Concomitant Polymorphism of Prasugrel Hydrochloride in Reactive

Article pubs.acs.org/IECR

Concomitant Polymorphism of Prasugrel Hydrochloride in Reactive Crystallization Wei Du,† Qiuxiang Yin,†,‡ Ying Bao,† Chuang Xie,† Baohong Hou,† Hongxun Hao,† Wei Chen,† Jingkang Wang,†,‡ and Junbo Gong*,†,‡ †

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, and ‡Tianjin Key Laboratory of Modern Drug Delivery and High-Efficiency, Tianjin University, Tianjin 300072, People’s Republic of China S Supporting Information *

ABSTRACT: Concomitant polymorphism of prasugrel hydrochloride was investigated in reactive batch crystallization experiments at 20 and 40 °C. The solubility of prasugrel hydrochloride form I and form II was experimentally determined. To understand the effects of reaction kinetics, supersaturation ratio, and nucleation kinetics on the behavior of concomitant polymorphism of prasugrel hydrochloride and the solvent-mediated transformation process, online techniques such as attenuated transform reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, Raman spectroscopy, and focused beam reflectance measurement (FBRM) were used to in situ monitor the reactive crystallization of prasugrel hydrochloride. It was found that prasugrel and hydrochloric acid react promptly and the designed supersaturation can be established almost instantly. The interfacial energies and thus relative nucleation rates of prasugrel hydrochloride form I and form II were calculated, and it was concluded that, at all investigated supersaturations, the nucleation rate of form II is always higher than the nucleation rate of form I. At lower supersaturation, thermodynamics dominated the crystallization process and form I was obtained, while at higher supersaturation, kinetics was critical in the crystallization process and form II was produced. At moderate supersaturation, both thermodynamics and kinetics played important roles and concomitant polymorphism of form I and form II was observed. Solvent-mediated transformation experiments were performed with and without seeding. It turns out that the transformation cannot happen without seeding of form I. Therefore, not reaction kinetics and polymorphic transformation but the concomitant nucleation should be the inherent reason for the observed concomitant polymorphism.

1. INTRODUCTION Polymorphism is a common phenomenon in organic substances.1 Different polymorphs have different free energies and therefore different physical properties, such as solubility, chemical stability, melting point, density, crystal habit, etc.2−4 These property differences can influence the performance of the material. For instance, the difference in solubility between polymorphs may affect the absorption of the active pharmaceutical ingredient (API) into the body.5 To produce pure polymorphs is crucial in chemical manufacturing, especially in the pharmaceutical industry where consistency and reliability are of importance.6 However, sometimes it is unfortunate to encounter problems such that the particular crystallization conditions lead to the production of multiple polymorphs, which are present in the crystallizing medium or vessel at the time the crystals are harvested. The formation of two different polymorphs of a material simultaneously in the same environment is termed “concomitant polymorphism”.7 This phenomenon was recognized for the first time in 1832 by Wöhler and Liebig8 in their research in benzamide which showed two different melting points and different modifications. When observed by microscopy, it manifested that the two modifications crystallize concomitantly. In Groth’s book9 on chemical crystallography in 1906, a list of examples of concomitant polymorphs was compiled such as sulfur, ammonium fluorosilicate, mannitol, and so on. Many other researchers’ work10−12 in concomitant polymorphism can be found, and they tried to explain this phenomenon in © 2013 American Chemical Society

crystallization mechanisms or by structural formulations, which is limited since it is not always possible to cultivate single crystals of each polymorph. Recently, concomitant polymorphism has been generally thought to depend on the subtle interplay between kinetic and thermodynamic factors.13 Jiang and ter Horst6 studied the concomitant polymorphism of oaminobenzoic acid in antisolvent crystallization with the help of a microscope. They concluded that the concomitant polymorphism is due to the competition of the two different polymorphs in the growth rate. Teychené and Biscans14 discussed the concomitant polymorphism of eflucimibe in cooling crystallization from the aspect of nucleation kinetics of its different polymorphs, and drew a conclusion that nucleation kinetics plays a key role in the concomitant appearance of the two polymorphs. The occurrence of concomitant polymorphs is rarely studied and tends to be even more complicated in the reactive crystallization process, where the supersaturation of the crystallizing compound is created by its formation through chemical reaction. Therefore, chemical reaction, nucleation, and crystal growth occur simultaneously with their own kinetics. All the kinetic and thermodynamic factors have to be taken into account together.15 Received: Revised: Accepted: Published: 16182

July 2, 2013 October 16, 2013 October 22, 2013 October 22, 2013 dx.doi.org/10.1021/ie4020815 | Ind. Eng. Chem. Res. 2013, 52, 16182−16189

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equivalent of hydrochloric acid and 20 mL of 2-propanol was added into the suspension at once. A microscope was further used to identify the two polymorphs due to their distinct morphologies. Two grams of prasugrel and 1 mol equivalent of hydrochloric acid were added to 150 mL of 2-propanol at 20 °C to produce prasugrel hydrochloride form I. Also, 15 g of prasugrel and 1 mol equivalent of hydrochloric acid were added to 150 mL of 2propanol at 20 °C to produce prasugrel hydrochloride form II. 2.4. Solubility and Induction Time Measurement of Prasugrel Hydrochloride. The solubilities of both form I and form II of prasugrel hydrochloride in 2-propanol were measured as a function of the temperature in the range 283− 343 K. Excess amounts of both forms were respectively dissolved in 20 mL of 2-propanol to saturate the solutions. After stirring for 3 h at each temperature, the suspension was filtered over a 0.45 μm filter. The residue undissolved crystals were separated and identified to be the initial polymorph by PXRD, indicating no solvent-mediated polymorphic transformation during solubility experiments. Samples of the saturated solutions were dried at 313 K until the solvent completely evaporated. The solubility was determined from the mass of the remaining crystalline material. The induction time measurement was also conducted in reactive crystallization at 20 and 40 °C, respectively. By changing the initial amounts of prasugrel and hydrochloric acid, different supersaturations were prepared. FBRM probe was used to in situ measure chord length distribution and trace the nucleation and growth in the solution.16 In this study, induction time is defined as the time from the addition of hydrochloric acid to the sudden increase in crystal number.17

The chemical name of the model compound, prasugrel hydrochloride, is 2-acetoxy-5-(α-cyclopropylcarbonyl-2-f1uorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride. Its molecular structure is shown in Figure 1.

Figure 1. Molecular structure of prasugrel hydrochloride.

In this study the effects of the reaction kinetics, supersaturation ratio, and nucleation kinetics on the behavior of concomitant polymorphism of prasugrel hydrochloride in reactive crystallization and the solvent-mediated transformation process were investigated. It was achieved by using online techniques such as attenuated transform reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, Raman spectroscopy, and focused beam reflectance measurement (FBRM) to monitor simultaneously the solute concentration and polymorphic state of the crystals.

2. EXPERIMENTAL SECTION 2.1. Materials. Prasugrel (supplied by Jiaxing Zhonghua Chemical Co., Ltd. of China) was used without further purification. Its mass fraction purity is higher than 99%, which was determined by HPLC (Type Agilent 1100, Agilent Technologies, USA). Analytical-grade 2-propanol and hydrochloric acid with mass fraction purity higher than 99.8% were purchased from Tianjin Kewei Chemical Co., Ltd. of China. 2.2. Process Analysis Tools. Powder X-ray diffraction (PXRD; Type D/max-2500, Rigaku, Japan) was used to determine the polymorphic form of the solid. A polarizing microscope (Olympus BX51, Japan) was used to observe the morphology of the polymorphs. A Raman spectrometer (RXN2, Kaiser Optical Systems, Inc., USA) was applied to determine the polymorphic forms in the suspension, and an ATR-FTIR React IR 45m reaction analysis system coupled with iC IR 4.2 software from Mettler Toledo and equipped with Duradisc DiComp probe was used to monitor the solution concentration. A laboratory scale FBRM system (Model M400LF) coupled with iC FBRM software from Mettler Toledo was applied to detect the change of the crystal numbers and measure the particle size with a 10s duration. 2.3. In Situ Measurement for Reactive Crystallization of Prasugrel Hydrochloride. The formation of prasugrel hydrochloride was investigated in reactive crystallization in 2propanol at 20 and 40 °C, respectively. Raman spectroscopy was applied in situ to identify the suspended crystals and polymorphs, and ATR-FTIR spectroscopy was used in situ to detect the solution concentration. Suspensions at 20 and 40 °C were prepared by adding 1.12−15 g of prasugrel in 150 mL of 2-propanol. The suspensions were kept under an agitation speed of 300 rpm for 15 min, and then a mixture of 1 mol

3. RESULTS AND DISCUSSION 3.1. Identification of Form I and Form II of Prasugrel Hydrochloride. Prasugrel hydrochloride has two forms, forms I and II, whose powder X-ray diffraction patterns are shown in Figure 2. Form I shows needlelike shape, and form II is platelike under the polarizing microscope, as shown in Figure 3. ATR-FTIR spectra of 2-propanol and prasugrel hydrochloride were respectively recorded according to the experiment process. As shown in Figure 4, prasugrel hydrochloride has characteristic peaks at wavenumbers 767, 1107, 1200, 1717,

Figure 2. Powder X-ray diffraction (PXRD) for both forms and the concomitant polymorphs. 16183

dx.doi.org/10.1021/ie4020815 | Ind. Eng. Chem. Res. 2013, 52, 16182−16189


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Figure 3. Polymorphic morphology in polarizing microscope: (a) form I (magnified by 500); (b) concomitant polymorphs of forms I and II (magnified by 100); (c) concomitant polymorphs of forms I and II (magnified by 200); (d) form II (magnified by 100).

Figure 5. Raman spectra of prasugrel and forms I and II of prasugrel hydrochloride.

Figure 4. ATR-FTIR spectra of 2-propanol and prasugrel hydrochloride.

and 1771 cm−1, and the peak at 1771 cm−1 is chosen to monitor the concentration−time profile of prasugrel hydrochloride in solution. Raman spectra of prasugrel and pure form I and form II of prasugrel hydrochloride were respectively recorded. All of the materials used were confirmed as pure forms by PXRD. As shown in Figure 5, prasugrel has characteristic peaks at 667 cm−1, and both form I and form II of prasugrel hydrochloride have characteristic peaks at 1501 cm−1. The Raman spectra of form I and form II of prasugrel hydrochloride are very similar, but the spectrum of form II has a sharp characteristic peak at the Raman shift of 692 cm−1. 3.2. Solubilities of Forms I and II of Prasugrel Hydrochloride. The solubility data of form I and form II in 2-propanol in the temperature range 283−343 K are presented in Figure 6, where each point is the average saturation

Figure 6. Polymorphic nucleation results with concentration relative to solubility.

concentration value of three measurements. The solubility of form II is higher than that of form I at the tested temperature. This indicates that form II is the metastable form. It can also be seen that the solubility of the two forms and the solubility difference between the two forms increase with increasing temperature. 16184



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⎛ ⎞ −4fs, i γi 3v 2 ⎟ Ji = Ai exp⎜⎜ 3 3 2⎟ ⎝ 27fv, i k T (ln Si) ⎠

3.3. Concomitant Polymorphism and Nucleation Kinetics of Different Forms of Prasugrel Hydrochloride. In order to understand how concentration or supersaturation influences the polymorphic form of prasugrel hydrochloride during reactive crystallization, some of the crystallization experiments were designed. In these experiments, the supersaturation ratio S which varied from 1.38 to 10.59 was prepared either by changing the initial suspension density of prasugrel in 2-propanol or by changing the temperature from 20 to 40 °C. The experimental results are shown in Figure 6 with the solubility curves of the two polymorphs. It can be clearly seen from Figure 6 that only form I was obtained when the concentration was below 0.002 at 20 °Cand below 0.006 at 40 °C. The crystals obtained were observed under a polarizing microscope, and all of them were needlelike as shown in Figure 3a. Concomitant polymorphism was observed when concentration was between 0.002 and 0.003 at 20 °C and between 0.006 and 0.009 at 40 °C. Both needlelike form I and platelike form II were observed by the polarizing microscope as shown in Figure 3b,c. When the concentration was increased to above 0.003 at 20 °C and 0.009 at 40 °C, only form II was obtained at all temperatures and all the crystals obtained showed a platelike shape as shown in Figure 3d. From Figure 6, it is quite interesting to find that different forms can be obtained by controlling the supersaturation. Considering both the thermodynamic and kinetic factors of the crystallization processes, these results are not unreasonable. Since form I is the thermodynamically favored form, it should be obtained at a low superaturation level where thermodynamics dominates the crystallization process. At high supersaturation where both form I and form II are highly supersaturated, kinetics will dominate the process. In this case, the metastable form II will crystallize out first since it is kinetically favored according to Ostwald’s rule.18 At moderate supersaturation where both forms are lightly supersaturated, both kinetics and thermodynamics will contribute to the crystallization and concomitant polymorphism will be observed. In order to further understand the mechanism of the concomitant polymorphism of prasugrel hydrochloride, nucleation processes of it were investigated in detail. The classical theory of nucleation assumes that clusters are formed in solution by an addition mechanism that continues until a critical size is reached. If the size of clusters is below this critical size, the clusters will dissolve, while the clusters will transform into nuclei when the size of the clusters is above this critical size.19 To simplify the description of the process, assumptions such as the clusters are modeled as spherical droplets having uniform interior densities and sharp interfaces, the surface tension of a liquid droplet is equal to the respective value of this quantity for a stable coexistence of both phases at an infinite planar interface, the clusters are incompressible and the vapor surrounding them is an ideal gas with a constant pressure, etc. were made. The assumptions which should be emphasized here are that (a) there is a quasi-equilibrium between the clusters and the nucleus, (b) the nucleus has the same packing as the crystal, and (c) the shape of the nucleus is described as fs/f v. The various assumptions inherent in the classical theory of nucleation have been discussed by numerous authors,20−22 and most recently Davey et al.23 have discussed specifically the question of the structure of the nucleus and the nature of the effective interfacial tension. On the basis of this background, the polymorphic nucleation rates can be written as follows:

(1)

where A is the pre-exponential factor, k is the Boltzmann constant, T is the absolute temperature, γ is the interfacial free energy, v is the molecular volume, S is the supersaturation ratio, fs and f v are the surface and volume shape factors, respectively, and i indicates different polymorphs. According to Mullin,22 the induction time can be considered to be inversely proportional to the rate of nucleation, as described in eq 2, which can only be justified if the data relate to true homogeneous nucleation. t ind ∝ J −1

(2)

19

Myerson discussed the relationship between the induction time and nucleation and growth time. The induction time (tind) is the sum of the time needed for reaching steady-state nucleation (ttr), the nucleation time (tn), and the time required for the critical nucleus to grow to a detectable size (tg). Generally, ttr can be ignored. If the nucleation time is much greater than the growth time (tn ≫ tg), the induction time is inversely proportional to the steady-state nucleation rate, described as eq 2, which has been verified for a number of systems from sparingly soluble, e.g., BaSO4, BaCrO4, and SrSO4, to readily soluble potassium and potassium aluminum phosphates. Equation 3 can be obtained as ln t ind = K i +

4fs, i 3 γi 3v 2 27fv, i 2 k3T 3(ln Si)2

(3)

As shown in eq 3, ln tind has a linear relationship with 1/(ln Si) 2 and the line slope is αi =

4fs, i 3 γi 3v 2 27fv, i 2 k3T 3

(4)

Therefore, the interfacial tension can be obtained by using the line slope, as shown by

⎛ 27α f 2 k3T 3 ⎞1/3 i v, i ⎟ γi = ⎜⎜ 3 2 ⎟ 4 f v ⎝ ⎠ s, i

(5)

The data of induction time measurement with FBRM in three different supersaturation ratios at 20 °C are shown in Figure 7. To analyze the tind experimental data according to eq 3, a plot of ln(tind) vs 1/(ln2S) was drawn. The nature of the polymorph that nucleates depends on the initial supersaturation. As shown in Figure 8, form I nucleates at low S while form II nucleates at high S. Therefore, the two straight lines in Figure 8 actually represent the primary nucleation of different polymorphs. From Figure 8 and according to eq 5, the values of interfacial energies of the two forms can be calculated from the slopes of the straight lines in the two regions of supersaturation at 20 and 40 °C. The results are given in Table 1. Some other methods have also been used to determine the interfacial energy. Mersmann24 discussed the interfacial energy between solid and liquid and gave an equation for a binary system under a series of simplifications: 16185



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the higher its value the more difficult it is for the solute to crystallize. This indicates that the nucleation of form II will be easier than that of form I at the same supersaturation. This result is consistent with Ostwald’s rule. The pre-exponential factor in eq 1 has different expressions due to the model used for describing the kinetics association. Kind and Schubert14 proposed the expression for A as follows: A=

Figure 8. Dependence of induction time, tind, on supersaturation ratio, S, and nature of the polymorphs that crystallize at 20 and 40 °C. The lines represent the simulations according to eq 3

Figure 9. Dependence of relative nucleation rates of prasugrel hydrochloride polymorphs at 20 and 40 °C as a function of supersaturation ratio.

Table 1. Interfacial Energy (γ (mJ/m2)) from Experiment and Theoretical Equations eq 5 I II

γ=

20 °C

40 °C

1.19 0.95

1.31 1.13

5.27 5.09

4.67 4.25

0.414kT (c jSNA )2/3

From Figure 9, it can be seen that the nucleation rate of form II is always higher than that of form I. This confirms again that form II is the kinetically favored form. Thus, the concomitant crystallization of the two forms becomes possible when the supersaturation reaches the area where kinetic and thermodynamic factors affect the crystallization process equally. 3.4. In Situ Monitoring of the Reactive Crystallization of Prasugrel Hydrochloride. The chemical reaction between prasugrel and hydrochloric acid leads to a more or less soluble molecule prasugrel hydrochloride, which then crystallizes out when the concentration passes the supersaturation limit of nucleation. This is the case for many compounds15 and can be described as follows:

eq 6 40 °C

⎛ cS ⎞ j ln⎜⎜ L ⎟⎟ ⎝ cj ⎠

(7)

where Dsl is the diffusion coefficient of the solute in the solvent, dm is the molecular diameter of the molecule, and C is the solution concentration. By using eqs 1 and 7, the primary nucleation kinetics of the two polymorphs at 20 and 40 °C can be determined from the value of γ obtained from the plot in Figure 8. The results are shown in Figure 9.

Figure 7. Induction time measurement with FBRM at 20 °C.

20 °C

⎛ γ d 2 ⎞1/2 3 m ⎟⎟ Dsl dm 2(CNA )7/3 ⎜⎜ sl 2 kT ⎝ ⎠

(6)

where k is the Boltzmann constant, T is the temperature, cSj is the solid concentration of composition j (always the solute), cLj is the liquid concentration of composition j, and NA is the Avogadro number 6.02 × 1023 mol−1; the superscripts “S” and “L” indicate the solid and liquid phases, respectively. The calculated results of interfacial energies of the two polymorphs by eq 6 are also reported in Table 1. From Table 1, it can be seen that the γ values for different polymorphs change with the temperature and the interfacial energies of the metastable form II are always less than those of stable form I. From the literature17 the value of γ can serve as an indicator of the ability of solute to crystallize from solution spontaneously:

prasugrel + HCl ⇌ prasugrel hydrochloride ⇌ prasugrel hydrochloride (solid)↓

To understand the reactive crystallization process and to know which step (either crystallization or reaction) is the controlling step, the reactive crystallization processes of prasugrel hydrochloride in 2-propanol at 20 and 40 °C were in situ monitored by process analysis tools. Both ATR-FTIR and Raman spectroscopies were used to monitor the processes. 16186



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The IR characteristic peak of 1771 cm−1 was used to represent the liquid concentration of prasugrel hydrochloride. The Raman shift at 692 cm−1 was used to monitor the solid concentration of prasugrel hydrochloride, while the Raman shift at 1501 cm−1 was used to monitor the liquid concentration of prasugrel hydrochloride. The results are shown in Figures 10 and 11.

remained at the lowest point until the end of the experiment after the addition of hydrochloric acid, which confirmed that the chemical reaction rate of prasugrel and hydrochloric acid at 20 and 40 °C is very fast and the reaction has completed almost instantly. As discussed above, the fast chemical reaction can build a high supersaturation in solution and the supersaturation of prasugrel hydrochloride reached the highest value in less than 10 s. On the other hand, it took a much longer time for the crystal to nucleate and grow. Therefore, it can be concluded that the nucleation and growth, not the reaction kinetics, of prasugrel hydrochloride is the control step of the reactive crystallization of prasugrel hydrochloride. 3.5. Polymorphic Transformation between Form I and Form II of Prasugrel Hydrochloride. According to Ostwald’s rule, the metastable form is likely to nucleate first during the crystallization process. It will then transform into the more stable form over time. If form II could transform into form I, the gravimetric method should not be used to determine the solubility of form II. Thus, it is necessary to determine whether the transformation between form I and form II of prasugrel hydrochloride will happen and whether the occurrence of concomitant polymorphs is due to the transformation process. The polymorph transformation process of prasugrel hydrochloride form I and form II at 40 °C was monitored by using in situ Raman spectroscopy. Experiments were divided into two groups, with one group having the seed of form I to induce the transformation of the metastable form II and the other group without seeding of form I. The experimental result at 40 °C is shown in Figure 12.

Figure 10. Trend of IR characteristic peak of prasugrel hydrochloride at wavenumber of 1771 cm−1.

Figure 11. Raman profiles of prasugrel and hydrochloric acid to prasugrel hydrochloride at 40 °C.

From Figures 10 and 11, it can be seen that the liquid concentration of prasugrel hydrochloride (indicated by both Raman and ATR-FTIR data) increased straightaway after the addition of hydrochloric acid while the concentration of prasugrel (indicated by Raman data) decreased to the lowest point at the same time. This indicates that prasugrel and hydrochloric acid react quickly into prasugrel hydrochloride. Then, the concentration of prasugrel hydrochloride (indicated by both Raman and ATR-FTIR data) remained constant for about 8000 s at 40 °C and 2000 s at 20 °C, which are the induction times of nucleation and differ with different temperatures. After that, the liquid concentration of prasugrel hydrochloride started to decrease while the solid concentration of prasugrel hydrochloride started to increase (indicated by Raman data), which indicates the nucleation and crystal growth of prasugrel hydrochloride happened. It is worth noting that the concentration of prasugrel (represented by Raman data)

Figure 12. Solvent-mediated transformation profiles of mixtures of prasugrel hydrochloride form I and form II at 40 °C.

For the experiments without the seeding of form I, the transformation process did not happen within 10 days. However, when the seeds of form I were introduced, as seen from Figure 12, the characteristic peak of form II started to decrease after seeding while the characteristic peak of form I began to increase. This clearly shows that the transformation process started. It took 42 h to finish this process at 40 °C for form II to completely transform to form I because of the smaller difference in solubility between form I and form II. From Figure 3, it can be calculated that the solubility difference at 40 °C is only 1.176 g/100 g solvent. 16187


Industrial & Engineering Chemistry Research From the discussion above, it can be seen that the transformation process will not happen within several days if there is no seed of form I. Therefore, it can be confirmed that the formation of form I in lower supersaturation during the crystallization experiments discussed above is not due to the transformation from form II to form I but because of the nucleation of form I. Thus, concomitant nucleation of both forms should be the real reason for concomitant polymorphism in 2-propanol.

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REFERENCES

(1) Hilfiker, R. Polymorphism in the Pharmaceutical Industry; WileyVCH: Weinheim, Germany, 2006; pp 1−3. (2) An, J. H.; Choi, G. J.; Kim, W. Polymorphic and kinetic investigation of adefovir dipivoxil during phase transformation. Int. J. Pharm. 2012, 422, 185−193. (3) Cui, P.; Yin, Q.; Guo, Y.; Gong, J. Polymorphic Crystallization and Transformation of Candesartan Cilexetil. Ind. Eng. Chem. Res. 2012, 51, 12910−12916. (4) Qu, H. Y.; Alatalo, H.; Hatakka, H.; Kohonen, J. Raman and ATR-FTIR spectroscopy in reactive crystallization: Simultaneous monitoring of solute concentration and polymorphic state of the crystals. J. Cryst. Growth 2009, 311, 3466−3475. (5) Jiang, S.; Jansens, P. J.; ter Horst, J. H. Control over Polymorph Formation of o-Aminobenzoic Acid. Cryst. Growth Des. 2010, 10, 2541−2547. (6) Jiang, S.; ter Horst, J. H.; Jansens, P. J. Concomitant Polymorphism of o-Aminobenzoic Acid in Antisolvent Crystallization. Cryst. Growth Des. 2008, 8, 37−43. (7) Ö zdemir, N.; Dayan, O.; Cetinkaya, B. Concomitant polymorphism of a pyridine-2,6-dicarboxamide derivative in a single space group: Experimental and molecular modeling study. Spectrochim. Acta, Part A 2012, 86, 614−624. (8) Bernstein, J.; Davey, R. J.; Henck, J. Concomitant polymorphs. Angew. Chem., Int. Ed. 1999, 38, 3440−3461. (9) Groth, P. H. R. An Introduction to Chemical Crystallography; Gurney & Jackson: London, 1906; pp 28−31. (10) Užarević, K.; Kokan, Z.; Perić, B.; Bregović, N.; Kirin, S. I. Concomitant polymorphism in the pseudo-peptide Me2N-pC6H4C(O)-Phe-OEt. J. Mol. Struct. 2013, 1031, 160−167. (11) Lennartson, A.; Olsson, S.; Sundberg, J.; Håkansson, M. Concomitant polymorphism: Crystallising dichloro-bis(2,4-lutidine)zinc as both chiral and racemic phases. Inorg. Chim. Acta 2010, 363, 257−262. (12) Rath, N. P.; Kumar, V. S.; Janka, M.; Anderson, G. K. Concomitant polymorphism and conformational polymorphism in diiodobis [1,2-bis (diphenylphosphino) ethane] platinum (II). Inorg. Chim. Acta 2007, 360, 2997−3001. (13) Munshi, P.; Venugopala, K. N.; Jayashree, B. S.; Guru Row, T. N. Concomitant Polymorphism in 3-Acetylcoumarin: Role of Weak CH···O and C-H···π Interactions. Cryst. Growth Des. 2004, 4, 1105− 1107. (14) Teychené, S.; Biscans, B. Nucleation Kinetics of Polymorphs: Induction Period and Interfacial Energy Measurements. Cryst. Growth Des. 2008, 8, 1133−1139. (15) Tung, H.; Paul, E. L.; Midler, M.; McCauley, J. A. Crystallization of Organic Compounds: An Industrial Perspective; Wiley: Hoboken, NJ, 2009; pp 207−234. (16) Zhao, Y.; Yuan, J.; Ji, Z.; Wang, J.; Rohani, S. Combined Application of in Situ FBRM, ATR-FTIR, and Raman on Polymorphism Transformation Monitoring During the Cooling Crystallization. Ind. Eng. Chem. Res. 2012, 51, 12530−12536. (17) Kuldipkumar, A.; Kwon, G. S.; Zhang, G. Z. Determining the Growth Mechanism of Tolazamide by Induction Time Measurement. Cryst. Growth Des. 2007, 7, 234−242. (18) Grant, D. J. W. Polymorphism in Pharmaceutical Solids; Marcel Dekker: New York, 1999; pp 1−33. (19) Myerson, A. S. Handbook of Industrial Crystallization; Elsevier Science & Technology Books: Amsterdam, 2001; pp 43−52.

ASSOCIATED CONTENT

S Supporting Information *

Derivation of eq 1; calculation of shape factors and solubilities of the two polymorphs are listed in Tables a1 and a2, respectively. This material is available free of charge via the Internet at http://pubs.acs.org.

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ACKNOWLEDGMENTS

The analysis tools used in this study were supported by the National Natural Science Foundation of China (No. NNSFC 21176173), Tianjin Municipal Natural Science Foundation (No. 11JCZDJC 20700), and National high technology research and development program (863 Program No. 2012AA021202).

4. CONCLUSIONS In this study, the concomitant polymorphism of prasugrel hydrochloride was investigated in detail. To fully understand the mechanism of the concomitant polymorphism, the reaction process, the crystal nucleation and growth processes, the transformation process, and the solubilities of the two forms of prasugrel hydrochloride were discussed. It was found that prasugrel and hydrochloric acid react promptly and the reaction process can finish almost instantly, and thus the designed supersaturation can be built immediately. Without the seeding of form I, the transformation from form II to form I of prasugrel hydrochloride cannot happen due to the low solubility difference between the two forms which was shown by the measured solubility data of these two forms. Even when seeds of form I were introduced, the transformation process still needs a very long time to complete. Therefore, the reaction and the transformation process are not the reason for the occurrence of concomitant polymorphs. The occurrence of concomitant polymorph for prasugrel hydrochloride depends on the supersaturation ratio and temperature. Through the induction time experiments, the interfacial energies as well as the relative nucleation rates of the two forms were calculated. It was found that JII is always higher than JI at the supersaturation level investigated. Therefore, it was confirmed that form II is the kinetically favored form. At lower supersaturation, thermodynamics dominates the reactive crystallization process of prasugrel hydrochloride and only form I can be obtained, while kinetics dominates at higher supersaturation and form II can be obtained. For moderate supersaturation, concomitant polymorphs of the two forms are observed because of the the nearly equal importance and effect of thermodynamics and kinetics. By using the fundamental data of this study, control and optimization of the reactive crystallization of prasugrel hydrochloride could be achieved to avoid or suppress concomitant polymorphism and to obtain pure polymorphs.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: 86-22-27405754. Fax: 86-22-27314971. E-mail: junbo_ gong @tju.edu.cn. Notes

The authors declare no competing financial interest. 16188



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(20) Kashchiev, D. Nucleation: Basic Theory with Applications; Butterworth-Heinemann: Oxford, 2000. (21) Erdemir, D.; Lee, A. Y.; Myerson, A. S. Nucleation of Crystals from Solution: Classical and Two-Step Models. Acc. Chem. Res. 2009, 42 (5), 612−629. (22) Mullin, J. W. Crystallization, 4th ed.; Butterworth-Heinemann: Oxford, 2001; pp 206−214. (23) Davey, R. J.; Schroeder, S. L. M.; ter Horst, J. H. Nucleation of Organic CrystalsA Molecular Perspective. Angew. Chem., Int. Ed. 2013, 52, 2166−2179. (24) Mersmann, A. Calculation of interfacial tensions. J. Cryst. Growth 1990, 102, 841−847.

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Concomitant Polymorphism of Prasugrel Hydrochloride in Reactive

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