Solution-Mediated Polymorphic Transformation of Prasugrel

Mar 11, 2014 - The polymorphic transformation rate in a given solvent is affected by many operating parameters.(7, 18-21) At 278 K, α-mannitol requir...
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Solution-Mediated Polymorphic Transformation of Prasugrel Hydrochloride from Form II to Form I Wei Du,† Qiuxiang Yin,†,‡ Hongxun Hao,† Ying Bao,†,‡ Xia Zhang,† Jiting Huang,† Xiang Li,† Chuang Xie,†,‡ and Junbo Gong*,†,‡ †

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, People’s Republic of China ‡ Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin), Tianjin 300072, People’s Republic of China S Supporting Information *

ABSTRACT: In situ Raman spectroscopy was applied for the analysis of the solution-mediated polymorphic transformation of prasugrel hydrochloride from the metastable form II to the stable form I. The solution concentration during the transition process was monitored by a gravimetric method. The main factors studied were solvent, temperature, solid loading, and agitation speed. Because of the balance between the solubility and the strength of solute−solvent interactions, the transformation rate was highest in ethyl acetate and lowest in butanone at all three temperatures studied (20, 30, and 40 °C). The thermodynamic driving force of the polymorphic transformation from form II to form I was evaluated through solubility measurements of the two forms in ethyl acetate, acetone, and butanone. At increasing temperature, the nucleation induction time and the overall transformation time decreased despite the decreasing driving force. The solid loading seemed to have no effect on the transformation time because of surface nucleation of form I on form II, as determined from the morphology−time profile through polarizing microscope analysis, whereas increasing the agitation rate resulted in a faster polymorphic transformation process. It was confirmed by transformation experiments that the polymorphic transformation from form II to form I is controlled by the nucleation and growth of the stable form I crystal. solid phase, and (c) growth of the stable phase.3,11−13 Polymorphic transformations are not certain because of the complication of these three steps, each of which or a combination of which can be the rate-determining step. O’Mahony et al.14 summarized four principal scenarios in which dissolution, growth, dissolution−nucleation, or nucleation−growth can determine the overall transformation rate. They investigated the polymorphic transformations of carbamazepine and piracetam and found that the growth of the stable form controlled the transformation processes of both chemicals. Maher et al.5 studied the transformation of piracetam in ethanol and found that the transformation rate is governed by the nucleation and growth of the stable form. Cardew and Davey15 related the rate-determining step to the steady-state plateau region of concentration in the transformation process. If the plateau lies close to the solubility of the stable form, then dissolution of the metastable form will be the rate-determining step, whereas if the plateau lies close to the solubility of the metastable form, the growth of the stable form will be the rate-determining step. In a study of 2,6dihydroxybenzoic acid,16 Davey et al. provided a full description of the rate-determining process in the polymorphic transformation and found that secondary nucleation of the stable form dominated the process.

1. INTRODUCTION Polymorphism is a well-appreciated phenomenon related to the ability of a substance to crystallize in two or more distinct crystalline forms, each of which displays different functionalities and physical properties, such as bioavailability, stability, and solubility.1−3 Its importance is now widely recognized in the chemical and pharmaceutical industries because of the significance of consistency and reliability.4 Although the crystallization of an active pharmaceutical ingredient in a proper form is an important step in the manufacture of a pharmaceutical product, the stability of that form in the final product and during its shelf life is just as critical.5 Polymorphs of one compound exhibit a stability hierarchy whereby the stable form represents the lowest free energy for the system and others are termed metastable and have the tendency to transform into the stable form if possible.6 Two types of transformation mechanisms have been proposed in the literature,7−10 with solid-state polymorphic transformation (SST) taking place through the positional rearrangement of the ions or molecules in the solid state and solution-mediated polymorphic transformation (SMT) occurring through dissolution of the metastable phase and crystallization of the stable phase. It is essential to investigate the possible transformations in a polymorphic system and to understand the transformation mechanism under different conditions. Solution-mediated transformations can be described by three essential processes: (a) dissolution of the metastable solid, (b) self-recognition of the molecular units to nucleate a more stable © 2014 American Chemical Society

Received: Revised: Accepted: Published: 5652

December 16, 2013 March 6, 2014 March 11, 2014 March 11, 2014 dx.doi.org/10.1021/ie404245s | Ind. Eng. Chem. Res. 2014, 53, 5652−5659

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Nucleation of the stable form can be primary heterogeneous nucleation or secondary nucleation.6,16,17 Recently, the importance of the surface of the metastable form in nucleation has aroused much interest. Davey et al.16 speculated that a higher local supersaturation with respect to form 2 of 2,6dihydroxybenzoic acid (DHB) existed at the surface of form 1 because of dissolution, which can encourage heterogeneous nucleation of form 2 on the surface according to their morphological observation during DHB transformation experiments. Maher et al.5 confirmed the surface-mediated nature of the metastable form when they found that a smaller particle size of piracetam can facilitate the nucleation of the stable form because of the increase in the surface area of the metastable form. The polymorphic transformation rate in a given solvent is affected by many operating parameters.7,18−21 At 278 K, αmannitol requires 500 min to completely transform to β form, whereas at 313 K, only 50 min is needed for the completion of the transformation.7 In the case of piracetam,5 the driving force decreases with increasing temperature, whereas the kinetics is sufficiently increased with increasing temperature to then shorten the transformation time. Therefore, an increase in temperature can notably decrease the overall transformation rate. Zhao et al.21 investigated the influence of different amounts (0.17 and 0.2 g) of added imidacloprid on the transformation process from form II to form I in 100 mL of saturated ethanol solution under isothermal conditions at 65 °C. They found that the larger amount of substrate required a longer time to finish the transformation because the supersaturation was the same for the same temperature and solvent and the constant crystal growth rate. However, when the nucleation of the stable form is surface-mediated, higher loadings should not increase the overall transformation time because of the corresponding increase in the surface of metastable form.5,6 The chemical name of the model compound, prasugrel hydrochloride, is 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride. It has two polymorphs: Form I has a needlelike morphology, whereas form II has a platelike morphology. The relative stability of the two forms of prasugrel hydrochloride has rarely been studied, and in our previous study,22 concomitant polymorphs were produced under some certain conditions. To determine the relative stability of the two forms and to ensure that pure polymorphs are produced, it is necessary to study the polymorphic transformation process of this compound. In this study, the solubilities of the two forms were measured to estimate the thermodynamic driving force of the polymorphic transformation from form II to form I. Raman spectroscopy was used to monitor the polymorphic form in the solid phase, and a gravimetric method was applied to determine the concentration−time profile in the liquid phase. A polarizing microscope was used to observe the morphology−time profile during the polymorphic transformation process. The ratedetermining step and the effects of solvent, temperature, solid loading of form II, and agitation speed were examined.

Figure 1. Powder X-ray diffraction patterns of form I and form II of prasugrel hydrochloride.

Ethyl acetate, acetone, and butanone were purchased from Tianjin Kewei Chemical Co., Tianjin, China. All of the solvents were of analytical reagent grade, and the molar purities were >99.5%, as determined by high-performance liquid chromatography (HPLC; Agilent 1100, Agilent Technologies, Palo Alto, CA). 2.2. Process Analysis Tools. Powder X-ray diffraction (PXRD) (D/max-2500, Rigaku, Tokyo, Japan) was used to determine the polymorphic forms of the solids. Differential scanning calorimetry (DSC; model DSC 1/500, MettlerToledo, Greifensee, Switzerland) was used to monitor the melting processes of the two forms. Thermogravimetry (TG) was performed using a model TGA 1/SF thermogravimetric analysis system (Mettler-Toledo, Greifensee, Switzerland). A polarizing microscope (Olympus BX51, Tokyo, Japan) was used to observe the morphologies of the polymorphs. A Raman spectrometer (RXN2, Kaiser Optical Systems, Inc., Ann Arbor, MI) was used to determine the polymorphic forms in the solid state during the polymorphic transformation process. 2.3. Solubility Measurements. The solubilities of form I of prasugrel hydrochloride in ethyl acetate, acetone, and butanone were measured as functions of temperature in the range of 283−343 K. Excess amounts of form I were dissolved in 20 mL of solvent to saturate the solutions. The desired temperatures were controlled by a thermostatic bath (model 501 A, Shanghai Laboratory Instrument Works Co., Ltd., Shanghai, China) with an accuracy of ±0.05 K. After being stirred for 3 h at each temperature, the suspension was filtered through a 0.45-μm filter. The residue of undissolved crystals was separated and identified to be the initial polymorph by PXRD, indicating that no solution-mediated polymorphic transformation occurred during solubility experiments. Samples of the saturated solutions were dried at 313 K until the solvent was completely evaporated. The solubility was determined from the mass of the remaining crystalline material. The solubilities of form II in the same solvents cannot be measured by the same procedures as used for form I because of a relatively fast solution-mediated transformation from form II to form I. During the solution-mediated transformation, the general features of the concentration−time profile are described by three steps, as shown in Figure 2:12,13 (a) an increase in concentration because of the dissolution of form II, (b) a concentration plateau during which the nucleation and growth of form I are balanced by the dissolution of form II, and (c) a

2. EXPERIMENTAL SECTION 2.1. Materials. Form I and form II of solid-state prasugrel hydrochloride (supplied by Jiaxing Zhonghua Chemical Co., Ltd., Jiaxing, China) were used without further purification. They were both pure forms as identified by their powder X-ray diffraction (PXRD) patterns, which are shown in Figure 1. 5653

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mL crystallizer, and the slurries were agitated by an overhead paddle impeller. For each experiment, 8.00 g form II was added to 250 mL of ethyl acetate solution saturated with respect to form I at 40 °C. As the suspension was agitated at 250 rpm, the composition of the solid phase was monitored by in situ Raman spectroscopy, and the concentration of the liquid phase was determined using a gravimetric method. The solution was withdrawn at 5-min intervals using a syringe to a membrane filter (0.45 μm) and poured into a preweighed dish (the mass of a blank dish is denoted as m0). The dish with the clear solution was quickly weighed to determine the mass (denoted as m1) and placed in a blast oven (DZF-101, Beijing Scientific Instrument Co., Ltd., Beijing, China) at 40 °C. When the solvent had completely evaporated, the dish with the remaining crystalline material was reweighed to determine the weight (denoted as m2). These three masses (m0, m1, and m2) were measured using an analytical balance (AB-204, Mettler-Toledo, Greifensee, Switzerland) with an accuracy of ±0.0001 g. In this study, the induction time is defined as the time from the addition of form II to the sudden Raman intensity increase of form I, whereas the transformation time is defined as the time from the addition of form II to the point when the Raman intensity of form II decreased to a constant value.

Figure 2. Schematic profile of the concentration in solution as a function of time displaying the behavior of a metastable solid phase in contact with a solvent in which it transforms into a stable form.

decrease in concentration when form II has completely dissolved and form I still needs to nucleate and grow. The solubility of form II was studied in the temperature range of 283−343 K by in situ Raman spectroscopy. A slurry of form II was obtained by mixing 20 mL of solvent and 1.00 g of form II of prasugrel hydrochloride. Raman spectra were recorded at an interval of 1 min. During each experiment, a 5-mL sample of the clear solution was taken using a syringe with a membrane filter (0.45 μm) as soon as a decrease in the Raman intensity of form II was observed, indicating that the concentration plateau was established. This clear solution was dried at 313 K until the solvent was completely evaporated. The solubility of form II was determined from the mass of the remaining crystalline material. 2.4. Polymorphic Transformation Experiments. Experiments examining the solution-mediated polymorphic transformation from form II to form I of prasugrel hydrochloride were performed on scales of 50, 100, and 250 mL. The smallest-scale experiments were carried out to investigate the effects of solvent, temperature, and mass loading on the transformation. The effect of solvent was examined among ethyl acetate, acetone, and butanone at 298, 303, and 313 K to estimate the total transformation time. The effect of temperature was investigated between 283 and 313 K at increments of 5 K in ethyl acetate, allowing for an estimation of the time for form I to nucleate and the time for form II to finish the transformation to form I. The temperatures were controlled by the same thermostatic bath as used in the solubility measurements. For each solvent and temperature, 50 mL of solvent was initially saturated with respect to form I. An extra 2.0 g of form II was then added to the saturated solution. The slurry was agitated with a magnetic stirrer at the same rate. The transformation of form II to form I was monitored by in situ Raman spectroscopy to identify the solid forms in the slurry at an interval of 1 min. The effect of the mass loading of form II on the transformation rate was also investigated on a 50-mL scale. Three 50-mL samples of ethyl acetate solution saturated with respect to form I were prepared at 40 °C. The mass loading of form II in each crystallizer was increased from 2 to 5 g. The slurries were agitated by magnetic stirrer and monitored by in situ Raman spectroscopy. The effect of the agitation speed on the transformation rate was tested on a 100-mL scale. During each experiment, 3.00 g of prasugrel hydrochloride form II was added to 100 mL of ethyl acetate, and the agitation speed, controlled by an overhead paddle impeller, was varied from 200 to 600 rpm. The 250-mL-scale experiments were performed at 40 °C to establish the rate-determining steps in the polymorphic transformation. The experiments were carried out in a 300-

3. RESULTS AND DISCUSSION 3.1. Identification of Form I and Form II. Prasugrel hydrochloride form I is needlelike, and form II is platelike, as shown in the polarizing microscope images in Figure 3. Raman

Figure 3. Prasugrel hydrochloride crystal morphology: (a) needlelike form I and (b) platelike form II.

spectroscopy was successfully used to identify the crystalline forms, as shown in Figure 4. The Raman spectra of the two forms exhibit some distinct differences that can be chosen as the characteristic peaks for each form. In this study, the peaks at 1186 and 1695 cm−1 were chosen as the characteristic peaks of form I, and the peak at 1194 cm−1 was selected to monitor form II. Because of the fluorescence of prasugrel hydrochloride, the Raman spectra of both forms are slightly inclined upward, so baseline correlation of the data was employed for all spectra and the reported Raman intensities are relative intensities, defined as the peak height with respect to the two-point baseline. The melting processes of both of the forms are concomitant with decomposition, as shown in Figures S1−S3 of the Supporting Information. 3.2. Solubility and Thermodynamic Driving Force for the Polymorphic Transformation. The solubilities of polymorphs are important thermodynamic data for selecting a proper solvent and determining the relative stability of and relationship between different polymorphs. The solubility data for form I and form II in ethyl acetate, acetone, and butanone were determined experimentally. The results are presented in 5654

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profile during the transformation process is essential as well. Because of the low solubility of prasugrel hydrochloride and the detection limitations of in-line analysis tools, attenuatedtransform-reflectance Fourier transform infrared (ATR-FTIR) spectroscopy could not be applied in this study, whereas the off-line gravimetric method provides very important information about the liquid phase. First, Raman spectroscopy was applied to monitor the solid composition on a 250-mL scale at 40 °C until the process finished. Then, the experiment was repeated three times without Raman spectroscopy but with the gravimetric method. Figure 6 shows the concentration−time profile and the changes in the characteristic peaks of the two forms with time. The solution was saturated with respect to form II within a short period of time after the addition of form II. After 0.56 h, the characteristic peak of form II started to decline, and the peak of form I began to increase, indicating the end of the induction time and the beginning of the nucleation and growth of form I. A total of 1.32 h was required for the process to finish, as determined by the time when the peak intensities no longer changed. The liquid concentration remained at the equilibrium solubility of form II for about 0.92 h, after which it decayed gradually, requiring 1.5 h for the solution to reach the solubility of form I. According to the four scenarios described by O’Mahony et al.,14 the polymorphic transformation process of prasugrel hydrochloride from form II to form I is controlled by the nucleation and growth of form I. 3.4. Effects of Operating Parameters on the Polymorphic Transformation of Prasugrel Hydrochloride. Effect of Solvent on the Polymorphic Transformation Rate. Ethyl acetate, acetone, and butanone were used to examine the influence of the solvent on the transformation time of prasugrel hydrochloride, which is defined as the time from the addition of form II to the point when the Raman relative intensity of form II declined to a constant value. Differences in solvents have a significant influence on the transformation time, especially in solution-mediated polymorphic transformation processes. Solubility is important in determining the transformation time, which is shorter in solvents providing higher solubilities. From Figure 7, it is clear that the induction times of nucleation of form I at the same temperature differed dramatically for the three tested solvents, indicating that the nucleation rates of form I in the three solvents are very different. The influence of solubility on the nucleation rate of form I can be explained by the classical nucleation rate theory, in which the nucleation rate can be written as

Figure 4. Raman spectra of form I and form II of prasugrel hydrochloride.

Tables S1−S3 and Figure S4 in the Supporting Information and in Figure 5, where each point is the average saturation concentration of three measurements. The solubility of form II was found to be higher than that of form I in the tested solvents at the experimental temperatures. According to the thermodynamic rule,1,23 form II is the metastable form, and the two forms have a monotropic relationship. It can also be seen that the solubilities of the two forms and the solubility difference between the two forms increase with increasing temperature. The thermodynamic driving force (ΔGII→I) for the polymorphic transformation from form II to form I, defined as the Gibbs free energy difference1 between the two polymorphs, can be written as ΔG II → I

⎛f ⎞ ⎛x ⎞ ⎛α ⎞ = RT ln⎜⎜ I ⎟⎟ = RT ln⎜ I ⎟ ≈ RT ln⎜ I ⎟ ⎝ x II ⎠ ⎝ αII ⎠ ⎝ fII ⎠

⎛ ΔG*φ ⎞ ⎟ J = N0V exp⎜ − ⎝ kT ⎠

(2)

where J is the number of nuclei formed per unit time per unit volume, N0 is the number of solute molecules per unit volume, V is the frequency of molecular transport at the nucleation liquid interface, φ is the heterogeneous nucleation factor, k is the Boltzmann constant, and T is the absolute temperature. The critical free energy barrier for nucleation, ΔG*, is given by

(1)

where f is the fugacity, α is the thermodynamic activity ratio, x is the equilibrium mole fraction, and T is the temperature (K). As shown in Figure 5d, the values of ΔGII→I in ethyl acetate were all less than 0, indicating that the transformation process occurs spontaneously. The absolute value of ΔGII→I was found to decrease with increasing temperature, which means that the driving force decreases with increasing temperature. 3.3. Measurement of the Rate-Determining Step in the Polymorphic Transformation. The polymorphic transformation process of prasugrel hydrochloride from form II to form I was monitored successfully by Raman spectroscopy in the solid phase, but knowledge of the concentration−time

ΔG* =

16πv 2γ 3 3(kT )2 (ln S)2

(3)

where v is the molecular volume of the solute; S is the supersaturation ratio; and the interfacial energy, γ, can be written as γ = 0.414kT (csNA )2/3 (ln cs − ln ceq) 5655

(4)

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Figure 5. (a−c) Solubility and (d) thermodynamic driving force of the polymorphic transformation: (a) ethyl acetate, (b) acetone, (c) butanone, (d) ethyl acetate.

at the same temperature. The value of φ is mainly determined by the affinity between the prenuclei of form I and the suspended particles if form II, so it should be identical in the three solvents. N0 is equivalent to the concentration of solute molecules in the solution and is thus greater in a solvent giving a higher solubility. The value of V is mainly determined by the agitation rate, which was designed to be constant in different experiments. The γ value is inversely proportional to the natural logarithm of the solubility according to eq 4. Therefore, in the solvent that gives a higher solubility, N0 is greater in eq 1, and γ is smaller in eq 4, whereas the other factors remain identical, leading to a greater value of J in eq 2, corresponding to higher nucleation and transformation rates. According to Figures 5 and 7, the solubility of form I in acetone is higher than that in butanone, so the nucleation rate and overall transformation rate are higher in acetone than in butanone. However, the situation in ethyl acetate does not follow this rule: The solubility of form I is lowest in ethyl acetate, so the nucleation and transformation rates should be lowest in this solvent, which is contradicted by the fact that the nucleation and transformation rates in ethyl acetate are actually the highest among the three solvents. These counterintuitive results indicate that solubility is not the only factor that determines the nucleation rate and transformation time. From Figure 5d, the driving forces in the three solvents are not the same at the same temperatures, which suggests that the solutions are not ideal. Thus, solute−solute and/or solute−

Figure 6. Solution-mediated polymorphic transformation from form II to form I of prasugrel hydrochloride in ethyl acetate at 40 °C. The solution concentration profile, as measured by the gravimetric method, and the polymorphic transformation, as measured by Raman spectroscopy, are indicated. (▲) Concentration of prasugrel hydrochloride in the liquid phase.

where cs is equal to the ratio of the density of the solute to the molar mass of the solute, NA is Avogadro’s number, and ceq is the equilibrium solubility. Because S is fixed by the free energy difference between form I and form II, it should have the same value in different solvents 5656

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bond-donation (HBD) ability α, and the hydrogen-bondacceptance (HBA) ability β. The values of α and β of the three solvents are listed in Table 1.24 From Table 1, it can be seen that there is no significant difference among the HBA abilities of the three solvents, but both the HBD ability and the dipolar polarizability of ethyl acetate are the lowest among the three solvents, which suggests that the interaction between prasugrel hydrochloride and ethyl acetate ight be the weakest. It can be speculated that the weakness of the ethyl acetate−form I interactions might be enough to compensate for the lowest nucleation rate in ethyl acetate. Thus, the balance of the solubility and the strength of the solute−solvent interactions determines the total transformation time from form II to form I of prasugrel hydrochloride. Effect of Temperature on the Polymorphic Transformation Rate. The influence of temperature on the transformation time can be deduced from Figure 7, where the total transformation time shows a declining profile with increasing temperature in all three solvents. This is especially obvious in butanone, for which the transformation time is more than 50 h at 20 °C but only 10 h at 40 °C. The effect of temperature can be further revealed in Figure 8, which presents the induction time of form I and the

Figure 8. Plot of (▲) induction time and (■) transformation time for the polymorphic transformation of prasugrel hydrochloride in ethyl acetate on a 50-mL scale over the temperature range of 10−40 °C.

Figure 7. Profiles of the solution-mediated polymorphic transformation of form II to form I in ethyl acetate, acetone, and butanone, in terms of the relative intensity of form II measured in situ by Raman spectroscopy.

transformation time from form II to form I on a 50-mL scale in ethyl acetate over the temperature range of 283−313 K. It is clear that, as the temperature increased, the transformation rate decreased notably. The induction time decreased from 10380 s at 283 K to 1200 s at 313 K, whereas the transformation time decreased from 34200 s at 283 K to 2760 s at 313 K. The absolute value of the thermodynamic driving force (ΔGII→I) during the process, as shown in Figure 5d, decreases with increasing temperature, indicating that the driving force decreases with increasing temperature. However, it is unreasonable to only consider the driving force in the polymorphic transformation process, especially when the nucleation and growth of form I are the rate-determining step. According to the classical theory, molecular motion can be accelerated by higher temperature, which can facilitate the transformation process. When the temperature is increased, the solubility of form I in ethyl acetate increases as well, which means that the interfacial energy between the solid and liquid phases is lower; consequently, the free energy associated with the formation of a critical nucleus decreases. Therefore,

solvent interactions must be taken into consideration because of their possible influence on the nucleation kinetics.3 The solute−solvent interactions are mainly composed of van der Waals forces and hydrogen bonding.3 The strength of van der Waals interactions between solute and solvent is determined by the dipolar polarizability, π*, the values of which are listed in Table 1.24 The strength of solute−solvent hydrogen-bonding interactions is determined by the hydrogenTable 1. Values of HBD Ability α, HBA Ability β, and Polarity/Polarizability π* of Acetone, Butanone, and Ethyl Acetate solvent

α

β

π*

acetone butanone ethyl acetate

8 6 0

43 48 45

71 67 55 5657

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according to eq 2, the nucleation rate of form I increases with increasing temperature, and temperature has a positive influence on the solution-mediated polymorphic transformation process, which leads directly to the decreases of the induction time and the transformation time. Effect of Solid Loading on the Polymorphic Transformation Rate. The influence of the solid loading of form II on the transformation process was also studied. Different amounts of form II (2.00, 3.00, and 5.00 g) were added to the same 50 mL of ethyl acetate at 40 °C. The induction and transformation times were observed to be almost constant, as shown in Figure 9.

Figure 10. Morphology variation during the polymorphic transformation from form II to form I of prasugrel hydrochloride in ethyl acetate at 40 °C. Figure 9. Effect of solid loading on the transformation time from form II to form I of prasugrel hydrochloride in ethyl acetate at 40 °C, in terms of the relative intensity of form II. Solid loading: (■, black) 2, (▲, blue) 3, and (●, red) 5 g/50 mL of solvent.

Effect of Agitation Rate on the Polymorphic Transformation Rate. As discussed above, the surface nucleation of form I is driven by the higher supersaturation at the dissolving interface of form II, so mechanical action is an effective way of removing these surface nuclei. Hence, the more mechanical energy utilized, the higher the surface area of free growing form I crystals, and the faster the transformation. On the other hand, the transformation process comprises dissolution, nucleation, and growth. It obvious that the agitation rate has a positive effect on the convective mass transfer, which can facilitate all three steps during the solution-mediated polymorphic transformation process. As shown in Figure 11, it took only 0.8 h for form II to transform completely into form I at 600 rpm, whereas almost twice that time was required when the agitation

The rate of crystal growth should be constant because the supersaturation does not change in the same solvent at the same temperature in a solution-mediated polymorphic transformation. In accordance with the work of Croker and Hodnett,6 it is considered that the nucleation of the stable form tends to occur on, or at, the surface of the metastable form. As discussed above, the polymorphic transformation of prasugrel hydrochloride is controlled by the nucleation and growth of form I, so if the nucleation of form I is governed by the surface of form II, the transformation time should depend on the available surface area per unit mass of form II. The transformation experiments were monitored by polarizing microscope, as shown in Figure 10. It can be clearly observed that form I (with a needlelike shape) nucleated on the surface of form II (with a platelike shape) during the transformation process. The needles of form I grew threedimensionally on the surface of form II to form a cactus type of shape. With the agitation of the paddle impeller, the needles of form I dispersed throughout the entire solution, and after the transformation finished, no form II existed, and only needles of form I were left in solution. It seems plausible to assume that the surface nucleation of form I is driven by the higher local supersaturation, with respect to form I, existing at the dissolving surface of form II. This encourages heterogeneous nucleation of form I on the surface. Because nucleation occurs on the faces of the form II crystals, the nucleation rate is approximately proportional to the surface area, and there will be more form I nuclei per unit mass in the experiments with greater dissolution of the seeds.

Figure 11. Effect of agitation rate on the transformation time from form II to form I of prasugrel hydrochloride in ethyl acetate at 40 °C. 5658

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rate was set at 200 rpm. Therefore, increasing the agitation rate can significantly shorten the overall transformation time.

4. CONCLUSIONS The solution-mediated polymorphic transformation from form II to form I of prasugrel hydrochloride was studied in this work by Raman spectroscopy and a gravimetric method. The results show that the transformation process is controlled by the nucleation and growth of the stable form I and belongs to “scenario d” as outlined by O’Mahony et al.14 The transformation rates differ dramatically in different solvents because of the balance of the solubility, strength of solvent−solute interactions, and surface integration processes. Further, the induction and transformation times were found to decrease quite strongly with increasing temperature, despite a decreasing driving force, as determined from solubility measurements of the two forms. This work clearly reveals that nucleation of the stable phase of prasugrel hydrochloride occurs on the surfaces of the metastable phase and is approximately proportional to the available surface area, through the monitor of polarizing microscope. Therefore, the overall transformation time remains constant at different solid loadings, whereas increasing the agitation rate should result in a faster process.

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ASSOCIATED CONTENT

* Supporting Information S

DSC and TGA data (Figures S1−S3) and solubilities of the two polymorphs (Tables S1−S3, Figure S4). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: 86-22-27405754. Fax: 86-22-27314971. E-mail: junbo_ [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 21176173) and the Tianjin Municipal Natural Science Foundation (No. 11JCZDJC20700), and National High Technology Research and Development Program (863 Program No. 2012AA021202). We especially thank Professor Roger Davey for constructive suggestions. In addition, we thank Mr. Adrian Hutchinson for helpful discussion.

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REFERENCES

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dx.doi.org/10.1021/ie404245s | Ind. Eng. Chem. Res. 2014, 53, 5652−5659