Thermodynamic and kinetic investigation of ...

http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–8 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2014.982824

RESEARCH ARTICLE

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Thermodynamic and kinetic investigation of agomelatine polymorph transformation Qi Zhang, Linglei Jiang, and Xuefeng Mei Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China Abstract

Keywords

Thermodynamic properties of polymorphic forms I and II of Agomelatine were investigated and the bimorphism was determined to be monotropically related. The phase transition kinetics from metastable form I to thermodynamically stable form II was studied and a quantification method was developed based on X-ray powder diffraction technique. Various solid-state kinetic models were examined and the results were fit to the experimental data. The nucleation kinetic models were found to be the best fit to describe the experimental data across the temperature range. The activation energy of the form transformation was calculated in the range of 116–122 kJ mol1, irrespective of which kinetic model selected.

Activation energy, kinetic, phase transformation, polymorph

Introduction Polymorphism is usually defined as the ability of a solid to exist in at least two crystalline phases that present different arrangements and/or conformations of molecules in the crystal lattice1. Polymorphism is ubiquitous in pharmaceutics. It was reported that more than half of the drugs on the market exhibit more than one crystal form2. In the meantime, throughout the drug development life-cycle, the active pharmaceutical ingredients (APIs) are subjected to various stress conditions, such as crystallization, compression or granulation. These manufacture processes or formulation processing may cause phase transitions during drug manufacture and storage, occasionally leading to altered physic-chemical property, less bioavailability or impaired efficacy profile3. Consequently, a comprehensive investigation of phase transition behaviors in polymorphic drugs was believed to be critical in the content of quality control, and hence, quantitative solid-state analytical methods and studies of polymorphic transition kinetics under various process conditions are needed to ensure that the polymorphic composition remains within accepted limits throughout the manufacture process and storage4,5. In recent years, polymorph transformation of crystalline drugs have been studied extensively using a varieties of analytical methods, such as differential scanning calorimetry (DSC)6–10, X-ray powder diffraction (XRPD)11–15, solid-state nuclear magnetic resonance spectroscopy (SS-NMR)16, Raman17–20 and FTIR spectroscopy21–23. Depending on the spectroscopic properties

Address for correspondence: Prof. Xuefeng Mei, Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang High-Tech Park, Shanghai 201203, China. Tel: +86 21 50800934. Fax: +86 21 50807088. E-mail: [email protected]

History Received 18 August 2014 Revised 23 October 2014 Accepted 28 October 2014 Published online 20 November 2014

of a particular substrate, employing more than one analytical method is encouraged to describe phase transition kinetics. Agomelatine (Figure 1) is an anti-depressant drug with a melatonergic receptor agonist (MT1/MT2) and 5HT2C receptor antagonist activity24. It was licensed in the UK for treatment of major depressive episodes in adults and marketed in the UK as Valdoxan. Agomelatine is currently undergoing phase III clinical trial in US25. Up to date, there are six different polymorphs of agomelatine have been reported, designated as forms IVI, respectively. Form I was first disclosed in 1992 by crystallization from a biphasic medium of H2O-CHCl326. Form I is easily accessible and was found to be prepared by other methods such as slow cooling27 and anti-solvent28, etc. Form II can be obtained from a slurry mixture of ethanol and H2O29. Form III was prepared by slowly cooling the melted agomelatine30. Form IV was prepared by cooling the melted agomelatine to 70 C and then hold for 5 h31. Forms V and VI were prepared by high-energy grinding32 and spray drying33, respectively. Form I and II were prepared by solution method, while forms II–V were prepared through melting or grinding, which were not favorable processes as far as stability and scale-up concerns. It was also found that form I has a greater solubility than the other forms34. Therefore, form I may presents some advantages if used in the drug product. However, employing a metastable form in drug development is risky and may present substantial challenges in processing and storage down the road. The extent of phase transition is usually determined by process and storage conditions, packaging, and also the magnitude of difference in relative free energy of the unstable form compared with stable form. A thorough understanding of the thermodynamic properties of different polymorphs is necessary. Investigation of phase transition kinetics is essential to establish key processing parameters, storage conditions, analytical methods, polymorph specification, etc. Furthermore, a comprehensive understanding of the impacts of form changes to

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Pharm Dev Technol, Early Online: 1–8

O O

N H


Figure 1. Structure of agomelatine.

the drug quality is mandatory to meet health authorities’ requirements for any new drug application (NDA). Although several polymorphs of agomelatine have been synthesized, there is no related polymorph study that has been reported. In this work, we first reveal the thermodynamic and kinetic properties of agomelatine polymorphs and develop a reliable analytic method for phase purity determination. After a detailed comparison of single crystal structure and thermal behaviors, thermodynamic relationship between form I and II were established. The effect of temperature on the transformation rates of form I to II was also investigated. The quantification of agomelatine form I and form II binary mixture and the phase transition kinetics from agomelatine form I to form II were monitored by XRPD. The polymorphic transition activation energy (116–122 kJ mol1) and the transition half-time at 25 C (29–58 d) of the transformation were found to be similar for the six best models, irrespective of the model selected. Such results indicated the risk of the transformation of metastable form during storage. Hence, if a metastable form was employed in drug development, its thermodynamic stability and phase transformation should be studied systematically to guide the manufacture and storage of the metastable form.

Materials and methods Samples preparation and crystallization experiments Agomelatine raw material (form I) was obtained from Zhejiang Huahai Pharmaceutical Company Limited, the polymorphic form was confirmed by thermal analysis and powder X-ray diffraction. Agomelatine form II was prepared by heating agomelatine polymorph I at 95 C in an oven for 1 h and subsequently cooling down to room temperature.

Figure 2. Overlay of unique molecules in the crystal structure of agomelatine form I (upper) and form II (below).

form I was confirmed by XRPD and DSC, the relative humidity was controlled being about 0%, the raw material form I was sieved and only particles in the size range of 10–20 lm were used and the sample thickness was also stayed the same (5 mm) by using carved glass models. Differential scanning calorimetry Differential scanning calorimetry was performed with a PerkinElmer DSC 8500 instrument. Samples weighting 3–5 mg were heated in standard aluminum pans at scan rates from 5 C /min to 50 C /min under nitrogen gas flow of 20 mL/min. Two-point calibration using indium and tin was carried out to check the temperature axis and heat flow of the equipment. X-ray powder diffraction XRPD patterns were obtained using a Bruker D8-ADVANCE X-ray diffractometer (CuKa radiation). The voltage and current applied were 40 kV and 40 mA, respectively. Samples were measured in reflection mode in the 2y range 3–40 with a scan speed of 1.2 /min (step size 0.025 , step time 1.0 s) using a LynxEye detector. All data were acquired at ambient temperature (20 C). Data were imaged and integrated with RINT Rapid and peak-analyzed with Jade 6.0 software from Rigaku. Calibration of the instrument was performed using corindon (Bruker AXS Korundprobe, Karlsruhe, Germany) standard.

Preparation of calibration standard mixtures The pure forms I and II were grounded in a ball-mill for 5 min. The possibility of any phase change occurred during sample treatment was discounted by testing a control sample before and after grinding. Binary calibration mixtures (100 mg) containing 0, 10, 20, 30, 40, 50 60, 70, 80, 90, 95, 95.5, 96, 96.5, 97, 97.5, 98, 98.5, 99, 99.5 and 100% of form I, with the remaining mass balanced by form II, were prepared by mixing of fixed combination of both polymorphic fine powder. Check standard mixtures containing 5, 20, 50, 70, 90, 97, and 99.25% of form I were prepared following the same sample preparation procedure. Analytical methodology Phase transition kinetic studies Phase transition kinetics of agomelatine form I to form II were studied under a range of temperature. The samples were preweighted and placed under 60, 80 and 95 C in an oven. The samples were periodically pulled out and subject for XPRD and DSC analysis. Content of polymorph form I in the sample mixtures was determined by comparison of the characteristic XPRD peak heights with regard to a predetermined calibration curve. In addition, for all the kinetic experiments, the purity of

Results and discussions Characterization and thermodynamic stability of agomelatine forms I and II Sample of agomelatine form I was obtained from Zhejiang Huahai Pharmaceutical Company Limited, the polymorphic form purity was confirmed by thermal analysis and powder X-ray diffraction. Agomelatine form II was prepared by heating agomelatine polymorph I at 95 C in an oven for 1 h. single crystal structures for both forms I and II were reported in the literature26,35. In the single crystal structure, agomelatine form I and form II shows both conformational and packing differences (Figures 2 and 3). The XRPD patterns of agomelatine form I and form II present readily distinguishable difference. Form I shows some characteristic peaks at 2y 10.8, 11.2, 11.9, 17.6, 18.4, 19.6, 19.8, 21.9 . Form II shows some different distinct peaks at 2y 9.4, 10.6, 12.7, 15.4, 17.3, 18.8, 19.1, 20.3 . A comparison of simulated and experimental XRPD patterns of agomelatine form I and form II are shown in Figure 4. The experimental XPRD data agrees well with the corresponding simulated patterns for both form I and form II. The results also demonstrate that the agomelatine form I and form II samples prepared were pure phase and did not contain any polymorph impurities.


DOI: 10.3109/10837450.2014.982824

Polymorphic forms I and II of agomelatine

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Figure 3. Two dimensional packing of form I (a) and form II (b) view down the a axis.

Figure 4. XRPD patterns of agomelatine Form I and Form II. (a) simulated pattern of Form I, (b) experimental pattern of Form I, (c) simulated pattern of Form II, and (d) experimental pattern of Form II.

Figure 5. DSC curves of agomelatine form I and form II (25 C/min).

Figure 6. Energy versus temperature diagram for agomelatine forms I and II.

The DSC diagrams for agomelatine form I and form II (heating rate of 25 C/min) were shown in Figure 5. Form I and form II presented sharp endothermic peaks corresponding to melting in DSC at temperature T ¼ 99.0 C and T ¼ 109.2 C, respectively. The heat of fusion of form I and II are measured as 108.24 J/g and 125.49 J/g, respectively. The heating rate was set at 25 C to prevent phase transformation of metastable polymorph form I, which will be discussed further below. From the DSC profiles, it could be derived that the melting temperature of form II (Tm, II ¼ 109.2 C) was higher than that of form I (Tm, I ¼ 99.0 C) and the heat of fusion of form II (DHf,II ¼ 125.49 J/g) was also higher than that of form I (DHf,I ¼ 108.24 J/g). According the heat-of-fusion rule36, form I and form II should be monotropically related with form II being the more thermodynamically stable form. From the DSC analysis, a schematic energy versus temperature diagram was depicted in Figure 6. In order to study the thermodynamic properties of form I, Hyper DSC was employed to study the metastable polymorphic form


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Figure 7. DSC curves of agomelatine form I at different scan rates.


transformation behaviors under a range of heating rates. The DSC diagrams of form I conducted at different temperature ramping rates were shown in Figure 7. Under a low heating rate, form I converted to form II completely. However, the phase transformation could be fully inhibited when elevated heating rate applied. As shown in Figure 7, when the scan rate was 1 C/min, form I presents a small endothermic peak followed by an exothermic transition at 97–100 C, corresponding to form I converts to form II. As the temperature ramping up, form II start to melt at temperature T ¼ 108.3 C. As the scan rate increased to 5 C /min, form I presents three endothermic peaks in DSC at temperature T ¼ 99.3, 100.5 and 108.2 C, respectively. At this heating rate, only a small portion of form I converted to form II. Consequently, form I melting endothermic peak can be clearly identified at temperature T ¼ 99.3 C. Furthermore, when the scan rate was set up to 25 C/min or higher, form I presented only one endothermic peak corresponding to the melting of form I at temperature T ¼ 99.3 C. Quantification of agomelatine form I and form II binary mixture

Figure 8. XRPD diffractograms of different agomelatine form I and form II binary mixtures.

The quantification of agomelatine forms I and II binary mixtures was performed at ambient conditions by XRPD. It is a generally accepted idea that particle size can affect XRPD measurement results. Hence, in order to minimize the particle size effect on the measurement, polymorphs of agomelatine were grinded individually in a ball-mill for 5 min for each sample. The possibility of any phase change occurring during grinding was discounted by testing a control sample before and after grinding. The XRPD patterns of agomelatine binary mixtures with different content of form I were shown in Figure 8. As the ratios of form I content increasing, the characteristic peak of form I at 2y11.8 increased gradually as well. Accordingly, the characteristic peak of form II at 2y9.2 decreased. The two characteristic peaks were then selected for quantification studies. A univariate quantification method was employed to establish a calibration curve37. The fractions of agomelatine form I was calculated according to Equation (1) using peak height or area, respectively. A response factor, K, was used to account for the difference in the response factor between the two forms. The factor K equals to the ratio of response of the two selected XRPD peaks when equal amount of sample was used. XA ¼

IA IA0 K¼ IA þ K 0 IB IB0

ð1Þ

Figure 9. Calibration curve for determination of the fraction of form I in mixtures using the form I and form II (a) peak height, and (b) peak area as per Equation (1).


DOI: 10.3109/10837450.2014.982824

The univariate calibration correlations for form I calculated using peak height and peak area were shown in Figure 9. A slightly greater linear correlation coefficient was achieved when the peak height data was used. In order to test the accuracy of the method, three check standard samples containing a range of

amount of form I were prepared and analyzed based on a predetermined calibration curve. The results were shown in Table 1. It was found that the measured results were agreed well using both peak height and peak area in the calculation. For convince, calculations based on peak height was chosen for calculations in the following discussion.

Table 1. The quantification of form I content in binary mixtures.

Kinetic evaluation of agomelatine form I to form II

Form I content (%) determined by Actual content of form I (%) Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Institute of Microbiology CAS on 03/07/15 For personal use only.

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99.25 96.98 90.07 70.02 49.88 19.94 5.05

XRPD (peak height)

XRPD (peak area)

99.31 ± 0.18 97.60 ± 0.18 89.98 ± 0.68 70.11 ± 3.09 49.59 ± 0.85 21.52 ± 1.14 3.83 ± 0.63

99.49 ± 0.35 98.25 ± 0.77 90.84 ± 2.03 70.90 ± 0.58 48.82 ± 1.26 23.67 ± 3.21 3.44 ± 1.32

Figure 10. Fraction of agomelatine from I transformed to form II against time at different temperatures.

It is well documented that there are two approaches widely utilized to obtain solid-state kinetic data, namely isothermal and non-isothermal approaches. Analysis of isothermal kinetic experiments is traditionally believed to be more reliable, because only one variable (usually is experiment temperature, T) is held constant during each experiment, thereby reducing the number of kinetic parameters that are determined simultaneously by fitting38. In this study, the isothermal experiments were employed to evaluate the kinetics of the transformation of agomelatine polymorph I to polymorph II. Based on the above pre-determined calibration curve (peak height), the content of polymorph form I can be derived according to the relative peak heights. The kinetics of agomelatine form I transformed to form II was carried out at different temperatures. The fractions of form I transformed to form II was calculated in the time range of 0–10 h at 60, 80, and 95 C, respectively (Figure 10). Various solid-state kinetic models27,39 were used to fit the experimental data. The correlation coefficients (Table 2), derived from different fittings, were used to evaluate the goodness of fit. Plots for the six best fit models (r240.9) are given in Figure 11(a–f). At low temperature (60 C), several different mechanisms fitted the data with good correlation, however, at higher temperature (80 and 90 C), only the nucleation models fitted the data well. To be more specific, at 60 C, the random nucleation process with two (n ¼ 1/2), three (n ¼ 1/3) or four (n ¼ 1/4) dimensional growth of nuclei (Avrami–Erofeev), and the Prout-Tompkins (B1) model are all fit the experimental data well. However, the Power law model with two (n ¼ 1/2), three (n ¼ 1/3) or four (n ¼ 1/4) dimensional gave better results at 80 and 90 C, respectively. Overall, according to the values of correlation coefficients, the nucleation kinetic models best describes the data across the temperature range.

Table 2. Correlation coefficients calculated for agomelatine form I to form II transformation for different kinetic models. Correlation coefficient (r2) Kinetic model Nucleation models Power law (P2) Power law (P3) Power law (P4) Avrami–Erofe’ev (A2) Avrami–Erofe’ev (A3) Avrami–Erofe’ev (A4) Prout-Tompkins (B1) Geometrical Contraction models Contracting area (R1) Contracting area (R2) Contracting area (R3) Diffusion models 1-D diffusion (D1) 2-D diffusion (D2) 3-D diffusion-Jander equation (D3) Ginstling–Brounshtein (D4) Reaction-order models First-order (F1)

Equation

60 C

80 C

95 C

a1/2 ¼ kt a1/3 ¼ kt a1/4 ¼ kt [ln(1 a)]1/2 ¼ kt [ln(1 a)]1/3 ¼ kt [ln(1 a)]1/4 ¼ kt ln a /(1 a) ¼ kt

0.956 0.953 0.952 0.965 0.964 0.964 0.966

0.945 0.958 0.963 0.914 0.937 0.946 0.957

0.955 0.967 0.972 0.878 0.920 0.938 0.938

a ¼ kt 1(1 a)½ ¼ kt 1 (1 a)i ¼ kt

0.957 0.957 0.957

0.894 0.865 0.853

0.902 0.840 0.810

a 2 ¼ kt (1 a)ln(1 a) + a ¼ kt [1 (1 a)1/3]2 ¼ kt [1(2a /3)] (1 a)2/3 ¼ kt

0.937 0.928 0.915 0.924

0.762 0.727 0.687 0.713

0.779 0.715 0.626 0.684

ln(1 a) ¼ kt

0.953

0.829

0.739

Q. Zhang et al.



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Figure 11. Isothermal transformation of agomelatine form I to form II: (a) Power law (P2), (b) Power law (P3), (c) Power law (P4), (d) Avrami–Erofeev, (A3), (e) Avrami–Erofeev, (A4), (f) Prout-Tompkins (B1). Key: (g) 90 C, () 80 C, (m) 60 C.

The Arrhenius equation has been widely used to describe temperature dependence of many thermally activated solid state processes, such as nucleation, nuclei growth and diffusion. Underlying theses thermodynamic transformation processes, two generally accepted principals are essential: First, a thermodynamic system must overcome a potential energy barrier in order for a change to occur; and second, the energy distribution along the relevant coordinate is governed by Boltzmann statistics [27]. The Arrhenius plots for analysis of phase

transition of agomelatine form I to form II using different kinetic models were shown in Figure 12. The activation energy and the transition half-time at 25 C calculated from Arrhenius plots for the six best models (with r240.9) were summarized in Table 3. It was found that the Arrhenius curves were approximately parallel, the activation energy (116– 122 kJ mol1) and the transition half-time at 25 C (29–58 d) derived were similar for the six best models, irrespective of the model selected.



DOI: 10.3109/10837450.2014.982824

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Figure 12. Arrhenius plots for agomelatine form I to form II transition using different kinetic models.

Table 3. Calculated activation energies, correlation coefficients and halftime for agomelatine form I to form II transition using six kinetic models.

Kinetic model

Transition Activation energy half-time Correlation 1 (t1/2, 25 C, d) coefficient (r2) (kJ mol )

Power law (P2) Power law (P3) Power law (P4) Avrami–Erofe’ev (A3) Avrami–Erofe’ev (A4) Prout-Tompkins (B1)

116.0 117.9 117.0 120.4 120.3 122.3

29.0 47.1 55.7 45.7 58.0 36.5

0.997 0.995 0.995 0.999 0.999 0.990

Conclusion The bimorphism of forms I and II of agomelatine was derived to be monotropically related according to the DSC experimental data. The phase transformation kinetics was fully investigated by isothermal experiments and various solid-state kinetic models were used to fit the experimental data. The results showed that the nucleation kinetic models best described the data across the temperature range. The activation energy (116–122 kJ mol1) and the transition half-time at 25 C (29–58 d) of the transformation were similar for the six best fitted models, irrespective of which model selected. Such results show that agomelatine form I is not stable under ambient conditions and should be stored under low temperature to slow down its transition to a thermodynamically stable form.

Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.

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