DOI: 10.1021/cg1005924
Investigating the Intermolecular Interactions in Concentration-Dependent Solution Cocrystallization of Caffeine and p-Hydroxybenzoic Acid
2010, Vol. 10 3763–3769
Guangwen He,*,† Pui Shan Chow,† and Reginald B. H. Tan*,†,‡ † Institute of Chemical & Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833, and ‡Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576
Received May 4, 2010; Revised Manuscript Received June 22, 2010
ABSTRACT: Cooling crystallization of methanol solutions of caffeine (CAF) and p-hydroxybenzoic acid (PHBA) with different initial concentration ratios has produced single-component crystals, CAF or PHBA, or cocrystals, 2(CAF) 3 PHBA or CAF 3 2(PHBA), or mixtures of them. With high concentration ratio between PHBA and CAF, the crystal formation tendency is on the order of PHBA, CAF 3 2(PHBA), 2(CAF) 3 PHBA, and CAF; that is, there is a higher chance to produce crystals with higher PHBA content. Rational explanation can be sought by characterizing the intermolecular interactions of CAF and PHBA molecules in solutions using pulsed gradient spin-echo nuclear magnetic resonance. The relative magnitudes of the CAFPHBA, CAF-CAF, and PHBA-PHBA pair interactions are found to vary systematically with the initial concentration ratio, PHBA/CAF. The results indicate that the tendency of growing respective single-component crystals or cocrystals shifts systematically with the concentration ratio. This contribution has shown that the microscopic intermolecular interactions determined in the solution state may serve as qualitative and predictive indicators for the final crystalline products. This novel approach can be used in conjunction with the ternary phase diagrams in depicting the regions of thermodynamic stability and predicting the potential formation of crystals/cocrystals in a multicomponent crystal system.
*Corresponding author. Telephone: (65) 6796 3779. E-mail: he_guangwen@ ices.a-star.edu.sg.
coformer with different initial concentration ratios based on our previous experience in characterizing the intermolecular interactions of the API and coformer molecules in solutions.16,17 Caffeine/p-hydroxybenzoic acid (CAF/PHBA) was chosen as a model cocrystal system (Scheme 1). The CAF/PHBA system is known to form two cocrystals with 2:1 and 1:2 solidstate stoichiometry, 2(CAF) 3 PHBA and CAF 3 2(PHBA), respectively.15 Bucar et al. have reported that both cocrystals were obtained simultaneously in acetonitrile or acetonitrile/ water (1/1 v/v) from the same crystallization trial through slow evaporation.15 The objective of this work is to investigate how the intermolecular pair interactions between CAF and PHBA molecules in solutions can be correlated with the product crystal compositions. Cooling crystallization experiments of methanol solutions of CAF and PHBA with different initial concentration ratios were conducted. The product crystals, either pure forms or mixtures of CAF (β form), PHBA, 2(CAF) 3 PHBA, and CAF 3 2(PHBA), have been analyzed using powder X-ray diffraction (PXRD) to determine the compositions. Furthermore, we determined the long-time self-diffusivities of CAF and PHBA in the methanol solutions using pulsed gradient spin-echo nuclear magnetic resonance (PGSE NMR).18 The molecular diffusivity is determined by the attenuation of a spin-echo signal resulting from the combinatory effect of the translational motion of nuclear spins and the impositions of spatially well-defined gradient pulses. The pair contribution of the long-time self-diffusivity was then used as a probe for the intermolecular interactions of CAF and PHBA in solutions. Finally, we tried to rationally correlate the crystallization outcome and the intermolecular interactions in solutions and to obtain insightful information of solution chemistry for cocrystallizing systems in general.
r 2010 American Chemical Society
Published on Web 07/12/2010
Introduction Many active pharmaceutical ingredients (APIs) are delivered to patients as solid formulations with appropriate dosages. Current approaches to improving solid-state properties of APIs without changing desirable therapeutic behavior include the formation of alternative forms of APIs such as cocrystals.1-11 Pharmaceutical cocrystals have rapidly emerged as a new class of API solids for their enhanced physicochemical properties, such as solubility, bioavailability, dissolution rate, stability, hygroscopicity, and crystallinity. Pharmaceutical cocrystals have been defined as “cocrystals that are formed between a molecular or ionic API and a coformer that is a solid under ambient conditions”5 that clearly distinguish themselves from other solid forms, such as solvates, clathrates, inclusion compounds, and hydrates. A given pair of API and coformer usually forms a cocrystal with fixed solidstate stoichiometry; however, under certain circumstances, pharmaceutical cocrystals of different solid-state stoichiometry with the same APIs and coformers could be obtained.12-15 These cocrystals with different solid-state stoichiometries form either from the same crystallization trial simultaneously or under different experimental conditions, such as different solvents, different crystallization pathways and processes, etc. Jayasankar et al. studied the governing factors for the formation and stability of carbamazepine/p-aminobenzoic acid (CBZ/PABA) cocrystals with different solid-state stoichiometries in ethanol using a ternary phase diagram. They have discovered that the stability of 2:1 and 1:1 CBZ/PABA cocrystals depends on the coformer (PABA) concentration.14 In this contribution we have taken a different approach by understanding the cocrystallization outcome of an API and a
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Experimental Section Materials. Caffeine (CAF, 99%) and deuterated methanol (methanol-d4, 99.8 atom % D) were purchased from Sigma Aldrich. p-Hydroxybenzoic acid (PHBA, 99%) was purchased from Alfa Aesar. HPLC grade methanol (MeOH, g99.8%) was purchased from VWR International. All chemicals were used as received. Solution Crystallization. Methanol solutions of CAF and PHBA have been prepared with different concentration ratios (molar ratios): 0.5, 1, 2, 4, 6, 8, 10, 14, and 18 (please refer to the Supporting Information for detailed solution concentrations). The solutions were filtered (0.2 μm syringe filter, Teknokroma) into a 50 mL jacketed crystallizer that was preheated to 45 C. The solutions were stirred at a rate of 500 rpm using a multiple magnetic stirrer (Variomag Poly 15), and the temperature of the solutions was controlled using a thermostat bath (Julabo FP50 HL). The solutions were held at 45 C for 30 min, followed by cooling down to 10 C at a rate of 0.5 C/min. The solutions were then kept at 10 C for 24 h to provide sufficient time for the growth of crystals/cocrystals. The resulting crystals were collected and dried before characterization. All crystallization experiments have been repeated for at least three times to obtain a statistical description of product crystal compositions. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction data of the ground product crystals were collected using a Bruker D8-ADVANCE X-ray diffractometer with Cu KR radiation (wavelength= 1.54 A˚) at room temperature. The tube voltage and tube current applied were 35 kV and 40 mA, respectively. Each sample was continuously scanned from 4 to 45 2θ at a scan rate of 0.02/s. Pulsed Gradient Spin-Echo Nuclear Magnetic Resonance (PGSE NMR). The long-time self-diffusivities of CAF and PHBA in methanol-d4 were measured using 1H PGSE NMR with a 400 MHz spectrometer (Bruker AVANCE 400) at 295.8 K. The selfdiffusivities of individual molecules were resolved by measuring the time-dependent spatial attenuation of the characteristic NMR peaks.19,20 Deuterated solvent, methanol-d4, instead of methanol was used in the 1H PGSE NMR experimentation for two reasons: (i) the resulting NMR spectra show remarkably improved signal-to-noise ratio due to the suppressed solvent peaks; (ii) the use of deuterated solvent permits the application
Scheme 1. Molecular Structures of Caffeine and p-Hydroxybenzoic Acid
He et al. of a deuterium frequency-field lock to offset the effect of the natural drift of the NMR magnetic field. The intermolecular interactions between the solute molecules in solutions can subsequently be determined from the self-diffusivities of the solute molecules.
Results and Discussion Initial Concentration Ratio and Crystallization Outcome. The product crystals resulting from cooling crystallization experiments were CAF (β form), PHBA, 2:1 cocrystal 2(CAF) 3 PHBA, 1:2 cocrystal CAF 3 2(PHBA), or mixtures of them. The experimental PXRD patterns (Figure 1) of CAF (β form), PHBA, 2(CAF) 3 PHBA, and CAF 3 2(PHBA) compared well with those simulated from the Crystallographic Information Files (CIFs) in the Cambridge Structural Database (CSD refcodes: NIWFEE03, JOZZIH, MOZCUA, and MOZDAH, respectively) using Mercury v2.3.21 In the cases where the product crystals were mixtures, the experimental PXRD patterns were used as reference to determine the compositions of the mixed crystals:22 xn ¼
Inexp =Inref
4 P
ð1Þ
ðInexp =Inref Þ
n¼1
where x is the molar fraction, n represents the species, CAF (β form), PHBA, 2(CAF) 3 PHBA, and CAF 3 2(PHBA), Iref is the characteristic peak intensity that is normalized to the highest peak in the individual patterns of the pure crystal forms, and Iexp is the characteristic peak intensity in the experimental patterns of the crystal mixtures. Cooling crystallization of methanol solutions of CAF and PHBA with different initial concentration ratios (molar ratios) gave rise to product crystals of different compositions. The detailed compositions with regard to initial concentration ratio are shown in Figure 2a. When we conducted the solution crystallization with a low concentration ratio PHBA/CAF (0.5 or 1), CAF crystals have been constantly obtained. Cooling experiments of solutions containing more PHBA (PHBA/CAF = 2) produced a mixed result of CAF crystals and 2(CAF) 3 PHBA cocrystals. Pure 2(CAF) 3 PHBA cocrystals were repeatedly grown in the experiments when PHBA/CAF was kept at 4 and 6. We have observed the emergence of mixtures of the two cocrystals 2(CAF) 3 PHBA and CAF 3 2(PHBA) when the concentration ratio was 8. When the ratios were kept at 10 and 14, only the 1:2 cocrystals,
Figure 1. PXRD patterns of (a) CAF and PHBA; and (b) 2:1 and 1:2 CAF 3 PHBA cocrystals: 2(CAF) 3 PHBA and CAF 3 2(PHBA).
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Figure 2. Schematic diagrams of (a) the product crystal compositions and (b) the coformer scale of the product crystals (described in the text) with regard to the concentration ratio, PHBA/CAF. The solid line in part b represents a best fit of the data.
Figure 3. Normalized long-time self-diffusivities of (a) CAF and (b) PHBA in methanol-d4 at 295.8 K.
CAF 3 2(PHBA), would form. Last but not least, if the initial PHBA/CAF ratio was raised to 18, the resulting crystals appeared to be mixtures of CAF 3 2(PHBA) and PHBA. We observed that if the initial concentration of PHBA is increased, the likelihood of growing crystals with a higher content of PHBA molecules will be higher. The phenomenon can be quantitatively described if we define a coformer scale (CS): the molar fraction of the coformer molecule in a sample. The coformer scale has a range from 0 to 1. For instance, CSCAF = 0 and CSPHBA = 1 for pure CAF and PHBA, respectively. For the two cocrystals, 2(CAF) 3 PHBA or CAF 3 2(PHBA), CS2(CAF) 3 PHBA = 1/3 and CSCAF 3 2(PHBA) = 2/3. The coformer scale for the mixed product crystals can be calculated as follows: 4 X xn CSn ð2Þ CS ¼ n¼1
where xn stands for the molar fraction of compound n in the final product crystals. A plot of the coformer scale versus the concentration ratio, PHBA/CAF (Figure 2b), shows a correlation between the two. When more coformer, PHBA, is introduced to the initial solution, cooling crystallization tends to produce crystals (or mixed crystals) that contain more species with high coformer scale. The results obtained here are similar to the observation reported by Jayasankar at al., in which the authors have provided a rational explanation of the cocrystal stability based on the identification of the isothermal invariant points in the solution phase diagram.14 In this study, we will discuss the dependence of the intermolecular pair interactions in solutions on the concentration ratio. We hope to provide an alternative view of the plausible correlation between the intermolecular interactions and the crystallization outcome.
Self Diffusivity and Intermolecular Interactions. The classical theory of Brownian motion for a ternary system (two solutes and one solvent) deals with the random movement of an individual solute molecule due to stochastic collisions with solute molecules of its own species, those of the other species and the solvent molecules of the surrounding fluid. When solutes i and j are dissolved into a solvent, the longtime self-diffusivities of i and j in the solution can be respectively written as follows:23 ! Di Φj ¼ 1 þ Kii Φi þ Kij Φj ¼ 1 þ Kii þ Kij Φi ¼ 1 Di0 Φi þ ðKii þ Kij0 ÞΦi
!
ð3aÞ
Dj Φi Φj ¼ 1 ¼ 1 þ Kjj Φj þ Kji Φi ¼ 1 þ Kjj þ Kji Dj0 Φj þ ðKjj þ Kji0 ÞΦj
ð3bÞ
These equations are valid in the dilute limit when only pair interactions are considered. D and D0 are the absolute and zero-concentration long-time self-diffusivities of the solute molecules, and Φ is the volume fraction of the solute, which can be represented by Φ = Nv/V, where N is the number of molecules, v is the volume of one molecule, and V is the total volume of the system. In eq 3a, the pair contribution of the long-time self-diffusivity, Kii and Kij0 , characterizes the mobility hindrance of the self-diffusing solute i in the absence and presence of solute j, respectively. The values of K are the integral measures of the hydrodynamically weighted intermolecular pair interactions.23 A more negative value of K indicates stronger attraction between respective molecules. When compound j is not present in the solutions, eq 3a can be
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Figure 4. Normalized long-time self-diffusivities of (a) CAF and (b) PHBA in the two-solute methanol-d4 solution at 295.8 K. The concentration ratio of PHBA and CAF (molar ratio) in the two-solute solution equals 0.5.
reduced to Di/Di0 = 1 þ KiiΦi. The value of Kii can be readily obtained from the slope of the plot shown in Figure 3a. Caffeine displays less negative values of K as compared to p-hydroxybenzoic acid in methanol-d4, suggesting that intermolecular interactions between the CAF molecules are stronger than those between PHBA molecules.24 This is verified by the much lower solubility of CAF than PHBA25 in methanol (0.068 vs 4.022 mol/kg solvent at 298 K). When both solutes i and j are present in the solution, the overall mobility hindrance on molecules i and j can be characterized by (Kii þ Kij0 ) and (Kjj þ Kji0 ), respectively (Figure 4). By carefully designing experiments in which the concentration ratio of the two solutes is kept constant (i.e., the ratio of the volume fractions Φj/Φi is also constant), values of (Kii þ Kij0 ) and (Kjj þ Kji0 ) can be deduced from the linear plots shown in Figure 4. (Kii þ Kij0 ) is the overall mobility hindrance on i molecules by taking into account the effects of the presence of j molecules in the continuum (solvent). Similar definition goes to (Kjj þ Kji0 ). Values of Kij0 and Kji0 for all concentration ratios under study are listed in Table 1. The pair contribution of the long-time self-diffusivity, K, integrates the effects of intermolecular interactions and hydrodynamic contributions on the molecular mobility in solutions to the first-order correction of the volume fraction. In the dilute limit, the long-time self-diffusivity of spherical molecules has been well studied, suggesting that K can be expressed as follows:23,26-28 Z ¥ K ¼ ð- 3 þ A11 þ 2B11 ÞgðrÞr2 dr 2
Z
¥
A11 - A12 - B11 þ B12 r 1 dA11 dA12 þ QðrÞgðrÞr2 dr 2 dr dr þ
2
ð4Þ
The first integral is the first-order correction to the shorttime self-diffusivity, while the second integral is the long-time correction due to the modification of the pair distribution function of the interacting Brownian molecules. Detailed simulation studies indicate that the above-mentioned continuum model is an accurate description of self-diffusivity of solute molecules as long as the solutes are on the order of, if not larger than, the size of the solvent molecules.23,26,29 r is the normalized (by the radius of the molecule) center-tocenter spacing between the molecules. Q(r) characterizes the perturbation of the Maxwell-Boltzmann form of the pair
Table 1. Pair Contribution of the Long-Time Self Diffusivity of CAF (i) and PHBA (j) in Methanol-d4 Solutions with Different Concentration Ratiosa pair contribution of the long-time self-diffusivity PHBA (j)/CAF (i) (molar ratio) 0.5 1 2 4 6 8 10 14 18
Kii
-18.42
Kij0 = Kij(Φj/Φi) -8.82 -14.63 -23.70 -23.08 -32.92 -36.98 -42.57 -53.79 -67.19
Kjj
-5.09
Kji0 = Kij(Φi/Φj) -73.57 -35.87 -18.26 -8.52 -5.07 -3.08 -1.78 -0.84 -0.44
a Note that even for the highest concentration used in this study, the volume fraction of the solute is still low at ca. 5%. Therefore, the solutions are still in the dilute limit such that eqs -9 are valid.
distribution function due to the forces applied to the molecules. Values of Q(r) as well as of the mobility functions A11, A12, B11, and B12 are well-defined in the hydrodynamic limit.27,30 In the dilute limit, the pair correlation function g(r) is written as follows:31 gðrÞ ¼ e - uðrÞ=kT
ð5Þ
where u(r) is the pair interaction potential, k is the Boltzmann constant, and T is the absolute temperature. The theoretical approaches used to study the phase behavior of molecular solutions used in this study are analogous to those used in liquid state physics.31 A commonly used interaction potential of simple fluids is the square-well potential that successfully captures the essence of both the repulsive and attractive nature of the interaction yet maintains remarkable mathematical simplicity. The square-well potential can be expressed as follows: 8
