SiO2-layered double hydroxide microspheres and methods of making them

Abstract

Porous particles comprising an active ingredient and a coating exhibiting greater dissolution rate in aqueous media than in alcoholic media are disclosed. A process for the manufacture of the particles is also disclosed, as well as tamper-proof particles and solid dosage forms comprising the coated particles. The differential solubility characteristics of the particle coating allow the particles to be incorporated into abuse-deterrent medicaments.

Claims

1. Silica-layered double hydroxide microspheres having the formula I below
(SiO.sub.2).sub.p@{[M.sup.z+.sub.(1-x)M′.sup.y+.sub.x(OH).sub.2].sup.a+(X.sup.n−).sub.a/n.bH.sub.2O.c(AMO-solvent)}.sub.q  (I) wherein, M.sup.z+ and M′.sup.y+ are two different charged metal cations; z=1 or 2; y=3 or 4; 0<x<0.9; b is 0 to 10; c is 0 to 10; p>0, q>0; X.sup.n− is an anion; with n>0; a=z(1−x)+xy−2; and AMO-solvent is an 100% aqueous miscible organic solvent, wherein the silica-layered double hydroxide microspheres each comprise a SiO.sub.2 microsphere having solid layered double hydroxide attached to its surface, and wherein: A. the silica-layered double hydroxide microspheres are core-shell materials wherein the SiO.sub.2 microsphere is a solid sphere, and wherein the specific surface area of the core-shell materials is at least 100 m.sup.2/g, or B. the silica-layered double hydroxide microspheres are yolk-shell materials wherein the SiO.sub.2 microsphere comprises an outer shell and a smaller SiO.sub.2 sphere contained within the outer shell, wherein there is a hollow portion between the smaller sphere and the inner surface of the outer shell, and wherein the specific surface area of the yolk-shell materials is at least 100 m.sup.2/g, or C. the silica-layered double hydroxide microspheres are hollow shell materials wherein the SiO.sub.2 microsphere has a hollow interior, and wherein the hollow shell materials have a specific surface area of at least 130 m.sup.2/g; and wherein the silica-layered double hydroxide microspheres have a thickness of layered double hydroxide layer larger than 110 nm.

2. Silica-layered double hydroxide microspheres according to claim 1, wherein M′ is one or more trivalent cations and M is one or more divalent cations.

3. Silica-layered double hydroxide microspheres according to claim 1, wherein M′ is Al or Fe.

4. Silica-layered double hydroxide microspheres according to claim 1, wherein M is Ca, Cu, Ni or Mg.

5. Silica-layered double hydroxide microspheres according to claim 1, wherein X.sup.n− is carbonate, hydroxide, nitrate, borate, sulphate, phosphate, halide or a mixture of two or more thereof.

6. Silica-layered double hydroxide microspheres according to claim 1, wherein X.sup.n− is CO.sub.3.sup.2−, Cl.sup.−, NO.sub.3.sup.− or a mixture of two or more thereof.

7. Silica-layered double hydroxide microspheres according to claim 1, wherein M′ is Al or Fe, M is Ca, Cu, Ni or Mg, and X.sup.n− is CO.sub.3.sup.2−, Cl.sup.−, NO.sub.3.sup.− or a mixture of two or more thereof.

8. Silica-layered double hydroxide microspheres according to claim 1, wherein M is Mg, M′ is Al and X.sup.n− is CO.sub.3.sup.2−.

9. Silica-layered double hydroxide microspheres according to claim 1, wherein the silica microspheres comprise greater than 95% w/w SiO.sub.2.

10. Silica-layered double hydroxide microspheres according to claim 9, wherein M′ is Al or Fe, M is Ca, Cu, Ni or Mg, and X.sup.n− is CO.sub.3.sup.2−, Cl.sup.−, NO.sub.3.sup.− or a mixture of two or more thereof.

11. Silica-layered double hydroxide microspheres according to claim 9, wherein M is Mg, M′ is Al and X.sup.n− is CO.sub.3.sup.2−.

12. Silica-layered double hydroxide microspheres according to claim 1, wherein the silica microspheres do not contain iron.

13. Silica-layered double hydroxide microspheres according to claim 12, wherein M′ is Al or Fe, M is Ca, Cu, Ni or Mg, and X.sup.n− is CO.sub.3.sup.2−, Cl.sup.−, NO.sub.3.sup.− or a mixture of two or more thereof.

14. Silica-layered double hydroxide microspheres according to claim 12, wherein M is Mg, M′ is Al and X.sup.n− is CO.sub.3.sup.2−.

15. Silica-layered double hydroxide microspheres according to claim 1, wherein c is greater than zero.

16. Silica-layered double hydroxide microspheres according to claim 15, wherein the AMO-solvent is acetone, ethanol, methanol or a mixture of two or more thereof.

17. Silica-layered double hydroxide microspheres according to claim 16, wherein M′ is Al or Fe, M is Ca, Cu, Ni or Mg, and X.sup.n− is CO.sub.3.sup.2−, Cl.sup.−, NO.sub.3.sup.− or a mixture of two or more thereof.

18. Silica-layered double hydroxide microspheres according to claim 17, wherein the silica microspheres comprise greater than 95% w/w SiO.sub.2.

19. Silica-layered double hydroxide microspheres according to claim 16, wherein M is Mg, M′ is Al and X.sup.n− is CO.sub.3.sup.2−.

20. Silica-layered double hydroxide microspheres according to claim 19, wherein the silica microspheres do not contain iron.

Description

FIGURES

(1) FIG. 1. XRD patterns showing three sizes of silica nanoparticles (a) 300 nm, (b) 550 nm and (c) 800 nm.

(2) FIG. 2. TGA curves of differently sized silica nanoparticles (a) 800 nm, (b) 550 nm and (c) 300 nm.

(3) FIG. 3. SEM images of 800 nm silica microspheres prepared via seeded growth.

(4) FIG. 4. XRD patterns of (a) 550 nm silica microspheres, (b) LDH nano-particles and (c) SiO.sub.2@LDH microspheres ((b) and (c) were synthesized according to example 1).

(5) FIG. 5. Percentage weight loss of (a) LDH, (b) SiO.sub.2@LDH microspheres and (c) silica nanoparticles ((a) and (b) were synthesized according to example 1).

(6) FIG. 6. .sup.29Si Solid-state NMR of (a) silica microspheres and (b) SiO.sub.2@LDH microspheres ((b) were synthesized according to example 1).

(7) FIG. 7. XRD patterns of SiO.sub.2@LDH microspheres prepared at different pH conditions (a) ammonia method (example 4), (b) pH 9, (c) pH 10 and (d) pH 11 ((b)-(d): example 1).

(8) FIG. 8. TGA of SiO.sub.2@LDH microspheres prepared at different pH conditions (a) pH 11, (b) pH 10, (c) ammonia method and (d) pH 9.

(9) FIG. 9. TEM images of SiO.sub.2@LDH microspheres synthesized according to example 1 except at different temperatures (a) room temperature (b) 40° C.

(10) FIG. 10. TGA and dTGA curves of SiO.sub.2@LDH microspheres prepared according to example 1 except at different temperature (a) room temperature and (b) 40° C., (i) TGA curve, (ii) dTGA curve.

(11) FIG. 11. Solid state NMR (a).sup.29Si (b).sup.27Al. SiO.sub.2 @ LDH prepared according to example 1 except at different temperature (i) at room temperature (ii) at 40° C.

(12) FIG. 12. XRD patterns of SiO.sub.2@LDH microspheres prepared with different Mg:Al ratios (a) 1:1 (example 2), (b) 3:1 (example 3).

(13) FIG. 13. XRD patterns of SiO.sub.2@LDH microspheres prepared according to example 1 (a) conventional water washing (b) acetone washing.

(14) FIG. 14. TGA of SiO.sub.2@LDH microspheres prepared according to example 2 (a) conventional water washing (b) acetone washing.

(15) FIG. 15. TEM image of SiO.sub.2@LDH microspheres with different ratio of Mg/Al (a) 1:1 (example 2), (b) 2:1 (example 1) and (c) 3:1 (example 3).

(16) FIG. 16. TEM image of SiO.sub.2@LDH microspheres according to example 1 except with different size of silica (a) 300 nm, (b) 550 nm and (c) 800 nm.

(17) FIG. 17. TEM image of SiO.sub.2@LDH microspheres with different morphology (a) solid (example 1), (b) yolk-shell (example 1 at 40° C.) and (c) hollow (example 1 at pH 11).

(18) FIG. 18. XRD patterns of SiO.sub.2@AMO-LDH with an Mg:Al=3:1 (a) pH=10 and room temperature (b) pH=10 and 40° C. (c) pH=11 and 40° C.

(19) FIG. 19. XRD patterns of SiO.sub.2@AMO-LDH with Mg:Ni:Al=2.7:0.3:1 (a) pH=10 and room temperature (b) pH=10 and 40° C. (c) pH=11 and 40° C.

(20) FIG. 20. XRD patterns of SiO.sub.2@AMO-LDH with an Mg:Al:Fe=3:0.9:0.1 (a) pH=10 and room temperature (b) pH=10 and 40° C. (c) pH=11 and 40° C.;

(21) FIG. 21. TEM image of SiO.sub.2@AMO LDH microspheres according to examples 5 and 7 at pH=10 and room temperature (a) Mg:Al=3:1 (b) Mg:Al:Fe=3:0.9:0.1.

(22) FIG. 22. TEM image of SiO.sub.2@AMO-LDH with Mg:Ni:Al=2.7:0.3:1 microspheres with different morphology according to example 6 (a) pH=10 and room temperature (b) pH=10 and 40° C. (c) pH=11 and 40° C.

EXPERIMENTAL METHODS

(23) 1. General Details

(24) 1.1 Powder X-Ray Diffraction

(25) Powder X-ray diffraction (XRD) data were collected on a PANAnalytical X'Pert Pro diffractometer in reflection mode and a PANAnalytical Empyrean Series 2 at 40 kV and 40 mA using Cu Kα radiation (α1=1.54057 Å, α2=1.54433 Å, weighted average=1.54178 Å). Scans were recorded from 5°≤0≤70° with varying scan speeds and slit sizes. Samples were mounted on stainless steel sample holders. The peaks at 43-44° are produced by the XRD sample holder and can be disregarded.

(26) 1.2 Thermogravimetric Analysis

(27) Thermogravimetric analysis (TGA) measurements were collected using a Netzsch STA 409 PC instrument. The sample (10-20 mg) was heated in a corundum crucible between 30° C. and 800° C. at a heating rate of 5° C. min-1 under a flowing stream of nitrogen.

(28) 1.3 Solid State NMR Spectroscopy

(29) .sup.29Si and .sup.27Al MAS NMR spectra were recorded on a Varian Chemagnetics CMX Infinity 200 (4.7 T). Samples were packed in 7.5 mm zirconia rotors. A double resonance MAS probe was used for all measurements and a MAS rate of 4 kHz for .sup.29Si, whereas MAS rate of 6 kHz was used for .sup.27Al. .sup.27Al MAS NMR spectra were acquired with a single pulse excitation applied using a short pulse length (0.7 μs). Each spectrum resulted from 2000 scans separated by 1 s delay. The .sup.27Al chemical shifts are referenced to an aqueous solution of Al(NO.sub.3).sub.3 (δ=0 ppm). In order to obtain the quantitative .sup.29Si DPMAS NMR spectra, 5000 transients were typically acquired with an acquisition time of 68 ms (1024 data points zero filled to 16K) and recycle delay of 30 s. All .sup.29Si spectra were externally referenced to kaolinite (taken to be at δ=−91.7 ppm on a scale where δ(TMS)=0 ppm) as a secondary reference.

(30) 1.4 Transmission Electron Microscopy

(31) Transmission Electron Microscopy (TEM) analysis was performed on a JEOL 2100 microscope with an accelerating voltage of 200 kV. Particles were dispersed in water or ethanol with sonication and then cast onto copper grids coated with carbon film and left to dry.

(32) 1.5 Scanning Electron Microscopy

(33) Scanning Electron Microscopy (SEM) analysis was performed on a JEOL JSM 6610 scanning electron microscope. Particles were dispersed in water and cast onto a clean silica wafer. Before imaging, the samples were coated with a thin platinum layer to prevent charging and to improve the image quality. Energy dispersive X-ray spectroscopy (EDX), also carried out on this instrument, was used to determine the relative quantities of constituent elements on the surface of the sample.

(34) 1.6 Brunauer-Emmett-Teller Surface Area Analysis

(35) Brunauer-Emmett-Teller (BET) specific surface areas were measured from the N.sub.2 adsorption and desorption isotherms at 77 K collected from a Quantachrome Autosorb surface area and pore size analyser.

Example 1

(36) Silica spheres (100 mg, 550 nm) were dispersed in deionised water (20 mL) using ultrasound treatment. After 30 min., Na.sub.2CO.sub.3 (0.96 mmol) was added to the solution and a further 5 min of sonication was carried out to form solution A. Next an aqueous solution (19.2 mL) containing Mg(NO.sub.3).sub.2.6H.sub.2O (0.96 mmol) and Al(NO.sub.3).sub.3.9H.sub.2O (0.48 mmol) was added at a rate of 60 mL/h to solution A under vigorous stirring at room temperature. The pH of the reaction solution was controlled to be 10 with the addition of 1 M NaOH. The obtained solid was collected with centrifugation at 4000 rpm for 5 min and then re-dispersed in deionised water (40 mL) and stirred for 1 h. The collection and re-dispersion were repeated twice. Afterward, the solid was washed with acetone (40 mL) and then re-dispersed in acetone (40 mL) and left to stir overnight. The solid was then dried under vacuum.

(37) The SiO.sub.2@LDH obtained in this Example, before the treatment with acetone, has the formula:—
(SiO.sub.2).sub.0.04@{[Mg.sub.0.75Al.sub.0.25(OH).sub.2](CO.sub.3).sub.0.125.1.34(H.sub.2O)}.sub.0.05

(38) The SiO.sub.2@AMO-LDH, obtained after acetone treatment, has the formula:—
(SiO.sub.2).sub.0.04@{[Mg.sub.0.75Al.sub.0.25(OH).sub.2](CO.sub.3).sub.0.125.0.29(H.sub.2O).0.15(acetone)}.sub.0.05

(39) Yolk shell particles were obtained by carrying out the addition of the aqueous solution containing the Mg(NO.sub.3).sub.2.6H.sub.2O and Al(NO.sub.3).sub.3.9H.sub.2O at 40° C. and pH10.

(40) Hollow shell particles were obtained by carrying out the addition of the aqueous solution containing Mg(NO.sub.3).sub.2.6H.sub.2O and Al(NO.sub.3).sub.3.9H.sub.2O at room temperature but at pH11.

(41) Surface Area Analysis

(42) The solid SiO.sub.2@LDH, the yolk shell SiO.sub.2@LDH and the hollow shell SiO.sub.2@LDH prepared as described above but without acetone treatment were subjected to Brunauer-Emmett-Teller (BET) surface area analysis.

(43) The N.sub.2 BET surface areas of the products were:

(44) TABLE-US-00001 BET surface area (m.sup.2g.sup.−1) Solid (i.e. core-shell) SiO.sub.2@LDH 107 Yolk-shell SiO.sub.2@LDH 118 Hollow-shell SiO.sub.2@LDH 177

(45) The BET surface areas reported above may be favourably compared to those of SiO.sub.2@LDHs prepared according to (A) Shao et a. Chem. Mater. 2012, 24, pages 1192-1197 and to those of SiO.sub.2@LDHs prepared according to (B) Chen et a. J. Mater. Chem. A, 1, 3877-3880.

(46) (A) SiO.sub.2 Microspheres Pre-Treated with Al(OOH).

(47) TABLE-US-00002 Product SiO.sub.2@NiAl LDH. BET surface area (m.sup.2g.sup.−1) Solid (i.e. core-shell) SiO.sub.2 microspheres 42.3 Yolk-shell SiO.sub.2@LDH microspheres 68 Hollow-shell SiO.sub.2@LDH microspheres 124
(B) SiO.sub.2 Microspheres—No Pre-Treatment—Ammonia Method.

(48) TABLE-US-00003 Product SiO.sub.2@LDH. BET surface area (m.sup.2g.sup.−1) Solid (i.e. core-shell) SiO.sub.2@LDH microspheres 61

(49) Core-shell SiO.sub.2@LDHs were prepared according to the procedures described in Example 1 and in the Examples 2 and 3 below having different thicknesses of LDH layer. The ratio of Mg/Al was varied to control the thickness of the LDH layer. A Mg:Al ratio of 1:1 was found to give an LDH layer of thickness 65 nm, a ratio of 2:1 was found to give an LDH layer of thickness 110 nm and a layer of thickness of 160 nm was obtained using a Mg:Al ratio of 3:1. TEM images are shown in FIG. 15. Core-shell SiO.sub.2@LDHs were also prepared according to the procedure described in Example 1 above using different sized SiO.sub.2 microspheres, 300 nm, 550 nm and 800 nm. TEM images are shown in FIG. 16. TEM images of the SiO.sub.2@LDHs produced with different morphology (a) solid (Example 1), (b) yolk shell (Example 1 at 40° C.) and (c) hollow (Example 1 at pH11), as described above, are shown in FIG. 17.

Example 2

(50) In order to obtain a 1:1 Mg:Al LDH, the procedure described above in Example 1 was repeated with the exception that an aqueous solution (19.2 mL) containing Mg(NO.sub.3).sub.2.6H.sub.2O (0.72 mmol) and Al(NO.sub.3).sub.3.9H.sub.2O (0.72 mmol) was added at a rate of 60 mL/h to solution A under vigorous stirring.

Example 3

(51) In order to obtain a 3:1 Mg:Al LDH, the procedure described above in Example 1 was repeated with the exception that an aqueous solution (19.2 mL) containing Mg(NO.sub.3).sub.2.6H.sub.2O (1.08 mmol) and Al(NO.sub.3).sub.3.9H.sub.2O (0.36 mmol) was added at a rate of 60 mL/h to solution A under vigorous stirring.

(52) The XRD patterns of the SiO.sub.2@LDH samples prepared with Mg:Al ratios of 1:1 (Example 2) and 3:1 (Example 3) are shown in FIG. 12.

Example 4

(53) The silica@LDH particles were synthesised via the coprecipation method. Silica spheres (100 mg, 550 nm) were dispersed in deionised water (20 mL) using ultrasound treatment. After 30 min, the anion salt (0.96 mmol), Na.sub.2CO.sub.3, was added to the solution containing ammonia (0.8 mL, 35%) and a further 5 min of sonication was carried out to form solution A. Next an aqueous solution (19.2 mL) containing Mg(NO.sub.3).sub.2.6H.sub.2O) (0.96 mmol) and Al(NO.sub.3).sub.3.9H.sub.2O (0.48 mmol) was added at a rate of 60 mL/h to solution A under vigorous stirring. The obtained solid was collected with centrifugation at 4000 rpm for 5 min and then re-dispersed in deionised water (40 mL) and stirred for 1 h. The collection and re-dispersion were repeated twice. Afterward, the solid was washed with acetone (40 mL) and then re-dispersed in acetone (40 mL) and left to stir overnight. The solid was then dried under vacuum. The suspension was then dried under vacuum for materials characterisation.

(54) The features disclosed in the foregoing description, in the claims as well as in the accompanying drawings, may both separately and in any combination thereof be material for realizing the invention in diverse forms thereof.

Example 5

(55) In order to obtain Silica@AMO-LDHs in Mg:Al=3:1. Synthesise the Silica@LDH particles by using the co-precipitation method, disperse silica spheres (100 mg) in the deionised water (20 mL) by using ultrasound treatment for 30 min, add the anion salt Na.sub.2CO.sub.3 (0.96 mmol) in the solution and further treat by ultrasound for 5 min, the finally solution named A. Then add an aqueous solution (19.2 mL) containing (1.08 mmol) Mg.sup.2+ and (0.36 mmol) Al.sup.3+ in the solution A at the rate of 60 mL/h with vigorous stirring. The pH of the reaction solution is controlled with the addition of 1 M NaOH by an autotitrator. And the morphology of Silica@LDH is controlled by pH and temperature. The obtained solid is collected with centrifugation at 5000 rpm for 5 min and then re-dispersed in deionised water (40 mL) and stir for 1 h, the washing need repeated twice. Before final isolation, the solid is washed with acetone (40 mL) and left to stir over night, and the suspension is then dried under vacuum

Example 6

(56) In order to obtain Silica@AMO-LDHs in Mg:Ni:Al=2.7:0.3:1. The Silica@LDH particles will be synthesized by using the co-precipitation method, disperse silica spheres (100 mg) in the deionised water (20 mL) by using ultrasound treatment for 30 min, add the anion salt Na.sub.2CO.sub.3 (0.96 mmol) in the solution and further treat by ultrasound for 5 min, the finally solution named A. Then add an aqueous solution (19.2 mL) containing (0.972 mmol) Mg.sup.2+, (0.108 mmol) Ni.sup.2+ and (0.36 mmol) Al.sup.3+ in the solution A at the rate of 60 mL/h with vigorous stirring. The pH of the reaction solution is controlled with the addition of 1 M NaOH by an autotitrator. As followed the morphology of Silica@LDH is controlled by pH and temperature. The obtained solid is collected with centrifugation at 5000 rpm for 5 min and then re-dispersed in deionised water (40 mL) and stir for 1 h, the washing need repeated twice. Before final isolation, the solid is washed with acetone (40 mL) and left to stir over night, and the suspension is then dried under vacuum.

Example 7

(57) In order to obtain Silica@AMO-LDHs in Mg:Al:Fe=3:0.9:0.1. The Silica@LDH particles synthesise using the co-precipitation method, disperse silica spheres (100 mg) in the deionised water (20 mL) by using ultrasound treatment for 30 min, add the anion salt Na.sub.2CO.sub.3 (0.96 mmol) in the solution and further treat by ultrasound for 5 min, the finally solution named A. Then add an aqueous solution (19.2 mL) containing (1.08 mmol) Mg.sup.2+, (0.324 mmol) Al.sup.3+ and (0.036 mmol) Fe.sup.3+ in the solution A at the rate of 60 mL/h with vigorous stirring. The pH of the reaction solution is controlled with the addition of 1 M NaOH by an autotitrator. As followed the morphology of Silica@LDH is controlled by pH and temperature. The obtained solid is collected with centrifugation at 5000 rpm for 5 min and then re-dispersed in deionised water (40 mL) and stir for 1 h, the washing need repeated twice. Before final isolation, the solid is washed with acetone (40 mL) and left to stir over night, and the suspension is then dried under vacuum