There is a controversy about the extent to which the primary and secondary dielectric relaxations influence the crystallisation of amorphous organic compounds below the glass transition temperature. Recent studies also point to the importance of fast molecular dynamics on picosecond-to-nanosecond time scales with respect to the glass stability. Here we show terahertz (THz) spectroscopy evidence on the crystallisation of amorphous drugs well below their glass transition temperature and confirm the direct role of Johari-Goldstein (JG) secondary relaxation as a facilitator of the crystallisation. We determine the onset temperature Tβ above which the JG relaxation contributes to the fast molecular dynamics and analytically quantify the level of this contribution. We then show there is a strong correlation between the increase in the fast molecular dynamics and onset of crystallisation in several chosen amorphous drugs. We believe that this technique has immediate applications to quantify the stability of amorphous drug materials.
Spectroscopy is the study of the quantized interaction of energy with the matter. In the electromagnetic spectrum, there are radiations of different energy which lead to a wide range of spectroscopy techniques like UV-Vis, Infrared, NMR etc. The spectral range from around 3.3 cm-1 to 333.6 cm-1 was mostly unexplored before 30 years and known as “terahertz gap” due to unavailability of Terahertz (THz) generators and detectors but in the last two decades, this has emerged as a field of great potential and various applications like THz imaging, chemical analysis and molecular spectroscopy, applications in biology, medicines, protein analysis and pharmaceuticals, in solid state where it can be an alternative to XRD, NMR, DSC, in radio astronomy, in environmental control, in explosive detection. The combination of all these applications falls under THz spectroscopy.
In this study, the development of Terahertz technology from past years to today, as well as the information and working principle about Terahertz technology are explained. In addition, various usage areas are given. Also the main topics are given below.
The general principles of the Terahertz Technology.
What is the Terahertz?
How can we generate the THz?
How can we detect it ?
Application areas of Terahertz technology
If there is a place you do not understand please contact me. (Mail, social media)
I hope you like. Please like and comment.
Spectroscopy is the study of the quantized interaction of energy with the matter. In the electromagnetic spectrum, there are radiations of different energy which lead to a wide range of spectroscopy techniques like UV-Vis, Infrared, NMR etc. The spectral range from around 3.3 cm-1 to 333.6 cm-1 was mostly unexplored before 30 years and known as “terahertz gap” due to unavailability of Terahertz (THz) generators and detectors but in the last two decades, this has emerged as a field of great potential and various applications like THz imaging, chemical analysis and molecular spectroscopy, applications in biology, medicines, protein analysis and pharmaceuticals, in solid state where it can be an alternative to XRD, NMR, DSC, in radio astronomy, in environmental control, in explosive detection. The combination of all these applications falls under THz spectroscopy.
In this study, the development of Terahertz technology from past years to today, as well as the information and working principle about Terahertz technology are explained. In addition, various usage areas are given. Also the main topics are given below.
The general principles of the Terahertz Technology.
What is the Terahertz?
How can we generate the THz?
How can we detect it ?
Application areas of Terahertz technology
If there is a place you do not understand please contact me. (Mail, social media)
I hope you like. Please like and comment.
The pdf contain all the information of various technique ,such as chromatography,spectroscopy,centrifugation,electrophoresis special thanks to Dr.Rambir Singh for helping out the topics easily.Contact for help or suggestion @7985214648 whattapp only
Presenting a presentation on the topic of Column chromatography with including basics of chromatography, principles, equations, graphs and data related to it.
Topics which covered in this ppt is
Principle of chromatography
classification of chromatography
partition coefficient
chromatogram
Resolution
plate theory
determination of N
band zone broadening
rate theory
https://www.linkedin.com/in/preeti-choudhary-266414182/
https://www.instagram.com/chaudharypreeti1997/
https://www.facebook.com/profile.php?id=100013419194533
https://twitter.com/preetic27018281
Please like, share, comment and follow.
stay connected
If any query then contact:
chaudharypreeti1997@gmail.com
Thanking-You
Preeti Choudhary
2016 Presentation at the University of Hawaii Cancer CenterCasey Greene
Date: February 19, 2016
Time: 10:30 am
Place: University of Hawaii Cancer Center 701 Ilalo Street, Sullivan Conference Room
Details: Dr. Casey Greene
Department of Systems Pharmacology and Translational Therapeutics
Department of Genetics
University of Pennsylvania
Moore Investigator, Gordon and Betty Moore Foundation
The pdf contain all the information of various technique ,such as chromatography,spectroscopy,centrifugation,electrophoresis special thanks to Dr.Rambir Singh for helping out the topics easily.Contact for help or suggestion @7985214648 whattapp only
Presenting a presentation on the topic of Column chromatography with including basics of chromatography, principles, equations, graphs and data related to it.
Topics which covered in this ppt is
Principle of chromatography
classification of chromatography
partition coefficient
chromatogram
Resolution
plate theory
determination of N
band zone broadening
rate theory
https://www.linkedin.com/in/preeti-choudhary-266414182/
https://www.instagram.com/chaudharypreeti1997/
https://www.facebook.com/profile.php?id=100013419194533
https://twitter.com/preetic27018281
Please like, share, comment and follow.
stay connected
If any query then contact:
chaudharypreeti1997@gmail.com
Thanking-You
Preeti Choudhary
2016 Presentation at the University of Hawaii Cancer CenterCasey Greene
Date: February 19, 2016
Time: 10:30 am
Place: University of Hawaii Cancer Center 701 Ilalo Street, Sullivan Conference Room
Details: Dr. Casey Greene
Department of Systems Pharmacology and Translational Therapeutics
Department of Genetics
University of Pennsylvania
Moore Investigator, Gordon and Betty Moore Foundation
Seminar slides presenting work on dark matter annihilation into light mediators which subsequently decay in to Standard Model particles. This is motivated by indirect detection signals in gamma rays, such as the recent excess seen in the Fermi Large Area Telescope.
Effect of inorganic fillers on Poly(ethylene oxide) crystallization and dynamicsEleni 'Hellen' Papananou
Polymer morphology, crystallization and chain conformation are investigated in hydrophilic poly(ethylene oxide)/SiO2 nanocomposites. PEO was able to crystallize in all cases; nevertheless differences were observed for high silica content hybrids. The crystallization process as well as the conformation of the chains close to the inorganic surfaces exhibit different characteristics than that of the neat polymer melt. The effect of the proximity to the silica surfaces on polymer dynamics is investigated as well.
Phase equillibrium studies of impure CO2 systems to underpin developments of CCS technologies, Jie Ke, University of Nottingham. Presented at CO2 Properties and EoS for Pipeline Engineering, 11th November 2014
Network-Growth Rule Dependence of Fractal Dimension of Percolation Cluster on...Shu Tanaka
Our paper entitled “Network-Growth Rule Dependence of Fractal Dimension of Percolation Cluster on Square Lattice" was published in Journal of the Physical Society of Japan. This work was done in collaboration with Dr. Ryo Tamura (NIMS).
http://journals.jps.jp/doi/abs/10.7566/JPSJ.82.053002
NIMSの田村亮さんとの共同研究論文 “Network-Growth Rule Dependence of Fractal Dimension of Percolation Cluster on Square Lattice" が Journal of the Physical Society of Japan に掲載されました。
http://journals.jps.jp/doi/abs/10.7566/JPSJ.82.053002
It is hard to understate the importance of ‘Thermodynamics’ in providing an almost complete (Grand Unified Theory) picture of the inner physics of energy transfer spanning machines and chemistry thro information.
Apparently, Einstein had two favourite theories: General Relativity and Thermodynamics! He championed both because of their ‘beauty’, completeness, and emergent properties purely derived from the fundamental consideration of how the universe works.
The origins of this topic mainly reside in the Industrial revolution and the realisation that the early machinery was grossly inefficient. E.G. Engines were only converting the energy consumed to ~2% of useful work output. This drew the attention of Savery (1698), Newcomen (1712), Carnot (1769), and for the next 200 years the conundrum of lost energy occupied many of the greatest scientific minds. This culminated in Rudolf Clausius (~1850)publishing his theory of Thermodynamics with further refinement by Boltzmann (1872).
Why was all this so important? In the 1700s a ‘beam engine’ weighing in at >20 tons consumed vast amounts of coal, to deliver an output ~10hp. Today a Turbofan jet Engine can deliver >30k hp at a weight of ~6 tons. This is the difference between working with little understanding, and today where our knowledge is far more complete. Our latest challenges tend around non-linear loss mechanisms associated with turbulent air and fuel flow.. And like many other fields we have to step beyond our generalise mathematical models and turn to the power of our computers for deeper insights.
Ultimately all machines, mechanisms, computing processes and information itself, involve the transformation of matter and/or bits, and thus they are Entropic and subject to the theory of Thermodynamics. This lecture therefore presents a foundation spanning the history and progress to date in preparation for the embracing other science and engineering disciplines.
A new incomplete data model, the trunsored model, in lifetime analysis is introduced. This model can be regarded as a unified model of the censored and truncated models. Using the model, we can not only estimate the ratio of the fragile population to the mixed fragile and durable populations, but also test a hypothesis that the ratio is equal to a prescribed value. A central point of the paper is that such a test can easily be realized through the newly introduced trunsored model, because it has been difficult to do such a hypothesis test under only the framework of censored and truncated models. Therefore, the relationship of the trunsored model to the censored and truncated models is clarified because the trunsored model unifies the censored and truncated models. The paper also shows how to obtain the estimates of the parameters in lifetime estimation, and corresponding confidence intervals for the fragile population. Typical examples applied to electronic board failures, and to breast cancer data, for lifetime estimation are demonstrated, and successfully worked using the trunsored model.
Similar to Terahertz Spectroscopy for the Solid State Characterisation of Amorphous Systems (20)
DERIVATION OF MODIFIED BERNOULLI EQUATION WITH VISCOUS EFFECTS AND TERMINAL V...Wasswaderrick3
In this book, we use conservation of energy techniques on a fluid element to derive the Modified Bernoulli equation of flow with viscous or friction effects. We derive the general equation of flow/ velocity and then from this we derive the Pouiselle flow equation, the transition flow equation and the turbulent flow equation. In the situations where there are no viscous effects , the equation reduces to the Bernoulli equation. From experimental results, we are able to include other terms in the Bernoulli equation. We also look at cases where pressure gradients exist. We use the Modified Bernoulli equation to derive equations of flow rate for pipes of different cross sectional areas connected together. We also extend our techniques of energy conservation to a sphere falling in a viscous medium under the effect of gravity. We demonstrate Stokes equation of terminal velocity and turbulent flow equation. We look at a way of calculating the time taken for a body to fall in a viscous medium. We also look at the general equation of terminal velocity.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Terahertz Spectroscopy for the Solid State Characterisation of Amorphous Systems
1. Terahertz Spectroscopy for the Solid State
Characterisation of Amorphous Systems
Juraj Sibik and Axel Zeitler
Department of Chemical Engineering and Biotechnology, University of Cambridge,
Pembroke Street, Cambridge CB2 3RA, UK
jaz22@cam.ac.uk
http://thz.ceb.cam.ac.uk – www.pssrc.org
19 June 2015
5. Introduction Dielectric Spectroscopy
Absorption Mechanisms
This technique spans
the frequency range
over 102 to 1012 Hz
Dipoles and charges
respond to the
excitation by an
external electric field
and move as a whole
during relaxation
ˆε = ε + iε = (n + iκ)2
where α = 4πκ/λ0
Image source: https://commons.wikimedia.org/wiki/file:
Dielectric_responses.svg 3 of 31
6. Introduction Dielectric Spectroscopy
Dielectric Relaxation – Molecular Mobility
α-relaxation
Structural relaxation
process
Relaxation time changes
from 10−12 to 102 s upon
glass transition
Concept of cooperatively
rearranging regions
(CRR)
β-relaxations
Local motions involving
the entire molecule or
intra-molecular
reorientations
Much faster than α
relaxations
Commonly observed
either as a separate peak
or as a high frequency
wing of the α-relaxation.
G. Adam, J.H. Gibbs, The Journal of Chemical Physics. 43, 139 (1965). 4 of 31
7. Introduction Dielectric Spectroscopy
Dielectric Relaxation in Amorphous Solids
α and β relaxation process are
separated in frequency (but are
very broad and often overlap)
The secondary β-relaxation
processes are typically related to
local mobility
It is possible to directly measure the
relaxation times using dielectric
spectroscopy
H. Wagner, R. Richert, J. Non-Cryst. Sol. 242, 19 (1998).
S. Bhattacharya, R. Suryanarayanan, 98, 2935 (2009). 5 of 31
9. Introduction Terahertz Radiation
What does Terahertz Radiation Refer to?
1 0
5
1 0
6
1 0
7
1 0
8
1 0
9
1 0
1 0
1 0
1 1
1 0
1 2
1 0
1 3
1 0
1 4
1 0
1 5
1 0
1 6
1 0
1 7
1 0
1 8
1 0
1 9
1 0
2 0
1 0
2 1
1 0
3
1 0
2
1 0
1
1 0
0
1 0
- 1
1 0
- 2
1 0
- 3
1 0
- 4
1 0
- 5
1 0
- 6
1 0
- 7
1 0
- 8
1 0
- 9
1 0
- 1 0
1 0
- 1 1
1 0
- 1 2
1 0
- 1 3
V i s i b l e L i g h t
I o n i s i n g
T r a n s p a r e n c y
I n f r a r e d U l t r a v i o l e t
T r a n s p a r e n c y
S p e c t r o s c o p i c I n f o r m a t i o n
T H zR a d i o w a v e s M i c r o w a v e s X - r a y s G a m m a
1 M H z 1 Z H z1 E H z1 P H z1 T H z1 G H z
F r e q u e n c y / H z
1 n m1 µm1 m m1 m1 k m
W a v e l e n g t h / m
0 . 0 1 0 . 1 1 1 0 1 0 0
F r e q u e n c y / T H z
1 . 0 1 0 . 0 1 0 0 . 0 1 0 0 0 . 0
H y d r o g e n - b o n d i n g s t r e t c h e s a n d t o r s i o n s ( l i q u i d s )
S e c o n d a r y d i e l e c t r i c r e l a x a t i o n s ( s o l i d )
I n t r a m o l e c u l a r v i b r a t i o n a l m o d e s
C r y s t a l l i n e p h o n o n v i b r a t i o n s ( s o l i d )
W a v e n u m b e r / c m
- 1
M o l e c u l a r r o t a t i o n s ( g a s )
6 of 31
10. Introduction Terahertz Radiation
Vibrational Spectroscopy
Mid-infrared
Intramolecular Modes
Information about the structure of a single
molecule, identification of molecules
Terahertz
Intermolecular Modes
Information about the structure and
dynamics of molecular interaction
7 of 31
11. Introduction Terahertz Radiation
Terahertz Time-Domain Spectroscopy
0 1 0 2 0 3 0 4 0 5 0
- 8
- 6
- 4
- 2
0
2
4
6
8
1 0
1 2
THzelectricfield/a.u.
t i m e / p s
1 2 3 4 5
0 . 1
1
1 0
1 0 0
power/a.u.
f r e q u e n c y / T H z
Typical terahertz pulse in time-domain (left) and frequency components of the pulse (right).
Coherent sub-picosecond pulses, bandwidth of 0.1 to 4.0 THz, excellent signal-to-noise
detection
8 of 31
12. Introduction Terahertz Radiation
Terahertz Time-Domain Technology
In THz-TDS both amplitude and phase of the electric field
is measured and not just its intensity
This means that the complex refractive index can be
extracted directly without resorting to Kramer-Kronig
relations:
ˆEsam(ω)
ˆEref(ω)
= T(ω)eiφ(ω)
In terms of absorption coefficient and refractive index:
α(ω) = −
2
d
ln
(nm + n)2
4nmn
T(ω)
n(ω) = 1 +
φ(ω)c
ωd
This can also directly be expressed in terms of dielectric
losses:
ˆn = n + iκ =
√
ˆε =
√
ε + iε
9 of 31
14. Amorphous Materials What Can be Measured at THz Frequencies?
Amorphous Materials
http://www.ndt-ed.org/EducationResources/CommunityCollege/
Materials/Structure/solidstate.htm
J. Bicerano, D. Adler, Pure & Appl. Chem., 59, 101 (1987) 10 of 31
15. Amorphous Materials What Can be Measured at THz Frequencies?
Disordered Materials – Losses at THz Frequencies
Amorphous Solids and Supercooled Liquids
Mid-IR: Bond vibrations, slight shift and
broadening compared to crystalline
materials
THz: No phonon vibrations occur as there
is no long range order
At lower frequencies molecular rotations
and translations take place
These molecular motions can be described
by the first order decay of macroscopic
polarisation as proposed by Debye in his
dielectric relaxation theory
11 of 31
17. Amorphous Materials Model System: Polyalcohols
Dielectric Response of Amorphous Materials
S. Kastner et al., J. Non-Cryst. Sol. 357, 510 (2011). 12 of 31
18. Amorphous Materials Model System: Polyalcohols
Dielectric Response of Amorphous Materials
S. Kastner et al., J. Non-Cryst. Sol. 357, 510 (2011). 12 of 31
19. Amorphous Materials Model System: Polyalcohols
Amorphous Sorbitol
100 150 200 250 300
0
50
100
150
200
1.5 THz
1.0 THz
0.5 THz
α[cm
-1
]
100wt% sorbitol
T [K]
Tg
Glass
transition
Structural relaxation at Tg leads to increase in absorption
J. Sibik et al., Phys. Chem. Chem. Phys. 15, 11931 (2013). 13 of 31
20. Amorphous Materials Model System: Polyalcohols
Amorphous Sorbitol
100 150 200 250 300
0
50
100
150
200
1.5 THz
1.0 THz
0.5 THz
α[cm
-1
]
100wt% sorbitol
T [K]
Tg
Glass
transition
Subtle but noticeable change in absorption below Tg – origin?
J. Sibik et al., Phys. Chem. Chem. Phys. 15, 11931 (2013). 13 of 31
21. Amorphous Materials Model System: Polyalcohols
Secondary Relaxation in Polyalcohols
A. Döss et al., Phys. Rev. Lett. 88 (2002), doi:10.1103/PhysRevLett.88.095701. 14 of 31
22. Amorphous Materials Model System: Polyalcohols
Terahertz Spectroscopy of Polyalcohols
10
0
10
-1
10
0
300 K
80 K
120 K
190 K
''()
(THz)
(a) glycerol
10
0
150 K
230 K
240 K
90 K
(THz)
(b) threitol
10
0
310 K
80 K
180 K
250 K
(THz)
(c) xylitol
10
0
310 K
(THz)
180 K
260 K
(d) sorbitol
90 K
10
1
10
2
(cm
-1
)
10
1
10
2
(cm
-1
)
10
1
10
2
(cm
-1
)
10
1
10
2
(cm
-1
)
The blue and red circles highlight the losses in the proximity of 0.65 Tg and Tg
respectively.
The sample of threitol recrystallised above 250 K – no data above this temperature
are shown.
J. Sibik et al., J. Phys. Chem. Lett. 5, 1968 (2014). 15 of 31
23. Amorphous Materials Model System: Polyalcohols
Terahertz Spectroscopy of Polyalcohols
0.5 1.0 1.5
0.1
0.3
0.5
0.7
T
T
(iii)(ii)
1.00 T
g
sorbitol(+0.1)
xylitol
threitol(+0.1)
glycerol(-0.1)
''(=1THz)
T/Tg
0.65 T
g
(i)
The sample of threitol recrystallised above 250 K – no data above this temperature
are shown.
J. Sibik et al., J. Phys. Chem. Lett. 5, 1968 (2014). 15 of 31
24. Amorphous Materials Model System: Polyalcohols
Terahertz Spectroscopy of Polyalcohols
At temperatures well below Tg, a
temperature-independent microscopic peak is
observed, which persists into the liquid phase
and which is identified as being due to
librational/torsional modes.
For 0.65 Tg < T < Tg, additional thermally
dependent contributions are observed, and we
found strong evidence for its relation to the
Johari-Goldstein secondary relaxation process.
Clear spectroscopic evidence is found for a
secondary glass transition at 0.65 Tg, which is not
related to the fragility of the glasses.
At temperatures above Tg, the losses become
dominated by primary α-relaxation processes.
Our results show that the thermal changes in the
losses seem to be underpinned by a universal
change in the hydrogen bonding structure of the
samples.
0.5 1.0
Molecular relaxations
0.67 T
g
''
THz
T/T
g
T
g
VDOS
JG-
Libration-vibration motions
Decoupling
(independent of m)
J. Sibik et al., J. Phys. Chem. Lett. 5, 1968 (2014). 16 of 31
26. Amorphous Materials Crystallisation
Phase Transitions – in situ Spectroscopy
0 . 7 5 0 . 9 0 1 . 0 5 1 . 2 0 1 . 3 5 1 . 5 0 1 . 6 5 1 . 8 0
0 . 5
1 . 0
1 . 5
2 . 0
2 . 5
2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0
w a v e n u m b e r / c m
- 1
absorbance/a.u.
f r e q u e n c y / T H z
f o r m I I I
f o r m I
Conversion of carbamazepine form III to I at 433 K
Terahertz spectroscopy is very sensitive to changes in supramolecular structure
J.A. Zeitler et al., Thermochimica Acta. 436, 71 (2005). 17 of 31
27. Amorphous Materials Crystallisation
Phase Transitions – Kinetics
Kinetics of the solid state transition. Mechanism occurs as
solid-gas-solid transition and can be resolved using THz-TDS.
J.A. Zeitler et al., ChemPhysChem. 8, 1924 (2007). 18 of 31
28. Amorphous Materials Crystallisation
Amorphous vs. Crystalline Organic Solids
1 0 2 0 3 0 4 0 5 0 6 0 7 0
0 . 0
0 . 5
1 . 0
1 . 5
2 . 0
2 . 5
a m o r p h o u s
c r y s t a l l i n e
Absorbance(decadic)
W a v e n u m b e r [ c m
- 1
]
Crystalline vs. amorphous indomethacine.
C.J. Strachan et al., Chem. Phys. Lett. 390, 20 (2004). 19 of 31
29. Amorphous Materials Crystallisation
Relaxation and Crystallisation
1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0
0
2
4
6
8
1 0
1 2
1 4
Absorbance(decadic)
W a v e n u m b e r [ c m
- 1
]
654321
330-340 K
1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0
0
2
4
6
8
1 0
1 2
1 4 65432
Absorbance(decadic)
W a v e n u m b e r [ c m
- 1
]
1
340-356 K
1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0
0
2
4
6
8
1 0
1 2
1 4 65432
Absorbance(decadic)
W a v e n u m b e r [ c m
- 1
]
1
357-368 K
1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0
0
2
4
6
8
1 0
1 2
1 4
Absorbance(decadic)
W a v e n u m b e r [ c m
- 1
]
654321
410-440 K
J.A. Zeitler et al., J. Pharm. Sci. 96, 2703 (2007). 20 of 31
30. Amorphous Materials Crystallisation
Change in Absorbance
2 9 0 3 0 0 3 1 0 3 2 0 3 3 0 3 4 0 3 5 0 3 6 0 3 7 0 3 8 0 3 9 0 4 0 0 4 1 0 4 2 0 4 3 0 4 4 0 4 5 0
0 . 5
1 . 0
1 . 5
2 . 0
3 0 0 3 1 0 3 2 0 3 3 0 3 4 0 3 5 0
0 . 9 0
0 . 9 5
1 . 0 0
1 . 0 5
f o r m IT g
f o r m I I Ig l a s s y
s t a t e
Normalisedabsorbance(decadic)
T e m p e r a t u r e [ K ]
f e a t u r e 1 f e a t u r e 2
f e a t u r e 3 f e a t u r e 4
f e a t u r e 5 f e a t u r e 6
r u b b e r y
s t a t e
c r y s t a l l -
i s a t i o n
p h a s e t r a n s i t i o n
At Tg sample relaxes and crystallises subsequently at higher temperature.
J.A. Zeitler et al., J. Pharm. Sci. 96, 2703 (2007). 21 of 31
31. Amorphous Materials Crystallisation
Crystallisation Kinetics
0 1 2
0
40
80
120
160
200
240
a )
α(cm
-1
)
Frequency (THz)
320 325 330 335 340 345
0.0
0.2
0.4
0.6
0.8
1.0
r a
, amorphous fraction
r c
, crystalline fraction
Avrami-Erofeev fit
Temperature (K)
ra
,rc
b )
a) Terahertz spectra of paracetamol crystallising form the amorphous phase. As
the crystallisation progresses distinct vibrational modes emerge from the VDOS.
b) Kinetics of the crystallisation process and corresponding fit using the
Avrami-Erofeev model.
J. Sibik et al., Molecular Pharmaceutics. 11, 1326 (2014). 22 of 31
33. Amorphous Materials Crystallisation
Crystallisation of Amorphous Paracetamol
0 1 2 3
0
100
200
300
400
300
350
400
450
T
e
m
p
e
ra
tu
re
(K
)
Frequency (THz)
(cm
-1
)
Crystallisation and subsequent phase transitions
J. Sibik et al., Molecular Pharmaceutics. 11, 1326 (2014). 23 of 31
35. Amorphous Materials Crystallisation
Crystallisation of Amorphous Paracetamol
0 1 2 3
0
100
200
300
0.6 0.9
20
40
(cm
-1
)
Frequency (THz)
325 K
330 K
335 K
0 25 50 75 100
Wavenumber (cm
-1
)
1 2
0
100
200
300
300 K
330 K
335 K
470 K
fit
n(cm
-1
)
Frequency (THz)
20 40 60
Wavenumber (cm
-1
)
Deviation from power law: onset of crystallisation
n (ν) α (ν) = A + C (ν − ν0)q
J. Sibik et al., Molecular Pharmaceutics. 11, 1326 (2014). 23 of 31
36. Amorphous Materials Crystallisation
Crystallisation of Amorphous Paracetamol
0
10
20
30
40
290 300 310 320 330 460 470
120
130
140
290 300 310 320 330 460 470
1.0
1.1
1.2
1.3
1.4
1.5
T (K)
A(cm
-1
)
(a)
(b)
C(cm
-1
THz
-q
)
(c)
T (K)
q
In paracetamol the crystallisation from the amorphous
phase is observed to form III
Subsequent phase transitions occur to forms II and I
before the sample melts
This observation is in agreement with a previous study
of paracetamol by low frequency Raman scattering
The featureless spectra of the supercooled liquid and
liquid melt can be fitted using a power law model
The melt spectrum is dominated by the dielectric
relaxation as well as the VDOS, while in the
supercooled liquid the contribution due to the dielectric
relaxation vanishes close to Tg (q changes from 2 in the
glassy state to 1 in the liquid melt state)
Using the simple power law model introduced previously,
the onset of crystallisation can be determined precisely
J. Sibik et al., Molecular Pharmaceutics. 11, 1326 (2014). 24 of 31
37. Amorphous Materials Crystallisation
Crystallisation Below Tg
0.5 1.0 1.5 2.0
0
100
200
(b)(a)
310 K
Naproxen
()(cm
-1
)
(THz)
100 K
0.4 0.6 0.8 1.0 1.2
50
100
150
200
250
1.2 THz
1.5 THz
1.8 THz
(T/T
g
)(cm
-1
)
T/T
g
0.67 Tg
~4x faster
Seeded crystallisation: rate increases at ≈ 0.67 Tg!
Role of molecular mobility below Tg
J. Sibik et al., Molecular Pharmaceutics, doi:10.1021/acs.molpharmaceut.5b00330
(2015). 25 of 31
39. Amorphous Materials Stability Prediction
Amorphous Drug Stability
J. Sibik et al., Molecular Pharmaceutics, doi:10.1021/acs.molpharmaceut.5b00330
(2015). 26 of 31
40. Amorphous Materials Stability Prediction
Amorphous Drug Stability
0.2 0.4 0.6 0.8 1.0 1.2
20
25
30
35
40
45
50
0.5 1.0 1.5 2.0 2.5
0
50
100
150
320 K
Indomethacin
Paracetamol
(cm
-1
)
Frequency (THz)
80 K
0.67 Tg
Paracetamol
Indomethacin
1.0THz
(cm
-1
)
T/Tg
J. Sibik et al., Molecular Pharmaceutics, doi:10.1021/acs.molpharmaceut.5b00330
(2015). 26 of 31
41. Amorphous Materials Stability Prediction
Amorphous Drug Stability
0.2 0.4 0.6 0.8 1.0 1.2
1.0
1.1
1.2
1.3 paracetamol
indomethacin
flufenamic acid
simvastatin
linear fit
0
T/T
g
J. Sibik et al., Molecular Pharmaceutics, doi:10.1021/acs.molpharmaceut.5b00330
(2015). 26 of 31
42. Amorphous Materials Stability Prediction
Prediction of Amorphous Stability
J. Sibik et al., Molecular Pharmaceutics, doi:10.1021/acs.molpharmaceut.5b00330
(2015). 27 of 31
43. Summary
Terahertz Spectroscopy
The terahertz molecular dynamics is strongly related to the molecular
mobility governing the stability of amorphous drugs.
While molecular relaxations are often extracted by dielectric spectroscopy or
DSC and used to predict the stability of the amorphous drugs, concerns have
been raised about the robustness of these methods.
DSC is useful mainly for measurements of molecular mobility around and
above Tg, but cannot be easily used to measure molecular mobility at lower
temperatures.
Measurements by dielectric spectroscopy are very useful to measure the
local mobility in terms of JG-β relaxation, except for cases where this
relaxation is submerged in the α-relaxation.
In contrast, terahertz spectroscopy does not suffer from this limitation as it
measures fast motions and only indirectly resolves the effect of the JG-β
relaxation, which may in principle be observed even when no clear JG-β
peak is present (such as in the case of indomethacin).
28 of 31
45. Summary Acknowledgments
Literature I
G. Adam and J. H. Gibbs, On the temperature dependence of cooperative relaxation properties in glass-forming liquids,
The Journal of Chemical Physics, 43:139, 1965.
S. Bhattacharya and R. Suryanarayanan, Local Mobility in Amorphous Pharmaceuticals-Characterization and
Implications on Stability, 98(9):2935–2953, January 2009, http://dx.doi.org/10.1002/jps.21728.
A. Döß, M. Paluch, H. Sillescu, and G. Hinze, From Strong to Fragile Glass Formers: Secondary Relaxation in
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http://dx.doi.org/10.1016/j.jnoncrysol.2010.06.074.
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1968–1972, 2014a, http://dx.doi.org/10.1021/jz5007302.
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Chem. Phys., 15(28):11931–11942, July 2013, http://dx.doi.org/10.1039/c3cp51936h.
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http://dx.doi.org/10.1021/acs.molpharmaceut.5b00330.
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46. Summary Acknowledgments
Literature II
C. J. Strachan, T. Rades, D. Newnham, K. C. Gordon, M. Pepper, and P. F. Taday, Using terahertz pulsed spectroscopy
to study crystallinity of pharmaceutical materials, Chem. Phys. Lett., 390(1-3):20–24, May 2004,
http://dx.doi.org/10.1016/j.cplett.2004.03.117.
H. Wagner and R. Richert, Spatial uniformity of the β-relaxation in D-sorbitol, J. Non-Cryst. Sol., 242(1):19–24, 1998.
J. A. Zeitler, P. F. Taday, K. C. Gordon, M. Pepper, and T. Rades, Solid-State Transition Mechanism in Carbamazepine
Polymorphs by Time-Resolved Terahertz Spectroscopy, ChemPhysChem, 8(13):1924–1927, 2007a,
http://dx.doi.org/10.1002/cphc.200700261.
J. A. Zeitler, P. F. Taday, M. Pepper, and T. Rades, Relaxation and crystallization of amorphous carbamazepine studied
by terahertz pulsed spectroscopy, J. Pharm. Sci., 96(10):2703–2709, October 2007b, http://dx.doi.org/10.1002/jps.20908.
J. A. Zeitler, D. A. Newnham, P. F. Taday, C. J. Strachan, M. Pepper, K. C. Gordon, and T. Rades, Temperature
dependent terahertz pulsed spectroscopy of carbamazepine, Thermochimica Acta, 436(1-2):71–77, October 2005,
http://dx.doi.org/10.1016/j.tca.2005.07.006.
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