Article

Relaxation and crystallization of amorphous carbamazepine studied by terahertz pulsed spectroscopy

School of Pharmacy, University of Otago, P.O. Box 913, Dunedin, New Zealand.
Journal of Pharmaceutical Sciences (Impact Factor: 2.59). 10/2007; 96(10):2703-9. DOI: 10.1002/jps.20908
Source: PubMed

ABSTRACT

At the example of carbamazepine the crystallization of a small organic molecule from its amorphous phase was studied using in situ variable temperature terahertz pulsed spectroscopy (TPS). Even though terahertz spectra of disordered materials in the glassy state exhibit no distinct spectral features we demonstrate subtle changes in the spectra with increasing temperature and discuss the findings in respect to the density of vibrational states. The crystallization leads to distinct spectral features allowing the crystallization and subsequent polymorphic phase transition at higher temperatures to be studied in detail. It is possible to study both relaxation and crystallization processes by variable temperature TPS.

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Available from: J. Axel Zeitler, Apr 29, 2014
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    • "Several methods can be used to extract the crystallisation kinetics from the terahertz spectra. Perhaps the most straightforward approach is to monitor the change in height or intensity of a crystalline resonance peak as crystallisation occurs[77].McIntosh et al.used the same approach and showed that it is possible to describe the change in peak intensity with time during crystallisation by employing Avrami type kinetics[79]. In addition, they also proposed that it is possible to describe the terahertz spectra during the course of crystallisation by a linear combination of a Lorentzian function, centred at the frequency of a crystalline resonance peak in the spectrum ν c of specified half width at half maximum γ, and a power law describing the background absorption, resulting in[79]: "
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    ABSTRACT: Despite much effort in the area, no comprehensive understanding of the formation and behaviour of amorphous solids has yet been achieved. This severely limits the industrial application of such materials, including drug delivery where, in principle, amorphous solids have demonstrated their great usefulness in increasing the bioavailability of poorly aqueous soluble active pharmaceutical ingredients. Terahertz time-domain spectroscopy is a relatively novel analytical technique that can be used to measure the fast molecular dynamics of molecules with high accuracy in a non-contact and non-destructive fashion. Over the past decade a number of applications for the characterisation of amorphous drug molecules and formulations have been developed and it has been demonstrated how this technique can be used to determine the onset and strength in molecular mobility that underpins the crystallisation of amorphous drugs. In this review we provide an overview of the history, fundamentals and future perspective of pharmaceutical applications related to the terahertz dynamics of amorphous systems.
    Full-text · Article · Jan 2016 · Advanced drug delivery reviews
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    • "diation . Thus , they cause no or little interference when investigating crystalline drugs . Recently , amorphous material was characterised using TPS while heating the sample . Structural relaxation and increase in molecular mobility for the amorphous sample were visible in the absorbance spectra when transforming to the glassy or rubbery state ( Zeitler et al . 2007c ) ."
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    ABSTRACT: In order to improve and continuously develop the quality of pharmaceutical products, the process analytical technology (PAT) framework has been adopted by the US Food and Drug Administration. One of the aims of PAT is to identify critical process parameters and their effect on the quality of the final product. Real time analysis of the process data enables better control of the processes to obtain a high quality product. The main purpose of this work was to monitor crucial pharmaceutical unit operations (from blending to coating) and to examine the effect of processing on solid-state transformations and physical properties. The tools used were near-infrared (NIR) and Raman spectroscopy combined with multivariate data analysis, as well as X-ray powder diffraction (XRPD) and terahertz pulsed imaging (TPI). To detect process-induced transformations in active pharmaceutical ingredients (APIs), samples were taken after blending, granulation, extrusion, spheronisation, and drying. These samples were monitored by XRPD, Raman, and NIR spectroscopy showing hydrate formation in the case of theophylline and nitrofurantoin. For erythromycin dihydrate formation of the isomorphic dehydrate was critical. Thus, the main focus was on the drying process. NIR spectroscopy was applied in-line during a fluid-bed drying process. Multivariate data analysis (principal component analysis) enabled detection of the dehydrate formation at temperatures above 45°C. Furthermore, a small-scale rotating plate device was tested to provide an insight into film coating. The process was monitored using NIR spectroscopy. A calibration model, using partial least squares regression, was set up and applied to data obtained by in-line NIR measurements of a coating drum process. The predicted coating thickness agreed with the measured coating thickness. For investigating the quality of film coatings TPI was used to create a 3-D image of a coated tablet. With this technique it was possible to determine coating layer thickness, distribution, reproducibility, and uniformity. In addition, it was possible to localise defects of either the coating or the tablet. It can be concluded from this work that the applied techniques increased the understanding of physico-chemical properties of drugs and drug products during and after processing. They additionally provided useful information to improve and verify the quality of pharmaceutical dosage forms
    Full-text · Thesis · Aug 2008
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    • "diation . Thus , they cause no or little interference when investigating crystalline drugs . Recently , amorphous material was characterised using TPS while heating the sample . Structural relaxation and increase in molecular mobility for the amorphous sample were visible in the absorbance spectra when transforming to the glassy or rubbery state ( Zeitler et al . 2007c ) ."
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to improve and continuously develop the quality of pharmaceutical products, the process analytical technology (PAT) framework has been adopted by the US Food and Drug Administration. One of the aims of PAT is to identify critical process parameters and their effect on the quality of the final product. Real time analysis of the process data enables better control of the processes to obtain a high quality product. The main purpose of this work was to monitor crucial pharmaceutical unit operations (from blending to coating) and to examine the effect of processing on solid-state transformations and physical properties. The tools used were near-infrared (NIR) and Raman spectroscopy combined with multivariate data analysis, as well as X-ray powder diffraction (XRPD) and terahertz pulsed imaging (TPI). To detect process-induced transformations in active pharmaceutical ingredients (APIs), samples were taken after blending, granulation, extrusion, spheronisation, and drying. These samples were monitored by XRPD, Raman, and NIR spectroscopy showing hydrate formation in the case of theophylline and nitrofurantoin. For erythromycin dihydrate formation of the isomorphic dehydrate was critical. Thus, the main focus was on the drying process. NIR spectroscopy was applied in-line during a fluid-bed drying process. Multivariate data analysis (principal component analysis) enabled detection of the dehydrate formation at temperatures above 45°C. Furthermore, a small-scale rotating plate device was tested to provide an insight into film coating. The process was monitored using NIR spectroscopy. A calibration model, using partial least squares regression, was set up and applied to data obtained by in-line NIR measurements of a coating drum process. The predicted coating thickness agreed with the measured coating thickness. For investigating the quality of film coatings TPI was used to create a 3-D image of a coated tablet. With this technique it was possible to determine coating layer thickness, distribution, reproducibility, and uniformity. In addition, it was possible to localise defects of either the coating or the tablet. It can be concluded from this work that the applied techniques increased the understanding of physico-chemical properties of drugs and drug products during and after processing. They additionally provided useful information to improve and verify the quality of pharmaceutical dosage forms Lääketeollisuudessa on tänä päivänä yhä kasvava kiinnostus siirtää laadunvarmistuksen painopistettä lopputuotteiden analysoinnista eri valmistusvaiheiden aikaiseen testaukseen. Tästä johtuen tässä työssä käytettiin erilaisia menetelmiä lääkevalmistuksen prosessivaiheiden kuten lääkeaineen ja apuaineen sekoittamisen, kostearakeistuksen, rakeiden kuivaamisen, tablettien puristamisen sekä päällystyksen tutkimiseen. Tutkimuksessa käytetyt prosessianalyysitekniikat olivat pääasiallisesti spektroskooppisia tekniikoita kuten lähialueen infrapunaspektroskopia. Näitä tekniikoita sovellettiin esimerkiksi lääkeaineen kiderakenteessa tapahtuvien muutosten selvittämiseen sekä tablettien kalvopäällysteen muodostumisen seuraamiseen päällystyksen aikana. Lisäksi käytettiin kalvopäällysteen laadunvarmistukseen uutta terahertsiteknologiaan perustuvaa kuvantamismenetelmää, joka mahdollistaa lääketablettien tutkimisen niitä vaurioittamatta.
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