Crystal Structure Determination of Dimenhydrinate after More than 60

Jul 22, 2016 - Synopsis. In this study, finally we determined the crystal structure of dimenhydrinate whose structure has not been determined over the...
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Crystal Structure Determination of Dimenhydrinate after More than 60 Years: Solving Salt−Cocrystal Ambiguity via Solid-State Characterizations and Solubility Study Okky Dwichandra Putra,† Tomomi Yoshida,§ Daiki Umeda,§ Kenjirou Higashi,‡ Hidehiro Uekusa,† and Etsuo Yonemochi*,§ †

Department of Chemistry and Materials Science, Tokyo Institute of Technology, 12-1-H62, Ookayama 2, Meguro, Tokyo 152-8551, Japan § School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41, Ebara, Shinagawa, Tokyo 142-8501, Japan ‡ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan S Supporting Information *

ABSTRACT: Dimenhydrinate (DIM) is an important drug used for the prevention of motion sickness. Surprisingly, the crystal structure of DIM has not been determined over the last 67 years. In this study, we have attempted to determine the structure of DIM through single crystal X-ray structure analysis and confirmed the salt−cocrystal ambiguity. Because of the existence of proton transfer, DIM exists as a salt crystal. The crystal structure of DIM contains the anionic form of 8chlorotheophylline whose existence was confirmed using density functional theory calculation. Other solid-state characterizations based on spectroscopy and thermal analysis were also conducted in order to fill the vacancy regarding the solid-state characterization. Kinetic and intrinsic solubility tests were also performed to evaluate the physicochemical properties of DIM raw material.

1. INTRODUCTION

It is important to note whether the multicomponent molecular crystal specifically exists in the salt form or neutral cocrystal form. Although the difference in both the forms is due to the existence of proton transfer, regulatory bodies such as the FDA treat both types of multicomponent crystals differently.10 In the case of the neutral cocrystal form, FDA considers the cocrystal to be the same as the parent drug and treats it as a new polymorph application. On the other hand, salt crystal requires a registration for new chemical entities. Therefore, the availability of reliable and precise information on proton transfer through comprehensive solid-state characterization is indispensable and crucial in product quality management. The salt or cocrystal form of the multicomponent molecular crystal can be identified by using the pKa rule.11 When the difference in pKa of the base and its conjugate is between 0 and 3, the status of either salt or cocrystal is ambiguous, and it is necessary to do further characterization. In this case, the predicted pKa values of diphenhydramine and 8-chlorotheophylline are 8.76 and 5.94, respectively.12 However, the salt− cocrystal status is not clear and requires comprehensive solidstate characterization in order to determine the form of the crystal.

Solid-state characterization is important in the regulation and development of drugs as well as an intellectual property matter.1 Its necessity is based on the requirement to determine existing crystals in drugs because pharmaceutical solids have an ability to exist in various forms such as polymorph, hydrate, and solvate.2 Moreover, the difference in the crystalline form is known to result in different physicochemical properties, which are related to bioavailability and manufacturing processes.3,4 Thus, solid-state characterization can be considered as an integral analytical method prior, during, and post manufacturing of drugs. Dimenhydrinate (DIM) is a widely used drug for the prevention of motion sickness, including nausea and vomiting.5,6 The commercially available DIM is known as a multicomponent crystal, which consists of two drugs of diphenhydramine (2-benzhydryloxy-N,N-dimethyl-ethanamine) and 8-chlorotheophylline (8-chloro-1,3-dimethyl-7Hpurine-2,6-dione). The antiemetic effect of DIM for the prevention of sickness is due to the presence of diphenhydramine, which is an antagonist of H1 histamine receptor.6 However, diphenhydramine is associated with the side effect of drowsiness.7 From the pharmacology point of view, the multicomponent crystal overcomes this side effect of diphenhydramine as it contains an additional stimulant, 8chlorotheophylline.8,9 © XXXX American Chemical Society

Received: May 22, 2016 Revised: July 22, 2016

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2.2.3. Powder X-ray Diffraction (PXRD). PXRD measurements were performed by using the SMART-LAB X-ray diffractometer (Rigaku, Japan). The samples were put in between the Myler films. The powder pattern was collected from 2θ = 3° to 40° at 25 °C with a step and scan speed of 0.01° and 3°/min, respectively (Cu Kα source, 45 kV, 200 mA). 2.2.4. 13Carbon Solid-State Nuclear Magnetic Resonance Spectroscopy (13C-SSNMR). 13C-SSNMR spectrum was measured on a JNM-L600 NMR spectrometer (JEOL Resonance, Japan) operating at an outer magnetic field of 14.1 T with 4 mm CP/MAS (crosspolarization/magic-angle spinning) probe. The conditions used were the following: inlet air temperature: 25 °C, MAS rate: 15 kHz, decoupling method: two-pulse phase-modulation, 1H 90 pulse width: 3.2 μs, contact time: 5 ms, relaxation delay: 7 s, number of scans: 20 000 times, sampling point: 4096, internal standard: hexamethylbenzene (17.3 ppm). 2.2.5. FTIR. The FTIR spectra were measured by the FTIR 4100 (Jasco, Japan). The sample powder was milled with dry potassium bromide in a weight ratio of 1:100. Then it was pressed into the pellet with a total pressure of 200 kg/cm2 (Seiki, Japan). A total of 64 scans per spectrum were acquired in the range 400−4000 cm−1. 2.2.6. Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TG). DSC measurements were performed by DSC 8230L, and the TG measurement was performed by TG-DTA 9320 (Rigaku, Japan). About 2−3 mg of the sample for DSC and 15 mg for TG were accurately weighed into the aluminum pan. The sample pans were run at a heating rate temperature of 3 °C/min from 30 to 200 °C under nitrogen purge of 100 mL/min, and an empty aluminum pan was used as a reference. A closed pan was used for DSC measurement, and an open pan was used for TG measurement. 2.2.7. Determination of pKa and Solubility Test. pKa determination and solubility tests were conducted using the Sirius T3 apparatus (Sirius Analytical Instrument, UK) equipped with Ag/AgCl pH electrode. These experiments were carried out in 0.15 M KCl solution under the purge of nitrogen gas at a temperature of 25 °C. All the tests were performed using standardized 0.5 M KOH and 0.5 M HCl solutions as titration agents. The intrinsic solubility was determined by the curve fitting solubility method.29,30 In this method, the dissolved DIM was titrated with acid or base until precipitation occurred and the equilibrium was established. The resulting Bjerrum curve was used to determine the shift between the theoretical aqueous pKa titration curve and the experimental precipitation titration curve. Since the distance of the shift depends only on the introduced known amount of the compound and the solubility of the compound, the solubility values could be calculated. The experiments were conducted in triplicates.

It has been a reality that DIM was introduced and formulated as a syrup and a tablet in 1949; however, no crystal structure of DIM has been reported either from single crystal or powder structure analysis.13 Thus, the fact that the crystal structure of DIM has remained undetermined (prior to the present work) is almost certainly due to the challenge of growing single crystals of sufficient size and quality for single crystal X-ray diffraction. In the case of unknown structure and clarification of salt− cocrystal uncertainty, the role of crystallography and spectroscopy is essential. Single crystal structure analysis can determine the three-dimensional structure and locate the transfer of a proton between molecules.14,15 The elaboration of spectroscopy data, i.e., solid state NMR and Fourier transform spectroscopy (FTIR), is unequivocally a good combination to verify the proton transfer. Furthermore, the spectroscopic method also adds value to the solid-state characterization.16−21 Therefore, the objective of this study is to provide precise and accurate information related to salt−cocrystal ambiguity via crystal structure determination and comprehensive solid-state characterization of DIM. This information is essential to related parties who use DIM as a compound of interest. Finally, the determination of pKa and the measurement of solubility were performed to complete the characterization, which is important in pharmaceutical field.

Figure 1. Molecular structure of DIM. Each component is drawn as a neutral form.

2. MATERIALS AND METHODS 2.1. Materials. DIM was purchased from Sigma-Aldrich Japan K.K. and used as received. Other chemicals and solvent employed in this study were analytical grade and used without any purification. 2.2. Methods. 2.2.1. Single Crystal X-ray Diffraction and Refinements. The single crystal X-ray diffraction data were collected at 173 K in a ω-scan mode with an R-AXIS RAPID II (Rigaku, Japan) using Cu Kα X-ray obtained from rotating anode source with graphite monochromator. The integrated and scaled data were empirically corrected for absorption effects with ABSCOR.22 The initial structure was solved by using the direct method with SIR 2004 and refined on F02 with SHELXL 2014.23,24 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were located from the differential Fourier map and were refined isotropically. The ORTEP drawing for the molecular structure was produced with the PLATON program,25 and other molecular graphics were produced from MERCURY software.26 2.2.2. Density Functional Theory (DFT) Calculation. The calculated structure of DIM was determined by using CASTEP in Materials Studio 7.0 package.27 GGA-PBE functional was used, and the quality setting was adjusted to fine. The cutoff energy was set at 520.0 kV with maximum SCF cycles at 200 and separation at 0.05 Å. A Grimme method was used for DFT-D correction. The geometry optimizations were conducted first for hydrogen atom only and followed for all positions of atoms. The geometry optimization was finally conducted for all molecules within the crystal lattice. All calculations for the calculated structure were submitted to Tsubame 2.5 supercomputer, and the results were extracted into laboratory PC. The calculated structure of 8-chlorotheophylline and calculated spectra of DIM were determined by using DFT B3LYP/6-31G** basis set in SPARTAN.28

3. RESULTS AND DISCUSSION 3.1. Solid-State Characterization of DIM. 3.1.1. Crystal Structure of DIM. Although DIM is widely used as a drug, to the best of our knowledge, the crystal structure has not been determined yet over the last 67 years. In the extensive crystallization experiments using various of solvents, conditions, and technique, we were not able to obtain the single crystal of DIM. Most of the product obtained from crystallization appeared to be powdery samples or oily liquids. Interestingly, the large rock-chunk crystal suitable for single crystal X-ray diffraction measurement was obtained by cutting the agglomerate solids from tetrahydrofuran solvent. The crystallographic data are summarized in Table 1. The thermal ellipsoid drawing for DIM is presented in Figure 2. In the difference Fourier map, a significant residual density peak is observed at the position where it is suitable for the N−H distance in N1 of diphenhydramine molecule (N−H distance: 0.930(17) Å), which is assigned as a transferred hydrogen atom. In addition, there are no significant residual density peaks both on N2 and N3 of 8-chlorotheophylline, which means a hydrogen atom has B

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Table 1. Crystallographic Data of DIM moiety formula formula weight crystal system space group a b c β volume Z D (calculated) absorption coefficient F(000) crystal size θ range for data collection index ranges reflections collected independent reflections completeness to θ = 67.686° color temperature radiation, wavelength measured reflections independent reflection data/restraints/ parameters goodness-of-fit on F2 final R indices [I > 2σ(I)] R indices (all data) largest diff peak and hole

C17H22NO·C7H6ClN4O2 469.96 monoclinic P21/n 8.7636(2) Å 10.1619(2) Å 26.3447(5) Å 90.2764(7)° 2346.10(8) Å3 4 1.331 Mg/m3 1.738 mm−1 992 0.278 × 0.178 × 0.101 mm3 3.355−68.218° −10 ≤ h ≤ 10, −12 ≤ k ≤ 12, −31 ≤ l ≤ 31 26720 4294 (Rint = 0.0311) 100% colorless 173(2) K Cu Kα, 1.54186 Å 26720 4294 [R(int) = 0.0311] 4294/0/410

Figure 3. Observed (a) and calculated (b−d) structure of 8chlorotheophylline molecule, and overlaid crystal packing between observed (blue) and calculated (red) of DIM (e). The distances of C18−N2 and C18−N3 in 8-chlototheophylline molecule was calculated as neutral (b) and anionic (c) form using DFT, and anionic form using DFT-D (d). Hydrogen atoms are omitted for clarity in (e).

1.055 R1 = 0.0358, wR2 = 0.0887 R1 = 0.0373, wR2 = 0.0901 0.342 and −0.487 e·Å3

theophylline molecule),31 C−N distance of C8−N2 in neutral five-membered ring of theophylline are also shorter than C18− N3 (the mean distances for C18−N2 and C18−N3 are 1.336 and 1.338 Å, respectively). It should be noted that the comparison with anionic 8-chlorotheophylline cannot be made due to the structure has not been reported yet. Therefore, the comparison to deprotonated theophylline derivative in this case is very important although its occurrence is relatively rare.32−34 From CSD analysis, there are only four hits of the anionic theophylline which two of them are considered as cocrystal continuum. By excluding the cocrystal continuum structures due to unclear status of ionic state, the mean distances for C18−N2 and C18−N3 are 1.318 and 1.366 Å, respectively, in which the C−N distance of C18−N2 is again shorter than C18−N3.33,34 In such a case, the assessment of proton transfer is considered as difficult from the bond distances only. Therefore, the role of the calculated structure together with spectroscopy study are indispensable to solve salt−cocrystal ambiguity (see section 3.1.2 for spectroscopy study). The second approach used in this study is utilization of the theoretical structure of 8-chlorotheophylline both in neutral and anionic form (Figure 3b,c). Therefore, the DFT calculations were carried out to obtain an optimized structure of those species. In neutral form, the distances of C18−N2 and C18−N3 in 8-chlorotheophylline are 1.357 and 1.320 Å, respectively. Meanwhile, the distances of C18−N2 and C18− N3 in anionic form are 1.318 and 1.362 Å, respectively. From these results, it can be seen that if the 8-chloroteophylline is neutral, C18−N2 is longer than C18−N3, and if it is anionic, C18−N2 is shorter than C18−N3. The observed distances of

Figure 2. Thermal ellipsoid drawing of the asymmetric unit of DIM showing atom labeling and 50% probability ellipsoids.

been transferred to diphenhydramine. Thus, this multicomponent crystal of DIM is categorized as a salt form molecular crystal. It is also very important to ensure that 8-chlorotheophylline is deprotonated from the structural point of view. To best of our knowledge, the existence of proton transfer should affect the molecular structure. Therefore, the theophylline molecular structure in this study was compared to known structures for confirmation of the proton transfer. As illustrated in Figure 3a, the observed distances between C18−N2 and C18−N3 are 1.3222(18) Å and 1.3502(18) Å, respectively. Thus, the C−N distance of C18−N2 is shorter than C18−N3. However, according the most recent version of the CSD (limited to C

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C18−N2 and C18−N2 in this study resemble the anionic form of 8-chlorotheophylline, not the neutral form. Lastly, the theoretical structure, including the proton transfer and the crystal packing effect, was also calculated in this study. The DFT-D calculation was carried out, and the whole observed crystal structure, including all molecules, was optimized. As shown in Figure 3d, the theoretically calculated distances between C18−N2 and C18−N3 are 1.340 and 1.359 Å, respectively, in which also the distance of C18−N2 is shorter than C18−N3. This result also strongly supported the single crystal X-ray structure that the DIM exists as the salt form. The slight differences in calculated distances can be due to the neglect of the thermal vibration effect. As shown in Figure 3e, both calculated and observed structures show satisfactory agreement with the root-mean-square deviation (RMSD) value of 0.0186 Å. This successful optimization indicates that the salt form model of this crystal is correct. From the Mogul geometry check,35 all bond distances, bond angles, and torsion angles in the DIM structure appear to be usual except the bond angles, which are related with the pentagonal ring in 8-chlorotheophylline. The bond angles of C18−N2−C19, C18−N3−C20, and C20−C19−N2 are 101.23(11)°, 100.12(11)°, and 107.95(11)°, respectively. From Mogul analysis which contains a similar five-membered ring,31 the mean values of those bond angles are 105.36°, 98.53°, and 111.02°, respectively. By excluding the cocrystal continuum structures from CSD analysis of anionic theophylline structures, the mean values of C18−N2−C19, C18−N3− C20, and C20−C19−N2 are 102.82°, 101.77°, and 107.97°, respectively, which are similar to observed bond angles.33,34 Thus, these observed values are acceptable due to the deprotonation of the nitrogen atom and the existence of an electrophilic atom in that ring. Moreover, the DFT-D calculated bond angles of C18−N2−C19, C18−N3−C20, and C20−C19−N2 are 102.16°, 101.06°, and 107.95°, respectively. The small differences between calculated and experimental bond angles are acceptable because thermal vibrations were neglected during calculation. Interestingly, only one strong intermolecular hydrogen bond was observed in the crystal. Charge-assisted hydrogen bond of N1−H1···N2 was apparently the strongest bond observed in the crystal with a distance of 1.819(17) Å. The auxiliary hydrogen bonds of C2−H2···N2, C15−H15A···O2, and C4− H4···O2 are recognized in order to stabilize the conformation of protonated diphenhydramine. The hydrogen bonds of C23− H23B···N3 and C24−H24A···N3 were observed as the result of the interaction between 8-chlorotheophylline molecules. These auxiliary hydrogen bonds are considered as weak hydrogen bonds. The hydrogen bonds of DIM are illustrated in Figure 4, while the details are listed in Table 2. The comparison of experimental and calculated powder patterns is necessary to make sure that the bulk powder and single crystal are the same phase. Figure 5 indicates the experimental and calculated powder patterns of DIM, which were calculated from the analyzed crystal structure. In particular, all patterns contained consistently the same peak, and the major prominent diffractions were observed at 10.7, 13.4, 19.6, 21.5, and 24.4°. The United States Pharmacopoeia has stated that the difference of scattering angle of the strongest reflection between the sample and reference may vary by ±0.10° in a well-established PXRD.36 Meanwhile, the small disagreement in peak positions and intensities can be influenced by the experimental conditions. Such small differ-

Figure 4. Intermolecular hydrogen bond observed in DIM. Bluedashed line and orange-dashed line indicate strong and weak hydrogen bond correspondingly.

Table 2. Intermolecular Hydrogen Bonds for DIM

a

D−H···A

d(H···A) Å

d(D···A) Å

∠(DHA)°

N1−H1···N2 C2−H2···N2 C15−H15A···O2 C4−H4···O2a C23−H23B···N3b C24−H24A···N3c

1.819(17) 2.628(16) 2.561(16) 2.601(16) 2.62(2) 2.569(19)

2.7249(15) 3.5290(17) 3.3955(17) 3.3063(16) 3.531(2) 3.4329(18)

163.8(14) 157.9(13) 146.5(12) 129.8(11) 157.5(15) 150.5(15)

x −1, y, z. b−x + 2, −y + 1, −z. c−x + 1, −y + 1, −z.

Figure 5. Experimental (a) and calculated (b) powder pattern of DIM.

ences observed in this study are considerably acceptable regarding the temperature difference (single crystal X-ray diffraction was measured at −100 °C, and PXRD at 25 °C). Thus, we suggest that the marketed powder and the structure reported in the present study are identical. 3.1.2. Spectroscopy Study of DIM. The 13C-SSNMR is a commonly used method for identifying the existence of proton transfer. It is well-known that a change in the chemical bond such as proton transfer can change the respective spectra, as well. In addition, the change in chemical bond can also be detected by vibrational spectroscopy such as FTIR. Compared to the single crystal X-ray diffraction technique, the spectroscopy method is more preferred in the routine analysis due to the easy sample preparation. It should be noted that diphenhydramine was not used in the FTIR experiments for comparison due its hygroscopicity and handling difficulties. D

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The 13C-CP/MAS NMR spectra and peak assignments of DIM are presented in Figure 6 and Table 3, respectively. By

400 cm−1.37 The FTIR spectra of DIM and 8-chlorotheophylline are shown in Figure 7. The protonation in this compound

Figure 6. 13C cross-polarization and magic-angle spinning (CP/MAS) NMR spectrum of DIM at the contact time of 5 ms and the MAS rate of 15 kHz. Black circles indicate spinning sidebands.

Figure 7. FTIR spectra of DIM (blue) and 8-chlorotheophylline (red).

Table 3. Chemical Shift and Peak Assignments of DIM experimental chemical shift (ppm)

calculated chemical shift (ppm)a

29.8 32.8 38.7, 45.2 55.3 60.9 83.6 115.4 125.7−131.2

28.3 29.6 42.9 58.0 59.2 84.4 117.1 128.1−128.8

143.5b 143.5b 150.9−151.7 158.1

140.9 151.1 153.0−153.6 161.4

was barely observable by vibrational spectroscopy. The most plausible difference is the diminishment of broad NH peak of 8chlorotheophylline (red spectrum in Figure 7) at around 3500−3300 cm−1. This region is a response of symmetric and asymmetric vibration of N−H in the pentagonal ring of 8chlorotheophylline. Because of the proton transfer, this NH peak was not observed in the DIM spectra (blue spectrum in Figure 7). Moreover, no peak was observed in 3400−3500 cm−1 in DIM due to the absence of primary and secondary amines in the structure. 3.1.3. Thermal Analysis of DIM. Thermal analysis data are necessary to understand the solid behavior during heating such as crystallization, phase transformation, dehydration, and decomposition. The most common thermal analysis methods are DSC and TG-DTA.37,38 The thermograms of DIM are shown in Figure 8. From DSC, a sharp endothermic peak began from 102.5 °C, and the highest onset seemed to be at 105.2 °C similar with DSC thermogram, from DTA a sharp endothermic peak began from 101.2 °C with the highest onset at 103.0 °C. We attribute these peaks as the melting points of DIM. The differences in temperature derived from DSC and DTA seem to be reasonable due the differences in the experimental conditions of both the methods. The closed pan system was used in DSC measurement, while the open pan system was applied in TG-DTA. The flat profile prior to melting indicates that the raw material of DIM tends to exist in only one polymorphic form. From the TG data, the loss of weight appeared at 140.1 °C. Around this temperature, exothermic peaks were also observed in both the DSC and DTA thermograms that are associated with the thermal decomposition of DIM. 3.1.4. Solubility Study of DIM. Solubility is one of the important topics related to bioavailability issues and product development. Equilibrium solubility and the concentration of solute when excessive solids exist are the common methods used to determine solubility. The weakness of equilibrium solubility is the consistency of the data due to instability when solution is supersaturated. Thus, in this study, we preferred to use kinetic solubility in which the first induced precipitate appeared in the solution. Since DIM appeared to be in the salt form, the solubility of DIM is strictly correlated with the ionization state of this compound. Controlling pH of the solution will correspond to the solubility of this class of

corresponding atom(s) C23 C24 C16, C17 C15 C14 C7 C19 C2, C3, C4, C5, C6, C9, C10, C11, C12, C13 C1,C8 C18 C20,C22 C21

a

The chemical shifts are calculated by DFT using atomic coordinate from crystal structure. bThe peak at 143.5 ppm are overlapped by three peaks.

comparing the experimental and calculated spectrum of DIM, we could determine the presence of proton transfer. As shown in Table 3, the chemical shifting occurs dominantly in C18, which indicates the change in chemical bonding. Since the difference is around 7 ppm, we consider this value as significant and support the data validity regarding proton transfer. The slight shifts in C15, C16, C17, and C19 also strengthen the presence of proton transfer since these atoms surround the protonation−deprotonation site in 8-chlorotheophylline and diphenhydramine molecules. The existence of proton transfer is also confirmed experimentally by comparison to diphenhydramine, diphenhydramine HCl, and 8-chlorotheophylline spectra (see Figure S1). The chemical shifts of carbon atoms around the proton transfer site (C14, C15, C16, C17, and C19) significantly change compared with the free form of diphenhydramine and 8-chlorotheophylline. In addition, the shifting of C14, C15, C16, and C17 in cationic diphenhydramine of DIM also shows a similar profile with the cationic form of diphenhydramine in its HCl salt. FTIR spectra are important for solid characterization, particularly for the identification of the pharmaceutical solids due to the specificity in the fingerprint region at around 1800− E

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Figure 8. DSC (a) and TG-DTA (b) thermograms of DIM.

results of the spectroscopy method (SSNMR and FTIR) also showed the presence of proton transfer, which is pointed out from the significant difference relative to 8-chlorotheophylline. Lastly, the solubility measurement indicated that DIM can also be considered as a soluble compound. The findings of this research will provide fundamental information to those who use this material as a compound of interest.

materials. In this case, we also conducted an intrinsic solubility test where DIM exists as a nonionized species in the solution. It is also necessary to determine pKa of DIM. The redetermination of pKa values was accomplished with the potentiometric titration method. The pKa measurement of DIM resulted in two inflection points, which indicate DIM has two pKa values (Figure 9). The first pKa appears to be 5.13, and

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b00771. SSNMR spectra and crystallographic details (PDF) Accession Codes

CCDC 1446743 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Figure 9. Bjerrum titration curve from low to high pH of DIM. Bluefilled triangles indicate the experimental points used for data refinement.

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the second pKa value is 8.98. The acidic pKa is caused from N acidic of 8-chlorotheophylline and the basic pKa corresponds to the quaternary nitrogen of diphenhydramine. Even with several attempts to measure DIM by the potentiometric chasing equilibrium solubility method,26 we failed to measure its intrinsic solubility. Thus, in this study, we utilized the curve fitting method. Kinetic and intrinsic solubility of DIM are 2.255 mM and 2.308 mM, respectively. Thus, DIM can be categorized as a soluble compound. It should be noted that the nonchasing compounds such as DIM cannot form supersaturated solution in the water, which means decreasing gradient concentration according to the Fick’s law. This phenomenon indicates that a special formulation may be necessary if the compound has inherently low permeability.39

AUTHOR INFORMATION

Corresponding Author

*Tel.: +81 03 5498 5048. Fax: +81 03 5498 5048. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We wish to thank CTCLS Japan for solubility measurements. O.D.P. thanks MEXT Japan for research fellowships. We also acknowledge the members of the focus group on Pharmaceutical Profiling of the Academy of Pharmaceutical Science and Technology (Japan) for their valuable discussions. This project was supported in part by a Grant-in-Aid for Scientific Research (C) 19 Japan Society for the promotion of science (KAKENHI Grant Number 26460048).

4. CONCLUSION In the present study, we report the comprehensive solid-state characterization of DIM by using X-ray diffraction, spectroscopies, and thermal analysis. Monoclinic salt crystal of DIM was first determined after more than six decades in this study. We also succeeded in determining the transfer of a proton from 8chlorotheophylline to diphenhydramine, which confirmed the existence of DIM as a salt crystal in this combination. The DIM structure contained an interesting feature related to proton transfer which was carefully determined by the latest advance in crystallographic analysis using density functional theory calculation. In accordance with the crystallographic study, the

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REFERENCES

(1) Morris, K. R.; Griesser, U. J.; Eckhardt, C. J.; Stowell, J. G. Adv. Drug Delivery Rev. 2001, 48, 91−114. (2) Spong, B. R.; Price, G. P.; Jayasankar, A.; Matzger, A. J.; Hornendo, N. R. Adv. Drug Delivery Rev. 2003, 56, 241−274. (3) Rajput, L. Cryst. Growth Des. 2014, 14, 5196−5205. (4) Sanphui, P.; Goud, N. R.; Khandavilli, U. B. R.; Bhanoth, S.; Nangia, A. Chem. Commun. 2011, 47, 5013−5015. F

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Crystal Growth & Design

Article

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DOI: 10.1021/acs.cgd.6b00771 Cryst. Growth Des. XXXX, XXX, XXX−XXX