In Situ Monitoring of Cocrystallization of Salicylic Acidâ4,4â²-Dipyridyl

Article pubs.acs.org/crystal

In Situ Monitoring of Cocrystallization of Salicylic Acid−4,4′-Dipyridyl in Solution Using Raman Spectroscopy Kyeong-Sill Lee,†,‡ Kwang-Joo Kim,*,† and Joachim Ulrich‡ †

Crystallization Process & Engineering Laboratory, Department of Chemical Engineering, Hanbat National University, San 16-1, Dukmyung-dong, Yuseong-Gu, Daejeon 305-719, South Korea ‡ Zentrum fȕ r Ingenieurwissenschaften, Martin-Luther-Universitȁt Halle-Wittenberg, Verfahrenstechnik/TVT, D-06099 Halle, Germany ABSTRACT: In situ analysis using Raman spectroscopy was used to monitor the cocrystallization process. Raman spectroscopy in the cocrystallization of acetylsalicylic acid (ASA) and 4,4′-dipyridyl (4DP) in solution was investigated. A 2:1 salicylic acid (SAA)−4DP cocrystal was identified from crystallographic data obtained by X-ray single-crystal diffraction meter. In addition, Raman spectroscopy provided additional information on crystal structure of SAA−4DP cocrystal. Raman spectra peaks of ASA−4DP solution and SAA−4DP cocrystal were observed during crystallization. By the intensity of the peaks selected, nucleation and growth of cocrystal in solution were monitored. As a result, formation of new cocrystal using aspirin and 4DP was successfully monitored by Raman spectroscopy.

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with fluconazloe,15 ezetimibe,16 and nicotinamide.17 However, cocrystal of salicylic acid as a host has been reported meagerly so far,18 and in situ monitoring during cocrystallization in solution is not reported at all. Therefore, this study aimed to monitor the formation of salicylic acid (SAA)−4,4′-dipyridyl (4DP) cocrystal in solution by using in situ Raman spectroscopy. Also the effect of SAA− 4DP ratio on the cocrystallization was investigated. Cocrystallization was carried out in various solvents by cooling mode.

INTRODUCTION Crystallization is a common process in the pharmaceutical field and chemical industries. In situ measuring techniques are required for control and optimization of the cocrystal formation in solution. Several methods such as Fourier transform infrared spectroscopy (FTIR) with attenuated total reflectance (ATR) mode and focused beam reflectance measurement (FBRM) are available for in situ analysis of crystallization process in order to monitor formation of solid phase.1,2 Raman spectroscopy also can be used to measure variation of crystal structure in the course of formation of the cocrystals. Raman spectroscopy is one of the fastest, most reliable and most suitable techniques to identify crystal forms in drug products.3−5 It has been used for the qualitative monitoring of chemical reactions in solution.3 In addition, in situ monitoring during the processing of solid pharmaceuticals has been studied including polymorphic transformation,4 measurement of supersaturation during crystallization, and formation of cocrystal.5−7 Cocrystallization in solution was not monitored by in situ measurement techniques. Salicylic acid is one of the medicines used for antipyretic analgesic. Also it is used for treating acne and psoriasis due to its antifungal properties to eliminate fungus involved in infection.8 However, salicylic acid has low solubility in water, which influences bioavailability. In order to enhance drug solubility, various novel techniques such as solid dispersion,9,10 nanoemulsions,11 nanosuspensions,12 and polymorph change13 have been utilized. Cocrystal is also one of alternative methods to overcome the poorly water-soluble problem and to enhance drug solubility, dissolution, and bioavailability in pharmaceutical field.14 Salicylic acid was used as a coformer of cocrystal formed © 2014 American Chemical Society

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EXPERIMENTAL SECTION

Materials. Acetylsalicylic acid (ASA) and 4,4′-dipyridyl (4DP) were purchased from Sigma-Aldrich. Ethanol of reagent grade was purchased from Duksan Co. (South Korea). All materials are used without further purification. Figure 1 indicates the molecular structure of starting materials and cocrystal structure obtained in this study. Cocrystal Preparation. Supersaturation was created by cooling a solution of 2:1 mixture of ASA and 4DP dissolved in solvent from 50 to 35 °C. ASA and 4DP were dissolved in solvent at 10 °C higher than the saturation temperature. Temperature of solution was then cooled to 35 °C at a cooling rate of 5 K/min. Cocrystal of ASA and 4DP was formed during the cooling. The solid products were isolated over a 3 μm filter paper (Whatman) using vacuum filtration and dried for 10 h in an oven temperature of 40 °C. The solid phases were analyzed by X-ray powder diffraction, Raman spectroscopy, and differential scanning calorimetry. In situ measurement was carried out by Raman spectroscopy during cocrystallization. Figure 2 shows the molecules of SAA− 4DP cocrystals at a stoichiometric molar ratio of 2:1. Received: February 5, 2014 Revised: April 16, 2014 Published: April 24, 2014 2893

dx.doi.org/10.1021/cg5001864 | Cryst. Growth Des. 2014, 14, 2893−2899

Crystal Growth & Design

Article

Figure 1. Molecular structures of ASA and 4DP and SAA−4DP cocrystal (carboxylic acid···pyridine, 1; carboxylic acid, 2).

Figure 2. Molecules of SAA−4DP cocrystals, showing the atom labeling scheme and the intermolecular hydrogen bonds (dashed line).

Table 2. Hydrogen Bonds for SAA−4DP Cocrystal [Å and deg]a

Table 1. Crystal Data and Structure Refinement empirical formula formula weight temperature wavelength crystal system, space group unit cell dimensions volume Z, calculated density absorption coefficient F(000) crystal size theta range for data collection limiting indices reflections collected/unique completeness to theta = 25.242 absorption correction refinement method data/restraints/parameters goodness-of-fit on F̂2 final R indices [I > 2sigma(I)] R indices (all data) extinction coefficient largest diff. peak and hole

C24H20N2O6 432.42 296(2) K 0.71073 Å triclinic, P1̅ a = 7.87120(10) Å; alpha = 88.6320(10) deg; b = 8.3851(2) Å; beta = 81.859(2) deg; c = 8.6683(2) Å; gamma = 66.234(3) deg 517.97(2) A3 1, 1.386 Mg/m3 0.101 mm−1 226 0.32 × 0.26 × 0.24 mm 2.375 to 28.327 deg −10 ≤ h ≤10, −11 ≤ k ≤11, −11 ≤ l ≤11 14177/2585 [R(int) = 0.0475] 100.0%

D−H···A

d(D−H)

d(H···A)

d(D···A)

∠(DHA)

O(9)−H(9)···N(11) O(10)−H(10)···O(8)

1.02(2) 1.06(2)

1.60(2) 1.58(2)

2.6237(12) 2.5625(13)

174.8(15) 152.7(17)

a

Symmetry transformations used to generate equivalent atoms. #1 −x, −y + 1, −z + 2.

probe was used to collect the spectra. The spectra of this system were in the range from 100 to 1890 cm−1, and the spectra were acquired with 4 cm−1 spectral width and 30 s exposure. The iCRaman software (Mettler-Toledo) was used in combination with this system. Analysis of Raman data for a cocrystal screening was performed by searching for the absence and occurrence of peaks originally found in spectra of the single components. Powder X-ray Diffraction (XRD). XRD pattern of SAA−4DP cocrystal was calculated using a SmartLab X-ray diffractometer (Rigaku) with Cu Kα radiation generated at 200 mA and 45 kV. Sample was placed on silicone plate at room temperature. Data were collected from 3 to 45° (2θ) at a step size of 0.02° and a scan rate of 5 °/min. Differential Scanning Calorimetry (DSC). DSC analysis was performed using a Mettler Toledo DSC 1 instrument with a scan range of 0−300 °C and a scan rate of 10 °C/min under nitrogen purge at 50 mL/min. Scanning Electron Microscopy (SEM). The shape of crystals was investigated by SEM. The specimens were scanned with an electron beam of voltage of 5−10 kV. SEM images were collected on a JEOL LTD JSM-6300 scanning electron microscope.

none full-matrix least-squares on F2 2585/0/154 1.081 R1 = 0.0447, wR2 = 0.1243 R1 = 0.0543, wR2 = 0.1326 0.065(11) 0.183 and −0.220 e·Å−3

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RESULTS AND DISCUSSION Identification of ASA-4DP Cocrystal. Single-Crystal X-ray Crystallography. The crystallographic data were obtained by X-ray single-crystal diffraction meter (SMART APEX II CCD diffractometer). It identified the crystals to be 2:1 SAA−4DP cocrystal. Even though aspirin was used as a feed

In-Line Measurement (Raman Spectroscopy). The Kaiser Raman RXN2 system was used for both off-line measurement of solid samples and in-line measurement of the cocrystal formation in solution. Raman spectra were recorded on RXN systems (Kaiser Optical Systems, Ann Arbor MI, USA) equipped with a light-emitting diode laser (785 nm, 450 mW) as an excitation source. One-fold objective lens with 2894



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Figure 3. Part of the crystal structure of SAA−4DP cocrystal, showing the formation of the supramolecular network through O−H···N and O−H···O hydrogen bonds.

Table 3. Details of the Experiments Conducted Using Aspirin: 4,4′-Dipyridyl by Crystallization solvents coformer 4,4′-dipyridyl

ratio (API− Coformer) 5:1 3:1 2:1 1.5:1 1:1 0.5:1 0.25:1

ethanol form3 form3 form3 form3 form3 mix mix

a

methanol

1-butanol

1-propanol

IPA

2-butanol

form3 form3 form3 form3 form3 mix mix

form3 and mix form3 form3 form3 form3 form3 mix

form3 and mix form3 form3 form3 form3 form3 mix

form3 and mix form3 and mix form3 form2b amorphous

form3 and mix

acetone

form3

mixc

form3 form3 and mix

mix

mix

a

Form 3 indicates SAA−4DP cocrystal mentioned in this article. bForm 2 indicates SAA−4DP cocrystal having different XRD pattern and DSC curve from form 3. cMix indicates mixture of ASA and 4DP crystals.

material for the preparation of the cocrystal, the ketene functional group of the aspirin has dropped off in course of the cocrystallization. It revealed structure in triclinic system with space group P1̅ and cell parameters a = 7.8712(10) Å, b = 8.3851(2) Å, and c = 8.6683(3) Å. Crystal structural data of 2:1 cocrystal of SAA and 4DP are presented in Table 1. SAA consists of carboxylic acid and hydroxyl groups, while 4DP contains a pyridine group. The arrangement of molecules of ASA−4DP cocrystals is shown in Figure 2. The asymmetric unit comprises two SAA molecules and one 4DP molecule, which are linked by carboxylic acid−pyridine hydrogen bonds. Such intermolecular forces also make contributions to the stability of crystal structure.19 The detailed hydrogen bonding interactions in the cocrystal structure are listed in Table 2. Figure 3 shows a part of the crystal structure of SAA−4DP cocrystal. In the supramolecular structure shown in Figure 3, the molecular components are linked by O−H···N and O−H···O hydrogen bonds. Especially, the carboxyl oxygen O(9) acts as a hydrogen bond donor and is bonded to atom N(11) of 4DP with the acid−pyridine packing motif. O(10) atom in the SAA molecules

acts as a strong hydrogen bond donor and is linked through H(10) to the O(8) in the other SAA molecules. Salicylic Acid−4,4′-Dipy Cocrystal XRD Analysis. Figure 4 shows powder X-ray diffraction patterns of starting materials, their physical mixture, and cocrystal obtained in ethanol solution. The experimental X-ray diffraction pattern of the 2:1 SAA−4DP was identified. The diffraction pattern of the crystal obtained by crystallization in ethanol solution supports the formation of a new cocrystal. It is different with XRD patterns of starting materials and physical mixture, but the same as the XRD pattern calculated by single-crystal X-ray crystallography. Experiments were carried out in other solvents such as methanol, 1-propanol, isopropanol, n-butanol, 2-butanol, and acetone at various stoichiometric molar ratios of SAA and 4DP. Details of these experiments are summarized in Table 3. SAA− 4DP cocrystal was formed in the solvents except acetone at a molar ratio of 2:1. Solvent amount was set at a saturation temperature of 50 °C. At a ratio of 0.25:1.0 of SAA−4DP, the mixture of crystals of SAA and 4DP was obtained for all solvents 2895



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Figure 4. Powder X-ray diffraction pattern of the product of crystallization in ethanol compared to starting materials, physical mixture, and calculated data.

investigated. Also different polymorph and amorphous forms were found in IPA solvent. Eventually, 2:1 SAA−4DP cocrystal was identified by XRD. DSC Analysis. Figure 5 shows DSC curves and thermal behavior for SAA, 4DP, their physical mixtures, and SAA−4DP Figure 6. SEM images of (a) cocrystal obtained in ethanol and (b) SAA.

Figure 5. DSC thermograms for SAA, 4DP, and cocrystal.

cocrystal. From DSC thermograms, melting points of SAA, 4DP, ASA−4DP mixture, and SAA−4DP cocrystal were found to be 159.58, 112.16, 59.87, and 155.52 °C, respectively. The thermal behavior of the new cocrystal is definitely different from those of SAA and 4DP. It provides further support for a new cocrystal. This different melting phenomenon of cocrystal revealed the changes of in-crystal packing and lattice energy. SEM Analysis. Figure 6 shows SEM photographs of cocrystal and SAA. As shown in Figure 6, SAA−4DP cocrystal presents prism-like habit. It is compared to SAA, which is a plate-like crystal. A possible epitaxial relationship between these shapes was presupposed. Raman Spectroscopy Analysis. Figure 7 shows the Raman spectra of solids for raw materials, physical mixtures, and SAA−4DP cocrystal. Raman spectroscopy cannot be used for metals or alloys and fluorescence of materials, which are not

Figure 7. Raman spectra of starting materials, mixtures, and SAA−4DP cocrystal.

found in pharmaceuticals. There are differences between physical mixture and cocrystal. For example, in the spectral range of 1100−1000 cm−1, the mixture has three characteristics peaks at 1043, 1022, and 1006 cm−1, whereas cocrystal has two characteristics peaks at 1033 and 1024 cm−1. This difference was used to identify cocrystal of SAA−4DP. In Situ Monitoring during Cocrystallization in Solution Using Raman Spectroscopy. In situ monitoring during cocrystallization of aspirin and 4DP in solution was carried out by Raman spectroscopy for 5 h. Figure 8 shows variation of Raman spectra with elapsed time. Nucleation starts at 130 min after the two solutions are mixed. Raman spectra are dramatically 2896



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Figure 8. (a) Variation of Raman spectra of ASA−4DP during cocrystallization in solution and (b) a close-up of Raman spectra in the section (1) of panel a.

time between 110 and 130 min. It suggests that the ASA and 4DP molecules in solution start to form SAA−4DP cocrystal in this period. To make sure of this behavior, a variation of Raman peak position with elapsed time is shown in Figure 9c. Characteristic peaks of ASA−4DP solution disappears gradually at 1609 and 1610 cm−1, while those of SAA−4DP cocrystal appear at 1614 and 1615 cm−1 and increase in their peak intensity with elapsed time. Also, Raman peak intensity relies on the concentration of materials. To quantify the solid-state change during formation of cocrystal, ratios of selected peak intensity are presented in Figure 10. The decrease of 1043 and 1006 cm−1 peaks, characteristic of ASA−4DP solution, and the appearance of 1024 and 1033 cm−1 peaks, characteristic of SAA−4DP cocrystal, were observed during the crystallization process (see Figure 10a). The intensity of the peaks selected was normalized using the consistent peak at 970 cm−1. Surely, the peak intensity ratios of

changed after nucleation. Raman spectra of solution of ASA and 4DP at a stoichiometric molar ratio of 2:1 in ethanol are presented until 300 min in Figure 8. After nucleation of cocrystal, Raman spectra in (1) 1600−1620 cm−1, (2) 1000−1045 cm−1, and (3) 750−790 cm−1 show a remarkable change (see Figure 8a). It suggests that Raman detects cocrystallization in solution as well as formation of a new crystalline form. It can ascertain clearly the progressive cocrystal formation of SAA− 4DP using cooling crystallization. Change in Raman spectra provides both physical and chemical information on cocrystal.20 At 1600−1620 cm−1, the formation of cocrystal from ASA and 4DP was characterized by peak shifts of the C−C stretch from 1609 to 1615 cm−1 (see Figure 8b). It results from change in the hydrogen bond interaction. Figure 9 shows a shift in the Raman spectra in the range of 1600−1620 cm−1 in the formation of cocrystal in solution. From Figure 9a,b, it is found that a change in Raman spectra of 1600−1620 cm−1 occurs at the operating 2897



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Figure 9. (a) Shift in the Raman spectra in the range of 1600− 1620 cm−1 in the formation of cocrystal; (b) 3D waterfall spectra; and (c) variation of Raman peak position cocrystallization of SAA−4DP in solution with elapsed time.

1043/970 cm−1 and 1006/970 cm−1 were declined from 3.38 to 2.53 and from 3.76 to 2.67 with increasing the operating time, respectively, but the peak intensity ratio of 1033/970 cm−1 and 1024/970 cm−1 increased from 1.91 to 4.22 and from 1.63 to 4.11, respectively (Figure 10b). It supports that metastable zone width and induction time can be measured by Raman spectra in cocrystallization of SAA−4DP using cooling mode. Figure 10c shows a change of peak area in the spectra of 1000−1015 cm−1 and 1028−1039 cm−1. As cocrystallization starts, the peak area of 1000−1015 cm−1 (solution peaks) decreases, while that of 1028−1039 cm−1 (cocrystal peaks) increases. Figure 11 shows spectra between 750 and 788 cm−1, which are changed significantly. At the beginning of the process, only the aspirin−4DP solution spectrum with characteristic peaks at

Figure 10. (a) Variation of Raman spectra in 960−1060 cm−1; (b) change of intensity ratio of Raman peaks in the formation of cocrystal with elapsed time; and (c) change of peak area between 1000 and 1015 cm−1 and 1028−1039 cm−1 during crystallization.

750, 762, and 778 cm−1 was observed (see Figure 11a,b). A peak at 788 cm−1 starts to appear after 120 min and its intensity then increases with respect to operating time. Using the cocrystal peak at 788 cm−1, it is possible to measure the formation of cocrystal. Figure 11c presents the peak ratios of 788/720 cm−1 and 750/ 720 cm−1 to evaluate the relative intensity. The intensity of peaks selected was normalized using the consistent peak at 720 cm−1. 2898



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a new cocrystal using aspirin and 4DP was successfully monitored by Raman spectroscopy.

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AUTHOR INFORMATION

Corresponding Author

*(K.-J.K.) Tel: +82 42 821 1527. Fax: +82 42 821 1598. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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REFERENCES

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Figure 11. (a) Change of Raman spectra in the range of 750−790 cm−1; (b) 3D waterfall spectra; and (c) change of intensity ratio of Raman peaks during cocrystallization.

Surely, the peak intensity ratio of 750/720 cm−1 was declined from 2.15 to 1.73 with increasing time, but the peak intensity ratio of 788/720 cm−1 increased from 1.42 to 3.45.

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CONCLUSIONS The formation of a cocrystal of SAA−4DP during crystallization was monitored by using in situ measurement of Raman spectroscopy. The cocrystal formed was identified with singlecrystal X-ray crystallography. From in situ measurement of the Raman spectroscopy, the shift of Raman spectra peaks of cocrystal and solution was analyzed in crystallization of SAA− 4DP cocrystal from ASA−4DP solution. As a result, formation of 2899


In Situ Monitoring of Cocrystallization of Salicylic Acidâ4,4â²-Dipyridyl

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