Pharmaceutical preparation

Abstract

The present invention relates to a solid pharmaceutical preparation of 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile, a method of making same, and medical uses thereof.

Claims

1. A composite comprising a solid dispersion of 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile, or a pharmaceutically acceptable salt thereof, in a polymeric matrix, wherein the polymeric matrix comprises hydroxypropyl methylcellulose acetate succinate and/or cellulose acetate phthalate.

2. The composite according to claim 1, wherein the solid dispersion is a solid solution.

3. The composite according to claim 1, wherein 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile is present in the polymeric matrix in a range of from 4 to 50 percent (w/w), based upon the total weight of the composite.

4. The composite according to claim 1, wherein the composite has a mean particle size characterized by a d.sub.50 value in the range from 1 μm to 300 μm.

5. A granulate comprising the composite according to claim 1, wherein the granulate has a particle size characterized by a d.sub.50 vlue of 1000 μm or less.

6. A pharmaceutical preparation comprising the composite according to claim 1.

7. The pharmaceutical preparation according to claim 6, which is a pharmaceutical preparation for oral administration.

8. The pharmaceutical preparation according to claim 6, which is an immediate release preparation.

9. The pharmaceutical preparation according to claim 6, which is a capsule comprising the composite and optionally one or more pharmaceutically acceptable excipients.

10. The pharmaceutical preparation according to claim 9, which contains 40 to 100% (w/w) of the composite; and 0 to 60% (w/w) of at least one pharmaceutically acceptable excipient, based upon the total weight of all material contained in the capsule.

11. The pharmaceutical preparation according to claim 6, which is a tablet comprising optionally one or more pharmaceutically acceptable excipient selected from a filler, a disintegrant, a glidant and a lubricant.

12. The pharmaceutical preparation according to claim 11, which comprises: 25 to 100% (w/w) of the composite; 0 to 45% (w/w) of a filler; 0 to 20% (w/w) of disintegrant; 0 to 5% (w/w) of a lubricant; 0 to 7,5% (w/w) of glidant; and a total of 0 to 20% (w/w) of one or more additional pharmaceutically acceptable excipients, based upon the total weight of the tablet.

13. The pharmaceutical preparation according to claim 11, which comprises: 60 to 80% (w/w) of the composite; 10 to 30% (w/w) of a filler; 4 to 15% (w/w) of disintegrant; 0 to 3% (w/w) of a lubricant; 0 to 5% (w/w) of a glidant; and a total of 0 to 10% (w/w) of one or more additional pharmaceutically acceptable excipients, based upon the total weight of the tablet.

14. The pharmaceutical preparation according to claim 11, which comprises: 65 to 75% (w/w) of the composite; 15 to 25% (w/w) of a filler; 5 to 10% (w/w) of disintegrant; 0.25 to 2% (w/w) of a lubricant; 0.5 to 2% (w/w) of a glidant; and a total of 0 to 10% (w/w) of one or more additional pharmaceutically acceptable excipients, based upon the total weight of the tablet.

15. The pharmaceutical preparation according to claim 11, wherein the filler is selected from lactose and/or microcrystalline cellulose, the disintegrant is selected from crospovidone, carboxymethylcellulose and salts and derivatives thereof, the lubricant is selected from magnesium stearate, calcium stearate and sodium stearyl fumarate, and/or the glidant is selected from colloidal silicon dioxide and derivatives thereof.

16. A method for preparing the composite according to claim 1, the method comprising: spray-drying, co-precipitation or lyophilization.

17. A method for preparing the composite according to claim 1, the method comprising: (a) dissolving 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile and the polymer of the polymeric matrix to be formed, and optionally one or more pharmaceutically acceptable excipient in a solvent to form a solution, (b) spray-drying the solution to form the composite, and (c) optionally drying the composite.

18. A method for preparing a pharmaceutical preparation, which is a tablet, comprising (a) conducting the method according to claim 16 to form the composite; (b) optionally granulating a mixture of the composite and one or more pharmaceutically acceptable excipients; (c) mixing the composite and one or more pharmaceutically acceptable excipients; (d) tableting the mixture prepared by (b) or the granulate prepared by (c); and (e) optionally film coating of the tablets prepared by (d).

19. A method for preparing a pharmaceutical preparation, which is a capsule, comprising (a) conducting the method according to claim 16 to form the composite; (b) optionally mixing the composite and one or more pharmaceutically acceptable excipient and optionally granulating the mixture obtained; (c) filling the mixture or granulate prepared by (b) or the composite prepared by (a) into capsules.

20. A method of treating cancer comprising administering to a subject in need thereof the pharmaceutical preparation according to claim 6, optionally together with radiotherapy.

21. The method according to claim 20, wherein the treatment further comprises chemotherapy.

22. The composite according to claim 1, wherein 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile is present in the polymeric matrix in a range of from 10 to 30 percent (w/w), based upon the total weight of the composite.

23. The composite according to claim 1, wherein 3-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-benzonitrile is present in the polymeric matrix in a range of from 15 to 25 percent (w/w) based upon the total weight of the composite.

24. The composite according to claim 1, wherein the composite has a mean particle size that is characterized by a d.sub.50 value in the range from 20 μm to 200 μm.

25. A granulate comprising the composite according to claim 1, wherein the granulate has a particle size that is characterized by a d.sub.50 value of 500 μm or less.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows dissolution curves for various embodiments of solid dispersions as described in EXAMPLE 1. Solid spheres: 10% Compound in cellulose acetate phthalate (CAP); open spheres: 20% Compound in CAP; solid triangles: 10% Compound in Eudragit® L100; open triangles: 20% Compound in Eudragit® L100; solid squares: 20% Compound in HPMCAS-M; open squares: 20% Compound in HPMCAS-L; solid diamonds: crystalline Compound;

(2) FIG. 2 shows dissolution curves for various embodiments of solid dispersions as described in EXAMPLE 4. Open Spheres: 20% Compound in CAP; solid triangles: 20% Compound in HPMCAS-M; open triangles: 20% Compound in HPMCAS-H; solid squares: 20% Compound in HPMCP HP50; solid diamonds: crystalline Compound.

(3) FIG. 3 shows a dissolution curve of a coprecipitate containing 16% (w/w) of Compound in CAP in FaSSIF at pH 6.5 as described in Example 5.

(4) FIG. 4. Shows dissolution curves of hot melt extrudates containing 10% Compound in PVAc-PVCap-PEG (open symbols) or HPMCAS-L (closed symbols) as described in Example 6.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(5) Solid dispersions comprising either 10 or 20% (w/w) Compound and either 90 or 80% (w/w) polymeric matrix are prepared by spray drying using a custom-built lab-scale spray dryer. The polymers used are: cellulose acetate phthalate (CAP), Eudragit® L100, HPMCAS-L and HPMCAS-M. 10 or 20 g solids are dissolved in a mixture of methylene chloride/methanol 80/20 (w/w) to a solid content of 2.5 or 5.0% (w/w) and spray dried using the following conditions:

(6) Atomization: pressurized nozzle with 150 psi atomizing pressure; Drying gas flow rate: 500 g/min; Liquid feed rate: 40 g/min; Inlet temperature: 105° C.; Outlet temperature: 40° C.; Secondary drying: vacuum desiccation for 2-4 days.

(7) Dissolution tests are run for all of the above samples, using the following test conditions: Spray dried powders are dispersed to 200 μg Compound per mL in 0.01 M HCl at 37° C. (time point −30 min). 30 minutes after dispersion, a concentrated solution of simulated intestinal fluid (SIF; for details see Galia et al., Evaluation of Various Dissolution Media for Predicting In Vivo Performance of Class I and II Drugs. Pharm. Research, Vol. 15 No. 5. 1998)) powder in phosphate buffered saline (PBS) is added to the samples to a resulting concentration and pH of 100 μg Compound per mL in 0.5% (w/w) SIF powder in PBS pH 6.5 (time point 0 min).

(8) At the according time points, samples are centrifuged and an aliquot of the supernatant analysed using HPLC. The remainder of the samples are redispersed. Sampling time points: −25, −15, −5 minutes. Buffer change at 0 minutes. Further sampling at 4, 10, 20, 40, 90 and 1200 minutes.

(9) The resulting dissolution curves are illustrated in FIG. 1. The solid dispersions in HPMCAS show the highest supersaturation in the gastric medium, but precipitate quickly upon transition to intestinal buffer. No difference is observed between the different grades of HPMCAS. Solid dispersions in Eudragit® L do not show supersaturation, independent of drug load. Solid dispersions in CAP show less free drug in the gastric medium than crystalline Compound, but considerable supersaturation upon transition to intestinal medium. The supersaturation is independent of drug load and remained stable after 20 hours.

(10) X-ray diffractometric analysis of the solid dispersions in CAP shows no evidence of crystalline material.

Example 2

(11) Further experiments are carried out on the preferred CAP based solid dispersions using the same equipment as in Example 1. Solid dispersions comprising either 15, 18, 20, 25 or 30% (w/w) Compound and either 85, 82, 80, 75, 70% (w/w) CAP are prepared by spray drying. The solids are dissolved in a mixture of methylene chloride/methanol 90/10 (w/w) and spray dried using the conditions described in Example 1.

(12) The resulting dispersions have glass transition temperatures between 146-149° C. at <5% relative humidity, and between 80-84° C. at 75% relative humidity. X-ray diffractometric analysis of the solid dispersions in CAP show no evidence of crystalline material independent of the drug load. The achieved supersaturation is comparable for all drug loads and similar to the CAP solid dispersion prototypes shown in Example 1.

Example 3

(13) Further process optimization is performed using a pilot scale commercial spray dryer (GEA Niro PSD-1). Two individual batches of solid dispersions comprising 20% (w/w) Compound and 80% (w/w) CAP are prepared by spray drying. 3000 g of solids are dissolved in a mixture of methylene chloride/methanol 90/10 (w/w) to a solid content of 3.9% (w/w) and spray dried using the following conditions:

(14) Atomization: pressurized nozzle with 450 psi atomizing pressure; Drying gas flow rate: 1850 g/min; Liquid feed rate: 210 g/min; Inlet temperature: 95° C.; Outlet temperature: 35° C.; Secondary drying: tray drying at 40° C./15% relative humidity for 18 hours, or tray drying at 40° C./15% relative humidity for 13 hours followed by 2 hours at 40° C./30% relative humidity.

(15) The spray drying yield (before secondary drying) is between 99-101%. The batch dried only at 15% relative humidity has a residual content of methylene chloride of 100 ppm, and <100 ppm of methanol (limit of quantification (LOQ)). The batch dried at 15 and 30% relative humidity has both methylene chloride and methanol <100 ppm (LOQ). Both batches show comparable supersaturation as observed in Examples 1 and 2. The glass transition temperature is 145° C. at <5% relative humidity for both batches. X-ray diffractometric analysis of the solid dispersions in CAP shows no evidence of crystalline material. The water content is determined between 2.5 and 2.8% by Karl Fischer titration. The volume-weighted particle size distribution is determined by laser diffraction as 7/23/49 μm (d.sub.10/d.sub.50/d.sub.90).

Example 4

(16) Solid dispersions comprising 20% (w/w) Compound and 80% (w/w) polymeric matrix are prepared by spray drying using a custom-built lab-scale spray dryer. The polymers used are: CAP, HPMCAS-H, HPMCAS-M and HPMCP HP50. Between 8-13 g solids are dissolved in a mixture of methylene chloride/methanol 90/10 (w/w) to a solid content of 3% (w/w) and spray dried using the following conditions:

(17) Atomization: pressurized nozzle with 140 psi atomizing pressure; Drying gas flow rate: 450 g/min; Liquid feed rate: 35 g/min; Inlet temperature: between 81-91° C.; Outlet temperature: 35° C.; Secondary drying: convection tray dryer at 40° C. for 15 hours.

(18) The spray drying yield is between 93-98%. The resulting dispersions have glass transition temperatures between 113-114° C. at <5% relative humidity, and between 58-62° C. at 75% relative humidity.

(19) Dissolution experiments are carried out according to Example 1. The resulting dissolution curves are illustrated in FIG. 2. The solid dispersion in HPMCP shows the highest supersaturation in the gastric medium, followed by rapid precipitation upon transition to the intestinal buffer. The solid dispersions in HPMCAS-M show a higher supersaturation in the gastric medium than a similar formulation from Example 1, but precipitate equally upon transition to the intestinal buffer. The solid dispersions in HPMCAS-H surprisingly show a lower supersaturation in the gastric medium than M and L grades, and sustain the supersaturation until 45 minutes after transition to the intestinal buffer.

Example 5 Co-Precipitation with CAP

(20) A solid dispersion comprising 16% (w/w) Compound and 84% (w/w) polymeric matrix (CAP) is prepared by co-precipitation. A clear solution of 16 mg/ml Compound and 64 mg/ml polymer (resembling 20% (w/w) of compound to polymer) in DMSO is prepared at 70° C. under stirring. The solution is subsequently cooled to ambient temperatures and remains clear. 1.3 ml of the clear DMSO solution is poured into the vortex of 15 ml of citric acid pH 4.0 under vigorously stirring in a beaker. The resulting suspension is filtered and the obtained cake washed with 20 ml hydrochloric acid solution pH 2.0. The washed cake is pre-dried by vacuum filtration and subsequently dried at 50° C. under nitrogen purge. The difference between the theoretical concentration of 20% (w/w) Compound to the final concentration of 16% (w/w) in the matrix results from loss of Compound during the precipitation as well as the washing steps.

(21) Dissolution test conditions: coprecipitate is dispersed to 6.7 mg/mi in a FaSSIF-V1 solution pH 6.5. FaSSIF powder is obtained from biorelevant

(22) (Na-taurocholate 3.0 mM,

(23) Lecitihin 0.75 mM, NaCl 105.9 mM, NaH.sub.2PO.sub.4 28.4 mM, NaOH 8.7 mM, pH 6.5) at 37° C. At the according time points, aliquots of the suspension are filtered and the filtrate analysed using HPLC. Sampling time points are: 5, 10, 15, 20, 30, 45, 60, 90 and 120 minutes.

(24) The resulting dissolution curve is illustrated in FIG. 4. Compared to the solubility of the Compound in FaSSIF of approx. 0.25 μg/ml the coprecipitate shows a good supersaturation of 5 μg/ml with a slight recrystallization down to approx. 3 μg/ml.

Example 6 Hot Melt Extrusion with PVAc-PVCap-PEG and HPMCAS-L

(25) Solid dispersions comprising 10% (w/w) Compound and 90% (w/w) polymeric matrix are prepared by hot melt extrusion. The polymers used are: HPMCAS-L and PVAc-PVCap-PEG. Approx. 10 g of a physical mixture containing 10% (w/w) Compound and 90% (w/w) polymeric matrix is blended with a Turbula T2F for 10 min. The obtained blend is subsequently extruded using a Haake Minilab with conical, co-rotating twinscrews at 100 rpm. For PVAc-PVCap-PEG an extrusion temperature of 170° C. and for HPMCAS-L of 180° C. is used. For milling of the strands a Pulverisette 23 with two 10 mm zirconium oxide grinding balls is used at an oscillation of 50 Hz.

(26) Dissolution tests are run for all of the above samples, using the following test conditions: milled strands are dispersed to 200 μg Compound per mL in 1.3 ml FaSSIF-V1 pH 6.5 from biorelevant (Na-taurocholate 3.0 mM, Lecitihin 0.75 mM, NaCl 105.9 mM, NaH.sub.2PO.sub.4 28.4 mM, NaOH 8.7 mM, pH 6.5) at 37° C. At the according time points, samples are centrifuged and an aliquot of the supernatant analysed using HPLC. The remainder of the samples are redispersed. Sampling time points are: 5, 10, 15, 20, 30, 45, 60, 90 and 120 minutes.

(27) The resulting dissolution curves are illustrated in FIG. 4. Both solid dispersions show a strong supersaturation, which is even more pronounced for PVAc-PVCap-PEG (approx. 50 μg/ml at 5 min.) compared to HPMCAS-L (approx. 15 μg/ml at 5 min.). PVAc-PVCap-PEG shows a rather strong recrystallization, but the residual solubility in FaSSIF after 120 min with approx. 15 μg/ml is rather high. HPMCAS-L stabilizes supersaturation better than PVAc-PVCap-PEG and ends at approx. 4 μg/ml after 120 min.

(28) The strong supersaturation is rather surprising as powder X-ray diffraction and polarized light microscopy analysis demonstrate that under the used conditions no purely amorphous solid dispersions are obtained.

Example 7: Exemplary Tablet Formulations (w/o Coating)

(29) Tablets are produced with a composition comprising the following ingredients at the indicated weight percentage of the tablet weight. The blends are pre-compacted to a solid fraction of 0.5, milled and sieved through a 800 μm screen. The resulting granules are compressed to achieve tablets with a tensile strength from 1.5 to 3.5 MPa.

(30) TABLE-US-00001 Tablet Disintegration # Composition % (w/w) time [s] 1 Solid dispersion in 80 wt % CAP 50.0 15 Microcrystalline cellulose (Avicel ® PH101) 28.3 Lactose Monohydrate 310 14.2 Croscarmellose sodium 6.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 2 Solid dispersion in 80 wt % CAP 50.0 14 Microcrystalline cellulose (Avicel ® PH101) 28.3 Lactose Monohydrate 310 14.2 Crospovidone 6.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 3 Solid dispersion in 80 wt % CAP 50.0 15 Microcrystalline cellulose (Avicel ® PH101) 25.7 Lactose Monohydrate 310 12.8 Croscarmellose sodium 10.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 4 Solid dispersion in 80 wt % CAP 62.5 15 Microcrystalline cellulose (Avicel ® PH101) 20.0 Lactose Monohydrate 310 10.0 Croscarmellose sodium 6.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 5 Solid dispersion in 80 wt % CAP 62.5 15 Microcrystalline cellulose (Avicel ® PH101) 22.0 Lactose Monohydrate 310 11.0 Croscarmellose sodium 3.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 6 Solid dispersion in 80 wt % CAP 62.5 20 Microcrystalline cellulose (Avicel ® PH101) 20.0 Lactose Monohydrate 310 10.0 Sodium starch glycolate 6.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 7 Solid dispersion in 80 wt % CAP 71.4 12 Microcrystalline cellulose (Avicel ® PH101) 14.1 Lactose Monohydrate 310 7.0 Croscarmellose sodium 6.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 8 Solid dispersion in 80 wt % CAP 62.5 24 Microcrystalline cellulose (Avicel ® PH101) 22.0 Mannitol 11.0 Croscarmellose sodium 3.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 9 Solid dispersion in 80 wt % CAP 62.5 17 Microcrystalline cellulose (Avicel ® PH101) 20.0 Lactose Monohydrate 310 10.0 Croscarmellose sodium 6.0 Colloidal silicon dioxide 1.0 Sodium stearyl fumarate 0.5 10 Solid dispersion in 80 wt % CAP 50.0 18 Microcrystalline cellulose (Avicel ® PH101) 14.2 Lactose Monohydrate 310 28.3 Croscarmellose sodium 6.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 11 Solid dispersion in 80 wt % CAP 50.0 15 Microcrystalline cellulose (Avicel ® PH101) 14.2 Lactose Monohydrate 313 28.3 Croscarmellose sodium 6.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5 12 Solid dispersion in 80 wt % CAP 50.0 93 Microcrystalline cellulose (Avicel ® PH101) 25.7 Lactose Monohydrate 310 12.8 Croscarmellose sodium 6.0 Sodium lauryl sulfate 4.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.5

(31) In the dissolution assay as described in Example 1, all tablet formulations achieve Compound solubilities far below the Compound solubilities of the solid dispersions. However, and surprisingly, when such tablets are grounded and suspended in a suitable vehicle for oral administration and given to rats by gavage, the resulting plasma concentration of the Compound is comparable to the concentration that is obtained after administration of a similar suspension made of the solid dispersion.

Example 8: Exemplary Capsule Formulations

(32) HPMC capsules are provided with a filler comprising the following ingredients at the indicated weight percentage of the filler. The disintegration of the formulations is below 6 minutes.

(33) TABLE-US-00002 Capsule # Ingredient % (w/w) 1 Solid dispersion in 80 wt % CAP 98.75 Colloidal silicon dioxide 1 Magnesium stearate 0.25 2 Solid dispersion in 80 wt % CAP 83.75 Sodium chloride 15 Colloidal silicon dioxide 1 Magnesium stearate 0.25

Example 9: Exemplary Capsule Formulations

(34) HPMC capsules are provided with a filler comprising the following ingredients at the indicated weight percentage of the filler. The filler is compacted before filling to achieve a bulk density between 0.4 and 0.5 g/cm.sup.3.

(35) TABLE-US-00003 Capsule # Ingredient % (w/w) 1 Solid dispersion in 80 wt % CAP 83.75 Sodium chloride 15 Colloidal silicon dioxide 1 Magnesium stearate 0.25 2 Solid dispersion in 80 wt % CAP 68.75 Sodium chloride 30 Colloidal silicon dioxide 1 Magnesium stearate 0.25 3 Solid dispersion in 80 wt % CAP 43.75 Sodium chloride 45 Colloidal silicon dioxide 1 Magnesium stearate 0.25

Example 10: Exemplary Tablet Pilot Scale Compression

(36) Tablets comprising a solid dispersion of the Compound in 80% CAP are manufactured on pilot scale equipment in strengths of 10, 50 and 100 mg Compound per tablet. About 4.2 kg blend of the solid dispersion and excipients as set forth in Example 6 Tablet #7, using half indicated the amount of silicon dioxide and magnesium stearate, are blended in a 50 L bin blender. The blend is granulated by roller compaction on pilot scale equipment using a roll force of 6 kN, 2 rpm roll speed, 2 mm gap, and a screen size of 0.8 mm. The granules are blended with the remainder of silicon dioxide and magnesium stearate and compressed on a pilot scale rotary press. Suitable press forces are chosen to compress tablets comprising 10, 50 or 100 mg Compound to a tensile strength of 2 or 3 MPa. For example, a press force of 3 kN, 10.2 kN, and 15.0 kN is used to produce round 10 mg tablets, oval 50 mg tablets, and oval 100 mg tablets to a tensile strength of 2 MPa. All tablets have acceptable appearance, disintegrate very fast (all below 1 min), have acceptable mass loss after friability (below 0.1%), and acceptable relative standard deviation of the weight of below 2% for 10 mg tablets, and below 1% for 50 and 100 mg tablets.

Example 11: Exemplary Tablet Coating

(37) Tablets comprising 10, 50, or 100 mg of Compound are coated in a Vector LDCS pan coater. The coating solution consists of 20% (w/w) Opadry II 85F in deionized water. The solution is sprayed on a bed of about 1 kg of tablet cores in a 1.3 L pan, rotated at 22 rpm. A spray rate between 9-11 g/min and a spray time of 15-16 min while drying with a drying gas flow of 40-41 CFM, an inlet temperature of 74° C. and an outlet temperature of 43-44° C. results in a coating weight of 2.4-3.2%. The coated tablets contain 2.3-2.6% residual water, which is less than before coating. No physical or chemical degradation of the formulation is observed after coating. The coated tablets disintegrate slightly slower than the uncoated tablet cores, but disintegration is still very fast (below 1 min for 10 mg, below 2 min for 50 and 100 mg).

(38) Tablet cores with a tensile strength of 1.7 MPa are generally deemed sufficient for coating, bulk handling, packaging etc (Pitt, K. G. and M. G. Heasley (2013). “Determination of the tensile strength of elongated tablets.” Powder Technology 238: 169-175). Surprisingly, tablets compressed to 2 MPa as set forth in Example 10 show surface defects after coating. Compression to a tensile strength of 3 MPa is sufficient to avoid any defects.