Evaluation of critical process parameters for inter-tablet coating uniformity of active-coated GITS using Terahertz Pulsed Imaging

Daniela Brock, J. Axel Zeitler, Adrian Funke, Klaus Knop, Peter Kleinebudde

Abstract

The aim of this study was the evaluation of critical process parameters (CPP) for inter-tablet coating uniformity in an active pan coating process using nondestructive Terahertz Pulsed Imaging (TPI). Coating uniformity was assessed by calculating the coefficient of variation (CV) of coating thickness measured by TPI, and the CV of API content measured by high performance liquid chromatography (HPLC). A design of experiments (DoE) was performed at pilot scale with drum load, drum speed, spray rate, run duration and spray pressure as factors. Good agreement in the CV of both analytical techniques was shown. The DoE models both revealed the same CPP: a low drum load, high drum speed, low spray rate and high run duration were beneficial for coating uniformity. The spray pressure was only significant in one of the DoE models. It was further shown that the negative impact of a high drum load on the CV cannot only be compensated by high drum speed, but also be compensated by a low spray rate and long run duration. It was demonstrated that TPI is a feasible tool for the measurement of inter-tablet coating uniformity and for the evaluation of CPP in an active pan coating process.

This study was performed using TeraView's Imaga 2000 system. (TeraView, Cambridge, UK)

Full Article: http://www.sciencedirect.com/science/article/pii/S0939641114002203

Assessment of Enamel Demineralisation and Remineralisation using Terahertz Pulsed Imaging

D. CHURCHLEY¹, F. LIPPERT², A. BUTLER¹, A. PORTIERI³, and R.J.M. LYNCH¹, ¹GlaxoSmithKline Consumer Healthcare, Weybridge, England, ²Indiana University School of Dentistry, Indianapolis, IN, ³TeraView Ltd, Cambridge, England

Objective

Transverse micro-radiography (TMR) is the “gold standard” for measuring mineral changes in enamel; however, it is destructive in nature. The aim of this study was to compare Terahertz Pulsed Imaging (TPI), a non-destructive technique, with TMR for measuring mineral changes in enamel.

Methods 

Lesions with diverse mineral characteristics were created in bovine and human enamel blocks (n=48 per enamel type) using three demineralising systems (MeC, Carbopol C907 & HEC).  Specimens were assigned to two treatment groups (n=24 per enamel type per group): Group 1: remineralisation for 5 days (1.5mM CaCl₂.2H₂O, 0.9mM KH₂PO₄, 20mM HEPES and 130mM KCl) Group 2: demineralisation for 2 days (50mM acetic acid, 2.25mM CaCl₂.2H₂O, 1.35mM KH₂PO₄, 130mM KCl and 5ppm F).  Lesions were imaged using a TPI imaga 1000. Reflection data were used to generate lesion mineral profiles.   Lesions were also radiographed.  For both techniques the integrated mineral loss (ΔZ), lesion depth (L), change in mineral content (ΔM), and change in lesion depth (ΔL) were calculated. Pearson correlation coefficients were calculated for the combined data set as well as by enamel type, treatment and lesion type.

Results

The table shows the Pearson correlation coefficients.  There is generally a good association (Pearson coefficients ≥ 0.70) between TPI and TMR measurements for most variables.

Variable	Combined	Enamel Type		Treatment		Lesion Type
		Bovine	Human	Demin	Remin	MeC	C907	HEC
ΔZ(baseline)	0.66	0.69	0.65	0.59	0.81	0.28	0.74	0.47
ΔZ(post-treatment)	0.84	0.92	0.71	0.78	0.83	0.82	0.82	0.77
ΔM	0.75	0.84	0.58	0.55	0.52	0.80	0.72	0.70
L(baseline)	0.79	0.77	0.80	0.76	0.87	0.19	0.75	0.20
L(post-treatment)	0.88	0.95	0.77	0.75	0.73	0.97	0.87	0.78
ΔL	0.84	0.93	0.65	0.49	0.51	0.94	0.80	0.82

Conclusion 

Whilst these initial findings demonstrate that TPI could be a useful technique for the non-destructive assessment of enamel mineral changes; further evaluation is required.

This study was performed using TeraView's Imaga 1000 system (TeraView, Cambridge, UK) 

Full Article: https://iadr.confex.com/iadr/14iags/webprogram/Paper189313.html

Evaluation of Coating Properties of Enteric-Coated Tablets Using Terahertz Pulsed Imaging

Masahiro Niwa, Yasuhiro Hiraishi, Katsuhide Terada

Abstract

Purpose

Enteric coatings are used to reduce gastrointestinal side effects and control the release properties of oral medications. Although widely used, the effect of formulation and process conditions on physicochemical and functional properties of enteric coatings remains unclear.

Methods

Terahertz pulsed imaging (TPI) was employed to evaluate the coat properties of enteric coated tablets (ECTs) with various acid resistance. Other analytic methods, such as loss on drying, scanning electron microscopy and X-ray computed tomography were then used to validate the relationships established among 4 TPI-derived parameters and the physicochemical properties of enteric coatings.

Results

Weight gain measurement did not provide any information to assess acid resistance of enteric coating, whereas four TPI-derived parameters non-destructively reflected the coating properties such as thickness, coat uniformity, density, and water distribution, allowing the identification of the causes of poor acid resistance in certain ECT batches using a single measurement. These parameters also revealed the effect of coating conditions; in particular, coating under dry conditions led to less dense and nonuniform coatings with poor acid resistance.

Conclusion

We demonstrated the utility of TPI to identify structural defects within ECTs with poor acid resistance. TPI-derived parameters can aid in formulation development and quality control of ECTs.

Full Article: http://link.springer.com/article/10.1007/s11095-014-1314-6

Quantitative analysis of visible surface defect risk in tablets during film coating using terahertz pulsed imaging

Masahiro Niwa, 

Yasuhiro Hiraishi

Abstract

Tablets are the most common form of solid oral dosage produced by pharmaceutical industries. There are several challenges to successful and consistent tablet manufacturing. One well-known quality issue is visible surface defects, which generally occur due to insufficient physical strength, causing breakage or abrasion during processing, packaging, or shipping. Techniques that allow quantitative evaluation of surface strength and the risk of surface defect would greatly aid in quality control. Here terahertz pulsed imaging (TPI) was employed to evaluate the surface properties of core tablets with visible surface defects of varying severity after film coating. Other analytical methods, such as tensile strength measurements, friability testing, and scanning electron microscopy (SEM), were used to validate TPI results. Tensile strength and friability provided no information on visible surface defect risk, whereas the TPI-derived unique parameter terahertz electric field peak strength (TEFPS) provided spatial distribution of surface density/roughness information on core tablets, which helped in estimating tablet abrasion risk prior to film coating and predicting the location of the defects. TPI also revealed the relationship between surface strength and blending condition and is a nondestructive, quantitative approach to aid formulation development and quality control that can reduce visible surface defect risk in tablets.

Full Article: http://www.sciencedirect.com/science/article/pii/S0378517313010454#fig0060

Terahertz Pulsed Imaging and Magnetic Resonance Imaging as Tools to Probe Formulation Stability

Qilei Zhang 1, Lynn F. Gladden 2, Paolo Avalle 3, J. Axel Zeitler 2;* and Michael D. Mantle 2

¹ Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China² Department of Chemical Engineering & Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK³ Merck Sharp & Dohme Ltd., Hoddesdon EN11 9BU, UK

Abstract

Dissolution stability over the entire shelf life duration is of critical importance to ensure the quality of solid dosage forms. Changes in the drug release profile during storage may affect the bioavailability of drug products. This study investigated the stability of a commercial tablet (Lescolr XL) when stored under accelerated conditions (40 ^oC/75% r.h.). Terahertz pulsed imaging (TPI) was used to investigate the structure of the tablet coating before and after the accelerated aging process. The results indicate that the coating was reduced in thickness and exhibited a higher density after being stored under accelerated conditions for four weeks. In situ magnetic resonance imaging (MRI) of the water penetration processes during tablet dissolution in a USP-IV dissolution cell equipped with an in-line UV-vis analyzer was carried out to study local differences in water uptake into the tablet matrix between the stressed and unstressed state. The drug release profiles of the Lescolr XL tablet before and after the accelerated storage stability testing were compared using a “difference” factor ∫1 and a “similarity” factor ∫2. The results reveal that even though the physical properties of the coating layers changed significantly during the stress testing, the coating protected the tablet matrix and the densification of the coating polymer had no adverse effect on the drug release performance.

The TPI studies were performed using TeraView's TPI imaga 2000 system (TeraView, Cambridge, UK) 
Original Article:   http://www.mdpi.com/1999-4923/5/4/591

Non-destructive measurement of polymer coatings on pharmaceutical tablets using X-ray micro CT and terahertz pulsed imaging

Authors: Isabelle-Sophie Russe^1,2, Daniela Brock^1,2, Klaus Knop², Peter Kleinebudde², J. Axel Zeitler¹⁼
1 Department of Chemical Engineering and Biotechnology, University of Cambridge,  Cambridge, UK
2 Institute of Pharmaceutics and Biopharmaceutics, University of Duesseldorf, Duesseldorf, Germany


Full text: http://www.skyscan.be/company/UM2013/15.pdf

Conclusion

We conclude that TPI is a robust technique, and, that due to its very simple measurement  principle, it is an ideal measurement technique to quantify the coating thickness in process control and quality monitoring applications. The method introduced in this paper will be useful to explore whether there is an influence on  the refractive index of a given coating formulation with changes in process conditions during  coating or curing. It furthermore opens the possibility, in pharmaceutical applications and  beyond, to develop metrology standards for coatings that can be used to calibrate TPI  measurements for absolute thickness.
Beyond its use as a calibration technique for TPI the XµCT method has provided some  intriguing insight into the coating properties at extremes of the tablet geometry, at the edges  of tablets where high curvature was thought to typically prevent quantitative TPI  measurements due to strong scattering. The main limitations of the XµCT technique are the  measurement, and in particular, processing time together with the high demands in  computational power and data storage as well as the limited contrast that can be resolved  between coating and core. We therefore envisage that the main impact of this technique is likely to be in research and development and to support techniques such as TPI rather than  in routine quality control or process measurements.

...Samples were measured on a TPI imaga 2000 (Teraview Ltd., Cambridge, UK), using a point spacing grid of 200 x 200 µm and a penetration depth of 1 mm in air...

Hardness and density distributions of pharmaceutical tablets measured by terahertz pulsed imaging

Journal of Pharmaceutical Sciences
22 Apr 2013; +Wiley Textbooks
DOI: 10.1002/jps.23560

Authors: Robert K. May^1,4, Ke Su¹, Lianghao Han², Shuncong Zhong³, James A. Elliott², Lynn F. Gladden¹, Mike Evans⁴, Yaochun Shen³, J. Axel Zeitler¹
1. Department of Chemical Engineering and Biotechnology,+Cambridge University Press Education, Cambridge CB2 3RA, UK
2. Department of Materials Science and Metallurgy, +Cambridge University Press Education, Cambridge CB2 3QZ, UK
3. Department of Electrical Engineering and Electronics, +University of Liverpool, Liverpool L69 3GJ, UK
4. +TeraView Ltd., St John’s Innovation Park, Cambridge, CB4 0WS, UK

Abstract

We present terahertz pulsed imaging (TPI) as a novel tool to quantify the hardness and surface density distribution of pharmaceutical tablets. Good agreement between the surface refractive index (SRI) measured by TPI and the crushing force measured from diametral compression tests was found using a set of tablets that were compacted at various compression forces. We also found a strong correlation between TPI results and tablet bulk density, and how these relate to tablet hardness. Numerical simulations of tablet surface density distribution by finite element analysis exhibit excellent agreement with the TPI measured SRI maps. These results show that TPI has an advantage over traditional diametral compression and is more suitable for nondestructive hardness and density distribution monitoring and control of pharmaceutical manufacturing processes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci

...Terahertz pulsed imaging reflection measurements of sample tablets were acquired using a TPI Imaga 2000 (TeraView Ltd., Cambridge, UK). A detailed description of the measurement technique was presented earlier. The system has a useful spectral range of 60GHz to 3 THz, corresponding to a wavelength range of 0.09–5mm...


More details at: http://onlinelibrary.wiley.com/doi/10.1002/jps.23560/abstract

Terahertz pulsed imaging as an advanced characterisation tool for film coatings—A review

International Journal of Pharmaceutics
Available online 6 April 2013
http://dx.doi.org/10.1016/j.ijpharm.2013.03.053

Authors: Miriam Haaser^{a, b, c}, Keith C. Gordon^d, Clare J. Strachan^e, Thomas Rades^f
a School of Pharmacy, +University of Otago, P.O. Box 56, Dunedin, New Zealand
b Cavendish Laboratory, +Cambridge University Press Education , Cambridge CB3 0HE, UK
c +TeraView Ltd., St. John's Innovation Park, Cambridge CB4 0WS, UK
d Department of Chemistry, MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, Dunedin, New Zealand
e Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
f Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Abstract

Solid dosage forms are the pharmaceutical drug delivery systems of choice for oral drug delivery. These solid dosage forms are often coated to modify the physico-chemical properties of the active pharmaceutical ingredients (APIs), in particular to alter release kinetics. Since the product performance of coated dosage forms is a function of their critical coating attributes, including coating thickness, uniformity, and density, more advanced quality control techniques than weight gain are required. A recently introduced non-destructive method to quantitatively characterise coating quality is terahertz pulsed imaging (TPI). The ability of terahertz radiation to penetrate many pharmaceutical materials enables structural features of coated solid dosage forms to be probed at depth, which is not readily achievable with other established imaging techniques, e.g. near-infrared (NIR) and Raman spectroscopy. In this review TPI is introduced and various applications of the technique in pharmaceutical coating analysis are discussed. These include evaluation of coating thickness, uniformity, surface morphology, density, defects and buried structures as well as correlation between TPI measurements and drug release performance, coating process monitoring and scale up. Furthermore, challenges and limitations of the technique are discussed.


... The imaging unit in TPI instruments such as the TPI imaga 2000 system (TeraView, Cambridge, UK), therefore comprises a six-axis robotic arm, the probe and a separate optical laser operating at 670 nm. ...

More info at :http://www.sciencedirect.com/science/article/pii/S0378517313002834