Communication pubs.acs.org/crystal
Crystallographic Analysis of Phase Dissociation Related to Anomalous Solubility of Irsogladine Maleate Okky Dwichandra Putra,†,# Tomomi Yoshida,‡,# Daiki Umeda,‡ Mihoko Gunji,‡ Hidehiro Uekusa,*,† and Etsuo Yonemochi*,‡ †
Department of Chemistry and Materials Science, Tokyo Institute of Technology, Ookayama 2-12-1, Meguro-ku, Tokyo 152-8551, Japan ‡ School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41, Ebara, Shinagawa, Tokyo 142-8501, Japan S Supporting Information *
ABSTRACT: We report the anomalous solubility of the pharmaceutical salt irsogladine maleate, which is associated with phase dissociation. The anomalous solubility was demonstrated by the similarity of solubility and miscibility between the salt and its base in ethanol solvent. The phase dissociation was revealed and confirmed by distinguishing irsogladine maleate and its free base using single-crystal X-ray analysis. Herein, the crystal structures of irsogladine maleate and its base were reported for the first time, and the plausible mechanism for phase dissociation was established based on the structural correlations between those phases.
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increases of multicomponent crystals of salts and cocrystals have attracted great interest because, in general, the solubility of such multicomponent crystals may be greater than that of their free forms. If the salt or cocrystal are highly soluble/miscible in solvents and form an incongruent system, the dissociation will presumably occur.9 In some cases, dissociation followed by crystallization gives rise to processing difficulties for manufacturing process.10 To our knowledge, information about phase dissociation is extremely important, especially for drug formulation. Moreover, the probability of phase dissociation increases with the existence of the solvent.11,12 Indeed, some pharmaceutical dosage forms, such as elixir syrup, and pharmaceutical manufacturing processes, such as wet granulation, requires the usage of water and edible organic solvents such as ethanol.12 Thus, it is necessary to confirm the occurrence of phase dissociation in these formulations or processes in order to ensure the safety, quality, and efficacy of drugs. To achieve a better understanding, the dissociation of the salt or cocrystal in particular solvents should be investigated further. The investigation should explore the solubility behavior of a multicomponent crystal as well as its constituents in the particular solvents.13 Without a priori knowledge of multicomponent crystals and their solubility, the phase dissociation is likely to be treated as accidental and left out of the scientific understanding.14 In this study, we investigate the phase dissociation of the pharmaceutical material irsogladine maleate (Scheme 1). Irsogladine maleate is known to be an enhancer of the gastric
he numerous different types of pharmaceutical crystals, e.g., salts, cocrystals, hydrates, solvates, and polymorphs, have attracted great interest from both crystallographers and pharmaceutical scientists because each crystalline form has unique physicochemical properties such as stability, solubility, dissolution rate, and hygroscopicity.1 Solid-state stability is one of the most important properties because it is strongly related with efficacy, safety, and bioavalaibility.2,3 In spite of careful consideration during drug development or processing, a new crystalline form can unexpectedly appear without warning during, for example, solubilization or storage.4−6 Once solid-state transformation, e.g., polymorphic conversion or phase dissociation, occurs, it might be difficult to recover the initial phase, which might have the desired properties as well as efficacy and safety.7 The failure to identify solid-state transformation leads to severe loss for the pharmaceutical industry and may influence the performance of drugs.4 Thus, it is important to ensure that the crystalline phases designed by the drug formulator remain unchanged in all steps of drug development and processing. One of the most well-known and well-publicized cases of undesired solid-state transformations, in particular, phase dissociation, was investigated by Merritt and co-workers.8 They clarified the effect of pharmaceutical formulation involving common excipients on the phase dissociation of 13 pharmaceutical multicomponent crystals. Information on phase dissociation is clearly important for risk assessment and formulation design of multicomponent crystals for pharmaceutical industries. However, to our knowledge, investigations on the raw materials of drugs are rare. Thus, we aimed to investigate the phase dissociation of the raw materials. Phase dissociation has become a great concern in multicomponent crystals. Moreover, in recent decades, the rapid © XXXX American Chemical Society
Received: September 14, 2016 Revised: October 21, 2016 Published: October 26, 2016 A
DOI: 10.1021/acs.cgd.6b01356 Cryst. Growth Des. XXXX, XXX, XXX−XXX
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Scheme 1. Chemical Structure of Irsogladine Maleatea
a
equal to 1,17 indicating that the solubilities between two materials are almost equally matched. We hypothesized that there are two reasons for the similarity in solubility between irsogladine maleate and its base. First, these materials naturally have similar solubilities. Second, the salt undergoes a phase transformation to its base, resulting in similar solubilities. Thus, these solvents were classified into one group, and further investigation was conducted. Since the equilibrium solubilities were measured, precipitation easily occurred during the experiments owing to the supersaturated condition. To analyze the precipitate solid obtained in the above-mentioned solvents, powder X-ray diffraction (PXRD) measurements were carried out (Figure 2). By comparing the powder pattern of the precipitate to that
Each component is shown in the neutral form.
mucosal protective factor, which accelerates gastric ulcer healing after the treatment of a Helicobacter pylori infection.15 In this report, the phase dissociation was first led by the equilibrium solubility profile between the salt and its base form in various solvents. We hypothesized that the salt and its base should have different solubilities. If the solubilities are similar or almost similar, phase dissociation is likely to have occurred. Then, phase dissociation was confirmed by characterizing the initial and dissociated product through X-ray crystallographic analysis. Furthermore, the rationalization of the phase dissociation was further established based on the solubility data of the salt and its components. The equilibrium solubilities of irsogladine maleate and irsogladine were determined using the standard flask method. Solubility was measured in various organic solvents at 37 °C. Then, the solubilities of irsogladine maleate and its free base were compared. The ratio of solubility between the irsogladine maleate and its base is the first central concept in this work; for simplicity, we defined this value as an empirical parameter, μ. The μ value is determined as the absolute value which has consequences the lower solubility of irsogladine maleate or its base will act as the numerator. For validity, the amount of solvent was kept constant in all experiments.16 Solubility data show that the solubilities of irsogladine maleate and its base depend on the type of solvent. As illustrated in Figure 1, we divided the solubility profile based on the μ value. Presumably, the solubility of the multicomponent crystal should be different from that of the single-component crystal, resulting in the trend where irsogladine maleate is more soluble than its base or vice versa. Interestingly, the μ values in diisopropyl ether, ethanol, ethyl acetate, diethyl ether, acetone, and THF solvents are nearly
Figure 2. PXRD patterns of irsogladine maleate (a), precipitate from diisopropylether (b), ethyl acetate (c), diethyl ether (d), acetone (e), THF (f), ethanol (g), and irsogladine (h).
of the raw material, it was determined that the precipitate obtained from diisopropyl ether, ethyl acetate, diethyl ether, acetone, and THF solvents remained as the original raw material. Interestingly, in ethanol, irsogladine maleate was transformed to its base, and no traces of irsogladine maleate could be detected in the obtained powder pattern. We attribute this result to the anomalous profile of the ethanol solvent
Figure 1. Solubility profile between irsogladine maleate and its base. The red chart indicates that the solubility of irsogladine is greater than that of irsogladine maleate, while the blue chart indicates that the solubility of irsogladine maleate is greater than that of irsogladine. The inset shows the solvents having μ values nearly equal to 1.17 B
DOI: 10.1021/acs.cgd.6b01356 Cryst. Growth Des. XXXX, XXX, XXX−XXX
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system, which results from the μ value being nearly 1 as well as the occurrence of phase dissociation. Notably, the phase dissociation did not occur in ethyl acetate, although the μ value of the ethyl-acetate system is identical to that of the ethanol system. We predict that, even though the μ values are similar, the irsogladine maleate and its base were not as soluble in ethyl acetate as in ethanol, and, consequently, dissociation did not occur. This is in accordance with the hypothesis proposed by Rajput and co-workers,9 in which dissociation is likely to occur in an extremely soluble or miscible solvent. By utilizing the solubility phase diagram, it can be seen that, in the ethanol solvent, irsogladine maleate and irsogladine had similar solubilities (S ≈ 1.7 mg/mL), while maleic acid appeared to be freely soluble (S = 2.7 g/mL).18 As shown in Figure 3, the complementary effects of irsogladine and maleic
The microscopic image (Figure 4) showed two types of solids in the crystal habit. The first type of solid appeared as needlelike crystals and is predominant. The other type of solid in the precipitate appears as small block-like crystals. Since both crystals showed a single-crystal nature, we were able to perform further characterization using single-crystal Xray crystallography. Structural analysis showed that the first type of crystal corresponded to irsogladine, while the minor second type corresponded to irsogladine maleate. This result is in agreement with PXRD data, which showed that irsogladine maleate was transformed to irsogladine. We were not able to observe any traces of irsogladine maleate in PXRD data, because it constituted a very small portion of the precipitate and its amount did not exceed the limit of detection for laboratory X-ray diffractometer measurements. Irsogladine maleate was crystallized in a triclinic crystal system with space group P1̅: a = 5.22770(10), b = 10.8698(2), c = 14.4546(3) Å, α = 70.5130(10), β = 80.5820(10), γ = 82.1160(10)°, T = 173(2) K, R1 (I > 2σ(I)) = 4.88%, wR2 (all data) = 13.74%. We were able to locate the hydrogen atoms attached to nitrogen and oxygen from the difference Fourier map, and they were refined isotropically. Irsogladine free base was crystallized in an orthorhombic crystal system with space group Fdd2: a = 23.3847(5), b = 25.2582(6), c = 7.0859(2) Å, T = 93 (2) K, R1 (I > 2σ(I)) = 3.89%, wR2 (all data) = 8.04%. The same treatment as with irsogladine maleate was applied to the atoms attached to nitrogen. Figure 5 shows a thermal ellipsoid diagram of irsogladine maleate and irsogladine in an asymmetric unit. In the irsogladine maleate, a significant residual density peak was observed around N1, which was assigned to the transferred hydrogen atom. In addition, there was no residual density peak around O2, which implies that the H atom has been transferred from maleic acid to the irsogladine molecule. Furthermore, the difference between C−O distances (ΔDC−O) in maleic acid are 0.073 (for C13−O4 and C14−O3) and 0.020 Å (for C10−O1 and C10−O2), which again support the existence of proton transfer.21 In addition, the angle of C7−N1−C8, which is a protonated N atom, is found to be 118.3(3)°. This value is significantly greater than the angle of the unprotonated C7− N3−C9 (114.9(2)°) as well as the corresponding angles in the free base, which are 113.7(3)° and 114.1(3)°. Thus, irsogladine maleate was categorized as a salt-type multicomponent crystal. In this article, we clarified the salt−cocrystal ambiguity in this multicomponent crystal based on X-ray crystallography. Notably, the ΔpKa value between irsogladine and maleic acid is only 0.38, which makes this multicomponent crystal difficult to assess as a salt or cocrystal based on the ΔpKa rule.22−24 On investigating the interaction between the molecules within the crystal lattice in more detail, the crystal structures of irsogladine maleate and its base were found to have some features in common. In particular, both irsogladine maleate and its base have the same dimeric structure of irsogladine molecules composed of R22(8) N2−H···N5 hydrogen bonds. Indirect interaction, by means of the dimeric structures of irsogladine bridged by coformer molecules, was observed in irsogladine maleate. Meanwhile, direct interaction between the dimeric structures is recognized in the irsogladine base. Both these indirect and direct interactions result in one-dimensional (1D) hydrogen bond chain architectures, which are illustrated in Figure 6a,b. In irsogladine maleate, the protonated nitrogen atom in the triazine ring forms an interaction with the carboxylate anion via
Figure 3. Semiempirical solubility phase diagram of irsogladine, maleic acid, and ethanol. From this diagram, it can be seen that the probability of obtaining irsogladine is much greater than that of obtaining irsogladine maleate.
acid in ethanol at 37 °C are clearly nonideal, resulting in the unorthodox solubility phase diagram. Consequently, the probability of obtaining irsogladine is much higher than the probability of obtaining the salt form owing to higher affinity of ethanol to maleic acid. These solubility data indicate that phase dissociation from the solvent is likely to occur and can be rationalized. Similar cases were also reported in the benzophenone/diphenylamine/methanol system and ephedrine/pimelic acid/water systems, making the task to grow multicomponent crystals challenging.19,20 In order to obtain more detailed information, the precipitate appearing in ethanol was microscopically observed (Figure 4).
Figure 4. Microscopic image of the precipitate in ethanol solution. A block crystal (center, irsogladine maleate) is surrounded by needle-like crystals (irsogladine). C
DOI: 10.1021/acs.cgd.6b01356 Cryst. Growth Des. XXXX, XXX, XXX−XXX
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Figure 5. Thermal ellipsoid diagram of (a) irsogladine maleate and (b) irsogladine at 50% probability level.
Figure 6. 1D hydrogen bond chains of irsogladine maleate (a) and irsogladine (b). The plausible dissociation mechanism of irsogladine maleate to irsogladine (c). The green oval represents maleic acid, while the blue and magenta charts represent the irsogladine molecule with different polarities.
ment, this dimeric structure can be considered as an important molecular unit structure in the rearrangement. In order to rationalize the occurrence of phase dissociation in pharmaceutical salts from the results presented in this paper, a range of different analyses should be performed and dictated from solubility data. The phase dissociation of irsogladine maleate to its base was confirmed based on X-ray crystallographic analysis. Furthermore, a feasible explanation based in the structural correlation between irsogladine maleate and irsogladine was established. This research is expected to provide a foundation for further study on, for example, the kinetic and thermodynamic aspects of phase dissociation. This research should also be emphasized as one of the cases that can be referred to by the pharmaceutical industry to pay more attention to the phase dissociation of pharmaceutical salts. In particular, for the case of irsogladine maleate, the usage of the common organic solvent, ethanol, should be avoided during the preparation of the pharmaceutical dosage form, e.g., in wet granulation or in dispensing elixir. This research is expected to provide fundamental information for more meticulous studies involving kinetic-mechanistic aspects of interconversion among the phases and the comparison of physicochemical performances.
charge-assisted hydrogen bond of N1−H···O2. In addition, one nitrogen atom from the amino moiety, N4, forms bifurcated hydrogen bonds of N4−H···O1 and N4−H···O4. Another nitrogen atom from the amino moiety, N5, made an interaction with the carboxylic-acid moiety of the coformer molecule via the N5−H···O4 hydrogen bond. Therefore, the 1D chain architecture in irsogladine maleate is constructed by the complicated interaction between the dimeric structures of cationic irsogladine and the maleic anion. On the other hand, the 1D chain architecture in irsogladine base is formed by the relatively facile interaction between two dimeric structures. In this case, the dimeric structure of the irsogladine molecule is only connected by the R22(8) hydrogen bond consisting of N5− H···N3 and N4−H···N1 hydrogen bonds. A plausible explanation for the occurrence of phase dissociation in this study can be proposed based on the structural correlation or similarity between the phases (see Figure 6c). When maleic acid molecules move out from the 1D chain structure due to the extraction by ethanol, the vacant hydrogen bonding donor and acceptor sites of adjacent irsogladine molecules likely form new direct hydrogen bonds for forming a related 1D chain architecture composed of irsogladine molecules, as shown in Figure 6a and b. Because the head-to-head dimeric structure of irsogladine molecules is the only feature that is naturally preserved even after rearrangeD
DOI: 10.1021/acs.cgd.6b01356 Cryst. Growth Des. XXXX, XXX, XXX−XXX
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(18) O’Neil, M. J. The Merck Index- An Encyclopedia of Chemical Drugs and Biologicals; Royal Society of Chemistry: Cambridge, 2013; pp 1059−1061. (19) Chadwick, K.; Davey, R. J.; Dent, G.; Pritchard, R. G.; Hunter, C. A.; Musumeci, D. Cryst. Growth Des. 2009, 9, 1990−1999. (20) Cooke, C. L.; Davey, R. J.; Black, S.; Muryn, C.; Pritchard, R. G. Cryst. Growth Des. 2010, 10, 5270−5278. (21) Allen, F. H.; Kennard, O.; Watson, D. G.; et al. J. Chem. Soc., Perkin Trans. 2 1987, 12, S1−S19. (22) Lemmerer, A.; Govindraju, S.; Johnston, M.; Motloung, X.; Savig, K. L. CrystEngComm 2015, 17, 3591−3595. (23) Food and Drugs Agency, Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystal, 2013. (24) Food and Drugs Agency, Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystal, 2016.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01356. Experimental and crystallographic details (PDF) Accession Codes
CCDC 1501783−1501784 contain 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
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (H.U.). *E-mail:
[email protected] (E.Y.). Author Contributions #
O.D.P. and T.Y. contributed equally to this article.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS 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 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).
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REFERENCES
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DOI: 10.1021/acs.cgd.6b01356 Cryst. Growth Des. XXXX, XXX, XXX−XXX
