: 4.5 µm

Sampling Device

Use Case

Characteristics

Image

SDP

At-line measurements mainly with pellets or tablets

  • Samples stay static and are not mechanically stressed during measurement

  • Samples can be measured in desired and specified positions

  • Only one tablet necessary to perform a measurement (but not limited to one – there can also be many samples)

  • Exchangeable discs available for different products/sizes

SDT

At-line measurement of tablets in a little perforated drum, mimicking an in-line coating process movement of the samples

  • Movement of samples as in a drum coater

  • Larger sample set can be evaluated at once compared to SDP

  • Measurements from different positions of the tablet are evaluated at the same time and give information about the whole batch’s variation with only one measurement

  • Min. 100 ml (ca. 100 tablets) of samples required

  • Depending on characteristics of coating, samples might be damaged during longer measurement periods

Probe

Use Case

In-line installation

Image

Pan Probe

Monitoring of drum coating processes, co-extrudates, films, patches

  • e.g. mounted below the drum of a pan coater with perforated drum

Fluid Bed Monitoring Probe

In-line monitoring for coating processes of pellets and other multi-particulates

  • Directly attached to a fluid bed coater window/port

  • Probe interface includes a funnel to guide pellets in front of the sensor (pellets need to be measured at a certain distance and a suitable velocity)

Application range of OSeeT

OSeeT was originally developed for direct measurement of transparent and semi-transparent materials. High concentrations of pigments in the coating formulation (i.e., titanium dioxide or iron oxide) are scattering the light beam and therefore limiting the direct insight into the material. By establishing advanced image analysis metrics, a second stream of OSeeT software has been developed to evaluate coatings with highly scattering pigments as well as uncoated dosage forms (beta version).

Application range of OSeeT (in the pharmaceutical field)

Transparent or semi-transparent coated products

OSeDirect measurement of coating thickness, roughness, homogeneity for:
• Tablets and capsules at-line and in-line
• Pellets at-line and in-line
• Co-extruded dosage forms
• Thin drug layer of transdermal patches and oral films

Uncoated products

Indirect measurement of uncoated samples and correlation with critical quality attributes (e.g. dissolution or tablet hardness) – beta version of the software

Non-transparent coated products

Indirect measurement of the thickness of scattering coatings (beta version) and correlation with critical quality attributes (e.g. dissolution) – beta version of the software