Lattice Vibrations of Crystalline Diazepam (Valium)

J. Dumetz Institut de Mbdecine Lbgale, Place Thbo Varlet, 59000 Lille, France

G. Vergoten, J. P. Huvenne and G. Fleury Laboratoire de Physique, Faculte de Pharmacie, rue du Pr. Laguesse, 59045 Lille Cedex, France, et Centre de Technologie Biombdicale INSERM, 13-17, rue Camille GuBrin, 59800 Lille, France

Low frequency Raman spectra of diazepam have been recorded at various temperatures between 103 and 396 K. Far IR spectra are also reported at room temperature. The observed frequencies of the lattice modes are compared with those calculated using a semi-empirical intermolecular potential. The transferability of the atom-atom potentials leads to good agreement between the two sets of frequencies.

INTRODUCTION

The chemotherapy of neuropsychic maladjustments made important progress with the discovery of psycho- tropic medicines. Among them, benzodiazepines are found to exhibit tranquilizing properties which reduce the mental activity while acting on the temper.

(7-chloro- 1,3-dihydro- 1 -methyl-5 - phenyl-2-H-1,4 benzodiazepin-2-one) is one of the most important antianxiety agent. Its chemical formula is given in Fig. 1. The crystal structure of diaze am has been determined by Camerman and Camerman as part of their investigation into the relationship between molecular shape and pharmacological activity of anti- convulsivant drugs. Until recent years, Raman spectro- scopy had had only limited application to the study of physiologically active substances. Some common barbit- urates had been studied in the high frequency range.*

Barbituric acids and their salts can be identified using characteristic Raman carbonyl stretching and ring vibra- tions. Mid-IR spectra of ring methylated amphetamines have also been reported.'

Such molecules are expected to show intense low frequency Raman bands due to the important diff eren-

Diazepam

P

Figure 1. Structural formula of diazepam.

ces between the electric polarizabilities along their main axes of inertia.

EXPERIMENTAL

Far IR spectra were measured using a Coderg fourier- spec 2000 spectrometer linked to a Digital PDP 8/E minicomputer. Raman spectra were recorded with the aid of a Coderg T 800 spectrometer also linked to the computer, using as exciting line the 514.5 nm line of an argon ion laser. The temperature dependence of the low frequency Raman spectra was investigated for diazepam powder in the range 103-396 K.

RESULTS AND DISCUSSION

The symmetry of the molecule is CI since it has two planes, one containing the C1-substituted benzene and the seven membered ring, and the other containing the second phenyl ring. The angle between the normals to these two planes is found to be 125.3'. Diazepam crys- tallizes in the monoclinic system,' space group P21,,(Cih), with four molecules in the unit cell located on C1 sites. The cell parameters are:a = 12.3284 A; b = 13.3537 A; c = 7.9763 A; p = 90.010".

The unit cell has 21 optically active lattice modes which classify according to the C 2 h factor group sym- metry as:

6A, + 6B, + SA, + 4B, The twelve vibrations of gerade species are active in

the Raman spectrum and the nine vibrations of ungerade species are IR active.

Typical low frequency Raman spectra at various tem- peratures are shown in Fig. 2.

Far IR spectra recorded at room temperature are presented in Fig. 3. Six Raman bands are observed in the spectral range 0-120 cm-' at 373 K with the follow- ing frequencies: 21.4, 29.6, 36.4, 55.2, 70.2 and 99 cm-', consisting of three (A, + B,) translational

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CCC-0377-0486/81/0011-0221 $02.00 JOURNAL OF RAMAN SPECTROSCOPY, VOL. 11, NO. 4, 1981 221

J. DUMETZ, G. VERGOTEN, J. P. HUVENNE AND G. FLEURY

29.6 r

31.8 22.2

,

?I R . ..

263 K

223 K

173 K

lU5.8

113.4 104.6 76.6 40.2

I I I I 200 I50 100 50

crn-1

Figure 2. Low frequency Raman spectra of diazepam at various temperatures.

modes and three (A, + B,) rotational lattice modes which may be much coupled.

In the same spectral range, eleven bands of medium or strong intensity are found at 103 K.

In order to give a rigorous assignment of lattice vibra- tions, a preliminary single crystal polarization study and a normal coordinate calculation were performed. The method of calculation has been described previ~usly.~

Figure 3. Far IR spectrum of diazepam at room temperature.

The rigid body approximation was used. The crystal potential is written as the sum of all pairwise interactions between molecules:

vnm= C C uij(rij) i j

where i and j label atoms, n and rn label molecules (atom i belongs to molecule n atom j to molecule m). These interactions depend only on the distance rli between atoms i and j . The second derivatives of Vij (rii) with respect to the Cartesian displacement coordinates give the force constant matrix elements which are characteristic of the interactions between atoms i and j . The actual form of Vii ( r j j ) , describing the short-range van der Waals forces, is:

V..(r..) = A ~ . exp (-B..r..) - c..rT6 V 11 11 11 11 11

Aij, Bij and Cij are parameters of the atom-atom poten- tial. Their numerical values were taken from the work of Dashe~skii .~ They are given in Table 1. Their units are taken so that V is expressed in Kcal mol-’ and r in A. If a 5 A ‘cut-off’ distance is taken, 259 interaction coordinates are defined. The calculated crystal energy is -14.413 kcal mol-’. If a 6 A ‘cut-off’ distance is used,

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LATTICE VIBRATIONS OF CRYSTALLINE DIAZEPAM (VALIUM)

Table 1. A, B and C parameters for the non-bonded atom- atom interactions

Pair C . . C Pair C..-H Pair H...H Pair CI...C Pair CI...H Pair CI...CI Pair N...C Pair N.-.H Pair N...CI Pair N...N Pair O-.C Pair O...H Pair O..,O Pair 0.. .N Pair O...CI

A

83 630.00 8 766.00 2 654.00

138 384.00 24 656.00 229 000.00 55 300.00 49 500.00 142 000.00 76 200.00 63 700.00 57 500.00 96 500.00 86 100.00 156 000.00

8

3.600 3.670 3.740 3.560 3.630 3.513 3.768 4.561 3.768 4.063 3.881 4.727 4.333 4.194 3.881

C

568.00 125.00 27.30

1283.00 282.00 2906.00 456.00 130.00 1180.00 402.00 441 .OO 122.00 346.00 374.00 1080.00

i-

I

\ / 84

cm-'

Figure 4. Low frequency Raman spectrum of a saturated solution of diazepam in CCI,.

974 interaction coordinates are obtained and the calcu- lated lattice energy is -24.1 kcal mol-'. Unfortunately, no experimental value is available for comparison. In the latter case, the agreement between calculated and observed frequencies is better for the low frequencies.

Table 2 gives the observed frequencies (at 173 K in the Raman spectrum, at 293 K in the IR spectrum). The calculated frequencies and the eigenvectors of the lattice modes are as defined in Ref. 3. It must be noted that low-frequency internal vibrations are expected in the range 0-200 cm-' in addition to the lattice vibrations. Raman bands at frequencies higher than 115 cm-' are assigned to internal vibrations. For the lower frequency range, a Raman spectrum of a solution of diazepam in carbon tetrachloride has been recorded using data

storage. Fifty spectra were added in the range 200- 30 cm-'. A shoulder centred at 84 cm- appears on the Rayleigh wing. This band is also assigned to an internal vibration. The corresponding spectrum is shown in Fig. 4.

From the temperature dependence of Raman frequencies, experimental assignments of bands with frequencies 111.6, 64.2 and 45.8cm-' (at 173K) to rotatory lattice modes may be proposed. The assign- ments are supported by the calculation.

The agreement between the observed and calculated frequencies is good except for the band at 100- 110 cm-'. In that case the coupling between internal and lattice vibrations is important and the calculation of the frequencies of the 'flexible' crystal has to be performed in order to get a better agreement.

Table 2. Observed and calculated frequencies and eigenvectors of the lattice modes of diazepam

Obs. Symmetry {cm-') calc.

species (173 K) (cm ' 1 T X TY Tz 8, R E RC

- - - 0.01 0 0.021 - A, 111.6 73.7 74.6 60.5 0.044 0.021 -0.006 - - -0.010 64.2 57.9 0.018 0.013 - -0.01 3 0.006 0.013 45.8 41.4 0.007 0.017 -0.036 0.016 - 0.007 30.6 28.4 -0.034 0.035 -0.020 -0.007 0.006 0.005 23.4 23.3 - 0.036 0.041 0.008

103.4 68.1 0.044 0.032 - -0.006 - -0.005 74.6 60.9 -0.016 0.019 0.006 0.017 0.005 -0.01 1 58.6 51.1 -0.01 8 0.028 -0.020 - 0.01 5 0.008 58.6 49.9 - -0.021 0.035 -0.006 0.016 - 39.0 35.5 0.031 -0.021 -0.015 0.01 5 0.007 0.006 34.6 32.9 - 0.021 0.041 0.008 -0.005 0.010

1 04 75.7 -0.029 - -0.017 0.016 -0.01 2 - 104 69 -0.01 0 - -0.018 -0.015 -0.007 0.012 40-43 38.3 -0.026 - -0.014 - 0.01 9 0.005 35 34.9 ~ 0.014 - 0.035 0.009 - 0.01 2

22-28 24.4 0.040 - -0.038 0.007

- -

A"

- - B" 104 66.2 - -0.030 - 0.006 0.01 5 0.010

72 65.1 - - - 0.023 - 0.008 54 47 - 0.049 48 42.4 - 0.01 6 - 0.009 -0.01 2 0.014

- - 0.013 -

X, V , Z refer to the crystalline Cartesian coordinate system; A, B, C refer to the principal axes of inertia

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J. DUMETZ, G. VERGOTEN, J. P. HUVENNE AND G. FLEURY

Low frequency Raman spectroscopy may be used in order to study the molecular interactions and also the behaviour with time Of the active substance (Diazepam) in its C~IMIWcial preparation as has been done for the nitrazepam.’~~

Acknowledgments

The authors are greatly indebted to the ‘Institut National de la Santi et de la Recherche MBdicale’ for i ts financial support under grant No. CRL.77.1.206.3 during the tenure of this work.

REFERENCES

1. A. Camerman and N. Camerman, Am. Chem. SOC. 94, 268

2. K. Bailey, Proc. Feature presentation on spectroscopy and

R. E. Hester, Vol. 4, p. 195. Heyden, London (1978). (1972). 6. G. Fleury, G. Vergoten, Y. Moschetto, J. Dumetz, P. Tran van

Ky and P. H. Muller, European Symposium of the International drugs, 21st Canadian Spectroscopy Symposium, October Association of Forensic Toxicologists, G hent, Belgium, 1974, Ottawa, Canada August 1976.

3. G. Vergoten, Thesis, Lille, France (1977). 4. B. G. Dasheviskii, Zh. Srrukt. Khim. 11,912 (1970). 5. G. Vergoten, G. Fleury and Y. Moschetto, in Advances in

Infrared and Raman Spectroscopy, ed. by R. J. H. Clark and

Received 24 June 1980

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