Impact of Intermolecular Interactions, Dimeric Structures on the Glass

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The impact of intermolecular interactions, dimeric structures on the glass forming ability of naproxen and a series of its derivatives. Aldona Minecka, Ewa Kaminska, Magdalena Tarnacka, Iwona Grudzka-Flak, Mariola Bartoszek, Kamila Wolnica, Mateusz Dulski, Kamil Kaminski, and Marian Paluch Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00725 • Publication Date (Web): 29 Aug 2018 Downloaded from http://pubs.acs.org on September 3, 2018

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Molecular Pharmaceutics

The impact of intermolecular interactions, dimeric structures on the glass forming ability of naproxen and a series of its derivatives Aldona Mineckaa*, Ewa Kaminskaa*, Magdalena Tarnackab,c, Iwona Grudzka-Flakb,c, Mariola Bartoszekd, Kamila Wolnicab,c, Mateusz Dulskib,e, Kamil Kaminskib,c, and Marian Paluchb,c a

Department of Pharmacognosy and Phytochemistry, Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Jagiellonska 4, 41-200 Sosnowiec, Poland b

Institute of Physics, University of Silesia, ul. 75 Pulku Piechoty 1, 41-500 Chorzow, Poland

c

Silesian Center for Education and Interdisciplinary Research, University of Silesia, ul. 75 Pulku Piechoty 1A,

41-500 Chorzow, Poland d

Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland

e

Institute of Material Sciences, University of Silesia, 75 Pulku Piechoty 1a, 41-500 Chorzow, Poland.

*

Corresponding authors: A.M. ([email protected]) and E.K. ([email protected])

ABSTRACT In this paper, thermal properties, molecular dynamics, crystallization kinetics and intermolecular interactions in pure naproxen (NAP), its amide (NH2-NAP) and four esters (methyl – Met-NAP, isopropyl – Iso-NAP, hexyl – Hex-NAP, benzyl – Ben-NAP), have been investigated using Differential Scanning Calorimetry (DSC), Broadband Dielectric (BD) and Fourier Transform Infrared (FTIR) spectroscopies. We found that the modification of NAP molecule by substituting a hydrogen atom from the hydroxyl group strongly inhibits the crystallization tendency of this Active Pharmaceutical Ingredient (API) and simultaneously increases its glass forming ability (GFA). In this context, it is worthwhile to stress that pure naproxen and its amide crystallized very quickly, regardless of the cooling rate. Therefore, these compounds cannot be classified as good glass-formers. On the other hand, ester derivatives of API can be easily vitrified. Moreover, dielectric measurements revealed that with an increasing molecular weight of the substituent, the rate of crystallization process slows down significantly. Consequently, Ben-NAP was characterized by the highest GFA among all investigated API esters. Comprehensive FTIR studies clearly indicated that the strong tendency to create dimeric structures in the non-modified NAP and NH2-NAP is 1 ACS Paragon Plus Environment

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responsible for their enhanced crystallization. At the first sight, our results stay in contrast to the most literature data showing that H-bonds favor glass formation ability. However, this effect is usually observed for the materials, which form extensive multidirectional hydrogen bonds and associates. In naproxen and its amide derivative, the situation is much different, since both compounds exist mainly as dimers. Therefore, one can postulate that specific intermolecular interactions are an important parameter determining the GFA of different materials, including APIs.

KEYWORDS: naproxen derivatives, crystallization kinetics, glass forming ability, molecular dynamics

INTRODUCTION The glass forming ability (GFA) of a material, defined as the ease of vitrification of a liquid on cooling, has been a subject of intensive research over the last few decades. The main aim of these studies was to understand, why some compounds can be easily transformed to the glassy state, while others, crystallize upon cooling and do not vitrify. As is well known, many factors may affect the GFA of inorganic and organic compounds, including active substances (APIs).1,2,3,4,5,6,7,8,9,10,11 The most important ones, discussed in literature, are related to the i) thermodynamic driving force for the crystallization, ii) kinetic factors, expressed by the viscosity, molecular mobility, etc. iii) chemical structure of the studied compound, iv) intermolecular interactions occurring in the sample. To understand the role of thermodynamic as well as kinetic factors in the glass formation ability or alternatively the tendency to crystallization of different classes of materials, one should refer to the Classical Nucleation Theory (CNT).12,13 Within this approach, the crystallization is described as two-step process. The first one is related to the nucleation (formation of the nuclei), while the second ‒ to the crystal growth. As predicted by 2 ACS Paragon Plus Environment

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the CNT, the relationship between the rates of nucleation and crystal growth has an impact on the GFA. In principal, the smaller overlapping of the rates of both crystallization stages, the greater tendency to form a glass. Moreover, this model also predicts a close correlation between the GFA and thermodynamic parameters, such as entropy and enthalpy of fusion (∆Sfus and ∆Hfus), Gibbs free energy difference between crystalline and amorphous state, termed as thermodynamic driving force (∆G), and interfacial free energy (γ). Interestingly, the lower values of ∆Sfus, ∆Hfus and ∆G, as well as higher γ, imply the smaller crystallization ability ‒ the greater GFA.1,14,15 Very important parameter related to the glass forming tendency, that can be understood within the frame of the CNT, is the critical cooling rate, defined as a minimum-cooling rate required to vitrify a material.1,8,10 Since we have known that due to the complexity of the crystallization process and the fact that the nucleation takes some time, one can avoid crystallization by fast enough cooling of the liquid. In this context, it should be stressed that basically each liquid even water, molten metals or alloys can be vitrified after application of fast enough quenching (million K/min). However, good glass formers are characterized by the very low critical cooling rate. The kinetic factors responsible for the enhanced glass formation ability are mainly related to the ratio of Tg and Tm, where Tg and Tm denote the glass transition temperature and the melting temperature, respectively.4,11,16 As shown by Kauzmann,17 the GFA is expected to be enhanced with increasing Tg/Tm (a lower-bound threshold for the glassy formation is Tg/Tm~2/3). Furthermore, taking into account the Classical Nucleation Theory one can add that also viscosity, diffusion, reorientational relaxation times play an important role in controlling both nucleation and crystal growth.18 Another parameter, which is correlated with the Tg/Tm ratio is the fragility (a measure of the non-Arrhenius characteristics of liquids/glasses). As shown in many papers,11,19,20,21,22 the more fragile systems, the lower glass forming tendency. This is in line with the predictions of the Two Order Parameter

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(TOP) model by Tanaka,20,23 which assumes that the fragile materials, due to weaker frustration against crystallization, are easier to crystallize. As pointed above, a chemical structure of the investigated material has also a tremendous impact on the glass formation ability. In particular, many researchers discuss the role of molecular weight, Mw on the GFA.1,7 As shown by Mahlin et. al., generally compounds with Mw > 300 can easily be transformed to the amorphous state.7 Other requirements for good glass-formers are directly related to the number of benzene rings (should be as low as possible), the presence of many rotatable bonds, the molecular asymmetry, the branched carbon skeletons, electronegative atoms,1,5,9 etc. In this context, it must be stressed that the chemical structure of given liquid directly determines the character of intermolecular interactions, which are as much important parameter in controlling the glass forming or crystallization ability. Finally, the relationship between intermolecular interactions in the system and the GFA is emphasized in literature.3,24,25,26,27 For example, Wang et al.,24 based on the results obtained for diaminotriazine derivatives, suggested that the hydrogen bonding, in contrast to van der Waals attractions, favors glass formation. The similar conclusions were drawn by Kaminski et. al.3 They showed that a highly associated D-glucose (D-GLU) has a weaker tendency to crystallization (and hence greater GFA) than its acetylated counterpart (acGLU) – van der Waals material. In this context, one can also mention the paper by Laventure et al.,25 where it was demonstrated that H-bonds, which are present in mexylaminotriazine derivatives incorporating 2,3,4,5,6-pentafluorostilbene moiety, impede crystallization, while noncovalent donor−acceptor aromatic interactions (pi stacking), dominating in their nonfluorinated analogues, promote this process. At the end, it is worthwhile to recall the studies of Koperwas et al.26 on the propylene carbonate and its less polar structural analog 3-methylcyclopentanone. The authors revealed that the enhancement of the dipole-dipole forces in the investigated van der Waals systems brought about the better GFA of the sample. 4 ACS Paragon Plus Environment

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In this article, we present the results of calorimetric, dielectric, and FTIR measurements carried out on naproxen (NAP), its four ester derivatives: methyl, isopropyl, hexyl and benzyl (Met-NAP, Iso-NAP, Hex-NAP, Ben-NAP), as well as NH2-NAP. One can mention that pure NAP is one of the most popular and widely used non-steroidal antiinflammatory drugs (NSAIDs) with pain‒ and fever‒ relieving properties. Importantly, this API has a very low GFA ‒ it cannot be prepared in the glassy state by quench cooling from the melt due to spontaneous crystallization regardless of the cooling rate.28,29 It is worth noting that NAP belongs to the propionic acid class. Due to the presence of carboxylic acid group, this pharmaceutical, as other acid derivatives, e.g. indomethacin,30 profens (ibuprofen,31,32 ketoprofen31, flurbiprofen33), acetylsalicylic acid (Aspirin),34 is capable of forming local hydrogen bonded (HB) structures, especially dimers.35,36 Herein, we modified the chemical structure of NAP to obtain systems (API esters) without the possibility of creating H-bonds. It turned out that the change of intermolecular interactions from H-bonded to the pure van der Waals type results in enhanced glass forming tendency. Such behavior shows the new face of H – bonding patterns with respect to the recent reports demonstrating that generally, H-bonds favor the liquid-glass transition.3,24,25 Moreover, our systematic studies allow to emphasize the role of dimeric structures that are formed in pure naproxen on the crystallization tendency of this pharmaceutical.

EXPERIMENTAL SECTION Materials and Methods

Materials Naproxen, NAP ([IUPAC name: (2S)-2-(6-methoxy-2-naphthyl)propanoic acid], C14H14O3, Mw = 230,259 g/mol, 99% purity), was supplied from TCI Europe and used as received. Methyl naproxen [Met-NAP, methyl 2-(6-methoxynaphthalen-2-yl)propanoate], isopropyl naproxen [Iso-NAP, propan-2-yl 2-(6-methoxynaphthalen-2-yl)propanoate], hexyl 5 ACS Paragon Plus Environment


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naproxen [Hex-NAP, hexyl 2-(6-methoxynaphthalen-2-yl)propanoate], benzyl naproxen [Ben-NAP, benzyl 2-(6-methoxynaphthalen-2-yl)propanoate] and naproxen amide [NH2NAP, 2-(6-methoxynaphthalen-2-yl)propanamide] of greater than 98% purities, have been synthesized for the purpose of this paper. The synthesis procedures, as well as NMR data of the obtained products, are presented in Supporting Information. Chemical formulas and molecular weights of NAP and its five derivatives are presented in Table 1. In turn, the chemical structures of investigated compounds are illustrated in Figure 1. CH3 X H3C

O O

X= O-R

X= R

NAP

R=OH

Met-NAP

R=CH3

Iso-NAP

R=CH(CH3)2

Hex-NAP

R=C6H13

Ben-NAP

R=C6H5CH2

NH2-NAP

R=NH2

Figure 1. The chemical structure of the studied NAP derivatives.

Methods Differential Scanning Calorimetry (DSC) Calorimetric measurements were carried out using a Mettler–Toledo DSC apparatus (Mettler–Toledo International, Inc., Greifensee, Switzerland) equipped with a liquid nitrogen cooling accessory and an HSS8 ceramic sensor (heat ﬂux sensor with 120 thermocouples). Temperature and enthalpy calibrations were performed by using indium and zinc standards. Each sample was heated above its melting temperature, quenched, and scanned at a rate of 10 6 ACS Paragon Plus Environment

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K/min over a temperature range from 150 K to well above the respective glass transition point (or melting temperatures).

Broadband Dielectric Spectroscopy (BDS) Isobaric measurements of the complex dielectric permittivity ε*(ω) = ε’(ω) – iε”(ω) were carried out using the Novocontrol Alpha dielectric spectrometer (Novocontrol Technologies GmbH & Co. KG, Hundsangen, Germany) over the frequency range from 10-2 to 106 Hz at ambient pressure. The samples were placed between two stainless-steel flat electrodes of the capacitor with gap 0.1 mm. The temperature stability controlled by a Quatro Cryosystem using a nitrogen gas cryostat was better than 0.1 K. The studies on the molecular dynamics were carried out after fast cooling of the liquid to the glassy state (Met-NAP, HexNAP, and Ben-NAP were heated in cryostat above the melting temperature before cooling) in the following temperature ranges: 173‒263 K (Met-NAP), 173‒265 K (Iso-NAP), 173 K‒245 K (Hex-NAP) and 173‒283 K (Ben-NAP). In turn, the crystallization kinetics studies (isothermal measurements) were performed at T=248 K, 253 K, 258 K (Met-NAP), T=233 K, 238 K, 243 K (Hex-NAP) and T=273 K, 279 K, 285 K, 289 K (Ben-NAP). Infrared Measurements Fourier transform infrared (FTIR) spectroscopy was used to follow the molecular rearrangement in a wide temperature range. FTIR measurements were carried out using the Agilent Cary 640 FTIR spectrometer equipped with a standard source and DTGS Peltiercooled detector. The spectra were obtained in the 400 – 4000 cm-1 range. They were recorded by the accumulation of 16 scans with a spectral resolution of 4 cm-1. Finally, infrared data were analyzed by the baseline, water, and carbon dioxide correction. Temperature-dependent spectra for pure naproxen and NH2-NAP were collected from T = 303 K to T = 463 K and from T = 463 K to T = 303 K, for Met-NAP from T = 298 K to T = 363 K and from T = 363 K to T = 298 K, while for Iso-NAP and Hex-NAP from T = 298 K to T = 323 K and from T = 7 ACS Paragon Plus Environment


323 K to T = 298 K. All measurements were carried out with the 1 K/min rate of the temperature change. The samples were equilibrated at the maximum temperature (around 20 K above the Tm) for 10 minutes. The delay between collected spectra was equal to 4 minutes. RESULTS AND DISCUSSION As a first step of our investigations, calorimetric measurements were carried out to determine thermal properties and phase transitions in pure naproxen and its derivatives. In Fig. 2, the thermograms obtained during heating of NAP (panel (a)) as well as representative modified compounds: NH2-NAP (panel (b)), Met-NAP (panel (c)) and Hex-NAP (panel (d)) are presented. As illustrated, DSC curves of NAP and NH2-NAP display only one endothermic process located approximately at T = 429 K and T = 434 K, respectively, which is connected to the melting process. Upon lowering temperature both compounds crystallized immediately, independently of the applied cooling rate. Therefore, there is no trace of the endothermic event in thermograms, associated with the liquid-glass transition. Completely different situation was noted in the case of the four investigated esters of naproxen. As presented in panels (c) and (d) of Fig. 2, Met-NAP and Hex-NAP, as well as Iso-NAP and Ben-NAP (data not shown) could be easily supercooled using standard cooling rate (10 K/min). In DSC thermograms of these compounds, one can observe two endothermic peaks (at higher and lower T), related to the melting process of the crystalline sample and the glass transition event (detected after cooling followed by heating of the glassy materials), respectively. In addition, for the methylated derivative of API, an exothermic peak at about 281 K, associated with the cold crystallization, is also noticed. Interestingly, the values of melting (Tm) as well as glass transition (Tg) temperatures of the methyl, isopropyl, hexyl and benzyl esters of NAP are lower than the respective temperatures obtained for the pure API and its amide derivative. All temperatures of phase transitions were included in Table 1. As can be observed, generally the value of Tg decreases with increasing molecular weight of the compound (a size of a substituent). It may be caused by the plasticizing effect generated by 8 ACS Paragon Plus Environment

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the flexible substituents, as was discussed by Carpenter et al.37 and Jedrzejowska et al.38 The exception to this rule is Ben-NAP. However, in this case, by the analogy to the studies on IBU esters,39 the higher Tg might be related to the reduced mobility of the benzyl moiety, which is substituted in place of the hydrogen atom in the carboxylic group of NAP. Alternatively, the higher Tg in this ester can be due to the enhancement of interactions between aromatic rings (possibly pi stacking) with respect to the other investigated herein esters of NAP.40 Having calculated Tg and Tm of all studied herein compounds, we decided to estimate the Tg/Tm ratio (see Table 1), which as discussed in the introduction, can be a quite good measure of the GFA.7,9,17 As can be seen, this ratio varies only slightly in the whole family of investigated naproxens. Interestingly, the Tg/Tm for pure NAP is very close to 0.65 indicating that it may form a glass, which is not the case. Therefore, this rule does not work for nonmodified API. On the other hand, it was observed that with increasing molecular weight of the naproxen derivatives, the Tg/Tm generally increases suggesting enhancement of their glass forming ability. As a consequence, one can expect Ben-IBU to be the best glass former of all studied materials.



heating rate 10 K/min (b) NH2-NAP

Tm = 429 K

Tc = 381 K

Tm = 434 K

liquid cooling crystal heating

HF [a.u.]

HF [a.u.]

(a) NAP

liquid cooling crystal heating 250

300

Tc = 373 K

350

400

250

300

350

Temp. [K]

(c) Met-NAP

400

450

Temp. [K] (d) Hex-NAP

Tm = 343 K

Tg = 235 K

Tm = 303 K

glass crystal

HF [a.u.]

glass crystal

HF [a.u.]

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

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Tg = 213 K Tc = 281 K

175

200

225

250

275

300

325

350

200

225

250

275

300

Temp. [K]

Temp. [K]

Figure 2. DSC curves measured for naproxen and its representative derivatives. Thermograms for NAP and NH2-NAP were obtained during the heating of the crystal compounds and cooling of the liquid samples; while thermograms for esters of NAP – during the heating of the crystal and glassy forms of studied materials.

Table 1. Summary molecular formulas and molecular weights, Mw of the investigated modified naproxens as well as their respective substituents. Values of the glass transition temperatures, Tg (from DSC and BDS techniques), isobaric fragilities (m), activation energies for β-process, melting points (Tm), and Tg/Tm ratios are also shown. * The value of Tg for an unmodified NAP (278.19 K) was estimated from the Gordon-Taylor equation by Löbmann et al.28

Molecular formula

Mw [g/mol]

Molecular formula of substituent

Mw of substituent [g/mol]

TgDSC [K]

TgBDS [K]

Fragility m

Eβ [kJ/mol]

Tm [K]

Tg/Tm

C14H14O3

230.26

H

1

-

-

-

-

429

0.65*

Met-NAP

C15H16O3

244.26

CH3

15

235

230±1

75±7

54.3±1.5

343

0.69

Iso-NAP

C17H20O3

272.26

C3H7

43

229

226±1

84±8

43.2±1.0

342

0.67

Hex-NAP

C20H26O3

314.26

C6H13

85

213

209±1

80±8

-

303

0.70

Ben-NAP

C21H20O3

320.26

C7H7

91

243

239±1

93±9

44.7±1.6

338

0.72

NH2-NAP

C14H13O3NH2

245.26

NH2

16

-

-

-

-

434

-

NAP


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In the next step, we performed dielectric measurements to characterize the molecular dynamics of four examined esters of naproxen. One can add that similar studies on pure NAP as well as its amide (NH2-NAP) were not possible due to their strong tendency to crystallization. Dielectric loss spectra collected at ambient pressure (p=0.1 MPa), in a wide range of temperatures are presented in Fig. 3. As illustrated, in the liquid state (T>Tg) all compounds reveal the dc conductivity, connected to the charge transport and structural (α) relaxation process, associated with the cooperative motions of the molecules in the samples. Both processes shift towards lower frequencies with decreasing temperature. In turn, in the glassy state (T>Tg), two secondary relaxations (β and γ) with clearly smaller amplitude dominate the spectra. It should be noted that the faster, γ-process did not enter the measurement window, even at the lowest temperatures. Therefore, it is not fully visible in panels (a)-(d) of Fig. 3. Moreover, in the case of Hex-NAP, the β-relaxation is poorly separated in the spectra. In Fig. 4, dielectric loss spectra registered for four esters of NAP in the close vicinity of the glass transition temperature were compared. For this purpose, we applied the following procedure ‒ the spectra measured for Iso-NAP, Hex-NAP and Ben-NAP were shifted vertically in the log-log plot to superimpose with the spectrum obtained for Met-IBU. As can be seen, the width of the α-peak is nearly the same for all compounds. This is well-illustrated by fitting the presented α-loss peaks to the Fourier transform of the stretch exponential function of Kohlrausch–Williams–Watts (KWW):41,42   t Φ KWW (t ) = exp −   τα 

  

β KWW

   

(1)

The fractional exponent, βKWW was equal to 0.60 for each NAP derivative. Interestingly, the values of the static permittivity, εs’ measured for the investigated compounds at temperatures close to the Tg were only slightly different (they changed from 2.62 – Met-NAP to 3.14 – 11 ACS Paragon Plus Environment


Hex-NAP). According to the recent paper by Paluch et al.43 one can suppose, that due to practically the same shape of the α-process, as well as εs’, the strength of dipole – dipole attractions in these systems is also identical. In this context, it is worthwhile to mention that the static permittivity, estimated at higher temperatures for pure NAP (εs’~3.5) was very close to the ones obtained for API derivatives. That means that intermolecular interactions (dipole – dipole type) in NAP and its modifications are very similar.

(b)

α-process

10

T>Tg

T>Tg

10-1

10-2

231 K 263 K ∆T231K-253K=2 K

Tg=230 K 173 K 229 K ∆T173K-213K=5 K

-4

10

∆T253K-263K=5 K 10

γ-process

-2

β -process

100

101

102

103

104

10-2

173 K 225 K ∆T173K-213K=5K

β -process

∆T213-227K=2K

105

TTg 10-1

102

103

104

α-process

209 K 245 K ∆T=2 K

10

Ben-NAP

100

α-process

10-1

10-1

-2

238 K 283 K ∆T238K-243K=5K

T>Tg 10-2

10-2

∆T243K-283K=2K

ε'' 10-3

-4

10

10-3

Tg=209 K

173 K 208 K ∆T=5 K

γ-process

β -process

T

Impact of Intermolecular Interactions, Dimeric Structures on the Glass

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