Influence of Temperature, Solvents, and Excipients on Crystal

Article pubs.acs.org/OPRD

Influence of Temperature, Solvents, and Excipients on Crystal Transformation of Agomelatine Yan Liu,† Huiru Gao,† Hao Xu, Fuzheng Ren,* and Guobin Ren* Laboratory of Pharmaceutical Crystal Engineering & Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 20037, People’s Republic of China S Supporting Information *

ABSTRACT: Agomelatine is a new and novel non-SSRI potential treatment option for major depressive disorders, discovered and developed by Servier Laboratories with first marketing approval in 2009. In this work, the solution-mediated crystal form I to II transformation process was studied. The influence factors, such as system temperature, crystallization solvents, and some pharmaceutical excipients, were investigated. DSC, XRPD, SEM, react IR, and in situ FBRM were used to monitor the transformation process. Compared with crystal form I of agomelatine, form II was the thermodynamic stable one, therefore, the transformation was a spontaneous process. By increasing the system temperature and/or the volume ratio of IPA in the solvent mixture, the transformation process would be accelerated. Lactose hydrate and HPMC would slightly inhibit the transformation, while PVP K30 would accelerate transformation process by increasing the solubility.

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INTRODUCTION Agomelatine (N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide, Figure 1) is a new and novel non-SSRI potential treatment

are used for the tablet formulation. However, the effect of the excipient on the physical stability tends to be neglected in the research. Process analytical technology (PAT) is an efficient tool to monitor the polymorphic transformation process.11−13 Brian O’Sullivan and co-workers14 combined the focused beam reflectance measurement (FBRM) probe and the react infrared (react IR) probe to monitor the polymorphic transformation process of D-mannitol. In this study, some factors of wet granulation process were investigated, such as heat,

Figure 1. Structure of agomelatine.

Table 1. Data of Melting Points and Heat of Fusion

option for major depressive disorders, discovered and developed by Servier Laboratories with first marketing approval in 2009.1,2 Agomelatine has several crystal forms,2 but the crystal form I and II materials were mainly used in pharmaceutical industry. The related research showed that, form II crystal was the thermodynamic stable one, the form I sample would gradually transform to form II. To ensure the crystal stability of form I in the tablet during its shelf life, the mechanism of transformation and effects of some excipient should be investigated. Polymorphism which is common in active pharmaceutical ingredients (APIs), is the ability of a substance crystallization into more than two crystalline forms.3,4 For the different arrangements in crystal lattices, different polymorphs of APIs have various stability, solubility, and bioavailability.5−7Generally, the thermodynamic stable crystal form would be selected for formulation. However, the thermodynamic metastable crystal with better solubility and bioavailability, would also be adopted for the pharmaceutical preparation.8 To ensure the safety of agomelatine tablet with the crystal form I as APIs, the crystal transformation must be avoided during manufacturing, transportation, and storage. Several factors, including crystallization and residual solvents, system and environment temperature, compress pressure,9 and pharmaceutical excipients,8,10 would affect the crystal stability of agomelatine. Pharmaceutical excipients are the indispensable inactive compounds, which © XXXX American Chemical Society

form I form II

Melting point (°C)

Heat of fusion (J/g)

99.51 109.36

104.37 130.87

Figure 2. DSC spectra of crystal form I sample. (Heating rate 0.5 °C/min.) Received: March 14, 2016

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DOI: 10.1021/acs.oprd.6b00084 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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EXPERIMENTAL SECTION Materials. Agomelatine, obtained from Jinkang Co. Ltd., China, is 99% pure and in form II, verified by HPLC and XRPD, respectively. Form I sample was prepared by cooling crystallization in IPA/H2O, verified by XRPD. Isopropyl alcohol, purchased from Sinopharm Chemical Reagent Co. Ltd., China, was of analytical reagent grade, purity >99%. Deionized water was prepared in the lab by Ming-che D 24 UV, China. Lactose hydrate was provided from Meggle, Germany. Pregelatin starch and hydroxy propyl methyl cellulose (HPMC) were purchased from Shin-Etsu Chemical Co., Ltd., Japan. Polyvinylpyrrolidone K30 (PVP K30) was purchased from Sinopharm Chemical Reagent Co. Ltd., China. Apparatus and Instruments. X-ray Technology. XRPD (D/teX Ultra, Rigaku) with Cu Kα radiation at 40 kV, 40 mA was utilized to identity the crystal forms of agomelatine. The scanning rate is 20°/min over the range of 2θ = 5−45°. Thermal Analysis. DSC (Q2000, TA Instruments, USA) was used to measure the fusion enthalpies and melting points of these two forms. All samples were sealed into aluminum DSC pans with vented lids that were placed in sample cells under a dry nitrogen flow. Samples were scanned from 30 to 120 °C at a heating rate of 10 °C/min. Morphology Observation. Crystal morphologies were examined by SEM (TM-3000, Hitach) operating at 15 kV. The samples were mounted on a glass stub with double adhesive tape. Process Analytical Techniques. FBRM probe (Particle Track G400, Mettler Toledo, Switzerland) with a chord length measurement range of 1−1000 μm, was set as 10 s sampling intervals. React IR probe (React IR 15, Mettler-Toledo) was used with sampling intervals set as 15 s. The react IR system was calibrated using standard solutions. FBRM was used to monitor the change of chord length of particle, while react IR was utilized to record the change of concertation of solution. All transformation experiments were performed in a 100 mL Easy-Max vessel (Mettler Toledo, Switzerland) in conjunction with iControl Easy max software. The accuracy of temperature control on this system is 0.01 °C. Slurry Experiments. Slurry experiments were designed to investigate the influence of operating conditions in the solutionmediated transition (SMT) process. For each experiment, the saturated solution (mixtures of IPA and water) (∼75 mL) of form II crystal, prepared under set temperatures, was added to the vessel, and then preweighed form I crystal was added. Agitation speed was set at 200 rpm. The volume ratio of IPA to water and system temperature were investigated, respectively. In addition, it was assumed that the

Table 2. Experimental Conditions and Parameters Measured in This Experiment IPA/H2O (v/v)

T (°C)

approximate form I added at t = 0 (g)

approximate ttrans (min)

1:2

20.00

1.00

109

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Figure 3. Variation curve of particle counts and mean of chord length.

Figure 4. Solution concentration change of agomelatine.

solvent, and excipients. The FBRM and react IR were utilized to monitor the crystal transformation process of agomelatine in isopropanol−water mixture. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and scanning electronic microscope (SEM) were used to determine crystal form.

Figure 5. Comparison diagram of XRPD. (a) Two θ from 3°to 45°. (b) Two θ from 5°to 18°. B



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Effect of Pharmaceutical Excipients. During granulation process, the formulation components may positively or negatively influence the stability of polymorph. In order to understand the influence of pharmaceutical excipients on transform possibility and tendency, the slurry experiments containing APIs and different pharmaceutical excipients were designed. For each experiment, the saturated solution (mixtures of IPA and water) (∼75 mL) of form II crystal, prepared under set temperatures, was added to vessel. One kind of pharmaceutical excipient was added into saturated solution, and then preweighed form I crystal (∼2 g) was added. Agitation speed was set at 200 rpm. The volume ratio of IPA to water was 1:2. System temperature was set at 20.00 °C. Different pharmaceutical excipients were added respectively to investigate their influence on crystal stability of form I. The pharmaceutical excipients investigated were lactose hydrate, HPMC, and PVP K30.

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RESULTS AND DISCUSSION Thermodynamic Stability Between Form I and Form II. In this work, the form I and II agomelatine samples were detected by the XRPD, DSC, and SEM, respectively. The testing results are shown in Figures S1, S2, and S3. As the XRPD patterns shown, the experimental samples were in a good agreement with published data.2,15 The melting point and heat of fusion data of form I and II crystals were listed in Table 1. The solubility data of crystal form I and II materials were measured in the previous work.16 As the solubility data showed, the crystal form I has higher solubility than form II samples in all the selected solvents and solvent mixtures. The crystal form I sample was also detected by DSC under different heating rate, shown in Figures S4 and S5 and Figure 2. The results show that the second endothermic peak (∼108 °C) was obtained under the heating rate 5 °C/min. Under heating rate 0.5 °C/min (Figure 2), there was an exothermic peak at 100.49 °C between the melting points of form I and form II, which demonstrated the crystal form transformation was an exothermic process. Based on the relevant thermodynamic data and phenomenon, crystal form I and form II of agomelatine is the monotropic system and the transformation process from form I to form II would occur spontaneously. Kinetic Characteristics of Solvent-Mediated Transformation Process. Although the transformation from form I to form II was a spontaneous process, the kinetic characteristics of transformation would be influenced by slurry conditions. Because of various crystal morphologies and different solubilities, chord length and concentration of agomelatine would be expected to change during transformation process between these two crystal forms. The following experiment was developed to investigate the transformation process, and the basic experiment information was listed in Table 2. The relevant variation curve of particle counts was shown in Figure 3. The solution concentration of agomelatine in the slurry was shown in Figure 4. The proper agomelatine samples

Figure 6. Variation curve of particle counts and mean of chord length in experiments #1−3.

insertion of PAT analyzers had no influence in the nature of the polymorphic transformation mechanism.

Table 3. Experimental Conditions and Parameters Measured in Experiment #1−3a

a

expt. #

T (°C)

approximatel form I added at t = 0(g)

supersaturation ratio

104(xForm I − xForm II)

approximate ta+b (min)

approximate tc (min)

1 2 3

20.00 23.00 25.00

2.00 2.00 2.00

2.27 2.57 2.65

8.57 13.54 16.95

50 23 20

135 64 60

IPA/H2O = 1:2 (v:v). C



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recorded by react IR. As the part (a) curve of Figure 3 shows, the particle counts of suspensions, which represented the adding of form I materials, decreased continually. There was no crystal form change in stage (a). The stage (b) was an induction period of crystal form II, without change of chord length of suspensions and solution concentration, which were shown as Figures 3 and 4. Cardew and Dawey had related the platform value of solution concentration with rate-determining step.17 If the solution concentration platform value was closer to the solubility of metastable form, the nucleation and growth of the stable crystal would determine the rate of transformation. Conversely, the dissolution process of metastable crystal would be the rate-determining step, when the platform value is nearly to the solubility of stable form. In this case, the solution concentration platform value was solubility of form I approximately. According to the above conclusion, the nucleation and growth process of form II crystal was the rate-determining step. There was also no crystal form change in stage (b). In the stage (c), the nucleation and growth of form II crystal occurred. As Figure 3 shows, from the t = 60 min moment, the counts of the sized 0−150 μm crystals increased while the counts of the sized 150−300 μm crystals decreased. The decrease of mean chord length meant that the appearance of many small crystal nucleus. The characteristic peak of form II (2θ = 17.04 ± 0.2°) was first observed in the XRPD pattern of the separated sample. The suspensions were the mixture of crystal form I and form II, as XRPD pattern shown in Figure 5. The solution concentration remained at platform value, shown in Figure 4. The continual dissolution of form I would supply the driving force to the nucleation and growth of form II. After the t = 180 min moment, it would be considered as the final stage (d). The suspended form I crystal disappeared, and only the form II existed until the experiment final, as shown in the XRPD pattern shown in Figure 5. In this period, the counts of sized 0−10 μm crystal significantly decreased while the mean chord length increased, shown in Figure 3. As the suspended form I material was completely consumed, with the growth of form II crystal, the solution concentration and supersaturation level began to rapidly decrease, as shown in Figure 4. The crystal counts and mean chord length of the final form II product would also be influenced by the secondary process (aging, aggregation, breakage etc.). To summarize, the whole transformation process can be divided into four periods: (a) dissolution of the suspended form I material, (b) nucleation induction period of form II crystal, (c) the nucleation and growth of form II crystal at platform concentration, and (d) the growth and aging period of form II crystal. Influence of System Temperature. The results of the experiments performed in IPA/H2O (v:v = 1:2) under a variety of system temperature are presented in Figure 6, and summarized in detail in Table 3. Supersaturation ratio, S, calculated by eq 1, was determined by the relevant solubilities data16 of agomelatine form I and II in IPA/H2O (v:v = 1:2).


S=

were separated from the slurry at different time points and examined by XRPD, and the relevant diagram of XRPD was shown in Figure 5. As stage (a) in Figure 4 shows, at the beginning, the solution concentration of agomelatine increased rapidly until the dissolution equilibrium of crystal form I was achieved, which was

x FormI x FormII

(1)

Where x is the mole fraction solubility. Because the time taken in stage (a) was short and stage (a) had little effect in transformation process, stage (a) and stage (b) were combined as the induction period. D



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Table 4. Experimental Conditions and Parameters Measured in Experiment #4−6a expt. #

IPA/H2O (v:v)

approximate form I added at t = 0 (g)

104* xform IIb

4 5 6

1:1 1:2 1:3

2.00 2.00 2.00

44.1 6.7 1.4

a



2.28 1.86

6 50 100

81 136 420

At 20.00 °C. bxform II is determined by the relevant solubilities data16 of agomelatine form I and II in IPA/H2O.

Table 5. Effect of Excipients on Transformation Processa

a


expt. #

excipients

amount of excipients added (g)

1 2 3 4 5

none HPMC lactose hydrate PVP K30 PVP K30

0.75 0.75 0.15 0.75

In this case, Cs was equal to solubility of form I, and Ceq was equal to solubility of form II. Because the difference of these two forms solubility and coefficient (k) increased with increasing temperature, the crystal growth process accelerated. Influence of Solvent Composition. The results of the experiments performed at 20.00 °C under a variety of volume ratio of IPA to H2O are presented in Figures 7 and S6, and summarized in detail in Table 4. As the above experiments results show, the lower composition of IPA in solvent mixture resulted in longer transformation. As the composition of IPA decreased, the induction period increased from 6 to 100 min, while time-consuming in stage (c) increased from 81 to 420 min. In experiment #5 and experiment #6, supersaturation ratio (S) decreased from 2.28 to 1.86 with decreasing composition of IPA in solvent mixture. Therefore, with increasing of composition of IPA, the nucleation rate became faster, transformation accelerated, time-consuming in the induction period was shorter. In experiment #4, the supersaturation ratio was hard to measure, however, according to the shortest timeconsuming in the induction period, it was speculated that the higher supersaturation ratio was obtained in IPA/H2O (v:v = 1:1). In addition, as the composition of IPA decreased, the difference of these two forms solubility decreased, corresponding to slower transfermation. Effect of Excipients. The effect of lactose, HPMC, and PVP K30 on transformation agomelatine form I in solution was examined, and the relevant experiment conditions were outlined in Table 5. The distributions of chord length after the end of stage (c) was shown in Figure 8. The same batch of crystal product was used to omit the influence of properties of crystal. First, the measured parameters in expt. # 1−3 were listed in Table 6. HPMC. The corresponding variation curve of particle counts and mean of chord length in experiments #1−2 are shown in Figures 9 and S7. After adding HPMC, the time-consuming in stage (a) and stage (b) decreases to 8 min, but the time-consuming in stage (c) increases to 144 min, compared to experiment # 1. As Figures 8 and 9 show, during the stage (c), the small particles (150 μm) decreased; at the end of stage (c), the chord length decreased significantly. In such solvent system, the solubility of form II decreased from 0.00067 to 0.00046, and the solubility of form I decreased from 0.00155 to 0.00114, corresponding to the higher supersaturation ratio (S) and the lower difference of solubility, which

At 20.00 °C in IPA/H2O (v:v = 1:2).

Figure 8. Distribution of chord length in experiments #1−5.

As the above experiments results show, the lower temperature resulted in longer time in transformation. The induction period decreased from 50 min at 20.00 °C to 20 min at 25.00 °C, while the time-consuming in stage (c) decreased from 135 min at 20.00 °C to 60 min at 25.00 °C. According to the relevant solubility data of agomelatine and data recorded by react IR, the supersaturation ratio (S) increased from 2.27 in 20.00 °C to 2.65 in 25.00 °C, the difference of solubilities increased from 0.000857 to 0.001695. Generally, the nucleation rate is positively proportional to supersaturation ratio (S) according to crystallization kinetic principle. Therefore, with increasing temperature, the higher supersaturation ratio (S) is obtained, the nucleation rate is faster, corresponding to shorter induction period. During the growth process, growth rate (G) is positively proportional to coefficient of crystal growth (k) according to eq 2. G ∝ k*(Cs − Ceq)

(2)

Where G is crystal growth rate, k is coefficient of crystal growth, Cs is the concentration of supersaturation solution, and Ceq is the concentration of equilibrium solution.

Table 6. Influence of Excipients on Transformation of Agomelatine in Expt. # 1−3a expt. # 1 2 3 a

final mean

chord length

174.50 120.15 179.42

(μm)



104*xForm I

104*xForm II


104*(xForm I− xForm II)

15 8 22

71 144 156

15.5 11.4 13.0

6.7 4.6 6.6

2.31 2.47 1.97

8.8 6.8 6.4

At 20.00 °C in IPA/H2O (v:v = 1:2) ∼75 mL. E



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After adding lactose, the induction period increases to 22 min, and the time-consuming in stage (c) increases to 156 min. In such solvent system, the solubility of form II decreased from 0.00067 to 0.00066, the solubility of form I decreased from 0.00155 to 0.00130, the supersaturation ratio (S) decreased from 2.31 to 1.97, and the difference of solubility decreased from 0.00088 to 0.00064. Therefore, nucleation rate and growth rate became slow, corresponding to longer time-consuming in stage (b) and stage (c). PVP K30. Experiments with different amounts of PVP K30 were performed. The corresponding variation curve of particle counts and mean of chord length in experiments #4−5 are shown in Figure 11. And relevant parameters measured are listed in Table 7.


can explain the shorter induction time and longer time-consuming in stage (c). Based on the above discussion and result, HPMC inhibited the growth process of agomelatine form II to extend the time of transformation, but increased the supersaturation ratio to reduce the induction time. Lactose Hydrate. The corresponding variation curve of particle counts and mean of chord length in experiment #3 are shown in Figure 10.


Table 7. Influence of PVP K30 on Transformation of Agomelatinea expt. #

final meanchord length (μm)


4 5

176.15 191.58

12 8

a

approximate tc (min) 104*xForm II 64 41

6.8 7.5

At 20.00 °C in IPA/H2O (v:v = 1:2) ∼75 mL.

The results shown that the amount of PVP K30 increased, the induction period decreased from 15 to 8 min, and the time-consuming in stage (c) decreased from 81 to 41 min.

Figure 10. Variation curve of particle counts and mean of chord length in experiments #3. F



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Meanwhile, small particles (

Influence of Temperature, Solvents, and Excipients on Crystal

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