Effects of Solvent on Polymorph Formation and Nucleation of

Jul 30, 2014 - Synopsis. The hydrogen bond donor ability (α), hydrogen bond acceptor ability (β), and dipolar polarizability (π*) of solvent were s...
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Effects of Solvent on Polymorph Formation and Nucleation of Prasugrel Hydrochloride Wei Du,† Qiuxiang Yin,†,‡ Junbo Gong,†,‡ Ying Bao,†,‡ Xia Zhang,† Xiaowei Sun,† Suping Ding,† Chuang Xie,†,‡ Meijing Zhang,†,‡ and Hongxun Hao*,†,‡ †

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: Three intrinsic properties of solvent were used to evaluate the effects of solvent on polymorph formation of prasugrel hydrochloride. In situ Raman spectroscopy, FTIR, and powder X-ray diffraction were used to characterize two solvent-free polymorphs and five solvates of prasugrel hydrochloride, the two of which were reported for the first time. Reactive crystallization in 24 different pure solvents was studied at 313.15 K. It was found that polymorph formation of prasugrel hydrochloride directly depends on the solvents used in the experiments. Form I was obtained in solvents with low values of hydrogen bond donor ability (HBD), while form II was obtained in solvents with high values of HBD. The thermodynamic and kinetic reasons for the solvent effects were explained by using the solubility data and the nucleation experiments. The solubilities of forms I and II were experimentally determined by a gravimetric method, and an equation based on the linear free energy approach for predicting solubility was applied to correlate the solubility of form II. It was found that the values of HBD of the solvents also affect the solubility of prasugrel hydrochloride. From desolvation experiments of the five solvates in seven pure solvents at 293.15 and 313.15 K, it was found that the polymorphs of prasugrel hydrochloride obtained after desolvation are closely related to the solvents. The heterogeneous nucleation of form I during the solventmediated polymorphic transformation was also studied at 313.15 K, and it was found that the solute−solvent interactions will also affect the nucleation rate of form I. A hypothesis was then proposed that prasugrel hydrochloride form I is prone to crystallize when van der Waals force dominates the interaction between the solute and the solvent molecules, while prasugrel hydrochloride form II is prone to nucleate and grow when hydrogen bonding dominates the interaction between the solute and the solvent molecules. for rational solvent selection.13 Hence, the effects of solvent on crystallization processes are important for understanding and developing methods to isolate crystal forms. Polymorphic formation, thermodynamic and kinetic factors such as nucleation rate and growth rate, and specific inter- and intramolecular interactions should be considered separately and collectively for selective crystallization of desired polymorphs.14 Effects of solvent on polymorph formation has been studied by many researchers.15−17 Davey et al.18 investigated the solvent effects on molecular self-assembly during nucleation of 2,6-dihydroxybenzoic acid and found that solution crystallization in toluene favored the formation of form 1 while crystallization in chloroform favored the formation of form 2. The UV data indicated that the supramolecular structure of prenucleation aggregates is solvent-dependent and consequently controls the polymorphic modification. Chen and

1. INTRODUCTION The importance of polymorphism in pharmaceutical, food and other chemical industries has been well recognized.1−9 Solution crystallization from different solvents is currently one of the most widely used methods to produce different polymorphs.9 Links between solvent used in solution crystallization and the obtained polymorphs have also been one of the main research topics for pharmaceutical polymorphism since investigation on the role played by solvent during crystallization can aid in the hunt for control over polymorphism. Solvent can affect the final crystal products in many ways, such as crystal polymorph, crystal size, and morphology.10−12 However, it still remains unclear how the solvent affects the final polymorphs and which properties of the solvent act as determinants in the crystallization pathway. Currently, techniques of solvent selection for solution crystallization remain ad hoc and typically do not have a theoretical foundation. Clarification of the interactions between solvent and solute molecules and the mechanism of the solvent effects on each aspect of the crystallization process as well as the properties of the final crystal product would be a major aid © 2014 American Chemical Society

Received: April 29, 2014 Revised: June 25, 2014 Published: July 30, 2014 4519

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Trout13 correlated the interaction between solute and solvent with polymorph formation in the computational study of tetrolic acid (TTA) and concluded that weak interactions between the solvent and TTA molecules prompt the formation of dimers while strong solute−solvent interactions prefer crystallization of catemer-based crystals or solvates. Thermodynamics differentiates the stability domains where multiple polymorphs exist. Threlfall17 studied comprehensively the thermodynamic role of solvent in polymorphic crystallization of the enantiotropic systems. It is suggested in his study that the observed polymorph is under total thermodynamic control when crystallization is conducted sufficiently above or sufficiently below the transition point. Once a metastable domain is reached, the subtle interplay between thermodynamics and kinetics will determine the final polymorphs that crystallize. Du et al.19 and other researchers20 found that with certain solvent and concentration, concomitant polymorphism can be encountered, which should be avoided during the crystallization processes. Gu et al.9 investigated the influence of solvent on solvent-mediated polymorphic transformation rate to gain knowledge of solvent effects in polymorphism screening. They believe that the balance between the solubility and solvent−solute interactions determines the total transformation rate. The chemical name of the model compound in this work, prasugrel hydrochloride, is 2-acetoxy-5(α-cyclopropylcarbonyl2-f1uorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride. It was selected as the model compound due to the strong link between the polymorphs and solvents. Prasugrel hydrochloride, whose molecular structure is shown in Figure 1,

further purification. Its mass fraction purity is higher than 99.0%, which was determined by HPLC (Type Agilent 1100, Agilent Technologies, USA). All of the solvents listed in Table 1, which were purchased from Tianjin Kewei Chemical Co., Ltd., of China, were analytical reagent grade (the molar purities are higher than 99.5%). Powder X-ray diffraction (PXRD; type D/max-2500, Rigaku, Japan) was used to determine the polymorphic forms of the solid. A Raman spectrometer (RXN2, Kaiser Optical Systems, Inc., USA) was used to determine the polymorphic forms in the suspension. 2.2. Polymorphic Formation Experiments of Prasugrel Hydrochloride. The formation of prasugrel hydrochloride by reactive crystallization was investigated in 24 different pure solvents at 313.15 K. Prasugrel (2.0000 g) was added into 15.0 mL of pure solvent, which was kept under an agitation speed of 250 rpm by a magnetic stirrer. Then a mixture of 1 mol equivalent of hydrochloric acid and 5 mL of the same solvent was added into the system at once. The desired temperature was controlled by a thermostat (model 501 A, Shanghai Laboratory Instrument Works Co., Ltd., China) with an accuracy of ±0.05 K. The solid was isolated from the suspension quickly after nucleation to avoid potential polymorphic transition and get enough crystals, which were then analyzed with PXRD to identify the form of the solid. 2.3. Solubility Measurement. Because form I is the thermodynamically stable form of prasugrel hydrochloride,21 the solubility of form I in 2-butanol, propyl acetate, and methyl isobutyl ketone (MIK) was measured as a function of temperature in the range of 283.15 to 353.15 K with a gravimetric method. Slurries of form I were prepared in 20 mL of solvent to saturate the solutions. After stirring for 3 h at each temperature, the suspension was filtered through a 0.45 μm membrane filter. Samples of the saturated solutions were dried at 313.15 K until the solvent completely evaporated. The solubility was determined from the mass of the remaining crystalline material and the total mass of the solution. The solubility of prasugrel hydrochloride form II in 2-butanol, propyl acetate, and MIK was measured in the temperature range of 283.15 to 343.15 K with the assistance of Raman spectroscopy, which was used to ensure the identity of form II. The slurries of form II were obtained by mixing 20 mL of solvent and 1.00 g of form II of prasugrel hydrochloride. Raman spectra were recorded in 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) before a decrease of Raman intensity of form II was observed. This clear solution was dried at 313.15 K until the solvent was completely evaporated. The solubility of form II was determined from the mass of the remaining crystalline material and the total mass of the solution. 2.4. Desolvation and Heterogeneous Nucleation during Polymorphic Transformation. The desolvation experiments of the five solvates were studied on 50 mL scales at 293.15 and 313.15 K under magnetic agitation. Acetone, butanone, ethyl acetate, 2propanol, 2-butanol, propyl acetate, and MIK were selected to evaluate the solvent effects on the desolvation process. During each experiment, 3.50 g of solvate was added into 50 mL of solvent. After agitation for 1 h, the crystals were separated and the solid forms were identified by PXRD. The solvent-mediated polymorphic transformation experiments from form II to form I of prasugrel hydrochloride were investigated on 50 mL scales. The effects of solvent on heterogeneous nucleation was examined among ethyl acetate, acetone, butanone, 2-propanol, 2butanol, propyl acetate, and MIK at 313.15 K by measuring the induction time, which is defined as the time from the addition of form II to the sudden Raman intensity increase of form I. In this study, Raman spectroscopy was applied to identify in situ the solid forms in the slurry at an interval of 1 min, and a thermostat was used to control the temperature. During each experiment, 50 mL of solvent was initially saturated with respect to form I. An extra 2.0 g of form II was then added into the saturated solution.

Figure 1. Molecular structure of prasugrel hydrochloride.

was reported to have two solvent-free forms, form I and form II, and three solvates with acetic acid, acetonitrile, and nitromethane as the solvent in crystal structure, respectively.21 In this study, two new solvates of prasugrel hydrochloride were discovered and characterized for the first time. The main aim of this work is to elucidate the link between solvent−solute interactions and the obtained polymorphs. Twenty-four different pure solvents were selected to investigate the relationship between the observed polymorph and solvent. To better understand the effects of solvent on the crystallization process, the thermodynamic and kinetic mechanisms of solvent effect were investigated using the solubility data and the desolvation and transformation experiments, respectively.

2. EXPERIMENTAL SECTION 2.1. Materials and Process Analysis Tools. Prasugrel (supplied by Jiaxing Zhonghua Chemical Co., Ltd. of China) was used without 4520

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3. RESULTS AND DISCUSSION 3.1. Identification of Prasugrel Hydrochloride Polymorphs. The PXRD patterns of the two solvent-free forms, form I and form II, of prasugrel hydrochloride and its three previously published solvates, acetic acid solvate, acetonitrile solvate, and nitromethane solvate are shown in Figure 2. Two

Figure 2. Powder X-ray diffraction (PXRD) patterns of prasugrel hydrochloride form I, form II and 5 solvates.

new solvates of prasugrel hydrochloride, methanol solvate and ethanol solvate, were discovered. Their PXRD patterns are also shown in Figure 2. It can be seen from this figure that the PXRD data of the two new solvates contain some distinct differences with the PXRD data of the known forms and solvates. The FTIR spectra of the two new solvates were collected from KBr disk with a Nicolet nexus spectrophotometer (Bruker TENSOR 27, German). As shown in Figure 3,

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

form II. Due to the fluorescence of prasugrel hydrochloride, the Raman spectra of both forms are slightly inclined upward, so baseline correction is applied to all the spectra, and the Raman intensity is relative intensity, which is defined as the peak height to the two-point baseline. 3.2. Effects of Solvent on Polymorphic Formation. Reactive crystallization of prasugrel hydrochloride was conducted in 24 different pure solvents at 313.15 K. The same amount of prasugrel, hydrochloric acid, and solvent were used when changing the solvent. The chemical reaction between prasugrel and hydrochloric acid leads to a more or less soluble salt, prasugrel hydrochloride, which then crystallizes when it reaches the induction time of nucleation.19 The procedure can be described as follow: prasugrel(aq) + HCl(aq) ⇋ prasugrel hydrochloride(aq)

Figure 3. Infrared spectra of prasugrel hydrochloride methanol solvate and ethanol solvate.

⇋ prasugrel hydrochloride(solid)↓

The solid samples crystallized were collected and analyzed to determine the polymorphic forms. PXRD was used to verify the solid-phase identity of these samples (Figure 2), which were obtained from the 24 different solvents and isolated quickly after nucleation. The results are given in Table 1. It can be seen clearly from Table 1 that form I of prasugrel hydrochloride was preferred in nonalcohol solvents such as esters and ketones while form II was favored in alcohols. In addition, solvates were obtained in acetonitrile, nitromethane, acetic acid, methanol, and ethanol. Thus, it can be speculated that the observed

the infrared spectra wavenumbers at 3427.11 and 3418.55 cm−1 represent the −OH group in the methanol solvate and ethanol solvate, respectively. Raman spectroscopy was successfully applied to identify the crystalline forms, as shown in Figure 4. The Raman spectra of the two solvent-free forms exhibit some distinct differences which can be chosen as the characteristic peaks for each form. In this study, the peaks at 1186 and 1695 cm−1 are chosen as the characteristic peaks of form I, while the peak at 1194 cm−1 is selected to represent 4521

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listed in Table 1. From Table 1, it seems that the hydrogen bond donor ability, α, is the main factor that affects the polymorph formation of prasugrel hydrochloride. In solvents whose α values are close to 0, form I tends to be produced, while form II or solvates tend to be generated when the solvents’ α-value increases over 20. This can be explained by the molecular structure of prasugrel hydrochloride, which has a high propensity to accept protons to form a hydrogen bond with solvent. From Figure 1, it can be seen that the two carbonyl groups, the sulfur, the nitrogen, and the fluorine atom can serve as hydrogen bond acceptor sites. So, the bigger the αvalue of the solvent, the more easily form II or solvates crystallize. It should be mentioned that prasugrel hydrochloride ethanol solvate and methanol solvate are the new solvates of prasugrel hydrochloride, which are reported for the first time in this study. It seems that the solvents’ hydrogen bond acceptor ability and the dipolar polarizability affect polymorph formation less than the hydrogen bond donor ability. Therefore, it can be speculated that the effects of solvent on polymorph formation of prasugrel hydrochloride is mainly reflected through the hydrogen bonding interactions between the solvent and solute molecules, and increasing the solvents’ hydrogen bond donor abilities can lead to the formation of form II or the solvates of prasugrel hydrochloride. To better understand this, the effects of solvent on solubility and heterogeneous nucleation of prasugrel hydrochloride were investigated. 3.3. Effects of Solvent on Thermodynamics. The effects of solvent on the solubility can be evaluated by the solute− solvent interactions. According to the linear free energy approach for predicting solubility,22 the molar solubility of a chemical in series of solvents can be described by the following equation:

Table 1. Properties of the Solvent and the Polymorphic Formation from Reactive Crystallization solvent

α

β

π*

observed polymorph

ethyl acetate pyridine toluene N-methyl pyrrolidone ethyl formate methyl acetate propyl acetate butyl acetate dimethylformamide dimethylacetamide MIK butanone acetone dichloromethane acetonitrile chloroform nitromethane 2-butanol 2-propanol ethanol methanol acetic acid propanoic acid

00 00 00 00 00 00 00 00 00 00 02 06 08 13 19 20 22 69 76 86 98 112 112

45 64 11 77 36 42 40 45 69 76 48 48 43 10 40 10 06 80 84 75 96 45 45

55 87 54 92 61 60

I I I I I I I I I I I I I I solvate I solvate II II solvate solvate solvate II

46 88 88 68 42 71 82 75 58 85 40 48 54 90 64 58

polymorph might be related to the solvents used during the reactive crystallization. In the reactive crystallization process of prasugrel hydrochloride, supersaturation is generated by the reaction between prasugrel and hydrochloric acid. Both reaction kinetics and crystallization kinetics will be affected by solvent. Du et al.19 have investigated the reaction process between prasugrel and hydrochloric acid and found that the effects of reaction kinetics can be neglected due to the fast reactive rate. Therefore, the effect of solvent on the polymorph formation during the reactive crystallization of prasugrel hydrochloride is mainly manifested in its influence on crystallization thermodynamics and kinetics, namely, nucleation and growth. The effects of solvent on the crystallization thermodynamics (mainly solubility) will be discussed in the next section. The effect of solvent on the crystallization kinetics can be represented by its effect on nucleation and growth. Generally, the solvent may affect the crystal nucleation and growth rate in two ways.9 On one hand, the solute molecules in the solution are associated with the solvent molecules, which are said to be solvated. During the nucleation and crystal growth step, desolvation of the solvated solute molecules must precede their integration into the crystal lattice. On the other hand, the solvent molecules are adsorbed on the surface of a cluster of nuclei or a growing crystal surface. The incoming solute molecules must replace the solvent molecules in order to become integrated into the crystal lattice. Both aspects can be evaluated through the solvent−solute interaction, which involves van der Waals force and hydrogen bonding.9,21 The strength of solute− solvent van der Waals interactions can be evaluated by the dipolar polarizability, π*, the values of which are listed in Table 1.22 The strength of hydrogen bonding between the solvent and the solute can be evaluated by the hydrogen bond donor ability, α, or the hydrogen bond acceptor ability, β. The values of α and β of the 24 solvents used in the reactive crystallization are also

ln x = a + bδ 2 + cα + dβ + eπ *

(1)

where x is the molar solubility, δ is the solvent solubility parameter corresponding to the cohesive energy density, a, b, c, d, and e are (solvent-independent) coefficients characteristic of the process and indicative of its sensitivity to the accompanying solvent properties, and α, β, and π* are defined as above. In eq 1, δ = 1.0 for aromatic solvents, 0.5 for polychlorinated aliphatic solvents, and 0 for all other aliphatic solvents. Thus, bδ2 should be equal to 0 in this study, and eq 1 can be rewritten as ln x = a + cα + dβ + eπ *

(2)

The solubility data of prasugrel hydrochloride form I and form II in 2-butanol, propyl acetate, and MIK are experimentally determined. The results are presented in Tables S1, S2, and S3 in the Supporting Information and Figure 5, where each point is the average saturation concentration value of three measurements. The solubility of form II is higher than that of form I in the tested solvents and temperatures, which is consistent with the solubility measurement in 2-propanol19 and confirms that form II is the metastable form and the two forms have a monotropic relationship. By fitting the solubility data obtained in this study and the data from Du et al.19,21 to eq 2, we can express the solubility of form II by the following relationships: ln x = − 0.01176α + 0.00375β + 0.000219π * − 5.66312 (3)

From eq 3, it can be seen that the coefficient for hydrogen bond donor ability is higher than that for hydrogen bond acceptor ability and higher than that for polarity/polarizability 4522

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desolvation process of the five solvates and the heterogeneous nucleation of form I during the polymorphic transformation process were studied experimentally. The desolvation results of the five solvates at 293.15 and 313.15 K are summarized in Table 2. From this table, it can be seen that all the five solvates Table 2. Desolvation Experiment Results solvent

polymorph 293.15 K

polymorph 313.15 K

acetone butanone ethyl acetate 2-propanol 2-butanol propyl acetate MIK

I I I II II I I

I I I II II I I

have lost the solvent in their crystal structures at both temperatures. In 2-propanol and 2-butanol, form II can be produced, while in acetone, butanone, ethyl acetate, propyl acetate, and MIK, form I can be obtained. It seems that solvent plays an important role in determining the final polymorphs during the desolvation process. It tends to prompt the crystallization of form I in the solvents with low hydrogen bond donor ability, while form II is preferred in the solvents with high values of hydrogen bond donor ability. The effect of solvent on the polymorphs obtained from desolvation is consistent with that during the reactive crystallization, which has been discussed above. To further investigate the effects of solvent on polymorph formation of prasugrel hydrochloride, the heterogeneous nucleation process during the polymorphic transformation was studied with the assistance of in situ Raman. Du et al.21 have studied the solvent effects on the total transformation rate from form II to form I of prasugrel hydrochloride and found that the balance of the solubility and the strength of the solute− solvent interactions determines the total transformation time. However, they only carried out their experiments in three solvents and did not find out which property of the solvent plays the key role in nucleation. In this study, the heterogeneous nucleation process was investigated in ethyl acetate, acetone, butanone, propyl acetate, MIK, 2-propanol, and 2-butanol to confirm the effects of solvent. According to classical nucleation rate theory,9,21 the heterogeneous nucleation rate can be written as followed: ⎛ 0.378πv 2c 2N 2(ln c − ln c )3 φ ⎞ s A s eq ⎟ J = N0v exp⎜⎜ − ⎟ 2 (ln S ) ⎝ ⎠

(4)

where J is the number of nuclei formed per unit volume, N0 is the number of solute molecules per unit volume, v is the molecular volume of the solute, cs is equal to the ratio of the density of the solute to the molar mass of the solute, ceq is the equilibrium solubility, NA is the Avogadro number, φ is the heterogeneous nucleation factor, and S is the supersaturation ratio. Generally, the nucleation rate is inversely proportional to the induction time, tind,23 namely,

Figure 5. Solubility of prasugrel hydrochloride forms I and II: (a) 2butanol; (b) propyl acetate; (c) MIK.

by 2 orders of magnitude. This result indicates that the solubility of form II is also mainly affected by the hydrogen bond donor ability. This can explain why the polymorph formation of prasugrel hydrochloride is mainly affected by the hydrogen bond donor ability from thermodynamic perspective. 3.4. Effects of Solvent on Desolvation and Nucleation Processes. The phenomenon of solvent inclusion has been found to instigate further happenings such as leading to the formation of a new polymorphic form upon desolvation.5 The

J ∝ t ind−1

(5)

Because all the parameters except N0 and ceq in eq 4 have been fixed21 and N0 is proportional to the concentration of the solute molecules in the solution and is thus greater in the 4523

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As discussed above, the link between solvent and the obtained polymorph lies in the hydrogen bond donor ability of the solvent, which serves as determinant in thermodynamics, heterogeneous nucleation, and finally polymorph formation. When reviewing the effect of solvent on the final crystalline forms, we found that prasugrel hydrochloride is not the only chemical whose polymorphs are determined by the hydrogen bond donor ability of the solvent. The anhydrous polymorphs of carbamazepine were found to have a tight relationship with the hydrogen bond donor/acceptor ability of the solvent.14 The metastable form II crystallizes preferentially in solvents that primarily accept hydrogen bonds (donor-to-acceptor ratio = 0) while the stable form III crystallizes simultaneously together with form II in solvents that accept and donate hydrogen bonds (donor-to-acceptor ratio > 0.5). The formation of isonicotinamide (INA) polymorphs was also investigated in terms of the hydrogen bond donor/acceptor ability of the solvent used during crystallization.24 The stable form II of INA crystallized from solvents with strong hydrogen bond donor ability or weak acceptor ability, while metastable form I or IV crystallized from solvents with strong hydrogen bond acceptor ability. According to Table 1 in this work, it can be deduced that the stable form I crystallizes preferentially from solvents with donor-to-acceptor ratio = 0 while the metastable form II or solvates crystallize preferentially from solvents with donor-to-acceptor ratio >0.475, except dichloromethane. Therefore, a polymorphic prediction method can be inferred here based on the hydrogen bond donor-to-acceptor ratio of the solvent, though further systematic analysis of the link between hydrogen bond donor/ acceptor ability and polymorphs still needs to be investigated.

solvent giving higher solubility, the heterogeneous nucleation rate of prasugrel hydrochloride in the solvent that gives the highest solubility should have the highest value. According to Table 3 and Figure 6, the solubility of form I in acetone is the Table 3. Solubility and Induction Time of Form I at 313.15 K solvent

solubility (mole fraction)

induction time (h)

ethyl acetate MIK propyl acetate butanone 2-propanol 2-butanol acetone

0.000104 0.000166 0.000192 0.000371 0.000613 0.000768 0.000998

0.66 0.38 2.11 5.28

1.46

4. CONCLUSIONS The effects of solvent on polymorph formation and nucleation of prasugrel hydrochloride were studied in this work. It was found that the formation of different forms and solvates directly depends on the solvent used during reactive crystallization. The thermodynamic mechanism of solvent effects on polymorph formation was investigated. It was found that the solute− solvent interactions can affect the solubility of prasugrel hydrochloride. The kinetic mechanism of solvent effects on polymorph formation was investigated by desolvation experiments of five+ solvates and by the heterogeneous nucleation experiments of form I during the solvent-mediated polymorphic transformation in seven pure solvents. It was found that the hydrogen bond donor ability plays a key role in determining the heterogeneous nucleation process. A hypothesis was proposed that prasugrel hydrochloride form I tends to crystallize when van der Waals force dominates the interaction between the solute and the solvent molecules while prasugrel hydrochloride form II is prone to nucleate and grow when hydrogen bonding dominates the interaction between the solute and solvent molecules.

Figure 6. Heterogeneous nucleation profiles of form I during solventmediated polymorphic transformation of form II to form I in seven pure solvents represented by the relative Raman intensity of form I.

greatest, while the solubility of form I in ethyl acetate is the lowest among the seven tested solvents. But the heterogeneous nucleation rates of form I in the two solvents are neither the fastest nor the slowest ones. It should also be mentioned that the solubilities of form I in 2-propanol and 2-butanol are higher than that in MIK. But the nucleation of form I in 2-propanol and 2-butanol did not occur within 240 h, while it took only 0.38 h for nucleation of form I in MIK. These counterintuitive results indicate that the solubility level is not the only factor that determines the nucleation rate. The effects of solvent− solute interactions on nucleation must be taken into account. It can be noted that the nucleation of form I in MIK, ethyl acetate, acetone, propyl acetate, and butanone started within 10 h at 313.15 K and all five solvents have very low values of hydrogen bond donor ability. It can be speculated then that van der Waals forces will dominate the interactions between the molecules of prasugrel hydrochloride and the molecules of the five solvents since their hydrogen bond donor abilities are very low. Strong hydrogen bonding will dominate the interactions between the solute and the solvent molecules in solvents with high values of hydrogen bond donor ability, which results in the nucleation of form II and restrains the nucleation of form I. Therefore, it can be inferred that prasugrel hydrochloride form I tends to crystallize when van der Waals force dominates the interaction between the solute and the solvent molecules while prasugrel hydrochloride form II tends to nucleate and grow when hydrogen bonding dominates the interaction between the solute and solvent molecules.

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ASSOCIATED CONTENT

S Supporting Information *

Solubilities of forms I and II. 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: [email protected]. 4524

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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 (Grant No. 21376165) and Key Project of Tianjin Science and Technology Supporting Programme (Grant No. 13ZCZDNC02000).

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REFERENCES

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