GRANULES COMPRISING SURFACE-REACTED CALCIUM CARBONATE AS EXCIPIENT

Abstract

The present invention refers to the use of granules comprising surface-reacted calcium carbonate and one or more binder(s) as excipient in a pharmaceutical, nutraceutical, agricultural, veterinary, cosmetic, home, food, packaging or personal care product, wherein the granules have i) a weight particle size d.sub.90 of 150 to 700 μm, as measured according to mechanical sieving, ii) a weight median particle size d.sub.50 of 45 to 300 μm, as measured according to mechanical sieving, iii) a weight particle size d.sub.10 of 18 to 100 μm, as measured according to mechanical sieving, and iv) a specific surface area of ≥15.0 m.sup.2/g as measured by the BET nitrogen method.

Claims

1. An excipient in a pharmaceutical, nutraceutical, agricultural, veterinary, cosmetic, home, food, packaging or personal care product, wherein the excipient comprises granules, and the granules comprise surface-reacted calcium carbonate and one or more binder(s), wherein the granules have i) a weight particle size d.sub.90 of 150 to 700 μm, as measured according to mechanical sieving, ii) a weight median particle size d.sub.50 of 45 to 300 μm, as measured according to mechanical sieving, iii) a weight particle size d.sub.10 of 18 to 100 μm, as measured according to mechanical sieving, and iv) a specific surface area of ≥15.0 m.sup.2/g as measured by the BET nitrogen method.

2. The excipient according to claim 1, wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H.sub.3O.sup.+ ion donors in an aqueous medium, wherein the carbon dioxide is formed in-situ by the H.sub.3O.sup.+ ion donor treatment and/or is supplied from an external source.

3. The excipient according to claim 2, wherein the natural ground calcium carbonate is selected from calcium carbonate containing minerals selected from the group comprising marble, chalk, limestone and mixtures thereof; and that the precipitated calcium carbonate is selected from the group comprising precipitated calcium carbonates having aragonitic, vateritic or calcitic mineralogical crystal forms or mixtures thereof.

4. The excipient according to claim 1, wherein the surface-reacted calcium carbonate has i) a BET specific surface area of from 20 m.sup.2/g to 450 m.sup.2/g, measured using the nitrogen and BET method according to ISO 9277:2010, and/or ii) a volume median particle diameter d.sub.50 of from 1 μm to 50 μm, and/or iii) an intra-particle intruded specific pore volume within the range from 0.15 to 1.35 cm.sup.3/g, calculated from a mercury intrusion porosimetry measurement.

5. The excipient according to claim 1, wherein the one or more binder(s) is/are selected from the group comprising synthetic polymers; natural binders; proteins; saccharides and polysaccharides; animal exudates; and mixtures thereof.

6. The excipient according to claim 1, wherein the granules comprise the one or more binder(s) in an amount of from 0.25 to 35 wt.-%, based on the total dry weight of the granules.

7. The excipient according to claim 1, wherein the granules comprise and/or are mixed with at least one active ingredient and/or inactive precursor thereof selected from the group comprising fragrances, flavours, herbal extracts and oils, fruit extracts and oils, nutrients, trace minerals, repellents, food, cosmetics, flame retardants, enzymes, macromolecules, pesticides, fertilizers, preserving agents, antioxidants, reactive chemicals, pharmaceutical and/or nutraceutical and/or veterinary active agents or pharmaceutical and/or nutraceutical and/or veterinary inactive precursors of synthetic origin, semi-synthetic origin, natural origin thereof, and mixtures thereof, and/or one or more lubricant(s) and/or one or more disintegrant(s).

8. The excipient according to claim 7, wherein the granules comprise the at least one active ingredient and/or inactive precursor thereof in an amount from 0.5 to 80 wt.-%, based on the total dry weight of the granules.

9. The excipient according to claim 1, wherein the granules are obtained under agitation in an agitation device selected from Eirich mixers, fluidized bed dryers/granulators, plate granulators, table granulators, drum granulators, disc granulators, dish granulators, ploughshare mixer, vertical or horizontal mixers, high or low shear mixer, high speed blenders and rapid mixer granulators.

10. The excipient according to claim 1, wherein the granules have an intra-granular specific pore volume within the range from 0.15 to 2.75 cm.sup.3/g, calculated from a mercury intrusion porosimetry measurement.

11. The excipient according to claim 1, wherein the granules are compressed in a compression process into mini-tablets or tablets.

12. The excipient according to claim 11, wherein the granules are compressed in a direct compression process using a force in the range from 1 to 40 kN.

13. The excipient according to claim 1, wherein the granules are filled into capsules or pliable packagings.

14. The excipient according to claim 1, wherein the granules provide an improved flowability and/or compactability.

15. The excipient according to claim 14, wherein the improvement is achieved if the ratio of hardness [N] to compression force [kN] (hardness/compression force) is at least 16.

16. The excipient according to claim 5, wherein: the synthetic polymers are selected from methylcellulose, ethylcellulose, sodium carboxymethylcellulose, sodium crosscarmellose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), ethylhydroxyethylcellulose (EHEC), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohols, and polymethacrylates; the natural binders are plant gums, and wherein the plant gums are selected from acacia, tragacanth, sandarac, ghatti, karaya, locust bean, carnauba wax, and guar; the proteins are selected from gelatin, casein, and collagen; the saccharides and polysaccharides are selected from starch and starch derivatives, wherein the starch derivatives are selected from pregelatinised starch, maltodextrins, inulin, cellulose, pectins, carrageenans and sugars; and/or the animal exudate is chosen from shellac, beeswax, and alginic acid.

17. The excipient according to claim 16, wherein: the synthetic polymers are selected from methylcellulose, ethylcellulose, sodium carboxymethylcellulose, sodium crosscarmellose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), ethylhydroxyethylcellulose (EHEC), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohols, and polymethacrylates; the natural binders are plant gums, and wherein the plant gums are selected from acacia, tragacanth, sandarac, ghatti, karaya, locust bean, carnauba wax, and guar; the proteins are selected from gelatin, casein, and collagen; and/or the animal exudate is chosen from shellac, beeswax, and alginic acid.

18. An excipient according to claim 17, wherein the one or more binder(s) is in an amount of from 0.25 to 35 wt.-%.

19. A tablet with improved flowability and/or compactability, comprising granules, the granules comprising surface-reacted calcium carbonate, one or more binder(s), at least one active ingredient, and/or an inactive precursor; wherein the granules have (i) a weight particle size d.sub.90 of 150 to 700 μm, as measured according to mechanical sieving, (ii) a weight median particle size d.sub.50 of 45 to 300 μm, as measured according to mechanical sieving, (iii) a weight particle size d.sub.10 of 18 to 100 μm, as measured according to mechanical sieving, and (iv) a specific surface area of ≥15.0 m.sup.2/g as measured by the BET nitrogen method; wherein the tablet has a weight median particle size d.sub.50 of from 0.1 to 20.0 mm, as measured according to mechanical sieving, and a ratio of hardness to compression force of at least 16.

20. The tablet according to claim 21, wherein the one or more binder(s) is in an amount of from 0.25 to 35 wt.-% and the one or more binder(s) is selected from the group comprising: synthetic polymers, wherein the synthetic polymers are selected from methylcellulose, ethylcellulose, sodium carboxymethylcellulose, sodium crosscarmellose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), ethylhydroxyethylcellulose (EHEC), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohols, and polymethacrylates; and/or natural binders, wherein the natural binders are plant gums, and wherein the plant gums are selected from acacia, tragacanth, sandarac, ghatti, karaya, locust bean, carnauba wax, and guar; and/or proteins, wherein the proteins are selected from gelatin, casein, and collagen; and/or animal exudates, wherein the animal exudate is chosen from shellac, beeswax, and alginic acid; and/or mixtures thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0194] FIG. 1 shows how to calculate the angle of repose B.

[0195] FIG. 2 shows a comparison of the tablet hardness [N] of the mixtures as a function of the main compression force [kN].

[0196] FIG. 3 shows a comparison of the friability of the mixtures as a function tablet hardness [N].

[0197] FIG. 4 shows a comparison of the disintegration time of the mixtures as a function tablet hardness [N].

[0198] FIG. 5 shows a comparison of the tablet hardness [N] of the mixtures as a function of the main compression force [kN].

[0199] FIG. 6 shows a comparison of the friability of the sample 7 as a function tablet hardness [N].

[0200] FIG. 7 shows a comparison of the disintegration time of sample 7 as a function tablet hardness [N].

[0201] The following examples and tests will illustrate the present invention, but are not intended to limit the invention in any way.

EXAMPLES

1. Measurement Methods

[0202] In the following, measurement methods implemented in the examples are described.

Particle Size Distribution

[0203] Volume determined median particle size d.sub.50 (vol) and the volume determined top cut particle size d.sub.98(vol) was evaluated using a Malvern Mastersizer 3000 Laser Diffraction System (Malvern Instruments Plc., Great Britain). The d.sub.50(vol) or d.sub.98(vol) value indicates a diameter value such that 50% or 98% by volume, respectively, of the particles have a diameter of less than this value. The raw data obtained by the measurement was analyzed using the Mie theory, with a particle refractive index of 1.57 and an absorption index of 0.005. The methods and instruments are known to the skilled person and are commonly used to determine particle size distributions of fillers and pigments. The sample was measured in dry condition without any prior treatment.

[0204] The weight determined median particle size d.sub.50(wt) was measured by the sedimentation method, which is an analysis of sedimentation behaviour in a gravimetric field. The measurement was made with a Sedigraph™ 5120 of Micromeritics Instrument Corporation, USA. The method and the instrument are known to the skilled person and are commonly used to determine particle size distributions of fillers and pigments. The measurement was carried out in an aqueous solution of 0.1 wt.-% Na.sub.4P.sub.2O.sub.7. The samples were dispersed using a high speed stirrer and supersonicated.

[0205] A vibrating sieve tower was used to analyse the particle size distribution of the granules. Aliquots of 120 g of granules were put on steel wire screens (Retsch, Germany) with mesh sizes of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm, 710 μm, 5 and 1 mm. The sieving tower was shaken for 6 minutes with 10 seconds interval at a shaking displacement of 1 mm.

[0206] The processes and instruments are known to the skilled person and are commonly used to determine grain size of fillers and pigments.

Specific Surface Area (SSA)

[0207] The specific surface area was measured via the BET method according to ISO 9277:2010 using nitrogen, following conditioning of the sample by heating at 250° C. for a period of 30 minutes. Prior to such measurements, the sample was filtered within a Buchner funnel, rinsed with deionised water and dried at 110° C. in an oven for at least 12 hours. Intra-particle intruded specific pore volume (in cm.sup.3/g)

[0208] The specific pore volume was measured using a mercury intrusion porosimetry measurement using a Micromeritics Autopore V 9620 mercury porosimeter having a maximum applied pressure of mercury 414 MPa (60 000 psi), equivalent to a Laplace throat diameter of 0.004 μm (˜nm). The equilibration time used at each pressure step was 20 seconds. The sample material was sealed in a 5 cm.sup.3 chamber powder penetrometer for analysis. The data were corrected for mercury compression, penetrometer expansion and sample material compression using the software Pore-Comp (Gane, P. A. C., Kettle, J. P., Matthews, G. P. and Ridgway, C. J., “Void Space Structure of Compressible Polymer Spheres and Consolidated Calcium Carbonate Paper-Coating Formulations”, Industrial and Engineering Chemistry Research, 35(5), 1996, p 1753-1764.).

[0209] The total pore volume seen in the cumulative intrusion data can be separated into two regions with the intrusion data from 214 μm down to about 1-4 μm showing the coarse packing of the sample between any agglomerate structures contributing strongly. Below these diameters lies the fine inter-particle packing of the particles themselves. If they also have intra-particle pores, then this region appears bi-modal, and by taking the specific pore volume intruded by mercury into pores finer than the modal turning point, i.e. finer than the bi-modal point of inflection, the specific intra-particle pore volume is defined. The sum of these three regions gives the total overall pore volume of the powder, but depends strongly on the original sample compaction/settling of the powder at the coarse pore end of the distribution.

[0210] By taking the first derivative of the cumulative intrusion curve the pore size distributions based on equivalent Laplace diameter, inevitably including pore-shielding, are revealed. The differential curves clearly show the coarse agglomerate pore structure region, the inter-particle pore region and the intra-particle pore region, if present. Knowing the intra-particle pore diameter range it is possible to subtract the remainder inter-particle and inter-agglomerate pore volume from the total pore volume to deliver the desired pore volume of the internal pores alone in terms of the pore volume per unit mass (specific pore volume). The same principle of subtraction, of course, applies for isolating any of the other pore size regions of interest.

Bulk Density

[0211] 100±0.5 g of the respective material were carefully filled through a powder funnel into the 250 mL measuring cylinder and the volume was read off to the nearest 1 mL. The loose bulk density was the calculated according the formula:

1. Loose bulk density [g/mL]=bulk volume [mL]/weighed sample [g]

[0212] and the result was recorded to the nearest 0.01 g/mL.

Tapped Density

[0213] 100±0.5 g of the respective material were carefully filled through a powder funnel into the 250 mL measuring cylinder.

[0214] The graduated cylinder is connected to a support provided with a settling apparatus capable of producing taps. The cylinder is secured in this support and the volume after 1 250 taps is read. A subsequent second tapping step consisting of 1 250 taps is performed and the value of the volume is read. When this second tapped volume value does not differ in more than 2 mL from this first tapped volume value, this is the tapped volume. When this value differs in more than 2 mL, the tapping step of 1 250 taps is repeated until no differences of more than 2 mL in subsequent steps is observed.

Hausner Ratio

[0215] The Hausner ratio is a number that is correlated to the flowability of a powder material and is calculated as follows:

Hausner Ratio=(Tapped density)/(Bulk density)  1.

Compressibility Index

[0216] The compressibility index is calculated as follows:

Compressibility Index (%)=(Tapped density−Bulk density)/Tapped density*100 Angle of repose  1.

[0217] The angle of repose is measured in a flowability tester. The hopper equipped with the 10 mm nozzle is filled with approximately 150 mL of the respective material. After emptying the hopper, the granulate bevel is measured by means of a laser beam and the angle of repose is calculated. The angle of repose B is the angle of the bevel flank opposite the horizontal line that is calculated as shown in FIG. 1: SEM

[0218] The samples were prepared by diluting 50 to 150 μl slurry samples with 5 ml water. The amount of slurry sample depends on solids content, mean value of the particle size and particle size distribution. The diluted samples were filtrated by using a 0.8 μm membrane filter. A finer filter was used when the filtrate is turbid. A doubled-sided conductive adhesive tape was mounted on a SEM stub. This SEM stub was then slightly pressed in the still wet filter cake on the filter. The SEM stub was then sputtered with 8 nm Au. The investigation under the FESEM (Zeiss Sigma VP) was done at 5 kV (Au). Subsequently, the prepared samples were examined by using a Sigma VP field emission scanning electron microscope (Carl Zeiss AG, Germany) and a secondary electron detector (SE2) at high vacuum (<10.sup.−2 Pa).

2. Materials Used

Surface-Reacted Calcium Carbonate

SRCC

[0219] Surface-reacted calcium carbonate (SRCC) (d.sub.50(vol)=6.6 μm, d.sub.98=13.7 μm, SSA=59.9 m.sup.2/g). The intra-particle intruded specific pore volume is 0.939 cm.sup.3/g (for the pore diameter range of 0.004 to 0.51 μm).

[0220] SRCC was obtained by preparing 350 litres of an aqueous suspension of ground calcium carbonate in a mixing vessel by adjusting the solids content of a ground limestone calcium carbonate from Omya SAS, Orgon having a weight based median particle size d.sub.50(wt) of 1.3 μm, as determined by sedimentation, such that a solids content of 10 wt.-%, based on the total weight of the aqueous suspension, is obtained.

[0221] Whilst mixing the slurry at a speed of 6.2 m/s, 11.2 kg phosphoric acid was added in form of an aqueous solution containing 30 wt.-% phosphoric acid to said suspension over a period of 20 minutes at a temperature of 70° C. After the addition of the acid, the slurry was stirred for additional 5 minutes, before removing it from the vessel and drying using a jet-dryer.

Other Materials

[0222] Polyvinylpyrrolidone—K90 from BASF

[0223] Sodium crosscarmellose—Ac-di-sol, from JRS

[0224] Manesium stereate, Ligamed MF-2V, from Peter Greven

[0225] HPMC 4M, Methocel 4M, hydroxypropylmethylcellulose from Dupont

3. Granulating FCC by Fluid Bed Experiments

A. Using Polyvinylpyrrolidone as Binder

[0226] Fluid-bed trials were performed on a GPC G2, Glatt, using a tangential spraying with the following settings: [0227] Air temp: 60° C. [0228] Air Volume Flow.: 5-30 m.sup.3/h [0229] Spray pump: 2-10 g/min [0230] Spray pressure 1.5 bar [0231] Batch size, surface reacted calcium carbonate: 500 g [0232] Polyvinylpyrrolidone (PVP) binder concentration: 4% w/w

[0233] Dry powder surface-reacted calcium carbonate (SRCC) were introduced in the fluid bed chamber in presence or absence of sodium crosscarmellose.

[0234] Table 1 shows proportions of polyvinylpyrrolidone (PVP) to surface-reacted calcium carbonate (SRCC) and sodium crosscarmellose (CCM) that have been used to prepare the excipients, i.e. granules:

TABLE-US-00001 TABLE 1 Composition of granules Surface-reacted Sodium Sample calcium carbonate Crosscarmellose Polyvinylpyrrolidone No. (SRCC) (%) (CCM) (%*) (PVP) (%*) 1 92.6 0 7.4 2 89.6 3 7.4 *% is given in weight-%, based on the total weight of the granules

[0235] The PSD of the granules are shown below in Table 2.

TABLE-US-00002 TABLE 2 PSD of different samples Sample No. d.sub.10 (μm) d.sub.50 (μm) d.sub.90 (μm) 1 22 120 325 2 28 155.7 384.6

[0236] The density and compressibility values of the obtained co-processed excipients, i.e. granules, are listed in Table 3.

TABLE-US-00003 TABLE 3 Density and compressibility values Bulk Tapped Sample density density Hausner Accord. Angle of No. (g/ml) (g/ml) ratio EuPh repose (°) 1 0.41 0.49 1.20 Fair 40.1 2 0.41 0.47 1.15 Good 40.3

[0237] Tabletting assays of fluid-bed granules (Samples 1 to 2)

[0238] The granules set out in Tables 1 to 3 were further subjected to a tabletting step. The compositions of the tablets are set out in the following Table 4.

TABLE-US-00004 TABLE 4 Mixtures composition Fluid Bed Fluid Bed Sodium Magnesium Sample Granules Sample Granules Sample Crosscarmellose Stearate Piroxicam Caffeine No. 1 (%*) 2 (%*) (%*) (%*) (%*) (%*) 1 95 0 3 2 0 0 2 0 98 0 2 0 0 3 65 0 3 2 0 30 4 0 68 0 2 0 30 5 75 0 3 2 20 0 6 0 78 0 2 20 0 *% is given in weight-%, based on the total weight of the tablets

[0239] The obtained excipients, i.e. granules, (Samples no. 1 to 2) were further mixed with 2 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas #557-04-0, Peter Greven) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5 minutes. The mix was further used to prepare tablets in a Fette 1200i using EU1″ tooling, a 10 mm fill cam, 8 standard convex round 10 mm punches and a tableting speed of 15000 tablets/hour. The fill depth was adjusted to obtain compression forces of 2 kN up to 20 kN and the tablet weight was fixed at 175 mg.

[0240] Alternatively, the obtained excipients were further mixed with a super disintegrant sodium crosscarmellose (CCM, Vivasol from JRS) and/or an active pharmaceutical ingredient, either caffeine anhydrous (BASF) or piroxicam (SelectChemie) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 10 minutes. These mixtures were further mixed with 2 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas #557-04-0, Peter Greven) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5 minutes and used to prepare tablets as above.

[0241] The tablet hardness [N] of the excipients as a function of the main compression force [kN] is shown in FIG. 2. The friability of the mixtures (%) as a function of the hardness [N] is shown in FIG. 3. FIG. 4 shows the disintegration time [sec] as a function of the tablet hardness [N] for the mixtures from table 4. The disintegration test was conducted with a DisiTest 50 Automatic Tablet Disintegration Tester of Pharmatron.

[0242] For the testing, a beaker was filled with 720 ml distilled water. The water was heated to 37.0° C., and then 6 Tablets were placed in a robust basket.

[0243] The apparatus automatically detects and records the disintegration time. In addition, the disintegration time was also monitored visually.

[0244] B. Using hydroxypropylmethylcellulose as binder

[0245] Fluid-bed trials were performed on a GPC G2, Glatt, using a tangential spraying with the following settings: [0246] Air temp: 60° C. [0247] Air Volume Flow.: 5-30 m3/h [0248] Spray pump: 2-10 g/min [0249] Spray pressure 1 bar [0250] Batch size, surface reacted calcium carbonate: 500 g [0251] Hydroxypropylmethylcellulose (HPMC) binder concentration: 0.5% w/w

[0252] Dry powder surface-reacted calcium carbonate (SRCC) were introduced in the fluid bed chamber in presence or absence of sodium crosscarmellose.

[0253] Table 5 shows proportions of Hydroxypropylmethylcellulose (HPMC) to surface-reacted calcium carbonate (SRCC) and have been used to prepare the excipient:

TABLE-US-00005 TABLE 5 proportions of HPMC to SRCC Surface-reacted Hydroxypropylmethyl calcium carbonate cellulose (HPMC) Sample No. (SRCC) (%*) (%*) 7 99 1 *% is given in weight-%, based on the total weight of the tablets

[0254] The PSD of sample 7 is shown below in Table 6

TABLE-US-00006 TABLE 6 PSD of sample 7 Sample No. d.sub.10 (μm) d.sub.50 (μm) d.sub.90 (μm) 7 41 140 247

TABLE-US-00007 TABLE 7 Density and compressibility values Bulk Tapped Sample density density Hausner Accord. Mean flow No. (g/ml) (g/ml) ratio EuPh (secs/100 g) 7 0.370 0.46 1.24 Fair 10

[0255] The obtained excipients (sample 7) were further mixed with 10% of caffeine anhydrous BASF) and 3% of sodium crsscarmellose (CCM, Vivasol from JRS)) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 10 minutes. Then, 2 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas #557-04-0, Peter Greven) were added to the mixture and further mixed in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5 minutes. The mix was further used to prepare tablets in a Fette 1200i using EU1″ tooling, a 10 mm fill cam, 8 standard convex round 10 mm punches and a tableting speed of 15000 tablets/hour. The fill depth was adjusted to obtain compression forces of 2 kN up to 20 kN and the tablet weight was fixed at 130 mg.

[0256] The results are shown in FIG. 5 to 7. FIG. 5 shows a comparison of the tablet hardness [N] of the mixtures as a function of the main compression force [kN]. FIG. 6 shows a comparison of the friability of the sample 7 as a function tablet hardness [N]. FIG. 7 shows a comparison of the disintegration time of sample 7 as a function tablet hardness [N].