THERMAL BEHAVIOUR, AND DECOMPOSITION KINETICS OF NOREPHEDRINE HYDROCHLORIDE UNDER NONSOTHERMAL CONDITIONS

THERMAL BEHAVIOUR, AND DECOMPOSITION KINETICS OF NOREPHEDRINE HYDROCHLORIDE UNDER NONSOTHERMAL CONDITIONS

Laila Tosson Kamel

Narcotic Department, National Centre for Social and Criminal Research

Zamalek , 11561, Cairo, Egypt

Key Words: Thermal decomposition; Norephedrine hydrochloride; Thermogravimetric analysis; Model free kinetics; Master plot

ABSTRACT

The thermal decomposition of norephedrine hydrochloride was investigated by nonisothermal thermogravimetric analysis under nitrogen atmosphere at three heating rates 5,10,20^o Cmin^-1, where the determination of kinetic triplet (activation energy, pre-exponential factor, and reaction model), was the key objective. The activation energy was determined using different isoconversional methods, Friedman, Flynn-Wall-Ozawa (FWO), Kissinger-Akahira-Sunose (KAS), and Tang. The pre-exponential factor was calculated using Kissinger’s equation; while the reaction model was predicted by comparison of z-master plot obtained from experimental values with the theoretical plots. Isoconversional methods revealed negligible variation of E_a with the conversion, showing that the nonisothermal decomposition process of norephedrine hydrochloride follows a single-step reaction. The kinetic triplet determined was, activation energy, E_a = 121.09 kJmol^-1, pre-exponential factor, A=5.39×10^-4 min^-1 and the reaction kinetic model follows Gintsling equation (three dimensional diffusion)                       D4 model , f(α) = 16321-خ±1/3-1"> ,   g(α) = 161-2خ±3-1-خ±23"> .

INTRODUCTION

Norephedrine hydrochloride, (NE), (±)-α-(1-aminoethyl) benzene methanol hydrochloride, is a well-known over-the-counter drug, is a synthetic form of the ephedrine alkaloid that occurs naturally in plants of the genus Ephedra. It is structurally related to catecholamine neurotransmitters, such as dopamine and norepinephrine.  Pharmacologically, NE is a sympathomimetic amine, prescribed widely as a bronchodilator (McEvoy, 2006), it is a common ingredient in cough–cold medications. NE combined with caffeine is used as appetite suppressants, these diet pills including both, was removed from the market in 1983 because of abuse potential (Lasagna,1988). However, NE is still available in many countries, especially as a component of pharmaceutical products for the treatment of cold. NE adverse effects vary widely ranging from headache and elevated blood pressure to cardiopulmonary arrest, intracranial hemorrhage, and death (Martindale, 2005) . Now-a-day’s use of NE is avoided due to its side effects such as cardiovascular adverse, over stimulation of the nervous system, psychiatric illness and hypersensitivity reaction. Fig (1) shows the molecular structure of NE.

Fig.(1) The molecular structure of norephedrine hydrochloride

Thermal analysis refers to the study of the changes on a physical property of the sample as a function of time and/or temperature, while the substance is subjected to a temperature programming, and it enrolls a group of techniques (Wendlandt, 1986, Lever et al., 2014). Regarding pharmaceuticals, thermal analysis is an important tool for studying properties such as polymorphic forms, phase transitions, active–excipients interactions, shelf life determinations, thermal stability, and products formed during decomposition, as in the case of final destination of drugs by incineration. Thus, knowledge of thermal behavior mechanism is very important regarding all this information and can be easily achieved by thermal analytical techniques. There are numerous reviews and studies reporting the use of thermal analysis, in association with other techniques for drug characterization.(Kamel, 2015; Kamel, 2014; Level et al., 2014; Chieng et al., 2011; Nunes et al., 2009; Llinas and Goodman 2008; Abu‐Eittah, and  Kamel, 2003; Wendlandt, 1986)

In this work, decomposition of norephedrine hydrochloride was studied using  thermogravimetric analysis (TGA). The activation energy of decomposition was estimated using isoconversional methods, the value of pre-exponential factor was calculated using Kissinger’s equation, and reaction model was predicted using z-master plot.

MATERIALS

Norephedrine hydrochloride (NE) of at least 98% purity was purchased from Sigma Chemical Co. (St. Louis, MO, USA).

INSTRUMENT

The TG and DTG, curves were obtained by Shimadzu TGA-50 thermobalance, under nitrogen atmosphere gas at a flowing rate of 20 mL/min, at heating rates 5, 10, and 20°C min^-1 with an average mass of samples, 8.084, 12.483 and 7.852 mg respectively, contained in an alumina crucible. Temperature range was from ambient one to 500°C.

THEORY

The kinetics of solid-state decomposition is extensively studied by nonisothermal methods. In non-isothermal decomposition study, kinetic parameters or kinetic triplet (activation energy, pre-exponential factor and reaction model) are easily calculated from thermo-kinetic analysis. (Dollimore et al.,1996) summarized various existing reaction models which are given in Table (1). Heterogeneous solid-state thermal decomposition is generally expressed by,

16dخ±dt=K(T)fخ±">                                                                                         (1)

16dخ±dt=A exp- EaRTfخ±">                                                                          (2)

Where α is the degree of conversion and it increase from 0 to 1.

16خ± = mo-mtmo-mf">  where, m_t represents the mass of the sample at time t (or temperature T), whereas m_o and m_f  are the mass of the sample at the beginning and at the end of the process, respectively. 16dخ±dt">  is the conversion rate, T is the absolute temperature. k(T) is the reaction rate constant and it follows the Arrhenius equation k(T) = A exp(-E_a/RT), where A is the pre-exponential factor, E_a is the apparent activation energy and R is the gas constant, and β is the heating rate (β = dT/dt).  f(α) is the differential conversion function (reaction model). f(α) is the reciprocal of the differentiation of g(α) with respect to α. The forms of g(α) and f(α) for different models are listed in Table (1).

• Isoconversional Methods

The isoconversional methods are model independent that estimates the apparent activation energy at progressive degree of conversion by conducting multiple experiments at different constant heating rates are highly recommended for obtaining the reliable kinetic description of the investigated process. (Jankovic et al., 2009)

• Freidman method (FR) (Freidman,1964)

16lndخ±dtâ‰،lnخ²dخ±dT =lnAfخ±-EaRT">                                                             (3)

• Kissinger–Akahira–Sunose method (KAS)(Akahira et al., 1971, Kissinger, 1957)

16lnخ²T2=lnAEgخ±R-EaRT">                                                                     (4)

• 217                                                  Egypt. J. of Appl. Sci., 34 (11) 2019

  Flynn–Wall–Ozawa method (FWO)(Flynn and Wall, 1966; Ozawa, 1965)

16lnخ²=lnAERgخ±- 5.331-1.052ERT">                                                         (5)

• Tang method (Tang, 2003)

16lnخ²T1.894661=lnAEaRgخ±+ 3.635041-1.894661lnEa-1.001450EaRT (6)">

The plots of dα /dt versus 1000/T (FR), lnβ/T² versus 1000/T (KAS), lnβ versus 1000/T (FWO) and 16lnخ²T1.894661">  vs 1000/T (Tang) corresponding to different conversions α can be obtained by a linear regression of the least square method respectively.

• Prediction of reaction model: z-master plots

Master-plot method is found to be one of the most accurate methods which is highly insensitive to experimental conditions. The reaction model, g(α) was predicted using z-master plot method (Vyazovkin et al., 2011). Master plots, are the theoretical curves that depend on the kinetic model of the reaction, but are independent of the kinetic parameters. They can be of integral and differential form. An experimental data set was used to create a master plot, which was compared with theoretical master plots of standard solid-state reaction models, Table (1). The appropriate reaction model was selected as the one showing closest fit with the experimental plot. z-master plots are a combination of integral and differential forms of reaction model,

16zخ±=fخ±gخ±">                                                                                    (7)

The experimental data is described in the following form Eq.(8) and compared with theoretical standard plot Eq. (7) corresponding to each model,

16zخ±د€xخ²dخ±dt T "> (8)

where, x = E_a/RT and π(x) is the integral term solved by Senum-Yang approximation (Senum and Yang, 1977).

16د€x=x3+18x2+88x+96x4+20x3+120x2+240x+120">                                                               (9) 

• Calculation of pre-exponential factor: Kissinger method

Although the isoconversional methods provide the values of activation energy very accurately, they do not yield pre-exponential factor or the reaction model of the solid state reactions. For determination of both activation energy and pre-exponential factor, the Kissinger’s equation (Kim, 2010; Yuan et al., 2017; Dhyana  et al., 2017) can be given as,

16lnخ²Tm2=-EaRTm+lnAREa">                                                                        (10)

where T_m is the peak temperature of the DTG curve or the temperature at maximum conversion rate. Although Kissinger’s method is based on multiple heating programs, it yields only a single value of activation energy for the overall process.

Therefore, it was not used for calculation of activation energy. However, if the value of activation energy at each value of conversion is known, the pre-exponential factor can be calculated as,

16Aخ±=خ²Ea expEaRTmRTm2">                                                                                       (11)

In the current work, pre-exponential factor was determined by substitution of average activation energy calculated in Eq. (11).

Table (1) Differential and integral forms of known solid state reaction models

RESULTS and DISCUSSION

1- Characterization Results 

The TG and DTG curves of the thermal decomposition process of NE samples obtained at different heating rates (5, 10, 20^oC min^-1) under nitrogen atmosphere are shown in Figs (2 and 3) respectively. As shown in Fig. (2) TG curves are shifted to higher temperatures as the heating rates increases from 5 to 20^oC min^-1. The shapes of the curves are quite similar, all curves showed one decomposition step. There is no mass loss up to 198^oC, as temperature increases the TG curves exhibit a total mass loss in the temperature range 281-327.97^oC. Fig. (3) shows the DTG peaks of the thermal decomposition of NE.  Peaks become stronger and wider as the heating rate increases from 5 to 20^oCmin^-1 and the peak temperature is promoted from 263.9 to 282. 2^oC.It is evident from both curves (TG/DTG) that the thermal decomposition of NE exhibited only one single step reaction.

Figs.(4,5,6,7) shows the plots of ln(dα /dt) vs. 1000/T (FR), ln(β/T²) vs. 1000/T (KAS), lnβ vs. 1000/T (FWO), and 16lnخ²T1.894661">  vs. 1000/T (Tang), at the conversion range of (0.2 ≤ α ≤ 0.8) respectively. The activation energies E_a values are calculated from the slopes of the straight lines, are shown in Table (2). As shown that all the isoconversional methods yielded nearly similar values of activation energy,  (FR) E_{a, FR} = 112.39kJmol^-1, (KAS),  E_{a, KAS} = 120.18kJmol^-1  (FWO) E_a,FWO = 130.58 kJmol^-1, (Tang),  E_a,Tang = 121.23kJmol^-1.

Table (2) The activation energy of NE calculated by different methods

Fig. (8) shows the E_a vs. α plot , it is observed that regardless of the calculation procedure used, the activation energy E_a  remains partially constant ,that means, E_a does not depend on α. (Budrugeac et al, 2001; Budrugeac et al. , 2001; Sbirrazuoli et al. , 1997). This suggests that the nonisothermal decomposition process of NE follows a single step reaction. The lowest values were obtained by Friedman method. It should be noted that the Friedman method being dependent on the instantaneous rate of conversion is more prone to experimental noise. The values of activation energy, E_a obtained from KAS method almost superimpose those obtained from Tang method, where the FWO shows the highest E_a values.

It should be noted that these results are obtained without any knowledge of the reaction model function.

2- Pre-exponential Factor

The values of the pre-exponential factor, A is calculated by substitution of average E_a values obtained from Friedman’s method into Kissinger’s equation, show variation from 1.05×10^-3 to 2.16×10^-4 min^-1.

Fig (9) shows the dependency of the pre-exponential factor, A, vs. α using the Kissinger’s equation at the different heating rates. It is clear that the values show variation with the heating rates, following an increasing trend with the heating rate, indicating increase in collision intensity at high heating rates.

3-      Selection of Reaction Model

Fig. (10) shows the comparison of experimental z-master plot with the close range theoretical plots of different solid-state reaction models, Table (1). The experimental z(α) values have been calculated at the heating rates 5,10, 20°Cmin^-1, using the calculated apparent activation energy E_a values obtained from Friedman’s method, in conversion fraction range (0.20 ≤ α ≤ 0.80). It is evident that the data has a very close resemblance for the D4 model, Gintsling equation (three dimensional diffusion)

f(α) = 16321-خ±1/3-1">   , g(α) = 161-2خ±3-1-خ±23"> .

The differences between the experimental and the theoretical, D4 model, z(α)master plots are considered to be the inaccuracy of the approximation of the temperature integral by Senum and Yang.

In order to confirm the established reaction mechanism, the integral I composite method, was applied. The composite method presupposes one single set of activation parameters for all conversions and heating rates. In this way, all the experimental data can be superimposed in one single master curve. The composite integral method I (Budrugeac and Segal, 2005; Gabal, 2003) is based on the Coats–Redfern equation (Coats and Redfern , 1964)  which is rewritten as follows:

16lnخ²gخ±T2=lnAREa- EaRT=-EaRTm+lnAREa">                                            (12)

For each form of g(α), the curve 16 lnخ²gخ±T2">  vs 1/T was plotted for the experimental data obtained at different heating rates. The kinetic model that gives the best correlation coefficient where the data falls in a single master straight line is chosen.

Fig.(11), shows that all the different heating rate data are in only one master curve, this confirms that D4 model , Gintsling equation (three dimensional diffusion)

f(α) = 16321-خ±1/3-1">   , g(α) = 161-2خ±3-1-خ±23"> , best fits the decomposition process.

The following equation is used to confirm the most probable reaction mechanism                      

16lngخ±=lnAEaE+lne-xx2+lnhx-lnخ²">                                                    (13)

The degrees of conversion α corresponding to multiple rates at the same temperature are put into the left side of eq. combined with the types of mechanism functions Table (1), the slope k_m and the correlation coefficient r² are obtained from the plot of lng (α) vs. lnβ . The probable mechanism function is the one for which the value of the slope k_m is near to -1.000 and the correlation coefficient r² is the higher (He, et al., 2013).

Eq. (13) is used to confirm the D4 mechanism. The degrees of conversion for β = 5, 10, 20^oC min^-1 at the same temperature are shown in Table (3). The appropriate temperatures are randomly selected. The corresponding degrees of conversion of three temperatures are chosen. The slope k_m correlation coefficient r² of the linear regression of lng(α) vs lnβ are obtained. Results show that the D4 mechanism which belongs to the three dimensional diffusion, Gintsling equation, is the most adjacent to -1.000 and the correlation coefficients are the better which are shown in Table 3.

Table (3) The relation between temperature and conversion α at different heating rates β(^oCmin^-1) and lng(α) vs. lnβ curves of probable mechanism function

CONCLUSION

The kinetic analysis of NE was performed using thermogravimetry and isoconversional methods. The accuracy of both differential and integral methods were critically analysed.

FR method which gave an average activation energy of 112.35 kJmol^-1 was seconded as accurate as it is free from any mathematical assumption. The values of activation energy obtained from Friedman method were further used for calculation of pre-exponential factor, prediction of reaction model. The apparent activation energy, E_{a ,}was not really changed and was nearly independent with respect to the level of conversion (α). This suggests that the nonisothermal decomposition process of NE follows a single-step reaction.

The master plots z(α) method was used to define the most probable mechanism, f(α), for the investigated decomposition process. From the obtained results, it was found that the most probable reaction mechanism belongs to Gintsling equation (three dimensional diffusion) D4 model , f(α) = 16321-خ±1/3-1">   , g(α) = 161-2خ±3-1-خ±23">  . Integral I composite method confirmed the predicted reaction model.

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التحلیل الحراری الحرکی للنورإیفیدرین هیدروکلورید بواسطة

القیاس الحراری غیر المتساوی

لیلى طوسون کامل

المرکز القومى للبحوث الاجتماعیة والجنائیة

قسم بحوث المخدرات

یعتبرعقار النورإیفیدرین هیدروکلورید من العقاقیر شائعة الاستخدام، والتى تستخدم على نطاق واسع کموسع للشعب الهوائیة، فی أدویة السعال والبرد کما انه یضاف مع الکافیین  ویستخدم فى هذه الحالة کمثبط للشهیة، وبسبب سوء الاستخدام المفرط لهذه الحبوب فقد تم إزالها من الاسوق عام 1983. ولا یزال هیدروکلورید النورإیفیدرین  متاحًا فی الصیدلیات، کمکون من المنتجات الصیدلانیة لعلاج البرد ویتم الان  تجنب استخدامه بسبب آثاره الجانبیة الضارة له مثل الإفراط فی تحفیز الجهاز العصبی، والأمراض النفسیة ورد فعل فرط الحساسیة.

تهدف هذه الدراسة الى التعرف على خصائص النورإیفیدرین الهیدروکلورید فى دراجات حرارة عالیة لتعرف على خصائص العقار وکیفیة تکسیره ونموذج التفاعل ومعرفة طاقة النتشیط اللازمة لتکسیر العقار فى درجات الحرارة العالیة. تساهم هذه النتائج فى تطویر خصائص العقار فى المستقبل.

تم التحلل الحراری للنورإیفیدرین هیدروکلورید فى جو نیتروجینى لثلاثة معدلات تسخین، حیث تم تحدید (طاقة التنشیط، عامل ما قبل الأس، ونموذج التفاعل). تم تحدید طاقة التنشیط باستخدام Friedman و Flynn-Wall-Ozawa و Kissinger-Akahira-Sunose و Tang. تم حساب عامل ما قبل الأس باستخدام معادلة کیسنجر. بینما تم التعرف على نموذج التفاعل من خلال z-master. کشفت طرق الانحدار المتغایر تباین ضئیل من _aE مع التحویل، مما یدل على أن عملیــة التحلــــل تتبع رد فعل خطوة واحدة. طاقة التنشیـط، _aE= 121.09^-1 kJmol، عامل ما قبل الأس ، A = 5.39 × 10^-4 min^-1 ونموذج التفاعل الحرکی یتبع معادلة Gintsling (الانتشار ثلاثی الأبعاد) نموذج D4.