Effects of Additives on the Morphology of Thiamine Nitrate: The Great

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Effects of additives on the morphology of thiamine nitrate: the great difference of two kinds of similar additives Dandan Han, Bo Yu, Yumin Liu, Shichao Du, Sohrab Rohani, Teng Zhang, Shiyuan Liu, Peng Shi, Haisheng Wang, Lina Zhou, and Junbo Gong Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01202 • Publication Date (Web): 18 Dec 2017 Downloaded from http://pubs.acs.org on December 24, 2017

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Crystal Growth & Design

Effects of additives on the morphology of thiamine nitrate: the great difference of two kinds of similar additives Dandan Han a,b, Bo Yu a,b, Yumin Liu a,b, Shichao Du a,b, Sohrab Rohani d, Teng Zhang a,b, Shiyuan Liu a,b, Peng Shi a,b,Haisheng Wang a,b, Lina Zhou a,b, Junbo Gong a,b,c,* a

State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology,

Tianjin University, Tianjin 300072, People’s Republic of China. b

Collaborative Innovation Center of Chemistry Science and Engineering, Tianjin 300072, People’s

Republic of China. c

Key Laboratory Modern Drug Delivery and High Efficiency in Tianjin University, Tianjin, China

d

The University of Western Ontario, Department of Chemical and Biochemical Engineering, London,

Ontario, N6A 5B9, Canada Abstract: The growth of thiamine nitrate, in supersaturated aqueous solutions in the absence and presence of sodium alkyl sulfates CH3(CH2)nSO4Na and sodium alkyl sulfonates CH3(CH2)nSO3Na was studied by single seed crystal growth experiment. It was surprisingly found that the growth of a-axis of thiamine nitrate is significantly inhibited by CH3(CH2)nSO4Na, thus reducing the aspect ratio of thiamine nitrate, while the aspect ratio of thiamine nitrate in the presence of CH3(CH2)nSO3Na remains almost constant. Furthermore, the mechanism of additives to modify the crystal morphology is proposed: both additives can inhibit the growth of thiamine nitrate by hindering the solute diffusion. However, the unusual behavior of them is due to the selective adsorption, which was caused by electrostatic and hydrogen bond interactions between solute and additive molecules. In particular, the anionic groups exposed at the end of the additives demonstrate an interesting case in which a small variation in the charge density and hydrogen bonding ability can lead to a marked difference in modifying the crystal growth behavior. The results obtained from this study should be helpful in the performance evaluation and selection of the morphology modifiers for 1

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thiamine nitrate crystals. Key words: thiamine nitrate; morphology; additive; electrostatic; hydrogen bonding interactions

1 Introduction Crystallization is a vital step in the manufacture of many pharmaceuticals and inorganic materials. In crystallization, controlling over crystal morphology, is important for the performances and physical properties of a material as well as its downstream processing units such as filtration, drying and compaction [1-4]. For example, flake-like crystals may be undesirable due to their tendency to pack as an impermeable layer on filter media leading to poor efficiency in filtration and washing. Also, due to the poor flowability of needle-like crystals, attrition can seriously impact the subsequent blending stage and the final tableting process. Generally, block-like crystals may filter and blend more readily and are therefore more desirable in the industry [5-7]. Specifically, crystal morphology and size uniformity may also affect the dissolution properties of a pharmaceutical material and thus its bioavailability [8]. So, it is of practical interest to develop efficient methods to modify the morphology of crystals to obtain a desired crystal morphology. For a given compound with fixed crystal form, the crystal morphology will be determined by the crystal growth under the designed crystallization conditions. Generally, the growth rate of different crystal faces depends on crystal structure, supersaturation, growth temperature, stirring rate and impurities present in the growth medium. The relative growth rates in different directions of crystals determine its external morphology. The faster the growth in a given direction, the smaller the face developed perpendicular to it. Up to now, many approaches have been explored to tailor the size and morphology of crystal [9-10]. Among those approaches, adding additives is one of the most versatile ways in which crystals with controlled size and morphology can be designed and fabricated. Conventionally, additives are often divided into three categories: tailor-made additives, small-molecule additives, and macromolecules. There is a number of examples in which additives 2


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have been shown to affect the crystal morphology in the crystallization process. Anti-solvent crystallization of salbutamol sulfate in the presence of small quantities (1.0 mg/mL) of polyvinylpyrrolidone (PVP K25) [11] was found to effectively modify the crystal morphology from needle-like to block crystals with a lower aspect ratio. Tan et al. [12] reported that both inhibition and facilitation effect of inorganic salt on the crystal growth rates of DL-alanine and γ-glycine. More recently, Song et al. [13] adopted surfactants to manipulate crystal morphology of calcium sulfate hemihydrate from needle to rod which reduce the aspect ratio of the product to a large extent, and the product is very favorable in the industry. Weissbuch et al. [14] demonstrated that as a crystal is grown in the presence of either resolved or racemic molecular additives, chiral molecules can be assigned an absolute configuration. Vetter et al. [15] studied the growth rate mechanism of ibuprofen and slowed the growth rate of the crystals using polymeric additives. All of the references give us a guide to optimize the crystal morphology and research on the crystal growth mechanism in the presence of selected additives, which mainly attributes to the molecular interactions among the additives and the crystals. The principles of the functional mechanism of different kinds of additives on various systems are obviously different. Sangwal [16] illustrated the kinetic effect of impurities on the crystal growth systematically and concluded that the similarity in the movement of impurity and solute molecules would impact the diffusion, migration and adsorption of solute to different extent. Additives may also disrupt crystal growth by being adsorbed and thus inhibiting growth on fast growing crystal faces where hydrogen bonding acceptor or donor sites may be positioned [17]. To quantitatively describe the rate of crystal growth in solution with impurities, in the late nineties, Kubota and Mullin [18-20] proposed a model to quantitatively describe the rate of crystal growth in solution with impurities. This model is based on the pinning mechanism proposed by Cabrera and Vermilyea [21], which considers the one-dimensional adsorption of impurities on the step lines for the inhibition of step advancement. Except these cases, there are still many other diverse functional mechanisms of 3



various kinds of additives that need to be investigated. Thiamine nitrate was chosen as the model compound for this research. As a vitamin, thiamine nitrate often takes solution crystallization as the final step to obtain solid state products. Due to the polarity of thiamine nitrate molecular structure, the morphology of thiamine nitrate is generally rod or needle by reactive crystallization or cooling crystallization, which may lead to a big problem in the subsequent downstream operations. Therefore, it is of practical significance to modify the morphology of thiamine nitrate so as to obtain a desirable crystal product. Many efforts have been invested with the aim of analyzing the single crystal structure of thiamine nitrate and combining a large number of experiments, such as controlling the supersaturation, adjusting the stirring speed and changing the crystallization ways, however, it has been hard to obtain the good morphology of thiamine nitrate. Then, additives have been considered to solve this problem. Various kinds of additives have been screened based on the molecular structure and preliminary experiments. In this work, effective additives, sodium alkyl sulfates CH3(CH2)nSO4Na, were successfully screened and for the first time obtained the block-like morphology of thiamine nitrate, with significant improvement in the bulk density and flowability of the products. Then additives with similar structure [22-24] such as sodium alkyl sulfonates CH3(CH2)nSO3Na were also chosen to optimize the morphology of thiamine nitrate. However, there was no influence of CH3(CH2)nSO3Na on the morphology of thiamine nitrate while tiny amount of CH3(CH2)nSO4Na can modify thiamine nitrate morphology from rod to the block. This phenomenon was strange and need to be deeply studied. In order to give a better understanding of the great difference of the two kinds of similar additives on the morphology of thiamine nitrate, several designed experiments and calculations have been accomplished. The dynamic method was used to measure the solubility of thiamine nitrate in the presence of additives, the Material Studio 5.0 was employed to predict the morphology of thiamine nitrate under the vacuum. The experimental morphology of thiamine nitrate was 4


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characterized by scanning electron microscope (SEM), and the crystal form was identified by powder X-ray diffraction (PXRD) and Infrared Spectroscopy (IR). The effects of additives on the morphology of thiamine nitrate were investigated by determining the growth rate of single seed crystals of thiamine nitrate in their supersaturated aqueous solutions in the absence and presence of sodium alkyl sulfates CH3(CH2)nSO4Na and sodium alkyl sulfonates CH3(CH2)nSO3Na. Further, the mechanism for the effects of additive has been developed, thereby enabling a better understanding of the additive screening and improving the powder properties of thiamine nitrate. 2 Material and methods 2.1 Materials Thiamine nitrate (>99%, C12H17N5O4S) was supplied by Xinfa Pharmaceutical Co., Ltd. (Shandong, China). The chemical structure of thiamine nitrate is shown in Figure S1. Distilled-deionized water (Resistivity =18.2 MΩ cm) made in our laboratory by NANOPURE system from BARNSTEAD (Thermo Scientific Co., China) was used throughout the experiments. Sodium alkyl sulfates CH3(CH2)nSO4Na and sodium alkyl sulfonates CH3(CH2)nSO3Na were adopted as additives to modify the morphology of thiamine nitrate in aqueous solution systems which were purchased from Beijing InnoChem Science&Technology Co., Ltd., China, with mass fraction purity higher than 0.98. 2.2 Measurement of solubility In order to obtain the growth rate of a given seed crystal of thiamine nitrate aqueous in the presence of additive at different supersaturations, the precise solubility of thiamine nitrate in the absence and presence of various surfactants in aqueous solutions in the temperature range from 293.15K to 323.15K was measured by a dynamic method. The apparatus and procedures were described in our previous publications [25-26] in detail. 2.3 Characterization The morphology of the single seed crystal of thiamine nitrate was observed using a Scanning 5



Electron Microscope (SEM, TM3000, Hitachi Co., Japan) and the Scanning Electron Microscope (X650, HITACHI, Japan). The phase compositions of raw material of thiamine nitrate, additives, and thiamine nitrate produced from pure water and solutions with additives were identified by Powder X-ray Diffraction (PXRD, Rigaku D/Max 2500) at 40 kV and 200 mA with Cu Kα radiation and the Fourier Transform Infrared Resonance (FTIR, Nicolet 6700) with KBr pellets. 2.4 Measurement of crystal growth rates The rod-like thiamine nitrate seed crystals with well-developed faces were obtained by natural cooling from its aqueous solutions with an approximate initial thiamine nitrate concentration of 4 g/100 g H2O at the elevated temperature. Then, the seed crystals were thoroughly rinsed with a saturated pure thiamine nitrate aqueous solution to remove any tiny broken crystals attached on the crystal surface and then dried at ambient conditions. For the growth experiment of a thiamine nitrate seed crystal, a thiamine nitrate aqueous solution in the presence of a given surfactant at known concentration was first prepared at an elevated temperature. Subsequently, the warm solution was cooled to 298.15 K using a water circulator (with a readability of 0.01 K) to generate a supersaturation, and then about 30 mL of such supersaturated solution was gently filtered (0.22 µm, FroFill membrane syringe filter) into a glass crystallization dish (6 cm in diameter) where a single thiamine nitrate seed crystal was loaded in advance. The temperature of the dish was controlled by a refrigerating machine (Type, CF41, Julabo Technology (Beijing) Co. LTD) at a constant temperature of 298.15 K. After that, the crystallization dish was sealed using parafilm with a small hole provided to focus the microscope objective. This ensured that the concentration of sample solution increased by evaporation was minimal. Therefore, the supersaturation maintained reasonably constant during the period of a crystal growth experiment. Growth of the seed crystal was monitored using an optical microscope (Olympus, BX51, equipped with a CCD camera) at a magnification of 4×. The images of the growing seed were acquired at regular time intervals. The detailed experimental procedure for measuring the crystal 6


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growth rates was shown in Figure S2. Besides, the size of the seeds may affect the accuracy of the final results. To avoid this, we prepared lots of seeds with similar size, here we set four of them as example which are shown in Figure S3. As the growth rate of thiamine nitrate is slow at low supersaturation, each experiment was repeated at least 6 times to make sure the accuracy of the experiment. 2.5 Simulation details All the calculations were run with the commercial molecular modeling software package Materials Studio 5.0, using the COMPASS force field based on the Forcite module. The force field has been widely used for the molecular simulation study of surfactant and other macromolecules [27-29]. Thiamine nitrate crystal structure was obtained in this study with unit cell dimensions of a = 6.5651 Å, b = 12.299 Å, c = 18.596 Å, β = 97.55°, and Z = 4. The crystal form is monoclinic with the space group P21/C. The morphology of thiamine nitrate in the vacuum was calculated by means of the attachment energy (AE) method. 3. Results and discussion 3.1 Solubility of thiamine nitrate in the presence of additives The measured solubility data of thiamine nitrate in the presence of additives was presented in Figure 1a-d. It can be concluded that the two kinds of additives, sodium alkyl sulfates CH3(CH2)nSO4Na and sodium alkyl sulfonates CH3(CH2)nSO3Na, have similar effects on the solubility of thiamine nitrate, both promoting the solubility of thiamine nitrate slightly with the increasing concentrations of additives. Based on the solubility data, the thiamine nitrate solution with different supersaturations can be prepared accurately in the whole experiment process.

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Figure 1. Effect of additives on the solubility of thiamine nitrate at different temperatures. a. Effect of carbon chain length of sodium alkyl sulfonates CH3(CH2)nSO3Na on the solubility of thiamine nitrate. b. Effect of concentrations of sodium dodecyl sulfonate CH3(CH2)11SO3Na on the solubility of thiamine nitrate. c. Effect of carbon chain length of sodium alkyl sulfates CH3(CH2)nSO4Na on the solubility of thiamine nitrate. d. Effect of concentrations of sodium dodecyl sulfate CH3(CH2)11SO3Na on the solubility of thiamine nitrate It is noting from Figure 2 (PXRD patterns) that the intensity of the (0 1 1) crystal plane which peaks at 2-Theta=8.636°, is relatively weak. Also, the crystal planes of (1 1 0) and (1 0 -2) almost

overlap together, which peak at 2-Theta=15.391° and 15.589°, respectively. This is because in the ideal conditions, the crystal is considered spherical, thus the anisotropy of the crystal has been eliminated, almost all the crystal planes are visible. However, when we carry out the PXRD pattern in actual condition, the intensity of the diffraction peak is related to the preferred orientation of the experimental crystal, the preparation of the sample including the crystal size and the test conditions. However, it can be seen that thiamine nitrate in the absence and presence of the surfactants have the 8


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same diffraction peaks in PXRD patterns which indicates the samples did not show any polymorphs, solvates or amorphous formation in those solutions.

Figure 2. A: PXRD of thiamine nitrate in sodium alkyl sulfates CH3(CH2)nSO3Na solutions at 298.15 K: a. raw materials, b. CH3(CH2)7SO3Na, c. CH3(CH2)9SO3Na, d. CH3(CH2)11SO3Na, e. CH3(CH2)13SO3Na (left). B: PXRD of thiamine nitrate in sodium alkyl sulfates CH3(CH2)nSO4Na solutions at 298.15 K: a. raw materials, b. CH3(CH2)7SO4Na, c. CH3(CH2)9SO4Na, d. CH3(CH2)10SO4Na, e. CH3(CH2)11SO4Na, f. CH3(CH2)12SO4Na, g. CH3(CH2)13SO4Na (right).

Figure 3. FTIR spectra of the additives and products prepared without and with 0.002 mol/L CH3(CH2)11SO3Na (SLS) and CH3(CH2)11SO4Na (SDS). Besides, in Figure 3, the FTIR spectrum of CH3(CH2)11SO4Na shows characteristic peaks at 591, 633, 721, 762, 835, 996, 1084, 1220, 1468, 1642, 2850, 2919 and 3457 cm-1, while the FTIR spectrum of CH3(CH2)11SO3Na shows characteristic peaks at 522, 620, 722, 801, 1066, 1204, 1468, 1642, 2850, 2919 and 3457 cm-1. It appears slight shift in peaks at some stretching vibration bands and there are also some new peaks in the FTIR spectrum of CH3(CH2)11SO4Na, specially the peaks at 9



762, 835 and 996 cm-1. Comparison of the FTIR spectra of thiamine nitrate in the absence and presence of the two surfactants, it can be noted that the characteristic peaks for the three FTIR spectra of thiamine nitrate are exactly the same. They all peak at 598, 748, 822, 1041, 1228, 1369, 1598 1678, 3045 and 3373 cm−1, which confirms no surfactants can implant the crystal lattice of thiamine nitrate. 3.2 Morphology and crystal form of thiamine nitrate crystals in the presence of additives Due to the structural integrity of thiamine nitrate crystals, the morphology of the products crystallized from pure water is rod as shown in Figure 4a. Surprisingly, we have found that CH3 (CH2 )n SO4 Na could modify the morphology of thiamine nitrate from rod to block while CH3 (CH2 )n SO3 Na could not change the morphology of thiamine nitrate, discernably. For example, as shown in Figure 4b and Figure 4c, tiny amount of CH3(CH2)11SO4Na can modify thiamine nitrate morphology from rod-like to block, while there was no influence of CH3(CH2)11SO3Na on the morphology of thiamine nitrate.

Figure 4. SEM of thiamine nitrate by cooling crystallization: (a) without additive; (b) with 0.002 mol/L CH3(CH2)11SO3Na; (c) with 0.002 mol/L CH3(CH2)11SO4Na. To get a better understanding of the mechanisms of these two kinds of similar additives on the morphology of thiamine nitrate, the growth rate of single seed crystals of thiamine nitrate in their supersaturated aqueous solutions in the absence and presence of sodium alkyl sulfates CH3(CH2)nSO4Na and sodium alkyl sulfonates CH3(CH2)nSO3Na was investigated and reported in the following. 10


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3.3 Effect of supersaturation on the morphology of thiamine nitrate crystals For previous studies, there is no doubt that supersaturation plays an important role in determining the morphology of crystals [30-32]. And the change of the supersaturation may change the crystal morphology to a large degree. To study the effect of supersaturation on the morphology of thiamine nitrate, the single seed crystal growth experiment was performed under different supersaturations at constant temperature of 298.15 K in aqueous solutions. And the supersaturation is expressed as follows:

S

c

(1)

Where c is the concentration of thiamine nitrate supersaturated solution and is the equilibrium solubility of thiamine nitrate at a certain temperature. The experimental morphology of thiamine nitrate and the effects of supersaturations on the growth rates of both a-axis and b-axis of thiamine nitrate were typically plotted in Figure 5 and exhibited in Figure 6.

Figure 5. The experimental morphology of thiamine nitrate (left); Growth rates of thiamine nitrate along the b-axis and a-axis at different supersaturations at 298.15 K (right). The error bar = 20%.

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Figure 6. Images of growing single seed crystal of thiamine nitrate in pure water at different supersaturations at 298.15 K. a. S= 1.04; b. S = 1.20; c. S = 1.32. Figure 5 shows that the growth rate of thiamine nitrate along both b-axis and a-axis increases steadily with the increasing supersaturation up to S = 1.32. Nevertheless, over the entire supersaturation range (S = 1.04 to 1.32) examined, there is a big difference between the growth rate of the two axis of thiamine nitrate as the growth rate of a-axis is far greater than b-axis, thus leading to the rod like morphology of thiamine nitrate with a large aspect ratio. Figure 6 particularly shows the evolution (after 24 h) of a thiamine nitrate seed crystal at a low supersaturation of S = 1.04, a medium supersaturation of σ = 1.20 and a high supersaturation of σ = 1.32, respectively. Apparently, at each supersaturation, the growth rate of thiamine nitrate crystal along the a-axis remains considerably faster than that along the b-axis. Collectively, it can be concluded that supersaturation simply increases the aspect ratio of crystals, but the morphology of them remains in rod shape. In combination with the pure crystal morphology (Figure 7) calculated by the attachment energy (AE) method with MS and the experimental morphology (Figure 5) observation, it can be easily found that the calculated/simulated pure crystal morphology could provide a good match to the experimental morphology observation. The seven main crystal faces are represented: (1 0 2), (1 1 0), (1 1 1), (1 0 -2), (0 1 1), (1 0 0) and (0 0 2). However, the crystal faces (1 0 0), (1 0 2), (1 1 0), (1 1 1) and (1 0 -2) and their equivalent crystal faces have a faster growth rate and show a smaller exposed 12


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area, while the growth rate of (0 1 1) and (0 0 2) and their equivalent crystal faces have a lower growth rate thus show a larger exposed area, which are known as the dominant crystal faces.

Figure 7. The crystal unit cell of thiamine nitrate (left) and the predicted morphology of thiamine nitrate (right) by the AE model in vacuum. The rod-like morphology of thiamine nitrate can be interpreted by the crystal structures. Different crystal faces exposed groups or atoms in different ways thus resulting in different competitive adsorption behaviors of solvent and solute molecules, which can affect the growth of crystals. The qualitative analysis of the arrangement and growth rate of each crystal face can be seen below. The unit cell structure and the cleaved main crystal faces of thiamine nitrate are shown in Figure 8.

（1 0 0）

（1 0 2）

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（1 0 -2）

（1 1 0）

（1 1 1）

（0 0 2）

（0 1 1） Figure. 8. The unit cell structure and the cleaved main crystal faces of thiamine nitrate In the a-axis direction of thiamine nitrate crystal, the exposed groups to the (1, 0, 0) crystal face are the hydroxyl and methyl group. Although the hydroxyl groups are easy to form hydrogen bonds with other adjacent thiamine sulfate thiazole ring sulfur, the presence of methyl increases the steric hindrance which weakens the interactions between thiamine nitrate molecules, thus it is understandable that the growth rate of this face is very slow. The (1 0 2) crystal face has a nitrate exposed, which is easy to establish electrostatic interactions with another nitrate from other solute molecules. The exposed groups to the chain on (1 0 -2) crystal face are hydroxyl and pyrimidine ring. 14


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The two groups are both feasible to form hydrogen bonds with other thiamine nitrate molecules, so the growth rate of (1, 0, -2) is faster with showing a smaller face. Besides, both (1 1 1) and (1 1 0) faces have thiazole ring and pyrimidine ring exposed, these two faces can form strong hydrogen bonds with other thiamine nitrate molecules which lead to the fast growth rate of the (1 1 1) and (1 1 0) faces. Overall, through above analysis, (1 1 1) and (1 1 0) crystal faces may have the fastest growth rate and smallest crystal face which is in consistent with our experimental results. For the b-axis direction of thiamine nitrate crystal, the hydroxyl group is exposed to the (0 0 2) and (0 1 1) crystal faces, but in this case, the hydrogen bond with other molecules is hardly formed due to the unfavorable angle and the evident space steric hindrance because of the presence of methyl group. Therefore, the growth rates of these two crystal faces are very slow showing a larger exposed surface. In all, the different growth rates of different crystal faces lead to the long rod-like morphology of thiamine nitrate. It is worth noting that the ratio of the growth rate of a-axis versus b-axis increases with the increasing supersaturation, which means that the aspect ratio of thiamine nitrate products increases with the increasing supersaturation. Consequently, it provides us with the guideline that it is better to maintain the supersaturation at a low level so as to avoid the needle-like morphology of thiamine nitrate in its crystallization process. 3.4 Growth of thiamine nitrate crystals in the presence of additives The effects of the type, chain length and concentrations of additives on the morphology of thiamine nitrate have been investigated by the single seed crystal growth experiment at 298.15K. According to the literatures [33-36], there are about four kinds of modification mechanisms suggested to be possible with additives on the morphology of thiamine nitrate: (1) the phase transformation obtained by adding an additive; (2) the selective adsorption of additive molecules onto different crystal faces; (3) the incorporation of additive molecules into crystals; (4) and the effect of additive on solute diffusion. PXRD and IR analyses proved that there is neither the phase transformation nor the incorporation of additive molecules into crystals. In addition, the 15



incorporation of additive molecules usually requires some similarity (e.g., similar ionic radius) between the foreign material and the atoms or molecules in the crystal lattice. Obviously, the used surfactants have no structural similarity to molecules of thiamine nitrate crystal lattice. Therefore, the additive molecules are scarcely possible to incorporate into the crystal lattice. All told, the morphology modification of thiamine nitrate crystals can be attributed to the surface adsorption or the solute diffusion block by the additives, or the combined effect of both ways. 3.4.1 Inhibitory effect of additives on the growth of thiamin nitrate crystals In the batch crystallization, we have found that the effects of similar kinds of additives, sodium dodecyl sulfate CH3(CH2)11SO4Na and sodium dodecyl sulfonate CH3(CH2)11SO3Na on the morphology of thiamin nitrate are significantly different. In order to learn understand these differences systematically, the single seed crystal growth experiment was performed which has been described in the literature in detail [37-38]. The single crystals grown from aqueous solutions in the presence of the two kinds of additives are presented in Figure 9. When in 0.002 mol/L CH3(CH2)11SO3Na aqueous solution at S = 1.32, thiamine nitrate single seed crystal showed similar phenomenon to the one presented in pure water, with a higher growth rate of a-axis than b-axis thus leading a high aspect ratio morphology of thiamine nitrate. But when compared with the seed crystal grown in the presence of CH3(CH2)11SO4Na, a crystal morphology of thiamine nitrate with a lower aspect ratio appeared. At S = 1.32, the less significant development along thiamine nitrate a-axis and the effect of CH3(CH2)11SO4Na on it were confirmed and then investigated by increasing supersaturation of thiamine nitrate CH3(CH2)11SO4Na aqueous solutions to a high level of S = 1.50. This is because the development of thiamine nitrate a-axis may become measurable at this high level of supersaturation in the presence of CH3(CH2)11SO4Na.

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Figure 9. Images of growing single thiamine nitrate seed crystals in solutions at 298.15 K in the presence of 0.002 mol/L CH3(CH2)11SO3Na and 0.002 mol/L CH3(CH2)11SO4Na. a. S = 1.32 (0.002 mol/L CH3(CH2)11SO3Na aqueous solutions); b. S = 1.50 (0.002 mol/L CH3(CH2)11SO4Na aqueous solutions). Comparison of the growth rates, it is clear that CH3(CH2)11SO4Na profoundly inhibits the growth of thiamine nitrate along the a-axis even at a high supersaturation S = 1.50. This is different from the slightly inhibiting effect of CH3(CH2)11SO3Na on the growth along both the b-axis and a-axis of thiamine nitrate presented in pure water. These observations are somewhat unexpected and surprising, given the fact that the structures of the two kinds of surfactants are strikingly akin. As common anionic surfactants, CH3(CH2)11SO3Na and CH3(CH2)11SO4Na would dissociate into two parts in the aqueous solution, rather than existing in molecular form: an anionic portion C H SO , C H SO ion as shown in Eqs. (2) and (3). The anionic portion plays a crucial role in and a Na

determining the surface activity of anionic surfactants. C H SO Na → C H SO Na

(2)

C H SO Na → C H SO Na

(3)

Comparing the molecular details of different crystal faces of thiamine nitrate in Figure 9, it was 17



assumed that the shortening of the thiamine nitrate crystals could be attributed to the growth retardation caused by the additives adsorbed on some faces of thiamine nitrate.

Figure 10. Optimized configurations and charge assignments for the headgroup of C H SO (a) and C H OSO (b).

Apparently, there are sulfonic acid groups at one end of the additive molecule, which are easy to generate the electronic interactions and even form hydrogen bonds with certain faces of thiamine nitrate. So, the additives adsorbed by crystalline surface occupies the active sites of the lattice, thus preventing solute molecules from integration into the crystal lattices and remarkably retarding the face growth. Specifically, perusal of structures of these two surfactants reveals one difference. In proposing the foregoing pathway to interpret the significant difference between CH3(CH2)11SO3Na and CH3(CH2)11SO4Na, the underlying premise is that there is a remarkable difference in electrostatic interactions between these two kinds of additives and thiamine nitrate. According to the Hofmeister series mechanism which has been extensively investigated and widely discussed in previous references [39-46], the charge of investigated ions plays a fundamental role in ionic property of anions especially for Hofmeister anions. Based on our observations, CH3(CH2)11SO4Na can modifying the morphology of thiamine nitrate from rod to block while there does not exit influence of CH3(CH2)11SO3Na on the morphology of thiamine nitrate although the structure of them are very similar. The big difference between these two kinds of additives is the 18


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charge density as CH3(CH2)11SO4Na has higher charge density with respect to CH3(CH2)11SO3Na, which means CH3(CH2)11SO4Na has stronger adsorption capacity with the crystal faces of thiamine nitrate compare to CH3(CH2)11SO3Na. As a result, CH3(CH2)11SO4Na could inhibit the crystal growth of thiamine nitrate by steric hindrance. This analysis is further supported by a computational study of these two additives. In fact, it was revealed by MS that −SO group has a charge density of as low as -0.644 net negative charges per 3 Å3, while −SO group has a high charge density of up to -1.338 net charges per Å , respectively,

highlighting the significance. Therefore, it is reasonable to suggest that the electrostatic interactions between CH3(CH2)11SO4Na and thiamine nitrate are stronger than that between CH3(CH2)11SO3Na and thiamine nitrate molecule, and growth inhibition of CH3(CH2)11SO4Na to thiamine nitrate a-axis is far greater than that of CH3(CH2)11SO3Na. Besides, the sulfonic acid groups of CH3(CH2)11SO4Na and CH3(CH2)11SO3Na are connected to oxygen atoms and methylene groups, respectively. Thus, the end of the molecular chain of CH3(CH2)11SO4Na can form strong conjugated π bonds and make the electronegativity of sulfonate stronger, thereby promoting surface blocking at the a-axis of thiamine nitrate. In that case, the inhibition is obvious and the growth rate of a-axis decreases significantly. Based on the above analysis, it can be concluded that the electrostatic and hydrogen bonding interactions play a crucial role in modifying the morphology of thiamine nitrate. 3.4.2. Effect of additive concentration on the morphology of thiamine nitrate crystals Based on the above experimental results, it is interesting that there is a big difference between CH3(CH2)11SO4Na and CH3(CH2)11SO3Na on the morphology of thiamine nitrate under the same conditions. Moreover, it is clear that additive concentration always plays an important role in modifying the morphology of crystal products [47-48], and thus gives us the insight to the influencing mechanism of additive concentrations on the morphology of crystals. Therefore, the single seed crystal experiment was also performed to illustrate the concentration influence on morphology of thiamine nitrate. 19



Figure 11a demonstrates that at the constant supersaturation S = 1.32, the growth rate of b-axis and a-axis of thiamine nitrate decreases gradually with the increasing concentration of CH3(CH2)11SO3Na and then stabilized up to a certain concentration, which indicates that the inhibitory effect of CH3(CH2)11SO3Na increased with its increasing concentration in a certain range of the additive concentrations. Most importantly, the growth rate of a-axis is always larger than b-axis of thiamine nitrate at the measured concentration of CH3(CH2)11SO3Na. Besides, when the concentration of CH3(CH2)11SO3Na reached 0.001 mol/L, the growth rate of thiamine nitrate remains unchanged even continuing to increase the concentration of CH3(CH2)11SO3Na. According to the above experimental results, we can draw a conclusion that the inhibitory effect of CH3(CH2)11SO3Na on the growth of thiamine nitrate is due to the increase of viscosity of the solution by adding the additives, thereby the diffusion of the solute being hindered. With the further increase of concentration of CH3(CH2)11SO4Na, the viscosity of the solution increases, thus the growth rate of both b-axis and c-axes of thiamine nitrate becomes slower. It is evident that the inhibition of CH3(CH2)11SO3Na on both b-axis and a-axis of thiamine nitrate is similar, therefore, the aspect ratio of the final product becomes changed slightly. Notably, in practice, the amount of CH3(CH2)11SO3Na present in the ionic form does not continue to increase by adding the surfactant which might be caused by the formation of CH3(CH2)11SO3Na micelles.

Figure 11. a. Crystal growth rates of b-axis and a-axis of thiamine nitrate in the presence of CH3(CH2)11SO3Na with different concentrations at the supersaturation of S = 1.32 at 298.15 K. b. 20


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Crystal growth rates of b-axis and a-axis of thiamine nitrate in the presence of CH3(CH2)11SO4Na with different concentrations at the supersaturation of S = 1.50 at 298.15 K. The error bar = 20%. As for Figure 11b, the growth rate of a-axis is larger than b-axis of thiamine nitrate at the concentration of 0.0001 mol/L of CH3(CH2)11SO4Na with the supersaturation S = 1.50. When the concentration of CH3(CH2)11SO4Na is increased to 0.005 mol/L, the growth rate of a-axis of thiamine nitrate is generally inhibited, thereby the growth rate of a-axis is lower than that of b-axis, leading to a decrease in aspect ratio of thiamine nitrate. With the further increase of CH3(CH2)11SO4Na concentration to 0.002 mol/L, the growth rates of both b-axis and a-axis of thiamine nitrate remain nearly constant. As for CH3(CH2)11SO4Na, it can be speculated that the inhibitory effect of CH3(CH2)11SO4Na on the growth of thiamine nitrate is mainly due to the selective adsorption of CH3(CH2)11SO4Na on the crystal faces of a-axis to hinder the growth site, and the adsorption strengthened by the electrostatic interactions. In fact, CH3(CH2)11SO4Na can be preferentially adsorbed in the faces of a-axis of thiamine nitrate, but as there is not enough CH3(CH2)11SO4Na to adsorb in the growth site, the growth rate of a-axis is still greater than that of b-axis at the low concentration. Then, with the further increase of CH3(CH2)11SO4Na concentration, the adsorption should be enhanced and the proportion of occupied sites in the crystal faces of a-axis increased gradually. Therefore, the inhibitory effect of CH3(CH2)11SO4Na on the a-axis of thiamine nitrate was enhanced. As a result, the morphology of thiamine nitrate changed from rod to block. However, when the concentration of CH3(CH2)11SO4Na reached a certain value, the adsorption sites became saturated with the further increase of the concentration of CH3(CH2)11SO4Na, the inhibitory effect thus remained almost constant. This is in good agreement with the observation that the morphology of thiamine nitrate remained unchanged when the concentration of CH3(CH2)11SO4Na was larger than 0.0005 mol/L. As CH3(CH2)11SO4Na is also a kind of surfactant like CH3(CH2)11SO3Na, it is worthwhile to mention that the effect of CH3(CH2)11SO4Na on the morphology of thiamine nitrate can be also attributed to the surface adsorption combining to the effect of solute diffusion. To further verify the effects of the surfactant relate to critical micelle concentrations, the corresponding 21



experiments and discussions have been put in the supporting information in Figure S4-S6, it illustrates that the effect of the surfactants in modifying the morphology of thiamine nitrate may not very relate to the critical micelle concentrations (CMC) of the additives. Also, the effect of mixing molar ratios of the surfactants to thiamine nitrate has also been considered and discussed which can be seen in the Table S1 of supplementary material. 3.4.3. Effect of carbon chain of additives on the morphology of thiamine nitrate crystals Based on the above analysis, we attribute the different effects of CH3(CH2)11SO4Na and CH3(CH2)11SO3Na on the morphology of thiamine nitrate to selective adsorption which is facilitated by electrostatic and hydrogen bonding interactions. Thus, the sulfuric acid root containing more negative charges should be a better inhibitor relative to sulfonic acid root, and providing a higher observed inhibition of crystal growth of thiamine nitrate. To further illustrate our speculation, herein, the inhibitory effects of CH3(CH2)nSO4Na and CH3(CH2)nSO3Na are studied more extensively under different conditions.

Figure. 12. a. Crystal growth rates of b-axis and a-axis of thiamine nitrate in the presence of 0.002 mol/L CH3(CH2)nSO3Na with different carbon chain length at the supersaturation of S = 1.32 at 298.15 K. b. Crystal growth rates of b-axis and a-axis of thiamine nitrate in the presence of 0.002 mol/L CH3(CH2)nSO4Na with different carbon chain length at the supersaturation of S = 1.32 at 298.15 K (n = 6, 9 ) and S = 1.50 (n = 10-13). The error bar = 20%.

Sodium alkyl sulfates CH3(CH2)nSO4Na and sodium alkyl sulfonates CH3(CH2)nSO3Na with different carbon chain length were adopted as additives in this study. The growth rates of both b-axis 22


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and a-axis of thiamine nitrate in the presence of CH3(CH2)nSO4Na and CH3(CH2)nSO3Na were illustrated in Figure 12a-b. Interestingly, for 0.002 mol/L CH3(CH2)nSO3Na, the growth rates of a-axis and b-axis of thiamine nitrate decreased with the increasing the length of carbon chains of the additive. In order to reduce the deviations of the experimental results caused by the low concentration of CH3(CH2)nSO3Na, we also adopted different concentrations of CH3(CH2)nSO3Na for the measurement of single seed crystals growth rate. It is verified that no matter how high the concentration of the additive is, the growth rate of a-axis is always greater than that of b-axis. That is to say, the morphology of thiamine nitrate always keeps a rod shape in the presence of CH3(CH2)nSO3Na. This is because the interactions between CH3(CH2)nSO3Na and thiamine nitrate are weak, and the inhibition effect of CH3(CH2)nSO3Na on the growth rate of thiamine nitrate is due to hindering the diffusion of solute, and the hindrance increases with the increasing concentration and the carbon chain length of the additives. This provides a rational explanation of the experimental results: the average aspect ratio of thiamine nitrate products hardly changes in the presence of CH3(CH2)nSO3Na. By analogy, we used the same additive concentrations to illustrate the effects of CH3(CH2)nSO4Na on the morphology of thiamine nitrate. Interestingly, the single seed crystal experiment determined in the presence of CH3(CH2)nSO4Na, revealed a big difference with the experimental phenomenon of CH3(CH2)nSO3Na. In spite of the same carbon chain length, CH3(CH2)nSO4Na can change the morphology of thiamine nitrate from rod to block as long as the concentration is high enough. This is due to the different structures of sulfuric acid root in CH3(CH2)nSO4Na and sulfonic acid root in CH3(CH2)nSO3Na, which makes electrostatic and hydrogen bonds interactions between additives and the crystal faces of thiamine nitrate greatly different. Because of the strong selective adsorption of CH3(CH2)nSO4Na on the crystal faces of thiamine nitrate, the adsorbed additive will block the crystal surface and consequently prevent solute molecules from integrating into the crystal lattice and retard the face growth. 23



Another interesting observation is that for certain kinds of additives, the lowest effective concentration decreases with the increase of chain length. The longer chain length of CH3(CH2)nSO4Na is, the more efficient will be in inhibiting crystal growth of thiamine nitrate compared to those with shorter chain at effective concentrations. This can owe to the increase of chain length leading to the increase of the molecular steric hindrance of the additive, thus the growth sites are occupied by the additive, and then the growth rate of thiamine nitrate can be inhibited to a larger extent. 3.5 Crystal growth mechanisms speculation between additives and lattice planes of crystals In order to get a further understanding and reasonable explanation of the big difference of the two kinds of similar additives, the experimental observations and the charges calculated by MS, suggest the mechanism illustrated in Figure 13.

Figure. 13. The mechanism of the two kinds of additives on the morphology of thiamine nitrate From the schematic diagram, it can be clearly seen that in the presence of CH3(CH2)nSO3Na, the morphology of thiamine nitrate remains rod, while the morphology of thiamine nitrate appears block in the presence of CH3(CH2)nSO4Na. One possible mechanism for the additive effect is that the additives may interact with the targeted faces of thiamine nitrate crystal selectively. When the 24


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targeted face was adsorbed by the additives, the growth rates of that face can be inhibited to a great extent and thus leading to crystal morphology modification. Further, the main reason of the different effect of the two kinds of additives is due to the electrostatic and hydrogen bonding interactions between additive molecules and the targeted faces of thiamine nitrate according to the structure analysis. CH3(CH2)11SO4Na has stronger electronic interactions with thiamine nitrate than CH3(CH2)11SO3Na. The stronger ability to form hydrogen bonding with thiamine nitrate, CH3(CH2)11SO4Na adsorbed on the corresponding crystal face of a-axis selectively, inhibits the growth of the a-axis of thiamine nitrate and retards the crystal growth. However, CH3(CH2)11SO3Na may only form a diffusion barrier at the crystal surface, leading to growth inhibition of both a-axis and b-axis of thiamine nitrate slightly. It is worth noting that similar to CH3(CH2)11SO4Na, the effect of CH3(CH2)11SO4Na on the morphology of thiamine nitrate can be attributed to the surface adsorption combining the hindrance of solute diffusion by additive as the growth rate of b-axis of thiamine nitrate can also be inhibited slightly in the presence of CH3(CH2)11SO4Na. 4. Conclusions In this work, the effects of supersaturation, the sorts, concentration and carbon chain length of additives on the growth rate of thiamine nitrate have been systematically investigated by single seed crystal growth experiment. It is observed that the growth rates of both b-axis and a-axis of thiamine nitrate increase with the increasing supersaturation. Nevertheless, the growth rate of a-axis is always higher than that of b-axis at the measured supersaturations, which leads to the rod morphology of thiamine nitrate by crystallization in pure water. It is found that CH3 (CH2 )n SO4 Na could modify the morphology of thiamine nitrate from rod to block crystals, while CH3 (CH2 )n SO3 Na could not change the morphology of thiamine nitrate significantly. Furthermore, the mechanism of additives to modify the crystal morphology was proposed: surfactant additive molecules may adsorb onto the target crystal face of thiamine nitrate and block the growth site by electrostatic and hydrogen bonding interactions, thereby changing the morphology 25



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of thiamine nitrate from rod-like to block. In all, the additive employed in this study enhances the properties of thiamine nitrate and reduces its production cost by tailoring the crystal size and morphology specifically. Also, it provides a guide to the evaluation and selection of the morphology modifiers the industrial batch crystallization processes.

ASSOCIATED CONTENT Supporting Information Figure S1 presents the chemical structure of thiamine nitrate (A); Figure S2 shows the detailed experimental procedures for crystal growth; Figure S3 illustrates the seeds used in the experiment with similar size; Figure S4-S6 was used to further verify whether the effects of the surfactants relate to critical micelle concentrations; (Table S1) was used to illustrate the effects of mixing molar ratios of the surfactants to thiamine nitrate on the growth of thiamine nitrate. AUTHOR INFORMATION Notes The authors declare no competing financial interest.

Acknowledgement The authors are grateful to the financial support of National Natural Science Foundation of China (NNSFC 81361140344 and NNSFC 91634117, National 863 Program (2015AA021002), Major Science

and

Technology

Program

for

Water

Pollution

Control

and

(NO.2015ZX07202-013) and Tianjin Science and Technology Project (15JCZDJC33200

Corresponding Author *Tel.: 86−22−27405754. Fax: + 86−22−27374971. E−mail: [email protected].

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Treatment

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References (1) Chow, K.; Tong, H. H. Y.; Lum, S.; Chow, A. H. L. J. Pharm. Sci. 2008, 97, 2855-2877 (2) Klapwijk, A. R.; Simone, E.; Nagy, Z. K.; Wilson, C. C. Cryst. Growth Des. 2016, 16, 4349-4359. (3) Ramamoorthy, S.; Kwak, J. H.; Karande, P.; Farmanesh, S.; Rimer, J. D. AIChE J. 2016, 62, 3538-3546. (4) Snyder, R. C.; Veesler, S.; Doherty, M. F. Cryst. Growth Des. 2008, 8, 1100-1101. (5) Simone, E.; Klapwijk, A. R.; Wilson, C. C.; Nagy, Z. K. Cryst. Growth Des, 2017, 17, 1695-1706. (6) Wood, W. M. L. Powder Technol. 2001, 121, 53-59 (7) Lekhal, A.; Girard, K. P.; Brown, M. A.; Kiang, S.; Khinast, J. G.; Glasser, B. J. Int. J. Pharm. 2004. 270, 263-277. (8) Variankaval, N.; Cote, A. S.; Doherty, M. F. AIChE J. 2008, 54, 1682-1688. (9) Clydesdale, G.; Roberts, K. J.; Docherty, R. J. Cryst. Growth. 1994, 135, 331−340. (10) Majumder, A.; Nagy, Z. K. Chem. Eng. Sci. 2013, 101, 593-602. (11) Xie, S.; Poornachary, S. K.; Chow, P. S.; Tan, R. B. Cryst. Growth Des. 2010, 10, 3363-3371. (12) Han, G.; Chow, P. S.; Tan, R. B. Cryst. Growth Des. 2015, 15, 1082-1088. (13) Mao, X.; Song, X.; Lu, G.; Xu, Y.; Sun, Y.; Yu, J. Chem. Eng. J. 2015, 278, 320-327. (14) Weissbuch, I.; Addadi, L.; Berkovitch-Yellin, Z.; Gati, E.; Weinstein, S.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1983, 105, 6615-6621. (15) Vetter, T.; Mazzotti, M.; Brozio, J. Cryst. Growth Des. 2011, 11, 3813-3821. (16) Sangwal, K. Prog. Cryst. Growth Charact. Mater. 1996, 32, 3-43. (17) Han, G.; Chow, P. S.; Tan, R. B. Cryst. Growth Des. 2012, 12, 5555-5560. (18) Kubota, N.; Mullin, J. W. J. Cryst. Growth. 1995, 152, 203-208. (19) Kubota, N.; Yokota, M.;Mullin, J. W. J. Cryst. Growth. 1997, 182, 86-94. (20) Kubota, N.; Yokota, M.; Mullin, J. W. J. Cryst. Growth. 2000, 212, 480-488. (21) Cabrera, N.; Vermilyea, D. A. Growth and Perfection of Crystals; Chapman and Hall: London, 1958, pp 393 (22) Chen, L.; Xiao, J. X.; Ma, J. Colloid Polym. Sci. 2004, 282, 524-529. (23) Rosen, M. J.; Kunjappu, J. T. Surfactants and interfacial phenomena. John Wiley & Sons. 2012. (24) Myers, D. Surfactant science and technology. John Wiley & Sons. 2005. (25) Wang, H.; Qin, Y.; Han, D.; Li, X.; Wang, Y.; Du, S.; Gong, J. Fluid Phase Equilib. 2015, 400, 53-61. (26) Li, X.; Han, D.; Wang, Y.; Du, S.; Liu, Y.; Zhang, J.; Gong, J. J. Chem. Eng. Data. 2016, 61, 3665-3678. (27) Ryjkina, E.; Kuhn, H.; Rehage, H.; Müller, F.; Peggau, J. Angew. Chem. Int. Ed. 2002, 41, 983-986. (28) Zhu, W.; Romanski, F. S.; Meng, X.; Mitra, S.; Tomassone, M. S. Eur. J. Pharm. Sci. 2011, 42, 452-461. (29) Wang, S.; Humphreys, E. S.; Chung, S. Y.; Delduco, D. F.; Lustig, S. R.; Wang, H.; Jagota, A. Nat. Mater. 2003, 2, 196-200. (30) Ma, M.; Ye, W.; Wang, X. X. Mate Lett. 2008, 62, 3875-3877. (31) Boerrigter, S. X. M.; Cuppen, H. M.; Ristic, R. I.; Sherwood, J. N.; Bennema, P.; Meekes, H. Cryst. Growth Des. 2002, 2, 357-361. (32) Tilbury, C. J.; Doherty, M. F. AIChE J. 2017, 63, 1338-1352. (33) Pan, Y.C.; Heryadi, D.; Zhou, F.; Zhao, L; Lestari, G.; Su, H.B.; Lai, Z.P. CrystEngComm. 2011, 13, 6937–6940. (34) Mao, X.; Song, X.; Lu, G.; Sun, Y.; Xu, Y.; Yu, J. Ind. Eng. Chem. Res. 2014, 53, 17625−17635. (35) Yin, H.; Wang, Q.; Chen, G. Chem. Eng. J. 2014, 236, 131–138. (36) Xu, B.; Zhang, Q.T.; Yuan, S.S.; Zhang, M.; Ohno, T. Chem. Eng. J. 2015, 260, 126–132 27



(37) Dowling, R.; Davey, R. J.; Curtis, R. A.; Han, G.; Poornachary, S. K.; Chow, P. S.; Tan, R. B. Chem. Commun. 2010, 46, 5924-5926. (38) Han, G.; Poornachary, S. K.; Chow, P. S.; Tan, R. B. Cryst. Growth Des. 2010, 10, 4883-4889. (39) Nezamzadreh-Ejhieh, A.; Raja, G. J. Chem. Vol. 2013, Article ID 685290, 13 pages (40) Hasheminejad, M.; Nezamzadeh-Ejhieh, A. Food Chem. 2015, 172, 794–801. (41) Nezamzadeh-Ejhieh, A.; Mirzaeyan. E. Mater. Sci. Eng. 2013, 33, 4751–4758 (42) Hoseini, Z.; Nezamzadeh-Ejhieh. A. Mater. Sci. Eng. 2016, 60, 119-125. (43) Mahdavi, M.; Nezamzadeh-Ejhieh. A. J. Colloid Interf. Sci. 2017, 494, 317–324. (44) Sharafzadeh, S.; Nezamzadeh-Ejhieh. A. Electrochim. Acta. 2015, 184, 371–380. (45) Nezamzadeh-Ejhieh, A.; Esmaeilian. A. Micropor. Mesopor. Mater. 2012, 147, 302-309. (46) Naghash, A.; Nezamzadeh-Ejhieh. A. J. Ind. Eng. Chem. 2015, 31, 185–191 (47) Majuste, D.; Bubani, F. C.; Bolmaro, R. E.; Martins; E. L. C.; Cetlin, P. R.; Ciminelli, V. S. T. Hydrometallurgy. 2017, 169, 330-338. (48) Fiebig, A.; Jones, M. J.; Ulrich, J. Cryst. Growth Des. 2007, 7, 1623-1627.

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For Table of Contents Use Only Effects of additives on the morphology of thiamine nitrate: the great difference of two kinds of similar additives Dandan Han a,b, Bo Yu a,b, Yumin Liu a,b, Shichao Du a,b, Sohrab Rohani d, Teng Zhang a,b, Shiyuan Liu a,b, Peng Shi a,b,Haisheng Wang a,b, Lina Zhou a,b, Junbo Gong a,b,c,* a

State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology,

Tianjin University, Tianjin 300072, People’s Republic of China. b

Collaborative Innovation Center of Chemistry Science and Engineering, Tianjin 300072, People’s

Republic of China. c

Key Laboratory Modern Drug Delivery and High Efficiency in Tianjin University, Tianjin, China

d

The University of Western Ontario, Department of Chemical and Biochemical Engineering, London,

Ontario, N6A 5B9, Canada

This graphic shows the different effects of two kinds of similar additives, CH3(CH2)nSO4Na and CH3(CH2)nSO3Na, on the morphology of thiamine nitrate. A detailed molecular-level analysis along with experiments provide a mechanism: the anionic groups exposed at the end of the additives with a small variation of charge density can lead to a marked difference in modifying the crystal growth behaviors.

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Effects of Additives on the Morphology of Thiamine Nitrate: The Great

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