Thermal behaviour of pharmacologically active lithium compounds

Article abstract of DOI:10.1023/A:1010192020465

The thermal decompositions of a series of simple lithium compounds (carbonate, sulfate, acetate, citrates, aspartates and glutamates) currently used in the treatment of manic-depressive psychosis and related disorders were investigated by means of TG and DTA measurements in oxygen atmosphere. Pyrolysis residues were characterized by infrared spectroscopy. The stabilities of the hydrates and intermediate phases generated during the degradation processes are discussed.

Full text of DOI:10.1023/A:1010192020465

Journal of Thermal Analysis and Calorimetry, Vol. 61 (2000) 29–35
THERMAL BEHAVIOUR OF PHARMACOLOGICALLY
ACTIVE LITHIUM COMPOUNDS
G. E. Tobón-Zapata, E. G. Ferrer, S. B. Etcheverry and E. J. Baran*
Centro de Química Inorgánica (CEQUINOR), Facultad de Ciencias Exactas, Universidad Nacional
de La Plata, C. Correo 962, 1900-La Plata, Argentina
(Received July 14, 1999)
Abstract
The thermal decompositions of a series of simple lithium compounds (carbonate, sulfate, acetate, ci-
trates, aspartates and glutamates) currently used in the treatment of manic-depressive psychosis and
related disorders were investigated by means of TG and DTA measurements in oxygen atmosphere.
Pyrolysis residues were characterized by infrared spectroscopy. The stabilities of the hydrates and
intermediate phases generated during the degradation processes are discussed.
Keywords: lithium drugs, thermal decomposition, thermal stability
Introduction
The effectivity of lithium compounds in the treatment of affective disorders and
manic-depressive psychosis has been well established [1–4], whereas recent investi-
gations also point to the possible essentiality of this element [3, 5].
Although lithium carbonate is the most frequently used lithium drug, other com-
pounds have also been used or tested, and some of them are commercially distributed
by the pharmaceutical industry [2, 6].
As part of our studies on the physicochemical properties of this type of drugs
[7, 8], we have now investigated the thermal behaviour of all of the compounds so far
suggested as being useful in medicine.
Although a certain amount of general information is available on the thermal be-
haviour of the sulfate and the carbonate [9], we have also re-measured these salts for
the sake of completeness in order to make comparisons with the other investigated
substances measured under the same experimental conditions.
Experimental
High-purity samples of lithium carbonate (Sigma) and lithium sulfate (Merck) were
used as provided. Lithium acetate was obtained by reaction between stoichiometric
*
Author to whom all correspondence should be addressed.
1418–2874/2000/ $ 5.00
Akadémiai Kiadó, Budapest
© 2000 Akadémiai Kiadó, Budapest
Kluwer Academic Publishers, Dordrecht

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TOBÓN-ZAPATA et al.: LITHIUM DRUGS
amounts of Li2CO3 and 50% acetic acid solutions, followed by slow evaporation of
the resulting solution at room temperature. Trilithium citrate was obtained in the fol-
lowing way: 0.95 g (4.5 mmol) of citric acid was slowly added to 0.50 g (6.77 mmol)
of Li2CO3 suspended in 10 ml of distilled water. The final pH ranged between 6.0 and
7.0. The solution was heated at 60°C during 30–45 min and then cooled. Well-formed
crystals were obtained after some weeks. The monolithium salt was obtained in a
similar way [8].
Lithium L- and DL-aspartates and the two investigated lithium L-glutamates (the
mono- and dilithium salts) were obtained by direct interaction of stoichiometric
amounts of Li2CO3 with aqueous solutions of the respective acids (ca 50 ml) [10]. Af-
ter the cessation of CO2 evolution, the solutions were heated during 3 h at 60°C and
then concentrated to 1/3 of the original volume in a rotary evaporator. After some
weeks, well-formed crystals were collected in all cases, which were dried between
filter-paper sheets.
The compositions of the different salts obtained were confirmed by elemental
analysis.
The thermal behaviour was investigated with a Shimadzu thermoanalytical sys-
tem (TG-50 and DTA-50 models), with compounds in platinum crucibles under a
constant oxygen flow of 50 ml min–1. The heating rate was 10°C min–1, with Al2O3 as
a DTA standard.
Infrared spectra were recorded on a Perkin Elmer 580 B spectrophotometer, the
KBr pellet technique being used.
Results and discussion
Li2CO3
The DTA curve obtained is shown in Fig. 1a. A very weak endothermic DTA peak
at ca 430°C is probably related to the known phase change (from the monoclinic
C2/C to an as yet unknown structure) [11]. This solid melts at around 730°C
[11, 12] and, as seen from the TG trace, CO2 loss begins at ca 800°C. The main
DTA signal, centred at 755°C, may be related to both processes.
Li2SO4×H2O
As shown in Fig. 1b, the thermolysis of this compound is rather simple. Water is
given off in the temperature range between 105 and 195°C (experimental mass
loss, 14.10%; loss calculated for 1 mol of water, 14.07%). This dehydration is re-
lated to the well-defined endothermic DTA signal centred at 148°C. The other two
observed DTA signals (594 and 865°C) correspond, respectively, to a phase
change of the anhydrous sulfate and to its fusion. In the older literature, the poly-
morphic transition is reported to lie in the interval 575–585°C and the fusion tem-
perature at 859°C [13].
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TOBÓN-ZAPATA et al.: LITHIUM DRUGS
31
Fig. 1 TG and DTA curves of a – Li2CO3; b – Li2SO4 H2O and c – Li(CH3COO) 2H2O
Li(CH3COO)×2H2O
The thermal curves of this compound (Fig. 1c) shows that the 2 water molecules
are released in a single step in the temperature range between 50 and 195°C, ac-
companied by two weak endothermic DTA signals, at 63 and 133°C (observed
mass loss, 35.55%; loss expected for 2H2O molecules, 35.35%). The anhydrous
acetate is stable up to ca 380°C; at this temperature, decomposition with the gen-
eration of Li2CO3 takes place. A mass loss of 28.46% is expected for this process,
in excellent agreement with the experimentally found value of 28.50%. This main
degradation is accompanied by a strong exothermic DTA signal at 438°C. The
other weak DTA signal found, at 730°C, is related to the fusion of the carbonate,
the presence of which in the final residue was confirmed by IR spectroscopy. In
the range of stability of the anhydrous phase, a weak DTA signal, observed at
287°C, may be related to a phase transition.
Li3(Cit)×5H2O
The thermal curves of this citrate is shown in Fig. 2. In this case, the water is released
in two steps. The first 2 molecules are given off between 97 and 130°C (mass loss,
11.90%; calculated loss, 12.00%). The other 3 molecules are given off up to 150°C
(mass loss found, 18.75%; calculated loss, 18.02%). These processes are related to
the endothermic DTA doublet at 95 and 124°C. Moreover, in this case the decompo-
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TOBÓN-ZAPATA et al.: LITHIUM DRUGS
Fig. 2 TG and DTA curves of Li3(Cit) 5H2O
sition of the anhydrous compound begins immediately after the dehydration and two
well-defined TG steps can be observed. Mass constancy begins at ca 330°C, and IR
spectroscopic analysis of the residues collected after heating up to 700°C clearly
demonstrates the generation of Li2CO3. Therefore, the full process can be repre-
sented by the following equations:
Li3(C6H5O7) 5H2O→Li3(C6H5O7) 3H2O+2H2O
Li3(C6H5O7) 3H2O→Li3(C6H5O7)+3H2O
2Li3(C6H5O7)→3Li2CO3+9CO2+5H2O
(1)
(2)
(3)
The total mass loss represented by the full degradation of the citrate to carbonate
implies a theoretical mass loss of 63.04%, which is in excellent agreement with the
experimentally found value of 63.4%. In the final degradation step, two weak exo-
thermic DTA signals can be observed, at 365 and 585°C.
As mentioned in the Experimental part, another salt of this type has been charac-
terized: lithium citrate monohydrate, Li(C6H7O7 H2O [8]; this is rather unstable and
highly hygroscopic, a situation which hampers its manipulation. Its thermal curves,
although scarcely reproducible, show that dehydration occurs in the temperature
range between 70 and 95°C, to the accompaniment of a weak endothermic DTA sig-
nal at 93°C. Degradation of the anhydrous compound starts immediately after dehy-
dration.
Li(DL-Asp)×H2O
As can be seen from Fig. 3a, this hydrate is rather stable, as the water molecule is re-
tained up to 178°C. Dehydration is completed at 195°C and the process is accompa-
nied by the endothermic DTA peak at 190°C. The experimentally found mass loss of
11.50% is in good agreement with the calculated value of 11.46%. After the water re-
lease, a rapid degradation of the sample takes place, generating a somewhat irregular
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TOBÓN-ZAPATA et al.: LITHIUM DRUGS
33
Fig. 3 TG and DTA curves of a – Li(DL-Asp) H2O and b – Li(L-Asp) H2O
and complex TG trace, but related to the appearance of a unique and very strong exo-
thermic DTA peak at 401°C. Constant mass is attained at around 470°C; no further
changes are observed up to 700°C. The IR spectra of the residues collected after treat-
ment at this temperature again show the presence of Li2CO3. The total decomposi-
tion, schematized as follows:
2Li(C4H6O4N) 2H2O→Li2CO3+7CO2+8H2O+2NO
(4)
implies a total mass loss of 76.41%, in agreement with the experimentally observed
value of 77.20%.
Li(L-Asp)×H2O
In this case, the dehydration begins earlier and covers a wider temperature range,
between 95 and 210°C (cf. Fig. 3b), with an observed mass loss of 11.70%. This
process is accompanied by a weak endothermic DTA signal at 185°C. The anhy-
drous species generated has a short stability range (of ca 50°C, between 210 and
260°C). The degradation of the anhydrous species occurs more quickly than for
the DL-aspartato complex, and constant mass is attained at around 450°C. The to-
tal observed mass loss is 77.63%, in agreement with expectations (76.41%), and
in this case too the IR spectra reveal formation of the carbonate. During this deg-
radation, a weak endothermic DTA signal (273°C) and a strong and sharp exother-
mic DTA peak (355°C) are observed.
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TOBÓN-ZAPATA et al.: LITHIUM DRUGS
Li(Glu)×2H2O
The TG curves of this compound is shown in Fig. 4a; it may be seen that the 2 water
molecules are released in a single step between 260 and 275°C (observed mass loss,
22.20%; loss calculated for 2H2O, 19.05%; the difference probably indicates that de-
composition of the anhydrous compound begins together with the release of water), a
process which is related to the weak endothermic DTA signal at 264°C.
Fig. 4 TG and DTA curves of a – Li(Glu) H2O and b – Li2(Glu) 2H2O
The subsequent degradation takes place in three well-defined steps, accompa-
nied by DTA signals at 327°C (weak, exo), 562/584°C (weak, exo) and 636°C
(broad, exo), and showing again the peak relating to the fusion of Li2CO3, the pres-
ence of which was confirmed in this case too by IR spectroscopy. The total mass loss
for
2Li(C5H8O4N) 2H2O→Li2CO3+9CO2+10H2O+2NO
(5)
is 80.45%, in excellent agreement with the experimentally observed loss of 79.50%.
Li2(Glu)×2H2O
For this compound, the water release occurs in two consecutive steps (Fig. 4b) be-
tween 50 and 300°C, with endothermic DTA signals at 82, 242 and 265°C. The ob-
served mass loss is 18.00% (calculated for 2H2O, 18.47%). Three consecutive steps,
extending up to 750°C, follow the dehydration process, involving a total mass loss of
63.50%, in agreement with the calculated one (62.10%). The final product is again
Li2CO3, as confirmed in this case too by IR spectroscopy and by the appearance of the
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TOBÓN-ZAPATA et al.: LITHIUM DRUGS
35
DTA signal related to its melting point. The last-mentioned three steps are accompa-
nied by the following DTA signals: 304 (weak endo), 321 (weak exo) and 688°C
(sharp exo).
Conclusions
Investigation of the thermal behaviour of a series of lithium-containing drugs by
means of TG and DTA measurements allows establishment of the stabilities of the
hydrates and the anhydrous compounds. In an oxygen atmosphere, all the lithium
salts of these organic acids were transformed to Li2CO3. However, the temperature at
which the carbonate is generated is highly variable: it occurs at relatively low temper-
atures in the cases of trilithium citrate (330°C) and acetate (380°C), and at very high
ones for the two glutamates investigated (ca 750°C). The carbonate produced remains
stable up to ca 800°C. In the case of Li2SO4 H2O, dehydration occurs up to 195°C and
the anhydrous compound remains stable up to at least 1050°C.
* * *
This work was supported by CONICET-Argentina and CIC-Provincia de Buenos Aires.
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