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      Crystallization and Phase Changes in Paracetamol from the Amorphous Solid to the Liquid Phase

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          Abstract

          For the case of paracetamol, we show how terahertz time-domain spectroscopy can be used to characterize the solid and liquid phase dynamics. Heating of supercooled amorphous paracetamol from 295 K in a covered sample under vacuum leads to its crystallization at 330 K. First, form III is formed followed by the transformation of form III to form II at 375 K, to form I at 405 K, and finally melting is observed around 455 K. We discuss the difference between the featureless spectra of the supercooled liquid and its liquid melt. Lastly, we studied the onset of crystallization from the supercooled liquid in detail and quantified its kinetics based on the Avrami–Erofeev model. We determined an effective rate constant of k = 0.056 min –1 with a corresponding onset of crystallization at T = 329.5 K for a heating rate of 0.4 K min –1.

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          Most cited references24

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          What is the true solubility advantage for amorphous pharmaceuticals?

          To evaluate the magnitude of the solubility advantage for amorphous pharmaceutical materials when compared to their crystalline counterparts. The thermal properties of several drugs in their amorphous and crystalline states were determined using differential scanning calorimetry. From these properties the solubility advantage for the amorphous form was predicted as a function of temperature using a simple thermodynamic analysis. These predictions were compared to the results of experimental measurements of the aqueous solubilities of the amorphous and crystalline forms of the drugs at several temperatures. By treating each amorphous drug as either an equilibrium supercooled liquid or a pseudo-equilibrium glass, the solubility advantage compared to the most stable crystalline form was predicted to be between 10 and 1,600 fold. The measured solubility advantage was usually considerably less than this, and for one compound studied in detail its temperature dependence was also less than predicted. It was calculated that even for partially amorphous materials the apparent solubility enhancement (theoretical or measured) is likely to influence in-vitro and in-vivo dissolution behavior. Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simple thermodynamic considerations. This appears to be the result of difficulties in determining the solubility of amorphous materials under true equilibrium conditions. Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage for amorphous pharmaceuticals, which directly reflects the driving force for their initial dissolution.
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            Terahertz time-domain spectroscopy and the quantitative monitoring of mechanochemical cocrystal formation.

            Terahertz (THz) radiation probes intermolecular interactions through crystal lattice vibrations, allowing the characterization of solid materials. Thus, THz spectroscopy is a promising alternative to mainstream solid-state analytical tools such as X-ray diffraction or thermal analysis. The method provides the benefits of online measurement, remote sampling and three-dimensional imaging, all of which are attractive for quality control and security applications. In the context of pharmaceutical solids, THz spectroscopy can differentiate and quantify different forms of active pharmaceutical ingredients. Here, we apply this technique to monitor a dynamic process involving two molecular crystals. In particular, we follow the mechanochemical construction of a two-component cocrystal by grinding together phenazine (phen) and mesaconic acid (mes). To rationalize the observed changes in the spectra, we conduct lattice dynamics calculations that lead to the tentative assignment of at least one feature in the cocrystal THz spectrum.
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              Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting--a review.

              Terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are two novel techniques for the physical characterization of pharmaceutical drug materials and final solid dosage forms, utilizing spectral information in the far infrared region of the electromagnetic spectrum. This review focuses on the development and performance of pharmaceutical applications of terahertz technology compared with other tools for physical characterization. TPS can be used to characterize crystalline properties of drugs and excipients. Different polymorphic forms of a drug can be readily distinguished and quantified. Recent developments towards a better understanding of the fundamental theory behind spectroscopy in the far infrared have been discussed. Applications for TPI include the measurement of coating thickness and uniformity in coated pharmaceutical tablets, structural imaging and 3D chemical imaging of solid dosage forms.
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                Author and article information

                Journal
                Mol Pharm
                Mol. Pharm
                mp
                mpohbp
                Molecular Pharmaceutics
                American Chemical Society
                1543-8384
                1543-8392
                28 February 2014
                07 April 2014
                : 11
                : 4
                : 1326-1334
                Affiliations
                [1]Department of Chemical Engineering and Biotechnology, University of Cambridge , New Museums Site, Pembroke Street, Cambridge CB2 3RA, United Kingdom
                Author notes
                Article
                10.1021/mp400768m
                3980750
                24579729
                22263c79-0dd3-4f2a-b96c-61de07b14f18
                Copyright © 2014 American Chemical Society

                Terms of Use CC-BY

                History
                : 20 December 2013
                : 28 February 2014
                : 25 February 2014
                Categories
                Article
                Custom metadata
                mp400768m
                mp-2013-00768m

                Pharmacology & Pharmaceutical medicine
                terahertz spectroscopy,paracetamol,acetaminophen,amorphous,crystallization,polymorph,kinetics

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