Spike particles, surface-porous spike particles, chromatography separation device, and method for forming spike particles

Abstract

Spiked particles are disclosed, including a core and a plurality of spikes attached to and extending from the core surface. The core may be non-porous, superficially porous, or porous. The plurality of spikes may be non-porous or superficially porous. Superficially porous spiked particles are disclosed, including a porous spiked particle shell disposed on a non-porous spiked particle. A method for forming spiked particles is disclosed, including mixing a dispersed aqueous phase having a plurality of core particles, a water emulsion droplet stabilizer, and a catalyst with a continuous oil phase having an organic solvent, polyvinylpyrrolidone, and a silane precursor to form a water-in-oil emulsion system, and reacting the mixture without stirring to form a plurality of chromatographic spiked particles. A chromatographic separation device is disclosed, including spiked particles randomly packed within the chromatographic separation device and having an external porosity ranging from about 0.4 to about 0.9.

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 992,598, entitled "Chromatographic Spike Particles, Methods for Forming Chromatographic Spike Particles, and Separation Devices Having Chromatographic Spike Particles", filed on March 20, 2020, which is hereby incorporated by reference in its entirety.

[0002]

[0002] This application is directed to chromatographic spike particles, chromatographic separation devices, and methods for forming chromatographic spike particles. In particular, this application is directed to chromatographic spike particles, chromatographic superficially porous spike particles, chromatographic separation devices incorporating chromatographic spike particles and / or chromatographic superficially porous spike particles, and methods for forming chromatographic spike particles and chromatographic superficially porous spike particles.

Background Art

[0003]

[0003] The packing materials of separation devices exemplified by chromatographic columns are generally classified into two types: spherical particles and monoliths. Both spherical particles and monoliths may be organic materials or inorganic materials (represented by silica). However, silica particles (more specifically, porous and superficially porous particles) are by far the most widely used packing materials.

[0004]

[0004] In chromatography columns, separation efficiency and column permeability are two of the most important factors determining their performance. Separation efficiency is an indicator of peak dispersion. Although not bound by theory, structural uniformity (especially radial structure), smaller through-pores, and smaller particle size, or monolithic skeletons, are believed to enhance separation efficiency. High separation efficiency results in a narrow peak width, enabling the separation of more peaks within a given analysis time, so high separation efficiency is desirable. Column permeability is inversely proportional to flow resistance and is also related to the size of the through-pores. Flow resistance depends strongly on the external porosity of the packed bed and is proportional up to the fifth power. "External porosity" refers to the proportion of the volume not occupied by solid components (either spherical particles or monoliths). Higher external porosity and larger through-pore size improve column permeability. The backpressure of the column is inversely proportional to column permeability. Higher column permeability is desirable as it results in lower backpressure and shorter analysis time. There are many other advantages to low backpressure in chromatography columns, including, among others, less energy required to push the fluid through the bed, lower capital investment costs, easier instrument operation, lower instrument maintenance costs, less demand for the mechanical rigidity of the packing material, and longer packed bed life.

[0005]

[0005] In columns packed with spherical particles, the particle size (d p ) controls both column efficiency and permeability. Therefore, since the birth of high-performance liquid chromatography (HPLC) over 50 years ago, the particle diameter has been continuously decreasing to improve column separation efficiency and speed up separation. On the other hand, since column permeability is proportional to d p 2 , the backpressure of the column is inversely proportional to d p 2 . This means that if the column size is kept the same and the particle size is changed from 5 μm to 1 μm, the efficiency doubles while the backpressure increases 25-fold. Currently, state-of-the-art UHPLC instruments can handle up to 1.5×10 8Columns packed with particles down to 1.5 μm can be operated at relatively high flow rates without exceeding the pressure limit, provided that a pressure of 1,500 bar is available. Moreover, high backpressure can generate excessive frictional heat, which can change the properties of the fluid and the analyte, and can have various adverse effects on separation efficiency, selectivity, retention, and reproducibility (Gritti et al., Anal. Chem., 81 (2009), 3365-3384). Thus, columns packed with particles below 1 μm, which would otherwise be expected to further improve column efficiency, are not suitable for use with state-of-the-art UHPLC equipment.

[0006] Unlike columns filled with spherical particles, where the external porosity is typically fixed at about 0.4, columns filled with monoliths may be stable even when the external porosity increases up to about 0.9. Therefore, monolith-based columns have much lower flow resistance than spherical particle-based columns, and thus higher column permeability and lower backpressure. Furthermore, the size of the through channels (which partially determines the column permeability) and the size of the solid skeleton of the monolith-based column (which partially determines the column efficiency) can be adjusted individually. Therefore, in principle, monolith-based columns can provide a better combination of column performance, offering higher efficiency and higher permeability. However, although promising in other respects, monolith-based columns suffer from inherent radial structural inhomogeneities, resulting in low column efficiency (Hlushkou et al., J. Chromatogr. A, 1303 (2013), 28 - 38). It has also been found that the structural inhomogeneity increases as the size of the through pores and the skeleton decreases (Broeckhoven and Desmet, Anal. Chem., 93 (2021), 257 - 272). Therefore, it is difficult to further improve the separation efficiency of monolith-based columns at the current level, and their separation efficiency is lower than that of columns filled with porous particles of 2 μm or less and superficially porous particles of 2 μm or less and 3 μm or less. Other drawbacks of monolith-based columns include the following. (1) Surface modification needs to be manufactured individually for each column (a major concern regarding cost and product reproducibility). (2) The column separation mode and dimensions are very limited. (3) The maximum operating pressure is very low, 4×10 7 Pascals (400 bar) (usually 2×10 7It is less than 200 bar (Pascal). Therefore, monolithic-based columns are only commercially competitive in the niche capillary column market and have not been able to fully utilize their potential in the high-speed separation column market so far. The high-speed separation column market is dominated by columns packed with porous spherical particles with a diameter of less than 2 μm and superficially porous spherical particles with diameters of less than 2 μm and less than 3 μm (the technologies of porous spherical particles and superficially porous spherical particles are still evolving).

[0007]

[0007] As suggested by the above description, current packing materials have several drawbacks. The separation efficiency of columns packed with spherical particles seems to have reached or almost reached its limit because the permeability of smaller spherical particles is low. Columns packed with particles smaller than 1.5 μm cannot be operated at high flow rates and / or optimal speeds under current state-of-the-art UHPLC devices. Recent research has shown that the potential velocity gain (related to efficiency) to operating pressures of 1,500 bar (Pascal) to 3,000 bar (Pascal) is relatively small. Moreover, there are many problems associated with such high pressures, such as frictional heat, mechanical stability of the packing, reliable instrument hardware (pumps, injectors, detectors) and column hardware, and instrument hardware design (to reduce extra-column band dispersion) (Broeckhoven and Desmet, Anal. Chem., 92 (2020), 554 - 560). On the other hand, monolithic-based columns have high permeability, but this advantage is mitigated because the backpressure during operation is low (usually 200 bar (Pascal) in analytical columns). More importantly, it is difficult to further improve the efficiency due to fundamental limitations including the non-uniformity of the radial structure and the increased fluctuations of through-holes and solid skeletons when these functions are miniaturized. Another limitation is that high efficiency and high permeability are essentially incompatible, which exists in both spherical particle-based columns and monolithic-based columns (Broeckhoven and Desmet, Anal. Chem., 93 (2021), 257 - 272). 8 Pascal (1,500 bar) to 3×10 8 Pascal (3,000 bar). Moreover, there are many problems associated with such high pressures, such as frictional heat, mechanical stability of the packing, reliable instrument hardware (pumps, injectors, detectors) and column hardware, and instrument hardware design (to reduce extra-column band dispersion) (Broeckhoven and Desmet, Anal. Chem., 92 (2020), 554 - 560). On the other hand, monolithic-based columns have high permeability, but this advantage is mitigated because the backpressure during operation is low (usually 2×10 7 Pascal (200 bar). More importantly, it is difficult to further improve the efficiency due to fundamental limitations including the non-uniformity of the radial structure and the increased fluctuations of through-holes and solid skeletons when these functions are miniaturized. Another limitation is that high efficiency and high permeability are essentially incompatible, which exists in both spherical particle-based columns and monolithic-based columns (Broeckhoven and Desmet, Anal. Chem., 93 (2021), 257 - 272).

[0008]

[0008] Therefore, it is desirable to develop an alternative packing material having a better compromise between column separation efficiency and permeability that can overcome the above problems.

[0009] Datskos et al. first reported the preparation of spike particles in a water-in-oil emulsion system under basic conditions (Datskos et al., Angew. Chem. Int. Ed., 54 (2015), 9011-9015). They demonstrated that rod-shaped spikes could be formed on hydrophilic spherical core particles such as silica and titania. Subsequently, spikes were formed under similar conditions on substrates having different compositions and shapes (Kim et al., J. Am. Chem. Soc., 140 (2018), 9230-9235; Li et al., Angew. Chem., 130 (2018), 383-3838; Zhao et al., Scientific Reports, 9 (2019), 8591).

[0009]

[0010] One drawback of Datskos' method was that sodium ions were inevitably present in the spikes because sodium citrate was used to stabilize the water emulsion droplets. It is well known that trace metal ion impurities in chromatographic silica particles (so-called type A silica) increase the acidity of the surface silanols, resulting in changes in retention time, band broadening and tailing, and a decrease in the sample recovery rate of basic compounds and biomolecules (Nawrocki and Buszewski, J. Chromatogr., 449 (1988), 1-24; U.S. Patent No. 5,256,386). Furthermore, chromatographic silica particles often include one or more calcination or sintering steps to remove organic additives to enhance mechanical stability, regardless of the method used for their preparation. For use in UHPLC columns, 1.5×10 8It may be necessary to sinter the silica particles at about 950 °C to have sufficient mechanical stability under filling pressures often exceeding 1,500 bar (Pascal). However, silica particles with a sufficiently high sodium ion content cannot be sintered at such high temperatures because of their low melting point. Therefore, type A silica is not considered a suitable material for chromatographic packing (Majors, LC GC North America, 33(2015), 818 - 840). Another drawback of Datskos' method was that only non-porous spike particles were considered.

Summary of the Invention

[0010]

[0011] In an exemplary embodiment, the spike particles include a core having an average core width and a core surface, and a plurality of spikes attached to the core surface. The plurality of spikes extend from the core surface by an average spike length and have an average spike width measured perpendicular to the average spike length. The spike particles are chromatographic particles having 100 ppm or less of sodium ions. The core includes a porosity selected from the group consisting of non-porous, surface-porous, porous, and combinations thereof. The plurality of spikes includes a porosity selected from the group consisting of non-porous, surface-porous, and combinations thereof.

[0011]

[0012] In another exemplary embodiment, the surface-porous spike particles include a core having an average core width and a core surface, the core is non-porous, a plurality of spikes are attached to the core surface, the plurality of spikes are non-porous, extend from the core surface by an average spike length, and have an average spike width measured perpendicular to the average spike length, and a porous spike particle shell is disposed on the core and the plurality of spikes. The spike particles are chromatographic particles having 100 ppm or less of sodium ions.

[0012]

[0013] In another exemplary embodiment, the chromatography separation device includes a plurality of spike particles. Each of the plurality of spike particles includes a core having an average core width and a core surface, and a plurality of spikes attached to the core surface, the plurality of spikes extending from the core surface by an average spike length and having an average spike width measured perpendicular to the average spike length. Each of the plurality of spike particles is a chromatography particle. The core includes a porosity selected from the group consisting of non-porous, surface porous, porous, and combinations thereof. The plurality of spikes includes a porosity selected from the group consisting of non-porous, surface porous, and combinations thereof. The plurality of spike particles are randomly packed within the chromatography separation device. The randomly packed plurality of spike particles have an external porosity in the range of about 0.4 to about 0.9. The chromatography separation device has an increased fluid permeability compared to a comparative chromatography separation device having a plurality of spherical particles that are identical in other respects but lack the plurality of spikes instead of the plurality of spike particles.

[0013]

[0014] In another exemplary embodiment, a method for forming a plurality of spike particles includes mixing a continuous oil phase and a dispersed water phase to form a water-in-oil emulsion system. The continuous oil phase includes an organic solvent, polyvinylpyrrolidone, and a silane precursor. The dispersed water phase includes a plurality of core particles, a water emulsion drop stabilizer, and a catalyst. Reacting the water-in-oil emulsion system without stirring to form a plurality of spike particles, and separating the plurality of spike particles from the water-in-oil emulsion system. Each of the plurality of spike particles includes a core having an average core width and a core surface, and a plurality of spikes attached to the core surface, the plurality of spikes extending from the core surface by an average spike length and having an average spike width measured perpendicular to the average spike length.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]

Figure 1

[0015] FIG. is a schematic diagram of an exemplary embodiment of spike particles according to an embodiment of the present disclosure.

Figure 2

[0016] FIG. showing SEM images of various spike particles illustrating the control of spike length, number, and width according to an embodiment of the present disclosure.

Figure 3(a)

[0017] Schematic diagram of spike particles having a non-porous core and non-porous spikes according to an embodiment of the present disclosure.

Figure 3(b)

[0018] Schematic diagram of spike particles having a surface-porous core and non-porous spikes according to an embodiment of the present disclosure. The surface-porous core has a non-porous central region and a porous shell having randomly oriented pores thereon.

Figure 3(c)

[0019] Schematic diagram of spike particles having a surface-porous core and non-porous spikes according to an embodiment of the present disclosure. The surface-porous core has a non-porous central region and a porous shell having radially oriented pores thereon.

Figure 3(d)

[0020] Schematic diagram of spike particles having a porous core with randomly oriented pores and non-porous spikes according to an embodiment of the present disclosure.

Figure 3(e)

[0021] Schematic diagram of surface-porous spike particles having radially oriented pores according to an embodiment of the present disclosure.

Figure 3(f)

[0022] Schematic diagram of surface-porous spike particles having randomly oriented pores according to an embodiment of the present disclosure.

Figure 4

[0023] FIG. showing SEM images of spike particles prepared according to the methods of Examples 1-4 according to an embodiment of the present disclosure. The scale bar is 5 μm and applies to all images.

Figure 5

[0024] Schematic diagram of randomly packed spherical particles according to an embodiment of the prior art.

Figure 6(a)

[0025] Schematic diagram of randomly packed spike particles having a spike length of approximately one-third of the core width, according to an embodiment of the present disclosure.

Figure 6(b)

[0026] Schematic diagram of randomly packed spike particles having a spike length approximately equal to the core width, according to an embodiment of the present disclosure.

Figure 7

[0027] Figure showing column backpressure vs. flow rate data obtained with a column (2.1×50 mm) filled with spike particles prepared according to the method of Example 5, compared with spherical particles having a width equal to the average core width of the spike particles, along with the SEM image of the spike particles.

Figure 8

[0028] Figure comparing chromatographic data obtained with a column filled with spike particles prepared according to the method of Example 6, compared with columns filled with porous spherical particles of 3 μm width and 5 μm width. Panel A is backpressure vs. mobile phase flow rate, and panel B is height equivalent to a theoretical plate vs. mobile phase velocity. Panel C is the SEM image of the spike particles.

[0015]

[0029] Wherever possible, the same reference numerals will be used throughout the drawings to represent the same components.

DETAILED DESCRIPTION OF THE INVENTION

[0016]

[0030] This specification discloses chromatographic spike particles, a chromatographic separation device, and a method for forming chromatographic spike particles. The spike particles have an inner core particle and a plurality of outer rod-shaped spikes, and these outer rod-shaped spikes are attached to the surface of the inner core particle. There are several advantages to using spike particles as a packing material. Column permeability is inversely proportional to flow resistance, and flow resistance strongly depends on external porosity and is proportional up to the fifth power. In a column filled with spherical particles, each spherical particle needs to contact a certain number of other spherical particles to form a stable packed bed, and their external porosity, which is a value independent of particle size, usually approaches 0.4. As the external porosity increases, the defects increase proportionally, the bed becomes unstable, and the column efficiency significantly decreases (Schure and Maier, J. Chromatogr. A, 1126 (2006), 58 - 69). In contrast, the extended outer spikes of the spike particles provide more paths for contacting each other, including spike-spike, spike-core, and core-core. Due to spike-spike and spike-core contacts, the core particles are kept separated, and the external porosity of the packed bed increases. Furthermore, each spike can contact a plurality of other spikes, and each spike particle has a plurality of spikes. Therefore, the average number of contacts of each spike particle in a column filled with spike particles can be much higher than that in a column filled with spherical particles. With an increase in the number of contacts, the packed bed can maintain a stable state even when the external porosity exceeds 0.4. Therefore, since the column filled with spike particles has a high external porosity, it has a lower flow resistance and a higher column permeability than a column filled with spherical particles.

[0017]

[0031] The number and / or length of the spikes of the spike particles can be easily adjusted. This provides a convenient method for adjusting the external porosity of the packed bed by simply changing the number and / or length of the spikes, with or without changing the core size. Generally, the larger the number of spikes and / or the longer the length of the spikes, the higher the external porosity and the higher the bed permeability.

[0018]

[0032] Therefore, a column filled with spike particles has a higher external porosity than a column filled with spherical particles. Furthermore, the external porosity of the filled spike particles can be adjusted, while the external porosity of the spherical particles is fixed at about 0.4. The spike particles and the monolith are similar with respect to these properties. However, unlike the monolith's skeleton, spike particles rarely aggregate into large chunks. Even if aggregates are formed, they can be separated by known methods. Furthermore, since the slurry method used for filling spherical particles is compatible with spike particles, it is possible to avoid the radial structural inhomogeneities present in monolith-based columns. Therefore, spike particles overcome the disadvantages of the low permeability of spherical particles and the low efficiency of monoliths. It may be possible to develop a column filled with spike particles having a core of 1 μm or less, which has better efficiency than a column filled with spherical particles of 2 μm or less, so that it can be continuously operated with current UHPLC equipment. Similarly, it may be possible to develop a column filled with spike particles having a core of 2 μm or less, which has similar efficiency compared to a column filled with spherical particles of 2 μm or less, so that it can be continuously operated with current HPLC equipment.

[0019]

[0033] A further advantage of spike particles is that the use of spike particles may somewhat alleviate the fundamental trade-off between column efficiency and permeability exhibited by both spherical particle-based columns and monolith-based columns. Columns with high external porosity (high permeability) have large through-pores. Although not bound by theory, large through-pores are thought to induce mass transfer in large moving zones and eddy dispersion, essentially reducing column efficiency. There are several differences in the through-pores of columns filled with spike particles compared to those of columns filled with spherical particles or monoliths. First, the contact variations of spike particles change the shape of the through-pores. However, it is not clear how this affects the efficiency and permeability of the column. Second, in columns filled with spike particles, the through-pores coexist with a specific number of spikes within the same flow domain. Long spikes can even pass through more than one through-pore. The presence of spikes in the through-pores can effectively reduce large through-pores into several small through-pores, potentially reducing the diffusion distance of the analyte's moving zone. These spikes can cause radial mixing and may reduce the diffusion of the analyte within the through-pores. Thus, even when the external porosity of a column filled with spike particles is relatively high (high permeability), the characteristic dimensions of the solid zones (core and spikes) and the moving zone (effective through-pores) may be relatively small. Therefore, columns filled with spike particles may have a relatively looser relationship between efficiency and permeability compared to columns filled with spherical particles or monoliths.

[0020]

[0034] Accordingly, the present invention provides spike particles comprising an inner core particle and a plurality of outer spikes attached to the surface of the inner core particle. The present invention also provides spike particles that can be used as a new packing material to substantially increase and easily adjust the flow permeability of a separation device exemplified by a chromatography column. The present invention also provides an improved method for producing thermally and mechanically stable spike particles that do not contain metal ions.

[0021]

[0035] Another aspect of the present invention is to provide a separation device having a stationary phase comprising a plurality of spike particles described herein, the separation device having improved and easily adjustable device permeability.

[0022]

[0036] Another aspect of the present invention is to provide a chromatography column having a stationary phase comprising a plurality of spike particles described herein, the chromatography column having improved and easily adjustable device permeability.

[0023]

[0037] A further aspect of the present invention provides a method of making thermally and mechanically stable spike particles free of metal ions in a water-in-oil emulsion system under basic conditions, subsequently separating the spike particles from the emulsion mixture, and calcining the spike particles up to 850 °C to remove organic residual materials. Additional process steps may include one or more of the following steps: coating the spike particles with a porous layer; sintering them up to 950 °C to increase mechanical rigidity; rehydrolyzing them to maximize the number of Si-OH groups on their surface; and modifying them to have a functional surface.

[0024]

[0038] As used herein, "about" represents a deviation of up to 10% of the value so modified, and includes absolute values in particular so as to disclose both a range of 1.8 to 2.2 and 2 for "about 2".

[0025]

[0039] Referring generally to FIGS. 1-4, in one embodiment, the spike particle 100 includes a core 102 and a plurality of spikes 104. The spike particle 100 is a chromatography particle. The core 102 has an average core width 106 and a core surface 108. The plurality of spikes 104 are attached to the core surface 108 and extend from the core surface 108 by an average spike length 110. The plurality of spikes have an average spike width 112 measured perpendicular to the average spike length 110. The core 102 may be non-porous, surface-porous, porous, or a combination thereof. The plurality of spikes 104 may be non-porous, surface-porous, or a combination thereof.

[0026]

[0040] In the case of the core 102 being spherical or an ellipsoid of revolution, the "average core width" 106 is synonymous with the core diameter, but in the case of the core 102 having a structure other than spherical or an ellipsoid of revolution, the "average core width" 106 is the average of all widths measured from the surfaces facing the core 102. In the case of the spike 104 having a circular cross-section orthogonal to the average spike length 110, the "average spike width" 112 is synonymous with the spike diameter averaged along the average spike length 110, but in the case of the spike 104 having a cross-section other than circular orthogonal to the average spike length 110, the "average spike width" 112 is the average of all widths measured from the opposing surfaces of the spike 104 along the average spike length 110.

[0027]

[0041] As used herein, "non-porous" refers to the absence of porosity in a material that permits only accidental defects in the structure that do not affect the properties of the material, "porous" refers to the presence of a continuous porous structure, although the porosity, the size of pores 200, and the distribution of pores 200 need not be uniform, and "surface-porous" refers to the presence of a porous shell 206 or a porous spike particle shell 502 surrounding a non-porous article such as, but not limited to, a non-porous central region 204 or non-porous spike particles 100. The pores 200 may be radially oriented or randomly oriented. Exemplary non-porous, surface-porous, or porous particles that can be used as core particles 102 are described in U.S. Patent No. 4,775,520, U.S. Patent Application Publication No. 2007 / 0189944A1, and U.S. Patent No. 5,256,386, respectively, the contents of which are incorporated herein by reference in their entirety. The core particles 102 can include two or more compositions, shapes, and porosities depending on their particular use. Exemplary particles having two or more compositions or porosities that can be used as core particles 102 are described in U.S. Patent No. 8,778,453 and U.S. Patent No. 10,434,496, respectively, the contents of which are incorporated herein by reference in their entirety.

[0028]

[0042] All combinations of core 102 that are non-porous, surface-porous, porous, or combinations thereof, a plurality of spikes 104 that are non-porous, surface-porous, or combinations thereof, and pores 200 that are radially oriented or randomly oriented are specifically included within the scope of this embodiment. By way of non-limiting example, in one embodiment, the core 102 is surface-porous and includes a non-porous central region 204 surrounded by a porous shell 206 having randomly oriented pores 200. In another embodiment, the core 102 is surface-porous and includes a non-porous central region 204 surrounded by a porous shell 206 having radially oriented pores 200.

[0029]

[0043] Exemplary porous shell 206 having a random pore orientation, a radial pore orientation, and a combination of a radial pore orientation and a random pore orientation that can be used as the core particles of the present invention is described in U.S. Patent Application Publication No. 2007 / 0189944, U.S. Patent No. 8,685,283, and U.S. Patent Application No. 2020 / 0338528, respectively, the contents of which are incorporated herein by reference in their entirety. The porous shell 206 may be formed from any suitable material including, but not limited to, silica, hybrid silica, alumina, titania, zirconia, or combinations thereof.

[0030]

[0044] In embodiments where the core 102, the plurality of spikes 104, or both are surface porous, the porous shell 206 can have any suitable shell thickness 208 including, but not limited to, a shell thickness 208 of about 1 nm to about 2 μm, or about 5 nm to about 2 μm, or about 5 nm to about 100 nm, or about 50 nm to about 500 nm, or about 250 nm to about 750 nm, or about 500 nm to about 1 μm, or about 750 nm to about 1.25 μm, or about 1 μm to about 1.5 μm, or about 1.25 μm to about 1.75 μm, or about 1.5 μm to about 2 μm, or any sub-range or combination thereof. The porous shell 206 can constitute any suitable volume of the core 102 (when the core 102 is surface porous) or the spikes 104 (when the spikes 104 are surface porous) that constitutes, but is not limited to, about 10% to about 90% by volume, or about 5% to about 70% by volume, or about 20% to about 70% by volume, or about 30% to about 60% by volume, or about 5% to about 15% by volume, or about 10% to about 20% by volume, or about 15% to about 25% by volume, or about 20% to about 30% by volume, or about 25% to about 35% by volume, or about 30% to about 40% by volume, or about 35% to about 45% by volume, or about 40% to about 50% by volume, or about 45% to about 55% by volume, or about 50% to about 60% by volume, or about 55% to about 65% by volume, or about 60% to about 70% by volume, or any sub-range or combination thereof.

[0031]

[0045] Each core 102 can have any suitable number of spikes 104, including but not limited to at least two, or at least three, or at least four, or at least four, or from 2 to 50, or from 1 to 100, or from 2 to 10, or from 5 to 15, or from 10 to 20, or from 15 to 25, or from 20 to 30, or from 25 to 35, or from 30 to 40, or from 35 to 45, or from 40 to 50, or any sub-range or combination thereof.

[0032]

[0046] The plurality of spikes 104 can have any suitable average spike length 110 (measured along the spike 104), including but not limited to from about 20 nm to about 20 μm, or from about 20 nm to about 100 nm, or from about 50 nm to about 500 nm, or from about 100 nm to about 1 μm, or from about 500 nm to about 2 μm, or from about 1 μm to about 10 μm, or from about 5 μm to about 15 μm, or from about 10 μm to about 20 μm, or any sub-range or combination thereof. The distribution of the average spike length 110 can be within ±80% or less, or ±50% or less, or ±40% or less, or ±30% or less, or ±20% or less of the average spike length 110.

[0033]

[0047] The plurality of spikes 104 can have any suitable average spike width 112 (measured orthogonal to the average spike length 110), including but not limited to from about 50 nm to about 5 μm, or from about 100 nm to about 3 μm, or from about 300 nm to about 1 μm, or from about 400 nm to about 1 μm, or from about 400 nm to about 700 nm, or from about 50 nm to about 250 nm, or from about 100 nm to about 500 nm, or from about 250 nm to about 1 μm, or from about 500 nm to about 1 μm, or from about 1 μm to about 3 μm, or from about 2 μm to about 5 μm, or any sub-range or combination thereof. The distribution of the average spike width 112 can be within ±50% or less, or ±40% or less, or ±30% or less, or ±20% or less of the average spike width 112.

[0034]

[0048] The spike particles 100 can have any suitable ratio of the average spike length 110 to the average core width 106, including but not limited to about 0.2 to about 30, or about 0.2 to about 10, or about 5 to about 15, or about 10 to about 20, or about 15 to about 25, or about 20 to about 30, or any sub-range or combination thereof.

[0035]

[0049] The plurality of spikes 104 can have any suitable ratio of the average spike length 110 to the average spike width 112, including but not limited to about 0.2 to about 50, or about 0.2 to about 10, or about 5 to about 15, or about 10 to about 20, or about 15 to about 25, or about 20 to about 30, or about 25 to about 35, or about 30 to about 40, or about 35 to about 45, or about 40 to about 50, or any sub-range or combination thereof.

[0036]

[0050] The core 102 may be formed from any suitable material including but not limited to silica, hybrid silica, alumina, titania, zirconia, ferric oxide, hematite, zinc oxide, carbon, silicon carbide, diamond, silver, gold, polystyrene, poly(methyl methacrylate), or combinations thereof. A typical hybrid silica is described in U.S. Patent No. 8,778,453, the contents of which are hereby incorporated by reference in their entirety.

[0037]

[0051] The plurality of spikes 104 may be formed from any suitable material including but not limited to silica, hybrid silica, alumina, titania, zirconia, or combinations thereof.

[0038]

[0052] The core 102 can have any suitable shape including, but not limited to, a sphere, an ellipsoid, a polyhedron, a cube, a cuboid, a prism, a pyramid, a cylinder, a tube, a cone, a frustum, a disc, an annulus, a toroid, or a combination thereof. The core 102 may have a continuous structure or may include a hollow center.

[0039]

[0053] The plurality of spikes 104 can have any suitable cross-sectional shape (orthogonal to the average spike length 110) including, but not limited to, a circle, an ellipse, a polyhedron, a triangle, a quadrilateral, a rectangle, a square, a pentagon, a hexagon, an irregular shape, or a combination thereof. The plurality of spikes 104 may have a continuous structure or may include a hollow center. The plurality of spikes 104 may be uniformly straight along the average spike length 110 or may taper along the average spike length 110 (Murphy et al., J. Colloid Interface Sci., 501 (2017), 45 - 53). While the spike 104 tapers, the spike width 112 may decrease gradually or abruptly. The plurality of spikes 104 may have a trailing tail where the spike width 112 decreases gradually or abruptly to form a relatively long tail. The plurality of spikes 104 may be bent or curved. "Bent" indicates that the spike 104 has one twist from one end to the other end. "Curved" indicates that the spike 104 has at least two twists from one end to the other end. The ends of the spike 104 may be open. The spike 104 may have a plurality of segments, and these segments may have different spike widths 112 or material compositions or both.

[0040]

[0054] The spike particles 100 are from about 5 cm 2 / g to about 1,000 cm 2 / g, or from about 5 m 2 / g to about 500 m 2 / g, or from about 20 m 2 / g to about 400 m 2 / g, or from about 30 m2 / g ~ about 300 m 2 / g, or about 50 m 2 / g ~ about 200 m 2 / g, or 5 cm 2 / g ~ about 100 cm 2 / g, or about 50 cm 2 / g ~ about 150 cm 2 / g, or about 100 cm 2 / g ~ about 200 cm 2 / g, or about 150 cm 2 / g ~ about 250 cm 2 / g, or about 200 cm 2 / g ~ about 300 cm 2 / g, or about 250 cm 2 / g ~ about 350 cm 2 / g, or about 300 cm 2 / g ~ about 400 cm 2 / g, or about 350 cm 2 / g ~ about 450 cm 2 / g, or about 400 cm 2 / g ~ about 500 cm 2 / g, or about 5 cm 2 Specific surface area less than / g, or any appropriate specific surface area including but not limited to those in any sub-range or combination range thereof. In one embodiment where the spike particles 100 are porous, the spike particles 100 are about 20 m 2 / g ~ about 1000 m 2 / g, or about 30 m 2 / g ~ about 600 m 2 / g, or about 50 m 2 / g ~ about 500 m 2 / g, or about 200 m 2 / g ~ about 400 m 2 / g.

[0041]

[0055] The spike particles 100 are about 0.05 cm 3 / g ~ about 1.5 cm 3 / g, or about 0.05 cm 3 / g ~ about 1.00 cm 3 / g, or about 0.10 cm3 / g ~ about 0.70 cm 3 / g, or about 0.20 cm 3 / g ~ about 0.50 cm 3 / g, or about 0.25 cm 3 / g ~ about 0.40 cm 3 / g, or about 0.05 cm 3 / g ~ about 0.5 cm 3 / g, or about 0.25 cm 3 / g ~ about 0.75 cm 3 / g, about 0.5 cm 3 / g ~ about 1 cm 3 / g, or about 0.75 cm 3 / g ~ about 1.25 cm 3 / g, or about 1 cm 3 / g ~ about 1.5 cm 3 / g, or any suitable ratio pore volume including but not limited to those of any lower range or combination of ranges thereof. In one embodiment where the core 102 is porous, the core 102 is about 0.10 cm 3 / g ~ about 1.50 cm 3 / g, or about 0.15 cm 3 / g ~ about 1.00 cm 3 / g, or about 0.20 cm 3 / g ~ about 0.90 cm 3 / g, or about 0.30 cm 3 / g ~ about 0.80 cm 3 / g, or about 0.30 cm 3 / g ~ about 0.70 cm 3 / g in the range of ratio pore volume.

[0042]

[0056] The spike particles 100 can have any suitable average pore diameter including, but not limited to, an average pore diameter in the range of about 2 nm to about 100 nm, or about 3 nm to about 100 nm, or about 6 nm to about 100 nm, or about 8 nm to about 50 nm, or about 10 nm to about 30 nm, or about 3 nm to 50 nm, or about 25 nm to 75 nm, or about 50 nm to 100 nm, or any sub-range or combination thereof. In one embodiment where the core 102 is porous, the core 102 has an average pore diameter in the range of about 2 nm to about 100 nm, or about 6 nm to about 100 nm, or about 8 nm to about 50 nm, or about 8 nm to about 50 nm, or about 10 nm to about 30 nm.

[0043]

[0057] In one embodiment, the core particles 102 have a narrow particle size distribution with a variation of 20% or less, or 10% or less, or 5% or less of the average core width 106.

[0058] The spike particles 100 are about 0.1 g / cm 3 to about 5.0 g / cm 3 or about 0.2 g / cm 3 to about 5.0 g / cm 3 or about 0.3 g / cm 3 to about 4.0 g / cm 3 or about 0.4 g / cm 3 to about 3.0 g / cm 3 or about 0.5 g / cm 3 to about 1.3 g / cm 3 or about 0.6 g / cm 3 to about 1.2 g / cm 3 or about 0.1 g / cm 3 to about 2.0 g / cm 3 or about 1.0 g / cm 3 to about 3.0 g / cm 3 or about 2.0 g / cm 3 to about 4.0 g / cm 3 or about 3.0 g / cm 3 to about 5.0 g / cm 3、or can have any suitable density including, but not limited to, the density of any of these or any sub - ranges or combinations thereof. In one embodiment where the core 102 is porous, the core 102 has a density in the range of about 0.20 g / cm 3 to about 5.00 g / cm 3 、or about 0.30 g / cm 3 to about 4.00 g / cm 3 、or about 0.40 g / cm 3 to about 3.00 g / cm 3 、or about 0.40 g / cm 3 to about 0.90 g / cm 3 、or about 0.40 g / cm 3 to about 0.80 g / cm 3 .

[0044]

[0059] In one embodiment, the spike particles 100 have a specific surface area in the range of about 5 cm 2 / g to about 500 cm 2 / g, a specific pore volume in the range of about 0.05 cm 3 / g to about 1.5 cm 3 / g, an average pore diameter in the range of about 3 nm to about 100 nm, and a density in the range of about 0.1 g / cm 3 to about 5.0 g / cm 3 . In another embodiment, the spike particles 100 have a specific surface area less than about 5 cm 2 / g, a specific pore volume less than about 0.05 cm 3 / g, and a density in the range of about 1.0 g / cm 3 to about 5.0 g / cm 3 、or 1.5 g / cm 3 to about 2.5 g / cm 3 .

[0045]

[0060] In one embodiment, the spike particles 100 contain sodium ions at 100 ppm or less, or 90 ppm or less, or 80 ppm or less, or 70 ppm or less, or 60 ppm or less, or 50 ppm or less, or 40 ppm or less, or 30 ppm or less, or 20 ppm or less, or 10 ppm or less, or 5 ppm or less, or 1 ppm or less, or 0.1 ppm or less, or contain no sodium ions.

[0046]

[0061] In one embodiment, the spike particles 100 substantially do not contain metal ions, and the content of metal impurities other than silicon is 100 ppm or less, or 90 ppm or less, or 80 ppm or less, or 70 ppm or less, or 60 ppm or less, or 50 ppm or less, or 40 ppm or less, or 30 ppm or less, or 20 ppm or less, or 10 ppm or less, or 5 ppm or less, or 1 ppm or less, or 0.1 ppm or less, or the spike particles 100 do not contain metal impurities other than silicon.

[0047]

[0062] The plurality of spikes 104 and the core 102 can have the same material composition or different material compositions. The plurality of spikes 104 may include different individual spikes 104 having different material compositions on the same core 102.

[0048]

[0063] Referring to FIG. 2, the SEM images of the spike particles 100 show the control of the average spike length 110, the number of spikes 104, and the average spike width 112. The average core widths 106 of Panels A - C and D - F are 0.9 μm and 2.0 μm, respectively. The scale bar is 5 μm and applies to all images.

[0049]

[0064] Referring to FIG. 3(a), in one embodiment, the spike particle 100 has a non-porous core 102 and a non-porous spike 104.

[0065] Referring to FIG. 3(b), in one embodiment, the spike particle 100 has a core 102 that is surface-porous and a non-porous spike 104. The surface-porous core 202 includes a non-porous central region 204 and a porous shell 206 that surrounds the non-porous central region 204. The porous shell 206 includes randomly oriented pores 200.

[0050]

[0066] Referring to FIG. 3(c), in one embodiment, the spike particle 100 has a core 102 that is surface-porous and a non-porous spike 104. The surface-porous core 202 includes a non-porous central region 204 and a porous shell 206 that surrounds the non-porous central region 204. The porous shell 206 includes radially oriented pores 200.

[0051]

[0067] Referring to FIG. 3(d), in one embodiment, the spike particle 100 has a porous core 102 with randomly oriented pores 200 and a non-porous spike 104.

[0052]

[0068] Referring to FIGS. 3(e) and 3(f), the surface-porous spike particles 500 may include spike particles 100 (as described above) having a non-porous core 102 and a plurality of non-porous spikes 104 on which a porous spike particle shell 502 is disposed. The porous spike particle shell 502 can have radially oriented pores 200 (FIG. 3(e)) or randomly oriented pores 200 (FIG. 3(f)). The porous spike particle shell 502 can be formed from any suitable material including, but not limited to, silica, hybrid silica, or combinations thereof. The porous spike particle shell 502 can have any suitable shell thickness 208, any suitable specific pore volume, any suitable pore size, and any suitable average pore diameter, and can constitute any suitable volume of surface-porous spike particles 500 as described above with respect to the porous shell 206 of the spike particles 100. The surface-porous spike particles 500 can include any suitable specific surface area, any suitable density, and any suitable dimensions as described above with respect to the spike particles 100.

[0053]

[0069] Referring to FIG. 4, SEM images of spike particles 100 prepared according to the methods of Examples 1-4 show control of the average spike length 110, spike number 104, and average spike width 112. The scale bar is 5 μm and applies to all images.

[0054]

[0070] Referring to FIG. 5, a two-dimensional cross-sectional view of randomly packed spherical particles 600 represents the random packing of a commercial HPLC column. The spherical particles 600 need to physically contact a specific number of nearest neighboring spherical particles to form a stable packed bed. This packing structure results in internal voids 602 that are the through-pores of the three-dimensional packed bed. The total volume of all through-pores on the packed volume is the external porosity, and the external porosity is fixed at about 0.4 in a column packed with spherical particles 600 regardless of the diameter of the spherical particles.

[0055]

[0071] Referring to Fig. 6(a), the two-dimensional cross-sectional view of the randomly packed spike particles 100 having an average spike length 110 of about 1 / 3 of the average core width 106 shows that the cores 102 of the spike particles 100 do not contact each other. The stability of the packed bed is ensured by various forms of spike-spike contact and spike-core contact. The packing of the spike particles 100 results in a larger internal void 602 and a higher external porosity than the packing of the spherical particles 600 shown in Fig. 5.

[0056]

[0072] Referring to Fig. 6(b), from the two-dimensional cross-sectional view of the randomly packed spike particles 100 having an average spike length 110 approximately equal to the average core width 106, for the spike particles 100 having a longer relative average spike length 110, it is shown that the internal void 602 is larger compared to the packing shown in Fig. 6(a).

[0057]

[0073] In one embodiment, the chromatography separation device includes a plurality of spike particles 100, and the plurality of spike particles 100 are randomly packed within the chromatography separation device. The randomly packed plurality of spike particles 100 can have any suitable external porosity, including but not limited to, an external porosity in the range of about 0.4 to about 0.9, or about 0.4 to about 0.6, or about 0.5 to about 0.7, or 0.6 to about 0.8, or about 0.7 to about 0.9, or any sub-range or combination thereof.

[0058]

[0074] The chromatography separation device can be easily adjustable and can have an increased fluid permeability compared to a comparative chromatography separation device having a plurality of spherical particles that are identical in other respects but lack the plurality of spikes 104 instead of the plurality of spike particles 100.

[0059]

[0075] The chromatographic separation device may be any container containing a bed randomly filled with spike particles 100, including but not limited to a chromatography column, a microfluidic channel, a filter disk, a solid phase separation cartridge, a petite tip, a centrifuge tube, a 96-well plate, or a combination thereof.

[0060]

[0076] Figure 5 shows a two-dimensional cross-sectional view of randomly packed spherical particles 600. This particle configuration represents the random packing of a commercial HPLC column. The spherical particles 600 need to physically contact a specific number of nearest neighboring spherical particles in order to form a stable packed bed. This packing structure results in internal voids 602 that are the through-pores of the three-dimensional packed bed. The total volume of all through-pores is the external porosity. The column packed with spherical particles 600 has a nearly fixed external porosity value of 0.4, regardless of the particle size. There is little flexibility to increase column permeability and reduce the backpressure of the spherical particle 600-based column by increasing the external porosity. The backpressure of these columns is inversely proportional to the square of the particle diameter. In practice, this makes it impossible to operate columns packed with particles less than 1.5 μm at the optimized flow rate (highest efficiency) with state-of-the-art UHPLC equipment without exceeding the pressure limit. Referring to FIGS. 6(a) and 6(b) showing two-dimensional cross-sectional views of randomly packed spike particles 100, the cores 102 of the spike particles 100 are not in contact with each other. However, there are various forms of contact including tip-tip, tip-core, tip-body, body-body, and spike-spike-spike. Furthermore, they are the multiple spikes 104 provided on each spike particle 100. Therefore, the average number of contacts between spike particles 100 can be much higher than the average number of contacts between spherical particles 600. Thus, the packed bed of spike particles 100 may be stable even with larger internal voids 602 and higher external porosity. Therefore, a column packed with spike particles 100 may be more permeable and have a lower backpressure than a column packed with spherical particles 600. By changing the average spike length 110, the external porosity of the packed bed can be easily adjusted. Furthermore, the number of spikes 104 and the average spike width 112 can also be used to adjust the external porosity. The higher the number of spikes 104 and the smaller the average spike width 112, the higher the external porosity. Referring to FIGS. 2 and 4, the length, number, and to some extent the width of the spikes 104 can be easily controlled.

[0061]

[0077] High efficiency and high permeability are essentially incompatible in both a monolithic column and a column packed with spherical particles 600. High permeability correlates with large through pores, large particle sizes, or large characteristic dimensions of the packed bed including the monolithic skeleton. Although not bound by theory, it is thought that as the characteristic dimension increases, various band dispersions increase and column efficiency decreases. A column packed with spike particles 100 can have both small characteristics (and thus high efficiency) and high permeability. First, under the same permeability conditions, the diameters of the core 102 and the spikes 104 of the spike particles 100 are smaller than the diameter of the spherical particles 600. Second, referring to FIGS. 6(a) and 6(b), the internal voids 602 (three-dimensional through pores) always accommodate a constant number of spikes 104. These spikes 104 in the through pores can create larger through pores that act like a smaller number of larger through pores. Further, these spikes 104 can act as a role of radial mixing and reduce the diffusion of the analyte in the through pores. Therefore, even if the column packed with spike particles 100 has a relatively high external porosity (high permeability), the characteristic dimensions of their solid zones (core 102 and spikes 104) and mobile zones (effective through pores) may be relatively small. Therefore, the column packed with spike particles 100 may have a relatively loose relationship between efficiency and permeability compared to the column packed with spherical particles 600 and the monolithic column.

[0062]

[0078] In one embodiment, a method of forming a plurality of spike particles 100 includes mixing a continuous oil phase and a dispersed water phase to form a water-in-oil emulsion system, the continuous oil phase including an organic solvent, polyvinylpyrrolidone, and a silane precursor, and the dispersed water phase including a plurality of core particles 102, a water emulsion droplet stabilizer, and a catalyst. The water-in-oil emulsion system is reacted without stirring to form a plurality of spike particles 100. The plurality of spike particles are separated from the water-in-oil emulsion system.

[0063]

[0079] Suitable organic solvents include those of the formula C such as 1-pentanol n H 2n+1Examples of the alcohol include, but are not limited to, alcohols having OH (wherein n is an integer of 5 to 10).

[0064]

[0080] Polyvinylpyrrolidone may have an average molecular weight of at least about 10 kDa, or at least 30 kDa, or at least 50 kDa, or at least 130 kDa, or from about 10 kDa to about 130 kDa, or from about 10 kDa to about 30 kDa, or from about 20 kDa to about 40 kDa, or from about 30 kDa to about 50 kDa, or from about 40 kDa to about 60 kDa, or from about 50 kDa to about 70 kDa, or from about 60 kDa to about 80 kDa, or from about 70 kDa to about 90 kDa, or from about 80 kDa to about 100 kDa, or from about 90 kDa to about 110 kDa, or from about 100 kDa to about 120 kDa, or from about 110 kDa to about 130 kDa, or any suitable molecular weight including any lower ranges or combinations thereof, but not limited thereto.

[0065]

[0081] The silica precursor may be any suitable precursor including, but not limited to, tetramethoxysilane, tetraethyl orthosilicate (“TEOS”), tetrapropoxysilane, tetrabutoxysilane, their prehydrolyzed derivatives, silicate oligomers, or combinations thereof.

[0066]

[0082] The catalyst may include any suitable species including, but not limited to, urea, basic amino acids, quaternary ammonium hydroxides, organic amines (primary, secondary, or tertiary), ammonium hydroxide, ammonium fluoride, and ammonium bifluoride, or combinations thereof.

[0067]

[0083] The dispersed aqueous phase may further contain a water emulsion droplet stabilizer. Suitable water emulsion droplet stabilizers include, but are not limited to, organic ammonium citrate salts, ammonium tartrate dibasic, ammonium acid urate, ammonium oxalate, ammonium citrate dibasic, di-ammonium hydrogen citrate, ammonium citrate tribasic, malic acid, lactic acid, uric acid, tartaric acid, oxalic acid, citric acid, and citric acid monohydrate, or combinations thereof.

[0068]

[0084] The reaction temperature may be in the range of about 0 °C to about 70 °C. The average spike width 112 is manipulated by the temperature. The average spike width 112 typically decreases with an increase in temperature. However, increasing the temperature may lead to an increase in rods and non-straight spikes 104 that are not attached to the core particles 102. The reaction time may be in the range of about 1 hour to about 7 days. The average spike length 110 increases with the reaction time and extends over several days. However, manipulating the average spike length 110 may be particularly effective in the first 15 hours of the reaction.

[0069]

[0085] In one embodiment, the organic solvent, polyvinylpyrrolidone, core particles 102, and catalyst are mixed for a mixing period of about 1 minute to about 2 days before the silane precursor is added.

[0070]

[0086] The continuous oil phase and the dispersed aqueous phase can further contain a co-solvent having substantial solubility in both the continuous oil phase and the dispersed aqueous phase. Suitable co-solvents include those of the formula C such as acetone, acetonitrile, tetrahydrofuran, ethanol, and isopropanol n H 2n+1One or more alcohols having OH (wherein n is an integer from 1 to 4), or combinations thereof, may be mentioned, but are not limited thereto.

[0071]

[0087] The core 102 may be surface-modified. The surface modifier may be covalently or physically adsorbed to the core 102. The surface modifier can enhance the hydrophilicity and uniformity of the core 102, and when the core 102 is porous or surface-porous, it can cover the pores 200, enabling water droplets to adhere to the core 102 better and more uniformly. Examples of suitable surface modifiers are various hydrophilic polymers, which can include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polyelectrolytes such as poly(diallyldimethylammonium) chloride, water-soluble cellulose derivatives, gelatin, and starch. Polyvinylpyrrolidone is hydrophilic and non-toxic, is strongly absorbed on the silica surface, and has the same composition as the polyvinylpyrrolidone in the continuous phase, so it can be advantageously used as a surface modifier. Polyvinylpyrrolidone helps in the stabilization of water droplets. The polyvinylpyrrolidone used as a surface modifier may have the same or different molecular weights as the polyvinylpyrrolidone used in the continuous phase.

[0072]

[0088] Steps for separating the plurality of spike particles 100 from the water-in-oil emulsion system can include at least one of centrifugation or filtration.

[0089] The organic residue can be removed from the plurality of spike particles 100 by any suitable technique including, but not limited to, calcination.

[0073]

[0090] The surface of the plurality of spike particles may be rehydrolyzed by etching. Procedures available for the rehydroxylation of silica can be found in U.S. Patent No. 4,874,518, which is hereby incorporated by reference in its entirety.

[0074]

[0091] In a further method, the spike particles 100 can be placed in a two-phase mixture comprising an aqueous lower phase and an organic upper phase, the aqueous lower phase comprising the spike particles 100, a template, and a catalyst, and the organic upper phase comprising an upper phase organic solvent and an upper phase silane precursor, and heating the two-phase mixture under reflux conditions to form surface-porous spike particles 500 having a porous spike particle shell 502 disposed on each of the spike particles 100. Suitable upper phase organic solvents include, but are not limited to, cyclohexane. Suitable templates include, but are not limited to, cetyltrimethylammonium bromide. The upper phase silica precursor may be any suitable precursor including, but not limited to, tetramethoxysilane, tetraethyl orthosilicate (“TEOS”), tetrapropoxysilane, tetrabutoxysilane, or combinations thereof.

[0075]

[0092] In one embodiment, based on 100 parts by weight of pentanol, (a) polyvinylpyrrolidone has an average molecular weight of about 40 kDa, and about 5 to 20 parts by weight of polyvinylpyrrolidone is dissolved in pentanol; (b) the co-solvent is ethanol, and ethanol is about 0 to 20 parts by weight; (c) the water content is NH 3, the total of all water including citrate and water in the core particles, where the water is about 3 to 15 parts by weight; (d) the water droplet stabilizer is ammonium dibasic citrate, and about 0.5 to 3 parts by weight of ammonium dibasic citrate is dissolved in water; (e) the catalyst is 28% ammonium hydroxide, and 28% ammonium hydroxide is about 0.3 to 5 parts by weight; (f) the silane precursor is TEOS, and TEOS is about 0.05 to 5 parts by weight; (g) the core 102 is spherical non-porous, surface-porous, or porous silica having a diameter in the range of about 0.5 to about 5 μm; (h) the core surface 108 is modified by polyvinylpyrrolidone having a molecular weight of about 40 KDa; (i) the core 102 or the surface-modified core is dispersed in water, and the core 102 is about 0.05 to 5 parts by weight; (j) the order of chemical mixing is pentanol-polyvinylpyrrolidone, silica core particles 102, water, ammonium dibasic citrate, ammonium hydroxide, and TEOS; (k) after the addition of each chemical, the mixture is agitated using methods such as shaking, stirring, sonication, vortex for about 10 seconds to about 10 minutes; (l) before adding TEOS, the water-in-oil emulsion mixture is allowed to stand for about 1 minute to 2 days without agitation; (m) the reaction occurs without agitation; (n) the reaction temperature is in the range of about 0 °C to about 70 °C; (o) the reaction time is about 2 hours to 2 days. The spike particles 100 prepared by the aforementioned method are separated from the emulsion system (including but not limited to by centrifugation or filtration, or both), and can be rinsed with any suitable rinsing liquid such as water, ethanol, acetone, or combinations thereof. Repeated rinsing including but not limited to any number from 1 to 10 times can be utilized. The separated spike particles 100 are then subjected to a calcination process, a solvent extraction process, or both to substantially remove organic residues. The calcination can be carried out at a higher temperature, at least 550 °C, or at least 650 °C, or at least 750 °C, or at least 850 °C. In addition to the removal of organic residues, two other changes are well known during calcination. First, the silanol groups (Si-OH) on the silica surface are gradually dehydrated and changed to siloxane group bonds (Si-O-Si).Second, the silica backbone gradually densifies, the surface area and pore volume decrease, and the mechanical strength increases. A rehydrolization step can be added to restore the surface silanol concentration. In some cases, a silica layer may form simultaneously with spikes 104 on core 102 that block pores 200 on core surface 108. This layer can be removed by etching spike particles 100 with diluted ammonium hydroxide, HF, or ammonium fluoride. Removal of the silica layer can be performed before or after removal of the organic residue.

[0076]

[0093] In one embodiment, surface porous spike particles 500 can be formed by forming a porous layer on spike particles 100. Methods such as those disclosed in U.S. Patent No. 8,685,283 may be suitable for the preparation of surface porous spike particles 500 having radially oriented pores 200 (FIG. 3(e)), which is hereby incorporated by reference in its entirety. Similarly, methods such as those disclosed in U.S. Patent No. 8,864,988 and U.S. Patent Application Publication No. 2007 / 0189944A1 may be suitable for the preparation of surface porous spike particles 500 having randomly oriented pores 200 (FIG. 3(f)), which is hereby incorporated by reference in its entirety.

[0077]

[0094] In one embodiment, the surface porous spike particles 500 are prepared by an alternating laminated two-phase method, which includes the following steps: (a) mixing an aqueous lower phase and an organic upper phase during a mixing period to form a two-phase mixture; (b) heating the two-phase mixture under reflux conditions for a reflux period to form the surface porous spike particles 500; (c) separating the surface porous spike particles 500 from the two-phase mixture by centrifugation or filtration; (d) optionally repeating steps (a) to (b) until a desired shell thickness 208 of the porous spike particle shell 502 is reached; (e) optionally removing organic residues from the surface porous spike particles 500 by calcination or solvent extraction; (f) optionally increasing the pore size and removing smaller mesopores less than 5 nm from the surface porous spike particles 500 by hydrothermal treatment or basic etching; (g) optionally increasing the mechanical strength of the surface porous spike particles 500 by hydrothermal treatment or sintering at a temperature up to 975 °C; (h) optionally activating the surface of the surface porous spike particles 500 by hydrothermal treatment or basic etching; and (i) optionally modifying the surface of the surface porous spike particles 500 with functional groups. The aqueous lower phase can include a plurality of spike particles 100, a template such as cetyltrimethylammonium bromide, and a catalyst such as urea. The organic upper phase can include an organic solvent such as cyclohexane and a silane precursor such as TEOS. A co-solvent soluble in both phases, such as isopropanol, may be added. The reaction can be carried out at 70 °C for about 24 hours. Step (c) of separating the as-prepared surface porous spike particles 500 from the two-phase mixture can be achieved by any suitable method such as centrifugation, filtration, or a combination thereof. The surface porous spike particles 500 can be rinsed with a rinsing liquid such as water, ethanol, acetone, or a combination thereof. A typical rinsing process includes 1 to 10 repetitions of rinsing.Step (e) of removing the organic residue in the surface-porous spike particles 500 can be carried out by calcining at a temperature of about 600 °C for about 12 hours. Alternatively, as described by Yue et al. in J. Am. Chem. Soc., 137 (2015), 13282-13289, the organic residue can be removed by solvent extraction, which is hereby incorporated by reference in its entirety. Step (f) of increasing the pore size and removing smaller mesoporous spike particles 500 with a pore size of less than 5 nm can be carried out by hydrothermal treatment, as described in WO2010 / 061367, which is hereby incorporated by reference in its entirety. Alternatively, etching with ammonium hydrogen fluoride can be effective in changing the porosity of the surface-porous spike particles 500, and the process described in European Patent No. 0272904B1 is hereby incorporated by reference in its entirety. The etching can also be carried out in an aqueous slurry containing one or more etching chemicals selected from the group consisting of urea, basic amino acids, quaternary ammonium hydroxides, organic amines (primary, secondary, or tertiary), ammonium hydroxide, or ammonium fluoride, at room temperature or under reflux conditions. Step (g) of sintering can be used to densify the skeleton and increase the mechanical strength of the surface-porous spike particles 500. Sintering can be carried out at a very high temperature, such as between about 900 °C and about 975 °C. Temperatures above 975 °C may induce the collapse of the porous network of the surface-porous spike particles 500, and further treatments such as re-hydroxylation may become very difficult. The sintered surface-porous spike particles 500 are 1.38×10. 8It can have sufficient structural strength to withstand a filling pressure of Pascal (20,000 psi). Nevertheless, these surface-porous spike particles 500 may be hydrophobic due to the very low concentration of Si-OH groups. Therefore, without further treatment such as re-hydroxylation, it may not be very useful as a packing material for chromatography applications. The re-hydroxylation in step (h) can be carried out under the same conditions as the etching process or hydrothermal treatment described in step (f). An exemplary process of re-hydroxylation is disclosed in U.S. Patent No. 4,874,518, which is hereby incorporated by reference in its entirety. The surface modification of the surface-porous spike particles 500 in step (i) may include modification for having surface functional groups. Suitable functionalized surface groups include, but are not limited to, alkyl groups, alkynyl groups, aryl groups, diol groups, amino groups, alcohol groups, amide groups, cyano groups, ether groups, nitro groups, carbonyl groups, epoxide groups, sulfonyl groups, cation exchange groups, anion exchange groups, carbamate groups, urea groups, dimethyloctyl groups, dimethyloctadecyl groups, methyldifilsilyl groups, or combinations thereof. An exemplary process of surface modification can be found in Lork et al., J. Chromatogr., 352 (1986), 199-211, which is hereby incorporated by reference in its entirety.

Example

[0078]

[0095] In the following examples, the average core width 106 was measured by Beckman Coulter counter technology. The average spike length 110 of the spike particles 100, the number of spikes 104 per core 102, the average spike width 112, and the average core width 106 were estimated from scanning electron microscope (SEM) images. The porosity, including the specific surface area, pore size, and specific pore volume of the surface-porous spike particles 500, was measured by nitrogen sorption analysis.

[0079]

[0096] Materials: Polyvinylpyrrolidone 40K and Polyvinylpyrrolidone 55K, Ammonium dibasic citrate (ACS reagent, 98%), Ethanol (200 proof), 1-Pentanol (REAGENTPLUS®, ≥99%), Ammonium hydroxide (ACS reagent, 28%), TEOS (reagent grade, 98%), Cyclohexane, Cetyltrimethylammonium bromide (>98%), Urea (ACS reagent, >99%), Acetone (ACS reagent, >99%), Isopropanol (ACS reagent, >99%), Ammonium fluoride (reagent grade, 98%) and Ammonium bifluoride (reagent grade, 98%) were purchased from Sigma Aldrich.

[0080]

[0097] A stock solution of Polyvinylpyrrolidone 40K or Polyvinylpyrrolidone 55K was prepared by dissolving 100 g of Polyvinylpyrrolidone in 1 L of 1-Pentanol. A 0.27 M ammonium dibasic citrate solution was prepared by dissolving 3.06 g of ammonium dibasic citrate in 50 mL of water. Silica core particles 102 with a size less than 1 μm were prepared by the Stober method (Stober et al., J. Colloid and Interface Sci., 26 (1968), 62 - 69). Using silica particles with a size less than 1 μm as seeds, silica core particles 102 with a width of about 2 μm were synthesized by the method disclosed in U.S. Patent No. 4,775,520. A 15% stock solution of surface-modified core particles 102 was prepared by adding 15 g of core particles 102 to 100 mL of water containing 7.5 g of Polyvinylpyrrolidone 40K or Polyvinylpyrrolidone 55K. A 5% stock solution of surface-modified core particles 102 was prepared by adding 5 g of core particles 102 to 100 mL of water containing 5 g of Polyvinylpyrrolidone 40K or Polyvinylpyrrolidone 55K.

[0081]

[0098] The following examples relate to the preparation of spike particles 100.

[0082]

[0099] Example 1

[0100] In a 1,000 mL glass bottle, 21.40 mL of surface-modified core particles 102 (2.10 μm, 15% stock solution) was added to 800 mL of a 1-pentanol-polyvinylpyrrolidone 55K stock solution. The mixture was sonicated for 5 minutes, and then 1.80 mL of water, 4.80 mL of 0.27 M ammonium dibasic citrate, and 16.00 mL of 28% ammonium hydroxide were added. The resulting mixture was sonicated for 2 minutes and then shaken by hand for 2 minutes to form a water / 1-pentanol emulsion. Subsequently, the above mixture was allowed to stand for about 30 minutes. Then, 20.00 mL of TEOS was quickly added to the above mixture. After further shaking by hand for about 2 minutes, the resulting mixture was allowed to stand and reacted for about 48 hours. Then, the resulting mixture was centrifuged and resuspended once in water and twice in 90% water / 10% ethanol (v / v) to collect spike particles 100. After drying at 100 °C and calcining at 600 °C to remove organic residues, about 3.3 g of spike particles 100 was obtained. Panel A of Figure 4 is an SEM image of spike particles 100. The average number of spikes 104, average spike length 110, and average spike width 112 of spike particles 100 are estimated to be about 6, 1 μm, and 0.5 μm, respectively.

[0083]

[0101] Example 2

[0102] In a 1,000 mL glass bottle, 22.47 mL of surface-modified core particles 102 (2.10 μm, 15% stock solution) were added to 840 mL of a 1-pentanol-polyvinylpyrrolidone 55K stock solution. After the mixture was sonicated for 5 minutes, 1.80 mL of water, 5.04 mL of 0.27 M ammonium dibasic citrate, and 16.80 mL of 28% ammonium hydroxide were added. The resulting mixture was sonicated for 2 minutes and then shaken by hand for 2 minutes to form a water / 1-pentanol emulsion. Subsequently, the above mixture was allowed to stand for about 20 minutes. Then, 21.00 mL of TEOS was quickly added to the above mixture. After further shaking by hand for about 2 minutes, the resulting mixture was allowed to stand and reacted for about 48 hours. Then, the resulting mixture was centrifuged and resuspended once in water and twice in 90% water / 10% ethanol (v / v) to collect the spike particles 100. After drying at 100 °C and calcining at 600 °C to remove organic residues, about 3.5 g of spike particles 100 were obtained. Panel B of Figure 4 is an SEM image of the spike particles 100. The average number of spikes 104, average spike length 110, and average spike width 112 of the spike particles 100 were estimated to be about 15, 0.8 μm, and 0.4 μm, respectively. The spike particles 100 of this example have a relatively wide distribution of spike lengths 110.

[0084]

[0103] Example 3

[0104] In a 1,000 mL glass bottle, 20.0 mL of surface-modified core particles 102 (2.1 μm, 15% stock solution) were added to 762 mL of a 1-pentanol-polyvinylpyrrolidone 55K stock solution. After sonicating the mixture for 2 minutes, 1.68 mL of water, 4.57 mL of 0.27 M ammonium dibasic citrate, and 14.95 mL of 28% ammonium hydroxide were added. The resulting mixture was sonicated for 2 minutes and then shaken by hand for 2 minutes to form a water / 1-pentanol emulsion. Subsequently, the above mixture was allowed to stand for about 20 minutes. Then, 19 mL of TEOS was quickly added to the above mixture. After further shaking by hand for about 2 minutes, the resulting mixture was allowed to stand and reacted for about 48 hours. Then, the resulting mixture was centrifuged and resuspended once in water and twice in 90% water / 10% ethanol (v / v) to collect the spike particles 100. After drying at 100 °C and calcining at 600 °C to remove the organic residues, about 3.0 g of spike particles 100 were obtained. Panel C of Figure 4 is the SEM of the spike particles. The average number of spikes 104, average spike length 110, and average spike width 112 of the spike particles 100 were estimated to be about 15, 1.5 μm, and 0.5 μm, respectively.

[0085]

[0105] Example 4

[0106] In a 1,000 mL glass bottle, 22.50 mL of surface-modified core particles 102 (2.20 μm, 15% stock solution) were added to 843 mL of a 1-pentanol-polyvinylpyrrolidone 55K stock solution. After sonicating the mixture for 5 minutes, 1.90 mL of water, 5.06 mL of 0.27 M ammonium dibasic citrate, and 21.60 mL of 28% ammonium hydroxide were added. The resulting mixture was sonicated for 2 minutes and then shaken by hand for 2 minutes to form a water / 1-pentanol emulsion. Subsequently, the above mixture was allowed to stand for about 30 minutes. Then, 21.60 mL of TEOS was quickly added to the above mixture. After further shaking by hand for about 2 minutes, the resulting mixture was allowed to stand and reacted for about 48 hours. Then, the resulting mixture was centrifuged and resuspended once in water and twice in 90% water / 10% ethanol (v / v) to collect spike particles 100. After drying at 100 °C and calcining at 600 °C to remove organic residues, about 4.0 g of spike particles 100 were obtained. Panel D of Figure 4 is an SEM image of spike particles 100. The average number of spikes 104, average spike length 110, and average spike width 112 of spike particles 100 are estimated to be more than about 20, 2 μm, and 0.4 μm, respectively. The spike particles 100 of this example have a relatively wide distribution of spike lengths 110.

[0086]

[0107] Example 5

[0108] In a 1,000 mL glass bottle, 102 core particles (2.1 μm, 5% stock solution) surface-modified with 12 mL of polyvinylpyrrolidone 40K were added to 500 mL of a 1-pentanol-PVP40K stock solution. After the mixture was sonicated for 2 minutes, 3 mL of 0.27 M ammonium dibasic citrate, 10 mL of 28% ammonium hydroxide, 12.5 mL of ethanol, and 1 mL of water were added. The resulting mixture was shaken by hand for about 2 minutes to form a water / n-pentanol emulsion. Subsequently, the above mixture was allowed to stand for about 30 minutes. Then, 10 mL of TEOS was quickly added to the above mixture. After further shaking by hand for about 2 minutes, the resulting mixture was allowed to stand and reacted for about 72 hours without stirring. Then, the resulting mixture was centrifuged and resuspended once in water and twice in 90% water / 10% ethanol (v / v) to collect spike particles 100. After drying at 100 °C and calcining at 600 °C to remove organic residues, about 0.6 g of spike particles 100 were obtained. Figure 7 includes SEM images of spike particles 100. The average number of spikes 104, average spike length 110, and average spike width 112 of spike particles 100 are estimated to be about 20, 0.8 μm, and 0.5 μm, respectively.

[0087]

[0109] Spike particles 100 were packed into a 2.1×50 mm column by the slurry method, and the backpressure of the column was evaluated. Slurry packing is well described in the literature. General guidelines can be found in a publication titled "Fundamental and Practical Insights on the Packing of Modern High-Efficiency Analytical and Capillary Columns" (Wahab et al., Anal. Chem., 89 (2017), 8177 - 8191), which is hereby incorporated by reference in its entirety.

[0088]

[0110] Figure 7 shows the column backpressure vs. flow rate data obtained on a column (2.1×50 mm) packed with spike particles 100 prepared according to the method of Example 5, compared to spherical particles 600 having a diameter equal to the core width (2.1 μm) of the spike particles 100. The attached SEM image shows the structure of the spike particles 100. The mobile phase is a 60 / 40 (V / V) water / acetonitrile mixture. Figure 7 shows that the backcrosse of the column packed with spike particles 100 is about 4 times lower than that of the column packed with spherical particles 600.

[0089]

[0111] Example 6 (Regarding the preparation of spike particles 100 and superficially porous spike particles 500)

[0112] Preparation of spike particles 100 having a non-porous core 102 and non-porous spikes 104 attached on the core surface 108 (see Figure 3(a)): In a 1,000 mL glass bottle, 10.7 mL of core particles 102 (2.1 μm, 15% stock solution) surface-modified with polyvinylpyrrolidone 40K were added to 400 mL of a 1-pentanol-polyvinylpyrrolidone 40K stock solution. After the mixture was sonicated for 2 minutes, 2.4 mL of 0.27 M ammonium dibasic citrate and 8.0 mL of 28% ammonium hydroxide were added. The resulting mixture was shaken by hand for about 2 minutes to form a water / n-pentanol emulsion. Subsequently, the above mixture was allowed to stand for about 30 minutes. Then, 10.3 mL of TEOS was quickly added to the above mixture. After further shaking by hand for about 2 minutes, the resulting mixture was allowed to stand and reacted for about 72 hours. Then, the resulting mixture was centrifuged and resuspended once in water and twice in 90% water / 10% ethanol (v / v) to collect the spike particles 100. After drying at 100 °C and calcining at 600 °C to remove the organic residues, 1.55 g of spike particles 100 was obtained. The calcined spike particles 100 were rehydrolyzed with 0.15 mL of 28% ammonium hydroxide and 15 mL of water for 2 hours. Then, the rehydrolyzed spike particles 100 were collected by centrifugation.

[0090]

[0113] Preparation of the surface-porous spike 500 having the above spike particles 100 and a porous spike particle shell 502 having radially oriented pores 200 (see Fig. 3(e)): The surface-porous spike particles 500 were prepared using the alternating lamination process disclosed in US Patent Application Publication No. 2020 / 0338528. 1.5 g of rehydrolyzed spike particles 100 were mixed in a 250 mL three-neck flask with 50 mL of water containing 1.5 g of cetyltrimethylammonium bromide and 0.90 g of urea. The mixture was sonicated for about 10 minutes to dissolve the cetyltrimethylammonium bromide and urea and to completely disperse the spike particles 100. Subsequently, 50 mL of cyclohexane and 1.5 mL of isopropanol were added to the aqueous mixture to form a two-phase system. After the mixture was magnetically stirred at 130 rpm for 30 minutes, 1.20 mL of TEOS was slowly added to the upper cyclohexane phase while raising the reaction temperature from 25 °C to 77 °C over about 20 minutes. The mixture was reacted under reflux conditions for 48 hours. The resulting product was then collected by centrifugation, designated as surface-porous spike particles-L1 500, and suspended in 10 mL of water.

[0091]

[0114] To prepare the porous spike particle shell 502, 1.5 g of cetyltrimethylammonium bromide and 0.90 g of urea were added together to 40 mL of water in a 250 mL three-neck flask and sonicated for about 5 minutes. The surface-porous spike particles-L1 500 were then transferred into the mixture of cetyltrimethylammonium bromide, urea, and water and sonicated for about 5 minutes. Subsequently, 50 mL of cyclohexane and 1.5 mL of isopropanol were added to the above aqueous mixture to form a two-phase system. After the mixture was magnetically stirred at 130 rpm for 30 minutes, 1.20 mL of TEOS was slowly added to the upper cyclohexane phase while raising the reaction temperature from 25 °C to 77 °C over about 20 minutes. The mixture was reacted under reflux conditions for 48 hours. The product was then centrifuged and resuspended once in water and twice in 50% water / 50% ethanol (v / v). The product was dried at 100 °C and calcined at 550 °C to remove organic residues.

[0092]

[0115] The calcined surface-porous spike particles 500 were etched in 30 mL of water containing 0.65 g of ammonium fluoride for 12 hours to modify the pore size of the spike particles. Subsequently, the surface-modified surface-porous spike particles 500 were sintered at 900 °C for 10 hours to increase their mechanical strength. Subsequently, the sintered surface-porous spike particles 500 were re-hydroxylated in 15 mL of water containing 0.13 g of ammonium hydrogen fluoride for 2 hours to increase their surface Si-OH concentration.

[0093]

[0116] The specific surface area, average pore size, and specific pore volume of the surface-porous spike particles 500 determined by nitrogen sorption analysis were 111 m 2 / g, 8.5 nm, and 0.27 cc / g, respectively. The average shell thickness 208 of the surface-porous spike particles 500 was estimated from the SEM images of the spike particles 100 and the surface-porous spike particles 500. The average shell thickness 208 is half of the shell width 504 of the core 102 on which the porous spike particle shell 502 is disposed, obtained by subtracting the width 106 of the core particle 102 of the spike particle 100, and the average shell thickness is about 0.25 μm.

[0094]

[0117] Figure 8 compares the chromatography data obtained with a column packed with superficially porous spike particles 500 prepared according to the method of Example 6 with columns packed with 3-μm and 5-μm fully porous spherical particles 600. Panel A is backpressure versus mobile phase flow rate, and panel B is HETP (height equivalent to a theoretical plate) versus mobile phase velocity. Panel C is an SEM image of the superficially porous spike particles 500. The column (2.1×50 mm) was tested on an Agilent 1260 series chromatograph equipped with a quaternary pump, an autosampler, a thermostatted column compartment, and a 5-μL flow cell variable wavelength detector using cytosine as the solute. The mobile phase was 97% water / 3% acetonitrile / 10 mM ammonium formate for the superficially porous spike particles 500 and 95% water / 5% acetonitrile / 10 mM ammonium formate for the 3-μm and 5-μm spherical particles 600. The slight change in the mobile phase is to adjust the retention time to similar values for a fair comparison of column efficiency. The plots show that while the backpressure of the superficially porous spike particles 500 is between that of the 3-μm and 5-μm spherical particles, the superficially porous spike particles 500 are superior to the porous spherical particles in terms of separation efficiency (lower HETP). These results indicate that the superficially porous spike particles 500 have excellent performance for chromatographic separation in terms of both higher efficiency and lower backpressure (higher permeability) than the 3-μm spherical particles.

[0095]

[0118] The foregoing specification has illustrated and described exemplary embodiments, but it will be apparent to those skilled in the art that various changes can be made and elements can be replaced with equivalents without departing from the scope of the invention. Further, many modifications can be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Accordingly, the invention is not intended to be limited to the particular embodiments disclosed as the best mode contemplated for carrying out the invention, but is intended to include all embodiments falling within the scope of the appended claims. Specific embodiments of the present invention are as follows. [Aspect 1] Spike particles, a core having an average core width and a core surface, a plurality of spikes attached to the core surface, extending from the core surface by an average spike length, and having an average spike width measured perpendicular to the average spike length, comprising wherein the spike particles are chromatography particles having sodium ions of 100 ppm or less, the core includes porosity selected from the group consisting of non-porous, surface-porous, porous, and combinations thereof, the plurality of spikes includes porosity selected from the group consisting of non-porous, surface-porous, and combinations thereof, the spike particles. [Aspect 2] The spike particles according to Aspect 1, wherein the core is surface-porous and includes a porous shell having randomly oriented pores. [Aspect 3] The spike particles according to Aspect 1, wherein the core is surface-porous and includes a porous shell having radially oriented pores. [Aspect 4] The spike particles according to Aspect 1, wherein the core is surface-porous and includes a porous shell thickness of about 5 nm to about 2 μm. [Aspect 5] The spike particles according to Aspect 1, wherein the core is surface-porous and includes a porous shell constituting about 5% to about 70% by volume of the core. [Aspect 6] The spike particles according to Aspect 1, wherein the ratio of the average spike length to the average core width is in the range of about 0.2 to about 30. [Aspect 7] The spike particles according to Aspect 1, wherein the aspect ratio of the average spike length to the average spike width is in the range of about 0.2 to about 50. [Aspect 8] The spike particles according to Aspect 1, wherein the core is formed from a material including silica, hybrid silica, alumina, titania, zirconia, ferric oxide, hematite, zinc oxide, carbon, silicon carbide, diamond, silver, gold, polystyrene, poly(methyl methacrylate), or combinations thereof. [Aspect 9] The spike particles according to Aspect 8, wherein the core and the plurality of spikes are formed from silica. [Aspect 10] The spike particles according to aspect 1, wherein the plurality of spikes are formed from a material comprising silica, hybrid silica, alumina, titania, zirconia, or a combination thereof. [Aspect 11] The spike particles according to aspect 1, wherein the core has a shape selected from the group consisting of a sphere, an ellipsoid of revolution, a polyhedron, a cube, a rectangular parallelepiped, a prism, a pyramid, a cylinder, a tube, a cone, a frustum of a cone, a disk, an annulus, an anchor ring, and combinations thereof. [Aspect 12] The spike particles according to aspect 1, wherein the number of the plurality of spikes is at least 4. [Aspect 13] The spike particles according to aspect 1, wherein the average spike length ranges from about 20 nm to about 20 μm. [Aspect 14] The spike particles according to aspect 1, wherein the average spike width ranges from about 50 nm to about 5 μm. [Aspect 15] About 5 cm 2 / g to about 500 cm 2 / g, a specific surface area in the range of about 0.05 cm 3 / g to about 1.5 cm3 / g, a specific pore volume in the range of about 3 nm to about 100 nm, an average pore diameter in the range of about 0.1 g / cm 3 to about 5.0 g / cm 3 The spike particles according to aspect 1 having a density in the range of. [Aspect 16] Less than about 5 cm 2 / g, a specific surface area of less than about 0.05 cm 3 / g, a specific pore volume of less than about 0.05 cm 3 / g, and a density in the range of about 1.5 g / cm 3 to about 2.5 g / cm [Aspect 17] The spike particles according to aspect 1, wherein the spike particles substantially do not contain metal ions and the content of metal impurities other than silicon is 100 ppm or less. [Aspect 18] Surface-porous spike particles, comprising: A core having an average core width and a core surface, the core being non-porous; A plurality of spikes attached to the core surface, the plurality of spikes being non-porous, extending from the core surface by an average spike length, and having an average spike width measured perpendicular to the average spike length; A porous spike particle shell disposed on the core and the plurality of spikes; Including, The spike particles are chromatography particles having sodium ions of 100 ppm or less. The surface-porous spike particles. [Aspect 19] A chromatography separation device comprising a plurality of spike particles, wherein each of the plurality of spike particles has: A core having an average core width and a core surface; A plurality of spikes adhering to the core surface, the plurality of spikes extending from the core surface by an average spike length and having an average spike width measured perpendicular to the average spike length comprising each of the plurality of spike particles being a chromatographic particle the core including porosity selected from the group consisting of non-porous, surface-porous, porous, and combinations thereof the plurality of spikes including porosity selected from the group consisting of non-porous, surface-porous, and combinations thereof the plurality of spike particles being randomly packed within the chromatographic separation device the randomly packed plurality of spike particles having an external porosity in the range of about 0.4 to about 0.9 the chromatographic separation device having increased fluid permeability compared to a comparative chromatographic separation device having a plurality of spherical particles that are identical in other respects but lack the plurality of spikes instead of the plurality of spike particles the chromatographic separation device [Aspect 20] The chromatographic separation device according to Aspect 19, which is a chromatographic column [Aspect 21] A method of forming a plurality of spike particles, comprising mixing a continuous oil phase and a dispersed water phase to form a water-in-oil emulsion system, wherein the continuous oil phase includes an organic solvent, polyvinylpyrrolidone, and a silane precursor the dispersed water phase includes a plurality of core particles, a water emulsion droplet stabilizer, and a catalyst said step and reacting the water-in-oil emulsion system without stirring to form the plurality of spike particles separating the plurality of spike particles from the water-in-oil emulsion system comprising each of the plurality of spike particles being a core having an average core width and a core surface, and a plurality of spikes adhering to the core surface, the plurality of spikes extending from the core surface by an average spike length and having an average spike width measured perpendicular to the average spike length including, the method [Aspect 22] The method according to embodiment 21, wherein the water emulsion droplet stabilizer is selected from the group consisting of organic ammonium citrate salts, ammonium dibasic tartrate, ammonium acidic urate, ammonium oxalate, ammonium dibasic citrate, diammonium hydrogen citrate, ammonium tribasic citrate, malic acid, lactic acid, uric acid, tartaric acid, oxalic acid, citric acid, and citric acid monohydrate. [Embodiment 23] The method according to embodiment 22, wherein the water emulsion droplet stabilizer contains ammonium dibasic citrate. [Embodiment 24] The method according to embodiment 21, which is carried out in the presence of a co-solvent having substantial solubility in both the continuous oil phase and the dispersed water phase. [Embodiment 25] The co-solvent is an alcohol having the formula C n H 2n+1 OH (wherein n is an integer from 1 to 4), according to the method of embodiment 24. [Embodiment 26] The method according to embodiment 25, wherein the alcohol is selected from the group consisting of ethanol, isopropanol, and combinations thereof. [Embodiment 27] The organic solvent is selected from alcohols having the formula C n H 2n+1 OH (wherein n is an integer from 5 to 10), according to the method of embodiment 21. [Embodiment 28] The method according to embodiment 21, wherein the organic solvent contains 1-pentanol. [Embodiment 29] The method according to embodiment 21, wherein the polyvinylpyrrolidone has an average molecular weight of about 10 kDa to about 130 kDa. [Embodiment 30] The method according to embodiment 21, wherein the silica precursor contains at least one of tetramethoxysilane, tetraethyl orthosilicate ("TEOS"), tetrapropoxysilane, or tetrabutoxysilane. [Embodiment 31] The method according to embodiment 30, wherein the silica precursor contains TEOS. [Embodiment 32] The method according to embodiment 21, wherein the catalyst contains a species selected from the group consisting of urea, amino acids, organic amines, quaternary ammonium hydroxides, ammonium hydroxide, and combinations thereof. [Embodiment 33] The method according to embodiment 32, wherein the catalyst contains ammonium hydroxide. [Embodiment 34] The method according to embodiment 21, wherein the organic solvent, the polyvinylpyrrolidone, the core particles, the water emulsion droplet stabilizer, and the catalyst are mixed for a mixing period of about 1 minute to about 2 days before the silane precursor is added. [Embodiment 35] The method according to embodiment 21, wherein the step of separating the plurality of spike particles from the water-in-oil emulsion system includes at least one of centrifugation or filtration. [Embodiment 36] The method according to aspect 21, further comprising the step of removing organic residues from the plurality of spike particles by calcination. [Aspect 37] The method according to aspect 21, further comprising the step of re-hydrolyzing the surface of the plurality of spike particles by etching. [Aspect 38] The step of placing the spike particles in a two-phase mixture comprising an aqueous lower phase and an organic upper phase, wherein the aqueous lower phase contains the spike particles, a template, and a catalyst, and the organic upper phase contains an upper-phase organic solvent and an upper-phase silane precursor; and heating the two-phase mixture under reflux conditions to form surface-porous spike particles each having a porous spike particle shell disposed on the spike particles. The method according to aspect 21, further comprising the step of [Aspect 39] The method according to aspect 38, wherein the two-phase mixed organic solvent contains cyclohexane. [Aspect 40] The method according to aspect 38, wherein the template contains cetyltrimethylammonium bromide.

Claims

1. A spike particle, comprising: a core having an average core width and a core surface; and a plurality of spikes attached to the core surface, extending from the core surface by an average spike length, and having an average spike width measured perpendicular to the average spike length. The spike particle further comprises: the spike particle is a chromatography particle having sodium ions of 100 ppm or less; the core is selected from the group consisting of non-porous, surface-porous, porous, and combinations thereof; the plurality of spikes is selected from the group consisting of non-porous, surface-porous, and combinations thereof; the spike particle.

2. The spike particle according to claim 1, wherein the core is surface-porous and comprises a porous shell having randomly oriented pores.

3. The spike particle according to claim 1, wherein the core is surface-porous and comprises a porous shell having radially oriented pores.

4. The spike particle according to claim 1, wherein the core is surface-porous and comprises a porous shell having a thickness of about 5 nm to about 2 μm.

5. The spike particle according to claim 1, wherein the core is surface-porous and comprises a porous shell constituting about 5 vol% to about 70 vol% of the core.

6. The spike particle according to claim 1, wherein the ratio of the average spike length to the average core width is in the range of about 0.2 to about 30.

7. The spike particle according to claim 1, wherein the aspect ratio of the average spike length to the average spike width is in the range of about 0.2 to about 50.

8. The spike particle according to claim 1, wherein the core is formed from a material comprising silica, hybrid silica, alumina, titania, zirconia, ferric oxide, hematite, zinc oxide, carbon, silicon carbide, diamond, silver, gold, polystyrene, poly(methyl methacrylate), or combinations thereof.

9. The spike particle according to claim 8, wherein the core and the plurality of spikes are formed from silica.

10. The spike particle according to claim 1, wherein the plurality of spikes is formed from a material comprising silica, hybrid silica, alumina, titania, zirconia, or combinations thereof.

11. The spike particle according to claim 1, wherein the core has a shape selected from the group consisting of a sphere, an ellipsoid of revolution, a polyhedron, a cube, a cuboid, a prism, a pyramid, a cylinder, a tube, a cone, a frustum of a cone, a disk, an annulus, an anchor ring body, and combinations thereof.

12. The spike particle according to claim 1, wherein the number of the plurality of spikes is at least 4.

13. The spike particle according to claim 1, wherein the average spike length is in the range of about 20 nm to about 20 μm.

14. The spike particle according to claim 1, wherein the average spike width is in the range of about 50 nm to about 5 μm.

15. About 5 cm ２ / g to about 500 cm ２ / g of specific surface area, about 0.05 cm ３ / g to about 1.5 cm ３ / g of specific pore volume, an average pore diameter in the range of about 3 nm to about 100 nm, and about 0.1 g / cm ３ to about 5.0 g / cm ３ The spike particles according to claim 1, having a density in the range of

16. About 5 cm ２ Specific surface area of less than / g, about 0.05 cm ３ Specific pore volume of less than / g, and about 1.5 g / cm ３ to about 2.5 g / cm ３ The spike particles according to claim 1, having a density in the range of.

17. The spike particle according to claim 1, wherein the spike particle substantially does not contain metal ions and the content of metal impurities other than silicon is 100 ppm or less.

18. Surface porous spike particles, comprising: a core having an average core width and a core surface, the core being non-porous; and a plurality of spikes attached to the core surface, the plurality of spikes being non-porous, extending from the core surface by an average spike length, and having an average spike width measured perpendicular to the average spike length; and a porous spike particle shell disposed on the core and the plurality of spikes. Including The surface porous spike particle is a chromatography particle having sodium ions of 100 ppm or less. The surface porous spike particle.

19. A chromatography separation device including a plurality of spike particles, wherein each of the plurality of spike particles has a core having an average core width and a core surface; and a plurality of spikes attached to the core surface, the plurality of spikes extending from the core surface by an average spike length and having an average spike width measured perpendicular to the average spike length. Including each of the plurality of spike particles is a chromatography particle; the core is selected from the group consisting of non-porous, surface porous, porous, and combinations thereof; the plurality of spikes is selected from the group consisting of non-porous, surface porous, and combinations thereof; the plurality of spike particles are randomly packed in the chromatography separation device; the randomly packed plurality of spike particles have an external porosity in the range of about 0.4 to about 0.

9. The chromatographic separation device has an increased fluid permeability compared to a comparative chromatographic separation device having a plurality of spherical particles that are otherwise identical but lack the plurality of spikes in place of the plurality of spike particles. The chromatographic separation device. **Claim 20** The chromatographic separation device according to claim 19, which is a chromatographic column. **Claim 21** A method for forming a plurality of spike particles, comprising: mixing a continuous oil phase and a dispersed water phase to form a water-in-oil emulsion system, wherein the continuous oil phase contains an organic solvent, polyvinylpyrrolidone, and a silica precursor, the dispersed water phase contains a plurality of core particles, a water emulsion droplet stabilizer, and a catalyst, said step; reacting the water-in-oil emulsion system without stirring to form the plurality of spike particles; separating the plurality of spike particles from the water-in-oil emulsion system; and each of the plurality of spike particles has a core having an average core width and a core surface, and a plurality of spikes attached to the core surface, the plurality of spikes extending from the core surface by an average spike length and having an average spike width measured perpendicular to the average spike length. The method as described above. **Claim 22** The method according to claim 21, wherein the water emulsion droplet stabilizer is selected from the group consisting of organic ammonium citrate salts, dibasic ammonium tartrate, acidic ammonium urate, ammonium oxalate, dibasic ammonium citrate, diammonium hydrogen citrate, tribasic ammonium citrate, malic acid, lactic acid, uric acid, tartaric acid, oxalic acid, citric acid, and citric acid monohydrate. **Claim 23** The method according to claim 22, wherein the water emulsion droplet stabilizer contains dibasic ammonium citrate. **Claim 24** The method according to claim 21, which is carried out in the presence of a co-solvent having substantial solubility in both the continuous oil phase and the dispersed water phase. **Claim 25** The co-solvent is an alcohol having the formula C ｎ H ２ｎ＋１ OH (wherein n is an integer of 1 to 4), the method according to claim 24. **Claim 26** The method according to claim 25, wherein the alcohol is selected from the group consisting of ethanol, isopropanol, and combinations thereof. **Claim 27** The organic solvent is selected from alcohols having the formula C ｎ H ２ｎ＋１ OH (wherein n is an integer from 5 to 10), the method according to claim 21. **Claim 28** The method according to claim 21, wherein the organic solvent contains 1-pentanol. **Claim 29** The method according to claim 21, wherein the polyvinylpyrrolidone has an average molecular weight of about 10 kDa to about 130 kDa.

30. The method according to claim 21, wherein the silica precursor comprises at least one of tetramethoxysilane, tetraethyl orthosilicate (“TEOS”), tetrapropoxysilane, or tetrabutoxysilane.

31. The method according to claim 30, wherein the silica precursor comprises TEOS.

32. The method according to claim 21, wherein the catalyst comprises a species selected from the group consisting of urea, amino acids, organic amines, quaternary ammonium hydroxides, ammonium hydroxide, and combinations thereof.

33. The method according to claim 32, wherein the catalyst comprises ammonium hydroxide.

34. The method according to claim 21, wherein the organic solvent, the polyvinylpyrrolidone, the core particles, the water emulsion droplet stabilizer, and the catalyst are mixed for a mixing period of about 1 minute to about 2 days before the silica precursor is added.

35. The method according to claim 21, wherein the step of separating the plurality of spike particles from the water-in-oil emulsion system comprises at least one of centrifugation or filtration.

36. The method according to claim 21, further comprising the step of removing organic residues from the plurality of spike particles by calcination.

37. The method according to claim 21, further comprising the step of re-hydrolyzing the surface of the plurality of spike particles by etching.

38. The step of placing the spike particles in a two-phase mixture comprising an aqueous lower phase and an organic upper phase, wherein the aqueous lower phase comprises the spike particles, a template, and a catalyst, and the organic upper phase comprises an upper-phase organic solvent and an upper-phase silica precursor; and heating the two-phase mixture under reflux conditions to form surface-porous spike particles each having a porous spike particle shell disposed on the spike particles.

39. The method according to claim 38, wherein the upper-phase organic solvent comprises cyclohexane.

40. The method according to claim 38, wherein the template comprises cetyltrimethylammonium bromide.

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