Direct Growth of Microspheres on Amorphous ... - ACS Publications

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Direct Growth of Microspheres on Amorphous Precursor Domains in Polymer-Controlled Crystallization of Indomethacin Yu Huang,† Yuan Jiang,*,† Xiangrui Yang,† Yue Ren,† Da Zhan,† Helmut Cölfen,§ Zhenqing Hou,*,†,‡ and Xiang Yang Liu∥,† †

Research Institute for Soft Matter and Biomimetics & Fujian Provincial Key Laboratory for Soft Functional Materials Research, College of Materials, Xiamen University, Xiamen 361005, China ‡ Department of Physics, Changji University, Changji 831100, China § Physical Chemistry, University of Konstanz, Universitätsstrasse 10, Box 714, 78457 Konstanz, Germany ∥ Department of Physics, National University of Singapore, 117542, Singapore S Supporting Information *

ABSTRACT: Polymer-controlled crystallization is becoming an increasingly important approach to achieve functional materials precipitated from the solution phase. Nevertheless, there exist multiple pathways under the control of yet unpredictable kinetic factors, which significantly hinder the mechanistic understanding. Herein, the mechanistic study of polymer-controlled precipitation of a typical drug compound, indomethacin, was performed. The presence of a nonionic additive poly(vinylpyrrolidone) induces the heterogeneous nucleation of networks of dumbbell-shaped crystalline microspheres on amorphous precursor domains, which is an emerging pathway in polymer-controlled crystallization. This pathway is also verified in the precipitation of L-histidine in the presence of poly(acrylic acid) in the current study. As a comparison, the presence of a cationic polymeric additive, branched polyethylenimine, promotes the formation of aggregates of amorphous nanoparticles and the subsequent crystallization of a spherical-shaped microsphere on each aggregate, a pathway in line with those in numerous studies of polymer-controlled crystallization of inorganic compounds. Our results suggest that the heterogeneous crystallization of microspheres on the amorphous precursor domains could be a specific pathway occurring in polymer-controlled precipitation of organic compounds mainly due to the fast kinetics of the precipitation process. In short, our study broadens our understanding of polymer-controlled crystallization of functional organic crystals.

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INTRODUCTION It is well-known that the presence of soluble polymeric additives can effectively control the kinetics of crystallization and, hence, lead to distinct morphological and polymorphic outcomes.1 For the rational understanding of the underlying mechanism of the polymer-controlled crystallization, a growing number of well-established studies have already indicated the multiple roles of soluble polymeric additives, particularly their capability of switching the classical nucleation−growth pathway into the nonclassical multistage one.2−4 Specifically, the presence of soluble polymers can effectively elongate the lifetime of the transiently existing precursor phases including nanocomplexes,5 clusters,6 amorphous particles,7,8 and liquidlike domains,9−13 followed by their transformation into crystalline forms, which are usually superstructures of nanocrystals. Among these precursors, the amorphous one has been studied most extensively, particularly in the polymer-controlled crystallization of inorganic compounds.14,15 First, this form has been evidenced in numerous biominerals, and their indispensable role in biomineralization was addressed extensively.16 © XXXX American Chemical Society

Second, it can be conveniently stabilized in the scalable polymer-controlled crystallization of CaCO317 and stored as dry powders for structural and compositional analyses.18,19 In addition to the syntheses and analyses of the amorphous precursor, the detection of its transformational kinetics into the crystalline forms is another focus of bioinspired crystallization. Excitingly, three well-accepted scenarios have been put forward to address the underlying mechanism of transformation. A number of time-resolved kinetic studies of polymer-controlled mineralization of calcium carbonate and phosphate under the transmission electron microscope indicate that structural transformation into the crystalline forms occurs within the aggregates of amorphous nanoparticles via a dissolution− recrystallization process.7,11,20 Alternatively, the in situ transformation of the amorphous thin films into the crystalline ones, initiated by artificial nuclei or an annealing process, is also Received: October 28, 2015 Revised: January 28, 2016

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DOI: 10.1021/acs.cgd.5b01522 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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lization of multiple dumbbell-shaped microspheres on the external surface of free-floating amorphous domains to obtain microsphere networks, a novel pathway so far never mentioned in the existing studies of polymer-controlled crystallization. As a comparison, the presence of another additive, the positively charged PEI, led to the crystallization of the spherical-shaped microspheres within each amorphous nanoparticulate aggregate, in line with one of the representative pathways in the polymer-controlled crystallization. Furthermore, microsphere networks on amorphous domains were also observable in the precipitation of L-histidine (L-His) in the presence of a countercharged polymeric additive, poly(acrylic acid) (PAA, the average Mw = 2000 g·mol−1) (see the SI materials). Hence, the mechanistic studies of the polymer-controlled precipitation of two typical organic compounds herein are an important addition to the current understanding of polymer-controlled crystallization. Engineering of practically insoluble drugs into a microsphere morphology bearing nanocrystalline structural subunits could be a promising design for drug formulations with enhanced drug delivery properties compared with their bulk counterparts.34,35

detectable by X-ray diffraction (XRD) and polarized optical microscopy (POM) techniques.21−24 The third scenario, however, highlights the dynamic accretion of amorphous nanoparticles onto the growing crystals, followed by their immediate in situ crystallization.25 The mechanistic studies of the polymer-controlled crystallization of inorganic compounds are highly instructive for understanding the crystallization details of organic compounds. Nevertheless, the antisolvent precipitation of organic compounds, characteristic of the immediate maximization of the supersaturation due to the fast mixing procedure, is usually used to obtain functional powders. Insertion of a fast mixing procedure, stopped-flow for example, causes the immediate maximization of the supersaturation, which causes the formation of liquid precursors, which can grow into macroscopic items via coalescing nanodroplets.26 Nevertheless, the fast kinetics leaves the time-resolved mechanistic studies difficult. For instance, though polymer-induced liquid precursors were detected in the antisolvent precipitation of amino acids12,27,28 and pigments,29 the transformational details from precursors to crystalline forms remain not well-known. Thus, finding appropriate precipitation case studies of functional organic compounds is crucial for the rational understanding of the underlying mechanism. An anti-inflammatory drug, indomethacin (INN), was deliberately selected for the mechanistic studies herein. Its amorphous form can be conveniently achieved via melting crystallization or crystallization in the presence of an inhibitor (Figure 1).30−32 For instance, its amorphous form was

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EXPERIMENTAL SECTION

Materials. All chemical reagents employed in this study were of analytical grade and used without any further purification unless otherwise stated. Indometacin (INN) and L-histidine (L-His) were received from Sigma-Aldrich. Polyvinylpyrrolidone (PVP K30) was a gift from BASF. The branched polyethylenimine (the average Mw at 600 g·mol−1) and poly(acrylic acid) (the average Mw at 2000 g·mol−1) were obtained from Aladdin. Dimethyl sulfoxide (DMSO) was purchased from Xilong Chemical. Absolute ethanol was purchased from Huada Chemical. Deionized water (18 MΩ·cm−1) was used throughout the work. Fabrication of INN Microspheres. INN microspheres were precipitated by using the antisolvent precipitation method. A certain amount of INN with or without the polymeric additive (PVP K30 or PEI 600) was dissolved in ethanol or DMSO. The concentration of INN was constant at 0.03 mol·L−1. The molar ratio of INN and the repeating unit of PVP was between 0.3 and 4.7. The molar ratio of INN and the repeating unit of PEI was constant at 2. The above mother liquor was stirred for 24 h before quickly charged into water at various volume ratios with the micropipette. The volume ratio of the mother liquor and water varied between 1 and 10 in a typical antisolvent precipitation process. After being shaken by hand for a few seconds, the mixture was kept quiescent for 24 h at RT for the completion of precipitation. Finally, the precipitates were rinsed with water and centrifuged at 5000 rpm for 10 min. The process was repeated three times to remove the unbound polymers completely. The obtained precipitates were frozen at −80 °C and lyophilized in a Scanvac Cool safe 110-4 lyophilizer (LaboGene, Denmark) for 24 h to obtain the dried powders. The time-resolved samples were thus collected at various periods of time without the rinsing procedure. Then, they were frozen at −80 °C and lyophilized for 24 h to permanently maintain the form. Fabrication of the L-His Microspheres. A volume of the aqueous solution containing a quantity of L-His and PAA was prepared at RT and stirred for 24 h before quickly charged into a volume of ethanol by using a micropipette. The molar concentration of L-His was 0.52 mol·L−1. The concentration of the repeating unit of PAA was 0.19 mol·L−1. The volume ratio of the L-His-PAA solution and ethanol was constant at 7 with the pH value at 5.5. After being shaken by hand for a few seconds, the mixture was then kept quiescent at RT for 48 h for the completion of precipitation. Finally, the precipitates were rinsed with ethanol three times to remove the unbound PAA completely. The time-resolved samples were collected at various periods without the rinsing procedure. Then, they were frozen at −80 °C and lyophilized for 24 h to permanently maintain the form.

Figure 1. Molecular formula of INN, PVP, and branched PEI.

obtainable in the presence of a comparable amount of a nonionic polymeric additive, poly(vinylpyrrolidone) (PVP; Figure 1), via a solvent evaporation procedure.31 As expected, increasing the INN/polymer ratio could switch the amorphous INN to crystallize guided by the polymeric additive used,33 where the polymer-controlled crystallization ensures the appearance of amorphous precursors and elongates their lifetime for the time-resolved detection. Herein, the antisolvent precipitation of INN in the presence of either of the two polymers selected, PVP (K30) and branched polyethylenimine (PEI, the average Mw at 600 g·mol−1; Figure 1), was performed for the time-resolved detection of the multistage crystallization of INN. Multiple techniques including scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman microscopy were applied for the morphological and structural determination. The presence of PVP promoted the crystalB



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Characterization. Scanning electron microscopy (SU-70, Hitachi) was employed to study the morphology of the INN microspheres. The samples were prepared by gluing the dried INN powders onto the conducting glue. Samples were coated with a thin layer of gold using the sputter coater for 30 s for the SEM observation at 15 kV. An Olympus BX53 polarized optical microscope was used for the (polarized) optical microscopic (OM and POM) observation. The samples were prepared by dropping the dry powders onto the glass microslide. The X-ray diffraction patterns were collected by using an XRD system (X’pert PRO, PANalytical) with the Cu−Kα radiation generated at 30 mA and 40 kV. The diffraction angle increased from 5° to 60° with the step size at 0.016°. The proton nuclear magnetic resonance (1H NMR) spectra were recorded with a Bruker AV400 NMR spectrometer, where the deuteriated DMSO was used as the solvent. FT-IR spectra were collected on a Nicolet IN10 Fourier transform infrared spectrometer (Thermo Scientific, UT, USA) from 2000 to 600 cm−1. The Raman analysis was performed on a Labram HR Evolution Raman microscope system equipped with a 532 nm Ar laser. Laser power and beam size were approximately at 2.5 mV and 1 μm, respectively. The integration time was adjusted to 15 s for the scanning of the organic nanocrystals.

solvents, respectively, are composed of the radially aligned and interwoven nanofibers as structural subunits (Figure 2a). The spherulitic form, a representative form via a far-fromequilibrium process observable in a number of crystallization studies, was obtained due to the fast increase of the supersaturation in the antisolvent precipitation.37−39 The precipitation follows the classical nucleation−growth process, as being detected in situ under the optical microscope (Figure s1; OM), in line with the existing viewpoint.36 Specifically, the dissolution−recrystallization occurred in the microspheres in the alcoholic−aqueous dispersion mixture to achieve the INN submicrofibers after 7 days (Figure 2b and Figure s2) in an Ostwald ripening process. The antisolvent precipitation of INN in the presence of either PVP or PEI also resulted in dumbbell- or sphericalshaped microspheres, respectively, as shown in the SEM images (Figure 2c−f; see overview OM and SEM images in Figure s3; see images of parameter optimization in the SI materials). For the dumbbell form, there was no further structural change into the spherical one in the current study, though reports elsewhere indicate that dumbbell-shaped microspheres could grow further into the spherical-shaped ones in the fabrication of fluorapatite−gelatin nanocomposites.40 The XRD data show that all INN microspheres precipitated from the aqueous phase are the pure α-form, as also mentioned in other studies (Figure 3).31

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RESULTS AND DISCUSSION First, spherical-shaped INN microspheres were achievable via the antisolvent precipitation technique in the absence of a polymeric additive, in accordance with a previous report (Figure 2a).36 Microspheres, achieved by using ethanol (or dimethyl sulfoxide − DMSO) and water as the good and poor

Figure 3. Powder XRD patterns of the INN crystals obtained in an antisolvent precipitation process. Patterns 1−5 were taken by using microspheres collected from the PVP−ethanol, PVP−DMSO, PEI− ethanol, PEI−DMSO, and DMSO precipitation systems in sequence. The sixth pattern was taken by using nanofibers precipitated from the INN−ethanol−water system. Water was used as the antisolvent in all the precipitation systems.

Figure 2. Images a−f illustrate the INN microspheres achieved via the antisolvent precipitation with or without the polymeric additive. Image a indicates the microspheres obtained by mixing the INN−ethanol mother liquor with water after 2 h. An OM image shows the INN nanofibers after the Ostwald ripening process after 7 days (image b). c and d are SEM images of the INN−PVP microspheres with ethanol and DMSO as the solvent, respectively. e and f are SEM images of the INN−PEI microspheres with ethanol and DMSO as the solvent, respectively. See the reaction conditions in the SI materials. a and b: [INN] = 0.03 mol·L−1, Vwater/Vetha. = 7; c: [INN] = 0.03 mol·L−1, nINN/nVP = 1.5, Vwater/Vetha. = 7; d: [INN] = 0.03 mol·L−1, nINN/nVP = 1.5, Vwater/VDMSO = 7; e: [INN] = 0.03 mol·L−1, nINN/nEI = 2, Vwater/ Vetha. = 7; f: [INN] = 0.03 mol·L−1, nINN/nEI = 2, Vwater/VDMSO = 7.

For the antisolvent precipitation in the presence of the polymeric additive, two parametersVwater/Vsolvent (the term “etha.” denotes ethanol) and nINN/nmonomer (the molar ratio of INN and the monomer instead of the polymer was used to present interactions between functional groups on INN and on the polymers used, where EI and VP denote ethylene imine and vinylpyrrolidone, respectively)are essential for the morpholC



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In case the Vwater/Vetha. value was constant at 7, pure dumbbell microspheres were achievable when the nINN/nVP value was between 1.5 and 3.1 (Figure 4b,c). The value higher than 3.1 led to the spherical-shaped microspheres because of the insufficient presence of the PVP molecules to stabilize the precursor domains (Figure 4a). On the other hand, crystalline impurities with the irregular morphology were achievable when the nINN/nVP value was lower than 1.5, as shown in Figure 4d. Also, the parameter Vwater/Vetha. was evaluated for the precipitation of the dumbbell-shaped microspheres when the value of nINN/nVP was constant at 1.5 (Figure s4). The particle size decreased when the Vwater/Vetha. values increased from 1 to 7 because of the enhancement of the supersaturation level. Nevertheless, further increasing the value led to the precipitation of a small amount of microspheres with an increased particle size due to the dilution effect. Interestingly, the microspheres obtained in the presence of PVP or PEI show different dispersibility after precipitation for 24 h. The dumbbell-shaped ones achieved in the presence of PVP tended to stay as aggregates, while those spherical-shaped ones obtained in the presence of PEI had good dispersibility after reacting for 10 h. Thus, careful time-resolved studies were performed to understand distinct pathways. Samples at different precipitation periods were treated with a lyophilization

ogy of the microspheres. Here, the INN−PVP−ethanol system was used as an example for parameter optimization (Figure 4).

Figure 4. SEM images show the effect of nINN/nVP on the size of the microspheres. The values of nINN/nVP in these images are 4.7, 3.1, 1.5, and 0.3 in sequence. [INN] = 0.03 mol·L−1, Vwater/VDMSO = 7. The length scale in all images is the same.

Figure 5. Time-resolved studies of two pathways of the polymer-controlled crystallization in the INN−PVP−ethanol−water (the Pathway 1 in images a−f) and INN−PEI−ethanol−water (the Pathway 2 in images i−l) case studies. The image g contains two Raman spectra, where the “1” curve denotes the macroscopic precursor domain and the “2” represents microspheres. Image h shows a representative free-floating amorphous domain in the dispersion mixture. The image m highlights the direct mass transfer from the amorphous nanoparticles to the nanofibers when the reaction period is about 1 h. The reaction conditions are as follows. [INN] = 0.03 mol·L−1, Vwater/Vetha. = 7, nINN/nVP = 1.5 (Pathway 1), nINN/nEI = 2 (Pathway 2). D



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aggregates of amorphous nanoparticles to grow into microspheres. Dramatically, there could exist a direct mass transfer between the growing nanofibers and the continuously forming amorphous nanoparticles (Figure 5m). As a comparison, in polymer-controlled crystallization of inorganic compounds, superstructures grow via the accretion of amorphous nanoparticles or the dissolution−recrystallization pathway.7,8,20 The direct mass transfer between amorphous nanoparticles and the nanofibers on the growing microspheres detected herein can be attributed to the high supersaturation in the precipitation process. PVP and PEI lead to different multistage crystallization pathways (Figure 6), which can be partially attributed to the

procedure to permanently maintain the form in the precipitating mixture. Particularly, the time-resolved observation indicates that both precipitation processes follow different pathways. In the INN−PVP−ethanol precipitation case study, the freefloating precursor domains of hundreds of micrometers were clearly observable under the OM (Figure 5h), which had no contrast under the POM due to their amorphous nature. The amorphous nature was also convincingly confirmed by Raman microscopy because a peak at 1681 cm−1 appears for the nonH-bonded mode of the benzoyl CO stretch (Figure 5g).31 Such macroscopic amorphous precursors could be regarded as the supercooled liquid precursors of high viscosity, which are seldom observed in the polymer-controlled crystallization of inorganic compounds because of their strong crystallization driving force.41 It would be interesting to detect their formation and transformation into the finally obtained crystalline forms. Herein, their formation mechanism was clarified by recording the structural transformation in a series of the time-resolved SEM images (Figure 5a−f). In the early stage of the multistage process, amorphous nanoparticles detected quickly merged into continuous amorphous precursor domains because the nonionic PVP chains on the surface of amorphous nanoparticles would promote steric attraction between adjacent nanoparticles to aggregate and merge. Subsequently, the precursor domains function as the substrates for the interfacial crystallization of shuttle-like superstructures with well-aligned nanofibers as structural subunits. The superstructure continued growing into dumbbell-shaped microspheres, while precursors simultaneously started to shrink into microfibers presumably due to the direct mass transfer between the growing microspheres and precursor domains. After precipitation for 24 h, the dumbbellshaped microspheres stayed aggregates due to the remaining interconnected microfibers. The aggregates slowly broke into the isolated ones only after a period of weeks after the interconnecting precursor fibers totally disappeared. Similarly, in the case study of the INN−PVP−DMSO precipitation, the interfacial crystallization of microspheres was detected to occur on the microfiber-like precursors to grow into a chain of microspheres after precipitation for 24 h (Figure s5). Simultaneously, the microfibers are getting shortened due to the mass transfer to the growing microspheres. Interestingly, the external surfaces of amorphous INN domains were used as the heterogeneous nuclei to grow crystalline INN microspheres, though previous studies show that microspheres can also grow from the bulk phase or from the inside of liquid precursors.12,29 The crystallization of spherical-shaped microspheres, however, occurs on the aggregates of amorphous nanoparticles in the presence of PEI (Figure 5i−l). Initially, the immediate mixing of the alcoholic mother liquor with the antisolvent− water generated a large number of amorphous nanoparticles, many of which aggregated to decrease the interfacial energy. Subsequently, a growing number of nanofibers started to stretch out from the amorphous aggregates to grow into microspheres, a typical pathway detected in numerous studies of polymer-controlled crystallization of inorganic compounds.7,8,11,20 We assume that the amorphous INN−PEI hybrid nanoparticles did not merge into the macroscopic domains due to the presence of the highly charged PEI molecules on the external surface of these nanoparticles, which generates strong electrostatic repulsion between the particles. Hence, the crystallization of the nanofibers starts from the

Figure 6. Two multistage pathways of the polymer-controlled crystallization, where the crystallization of the superstructures (blue; α-form INN) occurs on the surface of amorphous precursors (green).

intermolecular interactions between INN and the soluble polymeric additive used. Thus, FT-IR and 1 H NMR spectroscopic analyses were used to reveal the intermolecular interactions. The presence of the H-bonding interactions between INN and PVP was indicated in the peak (the asymmetric stretching vibration of the carbonyl group) shift from 1712 to 1724 cm−1 in the IR spectrum (Figure s6a). The lack of the chemical shift for carboxylic groups of INN in the INN−PVP−DMSO mixture hints at the H-bonding interactions in between (Figure s7a).31 As a comparison, both the altered 1H NMR chemical shifts of protons on the carboxylic groups and those on the secondary alkane functional group adjacent to the carboxylic acid group toward the high field suggest the presence of electrostatic interactions between INN and PEI (Figure s7b). This result was supported by the FT-IR results, where the intensity of the 1712 cm−1 peak was highly decreased in the presence of PEI (Figure s6b). Therefore, different molecular interactions between INN and PVP/PEI, plus the fast precipitation technique used, cause distinct pathways in the multistage precipitation. We performed another case studythe antisolvent precipitation of L-histidine (L-His) in the presence of a well-known soluble polymeric additive, PAA, to test whether this pathway could be a universal phenomenon (Figure s8). Though the morphological outcomes have been reported elsewhere,1 we focus on the time-resolved study herein to understand the underlying mechanism. The OM observation indicated the appearance of a continuous domain in the very low contrast embedded with the growing microspheres (Figure 7a,b). The precursor domains started to disappear during the in situ precipitation of the microspheres. Unlike the amorphous domains of the INN−PVP hybrids preservable via the lyophilization treatment, the same treatment led to the E



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Figure 7. Time-resolved studies of the crystallization of L-His in the presence of PAA. In both OM images, image a shows the crystallization of microspheres from the macroscopic matrix domain, while image b indicates the finally formed L-His microspheres. SEM images c−e show the structural character during the growth of microspheres, where a lyophilization process transforms the macroscopic domain into the aggregates of the nanoplatelets. Images f−h are the magnified images of c−e, respectively. The reaction conditions are as follows. [L-His] = 0.52 mol·L−1, [AA] = 0.19 mol·L−1 (AA denotes acrylic acid, the repeating structural unit of PAA), Vetha./Vaqueous = 7, and pH = 5.5.

in each liquid precursor domain to achieve single crystalline domains. Herein, however, the combination of the proper polymeric additive and the fast precipitation condition led to the interfacial crystallization of multiple crystals to form crystal networks. The novelty in the current study, including the formation of the macroscopic amorphous precursor items and the interfacial crystallization of multiple microspheres, can be attributed to the relatively low crystallization driving force of the organic compounds and the antisolvent precipitation technique used. The delicate control of the formation and transformation of the precursors in the polymer-controlled crystallization is promising to guide the crystallization of functional compounds into superstructures with the forms desired. For instance, the bioavailability of the practically insoluble drugs can be significantly enhanced in case these drugs could be fabricated into superstructures of nanocrystals with durable stability when compared with their amorphous or crystalline nanodrug suspensions (see in the SI materials).

crystallization of the precursor domains into a large number of weakly interconnected L-His−PAA hybrid nanoplatelets due to the strong crystallization driving force of L-His (Figure 7c−h). The percentage of the nanoplatelets decreased during the growth of the L-His microspheres under SEM, in accordance with the disappearance of the precursor domains.

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CONCLUSIONS Remarkably, amorphous domains formed in the antisolvent precipitation could initiate multiple interfacial crystallization processes to achieve microsphere networks. Though the amorphous phase has been extensively discussed in fabrication of amorphous INN formulations,30−32 there lacks direct evidence of using macroscopically sized amorphous precursors for the interfacial crystallization of INN microspheres. This scenario is also different from the existing pathways in polymercontrolled crystallization. This pathway was also evidenced in another case studythe antisolvent precipitation of L-histidine (L-His) in the presence of poly(acrylic acid). Though the exact forms of the precursors in the precipitation of INN and L-His vary, the precursor domains could function as the heterogeneous nuclei to initiate the interfacial crystallization of microsphere networks to fast lowering the system energy. Remarkably, the macroscopic amorphous domain of a wellstudied amorphous drug, INN, could be preserved as the site of the interfacial crystallization of microspheres due to the chemical similarity between amorphous precursors and the crystalline microspheres. Though the interfacial crystallization of the crystalline forms from the liquid precursors was detected in a number of crystallization studies including those from the melt and the solution phase,42−44 the crystallization occurring at the interface of the precursor domain is usually a single affair

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01522. OM images, SEM images, FT-IR spectra, 1H NMR spectra, molecular formulae, in vitro drug release studies, and in vitro release profiles (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (Y.J.). *E-mail: [email protected] (Z.H.). F



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Notes

(30) Yoshioka, M.; Hancock, B. C.; Zografi, G. J. Pharm. Sci. 1994, 83, 1700. (31) Taylor, L. S.; Zografi, G. Pharm. Res. 1997, 14, 1691. (32) Lee, H. E.; Lee, M. J.; Kim, W. S.; Jeong, M. Y.; Cho, Y. S.; Choi, G. J. Int. J. Pharm. 2011, 420, 274. (33) Matsumoto, T.; Zografi, G. Pharm. Res. 1999, 16, 1722. (34) Kawashima, Y.; Okumura, M.; Takenaka, H. Science 1982, 216, 1127. (35) Yang, X.; Wu, S.; Li, Y.; Huang, Y.; Lin, J.; Chang, D.; Ye, S.; Xie, L.; Jiang, Y.; Hou, Z. Chem. Sci. 2015, 6, 1650. (36) Dou, Y.; Jia, Y.; Zhou, X.; Zhang, J. X.; Li, X. H. Cryst. Growth Des. 2011, 11, 899. (37) Granasy, L.; Pusztai, T.; Tegze, G.; Warren, J. A.; Douglas, J. F. Phys. Rev. E 2005, 72, 011605. (38) Li, J. L.; Liu, X. Y. Adv. Funct. Mater. 2010, 20, 3196. (39) Shtukenberg, A. G.; Punin, Y. O.; Gunn, E.; Kahr, B. Chem. Rev. 2012, 112, 1805. (40) Tlatlik, H.; Simon, P.; Kawska, A.; Zahn, D.; Kniep, R. Angew. Chem., Int. Ed. 2006, 45, 1905. (41) Zhong, C.; Chu, C. C. Langmuir 2009, 25, 3045. (42) Galkin, O.; Chen, K.; Nagel, R. L.; Hirsch, R. E.; Vekilov, P. G. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 8479. (43) Sutter, P. W.; Sutter, E. A. Nat. Mater. 2007, 6, 363. (44) Nielsen, M. H.; Aloni, S.; De Yoreo, J. J. Science 2014, 345, 1158.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by the National Natural Science Foundation of China (21303144), the Science Foundation of the Fujian Province, China (2014J0101), the Scientific Research Staring Foundation for the Returned Overseas Chinese Scholars, the Ministry of Education of China, and the 111 Project (B16029). Y.H. thanks Mr. Yang Li and Cheng Liu for the IR and NMR discussions.

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