Amorphous Calcium Carbonate Constructed from Nanoparticle

Subscriber access provided by the Henry Madden Library | California State University, Fresno

Functional Nanostructured Materials (including low-D carbon)

Amorphous Calcium Carbonate Constructed from Nanoparticle Aggregates with Unprecedented Surface Area and Mesoporosity Rui Sun, Peng Zhang, Éva G. Bajnóczi, Alexandra Neagu, CheukWai Tai, Ingmar Persson, Maria Strømme, and Ocean Cheung ACS Appl. Mater. Interfaces, Just Accepted Manuscript • Publication Date (Web): 04 Jun 2018 Downloaded from http://pubs.acs.org on June 4, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

Amorphous Calcium Carbonate Constructed from Nanoparticle

Aggregates

with

Unprecedented

Surface Area and Mesoporosity. Rui Sun,†,‡ Peng Zhang,†,‡,

⊥

Éva G. Bajnóczi,§ Alexandra Neagu,⊥ Cheuk-Wai Tai,⊥ Ingmar

Persson,§ Maria Strømme*,‡ and Ocean Cheung *,‡ ‡Division of Nanotechnology and Functional Materials, Department of Engineering Sciences, Uppsala University, SE-751 21, Uppsala, Sweden ⊥ Department of Materials and Environmental Chemistry, Stockholm University, SE-106 91, Stockholm, Sweden § Department of Molecular Sciences, Swedish University of Agricultural Sciences, SE-750 07, Uppsala, Sweden KEYWORDs: amorphous calcium carbonate, Large-angle X-ray scattering, porous materials, drug delivery, nanoparticles.

ABSTRACT:

Amorphous calcium carbonate (ACC), with the highest reported specific surface area

of all current forms of calcium carbonate (over 350 m2g-1), was synthesized using a surfactantfree, one-pot method. Electron microscopy, helium pycnometry and nitrogen sorption analysis

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

revealed that this highly mesoporous ACC, with a pore volume of ~0.86 cm3g-1 and a pore-size distribution centered at 8-9 nm, is constructed from aggregated ACC nanoparticles with an estimated average diameter of 7.3 nm. The porous ACC remained amorphous and retained its high porosity for over 3 weeks under semi-air-tight storage conditions. Powder X-ray diffraction, large-angle X-ray scattering, infrared spectroscopy and electron diffraction exposed that the porous ACC did not resemble any of the known CaCO3 structures. The atomic order of porous ACC diminished at interatomic distances over 8 Å. Porous ACC was evaluated as a potential drug carrier of poorly soluble substances in vitro. Itraconazole and celecoxib remained stable in their amorphous forms within the pores of the material. Drug release rates were significantly enhanced for both drugs (up to 65 times the dissolution rates for the crystalline forms) and supersaturation release of celecoxib was also demonstrated. Citric acid was used to enhance the stability of the ACC nanoparticles within the aggregates, which increased the surface area of the material to over 600 m2g-1. This porous ACC has potential for use in various applications where surface area is important, including adsorption, catalysis, medication, and bone regeneration.

Introduction Calcium carbonate (CaCO3) is an essential biomineral in a number of organisms. Perhaps one of the most notable examples is its integration into shells and bones. The compound is an important part of the carbon cycle and has a number of industrial applications in, for example, building materials, plastics, paper fillers, and dietary supplements. Recent research has also explored the application of CaCO3 in tooth pastes,1 bone cement,2 drug delivery,3-6 cancer therapy,7 and protein adsorption.8-9 There are several polymorphs of CaCO3; the most common are the three crystalline forms calcite, aragonite and vaterite (in order of decreasing thermodynamic stability).10 Amorphous


Page 2 of 33

Page 3 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CaCO3 (often referred to as ACC) also exists. There has been significant research into the synthesis and characterization of ACC because of its vital role in biomineralization.11 The potential application of ACC in the biomimetic synthesis of functional materials has also been explored.12-14 Powdered ACC is made from the aggregation of individual ACC particles on a nm scale.15 The presence of nanoparticles means that ACC has a certain level of porosity. In fact, ACC has the highest specific surface area of the different polymorphs of CaCO3. As a result ACC exhibits outstanding performance where surface area is vital such as adsorption 9 and drug delivery.16-17 ACCs with a surface area between 100 and 200 m2g-1 have been independently reported by Cai et al.18 and Gebauer et al.19 Calcite with a surface area of ~130 m2g-1 has been synthesized by Zhao et al.20 The stability of ACC is poor compared with that of the crystalline forms. Crystallization can occur via solid-state transformation,21-22 but has also been observed to proceed via dissolutionrecrystallization.23-25 The water content of ACC has a crucial effect on its stability.26-28 The method of synthesis, and especially the solvent used, plays a vital role in the stability of pure ACC. ACC prepared with organic solvents, for example isopropanol or ethanol, is more stable under ambient conditions.29-30 ACC particles synthesized in organic solvents tend to be smaller than those obtained from aqueous solution. In addition, additives (e.g. magnesium ions, phosphate ions, polymers, or highly carboxylated species) can markedly increase the stability of ACC.31-34 In a typical synthesis of ACC, the ACC suspension in the reaction mixture obtained from aqueous solution is quenched in an organic solvent (e.g. ethanol, isopropanol or acetone) as part of the drying step.23, 30, 35 The organic solvent is used to isolate ACC from the water and to retard crystallization. Rapid freezing can also isolate ACC from a reaction mixture; Ihli et al.28 prepared


3


Page 4 of 33

dried pure ACC by quenching a saturated CaCO3 colloidal suspension in liquid nitrogen (N2) followed by sublimation of the solvent under vacuum. The fast freezing and sublimation steps removed water from the reaction mixture quickly and prevented crystallization of the ACC. Temperature and pressure also have an effect on the crystallization of ACC. ACC crystallizes into a more thermodynamically stable form (i.e. calcite) when heated to ~300 °C.36 High pressure can induce crystallization of ACC to a more stable form (vaterite or calcite), a process that depends on the water content of the ACC.37 In this study, we developed a reproducible, robust method of producing a stable, highly mesoporous ACC from CaO and CO2 using methanol as the solvent. The one-pot, facile synthesis method detailed in this study does not require any additives or surfactants and can easily be scaled up for low-cost industrial production. The resulting ACC has, to our knowledge, the highest specific surface area and mesoporosity reported for CaCO3. The synthesized ACC was comprehensively characterized using various techniques. The ability of this highly porous ACC (referred to as “porous ACC” in this study) to stabilize the amorphous state of poorly soluble drugs and enhance their dissolution rates was investigated. The effect of adding citric acid during synthesis on the stability of this highly porous ACC (referred to as “ACC-CA” in this study) was also investigated. The investigated ACC, with its high porosity and surface area, has potential for new applications for CaCO3 and may also improve performance in many of the existing applications where surface interactions are important. Experimental Methods Materials: Calcium oxide (CaO, 96-100.5%) and citric acid (>99.5%) were purchased from Sigma-Aldrich. Methanol (99.9% HPLC grade) and ethanol absolute (99.96%) were obtained from VWR International, Sweden. Crystalline celecoxib (CEL) was purchased from 3Way


4

Page 5 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Pharm Inc., P. R. China, and crystalline itraconazole (ITZ) was purchased from 3 Pharmaceutica, P. R. China. All chemicals were used as received. Synthesis of porous ACC: ACC was synthesized under methanolic conditions with CaO as precursor. In a typical synthesis, 1.25 g of CaO was dispersed in 75 mL of methanol under stirring in a 354 mL Lab-Crest® glass reaction vessel (Andrew Glass Company, Vineland, USA). When the mixture appeared to be homogeneous, the vessel was sealed and a CO2 pressure of 4 bar was fed into it. The reaction mixture was then left for 4 hours at 50 °C under stirring at 500 rpm. After 4 hours, the pressurized CO2 was released from the reaction vessel and the reaction mixture was centrifuged at 3800 rpm for 15 min to remove the small amount of unreacted CaO. An almost transparent ACC colloidal suspension in methanol was acquired after centrifugation. This colloidal suspension was rapidly heated to 150 °C in a ventilated oven. Highly porous ACC powder was obtained after 4 hours. The effect of the addition of water in the synthesis and stability of porous ACC is discussed in the Supporting Information (Figure S1-2). Synthesis of ACC stabilized with citric acid (ACC-CA): ACC-CA was synthesized using similar procedures to those described above. A mixture containing 1.25 g of CaO dispersed in 75 mL methanol was sealed in a 354 mL Lab-Crest® glass reaction vessel (Andrew Glass Company, Vineland, USA) under stirring and CO2 pressure of 4 bar was applied. After 4 hours, 0.75 g of citric acid was added to the reaction mixture which was subsequently re-pressurized with 4 bar of CO2 for one additional hour under stirring. The reaction mixture was then recovered, centrifuged, and dried using the same procedures as for the synthesis of porous ACC detailed above. Characterization: Detailed characterization procedures are given in the Supporting Information; a summary is given here. The porosities of porous ACC, ACC-CA and drug-loaded porous ACC


5


Page 6 of 33

were studied using N2 gas sorption in a Micromeritics ASAP 2020 (Norcross, GA, USA) volumetric gas sorption analyser. Helium (He) pycnometry was carried out using a Micromeritics ACCuPyc II 1340 pycnometer (Norcross, GA, USA) with a 1 cm3 cell. Dynamic light scattering (DLS) was carried out with Malvern Zetasizer Nano ZS (Malvern, UK) at room temperature. Infrared (IR) spectra, including in situ IR spectra, were recorded by a Varian 670IR spectrometer (Santa Clara, USA). Powder X-ray diffraction (PXRD) measurements were carried out in a Bruker D8 advance XRD Twin-Twin instrument (Bruker, Bremen, Germany) with Cu-Kα radiation (λ=1.5418 Å). Large angle X-ray scattering (LAXS) experiments were carried out using a custom-made large-angle Ɵ-Ɵ goniometer with Mo-Kα radiation (λ=0.71073 Å) (described elsewhere38). Scanning electron microscopy (SEM) images were recorded using a Zeiss LEO 1530 scanning electron microscope (Oberkochen, Germany). The samples were coated with a layer of gold-palladium to avoid the charge built up effect. Transmission electron microscopy (TEM) and Scanning TEM (STEM) measurements were carried out at room temperature using a JEOL JEM-2100 microscope (Tokyo, Japan) equipped with a Schottky fieldemission gun and operated at 200 kV. Thermogravimetric analysis (TGA) of the samples was carried out using a Mettler Toledo TGA2 (Schwerzenbach, Switzerland). The TGA curves were recorded in the temperature range 25 - 900 °C in air at a heating rate of 10 °C min-1. Differential scanning calorimetry (DSC) experiments were performed on a TA Instruments Q-2000 DSC instrument (New Castle, USA) at a heating rate of 5 °C min-1 from -35 to 200 °C. Drug loading and in vitro release test: CEL and ITZ were loaded (10 and 20 wt. %, respectively) into the pores of porous ACC by solvent evaporation. The in vitro release tests were carried out using a Sotax AT7 dissolution bath (Aesch, Switzerland) according to the USP II (paddles) method. ACC-CEL samples were analyzed in 1 L 0.05 M phosphate buffer (pH=6.8) while


6

Page 7 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ACC-ITZ samples were analyzed in 1 L of simulated gastric fluid without enzymes (pH=1.2) (supplied by Reagecon). UV/Vis absorbance of the released drug molecules was monitored using a Shimadzu UV-1800 spectrophotometer (Kyoto, Japan) with a photometric method. UV/Vis absorption at 253.8 nm and 250.5 nm was recorded for CEL and ITZ, respectively.39 A more detailed description of the drug loading and release experiments is given in the Supporting Information. Results and Discussion Synthesis and characterization of porous ACC ACC nanoparticles were prepared from the CaO precursor in CO2 pressurized methanol. The process was facilitated by the high solubility of CO2 in methanol. Methanol as a solvent can also retard the crystallization rate of ACC.40 Nanoparticles of ACC that were formed during the synthesis were dispersed in the reaction mixture. An almost transparent colloidal suspension was obtained after the unreacted CaO particles were separated by centrifugation. Tyndall scattering confirmed the presence of nanoparticles in the colloidal suspension (Figure S3). The average particle size determined by DLS in the colloidal suspension was around 12 nm and 15 nm, evaluated by number of particles and by volume (Figure S4). Porous ACC was obtained by rapid drying of the ACC colloidal suspension at 150 °C until a dried powder sample was obtained. Samples dried at a lower temperature (from room temperature up to 150 °C) were highly unstable. These samples first appeared as a dry powder, but “melted” into a white liquid during storage. We believe this process was related to the increased levels of adsorbed water (discussed in the Supporting Information) in the samples dried below 150 °C, as we expect methanol content of these samples to be negligible due to its low boiling point. The “melting” phenomenon was assumed to be the release of the structural water molecules from the ACC nanoparticles


7


during crystallization to a more thermodynamically stable form. In contrast, when the ACC colloidal suspension was dried at temperatures above 150 °C, crystalline CaCO3 polymorphs

-1

a)

Quantity Adsorbed (mmol g )

formed (Figure S5). 25 20 15 10 5 0 0.0

0.2

0.4

0.6

0.8

1.0

Relative Pressure (P/P0) -1

b)

dV/dlog(W) Pore Volume (cm³ g )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 33

4 3 2 1 0 0

10

20 30 Pore Size (nm)

40

50

Figure 1. a) N2 adsorption/desorption isotherm and b) pore size distributions of porous ACC. The N2 adsorption/desorption isotherm of porous ACC dried at 150 °C is shown in Figure 1. The Brunauer–Emmett–Teller (BET) surface area of the material was ~360 m2g-1 and the pore volume was ~0.86 cm3g-1. This porous ACC has, to the best of our knowledge, the highest N2 specific surface area of all CaCO3 forms reported in the literature (see Table S1 for a comparison with current and previous literature).18-19, 41-42 The pore size distribution (PSD) of porous ACC shown in Figure 1b was calculated using density function theory (assuming slit pore geometry). The PSD was relatively narrow, with an average pore size around 8 - 9 nm. SEM images of porous ACC, displayed in Figure 2a and b, clearly show that the material was constructed from


8

Page 9 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the aggregation of spherical nanoparticles. These nanoparticles appeared to be up to ~20 nm in diameter (with a layer of gold-palladium coating). TEM (Figure 2c and d) and STEM images (Figure S6) revealed that the porosity of the porous ACC arose from the spaces between aggregated nanoparticles that were < 10 nm in diameter. The < 10 nm particles were randomly arranged and had no easily distinguishable shapes, they appeared only to be aggregated, and not fused together (deduced from the significant porosity observed between the particles from the STEM images in Figure S6). Similar morphologies have been observed in ACC samples studied by others.25, 40 The size of the nanoparticles was estimated from the BET specific surface area and a sample density of 2.40 g cm-3 (obtained by He pycnometry), which showed that the ACC nanoparticles in the material had an estimated average diameter of ~ 7.3 nm (the particles were assumed to be spherical particles that are not fused together, with all of the particle surface preserved and accessible). The estimated average nanoparticle diameter was in good agreement with the size of the nanoparticles observed with TEM (Figure 2c and d) and STEM images (Figure S6). DLS also showed (Figure S4) the presence of comparably sized (peak at ~10 nm) nanoparticles in the colloidal suspension before drying. The average pore size of the material (~8 - 9 nm) was also similar to the estimated particle diameter. As all of the employed characterization techniques pointed to the presence of nm sized nanoparticles, we confidently believe that the porous ACC material in this study was constructed from nanoparticle agglomerates with an average nanoparticle diameter of < 10 nm. The high pore volume of porous ACC was from the void space between these particles. The high specific surface area recorded for porous ACC using N2 adsorption was the result of two main properties of porous ACC. Firstly, these aggregated particles were not physically fused together and the surfaces of the sub 10 nm nanoparticle remained accessible by N2 gas molecules in the agglomerates. Secondly, the


9


Page 10 of 33

ability to synthesize stable ACC particles agglomerates with an average particle size of less than 10 nm was essential for producing porous ACC with high specific surface area. Gebauer et al.19 reported a porous ACC with specific surface area of 142 m2 g-1. The specific surface area noted on their ACC sample also came from the surfaces of the aggregated nanoparticles, but the dimension of these particles were noticeably larger than 10 nm (around 20-50 nm in diameter, as shown by SEM). The effect of the larger nanoparticle size was also reflected in the larger average pore size of their sample when compared with porous ACC in this study. The synthesis methodology, morphology and porosity of various calcium carbonate reported in literature is listed in Table S1 for comparison.

Figure 2. a, b) SEM and c, d) TEM images of porous ACC. The insert in c) ED pattern taken from within the red circle. The amorphous structure of the porous ACC was demonstrated by the lack of diffraction peaks in the PXRD pattern (Figure 3a). Electron Diffraction (ED) further confirmed the lack of crystallinity in the sample, as only diffuse diffraction rings were observed (Figure 2c insert).


10

Page 11 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Despite the lack of X-ray crystallinity, Gebauer et al.35 showed that ACC can have a protocrystalline structure with a short-range order that resembles the crystalline polymorphs. We therefore investigated the structure of porous ACC using LAXS. LAXS is an outstanding method for determining the structure of liquids and amorphous solids. The scattering pattern of the assynthesized sample showed no diffraction peaks, which confirmed the amorphous structure of the porous ACC (Figure 3b). However, during the two-week period of the whole LAXS measurement, several diffraction peaks appeared in the pattern. These peaks were identified as being related to vaterite (Figure 3b and Supporting Information). The experimental and calculated LAXS radial distribution function (RDF) and reduced intensity functions are shown in Figure 4a and b, the interatomic distances for the porous ACC are listed in Table S2. The average Ca – O bond distance was found to be 2.52 Å, indicating that the coordination number of Ca in porous ACC was probably eight, with no crystalline long-range orders. Any signs of local order disappear above 8 Å. The other interatomic distances were also very different from either the corresponding values for vaterite (either shorter, longer or missing) or for the other polymorphs (see Supporting Information Table S3-4 for a list of atomic distances and structural information published in the literature). It was concluded that the structure of the porous ACC was different from any of the crystalline polymorphs of CaCO3, and cannot be described with any proto-crystalline structures. The IR spectrum of porous ACC is displayed in Figures 5 and S7; it shows the characteristic IR bands of ACC without the distinctive ν4 band that is typically observed for the crystalline forms of CaCO3 (calcite at 712 cm-1, vaterite at 744 cm-135). Instead, two low intensity, overlapping ν4 bands were observed at 697 cm-1 and 723 cm-1, which is typical for ACC. Other observable bands were the ν1 band at 1074 cm-1, the ν2 band at around 858 cm-1 and the (most intense) ν3 band at around 1400 cm-1. The positions of the bands were slightly


11


different from those shown by Gebauer et al.35 for proto-vaterite ACC (pv-ACC) and protocalcite ACC (pc-ACC). We therefore conclude that although short-range local order was observed for porous ACC using LAXS, porous ACC does not resemble pv-ACC or pc-ACC. The broad band in the region 2750 - 3800 cm-1 was related to structural and adsorbed water on ACC. It should be noted that no bands related to methanol were observed.30

Intensity(a. u.)

a)

20

30

40

50

60

70

2θ (°)

b) After two weeks

Intensity (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 33

As-synthesized

8

12

16

20

θ (°)

Figure 3. a) PXRD pattern for porous ACC and b) part of the LAXS pattern for an assynthesized sample and the same sample after two weeks of LAXS measurements under environmental condition. Note that the noise in the data of the as-synthesized sample is due to the short accumulation time (see experimental details in the Supporting Information).


12

Page 13 of 33

a)

Ca-O

Ca-Ca

Ca-C

Ca-O

Ca-Ca

Ca-O

1

C-O

2

2

-1

D(r)-4π r ρ0(e ⋅ Å )

2

Ca-O Ca-Ca

Caculated Experimental Difference

3

0 -1 0

b)

2

4 r (Å)

6

8

Calculated Experimental

200 100

-1

s⋅i(s)(e⋅u⋅Å )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0 -100 -200 0

4

8

12

16

-1

s (Å )

Figure 4. a) The calculated, experimental and difference (experimental-calculated) large-angle X-ray scattering radial distribution functions and b) the reduced intensity functions for porous ACC. Note that the misfit at low angles in the reduced intensity function was caused by not including distances longer than 8 Å, which are related to the small angle region, in the model. The TGA curve of porous ACC is shown in Figure 6. Two broad endothermic peaks were observed at ~100 °C and ~146 °C in the DSC porous ACC data (Figure S8). These peaks corresponded to physisorbed and structural water, respectively. The mass drop observed in the TGA curve below 100 °C was related to adsorbed (physisorbed) water (3.19 wt. %) whereas the mass drop between 100 and 300 °C was related to strongly bound (chemisorbed) or structural water (5.94 wt. %). In addition to the mass drops associated with water, a mass drop above 600 °C, which was related to the decomposition of CaCO3 to CaO, was also observed in the TGA


13


curve. The magnitude of this mass drop indicated that the porous ACC obtained in this study was over 99 wt. % CaCO3 with a CaO content of less than 0.80 wt. % (detailed in Supporting Information).

ν3

1392 cm

Adsorbance (a.u.)

1469 cm

-1

-1

ν2 ν4

1074 cm

1600

1200

723 cm -1 697 cm

-1

-1

-1

858 cm

ν1

2000

800

-1

ν (cm )

Figure 5. IR spectrum of porous ACC at room temperature.

100 H2O 90.87%

Weight (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 33

80 CO2

60 51.23%

40

200

400

600

800

Temperature (°C)

Figure 6. TGA curve for porous ACC. Both ACC studied by others and the porous ACC in this study transformed to more stable crystalline forms when heated. The in situ IR spectra of porous ACC heated from 25 to 500 °C


14

Page 15 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(Figure S9) demonstrated this behavior. When the temperature reached ~400 °C (under N2 atmosphere), porous ACC crystallized into calcite. The development of a sharp ν4 band at 709 cm-1 and the shift of the ν2 band from 856 to 870 cm-1 confirmed the transformation from porous ACC to calcite. The PXRD pattern of porous ACC heated to 400 °C (Figure S10) also showed that calcite was the dominant resultant phase. Stability of porous ACC ACC is typically known to be relatively unstable and crystallizes readily into vaterite and then calcite. heating.

43-46

Crystallization of ACC can also occur over time when it is stored, even without

25, 43

Crystallization is triggered by the adsorption of water (partial dissolution /

recrystallization), or by the release of structural water (dehydration). Porous ACC was observed to be stable for 3 weeks under semi-air-tight conditions with no change in BET surface area (Figure 7), as well as no evidence of crystallization from the PXRD pattern. Porous ACC appeared to be more stable than typical ACC studied by others. 43-46 The enhanced stability may be related to the low water content of porous ACC. The low water content of porous ACC was related to the synthesis conditions, in which methanol was used as a solvent with no additional water. The total amount of water in the porous ACC was 0.56 mol/mol CaCO3, of which 0.37 mol/mol CaCO3 was strongly bound/structural water (calculated from TGA, Figure 6). The water content in porous ACC was lower than that in the ACCs studied by Gebauer et al. (1 mol/mol CaCO3 in a water/ethanol system)30, Levi-Kalisman et al. (1 mol/mol CaCO3)47 and Ihli et al. (0.7 mol/mol CaCO3 in aqueous solution, freeze dried).28 The low water content on porous ACC could mean that the amount of adsorbed water required to trigger partial dissolution / recrystallization was increased when compared with ACC with a higher water content.

25

Furthermore, ACC with low water content has an increased activation energy for further


15


dehydration before transferring to the anhydrous crystalline form.

Page 16 of 33

26-27

Both of these hypothesis

could explain the high storage stability of porous ACC observed in this study. Kababya et al.48 demonstrated that low water content on similar, but phosphate stabilized ACC system, could “indefinitely stability” stabilize ACC. Although our system was not stabilized by phosphate, the effect of low water content may have enhanced the stability of porous ACC. The low water content may also be the reason for the lack of proto-structure observed in porous ACC, as Farhadi-Khouzani et al. showed that the water content is essential in rendering the protostructure of ACC.49 When porous ACC was stored in semi-air-tight conditions for 3-4 weeks, the BET surface area of the material was reduced to about 35% of the original value and it was down to less than 10% after 6 weeks. The PXRD pattern (Figure S11a) showed that porous ACC began to crystallize to vaterite after 3 weeks, and the more stable calcite phase was also observed after 6 weeks. The existence of vaterite and then calcite after 3 and 6 weeks was also in agreement with the crystallization pathways observed for ACC.43 The appearance of vaterite and then calcite corresponded to the two observed drops in BET surface area (Figure 7). The sharp ν4 band on the IR spectrum (Figure S12) centered at 713 cm-1 and the weak band at 744 cm-1 further confirmed that both calcite and vaterite existed in the final material. LAXS studies showed that porous ACC began to crystallize into vaterite after ~2 weeks under ambient conditions (see Figure 3b for comparison of the spectra for the as-synthesized sample with the same sample after two weeks of the LAXS experiment). Figure 7 also shows the changes in BET surface area for two other samples of porous ACC that had been exposed to different levels of water: i) ACC plus 4 mmol g-1 of water vapor in a N2 atmosphere (referred to as: ACC_4M_H2O) and ii) ACC stored at 100% relative humidity


16

Page 17 of 33

(referred to as ACC_100PC_H2O). The amount of water for the first sample was chosen according to Konard et al., who showed that ~ 4 mmol g-1 of physisorbed water would destabilize ACC (with a water content of 0.42 mol H2O/mol CaCO3) and facilitate its crystallization.25 The overall water content of the porous ACC samples in our study (0.56 mol H2O/mol CaCO3, plus ~4 mmol g-1 water) was slightly higher than that of the ACCs in Konard’s study; the higher water content ensured the destabilization of porous ACC and induced crystallization. According to Figure 7, the BET surface area declined more rapidly with time for porous ACC exposed to water than for porous ACC stored under semi-air-tight conditions. In both cases, calcite was the resulting phase, as identified by PXRD and IR spectroscopy (Figures S11b and S12). Relative surface area (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


100

Semi-air-tight ACC_4M_H2O ACC_100PC_H2O

80 60 40 20 0 -1

0

1

2

3

4

5

6

7

8

Time (week)

Figure 7. Changes in the BET surface area of porous ACC with time, under different storage conditions. From the PXRD, IR spectra and SEM analyses, it was clear that the decrease in BET surface area in porous ACC was related to the increased particle size that is partly due to crystallization. SEM images of the porous ACC samples after completion of the measurements described in Figure 7 are shown in Figure S13. Particles ranging from more than 100 nm to a few µm were observed,


17


Page 18 of 33

with some particle showing morphologies typically to crystalline CaCO3. We believe these particles had grown/ crystallized from the original ACC nanoparticles with an estimated size of ~ 7.3 nm. The largest particles were seen in the ACC_100PC_H2O sample. The morphology of the individual particles of ACC_100PC_H2O was very similar to that of typical calcite crystal particles. ACC stabilized with citric acid In an attempt to synthesize ACC with high porosity and a long shelf-life, we introduced citric acid into the reaction mixture during ACC synthesis. The obtained ACC-CA was reproducible and had a BET specific surface area over 600 m2 g-1 (Figure S14). The SEM and STEM images (Figure S15) of ACC-CA show that the material has similar morphology to porous ACC. According to the recorded BET surface area and density (2.20 g cm-3) recorded by He pycnometry, these nanoparticles were estimated to be around 4.6 nm (estimated using the same method and assumptions as for porous ACC), smaller for ACC-CA than for porous ACC (~ 7.3 nm). STEM images (Figure S15 e-h) were able to show that the nanoparticles that made up an agglomerates in ACC-CA were distinctively smaller (around 3-5 nm) than those in the agglomerates of porous ACC (up to 10 nm). IR spectrum of ACC-CA shown in Figure S16 displays the characteristic bands of porous ACC. A shoulder band around 1568 cm-1 was also observed, and could be attributed to the C=O stretching vibration of the carboxyl group. This C=O stretching band of the carboxyl group shifted from ~1743 cm-1 and ~1695 cm-1 to ~1568 cm-1, which demonstrated the interaction between carboxylate group of citric acid and the calcium ions in porous ACC. 50 ACC-CA was amorphous according to ED (Figure S15c), PXRD (Figure S17), and LAXS analyses (Figure S18a). LAXS data suggested that the local structure of ACC-CA is similar to that of porous ACC (see Figure S18 and Table S2). It was difficult to


18

Page 19 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


determine if there was any kind of Ca2+ - citrate ion coordination, as the calculated Ca-C distance for citrate ion coordination was 3.40 Å, quite similar to the Ca-C distance of CaCO3. It was therefore, not possible to determine whether the C atom came from the carbonate ions or citrate ion using LAXS, hence we refrain from drawing any firm conclusions regarding the possible citrate ion coordination to Ca2+. It was, however, clear that citrate ions to the Ca2+ ion could stabilized the possibly 8-coordinated, amorphous state of CaCO3 found in porous ACC (by restricting the transformation to the 6- or 8-coordinated crystalline states). As a result of the stabilization by citric acid, the PXRD pattern of ACC-CA showed no crystallinity even after 4 months' storage in a semi-air-tight container. However, a drop in the BET surface area (of 17% after 4 months) was still noted. Although ACC-CA appeared to be more stable than porous ACC and showed a higher surface area, the chemistry of the ACC-CA in this study is still relatively unclear to us. Additional work, such as further optimization on the synthesis of ACC-CA, biocompatibility and toxicity studies, and the investigation on coordination around the Ca2+ ion would be required before the material could be develop for application, especially for bioapplications. We therefore, focus the rest of this study on porous ACC (note that CaCO3 is already Food and Drug Administration (FDA) approved for food use and is generally recognizes as safe – GRAS). Porous ACC used as drug carrier The biocompatibility of CaCO3 allows for several applications of the material in life sciencerelated areas. In particular, the highly porous ACC form of CaCO3 is a very interesting material in applications such as drug delivery. Porous ACC was thus evaluated as a drug carrier of poorly soluble drugs. Two poorly soluble drugs (celecoxib, CEL, acidic39 and itraconazole, ITZ, basic),51 were loaded into the pores of porous ACC by solvent evaporation. The successful


19


Page 20 of 33

loading of the drugs was confirmed by PXRD, DSC and N2 sorption measurements. No crystalline peaks were observed in the PXRD pattern (Figure S19) for the drug-loaded samples. DSC curves (the lack of sharp exothermic peaks; Figure S20) also showed that the drugs were stable in their amorphous forms. The content of ITZ and CEL calculated from TGA curves (Figure S21 and Table S5) were 25.78 wt. % and 14.49 wt. %, respectively. The ITZ loading content was comparable with previous studies on mesoporous silica (30 wt.%) mesoporous magnesium carbonate (~30 wt.%)

53

52

and

. The CEL loading content on porous ACC

appeared to be higher than that for mesoporous magnesium carbonate (~5.6 wt.%) 39 and calcium carbonate (~4 wt. %).54 Note that we did not vary the drug loading level of ITZ and CEL on porous ACC. Thus, the maximum drug loading level of ITZ and CEL on porous ACC is not clearly known to us at this stage.

The very high residue porosity noted (Figure S22) on the drug loaded porous ACC samples suggested that the drug molecules resided inside the pore system of porous ACC, and not as a “coat” on the surface of the bulk material – ACC agglomerate. A complete loss of measureable porosity would be expected if the drug molecules had coated the ACC agglomerates and blocked gas molecules from entering the pores. On ACC-ITZ and ACC-CEL, the decrease in pore volume due to drug loading (when compared with porous ACC) corresponded well to the volume of the loaded drug (detailed calculation in Supporting Information, Table S6). This confirmed that the drug molecules were inside the pores of porous ACC agglomerates. It is important to note that no clear change in pore size was noted for ACC-ITZ when compared with porous ACC (Figure S22). In contrast, the pore volume of the large pores decreased noticeably for ACC-CEL (noted by the PSD shown in Figure S22). These observations suggested that the drug molecules


20

Page 21 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


were not stabilized as layers on the surface of the ACC nanoparticles within the agglomerate, but rather in the middle of the pores of porous ACC. The drug molecules in the pores could be described as “pore blocking” (three of the possible mechanisms for drug loading are illustrated in Figure S23). The pores were too small for the drug molecules to recrystallize into their crystalline forms and therefore, no crystallinity related to the loaded drugs was detected by PXRD or DSC. It was also interesting to note that for ACC-CEL, only the large pores were blocked by the drug molecules, but on ACC-ITZ, the pore volume decreased for all pore sizes. This difference could be attributed to the different amounts of drug loaded into ACC-CEL and ACC-ITZ. The lower drug loading amount on ACC-CEL (14.49 wt. %) than on ACC-ITZ (25.78 wt. %) could explain why the small pores on ACC-CEL remained unaffected by drug loading. The large pores on ACC-CEL had enough capacity to host all of the loaded drug molecules, whereas in ACC-ITZ, the drug hosting capacity of the small pores was also utilized due to the high amount of ITZ loading. For both ACC-ITZ and ACC-CEL, the residue porosity of ACCITZ and ACC-CEL were still high, most probably because a blocked pore from one direction could still be accessible from another direction (See Figure S23).

The time-resolved release of ITZ and CEL from ACC-ITZ and ACC-CEL, respectively, is shown in Figure 8. The ACC drug carrier was expected to promptly crystallize in water or be dissolved in acid, triggering the release of the loaded drug molecules. During the first 30 minutes, the release of ITZ from ACC-ITZ in simulated gastric fluid (pH=1.2) was enhanced 65fold compared with the dissolution of pure crystalline ITZ under the same conditions.57-58 The drug was fully released from ACC-ITZ within 50 minutes (as compared to ~20% dissolution of crystalline ITZ after 50 minutes). Furthermore, ITZ was released from ACC-ITZ faster than from


21


Page 22 of 33

the previously reported mesoporous magnesium carbonate (23-fold enhancement within the first 30 min).53 The fast release of ITZ may in part be the result of the low pH environment of the simulated gastric fluid. The low pH allowed the porous ACC carrier to dissolve rapidly. Rapid release of CEL from ACC-CEL was also observed in phosphate buffer (pH=6.8). The release of CEL from ACC-CEL was 29-fold faster than the dissolution of the pure crystalline CEL during the first 30 minutes. After 90 minutes, over 90% of the loaded CEL had been released from ACC-CEL (compared to ~13% dissolved from pure crystalline CEL). The rapid drug release when compared with the crystalline drug was partly related to the CEL molecules being stabilize in its amorphous form in ACC-CEL. Poorly soluble drug molecules stabilized in their amorphous forms are known to dissolute more rapidly than the crystalline forms. We further studied the supersaturation release of CEL from ACC-CEL by increasing the dosage (Figure S24a). Under these circumstances, there was a burst release of CEL from ACC-CEL in the first 2 hours. The concentration of CEL then started to decrease because the solubility limit of CEL prompted its recrystallization in the buffer solution. It should be emphasized that the long term concentration of CEL in the buffer solution depended on the amount of CEL in the ACC-CEL. The concentration of CEL decreased to ~2.5 mg L-1 after 23 hours (the solubility of CEL was 2.3 mg L-1, see Supporting Information). However, the CEL concentration in a buffer solution containing the same dose of pure crystalline CEL was just 1.48 mg L-1 even after 29 hours. The release rate of CEL from ACC-CEL and from ACC-CEL under supersaturation conditions and the dissolution rate of pure crystalline CEL are shown for comparison in Figure S24b. In summary, highly porous ACC released ITZ and CEL much more rapidly than the dissolution rates of the crystalline drugs. Supersaturation release was achieved with high dose of drug loaded ACC.


22

Page 23 of 33

Release Percentage (%)

a)

100 80 60

ACC-ITZ standard release Pure crystalline ITZ

40 20 0 0

1

2

3

4

5

Time (hour)

b) Release Percentage (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


100 80 ACC-CEL standard release Pure crystalline CEL

60 40 20 0 0

1

2 3 Time (hour)

4

5

Figure 8. a) Release rate of ITZ from ACC-ITZ compared with the dissolution rate of pure crystalline ITZ in simulated gastric fluid without enzymes (pH=1.2) and b) release rate of CEL from ACC-CEL and the dissolution rate of pure crystalline CEL in 0.05 M phosphate buffer (pH=6.8). Data are displayed as average concentrations with error bars representing standard deviations (n=3). Conclusions In conclusion, highly porous ACC was synthesized in a one-pot process without any additives or surfactants. This CaCO3 material, to our best knowledge, has the highest specific surface area (~360 m2g-1) yet reported for CaCO3. The porous ACC was constructed from aggregates of individual ACC nanoparticles with an estimated average particle diameter of ~7.3 nm. The synthesized ACC was amorphous, with a low water content (0.56 mol H2O per mol CaCO3). The porous ACC remained stable in a semi-air-tight container for 3 weeks without losing its porosity.


23


Page 24 of 33

The incorporation of citric acid further stabilized the ACC nanoparticles and produced porous ACC with a BET surface area over 600 m2g-1 that was stable for at least 4 months. In vitro dissolution tests suggested that this porous ACC (with a suitable enteric coating) could be a promising drug carrier for both basic and acidic poorly soluble drugs. Rapid release of loaded drugs was triggered by the crystallization of ACC (in water), or the dissolution of the ACC (in acid). This highly porous ACC has the potential to be further developed to fit applications such as aiding protein adsorption, gas adsorption, remediation of pollutants, cancer therapy and bone filling/regeneration etc.

ASSOCIATED CONTENT Supporting Information. Detailed description of the synthesis, characterization procedures, the additional data and discussion of LAXS analysis, as well as drug loading and release are available in the Supporting Information free of charge. AUTHOR INFORMATION Corresponding Author *[email protected], *[email protected] Author Contributions † These authors contributed equally Funding Sources The Swedish Research Council is acknowledged for financial support (grant # 2014-3929). R. Sun and P. Zhang thank the China Scholarship Council (CSC) for financial support. The Knut and Alice Wallenberg (KAW) Foundation is acknowledged for funding for the


24

Page 25 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


electron microscopy facilities at Stockholm University and financial support for A.N. and C.W.T. under the project 3DEM- NATUR. ABBRIVATION ACC- Amorphous Calcium Carbonate, BET - Brunauer–Emmett–Teller, CEL – Celecoxib, DLS - Dynamic Light Scattering, DSC – Differential Scanning Calorimetry, ED – Electron Diffraction, IR – Infrared, ITZ – Itraconazole, LAXS – Large Angle X-ray Scattering, PSD – Pore size distribution, PXRD – Powder X-ray diffraction, RDF – Radial Distribution Function, SEM – Scanning Electron Microscopy, TEM – Transmission Electron Microscopy, TGA – Thermogravimetric Analysis

REFERENCES 1.

Lynch, R.; Cate, J. t., The Anti-Caries Efficacy of Calcium Carbonate-Based Fluoride

Toothpastes. Int. Dent. J. 2005, 55, 175-178. 2.

Domb, A. J.; Manor, N.; Elmalak, O., Biodegradable Bone Cement Compositions Based

on Acrylate and Epoxide Terminated Poly (Propylene Fumarate) Oligomers and Calcium Salt Compositions. Biomaterials 1996, 17, 411-417. 3.

Wei, W.; Ma, G.-H.; Hu, G.; Yu, D.; McLeish, T.; Su, Z.-G.; Shen, Z.-Y., Preparation of

Hierarchical Hollow CaCO3 Particles and the Application as Anticancer Drug Carrier. J. Am. Chem. Soc. 2008, 130, 15808-15810. 4.

Parakhonskiy, B. V.; Haase, A.; Antolini, R., Sub-Micrometer Vaterite Containers:

Synthesis, Substance Loading, and Release. Angew. Chem. Int. Ed. 2012, 51, 1195-1197.


25


5.

Page 26 of 33

Zhang, J.; Li, Y.; Xie, H.; Su, B.-L.; Yao, B.; Yin, Y.; Li, S.; Chen, F.; Fu, Z., Calcium

Carbonate Nanoplate Assemblies with Directed High-Energy Facets: Additive-Free Synthesis, High Drug Loading, and Sustainable Releasing. ACS Appl. Mater. Interfaces 2015, 7, 1568615691. 6.

Begum, G.; Reddy, T. N.; Kumar, K. P.; Dhevendar, K.; Singh, S.; Amarnath, M.; Misra,

S.; Rangari, V. K.; Rana, R. K., In Situ Strategy to Encapsulate Antibiotics in a Bioinspired CaCO3 Structure Enabling pH-Sensitive Drug Release APT for Therapeutic and Imaging Applications. ACS Appl. Mater. Interfaces 2016, 8, 22056-22063. 7.

Som, A.; Raliya, R.; Tian, L.; Akers, W.; Ippolito, J. E.; Singamaneni, S.; Biswas, P.;

Achilefu, S., Monodispersed Calcium Carbonate Nanoparticles Modulate Local pH and Inhibit Tumor Growth in Vivo. Nanoscale 2016, 8, 12639-12647. 8.

Qi, C.; Zhu, Y.-J.; Chen, F., Microwave Hydrothermal Transformation of Amorphous

Calcium Carbonate Nanospheres and Application in Protein Adsorption. ACS Appl. Mater. Interfaces 2014, 6, 4310-4320. 9.

Qi, C.; Zhu, Y. J.; Lu, B. Q.; Zhao, X. Y.; Zhao, J.; Chen, F.; Wu, J., ATP-Stabilized

Amorphous Calcium Carbonate Nanospheres and Their Application in Protein Adsorption. Small 2014, 10, 2047-2056. 10.

Inorganic Crystal Structure Database , National Institute of Standards and Technology

and Fiz Karlsruhe. Inorganic Crystal Structure Database , National Institute of Standards and Technology and FIZ Karlsruhe, : Germany,, 2017. 11.

Gower, L. B., Biomimetic Model Systems for Investigating the Amorphous Precursor

Pathway and Its Role in Biomineralization. Chem. Rev. 2008, 108, 4551-4627.


26

Page 27 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


12.

Kim, S.; Park, C. B., Bio-Inspired Synthesis of Minerals for Energy, Environment, and

Medicinal Applications. Adv. Funct. Mater. 2013, 23, 10-25. 13.

Sun, S.; Mao, L. B.; Lei, Z.; Yu, S. H.; Cölfen, H., Hydrogels from Amorphous Calcium

Carbonate and Polyacrylic Acid: Bio-Inspired Materials for “Mineral Plastics”. Angew. Chem. Int. Ed. 2016, 55, 11765-11769. 14.

Farhadi-Khouzani, M.; Schütz, C.; Durak, G. M.; Fornell, J.; Sort, J.; Salazar-Alvarez,

G.; Bergström, L.; Gebauer, D., A CaCO3/Nanocellulose-Based Bioinspired Nacre-Like Material. J. Mat. Chem. A 2017. 5, 16128-16133 15.

Michel, F. M.; MacDonald, J.; Feng, J.; Phillips, B. L.; Ehm, L.; Tarabrella, C.; Parise, J.

B.; Reeder, R. J., Structural Characteristics of Synthetic Amorphous Calcium Carbonate. Chem. Mater. 2008, 20, 4720-4728. 16.

Zhao, Y.; Luo, Z.; Li, M.; Qu, Q.; Ma, X.; Yu, S. H.; Zhao, Y., A Preloaded Amorphous

Calcium Carbonate/Doxorubicin@ Silica Nanoreactor for pH-Responsive Delivery of an Anticancer Drug. Angew. Chem. Int. Ed. 2015, 54, 919-922. 17.

Wang, C.; Chen, S.; Yu, Q.; Hu, F.; Yuan, H., Taking Advantage of the Disadvantage:

Employing the High Aqueous Instability of Amorphous Calcium Carbonate to Realize Burst Drug Release within Cancer Cells. J. Mat. Chem. B 2017, 5, 2068-2073. 18.

Cai, G.-B.; Zhao, G.-X.; Wang, X.-K.; Yu, S.-H., Synthesis of Polyacrylic Acid Stabilized

Amorphous Calcium Carbonate Nanoparticles and Their Application for Removal of Toxic Heavy Metal Ions in Water. J. Phys. Chem. C 2010, 114, 12948-12954. 19.

Gebauer, D.; Liu, X.; Aziz, B.; Hedin, N.; Zhao, Z., Porous Tablets of Crystalline

Calcium Carbonate via Sintering of Amorphous Nanoparticles. CrystEngComm 2013, 15, 12571263.


27


20.

Page 28 of 33

Zhao, Z.; Zhang, L.; Dai, H.; Du, Y.; Meng, X.; Zhang, R.; Liu, Y.; Deng, J., Surfactant-

Assisted Solvo-or Hydrothermal Fabrication and Characterization of High-Surface-Area Porous Calcium Carbonate with Multiple Morphologies. Microporous Mesoporous Mater. 2011, 138, 191-199. 21.

Singer, J. W.; Yazaydin, A. Ö.; Kirkpatrick, R. J.; Bowers, G. M., Structure and

Transformation of Amorphous Calcium Carbonate: A Solid-State 43Ca NMR and Computational Molecular Dynamics Investigation. Chem. Mater. 2012, 24, 1828-1836. 22.

Walker, J. M.; Marzec, B.; Nudelman, F., Solid-State Transformation of Amorphous

Calcium Carbonate to Aragonite Captured by Cryotem. Angew. Chem. Int. Ed. 2017, 56, 1174011743. 23.

Rodriguez-Blanco, J. D.; Shaw, S.; Benning, L. G., The Kinetics and Mechanisms of

Amorphous Calcium Carbonate (ACC) Crystallization to Calcite, Via Vaterite. Nanoscale 2011, 3, 265-271. 24.

Bots, P.; Benning, L. G.; Rodriguez-Blanco, J.-D.; Roncal-Herrero, T.; Shaw, S.,

Mechanistic Insights into the Crystallization of Amorphous Calcium Carbonate (ACC). Cryst. Grow. Des. 2012, 12, 3806-3814. 25.

Konrad, F.; Gallien, F.; Gerard, D. E.; Dietzel, M., Transformation of Amorphous

Calcium Carbonate in Air. Cryst. Grow. Des. 2016, 16, 6310-6317. 26.

Saharay, M.; Yazaydin, A. O.; Kirkpatrick, R. J., Dehydration-Induced Amorphous

Phases of Calcium Carbonate. J. Phys. Chem. B 2013, 117, 3328-3336. 27.

Ihli, J.; Wong, W. C.; Noel, E. H.; Kim, Y.-Y.; Kulak, A. N.; Christenson, H. K.; Duer, M.

J.; Meldrum, F. C., Dehydration and Crystallization of Amorphous Calcium Carbonate in Solution and in Air. Nat. Comm. 2014, 5, 3169.


28

Page 29 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


28.

Ihli, J.; Kulak, A. N.; Meldrum, F. C., Freeze-Drying Yields Stable and Pure Amorphous

Calcium Carbonate (ACC). Chem. Comm. 2013, 49, 3134-3136. 29.

Chen, S.-F.; Cölfen, H.; Antonietti, M.; Yu, S.-H., Ethanol Assisted Synthesis of Pure and

Stable Amorphous Calcium Carbonate Nanoparticles. Chem. Comm. 2013, 49, 9564-9566. 30.

Khouzani, M. F.; Chevrier, D. M.; Güttlein, P.; Hauser, K.; Zhang, P.; Hedin, N.; Gebauer,

D., Disordered Amorphous Calcium Carbonate from Direct Precipitation. CrystEngComm 2015, 17, 4842-4849. 31.

Loste, E.; Wilson, R. M.; Seshadri, R.; Meldrum, F. C., The Role of Magnesium in

Stabilising Amorphous Calcium Carbonate and Controlling Calcite Morphologies. J. Cryst. Growth 2003, 254, 206-218. 32.

Ihli, J.; Kim, Y. Y.; Noel, E. H.; Meldrum, F. C., The Effect of Additives on Amorphous

Calcium Carbonate (ACC): Janus Behavior in Solution and the Solid State. Adv. Funct. Mater. 2013, 23, 1575-1585. 33.

Tobler, D. J.; Rodriguez-Blanco, J. D.; Dideriksen, K.; Bovet, N.; Sand, K. K.; Stipp, S.

L., Citrate Effects on Amorphous Calcium Carbonate (ACC) Structure, Stability, and Crystallization. Adv. Funct. Mater. 2015, 25, 3081-3090. 34.

Xu, A. W.; Yu, Q.; Dong, W. F.; Antonietti, M.; Cölfen, H., Stable Amorphous CaCO3

Microparticles with Hollow Spherical Superstructures Stabilized by Phytic Acid. Adv. Mater. 2005, 17, 2217-2221. 35.

Gebauer, D.; Gunawidjaja, P. N.; Ko, J.; Bacsik, Z.; Aziz, B.; Liu, L.; Hu, Y.; Bergström,

L.; Tai, C. W.; Sham, T. K.; Edén, M.; Hedin, N., Proto-Calcite and Proto-Vaterite in Amorphous Calcium Carbonates. Angew. Chem. 2010, 122, 9073-9075.


29


36.

Page 30 of 33

Zou, Z.; Bertinetti, L.; Politi, Y.; Jensen, A. C.; Weiner, S.; Addadi, L.; Fratzl, P.;

Habraken, W. J., Opposite Particle Size Effect on Amorphous Calcium Carbonate Crystallization in Water and During Heating in Air. Chem. Mater. 2015, 27, 4237-4246. 37.

Yoshino, T.; Maruyama, K.; Kagi, H.; Nara, M.; Kim, J. C., Pressure-Induced

Crystallization from Amorphous Calcium Carbonate. Cryst. Grow. Des. 2012, 12, 3357-3361. 38.

Stålhandske, C. M. V.; Persson, I.; Sandström, M.; Kamienska-Piotrowicz, E., Structure

of the Solvated Zinc (II), Cadmium (II), and Mercury (II) Ions in N, N-Dimethylthioformamide Solution. Inorg. Chem. 1997, 36, 3174-3182. 39.

Zhang, P.; de la Torre, T. Z. G.; Welch, K.; Bergström, C.; Strømme, M., Supersaturation

of Poorly Soluble Drugs Induced by Mesoporous Magnesium Carbonate. Eur. J. Pharm. Sci. 2016, 93, 468-474. 40.

Lei, Z.; Sun, S.; Wu, P., Ultrafast, Scale-up Synthesis of Pure and Stable Amorphous

Carbonate Mineral Nanoparticles. ACS Sus. Chem. Eng. 2017, 5, 4499-4504. 41.

Radha, A.; Forbes, T. Z.; Killian, C. E.; Gilbert, P.; Navrotsky, A., Transformation and

Crystallization Energetics of Synthetic and Biogenic Amorphous Calcium Carbonate. Proc. Natl. Acad. Sci. USA 2010, 107, 16438-16443. 42.

Johnson, M. L.; Noreland, D.; Gane, P.; Schoelkopf, J.; Ridgway, C.; Fureby, A. M.,

Porous Calcium Carbonate as a Carrier Material to Increase the Dissolution Rate of Poorly Soluble Flavouring Compounds. Food Funct. 2017, 8, 1627-1640. 43.

Rodriguez-Blanco, J. D.; Shaw, S.; Benning, L. G., The Kinetics and Mechanisms of

Amorphous Calcium Carbonate (ACC) Crystallization to Calcite, Viavaterite. Nanoscale 2011, 3, 265-271.


30

Page 31 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


44.

Pouget, E. M.; Bomans, P. H. H.; Goos, J. A. C. M.; Frederik, P. M.; de With, G.;

Sommerdijk, N. A. J. M., The Initial Stages of Template-Controlled CaCO3 Formation Revealed by Cryo-TEM. Science 2009, 323, 1455-1458. 45.

Pontoni, D.; Bolze, J.; Dingenouts, N.; Narayanan, T.; Ballauff, M., Crystallization of

Calcium Carbonate Observed in-Situ by Combined Small- and Wide-Angle X-Ray Scattering. J. Phys. Chem. B 2003, 107, 5123-5125. 46.

Sawada, K., The Mechanisms of Crystallization and Transformation of Calcium

Carbonates. In Pure Appl. Chem., 1997; Vol. 69, p 921. 47.

Levi-Kalisman, Y.; Raz, S.; Weiner, S.; Addadi, L.; Sagi, I., Structural Differences

between Biogenic Amorphous Calcium Carbonate Phases Using X-Ray Absorption Spectroscopy. Adv. Funct. Mater. 2002, 12, 43-48. 48.

Kababya, S.; Gal, A.; Kahil, K.; Weiner, S.; Addadi, L.; Schmidt, A., Phosphate–Water

Interplay Tunes Amorphous Calcium Carbonate Metastability: Spontaneous Phase Separation and Crystallization Vs Stabilization Viewed by Solid State Nmr. J. Am. Chem. Soc. 2015, 137, 990-998. 49.

Farhadi-Khouzani, M.; Chevrier Daniel, M.; Zhang, P.; Hedin, N.; Gebauer, D., Water as

the Key to Proto-Aragonite Amorphous CaCO3. Angew. Chem., Int. Ed. 2016, 55, 8117-8120. 50.

Sun, S.; Gebauer, D.; Cölfen, H., A Solvothermal Method for Synthesizing Monolayer

Protected Amorphous Calcium Carbonate Clusters. Chem. Comm. 2016, 52, 7036-7038. 51.

Six, K.; Daems, T.; de Hoon, J.; Van Hecken, A.; Depre, M.; Bouche, M.-P.; Prinsen, P.;

Verreck, G.; Peeters, J.; Brewster, M. E., Clinical Study of Solid Dispersions of Itraconazole Prepared by Hot-Stage Extrusion. Eur. J. Pharm. Sci. 2005, 24, 179-186.


31


52.

Page 32 of 33

Kinnari, P.; Mäkilä, E.; Heikkilä, T.; Salonen, J.; Hirvonen, J.; Santos, H. A., Comparison

of Mesoporous Silicon and Non-Ordered Mesoporous Silica Materials as Drug Carriers for Itraconazole. Int. J. Pharm. 2011, 414, 148-156. 53.

Cheung, O.; Zhang, P.; Frykstrand, S.; Zheng, H.; Yang, T.; Sommariva, M.; Zou, X.;

Strømme, M., Nanostructure and Pore Size Control of Template-Free Synthesised Mesoporous Magnesium Carbonate. RSC Adv. 2016, 6, 74241-74249. 54.

Forsgren, J.; Andersson, M.; Nilsson, P.; Mihranyan, A., Mesoporous Calcium Carbonate

as a Phase Stabilizer of Amorphous Celecoxib–an Approach to Increase the Bioavailability of Poorly Soluble Pharmaceutical Substances. Advanced healthcare materials 2013, 2, 1469-1476. 55.

Mellaerts, R.; Aerts, C. A.; Van Humbeeck, J.; Augustijns, P.; Van den Mooter, G.;

Martens, J. A., Enhanced Release of Itraconazole from Ordered Mesoporous SBA-15 Silica Materials. Chem. Comm. 2007, 1375-1377. 56.

Mellaerts, R.; Mols, R.; Jammaer, J. A.; Aerts, C. A.; Annaert, P.; Van Humbeeck, J.; Van

den Mooter, G.; Augustijns, P.; Martens, J. A., Increasing the Oral Bioavailability of the Poorly Water Soluble Drug Itraconazole with Ordered Mesoporous Silica. Euro. J. Pharm. Biopharm. 2008, 69, 223-230. 57.

Zhang, P.; Forsgren, J.; Strømme, M., Stabilisation of Amorphous Ibuprofen in Upsalite,

a Mesoporous Magnesium Carbonate, as an Approach to Increasing the Aqueous Solubility of Poorly Soluble Drugs. Int. J. Pharm. 2014, 472, 185-191. 58.

Zhang, P.; Gómez De La Torre, T. Z.; Forsgren, J.; Bergström, C. A. S.; Strømme, M.,

Diffusion-Controlled Drug Release from the Mesoporous Magnesium Carbonate Upsalite®. J. Pharm. Sci. 2016, 105, 657.


32

Page 33 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Graphical Abstract 85x47mm (300 x 300 DPI)


Amorphous Calcium Carbonate Constructed from Nanoparticle

Recommend Documents