thermodynamics of antiviral and antiparkinsonian drug

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Thermodynamics of antiviral and antiparkinsonian drug

amantadine hydrochloride: condensed state properties and decomposition

Journal: Journal of Chemical & Engineering Data

Manuscript ID je-2017-00107s.R1

Manuscript Type: Article

Date Submitted by the Author: n/a

Complete List of Authors: Bazyleva, Ala; National Institute of Standards and Technology, Thermodynamics Research Center (TRC), Applied Chemicals and Materials Division Blokhin, Andrey; Belarusian State University, Chemistry Zaitsau, Dzmitry; Uni-Rostock, Chemistry Kabo, Gennady; Belarusian State University, Chemical Faculty Paulechka, Eugene; National Institute of Standards and Technology, ; National Institute of Standards and Technology, Thermodynamics Research Center Kazakov, Andrei; NIST,

Shaw, John; University of Alberta, Chemical & Materials Engineering; University of Alberta, Chemical & Materials Engineering

ACS Paragon Plus Environment

Submitted to Journal of Chemical & Engineering Data

1

Thermodynamics of antiviral and antiparkinsonian

drug amantadine hydrochloride: condensed state

properties and decomposition

Ala Bazyleva a,*

, Andrey V. Blokhin b, Dzmitry H. Zaitsau

c,d, Gennady J. Kabo

b, Eugene

Paulechka a, Andrei Kazakov

a, John M. Shaw

e

a Applied Chemicals and Materials Division, National Institute of Standards and Technology,

Boulder, CO 80305-3337, USA

b Chemistry Faculty, Belarusian State University, Leningradskaya 14, Minsk 220030, Belarus

c Competence Center CALOR, Department Life Light and Matter, University of Rostock, Albert-

Einstein-Str. 25, 18059 Rostock, Germany

d Department of Physical Chemistry, Kazan Federal University, Kremlevskaya str. 18, 420008

Kazan, Russia

e Department of Chemical and Materials Engineering, University of Alberta, Edmonton, T6G

1H9 Alberta, Canada

*Corresponding author. Tel./Fax: +1-303-497-5981. E-mail address: [email protected]

(A. Bazyleva).

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KEYWORDS: Amantadine hydrochloride; thermodynamic properties; heat capacity;

decomposition; effusion; quantum-chemistry calculations.

ABSTRACT: Heat capacities of antiviral and antiparkinsonian drug amantadine hydrochloride in

the crystalline state were measured by adiabatic and differential scanning calorimetry in the

temperature range from (5 to 470) K. Two unresolved low-enthalpy solid-to-solid phase

transitions with peak maxima at 120.0 and 123.1 K were detected. Thermodynamic functions for

crystalline amantadine hydrochloride were derived from the data obtained. Decomposition of

amantadine hydrochloride was studied by the Knudsen effusion method. Quantum chemical

calculations supported completeness of the amantadine hydrochloride ionic pair disintegration

under the effusion conditions. A data treatment model considering the difference in effusion rates

of the decomposition products, anisotropy failure in the vicinity of the orifice, and vapor

undersaturation in the effusion cell was developed. Thermodynamic parameters for the

decomposition were thus derived and shown to be consistent with available literature data on

decomposition of similar organic hydrochlorides and with the entropy of reaction calculated

directly from the entropies of the decomposition reaction participants. The obtained set of

thermodynamic properties of the medication is expected to provide new key information

necessary for optimization of production and storage conditions.

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1. Introduction

Adamantane derivatives possess pronounced biological activity, which is likely due to their

dual molecular structure combining a hydrophobic tricyclic adamantane moiety (lipophilicity)

and specific hydrophilic functional groups.1 A number of adamantane-based medications have

been developed to treat viral and inflammatory diseases, brain disorders (Parkinson's disease,

Alzheimer's, neuro infections), alcohol and drug addiction, etc.2-3 One of the first adamantane

derivatives introduced into medical practice was 1-aminoadamantane hydrochloride, or

amantadine hydrochloride (Figure 1). It is an antiviral agent for the treatment and prevention of

influenza A.3-4 It was later shown that the medication has a dopaminergic effect, which widened

the range of applications to include treatment of dementia, Parkinson's and Alzheimer's disease,

anoxic brain injury, and neuro infections.2,5 It was also shown to have some antihyperalgesic

activity.6

Figure 1. Chemical structure of amantadine hydrochloride

Thermodynamic properties have recently been studied for the amine form of the drug – 1-

aminoadamantane.7,8 However, little information on physical and thermodynamic properties of

amantadine hydrochloride is available in the literature, despite of its long history of medical use.

Non-medical studies are typically focused on molecular/ion mobility in the solid phase,9-10

because many adamantane derivatives form orientationally disordered, or plastic, crystals

NH3Cl

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exhibiting extensive molecular rotations in their lattice sites,11 and regular changes in their

molecular structures can shed light on the interconnection between molecular structure

peculiarities and plastic crystal formation. For example, a DSC study over the temperature range

of (100 to 400) K9 showed that amantadine hydrochloride has a low-enthalpy solid-to-solid

phase transition at 124 K with an entropy of transition of 2.5 J⋅K-1⋅mol-1, which is too small to

correspond to any noticeable molecular disordering. IR, Raman and XRD studies showed that

both low- and high-temperature crystalline phases are ordered with a large barrier of rotation of

adamantane moiety about its C3 axis.9-10 The absence of an order-disorder phase transition,

typical for many adamantane derivatives, was expected for amantadine hydrochloride because of

its chemical nature. It has strong intermolecular interactions including ionic and hydrogen

bonding in the condensed phase.10 The crystallographic densities of crystalline amantadine

hydrochloride from XRD results at 143 K and “room temperature” were calculated to be 1.192

g⋅cm-3 and 1.167 g⋅cm-3, respectively.10,12

The current study addresses data and knowledge gaps in thermodynamic properties of

amantadine hydrochloride. High precision solid-state heat capacity, phase change and

decomposition data are reported. Quantum chemical computations are additionally involved to

get insight into the amantadine hydrochloride structure and stability in the gaseous phase.

2. Experimental

2.1. Sample preparation

A sample of amantadine hydrochloride (C10H18NCl) was provided by the pharmaceutical

factory “BORIMED: Borisovskiy Zavod Medicinskikh Preparatov", JSC (Borisov, Belarus). The

initial mass-fraction purity was better than 0.99 according to the manufacturer’s certificate of

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analysis. The sample was exposed to vacuum at room temperature (T ≈ 293 K) and p ≈ 0.4 kPa

for 2 h to remove volatile impurities and moisture if present prior to calorimetry and effusion

experiments. No in-house purity analysis was performed. The sample description is summarized

in Table 1. The atomic masses of elements recommended by IUPAC (conventional weights

reported in Table 3 in Meija et al.13) were used to derive the molar mass of amantadine

hydrochloride (0.18771 kg⋅mol-1).

2.2. Adiabatic calorimetry

Heat capacities at the saturated-vapor pressure (Cs,m) for crystalline amantadine hydrochloride

in the temperature range (5 to 370) K and the temperatures and enthalpies of its solid-phase

transitions were determined in a vacuum adiabatic calorimeter TAU-10 (“Termis”, Moscow,

Russia), described in detail previously.14 The relative expanded uncertainty (0.95 level of

confidence) of the Cs,m measurements was estimated to be 0.4% between T = (20 and 370) K,

then increasing below 20 K to not more than 2% at 5 K.14 The repeatability for the heat-capacity

measurements was observed to be better than ±0.1%. Temperature was measured with a Fe-Rh

resistance thermometer (R0 = 50 Ω) calibrated on ITS-90 at VNIIFTRI (Mendeleyevo, Moscow

Region, Russia), with the standard uncertainty of 0.01 K.

A calorimetric cell made of titanium (V ≈ 1.13 cm3) was loaded with a solid sample – 0.6440 g

for measurement in the liquid helium range (5 K to 84 K) and 0.7308 g for measurement in the

liquid nitrogen range (above 77 K). The masses were corrected for buoyancy. After loading, the

container was degassed under vacuum (residual pressure of ~10 Pa) for 0.5 h. Helium gas, at

p ≈ 10 kPa and T = 290 K, was introduced into the cell to facilitate heat transfer during

measurements. The container was sealed using an indium ring and a titanium head fixed with a

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bronze screw cap. The ratio of the sample heat capacity to the total (sample + cell) heat capacity

was not less than 0.5 in the range of (5 to 30) K and (0.3 to 0.5) at higher temperatures. The heat

capacity of helium gas sealed in the calorimetric cell was accounted for in the treatment of the

experimental data.

Heating periods were (60 to 150) s below 40 K, (200 to 250) s for T = (40 to 80) K, and 400 s

above 80 K. The thermal relaxation time was (25 to 100) s at T < 80 K and 150 s at higher

temperatures. The periods for the temperature-drift measurements were (200 to 250) s at

T < 80 K and (300 to 400) s at T > 80 K. The temperature step for the Cs,m measurements was

approximately equal to T/20 at T < 40 K and (1.5 to 2.5) K above 40 K; two additional series

with smaller temperature steps (1.0 and 0.5) K were done in the phase transition region between

(110 and 130) K. To obtain the overall enthalpy of phase transitions, a series of experiments with

continuous energy input was conducted, i.e., one-step heating of the sample from a temperature

below the beginning of the phase transition region to a temperature above it (more details are

given in Section 4.1).

As the vapor pressure of the sample is negligible in the temperature interval studied,

adjustment of Cs,m to om,pС was unnecessary (Cs,m ≈ o

m,pС ).

2.3. Differential scanning calorimetry

The isobaric heat capacity of crystalline amantadine hydrochloride was measured in a

differential scanning calorimeter TG-DSC 111 (Setaram, France) in the temperature range (310

to 470) K at a scanning rate of 5 K⋅min-1. A continuous three-step method was applied in this

work with NIST SRM-720 sapphire15 used as a reference material. A sample of 58.64 mg

(weighed with standard uncertainty of 0.05 mg) was loaded into a stainless-steel cell, which was

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then hermetically sealed. The temperature calibration of the calorimeter was done according to

the recommendations developed by GEFTA.16-17 The standard uncertainty of temperature values

was found to be 0.2 K. The relative expanded uncertainty (0.95 level of confidence) of the heat-

capacity measurements was estimated to be 2 %. More details about the DSC experiments and

uncertainty analysis can be found elsewhere.18 During the DSC experiments, the pressure in the

sealed crucible increases by less than a factor of two, and the vapor pressure of the sample is

well below 100 kPa. Therefore, the difference between the measured heat capacity and om,pС was

negligible.

2.4. Knudsen effusion method

Effusion measurements for crystalline amantadine hydrochloride in the temperature range

(383 to 463) K were carried out in an experimental set-up19-20 with a high-temperature copper

block thermostat described previously.21 Temperature was measured with a platinum resistance

thermometer (R0 = 10 Ω). The standard uncertainty for temperature determination was estimated

to be 0.05 K. Residual pressure in the system was maintained below 10-3 Pa with a diffusion

vacuum pump. The relative expanded uncertainty (0.95 level of confidence) of the vapor

pressure measurements was estimated to be 10%.

Crystalline samples were loaded into a cylindrical stainless-steel cell with 10.0 mm height and

10.0 mm internal diameter. In order to facilitate heat transfer, the sample was pressed against the

whole inner surface of the cell with a stainless-steel rod. Three nickel membranes with different

foil thickness (l) and orifice diameters (dor) were used to check for vapor undersaturation.

Detailed analysis of the effusion measurement results is presented in Section 4.2.

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3. Computations

Thermodynamic parameters of the amantadine hydrochloride decomposition reaction in the

gaseous phase, equation (1):

C10H18NCl (gas) C10H17N (gas) + HCl (gas), (1)

were computed using a procedure described elsewhere.22 ORCA v3.0.3 package23 was used for

geometry optimization and single point calculations, and Gaussian 09 package24 was applied for

vibrational frequency computations. Molecular geometries were optimized using RI-MP2/def2-

TZVP (the density-fitted, or also called “Resolution-of-Identity” – RI, approximation of the

second-order Møller-Plesset perturbation theory25-27 and the def2-TZVP basis set28). The RI-

MP2 geometries were used for high-level single-point energy calculations with the DLPNO-

CCSD(T) approach29-31 augmented with “TightPNO” settings30 and using the def2-QZVP basis

set. Vibrational frequencies were computed with the hybrid Density Functional Theory (DFT)

B3LYP-D3(BJ) method32 and the def2-TZVP basis set. The computed frequencies were then

scaled using scaling factors consistent with those recommended in the literature33 (0.96 for H-

stretches and 0.985 for all other vibrations).

4. Results and discussion

4.1. Thermodynamic properties of crystalline amantadine hydrochloride

Experimental molar heat capacities of crystalline amantadine hydrochloride measured in the

adiabatic calorimeter and differential scanning calorimeter are presented in Tables S1 and S2

(Supporting Information), respectively, and are shown graphically in Figure 2 together with the

heat capacity 1-aminoadamantane (molecular form of the medication) measured previously in

Bazyleva et al.7 The Cp,m results for both types of calorimetry (Figure 2) agree within 1.6% in the

overlap region, i.e., within the uncertainty claimed for DSC, and both sets of measurements show

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the same temperature dependence (slope). Small parallel shifts of heat capacity values without

changing heat capacity profiles (within the stated uncertainty) are typical for the DSC instrument

due to minute irreproducibilities in the position of a sample cell inside the DSC cylinder tubes

from one experiment to another. Adiabatic calorimetry results are not subject to this artifact.

Hence, the latter data were used as a benchmark for calculating thermodynamic functions above

370 K along with the temperature dependence from the DSC measurements to avoid non-

physical heat-capacity profile, which could arise, if simpler joint data treatments are applied.

Technically, this is equivalent to using a slope from the DSC results (first derivative with respect

to temperature) in the regression.

Crystalline amantadine hydrochloride exhibits two unresolved solid-to-solid phase transitions

(Figure 3), with maxima at (120.0 ± 0.4) K and (123.1 ± 0.4) K obtained from measurements

with a temperature increment of (0.4 to 0.5) K, i.e., from Series 5. The total enthalpy of these

two phase transitions obtained in a series of experiments with continuous energy input (Table 2)

is (198.1 ± 1.0) J⋅mol-1. A similar sharp phase transition in the salt was measured by DSC9 at 124

K, with a larger enthalpy change reported (310 J⋅mol-1). No information about temperature and

energy calibration of the instrument as well as uncertainty was provided, so it is not possible to

judge the reliability of the results by Harvey et al.9

The enthalpy of crIII-crII transition of (45 ± 3) J⋅mol-1 was obtained by direct integration of

heat capacity between the experimental points and the baseline from 111.3 K to 121.0 K (saddle

point between two peaks), as shown in Figure 3. The enthalpy of crII-crI transitions of (153 ± 3)

J⋅mol-1 was obtained by subtraction of the om

crIIcrIIIH∆ values from the total transition enthalpy from

Table 2. This choice of separation method for the two peaks does not impact values of derived

thermodynamic functions due to the temperature proximity of the peaks.

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Figure 2. Temperature dependence of isobaric heat capacities of crystalline amantadine

hydrochloride from this work (black empty circles, adiabatic calorimetry; solid line, DSC) and 1-

aminoadamantane from previous work7 (grey filled circles, adiabatic)

0

50

100

150

200

250

300

350

0 100 200 300 400 500

Cp

,m/

(J⋅K

-1⋅m

ol-1

)

T / K

0

5

10

15

0 5 10 15 20

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Figure 3. Temperature dependence of isobaric heat capacities of crystalline amantadine in the

vicinity of solid-to-solid phase transitions: black empty circles, experimental data; dashed line,

heat capacity baselines used in Table 2; dotted line, crIII-crII / crII-crI phase transition boundary;

dash-dotted line in the inset is used only to make a heat capacity anomaly after the solid-to-solid

phase transitions more visible

There are two small peculiarities in the amantadine hydrochloride heat capacity temperature

profile. One is a step-like anomaly observed immediately after the crIII-crII and crII-crI phase

transitions (Figure 3, insert). The nature of the anomaly is not known. The second reproducible

peculiarity is heat capacities at approximately (239 to 242) K by up to 0.6% above the smoothing

curve. This may be an indication of a minor impurity exhibiting a phase transition in that

80

100

120

140

160

180

200

220

240

260

110 115 120 125 130 135 140 145 150 155 160

Cp

,m/

(J⋅K

-1⋅m

ol-1

)

T / K

Ttrs,1 = 120.0 K(crIII-to-crII)

Ttrs,2 = 123.1 K (crII-to-crI)

80

85

90

95

100

105

110

115

100 110 120 130 140 150 160

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temperature range. 1-Aminoadamantane is a likely impurity, since it undergoes high-enthalpy

phase transformations in that temperature interval (Figure 2). If the assumption on impurity is

correct, its content is less than 0.1 mol%, which does not impact the derived thermodynamic

functions significantly.

Thermal behaviors of amantadine hydrochloride and 1-aminoadamantane (molecular form of

the drug) are compared in Figure 2. As expected, the heat capacity of the salt is higher than that

of 1-aminoadamantane at very low temperatures. However, this changes dramatically above 200

K. As it was shown previously,7 1-aminoadamantane forms a plastic crystal phase through two

phase transitions, which starts at approximately 170 K and ends at approximately 300 K.

Formation of plastic crystals is typically associated with a large heat capacity jump, as observed

for 1-aminoadamantane. The ionic crystal of amantadine hydrochloride remains ordered,9-10

despite of the two phase transitions (these transitions are not accompanied by significant heat

capacity jumps). Hence, it is not surprising that the heat capacity of the amine form is larger than

that of the salt above 200 K due to significant differences in the temperature dependence of

molecular mobility in the crystalline phases.

The thermodynamic functions for amantadine hydrochloride in the condensed state from (5 to

470) K were derived from the smoothed heat capacities and the parameters of its solid-to-solid

phase transitions. Smoothing of heat capacities above 5 K was carried out using overlapping

polynomials. Heat capacities below 5 K were extrapolated: it appeared that the low-temperature

heat capacity of crIII of amantadine hydrochloride was adequately represented by one Debye

function with three degrees of freedom and one Einstein function with one degree of freedom:

Cp,m = D3(⟨ΘD⟩ / T) + E(⟨ΘE⟩ / T), (2)

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where the average Debye and Einstein characteristic temperatures were derived to be

⟨ΘD⟩ = 75.1 K and ⟨ΘE⟩ = 56.9 K, respectively, from the experimental heat capacities between

(5.0 to 6.6) K. Table 3 summarizes the thermodynamic functions.

4.2. Decomposition of amantadine hydrochloride from effusion measurements

Mass loss data obtained in the effusion experiments for crystalline amantadine hydrochloride

are summarized in Table 4. A pH analysis of aqueous solutions containing effusion products

condensed on a cold trap shows the presence of an amine form, which indicates that amantadine

hydrochloride decomposes upon sublimation to form hydrogen chloride and 1-

aminoadamantane. The amine form was not detected by pH measurements on the residue left in

the cell after effusion, showing that 1-aminoadamantane does not accumulate in the cell during

the effusion experiments.

In order to analyze the effusion results, it is crucial to know the equilibrium degree of

amantadine hydrochloride decomposition. The quantum chemistry methods described in Section

3 were applied to the analysis of reaction (1).

The optimized structure of amantadine hydrochloride already provides important clues. Before

the calculations, it was expected that amantadine hydrochloride existed as an ionic pair with

chlorine anion symmetrically above the positively charged NH3-group (i.e., equal H–Cl

distances). However, quantum-chemical calculations at various levels of theory (DFT, MP2)

consistently give similar representations of the amantadine hydrochloride structure in the

gaseous phase: no true ionic pair is seen. The chlorine atom is, in fact, shifted to one of the

hydrogen atoms of the NH3-group in such a way that a ready-to-go fragment of HCl is formed

(Figure 4). For example, according to RI-MP2/def2-TZVP calculations, the bond length in the

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HCl fragment is 0.141 nm (for comparison, the bond length in a free HCl molecule is 0.128 nm

at the same level of theory); the N–H distance is 0.149 nm for the hydrogen located near

chlorine, while it comprises only 0.102 nm for two other hydrogen atoms.

Figure 4. RI-MP2/def2-TZVP optimized structure of amantadine hydrochloride (dotted line –

hydrogen bonding)

The computed thermodynamic parameters of reaction (1) are summarized in Table 5. The

enthalpy of reaction (1) at 0 K was calculated from the total energies of reaction participants and

their zero-point vibrational energies (ZPVE) derived from computed scaled frequencies:

ZPVE)K0( rtotromr ∆+∆=∆ EH (3)

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Ideal gas state entropies ( )(om TS ) and thermal enthalpies ( o

m0 HT∆ ) of reactants and products in

reaction (1) at selected temperatures were calculated by statistical thermodynamic method with

the use of molecular and spectral parameters obtained in this work as described in Section 3 (see

Table S3 in the supporting formation for the numerical values of the parameters). The

conventional rigid-rotor harmonic-oscillator approximation was used without special treatment

of the NH2 and NH3Cl torsions, since the arising systematic errors in both 1-aminoadamantane

and amantadine hydrochloride are expected to cancel out on subtraction.

The total pressure in the effusion cell did not exceed 100 Pa during effusion experiments, so

the mole fraction of amantadine hydrochloride calculated from the equilibrium constants from

Table 5 did not exceed 10-5. Even assuming the expanded uncertainty (0.95 level of confidence)

in calculated enthalpy and entropy of reaction to be, respectively, 4 kJ⋅mol-1 (typical uncertainty

of quantum chemical energy calculations) and 20 J⋅K-1⋅mol-1 (roughly estimated from the

possible contribution from low vibrational frequencies of the amantadine hydrochloride adduct),

the equilibrium mole fraction of amantadine hydrochloride should not be more than 2⋅10-4. Thus,

there is essentially no amantadine hydrochloride adduct in the gas phase.

For further calculations, it was assumed that decomposition of amantadine hydrochloride

occurs on the surface of the crystalline salt according to the reaction:

C10H18NCl (cr) C10H17N (gas) + HCl (gas) (4)

The equilibrium constant for this reaction ( oK ) can be expressed as:

( )2o

HCleq,amineeq,o

p

ppK

⋅= , (5)

where po is the standard pressure (105 Pa); peq,amine and peq,HCl are the equilibrium partial

pressures of 1-aminoadamantane and hydrogen chloride, respectively.

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The total mass loss rate upon effusion into vacuum is a sum of the mass loss rates of 1-

aminoadamantane and HCl:

∆+

∆=

∆

τ

m

τ

m

τ

m HClaminetot , (6)

where ∆mi is the integral mass loss of a component or the sample in total from the effusion cell

during exposition to vacuum during τ period. For each component i of the gas mixture, the mass

loss can be expressed through the Knudsen equation for effusion of vapors with pressure *ip into

vacuum:

RT

MSkp

m i

ii

i

πτ 2or

*=∆

(7)

giving

( )amine*amineamineHCl

*HClHClor

tot

2

1MpkMpk

TRπS

τ

m+=

∆, (8)

where *aminep and *

HClp are the partial pressures of 1-aminoadamantane and HCl in the cell; Sor is

the effusion orifice area; kamine and kHCl are the transmission probabilities for the molecules of 1-

aminoadamantane and HCl through the orifice, respectively; T is the average temperature in the

effusion experiment; Mamine and MHCl are the molar masses of the effusing vapors of 1-

aminoadamantane and HCl (M = (0.15125 and 0.03646) kg⋅mol-1, respectively); R is the gas

constant (R = 8.3144598 J·K-1·mol-1).

The initial molar rate of effusion of HCl is higher than that of 1-aminoadamantane due to the

difference in their molar masses – see equation (7). The rates are expected to become the same

very quickly. Since the initial rate difference should not have any noticeable effect on the

effusion results due to the small volume of the cell, only steady state effusion is considered:

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∆=

∆

τ

n

τ

n HClamine (9)

where ∆ni is the integral molar loss of a component from the effusion cell during exposition to

vacuum during τ period. If equation (9) is combined with equation (7) for each gas component:

*amine

amine

HCl

HCl

amine*HCl p

M

M

k

kp = , (10)

equation (8) becomes:

∆

+=

τ

m

MMSk

MTRπp tot

HClamineoramine

amine*amine

)(

2 (11)

The total pressure in the cell is obtained from equations (10)-(11) as a sum of partial pressures.

The challenge in treating the effusion results is to obtain transmission coefficients ki for each

component. As shown earlier,19-20,34 the mean free paths of a molecule inside an effusion cell and

in the vicinity of an effusion orifice differ (gas isotropy failure), which affects the transmission

probability coefficient in the Knudsen equation. Transmission probabilities of gas components

are calculated in terms of the Wahlbeck theory for gas mixtures35 and by extending the iteration

procedure developed elsewhere19-20 to gas mixtures. The effective diameters of 1-

aminoadamantane (0.682 nm) and hydrogen chloride (0.359 nm) molecules were evaluated from

their van-der-Waals volumes in Tinker 3.636 based on atomic van-der-Waals radii37 and

molecular geometric parameters calculated with the RI-MP2/def2-TZVP level of theory.

Figure 5a shows the temperature dependence of the total pressure (sum of *aminep and *

HClp )

obtained from the effusion measurements for crystalline amantadine hydrochloride with the use

of the above-described approach (Table 6). There is an obvious dependence of the apparent

vapor pressure in the cell on the orifice size. This is evidence of vapor undersaturation.

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-2

-1

0

1

2

3

4

5

2.1 2.2 2.3 2.4 2.5 2.6 2.7

ln(p

* tot/

Pa)

1000 K / T

(a)

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19

Figure 5. Temperature dependence of (a) apparent total pressure (sum of *aminep and *

HClp from

Table 6) and (b) equilibrium total pressures (sum of peq,amine and peg,HCl from Table 6) obtained

with the use of membranes with different orifice diameters: – dor = 0.1833 mm, – dor =

0.4470 mm, ∆ – dor = 0.8370 mm

Consequently, extrapolation to a zero-size orifice is needed. The extrapolation approach is

based on work by Nesmeyanov38 and is similar to that presented previously,39 with the only

difference being that components (1-aminoadamantane and hydrogen chloride) are treated

separately. The extrapolation equation becomes:

( )or*

eq, 1 SkApp iiii += , (12)

-2

-1

0

1

2

3

4

5

2.1 2.2 2.3 2.4 2.5 2.6 2.7

ln(p

eq,t

ot/

Pa)

1000 K / T

(b)

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where рeq,i is equilibrium partial pressure of component i at temperature T, *ip is the apparent

partial pressure of component i measured in the effusion experiments at temperature T (equations

(10) and (11)); Ai is the fitting coefficient combining the real sublimation surface (including

surface roughness) and the condensation coefficient for component i. This procedure accounts

for vapor undersaturation in the effusion cell. Trial application of equation (12) to each mixture

component separately gives Aamine similar to AHCl within 0.5%. Since this difference has a minor

effect on the calculated equilibrium pressures in comparison to the stated uncertainty, it was

assumed that Aamine = AHCl = A in the calculations.

The equilibrium constants of reaction (4) at each studied temperature can be calculated from

the equilibrium partial pressures by equation (5). Enthalpy and entropy of decomposition

reaction (4), )(omr TH∆ and )(o

mr TS∆ , can be obtained from the temperature dependence of

)(o TK according to the following thermodynamic expression:

[ ] )()()(ln omr

omr

o TSTTHTKRT ∆−∆=− , (13)

where the standard pressure po is 105 Pa.

Since the temperature range of the effusion study is wide (80 K), the temperature dependence

of )(omr TH∆ and )(o

mr TS∆ should be taken into account by analogy with the Clarke-Glew

equation:40

[ ] )/ln()()()(1

)(ln om,r

omr

om,r

omr

o θθθθ TCSTCHT

TKR pp ⋅∆+∆+−⋅∆+∆−= , (14)

[ ] )()(

1ln)(ln omr

omro

m,ro θ

θθθ

ST

H

T

TCTKR p ∆+

∆−=

+−

⋅∆− , (15)

where om,r pC∆ is the average heat-capacity change in reaction (4) for the studied temperature

range, θ is the reference temperature. The average om,r pC∆ value for reaction (4) for the studied

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temperature range was determined to be -24 J⋅K-1⋅mol-1 based on the heat capacity of crystalline

amantadine hydrochloride from Table 3, gaseous 1-aminoadamantane obtained in our previous

work by statistical thermodynamics,7 and gaseous HCl from the CODATA tables.41 The average

temperature of the studied temperature range (423 K) was taken as the reference temperature θ.

The value of A = 1.03·106 m-2 in equation (12) was determined by combining equations (12)

and (15) and conducting simultaneous least-squares fitting of the apparent partial pressures of 1-

aminodamantane and HCl obtained in the experiments with different orifice sizes (Table 6). The

equilibrium partial pressures were thus calculated and presented in Table 6. The resulted total

equilibrium pressure (Figure 5b) does not exhibit any effusion orifice size dependence. The

obtained equilibrium partial pressures of 1-aminoadamantane over crystalline amantadine

hydrochloride are several orders of magnitude lower than the saturated vapor pressure over

crystalline 1-aminoadamantane measured earlier7 (e.g., peq,amine of 10 Pa exists over crystalline 1-

aminadamatane at 296.5 K and over crystalline amantadine hydrochloride at 439 K). This

confirms our initial observation that there is no accumulation of condensed phase 1-

aminadamatane in the cell during the decomposition measurements.

The enthalpy and entropy of decomposition reaction (4) at reference temperature θ = 423 K

were obtained from equation (15): )(omr θH∆ = (203.7 ± 7.5) kJ·mol-1 and )(o

mr θS∆ = (305 ± 18)

J·K-1·mol-1, where the expanded uncertainties with 0.95 level of confidence are reported. In order

to account for possible systematic errors in the partial pressures from the Knudsen effusion

method, the changes in slope and intercept in the right side of equation (15) were calculated with

values at the temperature extremes with equilibrium constants fractionally shifted with opposite

sign by twice the percent standard uncertainty in Ko reported in Table 6, which was evaluated

from the partial pressure uncertainties.

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The standard decomposition entropy of amantadine hydrochloride derived in this way agrees

satisfactorily with the value (320.5 ± 3.6) J·K-1·mol-1 obtained at 423 K from the entropy of

crystalline amantadine hydrochloride (Table 3), gaseous 1-aminoadamantane,7 and gaseous

HCl.41 The enthalpy of decomposition reaction (4) was adjusted from 423 K to 298.15 K with the

use of heat-capacity data for the reaction participants: omr H∆ (298.15 K) = (206.0 ± 7.5) kJ·mol-1.

This methodology for deriving decomposition enthalpies from effusion results is indirectly

supported through comparison with literature values of enthalpies of decomposition of

crystalline organic hydrochlorides (similar to reaction (4)) as shown in Table 7. The measured

enthalpy of decomposition of crystalline amantadine hydrochloride is in a similar range of other

organic hydrochlorides.

The enthalpy of formation of crystalline amantadine hydrochloride at 298.15 K was obtained

from reaction (4) using the derived enthalpy of decomposition at 298.15 K, enthalpies of

formation of gaseous 1-aminoadamantane7 (-133.8 ± 2.4) kJ·mol–1 and gaseous hydrogen

chloride (-92.31 ± 0.10) kJ⋅mol-1 from the CODATA Tables.41 The calculated value is

)K15.298,cr(omf H∆ = (-432.1 ± 7.9) kJ·mol–1.

5. Conclusions

High-precision thermodynamic properties of crystalline amantadine hydrochloride, including

condensed-phase heat capacity, thermodynamic parameters of solid-to-solid phase transitions,

decomposition and formation are reported for the first time. These results comprising a

combination of careful experimental measurements and molecular simulations have been

validated where possible and should be of considerable interest to the pharmaceutical industry,

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where they can be applied to the optimization of production and storage conditions for this active

pharmaceutical ingredient.

Supporting Information. Experimental heat capacities of crystalline amantadine

hydrochloride measured in the adiabatic calorimeter (Table S1) and differential scanning

calorimeter (Table S2) as well as molecular and spectral parameters from quantum chemical

calculations (Table S3). This material is available free of charge via the Internet at

http://pubs.acs.org.

Funding Sources

D.H.Z. is grateful to the Russian Government Program of Competitive Growth of Kazan Federal

University for partial financial support of this work.

Notes

This article is, in part, a contribution of National Institute of Standards and Technology, and is

not subject to copyright in the United States for the authors A. B., A. K., and E. P. Trade names

are provided only to specify procedures adequately and do not imply endorsement by the

National Institute of Standards and Technology. Similar products by other manufacturers may be

found to work as well or better.

REFERENCES

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(1) Bagrii, E. I. Adamantanes: Production, properties, application; Nauka: Moscow, 1989 [in

Russian].

(2) Morozov, I. S.; Petrov, V. I.; Sergeeva, S. A. Pharmacology of Adamantanes. Volgograd

Medical Academy: Volgograd, 2001 [in Russian].

(3) Oxford, J. S.; Galbraith, A. Antiviral activity of amantadine: a review of laboratory and

clinical data. Pharmacol. Ther. 1980, 11, 181-262.

(4) De Clercq, E. Antiviral drugs in current clinical use. J. Clin. Virol. 2004, 30, 115-133.

(5) Morozov, I. S.; Ivanova, I. A.; Lukicheva, T. A. Actoprotector and Adaptogen Properties of

Adamantane Derivatives (A Review). Pharm. Chem. J. 2001, 35, 235-238.

(6) Amantadine hydrochloride: https://www.ncbi.nlm.nih.gov/medgen/181680 (accessed on

December 20, 2016).

(7) Bazyleva, A. B.; Blokhin, A. V.; Kabo, A. G.; Kabo, G. J.; Emel’yanenko, V. N.; Verevkin,

S. P. Thermodynamic properties of 1-aminoadamantane. J. Chem. Thermodyn. 2008, 40, 509-

522.

(8) Gobble, C.; Rath, N.; Chickos, J. The Vaporization Enthalpies and Vapor Pressures of

Some Primary Amines of Pharmaceutical Importance by Correlation Gas Chromatography. J.

Chem. Eng. Data 2013, 58, 2600-2609.

(9) Harvey, P. D.; Gilson, D. F. R.; Butler, I. S. A study of the phase transition and molecular

motion in adamantanamine hydrochloride. J. Phys. Chem. 1987, 91, 1267-1270

Page 24 of 40



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

25

(10) Bélanger-Gariépy, F.; Brisse, F.; Harvey, P. D.; Butler, I. S.; Gilson, D. F. R. Structure of

adamantanamine hydrochloride at 143 K. Acta Cryst. 1987, C43, 756-759.

(11) Parsonage, N. G.; Staveley, L. A. K. Disorder in Crystals; Clarendon Press: Oxford, 1978.

(12) Lasocha, B.; Gawel, B.; Lasocha, W. Powder diffraction investigations of some organic

hydrochlorides. Powder Diffraction 2006, 21, 310-313.

(13) Meija, J.; Coplen, T. B.; Berglund, M.; Brand, W. A.; De Bièvre, P.; Gröning, M.;

Holden, N. E.; Irrgeher, J.; Loss, R. D.; Walczyk, T.; Prohaska, T. Atomic weights of the

elements 2013. IUPAC Technical Report. Pure Appl. Chem. 2016, 88, 265-291.

(14) Blokhin, A. V.; Paulechka, Y. U.; Kabo, G. J. Thermodynamic Properties of

[C6mim][NTf2] in the Condensed State. J. Chem. Eng. Data 2006, 51, 1377-1388.

(15) Archer, D. G. Thermodynamic Properties of Synthetic Sapphire (α-Al2O3), Standard

Reference Material 720 and the Effect of Temperature-Scale Differences on Thermodynamic

Properties. J. Phys. Chem. Ref. Data 1993, 22, 1441-1453.

(16) Höhne, G. W. H.; Cammenga, H. K.; Eysel, W.; Gmelin, E.; Hemminger, W. The

temperature calibration of scanning calorimeters. Thermochim. Acta 1990, 160, 1-12.

(17) Gmelin, E.; Sarge, St. M. Calibration of differential scanning calorimeters. Pure Appl.

Chem. 1995, 67, 1789-1800.

(18) Bazyleva, A.; Fulem, M.; Becerra, M.; Zhao, B.; Shaw, J. M. Phase Behavior of

Athabasca Bitumen. J. Chem. Eng. Data 2011, 56, 3242-3253.

Page 25 of 40



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

26

(19) Zaitsau, Dz.; Kabo, G. J.; Kozyro, A. A.; Sevruk, V. M. The effect of the failure of

isotropy of a gas in an effusion cell on the vapor pressure and enthalpy of sublimation for alkyl

derivatives of carbamide. Thermochim. Acta 2003, 406, 17-28.

(20) Zaitsau, Dz. H.; Verevkin, S. P.; Paulechka, Y. U.; Kabo, G. J.; Sevruk, V. M.

Comprehensive Study of Vapor Pressures and Enthalpies of Vaporization of Cyclohexyl Esters.

J. Chem. Eng. Data 2003, 48, 1393-1400.

(21) Zaitsau, D. H.; Kabo, G. J.; Strechan, A. A.; Paulechka, Y. U.; Tschersich, A.; Verevkin,

S. P.; Heintz, A. Experimental Vapor Pressures of 1-Alkyl-3-methylimidazolium

Bis(trifluoromethylsulfonyl)imides and a Correlation Scheme for Estimation of Vaporization

Enthalpies of Ionic Liquids. J. Phys. Chem. A 2006, 110, 7303-7306.

(22) McQuarrie, D. A. Statistical thermodynamics; Harper and Row: New York, 1973.

(23) Neese, F. The ORCA program system. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2,

73-78.

(24) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J.

R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li,

X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara,

M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;

Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J.

J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;

Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene,

M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.

E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;

Page 26 of 40



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

27

Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.;

Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09

Revision D.01. Gaussian Inc., Wallingford, Connecticut, 2013.

(25) van Alsenoy, C. Ab initio calculations on large molecules: The multiplicative integral

approximation. J. Comput. Chem. 1988, 9, 620-626.

(26) Feyereisen, M.; Fitzgerald, G.; Komornicki, A. Use of approximate integrals in ab initio

theory. An application in MP2 energy calculations. Chem. Phys. Lett. 1993, 208, 359-363.

(27) Weigend, F.; Häser, M. RI-MP2: first derivatives and global consistency. Theor. Chem.

Acc. 1997, 97, 331-340.

(28) Weigend, F.; Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence and

quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. Phys. Chem.

Chem. Phys. 2005, 7, 3297-3305.

(29) Riplinger, C.; Neese, F. An efficient and near linear scaling pair natural orbital based local

coupled cluster method. J. Chem. Phys. 2013, 138, 034106.

(30) Liakos, D. G.; Sparta, M.; Kesharwani, M. K.; Martin, J. M. L.; Neese, F. Exploring the

Accuracy Limits of Local Pair Natural Orbital Coupled-Cluster Theory. J. Chem. Theory

Comput. 2015, 11, 1525-1539.

(31) Liakos, D. G.; Neese F. Is It Possible To Obtain Coupled Cluster Quality Energies at near

Density Functional Theory Cost? Domain-Based Local Pair Natural Orbital Coupled Cluster vs

Modern Density Functional Theory. J. Chem. Theory Comput. 2015, 11, 4054-4063.

Page 27 of 40



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

28

(32) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the damping function in dispersion

corrected density functional theory. J. Comput. Chem. 2011, 32, 1456-1465.

(33) Merrick, J. P.; Moran, D.; Radom, L. An Evaluation of Harmonic Vibrational Frequency

Scale Factors. J. Phys. Chem. A 2007, 111, 11683-11700.

(34) Wahlbeck, P. G. Effusion. VII. The failure of isotropy of a gas in an effusion cell and the

transition region. J. Chem. Phys. 1971, 55, 1709-1715.

(35) Wey, S. J., Wahlbeck, P. G. Effusion IX. Application of the Failure‐of‐Isotropy Theory

for the Effusion of Gaseous Mixtures. J. Chem. Phys. 1972, 57, 2937-2939.

(36) Pappu, R. V.; Hart, R. K.; Ponder, J. W. Analysis and Application of Potential Energy

Smoothing for Global Optimization. J. Phys. Chem. B 1998, 102, 9725-9742.

(37) Haynes, W. M. CRC Handbook of Chemistry and Physics, 93rd Edition; CRC Press: Boca

Raton, FL, 2012

(38) Nesmeyanov, A. N. Vapor Pressure of the Elements; Academic Press: New York, 1963.

(39) Bazyleva, A. B.; Blokhin, A. V.; Kabo, G. J.; Kabo, A. G.; Sevruk, V.M. Thermodynamic

properties of 2-adamantanone in the condensed and ideal gaseous states. Thermochim. Acta

2006, 451, 65-72.

(40) Clarke, E. C. W.; Glew, D. N. Evaluation of thermodynamic functions from equilibrium

constants. Trans. Faraday Soc. 1966, 62, 539-547.

(41) Cox, J. D.; Wagman, D. D.; Medvedev, V. A. CODATA Key Values for Thermodynamics;

Hemisphere Publishing Corp.: New York, 1989.

Page 28 of 40



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

29

(42) Pedley, J. B. Thermochemical Data and Structures of Organic Compounds, vol. 1;

Thermodynamic Research Center: College Station, TX, 1994.

(43) Steele, W. V. The standard enthalpies of formation of cyclohexylamine and

cyclohexylamine hydrochloride. J. Chem. Thermodynam. 1979, 11, 1185-1188.

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Figure captions

Figure 1. Chemical structure of amantadine hydrochloride

Figure 2. Temperature dependence of isobaric heat capacities of crystalline amantadine

hydrochloride from this work (black empty circles, adiabatic calorimetry; solid line, DSC – this

work) and 1-aminoadamantane (grey filled circles, adiabatic calorimetry7)

Figure 3. Temperature dependence of isobaric heat capacities of crystalline amantadine in the

vicinity of solid-to-solid phase transitions: black empty circles, experimental data; dashed line,

heat capacity baselines used in Table 2; dotted line, crIII-crII / crII-crI phase transition boundary;

dash-dotted line in the inset is used only to make a heat capacity anomaly after the solid-to-solid

phase transitions more visible

Figure 4. RI-MP2/def2-TZVP optimized structure of amantadine hydrochloride (dotted line –

hydrogen bonding)

Figure 5. Temperature dependence of (a) apparent total pressure (sum of *aminep and *

HClp from

Table 6) and (b) equilibrium total pressures (sum of peq,amine and peg,HCl from Table 6) obtained

with the use of membranes with different orifice diameters: – dor = 0.1833 mm, – dor =

0.4470 mm, ∆ – dor = 0.8370 mm

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Table 1. Sample description

Chemical Name Source Initial Mass-

Fraction Purity Purification

1-aminoadamantane hydrochloride (amantadine hydrochloride)

BORIMED: Borisovskiy Zavod Medicinskikh Preparatov, JSC (Borisov, Belarus)

0.99 a Vacuum treatment at T ≈ 293 K and p ≈ 0.4 kPa for 2 h

Sapphire NIST, SRM 720 >0.9995 None

a Stated by the supplier. No additional purity analysis was performed.

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Table 2. The results of the experiments on continuous energy input for crIII-to-crI transition of

amantadine hydrochloride a

Tstart / K Tend / K qexp / J qcont / J Qsample /

J·mol-1

Qbase /

J·mol-1

omtrs H∆ /

J·mol-1

100.94 131.02 37.6584 26.220 2938 2740 197.7

100.94 130.97 37.5964 26.176 2933 2736 197.8

101.16 131.22 37.6878 26.237 2941 2743 198.5

109.32 131.27 28.5045 19.683 2266 2068 198.2

Average: 198.1 ± 1.0 b

a qexp is the energy applied to heat the container with the sample from Tstart to Tend; qcont is the heat needed to increase temperature of the container from Tstart to Tend; Qsample is the energy

necessary for heating 1 mole of amantadine hydrochloride from Tstart to Tend; omtrs H∆ is the total

enthalpy change for crIII-to-crI transition calculated as follows:

TCQQQHT

Tp d)baseline(

end

startm,samplebasesample

omtrs ∫−=−=∆ ,

with the following joint baseline derived from the heat capacity values from (92.1 to 111.3) K for crIII and from (129.1 to 139.8) K for crI:

Cp,m / (J⋅K-1⋅mol-1) = 264.29 – 7.5637·(T / K) + 9.9411·10-2·(T / K)2 – 5.2477·10-4·(T / K)3 + 1.0255·10-6·(T / K)4 .

b The average value with the expanded uncertainty with 0.95 confidence level, including repeatability and uncertainty of the method.

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Table 3. Standard molar thermodynamic functions of amantadine hydrochloride (M = 0.187711

kg⋅mol-1) in the crystalline state at a standard pressure of 105 Pa a

K/T

om,pС TH /o

mT0∆ o

mT0 S∆ o

mФ b

J⋅K-1⋅mol-1

Crystal III

5 0.585 ± 0.012 0.1445 ± 0.0029 0.1924 ± 0.0038 0.0479 ± 0.0010

10 4.396 ± 0.064 1.170 ± 0.020 1.564 ± 0.027 0.3948 ± 0.0067

15 10.64 ± 0.10 3.244 ± 0.042 4.477 ± 0.061 1.233 ± 0.016

20 17.48 ± 0.07 5.953 ± 0.054 8.480 ± 0.087 2.527 ± 0.024

25 24.00 ± 0.10 8.917 ± 0.060 13.09 ± 0.11 4.171 ± 0.031

30 29.84 ± 0.12 11.93 ± 0.07 17.99 ± 0.13 6.064 ± 0.038

35 34.98 ± 0.14 14.86 ± 0.08 22.99 ± 0.15 8.124 ± 0.047

40 39.56 ± 0.16 17.67 ± 0.09 27.96 ± 0.17 10.29 ± 0.06

45 43.74 ± 0.17 20.34 ± 0.09 32.87 ± 0.18 12.53 ± 0.06

50 47.63 ± 0.19 22.87 ± 0.10 37.68 ± 0.20 14.80 ± 0.07

60 54.53 ± 0.22 27.59 ± 0.12 46.99 ± 0.24 19.40 ± 0.09

70 60.92 ± 0.24 31.90 ± 0.14 55.88 ± 0.28 23.98 ± 0.11

80 67.11 ± 0.27 35.91 ± 0.15 64.42 ± 0.31 28.50 ± 0.13

90 73.32 ± 0.29 39.72 ± 0.17 72.68 ± 0.34 32.95 ± 0.15

100 79.81 ± 0.32 43.40 ± 0.18 80.74 ± 0.38 37.33 ± 0.16

110 86.83 ± 0.35 47.03 ± 0.19 88.67 ± 0.41 41.64 ± 0.18

120.0 94.01 ± 0.38 50.65 ± 0.21 96.53 ± 0.44 45.89 ± 0.20

Crystal II

120.0 94.01 ± 0.38 51.02 ± 0.23 96.90 ± 0.46 45.89 ± 0.21

123.1 96.21 ± 0.38 52.13 ± 0.24 99.33 ± 0.47 47.20 ± 0.22

Crystal I

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K/T

om,pС TH /o

mT0∆ o

mT0 S∆ o

mФ b

J⋅K-1⋅mol-1

123.1 96.21 ± 0.38 53.37 ± 0.26 100.6 ± 0.5 47.20 ± 0.23

130 101.0 ± 0.4 55.78 ± 0.27 106.0 ± 0.5 50.18 ± 0.24

140 107.9 ± 0.4 59.25 ± 0.28 113.7 ± 0.6 54.44 ± 0.26

150 112.2 ± 0.4 62.64 ± 0.29 121.3 ± 0.6 58.64 ± 0.28

160 117.7 ± 0.5 65.91 ± 0.30 128.7 ± 0.6 62.79 ± 0.29

170 123.8 ± 0.5 69.13 ± 0.31 136.0 ± 0.6 66.88 ± 0.31

180 130.1 ± 0.5 72.35 ± 0.32 143.3 ± 0.7 70.92 ± 0.32

190 136.6 ± 0.5 75.56 ± 0.33 150.5 ± 0.7 74.92 ± 0.34

200 143.3 ± 0.6 78.78 ± 0.34 157.7 ± 0.7 78.88 ± 0.35

210 150.2 ± 0.6 82.02 ± 0.36 164.8 ± 0.8 82.80 ± 0.37

220 157.3 ± 0.6 85.28 ± 0.37 172.0 ± 0.8 86.69 ± 0.38

230 164.5 ± 0.7 88.56 ± 0.38 179.1 ± 0.8 90.56 ± 0.40

240 171.8 ± 0.7 91.88 ± 0.39 186.3 ± 0.8 94.39 ± 0.41

250 179.3 ± 0.7 95.22 ± 0.40 193.4 ± 0.9 98.21 ± 0.43

260 186.8 ± 0.7 98.60 ± 0.42 200.6 ± 0.9 102.0 ± 0.4

270 194.3 ± 0.8 102.0 ± 0.4 207.8 ± 0.9 105.8 ± 0.5

280 202.1 ± 0.8 105.4 ± 0.4 215.0 ± 1.0 109.6 ± 0.5

290 209.9 ± 0.8 108.9 ± 0.5 222.2 ± 1.0 113.3 ± 0.5

298.15 216.2 ± 0.9 111.8 ± 0.5 228.1 ± 1.0 116.4 ± 0.5

300 217.6 ± 0.9 112.4 ± 0.5 229.5 ± 1.0 117.1 ± 0.5

310 225.3 ± 0.9 115.9 ± 0.5 236.7 ± 1.0 120.8 ± 0.5

320 233.0 ± 0.9 119.5 ± 0.5 244.0 ± 1.1 124.6 ± 0.5

330 240.7 ± 1.0 123.0 ± 0.5 251.3 ± 1.1 128.3 ± 0.5

340 248.6 ± 1.0 126.6 ± 0.5 258.6 ± 1.1 132.0 ± 0.6

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35

K/T

om,pС TH /o

mT0∆ o

mT0 S∆ o

mФ b

J⋅K-1⋅mol-1

350 256.5 ± 1.0 130.2 ± 0.5 265.9 ± 1.2 135.7 ± 0.6

360 264.5 ± 1.1 133.8 ± 0.6 273.3 ± 1.2 139.5 ± 0.6

370 272.5 ± 1.1 137.5 ± 0.6 280.6 ± 1.2 143.2 ± 0.6

380 280 ± 11 141.1 ± 0.8 288.0 ± 1.5 146.9 ± 0.8

390 288 ± 12 144.8 ± 1.1 295.4 ± 1.8 150.6 ± 1.0

400 296 ± 12 148.5 ± 1.4 302.8 ± 2.1 154.3 ± 1.3

410 304 ± 12 152.2 ± 1.6 310.2 ± 2.4 158.0 ± 1.5

420 312 ± 12 155.9 ± 1.9 317.6 ± 2.7 161.7 ± 1.7

430 319 ± 13 159.6 ± 2.1 325.0 ± 3.0 165.4 ± 1.9

440 327 ± 13 163.3 ± 2.4 332.5 ± 3.3 169.2 ± 2.1

450 334 ± 13 167.0 ± 2.6 339.9 ± 3.6 172.9 ± 2.3

460 342 ± 14 170.7 ± 2.9 347.3 ± 3.9 176.6 ± 2.5

470 349 ± 14 174.5 ± 3.1 354.8 ± 4.2 180.3 ± 2.7

a Expanded uncertainties with 0.95 confidence level are reported inside the table.

b Function THSФ /om

T0

om

T0

om ∆−∆= .

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36

Table 4. Mass loss data for effusion experiments on crystalline amantadine hydrochloride a,b

Point # mm

ord

mµl

K

T

s

τ

mg

m∆

1 0.4467 72 413.09 10800 7.84

2 0.4467 72 423.02 7200 10.92

3 0.4467 72 433.04 3600 10.56

4 0.4467 72 403.03 20100 7.03

5 0.1833 50 442.99 10800 10.59

6 0.1833 50 433.04 19800 9.78

7 0.1833 50 453.04 5400 9.94

8 0.1833 50 463.06 3600 12.15

9 0.8370 50 403.06 10800 10.92

10 0.8370 50 393.03 19800 9.01

11 0.8370 50 383.03 21600 4.25

a ∆m is the experimental sample mass loss from effusion cell into the vacuum during time τ at temperature T; l is the membrane thickness, and dor is the effusion orifice diameter.

b Standard uncertainties u are u(T) = 0.05 K, u(dor) = 0.0005 mm, u(l) = 1 µm, u(∆m) = 0.02 mg, u(τ) = 5 s.

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37

Table 5. Calculated thermodynamic parameters of amantadine hydrochloride dissociation

according to gas-phase reaction (3) (po = 105 Pa) a,b,c

)K0(omr H∆ /

kJ·mol-1 T / K

)(omr TH∆ /

kJ·mol–1

)(omr TS∆ /

J·K-1·mol-1

)(omr TG∆ /

kJ·mol-1

)(o TK

35.4

298.15 38.1 122.7 1.5 0.55

400 38.1 122.9 -11.0 28

500 37.8 122.2 -23.3 2.7⋅102

a Symbols: )K0(omr H∆ and )(o

mr TH∆ are the enthalpies of reaction at 0 K and selected

temperature T; )(omr TS∆ and )(o

mr TG∆ are the entropy and Gibbs energy of reaction at selected

temperature T; )(o TK is the equilibrium constant of reaction at selected temperature T.

b The value )K0(omr H∆ was calculated by equation (4) with computed values totr E∆ =

43.09 kJ·mol-1 and ZPVEr∆ = -7.67 kJ·mol-1.

c The uncertainty estimation is presented is Section 4.2

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38

Table 6. Apparent ( *ip ) and equilibrium (peq,i) partial pressures (in Pa) together with

transmission probabilities for 1-aminoadamantane and HCl calculated as well as equilibrium

constant for reaction (5) from the effusion results (po = 105 Pa) a,b

Point # K

T *

aminep kamine *HClp kHCl peq,amine peq,HCl oK ⋅1010

1 413.09 1.51 0.933 0.773 0.895 1.74 0.885 1.54

2 423.02 3.04 0.981 1.59 0.922 3.52 1.82 6.41

3 433.04 5.64 1.034 2.99 0.958 6.58 3.45 22.7

4 403.03 0.744 0.902 0.375 0.879 0.852 0.427 0.364

5 442.99 12.6 0.927 6.66 0.864 13.0 6.81 88.2

6 433.04 6.62 0.881 3.43 0.834 6.78 3.51 23.8

7 453.04 22.9 0.973 12.1 0.901 23.5 12.4 291

8 463.06 40.7 1.012 21.4 0.945 41.8 22.0 919

9 403.06 0.549 1.006 0.279 0.971 0.861 0.432 0.372

10 393.03 0.252 0.975 0.126 0.957 0.390 0.194 0.0757

11 383.03 0.109 0.958 0.0542 0.950 0.168 0.0832 0.0140

a The direct experimental data are reported in Table 4 with the corresponding numeration.

b Standard uncertainties u are u(T) = 0.05 K, ur(p) = 0.05, ur(oK ) = 2ur(p) = 0.10.

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39

Table 7. Enthalpies of decomposition ( omr H∆ ) of crystalline organic hydrochlorides into gaseous amine and HCl at 298.15 K derived

from the corresponding literature values a,b

Amines )g(o

mf H∆ /

kJ·mol-1 Hydrochlorides

)cr(omf H∆ /

kJ·mol-1

omr H∆ /

kJ·mol-1

Methylamine42 -23.4 ± 1.0 Methylammonium chloride42 -298.1 ± 4.1 182.4 ± 4.2

Dimethylamine42 -18.8 ± 1.5 Dimethylammonium chloride42 -289.3 ± 4.2 178.2 ± 4.5

Trimethylamine42 -23.6 ± 1.3 Trimethylammonium chloride42 -282.9 ± 4.2 167.0 ± 4.4

1-Propylamine42 -70.1 ± 0.4 Propylammonium chloride42 -354.7 ± 0.4 192.3 ± 0.6

Diethylamine42 -72.2 ± 1.2 Diethylammonium chloride42 -358.6 ± 1.4 194.1 ± 1.8

Dipropylamine42 -116.0 ± 0.5 Dipropylammonium chloride42 -389.5 ± 1.0 181.2 ± 1.1

Di-isopropylamine42 -143.8 ± 0.5 Di-isopropylammonium chloride42 -417.8 ± 0.5 181.7 ± 0.7

Tripropylamine42 -161.0 ± 0.9 Tripropylammonium chloride42 -446.4 ± 1.0 193.1 ± 1.3

Cyclohexylamine43 -104.9 ± 1.3 Cyclohexylamine hydrochloride43 -408.2 ± 1.5 211.0 ± 2.0

a The enthalpy of formation of gaseous HCl used was taken from the CODATA tables.41

b The uncertainty is taken from the cited references, but the uncertainty type (whether standard uncertainty or expanded uncertainty with 0.95 level of confidence) is not identified there.

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40

TOC Graphics

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1

SUPPORTING INFORMATION

Thermodynamics of antiviral and antiparkinsonian

drug amantadine hydrochloride: condensed state

properties and decomposition

Ala Bazyleva a,*, Andrey V. Blokhin b, Dzmitry H. Zaitsau c,d, Gennady J. Kabo b, Eugene

Paulechka a, Andrei Kazakov a, John M. Shaw e

a Applied Chemicals and Materials Division, National Institute of Standards and Technology,

Boulder, CO 80305-3337, USA

b Chemistry Faculty, Belarusian State University, Leningradskaya 14, Minsk 220030, Belarus

c Competence Center CALOR, Department Life Light and Matter, University of Rostock, Albert-

Einstein-Str. 25, 18059 Rostock, Germany

d Department of Physical Chemistry, Kazan Federal University, Kremlevskaya str. 18, 420008

Kazan, Russia

e Department of Chemical and Materials Engineering, University of Alberta, Edmonton, T6G

1H9 Alberta, Canada

*Corresponding author. Tel./Fax: +1-303-497-5981. E-mail address: [email protected]

(A. Bazyleva).

2

Table S1. Experimental molar isobaric heat capacities for amantadine hydrochloride (M =

0.18771 kgmol-1) obtained by adiabatic calorimetry (po = 105 Pa) a

T / K o

m,pС / J∙K-1∙mol-1

Series 1

crIII

5.01 0.5801

5.25 0.6835

5.49 0.7946

5.75 0.9160

6.00 1.051

6.30 1.220

6.62 1.420

6.95 1.642

7.29 1.891

7.64 2.153

7.99 2.437

8.34 2.747

8.70 3.078

9.06 3.426

9.43 3.794

9.79 4.174

10.17 4.569

10.64 5.116

11.22 5.781

11.81 6.479

T / K o


12.40 7.208

13.00 7.971

13.60 8.754

14.21 9.533

14.82 10.38

15.54 11.36

16.37 12.56

17.21 13.72

18.05 14.85

18.89 15.98

19.74 17.10

20.86 18.62

22.27 20.49

23.70 22.36

25.12 24.15

26.55 25.89

27.96 27.53

29.45 29.22

31.06 31.00

32.82 32.84

34.59 34.60

36.37 36.26

T / K o


38.14 37.90

39.92 39.49

41.79 41.08

43.77 42.73

45.75 44.38

47.72 45.90

49.71 47.41

51.69 48.89

53.68 50.26

55.67 51.64

57.67 52.99

59.67 54.32

61.67 55.65

63.67 56.94

65.68 58.17

67.69 59.45

69.70 60.69

71.71 62.00

73.72 63.24

75.74 64.48

77.75 65.74

79.78 66.97

3

T / K o


81.80 68.23

83.83 69.44

Series 2

crIII

78.45 66.20

80.56 67.47

82.48 68.62

84.40 69.79

86.32 71.01

88.24 72.23

90.17 73.44

92.09 74.67

94.02 75.90

95.95 77.18

97.89 78.44

99.83 79.74

101.77 81.04

103.71 82.35

105.66 83.70

107.61 85.07

109.57 86.53

111.52 88.04

113.48 89.74

115.44 92.00

117.39 96.19

T / K o


119.31 108.3

crII

121.24 112.4

crI

123.07 165.2

125.12 99.65

127.30 99.61

129.28 100.6

131.26 101.8

133.24 103.2

135.22 104.5

137.20 105.9

139.19 107.3

141.18 108.6

143.17 109.5

145.16 110.1

147.16 110.9

149.15 111.8

151.15 112.7

153.15 113.8

155.14 114.9

157.14 116.1

159.14 117.2

161.14 118.4

163.14 119.6

T / K o


165.15 120.8

167.15 122.0

169.15 123.3

171.16 124.6

173.17 125.8

175.17 127.0

177.18 128.3

179.19 129.6

181.20 130.9

183.21 132.2

185.23 133.5

187.24 134.8

189.25 136.2

191.27 137.4

193.28 138.8

195.30 140.1

197.31 141.5

199.33 142.9

201.34 144.3

203.36 145.7

205.38 147.1

207.40 148.4

209.42 149.8

211.44 151.2

213.46 152.6

4

T / K o


215.49 154.1

217.51 155.5

219.54 156.9

221.56 158.4

223.59 159.8

225.62 161.3

227.64 162.8

229.67 164.3

231.70 165.8

233.72 167.3

235.75 169.0

237.78 170.3

239.81 172.1

241.84 174.1

243.87 174.6

245.91 176.1

247.94 177.7

249.97 179.2

252.00 180.7

254.03 182.2

256.06 183.7

258.09 185.3

260.12 186.8

262.15 188.4

264.19 189.9

T / K o


266.22 191.4

268.25 193.1

270.28 194.5

272.31 196.1

274.35 197.7

276.38 199.3

278.41 200.9

280.44 202.5

282.47 204.0

284.51 205.6

286.53 207.1

288.56 208.7

290.60 210.3

292.63 211.9

294.66 213.5

296.69 215.0

298.72 216.6

300.75 218.1

302.78 219.8

304.81 221.3

306.84 222.9

308.88 224.5

310.91 226.0

312.94 227.6

314.98 229.1

T / K o


317.01 230.8

319.04 232.3

321.08 233.9

323.11 235.4

325.15 237.0

327.19 238.6

329.23 240.1

331.26 241.7

333.30 243.3

335.34 244.9

337.38 246.5

339.42 248.1

341.46 249.6

343.50 251.3

345.54 252.9

347.58 254.6

349.62 256.2

351.66 257.8

353.70 259.4

355.74 261.1

357.78 262.8

359.82 264.4

361.86 266.0

363.90 267.5

365.94 269.3

5

T / K o


367.98 270.9

Series 3

crIII

100.61 80.30

102.13 81.29

103.66 82.26

105.19 83.26

106.71 84.46

108.24 85.55

109.77 86.68

111.30 87.82

112.83 89.22

114.36 90.60

115.89 92.64

117.40 96.04

118.90 105.3

crII

120.37 108.5

121.81 125.5

crI

123.13 176.4

124.50 100.8

126.03 99.11

127.57 99.64

129.10 100.5

T / K o


130.63 101.5

132.16 102.5

133.70 103.5

135.23 104.6

136.76 105.6

138.29 106.7

139.83 107.7

141.36 108.7

142.89 109.4

144.42 109.9

145.95 110.4

147.49 111.1

149.02 111.7

150.57 112.4

152.11 113.3

153.64 114.2

155.18 114.9

156.72 115.7

158.25 116.7

159.79 117.6

161.32 118.5

162.86 119.5

164.39 120.4

165.92 121.2

167.45 122.3

T / K o


168.98 123.2

170.51 124.1

172.04 125.0

173.57 126.0

175.10 127.0

176.62 127.9

178.14 128.9

179.67 130.0

181.19 130.9

182.70 131.9

184.22 132.8

185.74 133.8

187.25 134.8

188.76 135.8

190.27 136.9

191.79 137.9

193.30 138.9

194.80 139.9

196.30 140.9

197.81 141.9

199.31 142.8

200.81 143.9

202.30 144.9

203.80 146.1

205.30 147.0

6

T / K o


206.80 148.0

208.29 149.0

209.79 150.0

211.28 151.0

212.77 152.1

214.26 153.1

215.75 154.2

217.23 155.3

218.71 156.2

220.19 157.2

221.67 158.4

223.43 159.7

225.29 161.1

227.06 162.3

228.83 163.7

230.60 165.1

232.37 166.3

234.13 167.6

235.89 168.9

237.64 170.4

239.40 171.9

241.15 173.6

242.89 174.2

244.64 175.3

246.38 176.6

T / K o


248.13 177.9

249.87 179.2

251.60 180.5

253.34 181.7

255.07 183.1

256.80 184.4

258.52 185.6

260.24 186.9

Series 4

crIII

110.61 87.30

111.99 88.23

113.00 89.28

114.01 90.15

115.02 91.42

116.03 92.78

117.03 94.87

118.03 98.29

119.02 105.6

119.99 111.4

crII

120.95 106.2

121.91 126.5

122.76 187.7

crI

T / K o


123.61 138.3

124.56 99.57

125.57 98.89

126.58 99.15

Series 5

crIII

115.56 91.67

116.09 92.40

116.58 93.36

117.07 94.53

117.56 95.93

118.05 97.56

118.53 100.2

119.01 104.0

119.48 110.1

119.95 112.9

crII

120.42 108.5

120.89 104.8

121.37 108.6

121.84 120.0

122.28 146.1

122.69 168.0

crI

123.07 227.7

7

T / K o


123.47 148.0

123.92 106.3

T / K o


124.41 99.70

124.90 99.18

T / K o


125.39 98.80

125.88 98.68

a Average heat capacities at the mean temperatures of experiments. The measurements were

performed at P(He) / kPa = (10 ± 1)·(T / K) / 290; no adjustment of Cs,m to o

m,pС (i.e., Cs,m ≈

o

m,pС ) due to negligible sample vapor pressure. The expanded uncertainty is U(T) = 0.02 K, the

relative expanded uncertainties are Ur(o

m,pС ) = 0.02 – 1.07∙10–3((T / K) – 5) at 5 < (T / K) < 20,

Ur(o

m,pС ) = 0.004 at T > 20 K for 0.95 level of confidence (k = 2).

8

Table S2. Experimental molar isobaric heat capacities for crystalline amantadine hydrochloride

(M = 0.18771 kgmol-1) obtained by differential scanning calorimetry at 0.1 MPa a,b

T / K o


310.0 222.6

311.7 223.7

313.3 224.7

315.0 226.1

316.6 227.2

318.2 228.5

319.9 229.5

321.5 230.9

323.1 231.9

324.8 233.5

326.4 234.8

328.0 236.0

329.6 237.3

331.2 238.4

332.8 239.6

334.4 241.2

336.0 242.3

337.6 243.3

339.3 244.7

340.9 246.2

342.5 247.4

344.1 248.6

T / K o


345.7 249.8

347.2 251.1

348.8 252.4

350.4 253.7

352.0 254.9

353.6 256.1

355.2 257.6

356.8 259.0

358.4 260.3

360.0 261.8

361.6 263.1

363.2 264.7

364.8 265.8

366.3 267.1

367.9 268.2

369.5 269.4

371.1 270.6

372.7 271.9

374.3 273.2

375.9 274.4

377.4 275.5

379.0 276.5

T / K o


380.6 277.8

382.2 279.0

383.8 280.3

385.4 281.2

386.9 282.7

388.5 284.1

390.1 285.0

391.7 286.5

393.3 287.4

394.9 288.7

396.4 289.9

398.0 291.3

399.6 292.6

401.2 293.6

402.8 294.7

404.4 296.2

405.9 297.3

407.5 298.6

409.1 299.8

410.7 301.0

412.3 302.3

413.8 303.9

9

T / K o


415.4 305.3

417.0 306.5

418.6 307.7

420.2 308.7

421.7 309.9

423.3 311.5

424.9 312.6

426.5 313.6

428.1 314.7

429.7 315.8

431.2 317.0

432.8 318.4

T / K o


434.4 319.9

436.0 321.0

437.6 322.3

439.1 323.5

440.7 324.8

442.3 326.0

443.9 326.9

445.5 328.0

447.0 329.5

448.6 330.4

450.2 331.6

451.8 332.9

T / K o


453.4 334.4

454.9 335.7

456.5 336.7

458.1 337.3

459.7 338.7

461.3 339.3

462.8 340.6

464.4 341.7

466.0 343.0

467.6 344.1

469.2 345.0

470.7 346.4

a Standard uncertainties u are u(T) = 0.2 K, ur(o

m,pС ) = 0.02.

b Experimental pressure in the cell (not controlled) was estimated to be (0.15 ± 0.05) MPa.

The difference between the measured heat capacity and o

m,pС was negligible.

10

Table S3. Product of principle moments of inertial (IA·IB·IC) and scaled frequencies of normal

vibrations (ωscaled)a obtained by quantum chemical methods described in Section 3 and used for

statistical thermodynamic calculations for the given species with rigid-rotor harmonic-oscillator

approximation b

Species / symmetry

IA·IB·IC/

10-135

kg3·m6

ωscaled / cm-1

Amantadine

hydrochloride / C1 1589

41, 44, 120, 251, 282, 312, 342, 396, 400, 402, 404,

420, 451, 453, 544, 645, 647, 707, 765, 800, 801, 872,

884, 888, 890, 912, 917, 935, 956, 979, 987, 996, 1032,

1033, 1034, 1074, 1096, 1101, 1109, 1116, 1120, 1123,

1141, 1197, 1212, 1281, 1292, 1293, 1293, 1314, 1329,

1330, 1333, 1338, 1361, 1368, 1379, 1379, 1388, 1460,

1464, 1473, 1476, 1478, 1499, 1512, 1614, 2880, 2886,

2891, 2893, 2893, 2898, 2914, 2915, 2917, 2923, 2926,

2929, 2934, 2944, 2948, 3311, 3384

1-Aminoadamantane /

Cs 247.5

234, 263, 275, 313, 386, 387, 402, 405, 419, 449, 452,

546, 643, 647, 707, 765, 798, 800, 844, 883, 884, 888,

917, 922, 931, 962, 975, 986, 1020, 1029, 1030, 1093,

1099, 1105, 1110, 1117, 1133, 1149, 1192, 1207, 1266,

1286, 1288, 1290, 1319, 1324, 1327, 1330, 1337, 1359,

1366, 1372, 1378, 1386, 1458, 1461, 1472, 1473, 1475,

1496, 1627, 2878, 2883, 2888, 2888, 2889, 2890, 2907,

2908, 2913, 2916, 2922, 2922, 2927, 2931, 2936, 3320,

3393

a The computed frequencies were then scaled using the following scaling factors 0.96 for H-

stretches and 0.985 for all other vibrations.

b Hydrogen chloride molecule is linear with the principal moments of inertia IA = IB =

0.2645·10-46 kg·m2 and scaled frequency of its normal vibration ωscaled = 2823 cm-1.

thermodynamics of antiviral and antiparkinsonian drug

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