KINETIC OF THERMAL DECOMPOSITION OF DICLOFENAC SODIUM UNDER NON-ISOTHERMAL CONDITIONS

ABSTRACT

The thermal methods of analysis are widely employed in the study of stability and thermal decomposition of substances used in medicine, especially drugs.

Kinetic studies have become a crucial point in thermal analysis, in which the main purpose is to determine the mechanism(s) of decomposition and to calculate the parameters of the Arrhenius equation.

This work reports the kinetic study of the thermal decomposition of the diclofenac sodium, drug and tablets, performed under non-isothermal conditions, using 5, 7, 10 and 15^oC min^-1 heating rates and a nitrogen dynamic atmosphere.

The kinetic parameters were obtained from TG curves using the following methods: Friedman, Ozawa-Flynn-Wall, Coats-Redfern and Madhusudanan.

TG/DTG curves and the kinetic data showed that the diclofenac sodium drug is thermally more stable than the tablets. The decrease in stability was attributed to the presence of excipients.

Keywords: thermal stability, diclofenac sodium, TG/DTG, kinetic study, kinetic parameters.

INTRODUCTION

The thermal analysis techniques are used to characterize the 646b121g samples behaviour based on temperature. These methods include TG, DTG, DTA, DSC etc. It is well known that under a heating treatment the solid compounds suffer processes of thermal decomposition in one or more stages, according to the complexity of their structures.

The thermal analysis, which studies these processes, is a routine method for the medicine study and the study of the substances of pharmacological interest [ ].

For example, regarding the study of the stocking time which usually takes weeks or months, the kinetic analysis allows getting some data quick by heating the sample and hurrying its decomposition processes. This procedure needs only one stage of the decomposition reaction and an exigent static analysis [ ].

Even though these techniques can't replace completely the classical stability program which implies long observation time, they can foresee, on the other hand, an earlier alarm of the dangerous problems which would appear during high temperatures and this could indicate the most favourable ways to form a good formulation.

Actually, it is well known that during high temperature, the medicine chemic reactivity, the active compounds chemic reactivity in pure substance as in mixture, may be modified giving uncontrollable reactions, with later dangerous situations.

In conclusion it is imperative to determine the thermal stability, more clearly the temperature level above which a substance doesn't decompose itself at a high speed.

Regarding the evaluation of the kinetic parameters there are two opinions:

the kinetics parameters have a physical meaning and can be used to help understand the reaction's mechanisms in solid phase;

the kinetics parameters have not a physical meaning but can help foresee the speed of the processes in dangerous conditions as for example a very high temperature.

May seem agreed that the kinetic calculation can't be the most efficient means of determining the reaction mechanisms, even though these can be used to draw some reasonable conclusions.

Lately, a lot of authors made a real progress regarding kinetic analysis [ ].

The diclofenac, the [2−[(2,6−dichloro−phenyl)amino]−phenyl]acetic acid is a non− steroidal, anti−inflammatory medicine used in inflammation (infectious) and painful cases of rheumatic and anti−rheumatic origin. Actually, it is an anti−inflammatory, analgesic, antipyretic and anti-rheumatismal. Mostly, it is sold as a sodium salt (Fig.1.).

Fig.1. The chemical structure of the sodium salt of [2-[(2,6-dichlorophenyl)amino]-phenyl acetic acid

The literature studies regarding diclofenac are referring mostly to the preparation and the characterization of some of its salts, of its polymorphism, as to finding the melting point [ ].

The purpose of this paperwork is to study the thermal decomposition of the diclofenac sodium drug and tablets and to evaluate its thermal stability in solid stage.

Therefore, the kinetic parameters of the thermal decomposition have been determined, too, they representing criterion for the quality control of a product as well as the estimation of its thermal stability.

This work is in connection with a recent work [...], regarding the thermal behaviour of the same pharmaceutical products.

MATERIAL AND METHODS

The substances subjected to thermal analysis were the sodium salt of diclofenac sodium drug or active substance (AS) and the diclofenac sodium tablets (M).

The substance (drug) was available as pure compound, able to be used for medical purposes. It was obtained from Terapia S.A. / Ranbaxy, Cluj-Napoca, Romānia. Purity of this compound met requirements of European Pharmacopoeia. The pharmaceuticals (tablets) were commercial products, containing different (qualitative and quantitative) excipients.

TG/DTG experiments were performed with a TGA 7 Perkin-Elmer thermobalance, in the temperature range of 25-500^oC, under a dynamic atmosphere of nitrogen at a flow rate of 50 ml min^-1. Samples with the mass in the range of 5 to 20 mg were put into platinum crucibles, at a heating rate, β, of 5, 7, 10 and 15°C min^-1.

RESULTS AND DISCUSSIONS

Some of the thermal curves of the two substances, obtained under dynamic temperature condition are presented in Fig.2−3.

Fig. 2. The TG and DTG thermal curves of the diclofenac sodium AS.

Fig.3. The TG and DTG thermal curves of the diclofenac sodium M.

Kinetic analysis of decomposition process is traditionally expected to produce an adequate kinetic description of the process in terms of the reaction model and the Arrhenius parameters using a single-step kinetic equation:

(1)

where t is the time, T is the temperature and f(a) is the reaction model. The temperature dependence of the rate constant is introduced by replacing k(T) with Arrhenius equation, which gives:

(2)

where E (the activation energy) and A (the pre-exponential factor) are the Arrhenius parameters and R is the gas constant.

For non-isothermal conditions da/dt in Eq. 2 is replaced with β · da/dt where β is the heating rate giving:

(3)

The three components (f(α), E_a and A) called "kinetic triplet" define both in (2) and (3) a single-step reaction that disagrees with the multi-step nature of decomposition that usually occurs in solid state.

For compounds having complex structures, it can be hypothesised that several, steps with different energies will be involved.

If a process involves several steps with different activation energies, the relative contributions of these steps to the overall reaction rate will vary with both the temperature and the extent of conversion. This means that the effective activation energy, determined from the analysis of the results, will also be a function of these two variables. The use of Eqs. (2) and (3) determines reactions model that does not represent multi-step kinetics.

For this reason one cannot justify the establishment of the reaction mechanism from alone.

The thermal stability of the two substances was characterized by using the kinetic parameters as well, based on the kinetic study performed under non−isothermal conditions.

The kinetic parameters, the activation energy (E), the pre−exponential factor (A) and the rate constant (k) were obtained from the TG curves, by using the differential methods, Friedman isoconversional [ ] and Flynn-Wall [ ] and Ozawa (Oz) [ ], respectively integral methods, Coats-Redfern (CR) [ ] and Madhusudanan (MD) [ ].

The differential isoconversional Friedman method is based on the following equation:

(4)

where: α is the conversion degree; f(α)- the Arrhenius equation conversion function; β- the heating rate; T- the temperature in K; A- the pre-exponential factor and E- the activation energy, in sense of Arrhenius equation.

For α=constant, the graphic representation of the β·dα/dT values, in comparison with the reciprocal values of the absolute temperature, leads to a line of a slope and intercept which permit the obtaining of the activation energy and of the A∙f(α) product. Evidently, if f(α)=(1−α)ⁿ then the graphic representation of the ln[A∙f(α)] values is against ln(1−α) should also be linear.

Indeed, under such conditions: A · f(a) = A · (1−a)ⁿ

and  ln [A·f(a)] = ln A + n ∙ ln (1−a (5)

The slope and the ordinate at the intercept obtained in this way allow determine the reaction order and the pre-exponential factor.

Ozawa method is based on the following equation:

(6)

The values of the activation energy obtained using the differential methods are presented in Table 1, for different conversion degrees.

Table 1. The values of the activation energy for diclofenac sodium, according to Friedman (Fd) and Ozawa (Oz) methods.

A weak variation of E vs. α is observed, indicating the existence of a relatively complex decomposition process as the thermal curves indicate too.

Coats−Redfern method is based on the following equations:

for n=1 (7)

for n≠ 1 (8)

Madhusudanan method uses the equations:

for n=1 (9)

for n≠ 1 (10)

The values of kinetic parameters calculated by means of the Coats-Redfern and Madhusudanan methods are presented in Table 2.

Table 2. Kinetic parameters of diclofenac sodium obtained by methods of Coats-Redfern (CR) and Madhusudanan et al. (Md)

CONCLUSIONS

There was performed a kinetic study under non-isothermal conditions, regarding the thermal decomposition of the diclofenac sodium active substance and pharmaceuticals.

The TG/DTG curves of diclofenac sodium drug and tablets demonstrated the decrease of decomposition temperature when the drug was associated with excipients.

Four different methods were used to process the experimental data.

By comparing the values of the kinetic parameters from Tables 1 and 2, determined by the use of the four presented methods, their concordance is evinced, as well as the process of thermal decomposition takes place according to kinetics of first order, less in the case of Friedman's method.

The activation energies obtained with the integral methods were smaller than those found with the approximation methods.

The constant difference between the values of E and A, which values are higher in the case of diclofenac sodium active substance, indicates a somewhat higher thermal stability of the drug, as compared to the diclofenac sodium tablets.

The analysis of the obtained data shows possible interactions of the excipients with the diclofenac sodium. This aspect is confirmed by decrease in the pre−exponential factor and in the activation energy, as well as an increase in the rate constant of reaction for the diclofenac sodium tablets. That indicates a somewhat higher stability of the diclofenac sodium drug too.

It can be concluded that the kinetic study on the thermal decomposition can be used at the quality control of a product, together with the melting point which is mostly a preliminary identification parameter of the crystalline organic compounds and of getting their purity.

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