Impact of Processing Conditions on Inter-tablet Coating Thickness Variations Measured by Terahertz In-Line Sensing

HUNGYEN LIN, ROBERT K. MAY, MICHAEL J. EVANS, SHUNCONG ZHONG, LYNN F. GLADDEN, YAOCHUN SHEN,

J. AXEL ZEITLER

Abstract

A novel in-line technique utilising pulsed terahertz radiation for directmeasurement of the film coating thickness of individual tablets during the coating process was previously developed and demonstrated on a production-scale coater. Here, we use this technique to monitor the evolution of tablet film coating thickness and its inter-tablet variability during the coating process under a number of different

process conditions that have been purposefully induced in the production-scale coating process. The changes that were introduced to the coating process include removing the baffles from the coater, adding uncoated tablets to the running process, halting the drum, blockage of spray guns and changes to the spray rate. The terahertz sensor was able to pick up the resulting changes in average coating thickness in the coating drum and we report the impact of these process changes on the resulting coating quality. C⃝ 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci

This study was performed using TeraView's Spectra 3000 system. (TeraView, Cambridge, UK)

Full Article: http://onlinelibrary.wiley.com/doi/10.1002/jps.24503/full

Comparisons of intra-tablet coating variability using DEM simulations, asymptotic limit models, and experiments

Ben Freireich, Rahul Kumar, William Ketterhagen, Ke Su, Carl Wassgren, J. Axel Zeitler

Abstract

Discrete element method (DEM) computer simulations are used to investigate intra-tablet coating thickness variability. Two new post-processing algorithms are presented. The first algorithm uses an image-based method to track the exposure to a simulated spray of small area panels on each tablet's surface so that the distribution of spray exposure times over the tablet's surface can be determined directly from DEM data. The second algorithm predicts the asymptotic limit of intra-tablet coating uniformity. This second algorithm includes the influence of tablet orientation and shadowing when considering exposure to the spray, averaged over many tablets.

The DEM simulations produce the first direct evidence that non-spherical tablets approach asymptotic intra-tablet coating variability values. The asymptotic limits are predicted well using the new asymptotic prediction model. In general, tablet caps have thicker coatings than tablet bands. Moreover, tablets that have a more elongated shape tend to have less coating on the smaller radius of curvature portions of the bands. Of particular importance in this new asymptotic modeling approach is the inclusion of shadowing effects. When shadowing is not included and only tablet orientation is considered, the predictions over-predict the asymptotic intra-tablet coating variability values and also change the observed rank order of the asymptotic values for different tablet shapes. The asymptotic intra-tablet coating variability values using the new algorithm correlate reasonably well with tablet sphericity, with increasing sphericity improving coating uniformity.

This paper also presents the first attempt to directly compare experimental and simulated coating thickness distributions. The asymptotic coating thickness predictions compare well qualitatively with terahertz thickness measurements made on tablets from coating experiments. Unfortunately, only qualitative comparisons could be made due to the limited number of tablets sampled experimentally and differences in spray zone areas and flux distributions. The tablets in the experiments, however, displayed similar features as those found in the simulations.

This study was performed using TeraView's Spectra 3000 system. (TeraView, Cambridge, UK)

Full Article: http://www.sciencedirect.com/science/article/pii/S0009250915001852

Diffusion and Swelling Measurements in Pharmaceutical Powder Compacts Using Terahertz Pulsed Imaging

Samy Yassin, Ke Su, Hungyen Lin, Lynn F. Gladden andJ. Axel Zeitler

Abstract

Tablet dissolution is strongly affected by swelling and solvent penetration into its matrix. A terahertz-pulsed imaging (TPI) technique, in reflection mode, is introduced as a new tool to measure one-dimensional swelling and solvent ingress in flat-faced pharmaceutical compacts exposed to dissolution medium from one face of the tablet. The technique was demonstrated on three tableting excipients: hydroxypropylmethyl cellulose (HPMC), Eudragit RSPO, and lactose. Upon contact with water, HPMC initially shrinks to up to 13% of its original thickness before undergoing expansion. HPMC and lactose were shown to expand to up to 20% and 47% of their original size in 24 h and 13 min, respectively, whereas Eudragit does not undergo dimensional change. The TPI technique was used to measure the ingress of water into HPMC tablets over a period of 24 h and it was observed that water penetrates into the tablet by anomalous diffusion. X-ray microtomography was used to measure tablet porosity alongside helium pycnometry and was linked to the results obtained by TPI. Our results highlight a new application area of TPI in the pharmaceutical sciences that could be of interest in the development and quality testing of advanced drug delivery systems as well as immediate release formulations. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci

This study was performed using TeraView's Spectra 3000 system. (TeraView, Cambridge, UK)

Full Article: http://onlinelibrary.wiley.com/doi/10.1002/jps.24376/full

Terahertz time-domain spectroscopy for measurement of particle sizes of fexofenadine hydrochloride

Anna Sadloňová, Vojtech Kresalek, Tomas Bata

Abstract

Time domain spectroscopy is one of the new methods of terahertz radiation used for wide spectrum of the industry. More extended sector is the security system much like the sector of the medicine. The main focus is orientated to detection and identification of the substances. This study is focused on the measurement of the particle size of pharmaceuticals. The characteristic absorption features will be studied experimentally by Terahertz time-domain spectroscopy. The results are identified for processing by one of the statistical method usable for such variable groups. The three samples of the pharmaceutical– Fexofenadine Hydrochloride (antihistamine) will be compared between themselves. Mentioned samples are supplied by different suppliers. The main focus will be put on the pharmaceutical differences of the same pharmaceutical that are commonly available on the markets. Terahertz time-domain spectroscopy setup was used to measure absorbance spectra of each sample in the range from 1 THz to 3 THz (it was used the device TPS Spectra 3000 produced by TeraView Ltd . The device that belongs to the first commercial machine developed in this company for measurement of the substances by transmission spectroscopy method.). During the testing was used the vacuum for purging the measurement chamber from water vapors.

This study was performed using TeraView's Spectra 3000 system. (TeraView, Cambridge, UK)

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

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...

Quantitative analysis of the layer separation risk in bilayer tablets using terahertz pulsed imaging

International Journal of Pharmaceutics, DOI: 10.1016/j.ijpharm.2013.05.010 May 2013

Authors: Masahiro Niwa^a,Yasuhiro Hiraishi^a, Norio Iwasaki^a, Katsuhide Terada^b
a Pharmaceutical Technology R&D Laboratories, CMC Center, Takeda Pharmaceutical Company Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
b Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan

More details at: http://www.sciencedirect.com/science/article/pii/S0378517313004092

Highlights

• TPI could nondestructively detect cracks between the two layers.
• TPI could quantify adhesion integrity of bilayer tablet by interface index.
• Interface index showed good correlation to the layer separation tendency.
• TPI revealed the relationship between compression pressure and interface quality.

Abstract

Layer separation is a critical defect in many bilayer tablets. Despite its importance for product quality, few studies have investigated its root cause. We evaluated bilayer tablets with varying layer separation tendencies using terahertz pulsed imaging (TPI) in comparison with other analytical methods such as tensile strength measurements, friability testing, scanning electron microscopy (SEM), and X-ray computed tomography (XRCT). The layer separation risk was determined by friability testing and shown to be correlated with the final compression pressure used for bilayer tablet fabrication. TPI could nondestructively detect cracks between the component layers that lead to layer separation. The adhesion integrity of the interface was quantified by the interface index, a unique value derived from the time-domain terahertz waveform. The interface index showed good correlation to the layer separation tendency and could distinguish interface quality among seven batches of bilayer tablets. In contrast, SEM and XRCT detected structural defects but could not distinguish batches with high or low layer separation risk. TPI revealed the relationship between compression pressure and interface quality. Thus, TPI can aid in quality control by providing a precise estimate of the layer separation risk and robust quality of bilayer tablet development with better understanding of layer separation.

... 2.5. TPI. The TPI Imaga 2000 system (TeraView Ltd., Cambridge, UK) was used in this study. ... All data were acquired using the TPI Coating Scan software version 1.7.3 (TeraView) and analyzed using TPIcsView software version 2.3.4 (TeraView). 2.6. Statistical analysis. ... 

Terahertz pharmaceutical @ DeMontfont University - open for buisness

Terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are two novel techniques for the physical characterization of pharmaceutical drug materials & final solid dosage forms.

The Pharmaceutical Technologies facility is based around the TPS Spectra 3000 from TeraView. The TPS 3000 is the world’s first commercial terahertz spectrometer capable of performing both transmission and attenuated total reflection (ATR) measurements. The TPS Spectra 3000 yields superior analytical performance – all while operating under ambient conditions. TPS Spectra 3000’s modular sample compartment accepts standard IR sampling accessories for transmission measurements. ATR modules provide non-destructive measurements of solids, suspensions, slurries pastes and gels. ATR measurements are obtained from as little as 1 mg of solid sample. TPS Spectra 3000 offers enhanced flexibility to investigate intermolecular hydrogen-bonding vibrations, crystalline structure lattice vibrations or low-frequency internal vibrations without concern for thermal effects.

The facility (which is funded by the East Midlands Development Agency and De Montfort University's HEIF) is available to all East Midlands companies via demonstration workshops which are aimed at creating opportunities for process and product development and quality control.  Please see the Applications Section and Document Library for example pharmaceutical and biological uses of this instrument.

For more information, or to book a place on the demonstrator workshops, contact Geoff Smith +44 116 250 6298gsmith02@dmu.ac.uk or download the forms from thes links (Booking Form;   Invitation and Agenda)

Applications

Drug Polymorphism TPS can be used to characterize crystalline properties of drugs and excipients. Different polymorphic forms of a drug can be readily distinguished and quantified, ensuring product quality by maintaining the correct bioavailability of the formulation. Having the wrong polymorph in a formulation can dramatically alter the solubility and hence efficacy of the drug.  

Pharmaceutical Co-crystals These are drugs that have been crystallized with another compound/chemical embedded intimately within the crystal structure. The result is a sold with greater solubility than the pure drug crystal and hence higher therapeutic activity. Many new drugs are poorly soluble and co-crystals are being research intensively as a potential means of improving drug activity. Screening of potential co-crystals is time consuming. Owing to the particular sensitivity of TPS to intermolecular interactions, terahertz therefore offers a potential rapid screening of co-crystal formations.

In-Process Monitoring The pharmaceutical industry is increasing looking at a variety of in-process analytical technologies. TPI and time of flight TPS offers the opportunity of monitoring specific chemical formation processes, such as the batch crystallization of drugs & wet granulation of powders prior to tabletting.

Tablet Coating TPI greatly improves quality control in production and speeds up the development of new coating formulations and processes. Because the tablets are not destroyed during analysis, further tests can be carried out after TPI using the same samples. This approach provides a tool for the detection of problems with coating processes in a very early stage of formulation development.

Solid Dispersions These are mixtures of drug and polymers to form solid particles with high solubility. The distribution and form of the drug within these matrices is critical to their performance as drug delivery systems. TPI can provide imaging of the matrix to identify and control quality parameters related to the functionality of these materials.

Transdermal Drug delivery The skin provides for a convenient route for delivering drugs. However, the top layer of the skin, the stratum corneum, presents a significant barrier to drug delivery. TPI provides a convenient imaging tool for investigating the hydration and thickness of the stratum corneum, which are two of the most significant features defining the barrier function. In addition TPI can be used to image the disintegration of subcutaneous implants, and provide for models of drug dissolution in real time. Again this is essential knowledge for drug development companies in these efforts to use solid dispersions in drug delivery applications.

Dental TPI provides a convenient approach to the imaging of enamel thickness, the measurement of demineralization of imaging of early stage caries, which is either not-possible of difficult to achieve with X-Ray, which is also ionizing and hazardous. TPI is non-ionising and safe.

Oncology In working with the Leicestershire Hospitals trust a number of medical applications will be developed. One potential application is the use of TPI for a non-invasive imaging of sub-surface skin and mouth tumors. ‘Hot-spots’, below the skin surface, can highlight the progression of the tumor and help define intervention and treatment strategies.

Terahertz In-Line Sensor for Direct Coating Thickness Measurement of Individual Tablets during Film Coating in Real-Time

ROBERT K. MAY, MICHAEL J. EVANS, SHUNCONG ZHONG,  IAN WARR, LYNN F. GLADDEN, YAOCHUN SHEN,  J. AXEL ZEITLER

J Pharm Sci 100:1535–1544, 2011

http://onlinelibrary.wiley.com/doi/10.1002/jps.22359/abstract

ABSTRACT:

We present a new in-line measurement technique to determine the coating thickness of individual pharmaceutical tablets during film coating in a pan coating unit using pulsed terahertz technology. Results of these real-time terahertz measurements acquired during a production scale coating run are validated using both off-line high-resolution terahertz pulsed imaging of the whole dosage form as well as weight-gain measurements made on sample tablets removed at discrete time intervals during the process run. The terahertz measurements provide a direct method of determining the coating thickness, and no chemometric calibration models are required for the quantification. The results, and their repeatability, demonstrate that real-time monitoring of pharmaceutical tablet coating is not only possible but also provides substantially more information of the coating quality than the standard quality control method. Rather than providing the average coating thickness of a large number of tablets, the terahertz sensor provides the thickness of up to 100 individual tablet coatings per minute. Using this information, the operator can get additional information about the thickness distribution in the coating pan and adjust the process accordingly. At present, a minimum coating thickness of 40 µm is required to determine the coating thickness. The technique is applicable for coatings up to 1mm in thickness. Within that range, it provides thickness measurements of sub-micron resolution. Terahertz in-line coating process measurements show considerable potential for applications in real-time release, process analytical technology and quality by design.

For TeraView's range of products see http://www.teraview.com/products/index.html

For help with your pharmaceutical problems also see

http://www.teraview.com/services/applications-support/index.html

Prediction of dissolution time and coating thickness of sustained release formulations using Raman spectroscopy and terahertz pulsed imaging

·         European Journal of Pharmaceutics and Biopharmaceutics

Available online 5 January 2012

• Joshua Müller^a, 
• Daniela Brock^a, 
• Klaus Knop^a, 
• J. Axel Zeitler^b, 
• Peter Kleinebudde

• Abstract

  Raman spectroscopy was implemented successfully as a non-invasive and rapid process analytical technology (PAT) tool for in-line quantitative monitoring of functional coating. Coating experiments were performed at which diprophylline tablets were coated with a sustained release formulation based on Kollicoat® SR 30 D. Using PLS a multivariate model was constructed by correlating Raman spectral data with the mean dissolution time as determined by dissolution testing and the coating thickness as measured by terahertz pulsed imaging.
  By performing in-line measurements it was possible to monitor the progress of the coating process and to detect the end point of the process, where the acquired coating amount was achieved for the desired MDT or coating thickness.
  
  Mean dissolution time (MDT) over coating time predicted by Raman spectroscopy (top left) and in correlation to coating thickness measured by terahertz spectroscopy (top right). Layer thickness maps and histograms from TPI measurements after a short (left) and a longer (right) coating time.
  
  
  Terahertz results were acquired on a TeraView's TPI2000 instrument.
  
  
  For more information :
  http://www.sciencedirect.com/science/article/pii/S0939641111003614
  
  

  Keywords

  • Process analytical technology; 
  • Multivariate data analysis; 
  • Raman spectroscopy; 
  • Terahertz pulsed imaging; 
  • Functional coating; 
  • Mean dissolution time