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Molecular Mobility of an Amorphous Chiral Pharmaceutical Compound: Impact of Chirality and Chemical Purity Quentin Viel, Laurent Delbreilh, Gérard Coquerel, Samuel Petit, and Eric Dargent J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b05667 • Publication Date (Web): 20 Jul 2017 Downloaded from http://pubs.acs.org on July 29, 2017

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The Journal of Physical Chemistry

Molecular Mobility of an Amorphous Chiral Pharmaceutical Compound: Impact of Chirality and Chemical Purity Quentin Viel,#, † Laurent Delbreilh,# * Gérard Coquerel, † Samuel Petit, †Eric Dargent # # Normandie Univ, UNIROUEN Normandie, INSA Rouen, CNRS, Groupe de Physique des Matériaux, 76000 Rouen, France † Normandie Univ, UNIROUEN Normandie, Sciences et Méthodes Séparatives, 76000 Rouen, France

ABSTRACT: A dielectric relaxation spectroscopy (DRS) study was performed to investigate the molecular mobility of amorphous chiral diprophylline (DPL). For this purpose, both racemic DPL and a single enantiomer of DPL were considered. After fast cooling from the melt at very low temperature (-140 °C), progressive heating below and above the glass transition (Tg ≈ 37 °C) induces two secondary relaxations (γ- and δ-) and primary relaxations (α-) for both enantiomeric compositions. After chemical purification of our samples by means of cooling recrystallization, no γ- process could be detected by DRS. Hence, it was highlighted that the molecular mobility in the glassy state is influenced by the presence of theophylline (TPH), the main impurity in DPL samples. We also proved that the dynamic behavior of a single enantiomer and the racemic mixture of the same purified compound are quasi identical. This study demonstrates that the

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relative stability as well as the molecular mobility of chiral amorphous drugs are strongly sensitive to chemical purity.

INTRODUCTION

Most active pharmaceutical ingredients (API) are formulated in the solid state, either in crystalline or amorphous forms. The access to the amorphous form of an API is of high concern as the dissolution properties and bioavailability are significantly higher than in crystalline form.1– 5

Nevertheless, the glassy state of an API might exhibit a poor physical stability that could be

tricky for industrial process and/or scale-up.6–8 In recent years, various studies were devoted to the improvement of the physical stability of the amorphous state by using multicomponent systems such as solid dispersions, i.e. involving an API and polymer,9–17 or a co-amorphous drug.18–23 The fundamental mechanisms related to the physical instability of amorphous single components remain considerably unexplained and the scientific community tries to identify the physical factors governing the shelf life (i.e. recrystallization behavior) of non-crystalline pharmaceuticals. Among reported studies devoted to this issue, various internal factors have been outlined: mobility and molecular motions,6,24–33 primary and secondary relaxations,30,31,34,35 fragility,36,37 density,38 interfacial energy,39 structures,40 etc. However, experimental (i.e. external) conditions such as thermal history,41 surface effects,42,43 relative humidity,44,45 defects or cracks,46,47 and the amorphization itself34,48–50 seem to impact the process of recrystallization from an amorphous state. A wide set of experimental methods could be used to this purpose such as thermal analysis, Fourier transform infrared (FTIR) and Raman spectroscopies, temperatureresolved optical microscopy, dielectric relaxation spectroscopy (DRS), X-ray diffraction or wideangle scattering (WAXS), terahertz spectroscopy, etc.51–60


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Since the presence of a second component can affect the physicochemical properties and crystallization behaviors of amorphous APIs, we study here the effects of organic impurities contained in APIs, as recently reported.61–63 In the present work, we investigate a chiral pharmaceutical drug, namely diprophylline (7-(2,3-dihydroxypropyl)-1,3-dimethyl-3,7-dihydro1H-purine-2,6-dione; DPL hereafter, Chart 1), which is a theophylline (Chart 1, TPH) derivative. Chart 1. Molecular Structures of Diprophylline (DPL) and Theophylline (TPH)

This chiral drug, displaying broncho- and vasodilator properties used in the treatment of pulmonary diseases, presents a versatile behavior, at least for crystallization aspects.61,64 The polymorphic landscape of this chiral compound is rather complex since the phase diagram between the two enantiomers exist as a stable racemic compound and stable enantiomeric forms but also as metastable polymorphs and solid solutions that crystallize as a function of kinetic conditions and enantiomeric composition.61,63,64 Recent studies demonstrated that crystallization from the supercooled melt occurs as a complex multistep process involving the homogeneous nucleation and growth of a first population (PC: Primary Crystals) that is favored by a specific


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impurity (TPH).61,63 As the molecular mobility of amorphous DPL has never been meticulously investigated by taking into account these previous results, it appeared suitable to reconsider the global molecular mobility of both racemic (50 % of each enantiomer) and enantiopure (100 % of one enantiomer) compositions of this system. Among the numerous available strategies designed for the transformation of a crystalline drug into an amorphous one (i.e. milling, spray drying), glassy DPL samples could be obtained by the most common strategy, namely the melt quenching procedure. Although it was proved that an amorphous state of DPL can be obtained by cooling the melt, only a single enantiomeric composition (i.e. racemic) was previously reported,65 which lets the characterization of amorphous DPL uncomplete. Since more than 50 % of pharmaceutical compounds are chiral, the detailed understanding of the effect of enantiomeric composition in the amorphous state is of fundamental interest. As a consequence, the chiral pharmaceutical drug DPL appeared to be a good model compound for the characterization of the glass-to-crystal pathway. 1. MATERIALS AND METHODS 1.1. Materials: purification and sample preparations Racemic diprophylline ((DPL), C10H14N4O4, Mw = 254.24 g/mol) and theophylline ((TPH), C7H8N4O2, Mw = 180.16 g/mol), were purchased as crystalline white powders from SigmaAldrich (USA, purity 99%). Pure enantiomers (R)- and (S)- DPL were synthesized using a previously reported protocol.64 These samples were purified by cooling recrystallization in ethanol/water mixture (95:5 v/v) under stirring at room temperature for at least 24 h. Before and after purification, chromatographic analyses were performed with a Dionex HPLC apparatus (LPG-3400 SD, Courtaboeuf, France), consisting of a P680 pump, a manual injection valve (20


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µL) and a UV-vis detector (VWD-3100) at 271 nm. The Chromoleon software from Dionex (Courtaboeuf France) allowed to collect the data. Analyses were achieved on a Luna C18 column (150 mm × 4.6 mm × 3 µm) with the following experimental conditions: a mobile phase composed of an acetonitrile-water mixture (5:95 v/v), with phosphoric acid (0.1%, pH=3.5), a temperature of 22 °C, and a flow rate of 1 mL/min. As TPH is the main building unit of DPL (on which a propanediol substituent is added), it was expected to be the major impurity for all our samples. In our chromatographic conditions, retention times are 17.4 and 22.3 min for TPH and DPL, respectively. The amount of TPH in commercial racemic DPL is 0.14 wt %, while synthesized enantiopure DPL contains 0.52 wt % of TPH. Purified samples of either composition were shown to contain less than 0.03 wt % of TPH. In addition, other minor impurities were also detected, as shown in representative chromatograms provided as Supporting Information (Figure S1). 1.2. Thermal Characterization Netzsch STA 449 C instrument was used for simultaneous thermogravimetric (TG), and differential scanning calorimetry (DSC) analyses. The following conditions were applied for all experiments: 5-6 mg of a powdered sample in a 25 µL aluminum crucible, a heating rate of 5 K/min from 20 °C to 290 °C, and helium as purging gas. The Netzsch-TA Proteus Software v6.1.0 was used for data processing. Amorphous DPL was obtained by quenching (i.e. below Tg ≈ 37 °C, whatever the enantiomeric composition61) at 20 K/min from the melt reached at ca. 185 °C during at least 5 min starting from any crystalline form. TG-DSC analyses revealed the absence of mass loss which would


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have been indicative of either: (i) chemical degradation (ii) sublimation at temperatures lower than 265 °C (Supporting Information Figure S2). 1.3. Dielectric Relaxation Spectroscopy The complex dielectric function ε*(f) = ε’(f) - i ε”(f) (f, frequency; ε’, real part; ε”, imaginary part) associated with orientational fluctuation of dipoles was measured by an Alpha-N impedance analyzer from Novocontrol Technologies, covering a frequency range from 10-1 Hz to 106 Hz. DPL crystalline powder was slightly compressed between two stainless steel plated electrodes (upper electrode 30 mm diameter, separated by spacers) of a parallel plate capacitor. In order to investigate the molecular mobility in the glassy state, the sample was kept 5 min at 185 °C, above melting temperatures of the stable crystalline forms RI (Tm = 160 °C) and EI (Tm = 166 °C) to ensure complete melting. The molten sample was cooled down to a very low temperature through carefully depositing the sandwiched sample electrodes on a metallic plate immersed in liquid nitrogen bath. Immediately after quenching, the electrode assembly was inserted into the cryostat of the apparatus. The dielectric spectra were collected non-isothermally from -140 °C to 80 °C, increasing the temperature in different steps: in the range -140 °C to 0 °C in steps of 5 °C; from 0 to 80 °C in steps of 1 °C. Dielectric data are presented here in two terms: the complex dielectric function ε*(f), and the complex electrical modulus M*(f) = 1/ε*(f) that helps reducing the contribution of polarization effect and/or conductivity to improve the quality of signals.66 The maximum deviation from a set temperature was found to be ± 0.2 °C.

2. RESULTS AND DISCUSSION 2.1. Primary relaxations of commercial racemic and synthesized enantiopure DPL


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Preliminary investigations consisted in identifying the most adequate conditions for reliable observations and characterization of either primary or secondary relaxations in the glassy and supercooled liquid states. In order to have an overlook on the role of enantiomeric composition on the dynamic properties, it is very important to consider orientational motions in the supercooled liquid state of our compounds. In the dielectric loss spectra existing in the accessible frequency domain, molecular movements in the viscous fluid are manifested by relaxation processes of different time scales. The α-relaxation process is related to the dynamic glass transition, whereas the faster and less intense secondary relaxations reflect more local dynamics. Figure 1 (a) and (b) displays real parts of the complex dielectric permittivity spectra of racemic and enantiopure compositions of DPL in the supercooled liquid state (at temperatures T > Tg DPL, with an increment of 1 °C). First, at low frequencies, an increase of ε’ due to electrode polarization (i.e. (partial) blocking of charge carriers at the sample/electrode interface) is observed for both enantiomeric compositions, that occurs mainly for moderately to highly conducting material samples.66


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Figure 1. Real and imaginary parts (ε’, ε’’) of the complex dielectric permittivity vs frequency in the supercooled liquid state at temperatures T > Tg for the (a, c) racemic and (b, d) enantiopure compositions (Tg = 37 °C) of DPL. Dielectric strength ∆ε parameter of the Havriliak-Negami relaxation function as a function of temperature for racemic and enantiopure DPL (e). Their


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respective symmetric αHN (filled diamonds) and asymmetric βHN (open diamonds) broadening parameters of the Havriliak-Negami relaxation function as a function of temperature (f). Notwithstanding, a visible decrease of ε’ in nearly one step with increasing frequency is characteristic of the primary structural relaxation process (α relaxation) from 38 °C to 57 °C for racemic (rac-DPL), and from 38 °C to 69 °C for the single enantiomer (enantio-DPL). From the dielectric loss ε” data of both enantiomeric compositions (Figure 1 (c) and (d)), conductivity, i.e. translational motions of electrical charges such as ions, electrons, is present at low frequency, while α relaxations are characterized by their non-Debye character with increasing frequency. Moreover, from Figure 1 (e), it can be noticed that the dielectric strength of rac-DPL (∆εrac) is slightly higher than the dielectric strength of enantio-DPL (∆εenantio) at 44 °C (Tg + 7 °C). Besides, ∆εrac decreases at lower temperature in comparison with ∆εenantio (Tc rac - Tc enantio ≈ 12 °C). ∆ε could be defined from the generalized form of the Debye theory by Onsager, Fröhlich and Kirkwood as:66 ∆ε =

μ 1 g ( I) 3

with ε0 the dielectric permittivity of vacuum, µ the mean dipole moment of moving units in vacuum, gK the Kirkwood correlation factor and F the Onsager factor (equal to 1). The N/V ratio represents the density of dipoles involved in the relaxation process. As crystallization proceeds, the number of relaxing molecules decreases, causing a progressive weakening in the dielectric strength ∆ε of the α-process. Because ∆εrac > ∆εenantio at 44 °C, it can be suggested that both the dipole moment and/or the density of dipoles involved in the relaxation process for racemic and enantiopure DPL are not strictly similar. Anyhow, the distinct evolution of ∆ε as a function of


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temperature is related to a distinct kinetics of crystallization, as discussed earlier.61 To determine relaxation times of the structural relaxation process at various temperatures, the HavriliakNegami (HN) formula was used. Temperature dependence of the fit parameters αHN and βHN exponents keeps a nearly constant value of 0.85 and 0.60 for racemic and 0.90 and 0.60 for enantiopure samples of DPL, providing evidence that relaxation phenomena are quasi-identical for both enantiomeric compositions. In the supercooled liquid state, the nonlinear increase of τα, with decreasing the temperature was described by Vogel-Fulcher-Tammann equation:

τ = τ exp

DT " ( II) T − T

where τ∞, T0 are fitting parameters and D is the strength parameter.67–69 Relaxation times (τmax is used preferably) of DPL samples show curved temperature dependences when plotted as a function of 1000/T (Figure 2). The τα (T) dependence was measured only over 5 decades for enantiopure-DPL and 3 decades for racemic-DPL. This distinction is due to crystallization that occurs at lower temperature for racemic DPL samples compared to enantiopure ones.61


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Figure 2. Temperature dependence of structural α-relaxation times in the region of high temperature of commercial racemic (blue) and synthesized enantiopure (red) of DPL. Solid line is the VTF fit to the experimental data. Then, extrapolation of the τα (T) dependence to 100 seconds is a common way of defining the glass transition temperature Tg from dielectric measurements. From the estimated parameters of the VFT fit, the common value of Tg for both compositions was found to be 30 °C, determined at τα = 100 s. Besides, by comparing the value of Tg for τα = 10 s, closely related to the equivalent frequency of the TM-DSC analysis (period of T = 60 s, thus τα TM-DSC = 1/(2π(1/60)) ≈ 9.55 Hz), a value of 34 °C was found for racemic- DPL and enantiopure- DPL, while values of 37 °C were obtained for Tα via TM-DSC.61 On the basis of VFT parameters, one can also calculate the dynamic “fragility” m according to Böhmer et al.: 70

# ≡

/( 0 ) *

d (log () ) = ( III) d ( *+),-,. (1 − 1 0 2) ln (10) *


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Since the values of m

DPL

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are 87 ± 5, DPL (whatever the enantiomeric composition) can be

classified as an intermediate glass former (30 < m < 100).71 This is a typical value for common pharmaceutical compounds.72 2.2. Secondary relaxations of commercial racemic and synthesized enantiopure DPL Figure 3 (a) and (b) presents the frequency evolution of dielectric loss ε” at various temperatures within the glassy state for respectively the racemic and enantiopure compositions of DPL. It can be seen that the glassy state of DPL (whatever its enantiomeric composition) is characterized by a large molecular mobility reflected in two secondary relaxations: the slowest γ process and the fastest δ process (both described by Cole-Cole (CC) equation).73 These secondary relaxations in amorphous DPL were found to shift toward higher frequencies upon heating, reflecting a supposed increase in molecular mobility. In the literature, a large molecular mobility, i.e. the presence of several relaxations in the glassy state has been characterized for multicomponent systems, such as APIs/excipients,74 or for humid/moist materials.75,76 More information are provided in section 2.4.


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Figure 3. Dielectric loss spectra taken below Tg from -115 °C to – 35 °C, with a 5 °C step size, exhibiting the γ -relaxation and δ-relaxation occurring in the glassy state of (a) racemic and (b) enantiopure DPL. 2.3. Relaxation maps of commercial racemic and synthesized enantiopure DPL From the best fits of entire dielectric spectra obtained both in the glassy and liquid states of DPL (racemic and enantiopure), the temperature dependence for all dielectric processes were determined (see Figure 4).


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Figure 4. Experimental relaxation map of melt-quenched racemic (in blue) and enantiopure (in red) samples of DPL. Temperature dependence of the secondary γ- and δ-processes are illustrated by respectively open circles and open triangles. It was observed that δ processes of both enantiomeric compositions are strictly identical in terms of evolution of τα as a function of 1000/T in the relaxation map, while it is not the case for γ – processes. In the glassy state, the activation energies obtained from the Arrhenius equation for the δ secondary processes were found to be Ea δ racemic ≈ Ea δ enantiopure ≈ 37 kJ/mol while for the γ processes, it was found to be Ea γ

racemic

≈ 57 kJ/mol and Ea γ enantiopure ≈ 60 kJ/mol. According to

research on amorphous pharmaceuticals, there has been a growing recognition that high


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activation energy barriers (typically, Ea > 50 kJ/mol) for secondary relaxation processes may be related to motions involving the whole molecule or large conformational motions whereas low values (Ea < 50 kJ/mol) could be linked to limited intramolecular motions.77,78 Based on this classification, γ secondary processes of DPL may be related to intermolecular motions, whereas δ secondary processes are presumably from intramolecular origin. Besides, in order to describe such difference in a more qualitative way, both temperature dependencies were plotted versus each other (Figure 5 (a)). A straight line with the slope s = 0.97 indicates that the temperature evolution of the α-relaxation time for a single enantiomer and for the racemic mixture of DPL does not follow each other perfectly, but behave in a similar way. By comparison, Adrjanowicz et al. have found a slope s = 0.95 between a single enantiomer and the racemic mixture of Ketoprofen.79 In addition, the dispersion of the structural α-relaxation is not essentially the same for studied molecular liquids. The modulus M” values were normalized by setting the maximum value as the reference (M”/Mmax =1). It can be noticed in (Figure 5 (b)) that the curves of α-processes are not superimposable. From these data, it is evidenced that the relaxation behaviors of racemic and enantiopure DPL samples are quasi identical both in the glassy and the supercooled liquid melt, but some slight distinctions exist: in the glassy state, the dielectric strength of secondary γ processes are not similar for both samples.


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(b)

(a)

Figure 5. (a) Temperature dependence of τα for racemic-DPL and enantiopure-DPL plotted versus each other (b) Comparison of the normalized modulus M” for racemic-DPL and the enantiopure-DPL taken at 42 °C (Tg + 5 °C). In the supercooled liquid state, variations have been observed in the dielectric strengths of αrelaxations. Since crystallization from amorphous chiral DPL samples has been found to be sensitive to chemical purity,61 it was envisaged to remove the impurities from our samples in order to study their putative impact on the relaxation behaviors. Purification procedures were applied to racemic and enantiopure DPL samples by means of recrystallization from ethanol/water (95/5 v/v) and slurry at room temperature.61 The corresponding chromatograms obtained before and after purification are depicted in Supporting Information (Figure S1). As described in Materials and Methods, the quantity of TPH was determined as 0.52% wt for synthesized enantiopure DPL and less than 0.03% wt (detection threshold) after purification. The chromatograms obtained from the commercial batch and the purified samples (i.e. RAC-DPL) are depicted (Figure S1). In this case, the quantity of TPH was determined as 0.14% wt for commercial racemic DPL and less than 0.03% wt after purification.


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2.4. Chirality: comparative relaxation study of purified racemic and purified enantiopure compositions After purification of our samples, a direct comparative investigation has been performed on either racemic and enantiopure compositions of DPL (Figure 6). First, it is worth mentioning that no difference in the glass transition temperatures (compared to previous thermal protocol by TM-DSC) has been observed (Tg purified rac-DPL = 36.9 °C and Tg purified enantio-DPL = 37.3 °C, ± 0.4 °C,61 data not shown).


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Figure 6. Real and imaginary parts (ε’, ε’’) of the complex dielectric permittivity vs frequency in the supercooled liquid state at temperatures T > Tg for the (a, c) purified racemic and (b, d) purified enantiopure compositions (Tg = 37 °C) of DPL. Dielectric strength ∆ε parameter of the Havriliak-Negami relaxation function as a function of temperature on the range of analysis for


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purified racemic and enantiopure (e). Their respective symmetric αHN (filled diamonds) and asymmetric βHN (open diamonds) broadening parameters of the Havriliak-Negami relaxation function as a function of temperature (f). No lag between dielectric strengths of purified DPL samples has been evidenced, suggesting that enantiomeric excess do not affects the density of DPL dipoles in the relaxation process. Besides, it is worth noting that Tc enantiopure is influenced by the presence of impurities (Tc enantio - Tc enantio purified

≈ 9 °C) while Tc racemic is not (or barely) influenced. It confirms that the kinetics of DPL

crystallization might be impacted by the chemical purity,61 and/or may inhibit/delay the process of nucleation and growth, at least for enantiopure composition of DPL. Though, temperature dependence of the fit parameters αHN and βHN exponents keeps nearly constant values of 0.92 and 0.54 for purified racemic and 0.87 and 0.59 for purified enantiopure samples of DPL. Relaxation times of purified DPL samples are plotted as a function of 1000/T in Figure 7. The τα (T) dependence was measured only over 3 decades for both samples.


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Figure 7. Temperature dependence of structural α-relaxation times in the region of high temperatures for purified racemic (blue) and enantiopure (red) DPL samples. Solid line is VTF fit to the experimental data. From the estimated parameters of VFT fit, the value of Tg at τ = 100 s for purified DPL (29 ± 1 °C) is nearby the Tg at τ = 100 s for non-purified DPL = 30 ± 1 °C (as well as the value of Tg at τ = 10 s for purified DPL = 33 ± 1 °C is similar to Tg at τ = 10 s for non-purified DPL = 34 ± 1 °C). The glassy state (at very low temperature, -115 °C to -35 °C) of both compositions is only characterized by the fastest δ processes, while the slowest γ processes, observed for non-purified samples (Figure 3 (a) and (b)) are not present in these dielectric data (Figure 8 (a) and (b)). It was evidenced in the literature (for polymeric or composite systems essentially) that the humidity/moisture content may be the cause of the occurrence of secondary relaxations.75,76 Since all measurements were performed in identical experimental conditions and since no γprocess is occurring for purified samples (together with the absence of mass loss recorded after 100 °C by TG-DSC in Figure S2), it can be assumed that the emergence of this new relaxation process can be hardly attributed to the presence of water/humidity in DPL samples. Besides, the


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activation energies for the δ secondary processes of purified samples are very close to that of non-purified samples (Eaδ purified racemic ≈ 39 kJ/mol and Eaδ purified enantiopure ≈ 39 kJ/mol). These results suggest that: (i)

δ process is conceivably from intramolecular origin in DPL enantiomers.

(ii)

γ process could be presumably related to the presence of impurities.

A perspective of this work would consist in conducting theoretical density functional theory (DFT) calculations, in order to gain insights into the origin of these secondary relaxations.30

Figure 8. Dielectric loss spectra of purified DPL taken below Tg from -115 °C to – 35 °C, with a 5 °C step size, exhibiting only δ-relaxation occurring in the glassy state of racemic (a) and enantiopure (b) DPL. From the best fits of entire dielectric spectra obtained both in the liquid and glassy states of purified racemic and enantiopure DPL samples, the temperature dependences for all dielectric processes were determined and are presented in Figure 9.


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Figure 9. Experimental relaxation map of melt-quenched purified racemic (in blue) and purified enantiopure (in red) DPL. Temperature dependence of the secondary δ-process is illustrated by open triangles. Hence, by comparing both purified enantiomeric compositions, their τα(T) dependence are superimposed with a similar estimated values of fragility (m

purified DPL

= 98 ± 5). Moreover, a

straight line with the slope s = 1 indicates that their temperature evolutions of α-relaxation times follow each other perfectly (Figure 10 (a)). This is also confirmed by the superimposition of normalized modulus M” spectra (Figure 10 (b)). To summarize this comparative dielectric study of racemic- and enantiopure-DPL before and after the purification process, it was shown that the


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presence of chemical impurities could have an influence on the relaxation behavior of DPL. First, a γ process is occurring in the glassy state of non-purified DPL samples, whereas it disappears for purified samples.

(a)

(b)

Figure 10. (a) Temperature dependences of τα

for purified racemic-DPL and purified

enantiopure-DPL plotted versus each other (b) Comparison of the normalized modulus M” for purified racemic-DPL and the purified enantiopure-DPL taken at 42 °C (Tg + 5 °C). Secondly, the characterization of the primary structural relaxation of all our samples proves that the impurities slightly change the molecular mobility of DPL since several changes were denoted on the dielectric data before and after the purification process (i.e. the non-superimposition of τα (T), the lag between normalized modulus M” spectra and the shift between fragility values). Besides, once the samples were purified, no clear variation has been observed between the racemic mixture and the pure enantiomer of DPL, which suggests that the molecular mobility in the glassy and the supercooled liquid states of DPL is not a function of enantiomeric composition. From the comparative study of single enantiomer and racemic mixture of Ketoprofen,79 Adrjanowics et al. conclude in an analogous way about the similar dynamic behaviors between both enantiomeric compositions. Nevertheless, a study of τα (T) dependencies


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Page 24 of 35

measured in the vicinity of glass transition with elevated pressure showed promising results in terms of improving knowledge of glassy dynamics of chiral molecules.79 This could represent an interesting perspective for DPL. To gain insights into the role of impurities on the molecular mobility of DPL, dielectric measurements were conducted using purified DPL enriched with precise amounts of the major impurity in DPL samples (i.e. TPH). It is worth mentioning that the formation of pure glassy TPH is difficult via quenching (because of the fast crystallization) and its dielectric characterization has failed. 2.5. Influence of TPH on the relaxation behavior of DPL Because of the very slight differences observed for the relaxation processes (i.e. primary and secondary) at both enantiomeric compositions of DPL before and after purification, it was decided to substantially increase the impurity content (% wt TPH) in our purified samples in order to observe how it affects relaxation behaviors. Amounts of 2.5 % wt TPH and 5 % wt TPH were chosen. After a precise calibration of % wt TPH achieved using HPLC, the quantification of the % wt TPH in our samples has been carried out (see Supporting Information Table 3). The frequency evolution of dielectric loss ε” at various temperatures were performed for purified racemic DPL with (a) < 0.03 % wt (b) 2.6 % wt and (c) 5.1 % wt TPH, as well as for purified enantiopure-DPL with (d) < 0.03 % wt (e) 2.2 % wt and (f) 4.5 % wt TPH. The glassy state (at very low temperatures, -115 °C to -35 °C) of all samples is characterized by the fastest δ processes (Figure S3 (a-f)). Then, regarding the γ process, it is clear that it is not present for the purified samples. However, for rac-DPL enriched with 2.6 % wt TPH and enantio-DPL enriched with 2.2 % wt TPH, both dielectric loss spectra suggest a slight relaxation in the region of the γ


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process. By considering the racemic-DPL enriched with 5.1% wt TPH, a well-shaped γ process is observed while another slight contribution in the region of the γ process is observed for enantioDPL enriched with 4.5% wt TPH. All dielectric data are summarized in Table 1 and these results suggest that the δ secondary process is from intramolecular origin of the DPL enantiomers, while the γ process is presumably closely related to the presence of impurities. Finally, regarding the nature of the γ process, two non-exclusive hypotheses can be envisaged: (i) Since TPH is a rigid molecule, the only visible motions in dielectric spectroscopy could be their motions as a whole (which could therefore justify the value of activation energy of Eaγ > 50 kJ/mol). (ii) Since the γ relaxations were also well observed for commercial racemic samples and synthesized enantiopure samples with a relatively low amount of % wt TPH determined at 0.14 and 0.56 %wt, the other potential impurities (not identified) may play an important role as relaxing units in the glassy state of DPL and in the γ process.

Table 1. Summary of all dielectric data concerning purified and enriched DPL samples.

Secondary processes

Primary relaxation (VFT fit)

Ea γ (kJ/mol)

Ea δ (kJ/mol)

m

Tg (°C)

D

log (τ)

T0 (°C)

/

39

98

33

3.4

-9.4

-4.6

57

37

87

34

8.0

-13.6

-24.3

Rac-DPL + 2.6%TPH

/

39

98

33

3.4

-9.4

-4.6

Rac-DPL + 5.1%TPH

57

38

98

33

3.4

-9.4

-4.6

Purif Enant- DPL

/

39

99

33

4.4

-10.8

-4.6

Purif. Rac- DPL Com. Rac(0.14%TPH)

DPL


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Synth. Enant-DPL (0.56% TPH)

60

36

87

34

8.0

-13.6

-24.3

Enant-DPL + 2.2%TPH

/

37

99

33

4.4

-10.8

-4.6

Enant-DPL + 4.5%TPH

52

42

99

33

4.4

-10.8

-4.6

In order to investigate the influence of chemical purity on the primary structural relaxation, direct comparisons of the normalized modulus M” for racemic-DPL and enantiopure-DPL with various amounts of % wt TPH at 42 °C are shown in Figure 11 (a) and (b).

(b)

(a)

Figure 11. Comparison of the normalized modulus M” for (a) purified Rac-DPL; Rac-DPL + 2.6% wt TPH and Rac-DPL + 5.1% wt TPH. (b) Purified Enantio-DPL, Enantio-DPL + 2.2% wt TPH, Enantio-DPL + 4.5% wt TPH taken at 42 °C.

Once more, for both enantiomeric compositions, the higher the impurity content in our sample, the higher the position of the M”/Mmax at the high-frequency α-peak. This result suggests that


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this increase corresponds to the emergence of γ-peak, submerged under the dominating α – peak, as it has been already interpreted in the literature in other cases.80,81 In the supercooled liquid state, the nonlinear increase of τα with lowering the temperature was described by VFT equation for both enriched racemic and enantiopure compositions. Table 1 summarizes all the VFT fit parameters obtained for all samples. One can note that the glass transitions (at τ = 100 s and at τ = 10 s) and the fragility obtained for all samples whatever the enantiomeric composition or the chemical purity do not change substantially.

CONCLUSION The molecular mobility of the racemic mixture and the single enantiomer of amorphous DPL has been investigated by DRS for the first time, covering a temperature range of more than 200 °C. Whatever the enantiomeric composition, significant differences in the relaxation maps were observed before and after chemical purification of samples (via recrystallization in ethanol/water). Additionally, three distinct relaxation processes were detected for non-purified DPL samples, labeled as: (i) α associated to the primary structural relaxation processes of DPL (ii) γ representing the secondary relaxations observed in non-purified samples (iii) δ that are presumably secondary relaxations due to motions of the flexible part of the DPL molecule61,64 while only α and δ were observed for the purified samples. Thus, it is deduced that the impurities in our samples may have an impact on the dielectric data either in the supercooled liquid state or in the glassy state. Besides, by comparing the evolution of dielectric strength of their primary relaxations as function of temperature, it was confirmed that the kinetics of crystallization for purified DPL samples differs from that of non-purified DPL. In the glassy state, the γ-process is


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occurring for the non-purified materials (i.e. commercial racemic 0.14 % wt TPH, synthesized enantiopure 0.56 % wt TPH) as well as for the enriched samples (Rac + 5.1 % wt TPH and Enantio + 4.1 % wt TPH). The TPH (and/or the other impurities) could presumably play an important role in the mobility of DPL, resulting in the γ-process. The presence of other potential (chiral and achiral) impurities, such as etophylline, proxyphylline, and caffeine should not be underestimated, and will need to be considered in future experiments. A perspective of this work may also consist in conducting theoretical density functional theory (DFT) calculations, in order to gain insights into the origin of these secondary relaxations. After the purification process applied to our samples, the value of fragility of purified DPL samples has been found to be rather similar to that of non-purified DPL samples. Moreover, the comparative dielectric study between the purified samples has led to the conclusion that the dynamic behaviors of a single enantiomer and of the racemic mixture of DPL in the glassy and supercooled liquid states are very much alike, even quasi-identical (in the frame of thermal treatments applied here). SUPPORTING INFORMATION The High Performance Liquid Chromatography (HPLC) analyses of our samples before and after purification, the TG-DSC analyzes of both stables phases EI and RI from respectively enantiopure and racemic compositions of Diprophylline (DPL), a table with estimated parameters of the VTF fit obtained for structural relaxation, a table with estimated % wt Theophylline (TPH) remaining in enriched samples of racemic – and - enantiopure-DPL via HPLC analysis, dielectric loss spectra of DPL taken below Tg from -115 °C to – 35 °C with a 5 °C step size for purified and enriched samples of racemic and enantiopure of DPL. Corresponding Author *E-mail: [email protected]. Phone : +Tél : +33232955084


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Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT Région Haute-Normandie is acknowledged for financial support to this project through the ACDC program, including the PhD grant to Q.V. ABBREVIATIONS DPL, Diprophylline; ee, enantiomeric excess; SCM, supercooled melt; TPH, Theophylline; REFERENCES (1) Yu, L. Amorphous Pharmaceutical Solids: Preparation, Characterization and Stabilization. Adv. Drug Deliv. Rev. 2001, 48 (1), 27–42. (2) Hancock, B. C.; Zografi, G. Characteristics and Significance of the Amorphous State in Pharmaceutical Systems. J. Pharm. Sci. 1997, 86 (1), 1–12. (3) Murdande, S. B.; Pikal, M. J.; Shanker, R. M.; Bogner, R. H. Solubility Advantage of Amorphous Pharmaceuticals: II. Application of Quantitative Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble Pharmaceuticals. Pharm. Res. 2010, 27 (12), 2704–2714. (4) Babu, N. J.; Nangia, A. Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals. Cryst. Growth Des. 2011, 11 (7), 2662–2679. (5) Craig, D. Q.; Royall, P. G.; Kett, V. L.; Hopton, M. L. The Relevance of the Amorphous State to Pharmaceutical Dosage Forms: Glassy Drugs and Freeze Dried Systems. Int. J. Pharm. 1999, 179 (2), 179–207. (6) Wojnarowska, Z.; Grzybowska, K.; Hawelek, L.; Dulski, M.; Wrzalik, R.; Gruszka, I.; Paluch, M.; Pienkowska, K.; Sawicki, W.; Bujak, P.; et al. Molecular Dynamics, Physical Stability and Solubility Advantage from Amorphous Indapamide Drug. Mol. Pharm. 2013, 10 (10), 3612–3627. (7) Laitinen, R.; Löbmann, K.; Strachan, C. J.; Grohganz, H.; Rades, T. Emerging Trends in the Stabilization of Amorphous Drugs. Int. J. Pharm. 2013, 453 (1), 65–79.


29


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 35

(8) Dukeck, R.; Sieger, P.; Karmwar, P. Investigation and Correlation of Physical Stability, Dissolution Behaviour and Interaction Parameter of Amorphous Solid Dispersions of Telmisartan: A Drug Development Perspective. Eur. J. Pharm. Sci. 2013, 49 (4), 723–731. (9) Baird, J. A.; Taylor, L. S. Evaluation of Amorphous Solid Dispersion Properties Using Thermal Analysis Techniques. Adv. Drug Deliv. Rev. 2012, 64 (5), 396–421. (10) Bansal, K.; Baghel, U. S.; Thakral, S. Construction and Validation of Binary Phase Diagram for Amorphous Solid Dispersion Using Flory–Huggins Theory. AAPS PharmSciTech 2015, 17 (2), 318–327. (11) Bikiaris, D.; Papageorgiou, G. Z.; Stergiou, A.; Pavlidou, E.; Karavas, E.; Kanaze, F.; Georgarakis, M. Physicochemical Studies on Solid Dispersions of Poorly Water-Soluble Drugs. Thermochim. Acta 2005, 439 (1–2), 58–67. (12) Engers, D.; Teng, J.; Jimenez-Novoa, J.; Gent, P.; Hossack, S.; Campbell, C.; Thomson, J.; Ivanisevic, I.; Templeton, A.; Byrn, S.; et al. A Solid-State Approach to Enable Early Development Compounds: Selection and Animsal Bioavailability Studies of an Itraconazole Amorphous Solid Dispersion. J. Pharm. Sci. 2010, 99 (9), 3901–3922. (13) Guo, Y.; Shalaev, E.; Smith, S. Physical Stability of Pharmaceutical Formulations: SolidState Characterization of Amorphous Dispersions. TrAC Trends Anal. Chem. 2013, 49, 137–144. (14) Xie, T.; Taylor, L. S. Dissolution Performance of High Drug Loading Celecoxib Amorphous Solid Dispersions Formulated with Polymer Combinations. Pharm. Res. 2016, 33 (3), 739–750. (15) Wang, B.; Wang, D.; Zhao, S.; Huang, X.; Zhang, J.; Lv, Y.; Liu, X.; Lv, G.; Ma, X. Evaluate the Ability of PVP to Inhibit Crystallization of Amorphous Solid Dispersions by Density Functional Theory and Experimental Verify. Eur. J. Pharm. Sci. 2017, 96, 45–52. (16) Zhu, Q.; Toth, S. J.; Simpson, G. J.; Hsu, H.-Y.; Taylor, L. S.; Harris, M. T. Crystallization and Dissolution Behavior of Naproxen/Polyethylene Glycol Solid Dispersions. J. Phys. Chem. B 2013, 117 (5), 1494–1500. (17) Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Tajber, L.; Mesallati, H.; Paluch, K. J.; Paluch, M. Molecular Dynamics and Physical Stability of Amorphous Nimesulide Drug and Its Binary Drug–Polymer Systems. Mol. Pharm. 2016, 13 (6), 1937–1946. (18) Healy, A. M.; Worku, Z. A.; Kumar, D.; Madi, A. M. Pharmaceutical Solvates, Hydrates and Amorphous Forms: A Special Emphasis on Cocrystals. Adv. Drug Deliv. Rev. 2017, doi: 10.1016/j.addr.2017.03.002, in press. (19) Haneef, J.; Chadha, R. Drug-Drug Multicomponent Solid Forms: Cocrystal, Coamorphous and Eutectic of Three Poorly Soluble Antihypertensive Drugs Using Mechanochemical Approach. AAPS PharmSciTech 2017, doi: 10.1208/s12249-016-0701-1, in press. (20) Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Jurkiewicz, K.; Tajber, L.; Paluch, M. Molecular Dynamics and Physical Stability of Coamorphous Ezetimib and Indapamide Mixtures. Mol. Pharm. 2015, 12 (10), 3610–3619. (21) Wang, J.; Chang, R.; Zhao, Y.; Zhang, J.; Zhang, T.; Fu, Q.; Chang, C.; Zeng, A. Coamorphous Loratadine-Citric Acid System with Enhanced Physical Stability and Bioavailability. AAPS PharmSciTech 2017, doi: 10.1208/s12249-017-0734-0, in press. (22) Löbmann, K.; Laitinen, R.; Grohganz, H.; Gordon, K. C.; Strachan, C.; Rades, T. Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen. Mol. Pharm. 2011, 8 (5), 1919–1928.


30

Page 31 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(23) Jensen, K. T.; Larsen, F. H.; Cornett, C.; Löbmann, K.; Grohganz, H.; Rades, T. Formation Mechanism of Coamorphous Drug–Amino Acid Mixtures. Mol. Pharm. 2015, 12 (7), 2484–2492. (24) Gupta, P.; Chawla, G.; Bansal, A. K. Physical Stability and Solubility Advantage from Amorphous Celecoxib: The Role of Thermodynamic Quantities and Molecular Mobility. Mol. Pharm. 2004, 1 (6), 406–413. (25) Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Hawelek, L.; Sawicki, W.; Wlodarski, K.; Markowski, J.; Paluch, M. Physical Stability of the Amorphous Anticholesterol Agent (Ezetimibe): The Role of Molecular Mobility. Mol. Pharm. 2014, 11 (11), 4280–4290. (26) Alie, J.; Menegotto, J.; Cardon, P.; Duplaa, H.; Caron, A.; Lacabanne, C.; Bauer, M. Dielectric Study of the Molecular Mobility and the Isothermal Crystallization Kinetics of an Amorphous Pharmaceutical Drug Substance. J. Pharm. Sci. 2004, 93 (1), 218–233. (27) Mehta, M.; Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. Effect of Water on Molecular Mobility and Physical Stability of Amorphous Pharmaceuticals. Mol. Pharm. 2016, 13 (4), 1339–1346. (28) Adrjanowicz, K.; Wojnarowska, Z.; Wlodarczyk, P.; Kaminski, K.; Paluch, M.; Mazgalski, J. Molecular Mobility in Liquid and Glassy States of Telmisartan (TEL) Studied by Broadband Dielectric Spectroscopy. Eur. J. Pharm. Sci. 2009, 38 (4), 395–404. (29) Adrjanowicz, K.; Grzybowski, A.; Grzybowska, K.; Pionteck, J.; Paluch, M. Toward Better Understanding Crystallization of Supercooled Liquids under Compression: Isochronal Crystallization Kinetics Approach. Cryst. Growth Des. 2013, 13 (11), 4648–4654. (30) Schammé, B.; Mignot, M.; Couvrat, N.; Tognetti, V.; Joubert, L.; Dupray, V.; Delbreilh, L.; Dargent, E.; Coquerel, G. Molecular Relaxations in Supercooled Liquid and Glassy States of Amorphous Quinidine: Dielectric Spectroscopy and Density Functional Theory Approaches. J. Phys. Chem. B 2016, 120 (30), 7579–7592. (31) Carpentier, L.; Decressain, R.; De Gusseme, A.; Neves, C.; Descamps, M. Molecular Mobility in Glass Forming Fananserine: A Dielectric, NMR, and TMDSC Investigation. Pharm. Res. 2006, 23 (4), 798–805. (32) Bhattacharya, S.; Suryanarayanan, R. Local Mobility in Amorphous Pharmaceuticals— Characterization and Implications on Stability. J. Pharm. Sci. 2009, 98 (9), 2935–2953. (33) Brás, A. R.; Noronha, J. P.; Antunes, A. M. M.; Cardoso, M. M.; Schönhals, A.; Affouard, F.; Dionísio, M.; Correia, N. T. Molecular Motions in Amorphous Ibuprofen As Studied by Broadband Dielectric Spectroscopy. J. Phys. Chem. B 2008, 112 (35), 11087–11099. (34) Schammé, B.; Monnier, X.; Couvrat, N.; Delbreilh, L.; Dupray, V.; Dargent, E.; Coquerel, G. Insights on the Physical State Reached by an Active Pharmaceutical Ingredient upon High-Energy Milling. J. Phys. Chem. B 2017, 121 (19), 5142-5150. (35) Capaccioli, S.; Paluch, M.; Prevosto, D.; Wang, L.-M.; Ngai, K. L. Many-Body Nature of Relaxation Processes in Glass-Forming Systems. J. Phys. Chem. Lett. 2012, 3 (6), 735–743. (36) Schammé, B.; Couvrat, N.; Malpeli, P.; Delbreilh, L.; Dupray, V.; Dargent, É.; Coquerel, G. Crystallization Kinetics and Molecular Mobility of an Amorphous Active Pharmaceutical Ingredient: A Case Study with Biclotymol. Int. J. Pharm. 2015, 490 (1–2), 248–257. (37) Ke, P.; Hasegawa, S.; Al-Obaidi, H.; Buckton, G. Investigation of Preparation Methods on Surface/Bulk Structural Relaxation and Glass Fragility of Amorphous Solid Dispersions. Int. J. Pharm. 2012, 422 (1–2), 170–178.


31


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Page 32 of 35

(38) Hédoux, A.; Guinet, Y.; Capet, F.; Paccou, L.; Descamps, M. Evidence for a High-Density Amorphous Form in Indomethacin from Raman Scattering Investigations. Phys. Rev. B 2008, 77 (9), 094205. (39) Andronis, V.; Zografi, G. Crystal Nucleation and Growth of Indomethacin Polymorphs from the Amorphous State. J. Non-Cryst. Solids 2000, 271 (3), 236–248. (40) Zografi, G.; Newman, A. Interrelationships Between Structure and the Properties of Amorphous Solids of Pharmaceutical Interest. J. Pharm. Sci. 2017, 106 (1), 5–27. (41) Chang, R.; Fu, Q.; Li, Y.; Wang, M.; Du, W.; Chang, C.; Zeng, A. Crystallization and Relaxation Dynamics of Amorphous Loratadine under Different Quench-Cooling Temperatures. CrystEngComm 2017, 19 (2), 335–345. (42) Chattoraj, S.; Bhugra, C.; Telang, C.; Zhong, L.; Wang, Z.; Sun, C. C. Origin of Two Modes of Non-Isothermal Crystallization of Glasses Produced by Milling. Pharm. Res. 2012, 29 (4), 1020–1032. (43) Yu, L. Surface Mobility of Molecular Glasses and Its Importance in Physical Stability. Adv. Drug Deliv. Rev. 2016, 100, 3–9. (44) Price, R.; Young, P. M. Visualization of the Crystallization of Lactose from the Amorphous State. J. Pharm. Sci. 2004, 93 (1), 155–164. (45) Xie, T.; Taylor, L. S. Effect of Temperature and Moisture on the Physical Stability of Binary and Ternary Amorphous Solid Dispersions of Celecoxib. J. Pharm. Sci. 2017, 106 (1), 100–110. (46) Legrand, V.; Descamps, M.; Alba-Simionesco, C. Glass-Forming Meta-Toluidine: A Thermal and Structural Analysis of Its Crystalline Polymorphism and Devitrification. Thermochim. Acta 1997, 307 (1), 77–83. (47) Willart, J. F.; Dudognon, E.; Mahieu, A.; Eddleston, M.; Jones, W.; Descamps, M. The Role of Cracks in the Crystal Nucleation Process of Amorphous Griseofulvin. Eur. Phys. J. Spec. Top. 2017, 226 (5), 837–847. (48) Willart, J. F.; Descamps, M. Solid State Amorphization of Pharmaceuticals. Mol. Pharm. 2008, 5 (6), 905–920. (49) Descamps, M.; Willart, J. F. Perspectives on the Amorphisation/Milling Relationship in Pharmaceutical Materials. Adv. Drug Deliv. Rev. 2016, 100, 51–66. (50) Karmwar, P.; Graeser, K.; Gordon, K. C.; Strachan, C. J.; Rades, T. Investigation of Properties and Recrystallisation Behaviour of Amorphous Indomethacin Samples Prepared by Different Methods. Int. J. Pharm. 2011, 417 (1–2), 94–100. (51) Willart, J.-F.; Carpentier, L.; Danède, F.; Descamps, M. Solid-State Vitrification of Crystalline Griseofulvin by Mechanical Milling. J. Pharm. Sci. 2012, 101 (4), 1570–1577. (52) Hédoux, A.; Decroix, A.-A.; Guinet, Y.; Paccou, L.; Derollez, P.; Descamps, M. Low- and High-Frequency Raman Investigations on Caffeine: Polymorphism, Disorder and Phase Transformation. J. Phys. Chem. B 2011, 115 (19), 5746–5753. (53) Capsal, J.-F.; Dantras, E.; Lacabanne, C. Molecular Mobility Interpretation of the Dielectric Relaxor Behavior in Fluorinated Copolymers and Terpolymers. J. Non-Cryst. Solids 2013, 363, 20–25. (54) Esposito, A.; Delpouve, N.; Causin, V.; Dhotel, A.; Delbreilh, L.; Dargent, E. From a Three-Phase Model to a Continuous Description of Molecular Mobility in Semicrystalline Poly(Hydroxybutyrate- Co -Hydroxyvalerate). Macromolecules 2016, 49 (13), 4850–4861.


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(55) Grzybowska, K.; Capaccioli, S.; Paluch, M. Recent Developments in the Experimental Investigations of Relaxations in Pharmaceuticals by Dielectric Techniques at Ambient and Elevated Pressure. Adv. Drug Deliv. Rev. 2016, 100, 158–182. (56) Szklarz, G.; Adrjanowicz, K.; Dulski, M.; Knapik, J.; Paluch, M. Dielectric Relaxation Study at Ambient and Elevated Pressure of the Modeled Lipophilic Drug Fenofibrate. J. Phys. Chem. B 2016, 120 (43), 11298–11306. (57) Hédoux, A.; Paccou, L.; Guinet, Y.; Willart, J.-F.; Descamps, M. Using the Low-Frequency Raman Spectroscopy to Analyze the Crystallization of Amorphous Indomethacin. Eur. J. Pharm. Sci. 2009, 38 (2), 156–164. (58) Kaminski, K.; Adrjanowicz, K.; Wojnarowska, Z.; Dulski, M.; Wrzalik, R.; Paluch, M.; Kaminska, E.; Kasprzycka, A. Do Intermolecular Interactions Control Crystallization Abilities of Glass-Forming Liquids? J. Phys. Chem. B 2011, 115 (40), 11537–11547. (59) Palomäki, E.; Ahvenainen, P.; Ehlers, H.; Svedström, K.; Huotari, S.; Yliruusi, J. Monitoring the Recrystallisation of Amorphous Xylitol Using Raman Spectroscopy and Wide-Angle X-Ray Scattering. Int. J. Pharm. 2016, 508 (1–2), 71–82. (60) Sibik, J.; Zeitler, J. A. Direct Measurement of Molecular Mobility and Crystallisation of Amorphous Pharmaceuticals Using Terahertz Spectroscopy. Adv. Drug Deliv. Rev. 2016, 100, 147–157. (61) Viel, Q.; Brandel, C.; Cartigny, Y.; Eusébio, M. E. S.; Canotilho, J.; Dupray, V.; Dargent, E.; Coquerel, G.; Petit, S. Crystallization from the Amorphous State of a Pharmaceutical Compound: Impact of Chirality and Chemical Purity. Cryst. Growth Des. 2017, 17(1), 337346. (62) Hamada, Y.; Ono, M.; Ohara, M.; Yonemochi, E. Molecular Dynamics of Amorphous Sulfamethazine With Structurally Related Sulfonamide Impurities Evaluated Using Thermal Analysis. J. Pharm. Sci. 2017, 106 (4), 1062–1068. (63) Lemercier, A.; Viel, Q.; Brandel, C.; Cartigny, Y.; Dargent, E.; Petit, S.; Coquerel, G. Optimization of Experimental Conditions for the Monitoring of Nucleation and Growth of Racemic Diprophylline from the Supercooled Melt. J. Cryst. Growth 2017, 472, 11-17. (64) Brandel, C.; Amharar, Y.; Rollinger, J. M.; Griesser, U. J.; Cartigny, Y.; Petit, S.; Coquerel, G. Impact of Molecular Flexibility on Double Polymorphism, Solid Solutions and Chiral Discrimination during Crystallization of Diprophylline Enantiomers. Mol. Pharm. 2013, 10 (10), 3850–3861. (65) Fukuoka, E.; Makita, M.; Nakamura, Y. Glassy State of Pharmaceuticals. V. Relaxation during Cooling and Heating of Glass by Differential Scanning Calorimetry. Chem. Pharm. Bull. (Tokyo) 1991, 39 (8), 2087–2090. (66) Schönhals, A. Kremer, F. Theory of Dielectric Relaxation. In Broadband Dielectric Spectroscopy, Kremer, F. Schönhals, A., Eds.; Springer-Verlag Berlin Heidelberg Publisher: New York, 2003; Chapter 1, pp 1-32. (67) Vogel, H. The Law of the Relation between the Viscosity of Liquids and the Temperature. Phys. Z. 1921, 22, 645. (68) Fulcher, G. S. Analysis of Recent Measurements of the Viscosity of Glasses. J. Am. Ceram. Soc. 1925, 8 (6), 339–355. (69) Tammann, G.; Hesse, W. Die Abhängigkeit Der Viscosität von Der Temperatur Bie Unterkühlten Flüssigkeiten. Z. Für Anorg. Allg. Chem. 1926, 156 (1), 245–257. (70) Böhmer, R.; Ngai, K. L.; Angell, C. A.; Plazek, D. J. Nonexponential Relaxations in Strong and Fragile Glass Formers. J. Chem. Phys. 1993, 99 (5), 4201–4209.


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Page 34 of 35

(71) Angell, C. A. Proceedings of the International Discussion Meeting on Relaxations in Complex Systems Relaxation in Liquids, Polymers and Plastic Crystals — Strong/Fragile Patterns and Problems. J. Non-Cryst. Solids 1991, 131, 13–31. (72) Descamps, M. Willart J-F. Some Facets of Molecular Disorder in Crystalline and Amorphous Pharmaceuticals. In Disordered Pharmaceutical Materials, Descamps, M., Ed.; Wiley-VCH Publisher: Weinheim, 2016; Chapter 1, pp 1-56 (73) Cole, K. S.; Cole, R. H. Dispersion and Absorption in Dielectrics I. Alternating Current Characteristics. J. Chem. Phys. 1941, 9 (4), 341–351. (74) Grzybowska, K.; Chmiel, K.; Knapik-Kowalczuk, J.; Grzybowski, A.; Jurkiewicz, K.; Paluch, M. Molecular Factors Governing the Liquid and Glassy States Recrystallization of Celecoxib in Binary Mixtures with Excipients of Different Molecular Weights. Mol. Pharm. 2017, 14 (4), 1154-1168. (75) Zhao, H.; Li, R. K. Y. Effect of Water Absorption on the Mechanical and Dielectric Properties of Nano-Alumina Filled Epoxy Nanocomposites. Compos. Part Appl. Sci. Manuf. 2008, 39 (4), 602–611. (76) Hakme, C.; Stevenson, I.; David, L.; Boiteux, G.; Seytre, G.; Schönhals, A. Uniaxially Stretched Poly(Ethylene Naphthalene 2,6-Dicarboxylate) Films Studied by Broadband Dielectric Spectroscopy. J. Non-Cryst. Solids 2005, 351 (33–36), 2742–2752. (77) Wojnarowska, Z.; Adrjanowicz, K.; Wlodarczyk, P.; Kaminska, E.; Kaminski, K.; Grzybowska, K.; Wrzalik, R.; Paluch, M.; Ngai, K. L. Broadband Dielectric Relaxation Study at Ambient and Elevated Pressure of Molecular Dynamics of Pharmaceutical: Indomethacin. J. Phys. Chem. B 2009, 113 (37), 12536–12545. (78) Wlodarczyk, P.; Kaminski, K.; Adrjanowicz, K.; Wojnarowska, Z.; Czarnota, B.; Paluch, M.; Ziolo, J.; Pilch, J. Identification of the Slower Secondary Relaxation’s Nature in Maltose by Means of Theoretical and Dielectric Studies. J. Chem. Phys. 2009, 131 (12), 125103. (79) Adrjanowicz, K.; Kaminski, K.; Tarnacka, M.; Szutkowski, K.; Popenda, L.; Bartkowiak, G.; Paluch, M. The Effect of Hydrogen Bonding Propensity and Enantiomeric Composition on the Dynamics of Supercooled Ketoprofen – Dielectric, Rheological and NMR Studies. Phys. Chem. Chem. Phys. 2016, 18 (15), 10585–10593. (80) Schneider, U.; Brand, R.; Lunkenheimer, P.; Loidl, A. Excess Wing in the Dielectric Loss of Glass Formers: A Johari-Goldstein β Relaxation? Phys. Rev. Lett. 2000, 84 (24), 5560. (81) Ngai, K. L.; Lunkenheimer, P.; León, C.; Schneider, U.; Brand, R.; Loidl, A. Nature and Properties of the Johari–Goldstein β-Relaxation in the Equilibrium Liquid State of a Class of Glass-Formers. J. Chem. Phys. 2001, 115 (3), 1405–1413.

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