Comment on vibrational spectral investigation on xanthine and its derivatives—theophylline, caffeine and theobromine

Spectrochimica Acta Part A 61 (2005) 2796–2797

Short communication

Comment on vibrational spectral investigation on xanthine and its derivatives—theophylline, caffeine and theobromine Paulo J.A. Ribeiro-Claroa,∗ , Ana M. Amadob,1 b

a CICECO, Departamento de Qu´ımica, Universidade de Aveiro, P-3810-193 Aveiro, Portugal Qu´ımica-F´ısica Molecular, Departamento de Qu´ımica, FCTUC, Universidade de Coimbra, P-3004-535 Coimbra, Portugal

Received 9 November 2004; accepted 17 November 2004

Keywords: Theophylline, Caffeine, Vibrational spectra, Hydration

The assignment of the vibrational spectra of Xanthine and its derivatives theophylline, caffeine and theobromine, as proposed in [1], is of central importance for the study of these pharmacologically active molecules. However, some care should be taken in the sample preparation, since sample handling may affect the water content of samples. This is a very relevant issue, since it has been shown that water causes pseudopolymorphic transformations on both theophylline and caffeine, which affect their bioavailability and stability [2–5]. Both caffeine and theophylline can be crystallized under the dehydrated [6,7] and monohydrated forms [6,8]. The dehydrated form can be obtained commercially, while monohydrated forms are currently prepared from recrystallization in water. However, our studies show that anhydrous crystals can turn into the monohydrated ones by simple exposure to the humidity from surrounding atmosphere over a few days. A similar effect has already been described for ␣-cyclodextrin [9] and glucose [10], for instance. The dehydrated and monohydrated forms have quite different vibrational spectra, in result of the reorganization of the crystal packing—which implies a new network of intermolecular contacts [6–8]. Figs. 1 and 2 compare the FT-IR and FTRaman spectra of theophylline, in the anhydrous and monohydrated forms, respectively. The vibrational spectra of the monohydrated form is identical for the samples obtained from water recrystallization and from exposure of the anhydrous crystals to high relative humidity during a couple of days. ∗ 1

Corresponding author. Tel.: +351 234 370 729; fax: +351 234 370 084. E-mail address: [email protected] (P.J.A. Ribeiro-Claro). Tel.: +351 239 826 541; fax: +351 239 826 541.

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The comparison with Figs. 1 and 2 shows that the vibrational spectra of theophylline shown in Fig. 3 of Ref. [1] correspond to two different samples. In fact, the FT-IR spectrum (Fig. 3 [1], top) clearly refers to the monohydrated form, while the Raman spectrum (Fig. 3 [1], bottom) corresponds to the anhydrous sample. Since the authors state that the samples had been obtained commercially with high grade purity and used as such [1], it can be assumed that the Raman spectra was obtained from a “fresh” sample, while the sample for FT-IR was left in contact with atmosphere humidity for a few days before recording the spectrum. The description of IR and Raman spectra of different samples as “vibrational spectra of theophylline”, and their use as such, has two main effects: it can be misleading for future readers and it has been misleading to the authors themselves. In fact, there are several relevant changes in the positions and intensities of the vibrational bands from one form to another, which were not detected by the authors. The assignments present in Table 4 of [1], as well as the proposed correspondences between IR and Raman bands, must then be taken with caution. The structural changes occurring upon hydration of theophylline can be observed from the X-ray structures of anhydrous and monohydrated crystals [7,8]. The major change occurs in the hydrogen-bonding network. In the hydrated form, all the hydrogen bond acceptor atoms participate in the hydrogen bond network. The N(9) acceptor atoms are bonded to the water molecules and the carbonyl O acceptors are involved in N–H · · · O(6) and C–H · · · O(2) hydrogen bonds. In the anhydrous form, there is only an extensive N(7)–H · · · N(9) hydrogen bond network, leaving the carbonyl groups “unoccupied”. These changes have a direct effect on the corre-

P.J.A. Ribeiro-Claro, A.M. Amado / Spectrochimica Acta Part A 61 (2005) 2796–2797

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sponding vibrational spectra. In the region of the carbonyl stretching mode, the Raman spectrum of the anhydrous form presents two strong bands (1665, 1707 cm−1 ) while only one is observed for the hydrated form (1687 cm−1 ). In addition, the band assigned to the C(8) H stretching mode moves from 3123 cm−1 in the anhydrous form to 3109 cm−1 in the monohydrated form, as a result of the formation of a C–H · · · O hydrogen bond [11].

References

Fig. 1. FT-IR spectra of monohydrated (top) and anhydrous (bottom) forms of theophylline.

Fig. 2. FT-Raman spectra of monohydrated (top) and anhydrous (bottom) forms of theophylline.

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