ARTICLE pubs.acs.org/crystal
Spectroscopic Characterization of Molecular Aggregates in Solutions: Impact on Crystallization of Indomethacin Polymorphs from Acetonitrile and Ethanol Sachin Lohani,*,†,‡ Irina V. Nesmelova,§ Raj Suryanarayanan,† and David J.W. Grant†,|| †
Department of Pharmaceutics, University of Minnesota, 308 Harvard Street S.E., Minneapolis, Minnesota 55455, United States Department of Physics and Optical Sciences, University of North Carolina at Charlotte, Grigg Hall 306, 9201 University City Blvd, Charlotte, North Carolina 28223, United States
§
ABSTRACT: Infrared (IR), Raman, and nuclear magnetic resonance (NMR) spectroscopic techniques were used to investigate the nature of molecular aggregation of indomethacin (I) in acetonitrile and ethanol solutions. Spectroscopic data provided no evidence for self-aggregation of I in supersaturated solutions of acetonitrile or ethanol. As the concentration of I was increased by more than 130 fold, from 5 104 to 0.067 M in acetonitrile, the diffusion coefficients of I and water (residual) measured by pulse field gradient spin echo nuclear magnetic resonance (PFGSE-NMR) showed a decrease of about 5 and 27%, respectively, while the diffusion coefficient of acetonitrile did not change. The chemical shift and Nuclear Overhauser Effect Spectroscopy data confirmed formation of hydrogen bonds between the carboxyl group of I and residual water at low concentrations of I in acetonitrile, while IR-Raman data suggest formation of weak hydrogen bonds between I and acetonitrile at higher concentrations. In contrast, the diffusion coefficients of I and ethanol decreased by up to 15% as the concentration of I in ethanol was increased from 3.6 104 to 0.3 M. This together with IR and Raman data suggest formation of strong intermolecular hydrogen bonds between I and ethanol. In summary, our data suggest that solutesolvent interactions determine the critical supersaturation at the onset of nucleation (σcr) and thereby control the preferential crystallization of I polymorphs from supersaturated solutions of acetonitrile and ethanol. Furthermore, our data highlight the importance of intermolecular interactions between solute and residual water in aprotic solvents, such as acetonitrile.
’ INTRODUCTION Crystallization is a key processing technique during isolation and purification of fine chemicals in a wide range of industries including pharmaceuticals, agrochemicals, and foods. Crystallization is also central to various biological processes, for example mineralization of bones and teeth,1 formation of kidney stones,2 and progression of various diseases such as, malaria.3 Therefore, a thorough molecular level understanding of the crystallization process has a wide range impact and is highly desirable. Crystallization is generally believed to involve two steps. The first is nucleation and refers to the formation of nanoscopic clusters of solute molecules in the supersaturated solution which act as embryos for the formation of the new crystalline phase. The next step is crystal growth, whereby the nuclei increase in size to form macroscopic crystals. A given compound can exist in more than one crystalline structure (or polymorph), resulting from different arrangements or conformations of molecules in the crystal lattice.4 Polymorphs have identical chemical composition and are indistinguishable in vapor and solution phase.5 However, they exhibit differences in physical and chemical properties in the solid state. Under specified conditions (with the exception of thermodynamic transition points), one crystalline form has the lowest free energy and is the thermodynamically stable form. All other forms are metastable. Although the stable form has the greatest thermodynamic drive to crystallize, the r 2011 American Chemical Society
solutesolute and solutesolvent intermolecular interactions together determine the crystallization behavior of the supersaturated solutions. Literature reports on solutes such as 5-fluorouracil6 and tetrolic acid7 have demonstrated a clear link between molecular association in solution and the crystallization of polymorphs from these solutions. In contrast, a study by Saito et al.,8 on molecular aggregation in solutions of p-acetanisidide using NMR, concluded that although the hydrogen-bond motif in clusters was similar to that in the solid form that crystallizes, the conformation adopted by the molecules in the two states were different. Similarly, a study on lysozyme aggregation in supersaturated aqueous solutions concluded that the 3-dimensional structure in the crystal was different from that within the molecular clusters in the supersaturated solutions, which after a long induction period transforms into the nuclei of the crystalline phase.9 Investigation of molecular clustering in aqueous solution of various inorganic dihydrogen orthophosphate salts by Raman spectroscopy also concluded that the structure of clusters in supersaturated solution had little resemblance to the crystal structure of the salts.10 Even for the same system, different conclusions have been reported.11,12 For example, an earlier Received: January 27, 2011 Revised: March 16, 2011 Published: March 29, 2011 2368
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supersaturation, respectively. The overall objective of the work was to understand the solvent-effect mentioned above, in particular to investigate the role played by acetonitrile and ethanol in selective crystallization of I polymorphs from their respective supersaturated solutions. The ultimate goal is to obtain the desired polymorph in a predictable and reproducible fashion. One of the ways this can be accomplished is through understanding the “solvent effect” at a molecular level. The specific objectives of this work were: (i) to understand the nature of molecular aggregation (solutesolute and solutesolvent) as a function of concentration of I in acetonitrile and ethanol, the two solvents of interest, (ii) to probe the change in size of molecular aggregates as a function of concentration by diffusion measurement, and (iii) to analyze the hydrogen-bond motif in the crystal structures of the R- and γ- forms of I. We have used spectroscopy, specifically vibrational (infrared and Raman), and nuclear magnetic resonance techniques, to probe the nature of intermolecular interactions in solutions. Diffusion coefficient measurements, by pulse field gradient spin echo nuclear magnetic resonance (PFGSE-NMR), provided a measure of change in the average size of molecular aggregates.
’ EXPERIMENTAL SECTION Figure 1. (a) Indomethacin (I; 1-[4-chlorobenzoyl]-5-methoxy-2methyl-1-H-indole-3-acetic acid), showing two types of carbonyl group in the molecule. Also shown are the two torsion angles τ1 and τ2. (b) Hydrogen bonded dimer in the crystal structure γ-polymorph of I (left), wherein both molecules have the same cis conformation. Hydrogen bonded trimers in the crystal structure of R-polymorph (right); molecules labeled a and c have cis conformation, while b has trans conformation.
study based on “tailor-made” additives11 concluded that gylcine exists as hydrogen-bonded cyclic dimers in supersaturated aqueous solutions. However, Huang et al.12 have recently reported melting point depression data suggesting that glycine exists mainly as monomers in these solutions. In short, the nature of molecular self-assembly leading to nucleation and crystallization from supersaturated solutions is complicated and is not completely understood. Indomethacin, (I; Figure 1a), a weakly acidic non steroidal anti-inflammatory drug with a pKa of 4.5, was chosen as a model compound for this study. While there is some disagreement in the literature on the number of solid forms of I, the general consensus is that there are at least two polymorphs, R- and γ(stable form), that are monotropically related under atmospheric pressure. Analyses of the crystal structures of R- and γ- forms reveal that the hydrogen bonding motif between the nearest neighbors differs in the polymorphs (shown in Figure 1b), which makes this system ideal for experimentally investigating the link between the initial molecular associations in solutions and the polymorph obtained. Prior work in our laboratory, on the crystallization of I from ethanol and acetonitrile solutions, has shown that the polymorphic form of I obtained during crystallization, depended on the nature of the solvent as well as the degree of supersaturation (defined as the ratio of concentration to solubility) at the onset of spontaneous nucleation, referred to henceforth as the critical supersaturation or σcr.13,14 Crystallization from acetonitrile always yielded the γ- (stable) form, whereas crystallization from ethanol yielded the R- and γ- forms at high and low
Materials. Indomethacin, d6-ethanol (C2D5OD) and acetonitrile (99.8% pure; 0.02% w/w water content) were obtained from SigmaAldrich, d3-acetonitrile (CD3CN) from Cambridge Isotope Laboratories, ethanol (absolute 200 proof) from Apper Alcohol and Chemical Company and n-hexane (ACS grade) from EMD Chemicals. All the solvents were stored over molecular sieves to minimize the residual water content. Methods. Solubility determination. Excess γ- polymorph was dispersed in the solvent (ethanol or acetonitrile; 20 mL), maintained at 25 °C, and stirred. Aliquots were taken periodically and the absorbance was measured at 318 nm in a UV spectrophotometer (DW-2000, Olis Aminco, Bogart, GA). Equilibrium was assumed to have been reached when the change in the concentration, in successive measurements, was CdO stretch region for solutions of I in acetonitrile (25 °C). The numbers 16 respectively refer to pure acetonitrile (0 M), 0.01, 0.02, 0.04, 0.07, and 0.10 M solution of I in acetonitrile. Water Content. Karl Fischer titrimetry15 (KFT) (Moisture Meter, model CA-05, Mitshubishi Chemical Industry Ltd. Tokyo Japan) was used to coulometrically determine the water content. Solution State NMR. Solutions of I, in d3-acetonitrile and d6-ethanol, at concentrations ranging from 5.05 104 to 7.15 101 M (σ = 1.79), and 3.46 104 to 2.98 101 M (σ = 4.1), respectively, were analyzed. The residual water content in d3-acetonitrile was 0.023% w/w ((0.003). Chemical Shift Measurement. Chemical shifts were determined from proton spectra collected using a Inova Unity Plus 600 MHz spectrometer, equipped with HCN probe and triple-axis pulse field gradient unit, with respect to TMS (0.01% v/v) peak . The spectra were analyzed using VNMR software (Varian, Inc., Palo Alto, CA). At a given concentration of I, the relative chemical shift for a I-proton was calculated by subtracting its chemical shift at the lowest analyzed concentration from the observed chemical shift, while the relative chemical shift for a solventproton was calculated by subtracting its chemical shift in the pure solvent. Nuclear Overhauser Effect Spectroscopy (NOESY). 2D-NOESY experiments were performed in solutions of I in d3-acetonitrile using a mixing time of 0.65 s. The number of t1 increments was 512, each with 2048 complex data points over a spectral width of 5.4 kHz in both dimensions with the carrier placed on the water resonance. Sixteen scans were time averaged for each t1 increment. Diffusion Coefficient Measurement. The self-diffusion coefficients, D, of I and solvent molecules were determined by pulse field gradient spin echo nuclear magnetic resonance (PFGSE-NMR) technique. Double stimulated echo pulse sequence was employed to suppress convection artifacts, as described by Jerschow et al.16 The duration of rectangular gradient pulses, δ, was set to 2 ms, while the separation between them, Δ/2, was set to 100 ms. The number of transients acquired varied from 16 for the most concentrated samples to 128 for dilute samples. The amplitude of gradient pulses, g, was varied from 2 to 10 G cm1 as calibrated using a Varian deuterated water standard sample. Spin echo signal intensities, I, were determined by integration of the proton peaks, and the diffusion coefficient was calculated from the slope of linear fits of ln(I/I0) vs g2 according to the equation: 4δ γ 2δ2 Δ þ þ 2τ I=I0 ¼ expðmg 2 Þ, where m ¼ D^ ð1Þ 3
Here I0 is the spin echo signal intensity in the absence of gradient (g = 0), γ^ is the gyromagnetic ratio of proton (not to be confused with symbol γ used for the polymorph of I), and τ is the spacing between the gradient pulse and the following 90° radio frequency pulse. The diffusion coefficient of a species of interest was normalized by dividing the observed diffusion coefficient by its value in the solution at the lowest analyzed concentration of I.
’ RESULTS Molecular Aggregation in Acetonitrile Solutions. In acetonitrile solution, there are several possible aggregate states of I, such as dimers (as observed in γ-polymorph) or trimers (as observed in R-polymorph), as well as, hydrogen bond adducts of I with acetonitrile and with residual water. We first used infrared and Raman spectroscopy to examine the aggregation state of I in solutions at concentrations ranging from 0.0132 M (undersaturated) to 0.101 M (supersaturated). The concentration range was limited by the sensitivity (lowest concentration) and the stability of solution with respect to crystallization (highest concentration). The IR spectrum of I in acetonitrile solutions (Figure 2a) shows two peaks in the carbonyl (>CdO) stretch region corresponding to two types of >CdO groups in I (Figure 1a). Figure 2b shows the Raman spectrum of I in acetonitrile solutions with a single peak in the carbonyl (>CdO) stretch region. To assign the observed peaks to each type of >CdO, as suggested earlier, FTIR and Raman spectra were collected with progressively increasing concentration of triethylamine (TEA) in solution (data not shown).17 As the concentration of TEA increased, the IR peak at 1741 cm1 decreased in intensity and eventually disappeared, while the peaks at 1687 cm1 (IR) and 1683 cm1 (Raman) showed a small increase in intensity along with a small shift in the maxima to lower wavenumber values. TEA is a tertiary amine (pKa = 11.0) which is expected to predominantly interact with COOH (pKa = 4.5) of I by accepting its proton to form the COO ion thus shifting the 2370
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Crystal Growth & Design vibration of the carboxyl >CdO to a lower frequency,18 while the vibration of chlorobenzoyl >CdO is expected to be minimally affected. Consequently, the peaks at 1687 cm1 (IR) and 1683 cm1 (Raman) were assigned to symmetric chlorobenzoyl >CdO stretch. The peak with maxima around 1741 cm1 (IR) was assigned to the asymmetric stretch of carboxyl >CdO, the corresponding symmetric stretch was concluded to be Raman inactive, as had been confirmed by ab initio calculation.19 When carboxyl >CdO is not hydrogen-bonded, a band is expected in the 17601735 cm1 region, in both IR and Raman spectra, while a hydrogen-bonded centrosymmetric dimer of carboxyl group is expected to have a band between 1680 and 1640 cm1 in Raman and between 1720 and 1690 cm1 in IR spectra. The asymmetric stretch of carboxyl >CdO in crystalline γ- form, which is known to contain carboxyl dimers, is observed at 1717 cm1.2022 In contrast, the asymmetric stretch of carboxyl >CdO of I in acetonitrile solution was observed close to 1741 cm1 (or 24 cm1 higher than expected for a dimer), which suggests that the carboxyl group of I predominantly existed as a monomer at all analyzed concentrations. As the concentration of I was increased from 0.01 to 0.1 M, the peak maxima for carboxyl >CdO (Figure 2a) showed a small shift of 2 cm1 to a lower frequency, which may be attributed to formation of hydrogen bonds.23 However, the small magnitude of change suggests weak bonding. The chlorobenzoyl >CdO peak maximum was unaffected by solute concentration, both in the infrared (Figure 2a) and in the Raman spectra (Figure 2b). The frequency of chlorobenzoyl >CdO was expected to decrease if it were involved in formation of hydrogen bonds with increase in concentration of I. The lack of such a change suggests that chlorobenzoyl >CdO was not involved in any hydrogen bond formation in acetonitrile. Therefore, we conclude that IR data on acetonitrile solutions of I does not provide evidence for formation of dimers or trimers. Although IR and Raman data ruled out self-aggregation of I, the peak shifts in IR data suggests that the carboxyl group may form weak hydrogen bonds with other molecular species in acetonitrile solutions. We used NMR spectroscopic approach to investigate the possibility of interaction of I with acetonitrile and residual water molecules. Figure 3a shows the relative chemical shifts of the carboxyl proton (open triangles) and of water (open squares) calculated by subtracting respectively the chemical shift of the carboxyl proton δ0I= 9.120 ppm in 5 104 M solution of I in d3acetonitrile and of water δ0W= 2.217 ppm in d3-acetonitrile in absence of I. The residual water content in d3-acetonitrile was 0.027% w/w ((0.003) or 0.012 M ((0.001) as determined by Karl Fischer titrimetry. The water protons show a downfield shift as the concentration of I increases, which suggests a decrease in their diamagnetic shielding and is attributed to loss of charge on the protons due to formation of hydrogen bonds.24 The carboxyl proton (COOH) of I shows a small upfield shift at low concentrations followed by a downfield shift at concentrations higher than 0.04 M. Figure 3b shows the normalized diffusion coefficients of I (triangles), acetonitrile (circles), and water (squares). Diffusion coefficients of I were normalized by dividing by the value, D0I = 1.31 105 cm2s1, measured in the reference solution, which was selected as the lowest analyzed concentration of 5.05 104 M in d3-acetonitrile. Similarly, the diffusion coefficients of acetonitrile and water were normalized by dividing by their respective values, D0ACN = 3.91 105 cm2 s1 and D0W = 5.29 105 cm2 s1, measured in neat d3-acetonitrile.
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Figure 3. (a) Relative chemical shift (δδ0) of the carboxyl proton of I (Δ) and proton of residual water (0) in solutions of I in CD3CN at 25 °C. The vertical arrow refers to the concentration of the solution saturated with respect to γ-polymorph at 25 °C. (b) Normalized diffusion coefficients (D/D0) of various molecular species in solutions of I in CD3CN at 25 °C; I (2), ACN (O), and residual water (9). The solid line at the top reflects the average normalized diffusion coefficients of I (= 0.99) in unsaturated solutions while the solid line in the middle corresponds to the average normalized diffusion coefficients of I (= 0.95) in supersaturated solutions. The dotted line corresponds to the normalized diffusion coefficients of I upon dimer formation (= 0.79) estimated using StokesEinstein equation. The solid line at the bottom corresponds to the measured (0.73) normalized diffusion coefficient of water. The value of normalized diffusion coefficient of water calculated using the StokesEinstein equation for a 1:1 adduct with I is 0.57 (refer to the text for details on calculation of D/D0 and δδ0).
To interpret the diffusion data we used the StokesEinstein equation (shown below): D¼
kB T 6πηr
ð2Þ
where kB is the Boltzmann constant, T is the absolute temperature, η is bulk viscosity, and r is the radius of the diffusing species. Although not strictly applicable due to close relative sizes of the molecules involved, this equation has been used in previous studies to model the size of molecular aggregates formed by small 2371
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Table 1. Calculated and Estimated Diffusion Coefficients of Various Molecular Species in d3-Acetonitrile and d6-Ethanol diffusion
calculated using
experimentally
StokesEinstein
bulk viscosity (η) diffusing determined solvent (cPoise) species ( 105 cm2 s1) CD3CN
0.37346
CH3CN H2O
diffusion coefficient,
coefficient,
equation ( 105 cm2 s1)
3.91
3.96b
5.29
2.33c 5.28b 4.03c
C2D5OD
1.152
a
I
1.33
1.26c
C2H5OH
0.92
1.02d 0.73c
I
0.43
0.41c
Calculated using the “square root law”, that is, by multiplying the viscosity of C2H5OH (1.083 cP 39) by the square root of the ratio of the molecular weight of C2D5OD to C2H5OH. b Calculated by multiplying the previously reported diffusion coefficients in the bulk solvent CH3CN48 by the ratio of the viscosity of CH3CN (0.341 cP39) to CD3CN (0.373 cP46). c Calculated by StokesEinstein equation (eq 2), the molecular radii for CH3CN,49,50 I,32,33 and C2H5OH,51,52 were calculated form the respective crystal structure(s) available in the Cambridge Structural Database. Average value was taken for cases where compound exhibited polymorphs. Molecular radius of water was taken from Thiel et al.28 d Calculated by multiplying the previously reported diffusion coefficients in the bulk solvent C2H5OH53 by the ratio of the viscosity of C2H5OH (1.083 cP39) to C2D5OD (1.152 cP, calculated as explained in footnote a). a
47
molecules in solution.25 According to this equation the normalized diffusion coefficient (calculated as described above) is inversely proportional to the ratio of ’effective molecular radius’ of the diffusing species at the concentration of interest and at the reference concentration. Table 1 lists the experimentally determined and estimated diffusion coefficients of various molecular species in d3-acetonitrile. The molecular radii (r) of various species and the solvent viscosities (η) listed in Table 1 were obtained from the literature. As shown in Figure 3b the normalized diffusion coefficient of acetonitrile remains more or less constant even after more than a 130-fold increase in concentration of I from 5.05 104 to 0.0674 M. The diffusion coefficients of water and I show a stepwise concentration dependence that cannot be explained by merely increasing viscosity of solution, but the change of interactions patterns between different species in solution has to be taken into account. The diffusion coefficient of water decreased by about 27%, as the concentration of I was increased from zero to 0.0132 M, which suggest a relatively large increase in the effective molecular size of water in solution. At concentrations of I > 0.0132 M, the diffusion coefficient of water reaches a plateau and does not change. The chemical shift and diffusion data of water are shown only up to 0.0308 M I, because at higher concentrations, the peak corresponding to water protons overlaps with the H8 protons from the methyl group of I. The dependence of the chemical shift and the diffusion of water on the concentration of I suggest that it interacts with I. In the absence of I, water at residual concentration (∼0.0121 M) is expected to exist predominantly as 1:1 hydrogen bonded adduct of acetonitrile.26,27 The StokesEinstein eq 2 predicts a decrease in diffusion coefficient of water by 43% as its aggregation changes
from 1:1 adduct with acetonitrile to 1:1 adduct with I. For the above calculation, the molecular radius of water was taken from Thiel et al.,28 while molecular radii for acetonitrile, and I were calculated for molecular volumes reported in their crystal structures assuming a spherical molecular shape. The literature references for crystal structures and the bulk viscosities used in above calculations are listed in the footnote c of Table 1. We have also assumed that hydrogen bond adducts are spherical and that their volume is the sum of volumes of the individual components. On the other hand, the normalized diffusion coefficient of I shows a small (∼5%) decrease at concentrations of I > 0.0400 M (the saturation solubility of γ in acetonitrile at 25 °C), which suggest only a small increase in the molecular size of I and is consistent with the absence of dimers or trimers. Equation 2 predicts a decrease in diffusion coefficient of I by 1, 5, and 21% as it aggregates to form 1:1 adduct with water, 1:1 adduct with acetonitrile, and dimer (or I2), respectively. The difference between the diffusion coefficient of I and the 1:1 adduct of I with water is too small to be differentiated by this technique. As shown in Figure 3b, at concentrations >0.04 M, the observed normalized diffusion coefficient of I is close to that of the 1:1 adduct of I with acetonitrile. The normalized diffusion coefficients of acetonitrile and I decreased by ∼5% as the concentration of I increased by more than 130 fold, from 5.05 104 to 0.0674 M. The interaction between I and water was further confirmed by measuring 2D-NOESY spectra (Figure 4) in 0.0185 M solution of I in d3-acetonitrile with residual water concentration of 0.0132 M. A cross peak was observed between the water protons (∼2.5 ppm) and the carboxyl proton of I (∼9.2 ppm) on the NOESY spectra. Due to the labile nature of the carboxyl proton, the origin of cross-peak can be attributed to dipolar cross-relaxation between the two protons and/or to proton exchange - either of which suggests the spatial proximity of the corresponding molecular regions.29 Therefore, NOESY plot together with the chemical shift and diffusion coefficient data confirms the formation of hydrogen bonds between water and carboxyl group of I. In addition, the 2D-NOESY plot also confirms that I molecules exist in both cis and trans conformations in acetonitrile solution, as expected from the low rotational energy barrier between the two conformations (see Discussion section). As discussed earlier, in γ- polymorph, I exists only in cis conformation, while it exists in both cis and trans conformations in the R- polymorph. This suggests that the predominant crystallization of γ- from acetonitrile cannot be explained from the conformation of I in solution as both polymorphs are conformationally accessible. Molecular Aggregation in Ethanol Solutions. We studied molecular aggregation of I in ethanol solutions, using the same approach as for acetonitrile solutions. Unlike acetonitrile, ethanol is extensively self-associated and has a tendency to accept as well as donate protons.30 As a result, in addition to the hydrogen bonded dimers and trimers of I, several molecular aggregates such as hydrogen bond adducts of I with various self-associated ethanol species are also possible. Furthermore, due to the higher solubility of I in ethanol and the longer stability of supersaturated solution in ethanol, the maximum analyzed concentration of I in ethanol was four times that in acetonitrile. Figure 5 shows the vibrational spectra of I at concentration ranging from 0.020 to 0.392 M in ethanol. The choice of concentrations was limited by the signal-to-noise for the lowest concentration and stability of solution with respect to crystallization for the highest concentration. We observed two peaks in 2372
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Figure 4. 2D-NOESY plot of IND (0.02 M) in CD3CN with residual water content of 0.023% w/w (0.013 M). The circled cross peak is between the water proton and the carboxyl proton of I, and the respective peaks are highlighted (*) in the spectrum. The mix time was 0.65 s, and the temperature was 25 °C. Also shown is the proton peak assignment for I in CD3CN. Refer to Figure 1a for the numbering of protons.
Figure 5. (a) FT-IR and (b) Raman spectra in the >CdO stretch region for solutions with different concentration of I in ethanol, at 25 °C. The numbers 16 respectively refer to 0.020, 0.101, 0.175, 0.247, 0.321, and 0.392 M solution of I in ethanol.
IR (Figure 5a) and one peak in the Raman spectrum (Figure 5b) as with the acetonitrile solutions. In contrast to the acetonitrile solutions, the carboxyl and chlorobenzoyl carbonyl peaks are broad in the IR spectrum and they have merged to form a single band with a shoulder in ethanol solutions (Figure 5a). Such peak broadening is expected due to solutesolvent interaction in hydrogen bond forming solvents.21 Interaction with TEA was used to assign the peak observed at 1711 cm1 in the IR
spectrum to the carboxyl >CdO; in acetonitrile this peak was observed at a much higher wavenumber (1741 cm1). The peak at 1691 cm1 in IR spectrum and at 1688 cm1 in Raman spectrum were assigned to the chlorobenzoyl >CdO. The position of the carboxyl >CdO peak maxima in the IR spectra did not change with an increase in the concentration of I, while the chlorobenzoyl >CdO peak maxima in IR and Raman spectra showed a small shift toward the lower wavenumber 2373
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Crystal Growth & Design (1 cm1 in IR and 2 cm1 in Raman). This suggests that, with increase in the concentration of I, the chlorobenzoyl >CdO may be involved in the formation of hydrogen bonds. However, when a >CdO group is hydrogen-bonded but not dimerized, for example in alcohol-carbonyl bonds, a band in the 17301705 cm1 region is expected in the IR spectra, while a hydrogen-bonded centrosymmetric dimer of carboxyl group is expected to have a band between 1720 and 1690 cm1 in the IR spectra.21 Therefore, the IR band for the carboxyl >CdO of I in ethanol solution (at 1711 cm1) may either be due to formation of carboxylic acid dimers (as has been previously attributed31) or due to formation of strong hydrogen bonds between the carboxyl group of I and ethanol. To answer the above question, we performed the diffusion coefficient and chemical shift measurements in ethanol solutions of I. As shown in Table 1, there is good agreement between the experimentally determined diffusion coefficients of I at the lowest analyzed concentration in d6-ethanol, and the values estimated using eq 2 for monomers of I in d6-ethanol. Formation of a solute dimer (I2) will increase the “effective” molecular radius of I by 26% and thus reduce the diffusion coefficient by 21% based on eq 2. While formation of a 1:1 hydrogen bond adduct between I and ethanol will increase the “effective” molecular size by a mere 5% and will therefore have a minimal effect on the diffusion coefficient. Furthermore, the experimental diffusion coefficient of I determined at the lowest analyzed concentration in d3-acetonitrile is 3.1 times higher than that at the lowest analyzed concentration in d6-ethanol, which can be entirely accounted for by the higher viscosity of d6-ethanol. This suggests that at low concentrations, the “effective” molecular radius of I in ethanol is approximately the same as in acetonitrile, which we have shown above to be the 1:1 adduct of I with water. Therefore, our low concentration diffusion data clearly suggest that the observed IR band for the carboxyl >CdO of I in ethanol solution (at 1711 cm1) is due to formation of hydrogen bonds between the carboxyl group of I and ethanol and not due to solute dimers (I2). Figure 6a and b shows, as a function of the concentration of I, the normalized diffusion coefficients and the ratio of the normalized diffusion coefficients of the various molecular species to that of TMS in d6-ethanol at 25 °C. The normalized diffusion coefficients of I, ethanol, and tetramethyl silane (TMS) were calculated by dividing the observed diffusion coefficients by D0I, D0E, and D0T, respectively. Here, D0I = 0.43 105 cm2 s1, is the diffusion coefficient of I in 3.46 104 M solution (lowest analyzed concentration) in d6-ethanol, while D0E = 0.92 105 cm2 s1, and D0T = 1.22 105 cm2 s1, are respectively the diffusion coefficients of ethanol and TMS, in d6-ethanol. As shown in Figure 6a, the normalized diffusion coefficients of I, ethanol, and TMS decreased with an increase in concentration of I, attributed to the increase in the bulk viscosity of the solution. Furthermore, the normalized diffusion coefficients of ethanol and TMS stay within one standard deviation of each other, except at the highest analyzed concentration. However, the normalized diffusion coefficient of I becomes significantly lower compared to ethanol and TMS at concentrations >0.035 M suggesting that in addition of the increase in bulk viscosity some other mechanism such as association with higher ethanol aggregates is responsible for the decrease in the diffusion coefficient of I. This is in contrast to the acetonitrile solutions of I, where the normalized diffusion coefficient of the solvent and hence the bulk viscosity of the solutions did not change significantly over the
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Figure 6. (a) Normalized diffusion coefficients (D/D0) of various molecular species in solutions of I in d6-ethanol (C2D5OD) at 25 °C; I (2), TMS (b), and C2D5OD (9). (b) Plot showing the ratios of the normalized diffusion coefficient of I calculated with respect to the diffusion coefficients of TMS in solutions of d6-ethanol at 25 °C. The arrow corresponds to the saturated concentration of I in d6-ethanol, while the vertical dashed line on its left-hand side represents the 0.015 M solution of I (undersaturated), and the vertical dashed line on its right had side represents 0.123 M solution of I (supersaturated). The dashed horizontal lines, from top to bottom, respectively refer to the estimated ratios of normalized diffusion coefficients for I:ethanol for (1:1), (1:2), (1:4) and I2 (dimer). The ratios were estimated using the Stokes Einstein equation. Please refer to the text for details on the calculation of the normalized diffusion coefficient (D/D0) and its ratio.
entire concentration range (Figure 3b). This was attributed to a wider range of concentrations of I in ethanol that could be analyzed than in case of acetonitrile. To account for the viscosity dependence discussed above, d6-ethanol solutions were spiked with 0.1% v/v tetramethylsilane (TMS). We have used TMS as an internal standard, because interactions involving TMS are not expected to change significantly with increase in concentration. Hence a change in its diffusion coefficient can be taken as a measure of change in the bulk viscosity of the solution. The normalized diffusion coefficients of I determined at different concentrations were divided by the normalized diffusion coefficients of TMS measured in the same solution to eliminate the viscosity dependence (Figure 6b). At concentrations CdO due to formation of hydrogen bond is transferred to the chlorobenzene ring and is reflected in the more pronounced decrease in the relative chemical shift of the protons associated with this ring compared to the other protons (Figure 7). This is in agreement with the peaks shifts of the chlorobenzoyl >CdO observed in IR and Raman spectra. Therefore, at low concentrations of I, 1:1 (I:ethanol) hydrogen bond adduct is expected to predominate in solution, while at high concentrations, larger aggregates of I and ethanol, such as 1:2, 1:3, and 1:4, are expected to exist.
’ DISCUSSION
Figure 7. Relative chemical shift (δδ0) of various protons in solutions of I in C2D5OD at 25 °C; H1 and H10 protons of I (0), H2 and H20 protons of I ()), average relative chemical shift of protons H3, H4, H5 and H6 of I (Δ) with the error bars representing the standard deviation; residual >CH2 protons in C2D5OD (), residual CH3 protons in C2D5OD (O), and residual OH protons in C2D5OD (þ). The vertical arrow points the saturation concentration with respect to γ- polymorph at 25 °C. Refer to the text for details of the calculation of the relative chemical shift (δδ0).
0.015 and 0.123 M, and the decrease in the value of the ratio is close to that predicted for a 1:2 (I/ethanol) aggregate. The ratio decreases further at concentrations >0.123 M, and this is attributed to formation of higher solutesolvent aggregates, such as 1:4 (I/ethanol). Under limitations described earlier, the StokesEinstein equation predicts a decrease in diffusion coefficient by 4, 11, and 17%, as it aggregates to form 1:2 (I/ethanol), 1:4 (I/ethanol), and solute dimer (I2), respectively. The percent decrease was estimated relative to a 1:1 (I/ethanol) aggregate, under the assumption that it predominates at low concentrations. Figure 7 shows the relative chemical shift data of the various molecular species, as a function of the concentration of I in d6-ethanol. The chemical shifts of various protons of I (labeled in Figure 1a) at higher solute concentrations were calculated by subtracting the chemical shift of the respective protons at the lowest analyzed concentration of I in d6-ethanol (= 3.6 104 M). The relative chemical shifts of H1/H10 and H2/H20 protons of I showed a more pronounced decrease than the other protons of I. To aid the visual comparison, only the average value of the relative chemical shifts of all the remaining protons of I were plotted in Figure 7. The relative chemical shifts of the residual protons in C2D5OD were calculated by subtracting the chemical shift of the respective protons in d6-ethanol in the absence of I. As shown in Figure 7, the relative chemical shift of the hydroxyl proton of ethanol increases with an increase in the concentration of I, suggesting formation of hydrogen bond between ethanol and I. The two >CdO of I can act as possible hydrogen bond accepting sites and its carboxyl proton can be donated to form hydrogen bond (Figure 1a). However, due to steric hindrance associated with the chlorobenzoyl >CdO, the hydrogen bond formation will be more favorable with the carboxyl >CdO. Consequently, the carboxyl group of I is likely to be involved in hydrogen bonding with ethanol at all concentrations, whereas the chlorobenzoyl >CdO of I is likely to participate in the hydrogen bonding with ethanol only at higher concentrations.
Analysis of Polymorphism in Indomethacin. The crystal structure of γ- form belongs to the P1 space group. Its asymmetric unit has one molecule that exhibits cis conformation at the amide bond connecting the chlorobenzoyl and the indole rings.32 The hydrogen bond motif in γ- consists of classical hydrogen bonded cyclic dimers formed between the carboxyl groups of two molecules of I, which exist in cis conformation at the amide bond, as shown in Figure 1b. The crystal structure of R belongs to the P21 space group and has three molecules in the asymmetric unit (labeled a, b, c in Figure 1b).33 Molecules labeled a and c exhibit cis conformation similar to that in γ-, while molecule b exhibits trans conformation at the amide bond. The hydrogen bond motif is also different in R-, wherein molecules a and b from a hydrogen-bonded cyclic dimer similar to that in γ- polymorph. In addition, carboxyl OH of the molecule c forms a hydrogen bond with chlorobenzoyl >CdO of the molecule b to form a hydrogen bonded trimer (Figure 1b). The conformationalenergy space of I, as defined by the torsion angles τ1 and τ2 (Figure 1a), was searched in steps of 3° from 0 to 360° using molecular mechanics. At each step, geometry was optimized using COMPASS force field incorporated in Materials Studio. The cis and trans conformers differ by a 180° degree rotation about τ1 and have similar energy with cis being slightly more stable than trans.34,35 These calculations suggest a small energy difference of 0.01 kcal/mol between cis and trans conformers with a rotational energy barrier of less than 4 kcal/mol, suggesting that the two conformers can easily interconvert under ambient conditions. This was confirmed experimentally by the 2D-NOESY data. Crystallization of Indomethacin Polymorphs from Acetonitrile and Ethanol. Previous work in our laboratory13,14 has shown that on cooling a solution of I in acetonitrile, predominantly the stable polymorph (γ-) was obtained, both at fast (0.5 °C/min) as well as slow (0.1 °C/min) cooling rates. In addition, the average value for critical supersaturation at the onset of spontaneous nucleation σcr, was 1.4 ((0.1). Furthermore, σcr values in acetonitrile solution were found to increase significantly as a function of water content in the solvent. For example during crystallization of I from acetonitrile with 20 mol % water, the average value of σcr was 3.0 ((0.5). The nature of polymorph of I that crystallizes from ethanol solutions was found to depend on σcr: γ- form was obtained when σcr was low, which was achieved at a slow cooling rate (0.1 °C/min), while the metastable polymorph (R-), was obtained when σcr was high, which was achieved at a fast cooling rate (0.5 °C/min). In addition, higher σcr values were also observed during cooling crystallization of I from ethanol solutions, the average value of σcr being 3.5 ((1.2). According to the classical nucleation theory, the logarithm of σcr is directly proportional to the driving force 2375
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acetonitrile is explained by the low σcr attainable in acetonitrile. This results in very low supersaturation with respect to the metastable polymorph I-R at nucleation onset leading to preferred crystallization of I-γ. Practical Implications on Crystallization of Polymorphs. Our work suggests that the hydrogen-bonding propensity of a solvent significantly affects the energy barrier for nucleation. This has practical implications in polymorph selectivity in crystallization experiments performed without seeding—a common practice during early stages of drug development. Our work suggests that in order to consistently get the stable polymorph via spontaneous nucleation, a solvent system with low energy barrier for nucleation will be preferable, that is, one that does not form strong hydrogen bonds with the solute. On the other hand, a solvent system with a high energy barrier for nucleation, that is, one that forms strong hydrogen bond with the solute, will be preferable to improve the chances of obtaining a metastable polymorph.
’ CONCLUSIONS We studied molecular aggregation in supersaturated solutions of I in acetonitrile and ethanol with the goal of better understanding the preferential crystallization of γ- polymorph from acetonitrile as well as ethanol solutions at low supersaturation and R- from ethanol solutions at high supersaturation. The spectroscopic data presented in this work does not support self-aggregation of I in supersaturated solutions of acetonitrile or ethanol. In acetonitrile solutions, I forms hydrogen bonds with residual water and acetonitrile at low and high solute concentrations, respectively. In ethanol solutions, I forms strong hydrogen bonds with ethanol monomers at low concentration and with higher ethanol aggregates at higher concentrations. In summary, our data suggests that during crystallization of I, solutesolvent interactions propagate the observed “solvent-effect” by impacting the critical supersaturation at the onset of nucleation, which is a key determinant of the relative rates of nucleation and crystal growth of polymorphs. ’ AUTHOR INFORMATION Corresponding Author
*Sachin Lohani, Ph.D. Phone: 908-473-6620. E-mail: sachin_lohani@ merck.com. Present Addresses ‡
S-7-E-2 Analytical Research, Merck & Company, Summit, NJ 07901
Notes
)
required to overcome the energy barrier for nucleation. Therefore, the energy barrier for nucleation is greater in ethanol than in acetonitrile solutions. Implications of Molecular Aggregation in Acetonitrile and Ethanol Solutions. Molecular aggregation in solutions of carboxylic acid in acetonitrile depends on the structure of the carboxylic acid, for example, differential vapor pressure study found no evidence of aggregation of benzoic acid at concentrations up to 0.1 M in acetonitrile.36 While studies on acetic acid and butyric acid solutions in acetonitrile have suggested formation of solvated solute aggregates.37,38 Acetonitrile is an aprotic solvent with a high dielectric constant (ε = 36.01), high dipole moment (μ = 3.37 D at 25 °C), a moderate tendency to accept hydrogen bonds, and a weak tendency to donate hydrogen bonds.39,40 All these factors are likely to stabilize the monomers of I compared to higher aggregates (dimers or trimers). Moreover, spectroscopic data does not provide any evidence of selfaggregation of I in under- and super- saturated acetonitrile solutions. Similar observations have been reported in glycine system.12 However, our data does provide evidence that at low concentrations (CdO peak of I in the IR spectrum of acetonitrile solutions is 30 cm1 higher than that in ethanol solutions, suggesting that I is weakly hydrogen bonded in the former and strongly in the latter. As a result, molecules of I are expected to have a greater mobility in supersaturated acetonitrile solution than in supersaturated ethanol solutions. Consequently, the critical supersaturation (σcr) required to overcome the energy barrier to nucleation leading to crystallization is expected to be much lower in acetonitrile than in ethanol, which has been confirmed experiments The consistent crystallization of I-γ from
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’ ACKNOWLEDGMENT NMR instrumentation was provided with funds from the NSF (BIR-961477), the University of Minnesota Medical School, and the Minnesota Medical Foundation. S.L. thanks the United States Pharmacopeia (USP) Fellowship for partial funding of this study. ’ REFERENCES (1) Gibson, J. M.; Popham, J. M.; Raghunathan, V.; Stayton, P. S.; Drobny, G. P. A Solid-State NMR Study of the Dynamics and 2376
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