Noncommon Ion Effect on Phase Transformation of Guanosine 5

Article pubs.acs.org/IECR

Noncommon Ion Effect on Phase Transformation of Guanosine 5‑Monophosphate Disodium in Antisolvent Crystallization Anh-Tuan Nguyen, Jeongki Kang, and Woo-Sik Kim* Department of Chemical Engineering, ILRI, Kyung Hee University Seocheon-Dong, Giheung-Gu, 446-701 Yongin-Si, Korea

Downloaded by UNIV OF NEBRASKA-LINCOLN on September 1, 2015 | http://pubs.acs.org Publication Date (Web): May 22, 2015 | doi: 10.1021/acs.iecr.5b00813

S Supporting Information *

ABSTRACT: This study investigated the effect of noncommon ions on the phase transformation of guanosine 5monophosphate disodium (GMP disodium salt, Na2GMP) in the case of antisolvent crystallization. Thus, GMP was synthesized by biological fermentation and then purified by antisolvent crystallization, which included the phase transformation of the amorphous phase of GMP disodium salt into the crystalline phase via a recrystallization process in the solution. However, during this phase transformation, the addition of K+ and Ca2+ as noncommon ions had a significant impact as they were popular ionic impurities in the fermented solution. Thus, the Na+ ions in the GMP disodium salt were replaced with K+ and Ca2+ ions to form new amorphous GMP complex salts, such as Na/K·GMP or Na/Ca·GMP. The solid structures of these amorphous GMP complex salts were much more stable than the solid structures of the amorphous and crystalline GMP disodium salt, meaning that the solubility of the GMP complex salts in the solvent was much lower than the solubility of the GMP disodium salt. In addition, the replacement of the Na+ ions in the GMP disodium salt with K+ and Ca2+ ions inhibited the formation and orderedstacking of the GMP G-quartets. Thus, the amorphous GMP complex salts did not transform into a crystalline phase. This impact of the K+ and Ca2+ ions was confirmed by element mapping images and the element ratios in the GMP complex salts.

1. INTRODUCTION

Accordingly, the present study investigated the influence of noncommon ion additives on the phase transformation of guanosine 5-monophosphate disodium salt (GMP disodium salt, Na2GMP, Figure 1). In industry, GMP disodium salt is

The phase transformation of polymorphic crystals during crystallization is crucial in the case of food additives, pharmaceuticals, and fine chemicals, as different polymorphic crystals have different physical-chemical properties of solubility, hardness, stability, and bioavailability.1−5 Thus, many studies have already attempted to control the phase transformation in order to achieve the desired polymorphic product. Phase transformation during crystallization is generally affected by numerous factors, such as the additive/impurities, solvent, agitation speed, temperature, initial solute concentration, pH, and seeding.6−20 For example, adding trimesic acid retards the phase transformation of L-glutamic acid by over 3 weeks when compared to 35 min without an additive.6 This phenomenon has been explained by the preferential adsorption of the additive molecules to the stable phase, thereby hindering the growth of the stable phase. Meanwhile, the preferential adsorption of the additive L-phenyalanine to the metastable phase of L-glutamic acid has been found to stabilize the metastable phase, thereby significantly delaying the dissolution of the metastable phase and nucleation and growth of the stable phase.7 Plus, when further increasing the L-phenylalanine concentration, its preferential adsorption also influenced the growth and morphology of the metastable phase of L-glutamic acid.7,8 Additives are also known to influence the solubility of polymorphic crystals. According to Mukuta et al.,9 impurities increased the solubility of the stable phase of an active pharmaceutical ingredient (compound 1), thereby reducing the solubility difference between the stable and metastable phases, which is a driving force for the nucleation and growth of the stable phase. As a result, the phase transformation from the metastable phase to the stable phase was retarded. © 2015 American Chemical Society

Figure 1. Molecular structure of guanosine-5 monophosphate disodium salt.

synthesized using biological fermentation (CJ Co., Korea) and then purified/separated using antisolvent crystallization with methanol as the antisolvent. During this crystallization process, GMP disodium salt is first precipitated as amorphous solids (metastable phase) and then transformed into crystalline solids (stable phase) via recrystallization. This phase transformation process is typically slow and completely dependent on the Received: Revised: Accepted: Published: 5784

March 2, 2015 May 11, 2015 May 13, 2015 May 13, 2015 DOI: 10.1021/acs.iecr.5b00813 Ind. Eng. Chem. Res. 2015, 54, 5784−5792

Article


Industrial & Engineering Chemistry Research

England) and inductively coupled plasma (ICP) (Leeman Labs., Inc., Direct Reading Echelle ICP). The GMP concentration in the solution was monitored by UV−vis spectroscopy as using the absorbance at 256 nm of (Jasco, V570). In addition, X-ray diffraction (XRD; MAC Science, M18XHF-SRA, Cu Kα line, Japan) was used to confirm the structures of the GMP solids.

dissolution of the amorphous solids and growth of the crystalline solids. When using a stirred batch crystallizer (23 m 3 working volume), the phase transformation from amorphous GMP disodium salt to crystalline disodium salt takes over 6 h (Technical report of CJ Co., Korea). Even in a lab scale-batch crystallizer (1 L working volume), this phase transformation requires over 120 min.21,22 However, when using a continuous Taylor crystallizer, a 5 min mean residence time has been shown to be enough to achieve the complete phase transformation of GMP disodium salt, as the unique Taylor vortex fluid motion in the crystallizer significantly promotes the mass transfer rates for the dissolution of the amorphous solids and growth of the crystalline solids.23−25 It has also been demonstrated that the addition of NaCl markedly facilitates the phase transformation of GMP disodium salt due to the common ion effect of Na+26. Yet, in practice, the fermentation solution of GMP includes many kinds of soluble ionic impurities, such as sodium, potassium, calcium, and magnesium (Technical report of CJ Co., Korea). All such ionic impurities, except for the common ions of sodium, inhibit the phase transformation of the amorphous GMP solids into crystalline solids, resulting in a long phase transformation crystallization process and low-quality crystallization product. Therefore, this study investigated the influence of noncommon ionic impurities on the phase transformation of GMP salt. As potassium and calcium were identified as the most highly concentrated noncommon ionic impurities in the fermented solution, the focus was the impact of their presence on the phase transformation of the amorphous GMP solids into crystalline solids.

3. RESULTS AND DISCUSSION The influence of the noncommon ions (K+ and Ca2+) on the antisolvent crystallization of disodium 5′-monphosphate (GMP disodium salt, Na2GMP) is shown in Figure 2. It is already known that antisolvent crystallization initially produces the metastable phase of amorphous GMP disodium salt, which is then gradually transformed into the stable phase of crystalline GMP disodium salt (Na2GMP·7H2O) due to a difference in

2. EXPERIMENTS The raw guanosine 5-monophosphate disodium salt heptahydrate (Na2GMP·7H2O) (purity >99.9%) was supplied by the CJ Company (Korea) and used without further purification. The noncommon ion additives of KCl and CaCl2 were purchased from the Sigma-Aldrich Company (ACS grade). The methanol antisolvent was purchased from the Duksan Company (purity >99.9, Korea). A GMP solution of 61 g/L was prepared by dissolving the raw Na2 GMP in distilled water. Next, KCl or CaCl2 was dissolved in the GMP feed solution. The antisolvent crystallization of GMP salt was then initiated by the simultaneous mixing of equal volumes (250 mL) of the GMP feed solution and methanol in a batch crystallizer. The crystallizer was a standard Rushton tank made of pyrex glass and equipped with a propeller-type impeller for effective mixing.27 The impeller agitation speed and crystallization temperature were always fixed at 600 rpm and 25 °C, respectively. Samples of the product suspension were intermittently taken from the crystallizer and quickly filtered through 0.45 μm poresize filter paper using a vacuum. The filtered GMP solids were then washed with methanol to remove any ions attached to the solids and dried in a desiccators with a silica gel desiccant for 1 day before the analysis. The crystalline and amorphous phases of the GMP solids were calibrated using FTIR (Perkin, System 2000), which estimated the mass fraction of the crystalline phase in the product solids, as described in our previous study.23 The shapes of the solids were observed using an optical microscope (IT System, Sometech). The ion contents (Na+, K+, and Ca2+) in the GMP solids were detected by energy dispersive X-ray spectroscopy using a scanning electron microscope (SEM-EDX; Leica Cambridge, Stereoscan 440,

Figure 2. Typical transient behavior during phase transformation of GMP solids with various concentrations of K+ and Ca2+ as noncommon ion additives. The crystallization conditions were always fixed at a temperature of 25 °C, agitation speed of 600 rpm, GMP feed concentration of 30.5 g/L, 5:5 feed ratio (GMP solution−methanol), and pH = 6−8. (a) Mass fraction of crystalline GMP solids in product and (b) solute concentration in solution. 5785

DOI: 10.1021/acs.iecr.5b00813 Ind. Eng. Chem. Res. 2015, 54, 5784−5792

Article



Figure 3. Typical morphology of GMP solids produced with various concentrations of K+ and Ca2+ as noncommon ion additives. The crystallization conditions were always fixed at a temperature of 25 °C, agitation speed of 600 rpm, and GMP feed concentration of 30.5 g/L. (a) GMP solids initially precipitated without ion additive; (b) GMP solids after phase transformation of amorphous GMP solids precipitated without ion additive; (c) GMP solids produced with 0.02 mol/L of K+ ion additive; (d) GMP solids produced with 0.1 mol/L of Ca2+ ion additive; (e) GMP solids produced with 0.2 mol/L of K+ ion additive; and (f) GMP solids produced with 0.2 mol/L of Ca2+ ion additive.

their respective structural stability. That is, the metastable phase of amorphous GMP disodium salt (13.0 g/L of solubility) is more soluble than the stable phase of crystalline GMP disodium salt (9.5 g/L of solubility).21,23 Therefore, the metastable phase is recrystallized as the stable phase via the dissolution of the amorphous GMP disodium salt and the growth of crystalline GMP disodium salt in the solution. During this phase transformation, the present study simultaneously monitored the mass fraction of crystalline solids in the total solid products and the GMP concentration in the solution, as shown in Figure 2, panels a and b, respectively. When not using a noncommon ion additive, the amorphous GMP disodium salt was completely transformed into crystalline GMP disodium salt within a crystallization time of 120 min. However, when using a

noncommon ion additive, no complete phase transformation was achieved. Thus, with 0.02 mol/L of the K+ ion additive, 72% of the amorphous GMP solids were transformed into crystalline GMP solids (Figure 2a), and when increasing the K+ ion concentration above 0.2 mol/L, the phase transformation was completely blocked. Similarly, with 0.1 mol/L of the Ca2+ ion additive, only 27 wt % of the amorphous GMP solids were transformed into crystalline GMP solids, and when increasing the Ca2+ ion concentration over 0.2 mol/L, the phase transformation was also completely blocked. The GMP concentration profile during the phase transformation varied according to the addition of noncommon ions, as shown in Figure 2b.The GMP concentration in the solution gradually decreased during the crystallization until reaching the 5786


Article



disodium heptahydrate.21 However, when adding a small amount of K+ and Ca2+ as noncommon ions, only a part of the initial amorphous GMP solids was transformed into crystalline solids, resulting in a mixture of amorphous and crystalline GMP solids as the final state (Figure 3c,d). When further increasing the ion concentration above 0.2 mol/L, no amorphous GMP solids were transformed, as shown in Figures 3e,f, 4, and 5.

equilibrium concentration (solubility). However, this equilibrium concentration was changed with the addition of noncommon ions (K+ and Ca2+). Without an additive, the equilibrium concentration was about 9.5 g/L, which matched the solubility of the crystalline GMP disodium salt.21,23 However, with the addition of 0.02 mol/L of K+ and 0.1 of mol/L Ca2+, the equilibrium concentration was reduced to 7.9 and 3.1 g/L, respectively. When further increasing the K+ and Ca2+ concentration to 0.2 mol/L, the equilibrium concentration dropped to 4.1 and 0.12 g/L, respectively. In the latter case, since there was no fraction of crystalline GMP solids (Figure 2a), the equilibrium concentrations likely corresponded to the solubility of the amorphous GMP solids produced with 0.2 mol/L of the K+ and Ca2+ additives, respectively. These results also indicated that the GMP solids formed with the K+ and Ca2+ additives differed from the GMP disodium salts obtained without any ion additive, essentially due to cation substitution during the crystallization. That is, the Na+ ions in the GMP disodium salt were partly replaced by the K+ and Ca2+ noncommon ions, generating new amorphous GMP complex solids of Na/K·GMP and Na/Ca·GMP during the crystallization. This noncommon ion substitution will be discussed later. The influence of the noncommon ion additives on the phase transformation of GMP was also confirmed using optical microscope and XRD, as shown in Figures 3 and 4, respectively.

Figure 5. Mass fraction of crystalline GMP solids in product solids obtained with various ionic concentrations of K+ and Ca2+.

According to Gellert et al.29 and Wong and Wu,30 the tetrameric unit known as a G-quartet is the basic structural motif of GMP, in which the four GMP molecules form a twodimensional cyclic configuration with eight Hoogsteen-type hydrogen bonds. These G-quartets are then stacked in a helix axisto form a quadruple helix witha channel in the central space of the G-quartet, where the cation such as Na+, K+ and Ca2+ are bound with carbonyl groups inside the central channel (channel ions), and with phosphate groups outside the G-quartets (surface ions). In our previous work,26 it was demonstrated that the addition of Na+ common ions significantly facilitated the phase transformation of amorphous GMP disodium salt into crystalline solids. Meanwhile, according to Pinnavaia et al.31,32 and Hud et al.,33 when studying the preferential binding of noncommon monovalent ions, it was found that K+ ions replaced the Na+ ions bound with the carbonyl groups of GMP due to the higher affinity of K+ ions than Na+ ions to the carbonyl groups. However, K+ ions are unable to participate in the formation of the GMP G-quartet plane, as the ionic radius of K+ (1.33 A) is larger than that of Na+ (0.95 A) and it can not fit in the central space of the G-quartet plane,34 but can fit between G-quartet planes. Therefore, in the present antisolvent crystallization, the Na+ ions in the GMP disodium salt were seemingly partly substituted with the K+ and Ca2+ noncommon ion additives, resulting in the formation of new GMP complex salts of Na/K· GMP and Na/Ca·GMP, respectively, as shown inthe EDX element mapping images (Figure 6). When not using ionic additives, the crystallization initially precipitated amorphous GMP disodium salt, which was then completely transformed into crystalline solids. Thus, the element mapping images indicate that the Na and P elements were homogeneously distributed in both the amorphous and crystalline GMP disodium salts, as shown in Figure 6, panels a and b,

Figure 4. Powder XRD patterns of GMP solids produced with various ionic concentrations of K+ and Ca2+.

When not using an ion additive, the initially precipitated GMP disodium salt consisted of tiny particles (Figure 3a) and exhibited no characteristic peaks in the XRD spectrum ((b) in Figure 4), indicating the amorphous phase. These amorphous solids were then completely transformed into rectangular crystals, as shown in Figure 3b, and exhibited the characteristic crystalline peaks at 8.0°, 12.7°, 16.0°, 20.5°, and 22.7° in the XRD spectrum ((a) in Figure 4). These characteristic peaks then identified the crystals as GMP disodium heptahydrate (Na2GMP·7H2O).21 The amount of water incorporated in the crystals was confirmed by a thermal gravity analysis [Supporting Information Figure S1]. The crystal structure of GMP disodium salt heptahydrate (Na2GMP·7H2O) was analyzed in a previous study.28 The rectangular shape of the crystals is also consistent with the typical morphology of GMP 5787



Industrial & Engineering Chemistry Research Article

Figure 6. continued

5788


Article



Figure 6. Element mapping images of GMP solids with various concentrations of K+ and Ca2+ as noncommon ion additives. (a) Amorphous GMP solids initially precipitated without ion additive; (b) crystalline GMP solids obtained without ion additive; (c) amorphous GMP solids produced with 0.2 mol/L of K+ ion additive; (d) crystalline GMP solids produced with 0.02 mol/L of K+ ion additive; (e) amorphous GMP solids produced with 0.2 mol/L of Ca2+ ion additive; and (f) crystalline GMP solids produced with 0.1 mol/L of Ca2+ ion additive.

amorphous solids of GMP disodium salt and GMP complex salts were both initially precipitated, as depicted in Scheme 1. While the amorphous GMP disodium salt then changed into crystalline GMP disodium salt, the amorphous GMP complex salt did not transform, as the noncommon ions were unable to participate in the formation of the G-quartets and orderedstacking of the G-quartets for the crystalline structure. The fractions of the initial amorphous GMP disodium salt and GMP complex salt depended on the concentration of the noncommon ion additive. When increasing the additive concentration, the fraction of the initial amorphous GMP complex salt increased, thereby decreasing the final fraction of crystalline GMP disodium salt, as mentioned above in Figures 2 and 5. The substitution of sodium ions (Na+) with noncommon ions (K+ and Ca2+) in GMP complex salts during crystallization was investigated according to the noncommon ion concentration, as shown in Figure 7. Since the GMP phosphorus (S)

respectively. However, the GMP complex salts precipitated with the noncommon ion additives showed different element mapping images. When using the K+ ion additive, three elements, Na, P, and K, were detected in the amorphous domain (Figure 6c), whereas only two elements, Na and P, were detected in the crystalline domain (Figure 6d), indicating that the amorphous solids were a GMP complex salt of Na/K· GMP, while the crystalline solids were GMP disodium salt (Na2GMP). Similar element mappings were also observed for the amorphous and crystalline solids precipitated with the Ca2+ ion additive at 0.2 mol/L (Figure 6e,f).Thus, the elementary mapping images clearly indicated that the Na+ ions were partly replaced by the K+ and Ca2+ noncommon ions, generating amorphous GMP complex salts, such as Na/K·GMP and Na/ Ca·GMP, respectively. In addition, when linking the elementary mapping images (Figure 6) with the crystal fraction and varying the noncommon ion concentration (Figures 2 and 5), 5789


Article



Scheme 1. Scheme of Influence of Noncommon Ions (K+ and Ca2+) on Crystallization and Phase Transformation of GMP Solids

element was unaffected by the ion substitution, the salt ions in the GMP complex salts were quantified according to the ratio of salt ions to phosphorus. When increasing the additive concentration of K+ ions in the crystallization, the fraction of Na+ ions in the GMP complex salt (Na/K·GMP) decreased, whereas the fraction of K+ ions increased due to the substitution of Na+ ions with K+ ions. When further increasing the additive concentration of K+ ions above 0.2 mol/L, the fraction of K+ ions exceeded the fraction of Na+ ions. Yet, total substitution of the Na+ ions with K+ ions in a GMP complex salt was not obtained, even when using a K+ additive concentration of 0.7 mol/L (Figure 7a). This may have been due to the competitive affinity of the Na+ and K+ ions to GMP, where the K+ ions were preferred by the GMP carbonyl groups, while the Na+ ions were preferred by the phosphate groups of GMP. Thus, total replacement of the Na+ ions in the GMP disodium salt with K+ ions was seemingly impossible.29,30 Meanwhile, the substitution of the GMP Na+ions with Ca2+ ions was slightly different due to the divalency of the Ca2+ ions, where two Na+ ions were replaced with one Ca2+ ion. Thus, the fraction of Na+ ions in the GMP complex salt rapidly reduced when increasing the additive concentration of Ca2+ ions during crystallization. When using a Ca2+ additive concentration of 0.2 mol/L, a total substitution of Na+ ions with Ca2+ ions was achieved in the GMP complex salt, represented by Na+ and Ca2+ fractions of 0 and 1, respectively, as shown in Figure 7b. Therefore, these results indicate that the Ca2+ ions were preferred over the Na+ ions by both the GMP carbonyl and phosphate groups, meaning that the binding affinity of the divalent Ca2+ ions prevented the formation of a G-quartet motif and made it difficult for the GMP complex salt to be arranged in an ordered structure. The solubility of the GMP complex salts was measured in a mixed solvent of water and methanol, as shown in Figure 8. Since methanol was the antisolvent for the GMP complex salts, the solubility of the GMP complex salts was markedly reduced when increasing the methanol fraction in the mixed solvent. The solubility of amorphous and crystalline solids is directly related with their structural stability. That is, a stable-structured solid is less soluble in a solvent than an unstable-structured solid, as the molecular interaction in a stable-structured solid is

Figure 7. Element ratio of salt ions to phosphorus in GMP solids with various concentrations of K+ and Ca2+ as noncommon ion additives. The crystallization conditions were always fixed at a temperature of 25 °C, agitation speed of 600 rpm, GMP feed concentration of 30.5 g/L, 5:5 feed ratio (GMP solution−methanol), and pH = 6−8. (a) Element ratio in GMP solids according to K+ ion concentration and (b) element ratio in GMP solids according to Ca2+ ion concentration.

stronger than that in an unstable-structured solid. Consequently, the solubilities of the amorphous and crystalline GMP disodium salts inferred that the crystalline GMP disodium salts had a more stable structure than the amorphous GMP disodium salts. Thus, the amorphous GMP disodium salt was transformed into crystalline GMP disodium salt, and this transformation was driven by the solubility difference between the amorphous and crystalline GMP disodium salts. From this perspective, the solubility of the amorphous GMP complex salts indicated that they were much more structurally stable than the crystalline GMP disodium salt, representing a thermodynamic reason why the amorphous GMP complex salts could not be transformed into crystalline complex salts. In addition, it should be noted that the solubility of the amorphous GMP sodium/ calcium salt was much lower than that of the amorphous GMP sodium/potassium salt, indicating that the former had a more stable structure than the latter. 5790


Article


charge on the ACS Publications website at DOI: 10.1021/ acs.iecr.5b00813.

■

AUTHOR INFORMATION

Corresponding Author

*Tel.: +82-31-201-2970. Fax: +82-31-273-2971. E-mail: [email protected]. Notes

The authors declare no competing financial interest.


■

ACKNOWLEDGMENTS This work was supported through a Mid-Career Researcher based on a National Research Foundation grant funded by the Korean Ministry of Education, Science and Technology (Grant NRF-2010-0017993). This work was also supported by the Engineering Research Center of Excellence Program of the Korea Ministry of Science, ICT & Future Planning (MSIP)/ National Research Foundation of Korea (NRF) (Grant NRF2014-009799).

Figure 8. Solubility of GMP solids produced with various ionic concentrations of K+ and Ca2+.

■

4. CONCLUSION In the case of antisolvent crystallization, the phase transformation of amorphous GMP solids into crystalline solids was significantly affected when using K+ and Ca2+ as noncommon ion additives. That is, the crystallization of GMP with K+ and Ca2+ ions initially produced mixed solids of amorphous GMP disodium salt and amorphous GMP complex salts (Na/K·GMP and Na/Ca·GMP) due to the substitution of the Na+ ions in the GMP disodium salt with K+ and Ca2+ ions. However, while the amorphous GMP disodium salt was transformed into crystalline GMP disodium salt, the amorphous GMP complex salts did not transform into the stable phase due to their high structural stability. The fraction of amorphous GMP complex salts in the mixture of amorphous and crystalline solids increased when increasing the K+ and Ca2+ ion concentrations in the crystallization. Thus, when using K+ and Ca2+ ion concentrations over 0.2 mol/L, the initially precipitated solids were entirely amorphous GMP complex salts. As regards the ion substitution, the K+ and Ca2+ ions were preferred by the GMP carbonyl and phosphate groups over the Na+ ions, forming GMP complex salts. In these GMP complex salts, the K+ and Ca2+ ions strongly inhibited the formation and orderedstacking of G-quartets, the unit structural motif of GMP. This ion substitution of Na+ with K+ and Ca2+ was confirmed by element mapping images and the element ratio in the GMP complex salts. Furthermore, the amorphous GMP complex salts were less soluble than the amorphous GMP disodium salt and crystalline GMP disodium salt, indicating that the amorphous GMP complex salts were structurally more stable than the amorphous GMP disodium salt and crystalline GMP disodium salt. Consequently, as the most popular ionic impurities in the fermented solution of GMP, the noncommon K+ and Ca2+ ions significantly retarded and inhibited the phase transformation of the amorphous GMP solids into crystalline solids.

■

REFERENCES

(1) Mullin,J. W.Crystallization, 3th ed.; Butterworth-Heinemann: London, U.K., 1993. (2) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: oxford, U.K., 2002. (3) Hilfiker, R.Polymorphism: In the Pharmaceutical Industry; WILEYVCH: Germany, 2006. (4) Brittain,H. G. Polymorphism in Pharmaceutical Solids; Marcel Dekker, Inc.: New York, 1999. (5) Davey, R.; Garside, J. From Molecules to Crystallizers; Oxford University Press: Oxford, U.K., 2000. (6) Davey, R. J.; Blagden, N.; Potts, G. D.; Docherty, R. Polymorphism in Molecular Crystals: Stabilization of a Metastable Form by Conformational Mimicry. J. Am. Chem. Soc. 1997, 119, 1767. (7) Kitamura, M.; Funahara, H. Effect of L- and D-Phenyalanine on Crystallization and Transformation of L-Glutamic Acid Polymorphs. J. Chem. Eng. Jpn. 1994, 27, 124. (8) Cashell, C.; Corcoran, D.; Hodnett, B. K.Effect of Amino acid Additives on the Crystallization of L-Glutamic Acid. Cryst. Growth Des. 2005, 5, 593. (9) Mukuta, T.; Lee, A. Y.; Kawakami, T.; Myerson, A. S.Influence of Impurities on the Solution-Mediated Phase Transformation of an Active Pharmaceutical Ingredient. Cryst.Growth Des. 2005, 5, 1429. (10) Davey, R. J.; Cardew, P. T. The Kinetics of Solvent-Mediated Phase Transformations. Proc. R. Soc. 1985, A398, 415. (11) Davey, R. J.; Cardew, P. T. Rate Controlling Processes in Solvent-Mediated Phase Transformations. J. Cryst. Growth 1986, 79, 648. (12) Wikstrom, H.; Rantanen, J.; Gift, A. D.; Taylor, L. S. Toward an Understanding of the Factors Influencing Anhydrate-to-Hydrate Transformation Kinetics in Aqueous Environments. Cryst. Growth Des. 2008, 8, 2684. (13) Qu, H.; Kultanen, M. L.; Rantanen, J.; Kallas, J. SolventMediated Phase Transformation Kinetics of an Anhydrate/Hydrate System. Cryst.Growth Des. 2006, 6, 2053. (14) Maruyama, S.; Ooshima, H.; Kato, J. Crystal Structures and Solvent-Mediated Transformation of Taltireline Polymorphs. J. Chem. Eng. 1999, 75, 193. (15) Qu, H.; Kohonen, H.; Louhi-Kultanen, M.; Reinikainen, S. P.; Kallas, J. Spectroscopic Monitoring of Carbamazepine and Phase Transformation in Ethanol-Water Solution. Ind. Eng. Chem. Res. 2008, 47, 6991. (16) Caillet, A.; Rivoire, A.; Galvan, J. M.; Puel, F.; Fevotte, G. Crystallization of Monohydrate Citric Acid. 1. In-Situ Monitoring through the Joint Use of Raman Spectroscopy and Image Analysis. Cryst. Growth Des. 2007, 7, 2080.

ASSOCIATED CONTENT

S Supporting Information *

Thermal gravimetric analysis of amorphous GMP disodium salt and crystalline GMP disodium salt obtained in crystallization without an ionic additive. Here, the mass loss for the crystalline GMP disodium salt was 23% that refers to the crystalline heptahydrate. The Supporting Information is available free of 5791


Article


Industrial & Engineering Chemistry Research (17) Kitamura, M. Strategy for Control of Crystallization of Polymorphs. CrystEngComm 2009, 11, 949. (18) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Ferrari, E. S. Nucleation Control in Solution Mediated Polymorphic Phase Transformations: The Case of 2,6-Dihydroxybenzoic Acid. J. Phys. Chem. B 2002, 106, 1954. (19) Kubota, N.; Uchiyama, I.; Nakai, K.; Shimizu, K.; Mullin, J. W. Change of Solubility of Potassium, Sulfate in Water Caused by Traces of Chromium (III). Ind. Eng. Chem. Res. 1988, 27, 930. (20) Giffard, M.; Colloc’h, N.; Ferte, N.; Castro, B.; Bonnete, F. Salting-In Effects on Urate Oxidase Crystal Design. Cryst. Growth Des. 2008, 8, 4220. (21) Kang, J.; Nguyen, A. T.; Kim, J. M.; Chang, S. M.; Kim, W.-S. Study of Phase Transformation of Guanosine5′-Monophosphate in Drowning-out Crystallization. Appl. Biochem. Biotechnol. 2010, 16, 561. (22) Nguyen, A. T.; Kang, J.; Choi, G. J.; Kim, W.-S. Phase Transformation of Guanosine5′-Monophosphate in Drowning-out Crystallization: Comparison of Experiment andModeling. Cryst. Res. Technol. 2011, 46, 53. (23) Nguyen, A. T.; Kim, J. M.; Chang, S. M.; Kim, W.-S. Taylor Vortex Effect on Phase Transformation of Guanosine 5-Monophosphate in Drowning-out Crystallization. Ind. Eng. Chem. Res. 2010, 49, 4865. (24) Nguyen, A. T.; Kim, J. M.; Chang, S. M.; Kim, W.-S. Phase Transformation of Guanosine 5-Monophosphate in Continuous Couette-Taylor Crystallizer: Experiments and Numerical Modeling for Kinetics. Ind. Eng. Chem. Res. 2011, 50, 3483. (25) Nguyen, A. T.; Joo, Y. L.; Kim, W.-S. MultipleFeeding Strategy for Phase Transformation of GMP in Continuous Couette-Taylor Crystallizer. Cryst. Growth Des. 2012, 12, 2780. (26) Nguyen, A. T.; Kang, J.; Kim, W.-S. Influence of Salt Additives on Phase Transformation of Guanosine 5-Monophosphate Disodium in Anti-Solvent Crystallization. J. Cryst. Growth 2013, 373, 82. (27) McCabe, W. L.; Smith,J. C.; Harriott, P. Unit Operations of Chemical Engineering, 6th ed.; McGraw Hill: Boston, MA, 2001. (28) Barnes, C. L.; Hawkinson, S. W. Structure of Disodium Guanosine 5′-Phosphate Heptahydrate. Acta Crystallogr., Sect. B 1982, B38, 812. (29) Gellert, M.; Lipsett, M. N.; Davies, D. R. Helix Formation by Guanylic Acid. Proc. Natl. Acad. Sci. U.S.A. 1962, 48, 2013. (30) Wong, A.; Wu, G. Selective Binding of Monovalent Cations to the Stacking G-Quartet Structure Formed by Guanosine 5′Monphosphate: A Solid-State NMR Study. J. Am. Chem. Soc. 2003, 125, 13895. (31) Pinnavaia, T. J.; Miles, H. T.; Becker, E. D. Self-Assembled 5′Guanosine Monophosphate, Nuclear Magnetic Resonance Evidence for a Regular, Ordered Structure and Slow Chemical Exchange. J. Am. Chem. Soc. 1975, 97, 7198. (32) Pinnavaia, T. J.; Marshall, C. L.; Mettler, C. M.; Fisk, C. L.; Miles, H. T.; Becker, E. D. Alkali Metal Ion Specificity in Solution Ordering of a Nucleotide, 5′-Guanosine Monophosphate. J. Am. Chem. Soc. 1978, 100, 3625. (33) Hud, N. V.; Smith, F. W.; Anet, F. A. L.; Feigon, J. The Selectivity for K+ versus Na+ in DNA Quadruplexes Is Dominated by Relative Free Energies of Hydration: A Thermodynamic Analysis by 1 H NMR. Biochemistry 1996, 35, 15383. (34) Ross, W. S.; Hardin, C. C. Ion-Induced Stabilization of the GDNA Quadruplex: Free Energy Perturbation Studies. J. Am. Chem. Soc. 1994, 116, 6070.

5792


Noncommon Ion Effect on Phase Transformation of Guanosine 5

Recommend Documents