Layered double hydroxides

Abstract

The invention relates to layered double hydroxide (LDH) materials and in particular to new methods of preparing improved LDH materials which have intercalated active anionic compounds (improved LDH-active anion materials). The improved LDH-active anion materials are characterized by their high degree of robustness, demonstrated by their high Particle Robustness Factor values, and by their ability to retain substantially all of the intercalated active anionic compound, in the absence of ion exchange conditions and/or at pH>4.

Claims

1. A treatment process for preparing a treated layered double hydroxide-active anion material comprising a layered double hydroxide material intercalated with one or more active anions, comprising the steps: a) dispersing a layered double hydroxide-active anion starting material in a liquid dispersant, then heating and agitating the resulting suspension for a period of between 2 to 72 hours, at a specific temperature or over a range of temperatures, above 80 C. to 200 C.; b) cooling the heated suspension and separating the heat treated layered double hydroxide-active anion material from the suspension; c) washing the heat treated layered double hydroxide-active anion material one or more times with water and then a further washing liquid, and then drying the washed heat treated layered double hydroxide-active anion material at an elevated temperature of at least 50 C., and optionally under vacuum, to thereby yield the treated layered double hydroxide-active anion material; wherein the treated layered double hydroxide-active anion material consists of mixed hydroxides of one or more trivalent metal cations and one or more divalent metal cations, having an excess positive charge that is balanced by one or more intercalated active anions, and wherein the one or more divalent metal cations are selected from the group consisting of Co.sup.2+, Ni.sup.2+, Cu.sup.2+, Zn.sup.2+, Mn.sup.2+, Pd.sup.2+, Ti.sup.2+, Ca.sup.2+, Cd.sup.2+, and Mg.sup.2+.

2. A process according to claim 1, wherein drying in step c) comprises drying with agitation.

3. A treated layered double hydroxide-active anion material made by the treatment process of claim 1.

4. A treated layered double hydroxide-active anion material according to claim 3 combined with one or more pharmaceutically acceptable excipients.

5. A treated layered double hydroxide-active anion material according to claim 3, wherein the one or more intercalated active anions are derived from compounds selected from the group consisting of NSAIDS, gaba-analogues, antibiotics, statins, angiotensin-converting enzyme (ACE) inhibitors, antihistamines and dopamine precursors, anti-microbials, psychostimulants, prostaglandins, anti-depressants, anti-convulsants, coagulants, anti-cancer agents, immuno-suppressants, laxatives, dye compounds, agrochemicals, medicaments and food supplements and molecules or compounds used in food, beverages and pharmaceuticals.

6. A treated layered double hydroxide-active anion material according to claim 3, comprising one or more intercalated active anions derived from compounds selected from Ibuprofen, Naproxen and Diclofenac.

7. A treated layered double hydroxide-active anion material according to claim 3, comprising one or more intercalated active anions which are derived from poor tasting or irritating substances.

8. A formulation comprising a treated layered double hydroxide-active anion material made according to the process of claim 1 selected from the group consisting of dry granules, tablets, caplets, aqueous or non-aqueous liquids or suspensions, orally disintegrating tablets, orally disintegrating granules, lozenges, films, capsules, powders, effervescent formulations, buccal and sub-lingual formats, gels, syrups and gums.

9. A method of producing a formulation comprising formulating one or more treated layered double hydroxide-active anion materials made according to the process of claim 1, in a form selected from the group consisting of dry granules, tablets, caplets, aqueous or non-aqueous liquids or suspensions, orally disintegrating tablets, orally disintegrating granules, lozenges, films, capsules, powders, effervescent formulations, buccal and sub-lingual formats, gels, syrups and gums.

10. A method of producing a formulation according to claim 9, which exhibits a substantially zero taste sensation, burn or irritation, within the mouth, buccal cavity, larynx or gastrointestinal tract of the consumer or patient, comprising formulating one or more treated layered double hydroxide-active anion materials made according to the process of claim 1 in a form selected from the group consisting of dry granules, tablets, caplets, aqueous or non-aqueous liquids or suspensions, orally disintegrating tablets, orally disintegrating granules, lozenges, films, capsules, powders, effervescent formulations, buccal and sub-lingual formats, gels, syrups and gums.

11. The treated layered double hydroxide-active anion material according to claim 3, wherein one or more intercalated active anions are configured to leach a total of less than 5% by weight into a solvent suitable for dissolving the one or more active anions, in the absence of ion exchange conditions and/or at a pH>4.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows a typical X-Ray Powder Diffractogram of an LDH-Ibuprofen material made using the ion exchange process of the prior art;

(2) FIG. 2 shows a typical X-Ray Powder Diffractogram of LDH-Ibuprofen material produced by a Co-precipitation process;

(3) FIG. 3 shows a typical X-Ray Powder Diffractogram of LDH-Ibuprofen material produced by Co-precipitation method followed by a hydrothermal treatment as described in US2010/0233286 A1; and

(4) FIG. 4 shows a typical X-Ray Powder Diffractogram of LDH-Ibuprofen material produced by a Co-precipitation method followed by the process according to the present invention for preparing an improved LDH-Ibuprofen material.

EXAMPLE 1

The Preparation of Mg2Al(OH)6(C13H17O2).nH2O Ibuprofen Aluminium Magnesium Hydroxide by the Ion Exchange process described in EP1341556

(5) Starting Materials:

(6) Mg.sub.2Al(OH).sub.6(NO.sub.3), MgAlNO.sub.3: 0.885 g; 3.69 mmol C.sub.13H.sub.18O.sub.2, Ibuprofen: 1.521 g; 7.38 mmol

(7) NaOH, Sodium Hydroxide: 0.295 g; 7.38 mmol

(8) Method:

(9) The MgAlNO.sub.3 was added to 25 ml of distilled H.sub.2O in a round bottomed flask which was then sealed under N.sub.2 gas and sonicated for 15-30 minutes to form a suspension of MgAlNO.sub.3. A separate solution of ibuprofen was made by adding the ibuprofen with stirring to a solution of the NaOH dissolved in 25 ml of distilled H.sub.2O, whilst bubbling through with N.sub.2 gas on complete addition the N.sub.2 gas was bubbled through for a further 5-10 minutes. The alkaline sodium Ibuprofen solution was then added to the MgAlNO.sub.3 suspension and the stirred mixture was heated to 60 C. under a flow of N.sub.2 gas. Once at 60 C., the reaction vessel was sealed under N.sub.2 and stirred for a further 48 hours. Effort was made to maintain stirring of the mixture throughout. The resulting reaction mixture was then vacuum-filtered and the recovered Ibuprofen Aluminium Magnesium Hydroxide product washed with distilled H.sub.2O, and then acetone and finally allowed to air-dry. A typical XRP Diffractogram for this material is shown in FIG. 1.

EXAMPLE 2

The Preparation of Mg2Al(OH)6(C13H17O2).nH2O(MgAl-Ibuprofen) Using a One-Step Co-Precipitation Method

(10) Magnesium nitrate 257 g and aluminium nitrate 189 g were stirred in 1000 ml deionised water in a round bottomed flask, under N.sub.2 until they had dissolved. In a separate container, the active anionic compound Ibuprofen 258 g was dissolved with stirring in 1500 ml of deionised water under N.sub.2, and the pH was adjusted to 10.0 using 2M sodium hydroxide solution. The Ibuprofen solution was then heated to 80 C. and once up to temperature, the aqueous metal nitrate solution was added drop-wise using an addition funnel and the mixture was stirred vigorously. The pH was maintained at between 9.5 and 13 throughout the period of addition, using 2M sodium hydroxide solution via a second addition funnel. Addition of the Ibuprofen solution was complete within 30 minutes to 2 hours. Following complete addition, the reaction mixture was stirred for a further 10 minutes under N.sub.2 and then allowed to cool to room temperature. The resultant LDH-Ibuprofen compound was isolated from the reaction mixture using vacuum filtration, ensuring that the recovered solid product was washed at least twice with 1000 ml of deionised water. Solid Ibuprofen Aluminium Magnesium Hydroxide (200 g) was obtained. FIG. 2 shows a typical XRP Diffractogram for this product material.

EXAMPLE 3

Attempt to Optimise the Robustness of the Structure of the Ibuprofen Aluminium Magnesium Hydroxide Material from Example 2 Using a Hydrothermal Treatment Step Method as Described in US2010/0233286 A1

(11) Starting Materials:

(12) Ibuprofen aluminium magnesium hydroxide compound (200 g) obtained from the method of Example 2.

(13) Method:

(14) The solid product obtained from Example 2 was dispersed in 3750 ml deionised water as evenly as possible, and the dispersion was heated at 150 C. for 1-4 hours in an autoclave. The suspension was then cooled to room temperature, and the recovered solid product filtered, washed with 1000 ml deionised water and then air dried. A typical XRP Diffractogram for this product is shown in FIG. 3.

EXAMPLE 4

Optimising the Robustness of the Structure of the Ibuprofen Aluminium Magnesium Hydroxide Material from Example 2 Using the Method of the Present Invention to Produce Improved LDH-Ibuprofen Material

(15) Starting Materials:

(16) Ibuprofen Aluminium Magnesium Hydroxide compound (200 g) obtained from the method of Example 2.

(17) Method:

(18) The solid product obtained in Example 2 was dispersed as evenly as possible in 3750 ml of deionised water in an autoclave and heated to 150 C. for 2 hours under N.sub.2 with stirring. The reaction mixture was then cooled to room temperature, and the solid removed by vacuum filtration. The solid was then washed with 1000 ml deionised water and 1000 ml methanol. The lumps were broken up and the solid was dried with stirring under vacuum at 60 C., until a constant weight was achieved. A typical XRP Diffractogram for this material is shown in FIG. 4.

(19) Results: Determination of the Particle Robustness Factor for the Ibuprofen Aluminium Magnesium Hydroxide Compound Produced in Examples 1, 2, 3 and 4.

(20) Samples of Ibuprofen Aluminium Magnesium Hydroxide compound were prepared using one of the four methods described in Examples 1, 2, 3 and 4 above, and each was analysed using X-ray diffraction techniques. The XRP Diffractograms for these materials are given in FIGS. 1, 2, 3, and 4 respectively. The Scherrer equation was then used to determine the value of tau for each of the four most dominant peaks in the X-ray diffraction pattern, and from this an average value of tau (the Particle Robustness Factor, PRF) across these four most dominant peaks was calculated for each sample of LDH-Ibuprofen compound. All tau values were normalised using a zero background intensity silicon wafer standard. The Results are presented below in Tables 1, 2, 3 and 4.

(21) Typical operating conditions used to obtain the X-ray diffraction patterns are as follows:

(22) Slit sizes: Divergence slit fixed: 2, Receiving slit: 1.52

(23) Range: 2-75 2

(24) x-ray wavelength=K-Alpha1 wavelength: 1.540598, K-Alpha2 wavelength: 1.544426

(25) Scan type: Continuous

(26) Scan step size (2):0.0334225 Time per step (secs): 280.035.

(27) TABLE-US-00001 TABLE 1 Ion-Exchange (EXAMPLE 1) , degrees , radians , radians T, Tau Peak 1 (003) 2.0409 0.035620425 0.184 5.438232 Peak 2 (006) 4.0679 0.070998249 0.4015 2.496951 Peak 3 (009) 6.00755 0.104851527 0.4015 2.504414 Peak 4 (0012) 8.0593 0.14066132 0.5353 1.886746 Average (PRF) 3.081586

(28) TABLE-US-00002 TABLE 2 One-Step Co-precipitation (EXAMPLE 2) , degrees , radians , radians T, Tau Peak 1 (003) 1.9963 0.034842008 0.1338 7.47838 Peak 2 (006) 4.03385 0.070403964 0.4723 2.122557 Peak 3 (009) 5.9926 0.104590601 0.5038 1.995821 Peak 4 (0012) 7.98685 0.139396829 0.3779 2.672122 Average (PRF) 3.56722

(29) TABLE-US-00003 TABLE 3 One-Step Co-precipitation Followed by Hydrothermal Treatment (EXAMPLE 3) , degrees , radians , radians T, Tau Peak 1 (003) 2.0089 0.035061919 0.2249 4.449155 Peak 2 (006) 4.0565 0.070799281 0.1875 5.346728 Peak 3 (009) 6.07215 0.10597901 0.3374 2.980564 Peak 4 (0012) 8.1694 0.142582928 0.5248 1.925022 Average (PRF) 3.675367

(30) TABLE-US-00004 TABLE 4 One-step co-precipitation followed by the Optimisation Method of the Present Invention (EXAMPLE 4) , degrees , radians , radians T, Tau Peak 1 (003) 2.0014 0.03493102 0.1288 7.768714 Peak 2 (006) 4.0332 0.070392619 0.1473 6.805721 Peak 3 (009) 6.0405 0.105426613 0.1473 6.82677 Peak 4 (0012) 8.0891 0.141181428 0.1288 7.842 Average (PRF) 7.310801

(31) As is clearly observed from a comparison of the average tau values presented in the Tables 1 to 4 above, the particle optimisation method of the present invention (Example 4) is extremely surprisingly significantly more efficient at producing highly robust LDH-Ibuprofen compounds than either the hydrothermal process employed in Example 3 (taken from the method described in US 2010/0233286) or the ion-exchange process used in Example 1 (as described in EP1 341 556). Therefore these results demonstrate that the optimisation process of the present invention is highly effective at producing remarkably robust particles.

(32) Also as discussed above, the Applicant has found that such materials are particularly useful at reducing and or eliminating leaching of the intercalated anionic material from the LDH-Ibuprofen compound. The % w/w amount of active anionic compound that leaches from the LDH-active anion material may be determined using any convenient leaching method known in the art, for example as described in EP1341556B1.

(33) Results:

(34) The % w/w amount of Ibuprofen which leaches from samples of LDH-Ibuprofen materials prepared in Examples 1-4 was determined using standard analytical tools and presented in Table 5 below, together with taste data to show how effective each sample is at providing a formulation with low or no taste.

(35) TABLE-US-00005 TABLE 5 METHOD USED TO PREPARE BURN, IBUPROFEN ALUMINIUM IRRITATION OR MAGNESIUM HYDROXIDE (LDH- LEACHATE, POOR TASTE ACTIVE ANION COMPOUND) % w/w PRESENT? Ion Exchange (Example 1) Not tested YES One-step Co-precipitation 6.2 YES (Example 2) One-step Co-precipitation 10.7 YES followed by hydrothermal treatment from US2010/0233286 (Example 3) One-step Co-precipitation 0.7 NO followed by the optimisation method of the present invention (Example 4)

(36) The above results show that particle optimisation process of the present invention (Example 4) produces improved LDH-Ibuprofen materials which are capable of retaining almost 100% of the intercalated active anionic compound with only 0.7% w/w of ibuprofen leaching out.

(37) This result compares extremely favourably against the 10.7% w/w ibuprofen which was observed to leach from materials treated with the hydrothermal process of Example 3. Indeed the above results indicate that the hydrothermal treatment method described in US2010/0233286 actually increases the amount of ibuprofen that leaches from the material made in Example 2.

(38) In addition to this, the above leaching tests were conducted on samples where the deionised water had been in contact with the LDH-ibuprofen for 5 minutes. A parallel experiment in which the deionised water was in contact for 30 minutes produced identical low leaching level results (0.7% w/w) for the improved LDH-active anion material of the present invention. This is a clear demonstration that the ibuprofen is not continuously released from the improved LDH-active anion materials of the present invention and that the 0.7% w/w recorded is the total amount of material leached in the absence of ion exchange conditions and at a pH>4.

(39) As the results in Table 5 also demonstrate, the burn/poor taste associated with ibuprofen is detectable in the mouth when the leaching level is 6.2% w/w, but not detected when the ibuprofen leaching level is 0.7% w/w. Thus 0.7% w/w ibuprofen as determined by the above leaching test is advantageously below the threshold for bitter taste/irritation detection by humans, and consequently the improved LDH-active anion materials of the present invention are highly suitable for use in the preparation of taste, burn and/or irritation masked formulations.