Pharmaceutical formulation

Abstract

A pharmaceutical formulation has (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol or pharmaceutically acceptable salt thereof.

Claims

1. A composite, comprising: a solid dispersion of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol, or a pharmaceutically acceptable salt thereof, in a polymeric matrix consisting of a copolymer of polyvinylpyrrolidone and polyvinyl acetate.

2. The composite according to claim 1, consisting of: the solid dispersion of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol, or the pharmaceutically acceptable salt thereof, in the polymeric matrix.

3. The composite according to claim 1, wherein (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol is present in its free form.

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

5. The composite according to claim 1, wherein the solid dispersion is obtainable by hot melt extrusion.

6. The composite according to claim 1, wherein a concentration of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol, which may be present in free form or as a pharmaceutically acceptable salt, in the polymeric matrix is in a range of between 4 and 50 weight percent, based upon the total weight of the solid dispersion.

7. The composite according to claim 1, wherein the composite has a particle size characterized by a d50 value of 1000 μm or less.

8. A pharmaceutical composition, comprising: the composite according to claim 1.

9. The pharmaceutical composition according to claim 8, which is for oral administration.

10. The pharmaceutical composition according to claim 8, which is an immediate release composition.

11. The pharmaceutical composition according to claim 8, characterized by a disintegration time of 15 minutes or less.

12. The pharmaceutical composition according to claim 8, which is a capsule containing a filling, wherein the filling comprises the composite and optionally at least one pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12, which is a capsule, which contains the filling consisting of: 40 to 100 wt. % of the composite; and 0 to 60 wt. % of the at least one pharmaceutically acceptable excipient, based upon the total weight of the filling.

14. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient, and wherein the pharmaceutical composition is selected from the group consisting of a tablet and a granulate.

15. The pharmaceutical composition according to claim 14, which is a tablet, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of a filler, a disintegrant, a lubricant, a pore builder, and an inorganic alkaline metal salt.

16. The pharmaceutical composition according to claim 14, which is a tablet, comprising: 25 to 95 wt. % of the composite; 15 to 72.5 wt. % of a filler; 2.5 to 40 wt. % of a disintegrant; 0 to 5 wt. % of a lubricant; 0 to 20 wt. % of an inorganic alkaline metal salt; and a total of 0 to 20 wt. % of one or more additional pharmaceutically acceptable excipients, based upon the total weight of the tablet.

17. The pharmaceutical composition according to claim 14, which is a tablet, comprising: 40 to 60 wt. % of the composite; 25 to 55 wt. % of a filler; 5 to 30 wt. % of a disintegrant; 0 to 5 wt. % of a lubricant; 0 to 15 wt. % of an inorganic alkaline metal salt; and a total of 0 to 10 wt. % of one or more additional pharmaceutically acceptable excipients, based upon the total weight of the tablet.

18. The pharmaceutical composition according to claim 14, which is a tablet, comprising: 35 to 55 wt. % of the composite; 30 to 55 wt. % of a filler; 5 to 20 wt. % of a disintegrant; 0.25 to 2.5 wt. % of a lubricant; 2.5 to 15 wt. % of an inorganic alkaline metal salt; and a total of 0 to 10 wt. % of one or more additional pharmaceutically acceptable excipients, based upon the total weight of the tablet.

19. The pharmaceutical composition according to claim 14, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of a filler, a disintegrant, an inorganic alkaline metal salt, and a combination thereof, and wherein the filler is microcrystalline cellulose, the disintegrant is selected from the group consisting of crospovidone, carboxymethylcellulose, and salts or derivatives thereof, and the inorganic alkaline metal salt is an inorganic sodium salt.

20. A method of treating cancer in a patient in need thereof, comprising: administering to the patient the pharmaceutical composition according to claim 8, optionally in combination with radiotherapy or chemotherapy or both.

21. The method of treating cancer according to claim 20, wherein said method further comprises: administering at least one chemotherapy drug selected from the group consisting of cisplatin, etoposide and doxorubicin.

22. A method for preparing the composite according to claim 1, the method comprising: hot melt extruding or melt granulating to form the composite.

23. A method for preparing the composite according to claim 1, the method comprising: mixing and melting (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol or a pharmaceutically acceptable salt thereof and the copolymer of polyvinylpyrrolidone and polyvinyl acetate, and optionally at least one pharmaceutically acceptable excipient, hot melt extruding or melt granulating the mixture to form the composite, and optionally milling the formed composite.

24. A method for preparing the composite according to claim 1, the method comprising: dissolving (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol or a pharmaceutically acceptable salt thereof and the copolymer of polyvinylpyrrolidone and polyvinyl acetate, and optionally one or more pharmaceutically acceptable excipients, in a solvent to form a solution, spray-drying the solution to form the composite, and optionally drying the composite.

25. A method for preparing a pharmaceutical composition, comprising the composite according to claim 1, the method comprising: preparing the composite by mixing and melting (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol or a pharmaceutically acceptable salt thereof and the copolymer of polyvinylpyrrolidone and polyvinyl acetate; hot melt extruding or melt granulating the mixture to form the composite, and optionally milling the formed composite; or dissolving the (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol or the pharmaceutically acceptable salt thereof and polyvinylpyrrolidone and polyvinyl acetate in a solvent to form a solution, spray-drying the solution to form the composite, and optionally drying the composite, mixing the composite and one or more pharmaceutically acceptable excipients; optionally granulating the mixture of the composite and the one or more pharmaceutically acceptable excipients, and either filling the mixture into capsules or tableting the mixture.

26. The composite according to claim 1, wherein the solid dispersion is obtainable by melt granulation.

27. The composite according to claim 1, wherein the solid dispersion is obtainable by spray drying.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows dissolution curves for various embodiments of solid dispersions according to the present invention obtained by hot melt extrusion.

(2) FIG. 2 shows a powder Xray diffractogram of crystalline Form I, which is preferably used as a starting material in the present invention.

(3) FIG. 3 shows dissolution curves for various embodiments of solid dispersions according to the present invention obtained by spray-drying.

DETAILED DESCRIPTION OF THE INVENTION

Example 1: Preparation of crystalline anhydrous (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)methanol for use as a Starting Material in Hot Melt Extrusion or Melt Granulation or Spray Drying or Co-Precipitation

(4) Approx. 20 mg drug substance were dissolved or suspended in several solvents (see Table 2 below) at 50° C. The solutions/suspensions were filtered through 0.2 μm syringe filters. The obtained clear solutions were cooled down to 5° C. with a ramp of approx. 0.05 K/min. While cooling the solutions were stirred with PTFE coated stirring bars by a magnetic stirrer. The solid-/liquid-separations of obtained suspensions were done by centrifugation and the solid materials were dried overnight at room temperature with a dry nitrogen flow. The solvents used in these experiments are compiled in the table below.

(5) TABLE-US-00001 Solvent/solvent mixture Volume [ml] Methanol 4 Ethanol 4 1-Propanol 4 Acetone 4 Methyl ethyl ketone 4 Methyl isobutyl ketone 4 Ethyl acetate 4 Tetrahydrofuran 1 Acetonitrile 4 H.sub.2O/Dioxane, 1:1 (v:v) 2 H.sub.2O Pyridine, 1:0.4 (v:v) 1.4 Methanol/Tetrahydrofuran, 1:0.4 (v:v) 1.4 Methanol/Chloroform, 1:0.2 (v:v) 1.2 Methanol/N,N-Dimethylformamide, 1:0 (v:v) 1.3 Methanol/Pyridine, 1:0.2 (v:v) 1.2 2-Propanol/Tetrahydrofuran, 1:0.7 (v:v) 1.7 2-Propanol/N,N-Dimethylformamide, 1:0.5 (v:v) 1.5 2-Propanol/Pyridine, 1:0.4 (v:v) 1.4 Acetone/Dioxane, 1:0.6 (v:v) 1.6 Acetone/Tetrahydrofuran, 1:0.7 (v:v) 1.7 Acetone/Chloroform, 1:1.2 (v:v) 2.2 Acetone/N,N-Dimethylformamide, 1:0.2 (v:v) 1.2 Acetone/Pyridine, 1:0.2 (v:v) 1.2

(6) X-ray powder diffraction (XRPD) was obtained by standard techniques as described in the European Pharmacopeia 7th Edition chapter 2.9.33 (Cu-Kα.sub.1 radiation, λ=1.5406 Å, ambient temperature), and in particular: The measurement was performed in transmission geometry with Cu-K.sub.α1 radiation on a Stoe StadiP 611 diffractometer equipped with Mythen1K Si-strip detector (PSD). Approximately 10-100 mg of the sample were prepared between amorphous films. Measurement was carried out by setting following parameters: angular range: 1 °2θ-41 °2θ angular resolution: 0.015 °2θ PSD step with: 0.49 °2θ measurement time: 15 s/PSD-step generator settings: 40 mA, 40 kV

(7) The diffractogram is illustrated in FIG. 2 and exhibits the following peaks:

(8) TABLE-US-00002 Peak °2θ (Cu—Kα.sub.1 radiation) ± No. 0.2° 1 4.1 2 5.2 3 6.1 4 8.3 5 8.5 6 10.1 7 10.9 8 12.7 9 13.0 10 13.8 11 14.7 12 15.0 13 18.6 14 19.2 15 20.0 16 20.5 17 20.8 18 21.3 19 22.0 20 22.4 21 22.8 22 23.4 23 24.4

Example 2: Solid Dispersions Prepared by Hot Melt Extrusion

(9) Solid dispersions comprising either 20 or 30 wt. % drug substance (starting from the anhydrous crystalline Form I described above) and either 80 or 70 wt. % polymeric matrix were prepared by hot melt extrusion starting from 5 or 10 g material using a lab-scale extruder (HAAKE MiniLab II (Thermo Fisher Scientific)). The polymers used were: Aqoat®, Soluplus® and Kollidon® VA 64, which have been described in detail above, under the following conditions:

(10) 70 or 80 wt. % Kollidon® VA 64: Starting temperature extrusion: 160° C., temperature increase 5-10° C., Extrusion temperature: 200° C. (80% VA 64) or 195° C. (70% VA 64), Extrusion speed: 100 rpm (rounds per minute):

(11) 70 or 80 wt. % Aqoat®): Starting temperature extrusion: 160° C., temperature increase 5° C. (80 wt. % Aqoat®) or 5-10° C. (70 wt. % Aqoat®), Extrusion temperature: 175° C. (80% Aqoat®) or 178° C. (70% Aqoat®)), Extrusion speed: 100 rpm (rounds per minute).

(12) 70 or 80 wt. % Soluplus®: Starting temperature extrusion: 130° C. (80 wt. % Soluplus®) or 188° C. (70 wt. % Soluplus®), temperature increase 5° C. (80 wt. % Soluplus®) or 2-5° C. (70 wt. % Soluplus®), Extrusion temperature: 188° C. (80% Soluplus®) or 200° C. (70% Soluplus®), Extrusion speed: 100 rpm (rounds per minute).

(13) Extrudates were milled using a Pulverisette 23 LabScale mill (Fritsch). At once, one strand of extrudate was milled for 2 minutes at 30 oscillations/s using two 10 mm zirconium oxide grinding ball.

(14) Dissolution tests were run for all of the above samples, using the following test conditions: Approximately 30 mg milled extrudate were dispersed in 7 mL FaSSIF (composition see EXAMPLE 4) by shaking at 37° C. At the according time points 1 mL samples were taken, centrifuged and analysed using HPLC. Sampling time points: 5, 10, 15, 30, 60 and 120 minutes.

(15) The resulting dissolution curves are illustrated in FIG. 1. As apparent from the graph, the solid dispersions of drug substance in the Aqoat® matrix provided the best dissolution for both 20 and 30 wt. % drug substance dispersions. Kollidon® VA 64 provided better dissolution at 80 wt. % polymeric matrix than the Soluplus® based formulations, but only about equivalent dissolution at 70 wt. % Kollidon® VA 64.

(16) However, solubility of the solid dispersion is but one factor to be taken into account when assessing the quality of the solid dispersion. In terms of eutomer:distomer ratio, the Kollidon® VA 64 based solid dispersions surprisingly provided the best results, with eutomer contents of these first experimental formulations being above 95% even after 26 weeks of storage at 40° C. and 75% relative humidity. In terms of eutomer:distomer ratio, the Soluplus® based solid dispersions were clearly not as beneficial as Kollidon® VA 64 based dispersions, but still considerably better than the Aqoat® based solid dispersions.

(17) Therefore, solid dispersions in a polymeric matrix of Kollidon® VA 64, i.e. copovidone, are particularly preferred, in particular solid dispersions of about 20 wt. % drug substance in about 80 wt. % copovidone.

(18) X-ray diffractometric analysis of the samples revealed only amorphous material, wherein the drug substance is molecularly dispersed.

Example 3: Further Example of Solid Dispersion Prepared by Hot Melt Extrusion

(19) Further extrusion experiments were carried out on the preferred Kollidon® VA 64 (80 wt. %) based solid dispersions (i.e. 20 wt. % drug substance, starting from the anhydrous crystalline Form I described above)), using a larger scale extruder (PharmaLab 16; Thermo Fisher Scientific). The temperature profile in the extruder ranged from 60° C. at zone 2 to 150° C. at the die zone. The screw design comprised conveying elements with two kneading blocks. Screw speed was set to 300 rpm (rounds per minute) and the throughput was 1.6 kg/h. Melt temperature was estimated at about 154° C. and melt pressure at about 2 bar. The resulting solid dispersions comprised less than 0.5 wt. % of distomer. The resulting dispersion had a glass transition temperature of about 103° C. and the desired saturation solubility of more than 25 μg/mL was well reached. A hammer mill produced particles with a suitable particle size distribution, with the largest portion of the particles having a size in the range of from 100 to 355 μm.

(20) A further extrusion experiment was carried out on the preferred Kollidon® VA 64 based solid dispersions using the larger scale extruder with an even higher drug load: 30 wt. % drug substance (as above) and 70 wt. % Kollidon® VA 64. The temperature profile in the extruder ranged from 60° C. at zone 2 to 160° C. at the die zone. The screw design comprised conveying elements with two kneading blocks. Screw speed was set to 350 rpm (rounds per minute) and the throughput was 1.0 kg/h. Melt temperature was estimated at about 160° C. and melt pressure below 1 bar. The resulting solid dispersions comprised less than 1.5 wt. % of distomer. The resulting dispersion had a glass transition temperature of about 81-83° C. A hammer mill produced particles with a suitable particle size distribution, with the largest portion of the particles having a size in the range of from 100 to 355 μm.

(21) Thus, hot melt extrusion provided one-phasic amorphous solid dispersions, i.e. solid solutions with drugs substance molecularly dispersed in the polymeric matrix at a favourably high drug load, good bioavailability and favourably high eutomer content.

Example 4: Further Example of Solid Dispersion Prepared by Hot Melt Extrusion

(22) Further process optimization using a co-rotating twin screw extruder (ZSE 18 HP-PH; Leistritz) and a hammer mill allowed further process optimization providing even more advantageous eutomer:distomer ratios (down to 0.3 wt. % distomer), a glass transition temperature of 109° C., amorphous appearance and favourable dissolution properties in solid dispersions of 80 wt. % Kollidon® VA 64 and 20 wt. % drug substance. The results from measuring dissolution of various samples that were obtained at slightly different process conditions each (screw speed, process temperature, and feed rate) are represented in the table below:

(23) TABLE-US-00003 Sample Cmax90 AUC90 C90 # (μg/ml) (min* μg/ml) (μg/ml) 1 263 7720 53 2 257 8120 53 3 263 7460 51 4 241 5120 40 5 253 7340 50 AUC90: Area under the curve at (after) 90 minutes C90: concentration after 90 minutes Cmax90: maximum concentration within 90 minutes

(24) The dissolution test was carried out as follows: A 50 mg active tablet was added to a 100 mL dissolution vessel, Dissolution medium (FaSSIF pH 6.5) was prewarmed to 37° C. Paddles were run at 250 rpm. The timer was started and 100 mL dissolution medium was added to the vessel. After 1 minute, paddle speed was decreased to 200 rpm. 3 minutes before taking each sample time point, 1 mL of sample were removed with a syringe and cannula with 10 μm filter, which was then replaced with a 0.45 μm PTFE filter and the sample filtered into a HPLC vial. 50 μL filtrate were transferred into a new vial with 250 μL diluent, Samples were taken at 4, 10, 15, 20, 30, 40 and 90 minutes.

(25) FaSSIF: 3 mM sodium taurocholate; 0.75 mM lecithin; 105.9 mM sodium chloride; 28.4 mM monobasic sodium phosphate and 8.7 mM sodium hydroxide, pH 6.5

Example 5: Exemplary Capsule Formulations

(26) Hard gelatine capsules were provided with a filling comprising the following ingredients at the indicated weight percentage of the filling:

(27) TABLE-US-00004 Capsule # Ingredient wt. % 1 Solid dispersion in 80 wt % VA 64 50 Sodium sulfate anhydrous 15 Mannitol 15 Crospovidone 20 2 Solid dispersion in 80 wt % VA 64 50 Microcrystalline cellulose 34.5 Crospovidone 10 Sodium chloride 5 Magnesium stearate 0.5 3 Solid dispersion in 80 wt % VA 64 70 Sodium sulfate anhydrous 15 Mannitol 15

Example 6: Exemplary Tablet Formulations (w/o Coating)

(28) Tablets were produced with a composition comprising the following ingredients at the indicated weight percentage of the tablet weight. A tensile strength from 1.0 to 2.0 MPa was postulated.

(29) TABLE-US-00005 Tablet Disintegration # Composition wt. % time [min] 1 Solid dispersion in 80 % VA 64 50.0 ≤15 Microcrystalline cellulose (Avicel ® PH102) 39.5 Croscarmellose sodium 10.0 Magnesium stearate 0.5 2 Solid dispersion in 80 wt % VA 64 50.0 ≤10 Microcrystalline cellulose (Avicel ® PH102) 39.5 Crospovidone 10.0 Magnesium stearate 0.5 3 Solid dispersion in 80 wt % VA 64 50.0 ≤25 Microcrystalline cellulose (Avicel ® PH102) 44.5 Crospovidone 5.0 Magnesium stearate 0.5 4 Solid dispersion in 80 wt % VA 64 50.0 ≤10 Microcrystalline cellulose (Avicel ® PH102) 34.5 Croscarmellose sodium 10.0 Magnesium stearate 0.5 Sodium chloride 5.0

Example 7: Therapeutic Efficacy

(30) The therapeutic relevance of DNA-PK inhibition by the drug substance as such was investigated in vivo in combination with ionizing radiation (IR), a clinically established DSB-inducing treatment. The drug substance was tested for activity in six xenograft mouse models of human cancer. The models were chosen from different cancer indications (colon, lung, head and neck, pancreatic), and histological subtypes (adeno, squamous, large cell). Ionizing radiation was administered using a fractionated schedule of 2 Gy per day administered over five consecutive days (total radiation dose=10 Gy). was given orally 10 min prior to each fraction of radiation (ONC397-1-2AZ, ONC397-1-3AZ, ONC397-1-4AZ, ONC397-1-5AZ, ONC397-1-8AZ).

(31) In all models, oral administration of the drug substance resulted in a strong enhancement of the radiation effect. The radiotherapy enhancing effect was quantified across the tested models by the time to reaching 400% initial volume for the 150 mg/kg study arms. The resulting Kaplan-Meier plots were compared by the log-rank test. The enhancement ratio in this treatment setting was found to be between 1.5 (A549, HCT116), and 2.6 (NCI-H460).

Example 8: Solid Dispersions Prepared by Spray Drying

(32) Solid dispersions comprising either 10, 25 or 50 wt. % drug substance (starting from the anhydrous crystalline Form I described above) and either 50, 75 or 90 wt. % polymeric matrix were prepared by spray drying starting from 1.5 g material using a lab-scale spray dryer (4M8-TriX (ProCepT)). The polymers used were: Aqoat®, Eudragit® E PO and Kollidone VA 64, which have been described in detail above, under the following conditions:

(33) 50, 75 or 90 wt. % Aqoat®: Spray solution: 1%) (m/m) solids in 90:10 dichloromethane:methanol, inlet temperature: 80° C., air flow: 0.3 m.sup.3/min, atomizing air: 10 L/min, nozzle size: 1 mm, feed rate: 2 ml/min.

(34) 50, 75 or 90 wt. % Kollidon® VA 64: Spray solution: 2% (m/m) solids in 90:10 dichloromethane:methanol, inlet temperature: 80° C., air flow: 0.3 m.sup.3/min, atomizing air: 10 L/min, nozzle size: 1 mm, feed rate: 2 mL/min.

(35) 50, 75 or 90 wt. % Eudragit® E PO: Spray solution: 2% (m/m) solids in 90:10 dichloromethane:methanol, inlet temperature: 50° C., air flow: 0.3 m.sup.3/min, atomizing air: 10 L/min, nozzle size: 1 mm, feed rate: 2 mL/min.

(36) Secondary drying of the spray dried material was done in a desiccator at 200 mbar. The material was fully amorphous.

(37) Dissolution tests were run for all of the above samples, using the following test conditions: Approximately 6.5 mg solid dispersion for 10 wt. % drug substance, 2.6 mg solid dispersion for 25 wt. % drug substance and 1.3 mg solid dispersion for 50 wt. % drug substance (normalization of all tested samples to a drug substance amount of 650 μg) were weighed into a 1.5 mL Eppendorf cap.

(38) Dissolution medium (FaSSIF pH 6.5) was prewarmed to 37° C. 1.3 mL prewarmed dissolution medium was added to the Eppendorf Cap. The sample was vortexed for 1 minute and afterwards stored at 37° C. 2.5 minutes before taking each sample time point, the sample was centrifuged for 1 minute at 10000 rpm. 50 μL supernatant were transferred into a HPLC vial with 150 μL diluent and analysed using HPLC. The remaining sample was vortexed for 25 seconds and stored at 37° C. until next time point when the procedure was repeated. Sampling time points: 5, 10, 15, 30, 60, 90 and 120 minutes.

(39) The resulting dissolution curves are illustrated in FIG. 3. The solid dispersion of drug substance in the Eudragit® E PO matrix provided the best dissolution for 10 wt. % drug substance dispersion. However, a clear dependence of the dissolution behaviour on the amount of drug substance within the formulation was detected. The solid dispersion of drug substance in the Aqoat® matrix provided a clear supersaturation without precipitation. Only a slight influence of drug substance amount within the formulation was detected. The solid dispersion of drug substance in the Kollidon® VA64 matrix provided a clear supersaturation with subsequent precipitation. Only slight influence of drug substance amount within the formulation was detected. The 10 wt. % drug substance dispersion showed the highest supersaturation whereas the 25 wt. % and 50 wt. % drug substance dispersions showed almost the same supersaturation and precipitation.

(40) However, solubility of the solid dispersion is but one factor to be taken into account when assessing the quality of the solid dispersion. In terms of stability: The solid dispersion of drug substance in the Aqoat® matrix showed only negligible loss in dissolution performance. After 12 weeks of storage at 40° C. and 75% relative humidity X-ray diffractometric analysis of the samples revealed only amorphous material. Only an acceptable increase in impurities was detected, The solid dispersion of drug substance in the Kollidon® VA64 matrix showed no change in dissolution performance over time. After 12 weeks of storage at 25° C. and 60% relative humidity X-ray diffractometric analysis of the samples revealed only amorphous material, Only a very small increase in impurities was detected (even less than in the Aqoat matrix). While the solid dispersions of drug substance in the Eudragit® E PO matrix showed the best dissolution, dissolution performance and impurity levels after 12 weeks of storage at 40° C. and 75% relative humidity were notably inferior as compared to the Kollidon® VA64 and Aqoat® matrix dispersions.

(41) Therefore, solid dispersions in a polymeric matrix of HPMCAS, herein Aqoat®, manufactured by spray drying are amongst the particularly preferred embodiments, in particular solid dispersions of about 25 wt. % drug substance in about 75 wt. % HPMCAS.

Example 9: Further Examples of Solid Dispersions Prepared by Spray Drying

(42) Further spray drying experiments were carried out on Aqoat® (75 wt. %) based solid dispersions, using a custom-built lab-scale spray dryer. Spray drying was performed under the following conditions:

(43) Spray solution: 6 wt. % solids in 90:10 dichloromethane:methanol, temperature: 96° C., gas flow rate: 450 g/min, atomizing pressure: 120 psi, atomizer: pressure Swirl Schlick 2.0, Feed rate: 27 g/min.

(44) Secondary drying of the spray dried material was done in a convection tray dryer at 40° C. for 22 hours.

(45) X-ray diffractometric analysis of the sample revealed only amorphous material,

(46) In terms of eutomer:distomer ratio, the obtained Aqoat® based solid dispersion provided eutomer contents above 95%, even after 26 weeks of storage at 40° C. and 75% relative humidity. Advantageously, the sum of total degradation products was smaller than 2%.

Example 10: Solid Dispersions Prepared by Coprecipitation

(47) Solid dispersions comprising either 20 or 35 wt. % drug substance (using the anhydrous crystalline Form I described above in the preparation) and either 80 or 65 wt. % polymeric matrix were prepared by coprecipitation screening. The polymers used were: HPMCAS and HPMCP, which have been described in detail above.

(48) A clear solution of compound and polymer (about 20 or 35 wt. % of compound to polymer) in DMA is prepared. 70 μL of the clear DMA solution is poured drop-wise by a multi-channel pipette to a chilled and vigorously stirred antisolvent (700 μL HCl solution, 0.01N, pH 2) in 1-mL glass vials. The resulting suspension is filtered and the obtained cake is washed with water and dried under vacuum.

(49) X-ray diffractometric analysis of the solid dispersions showed no evidence of crystalline material for both drug substance concentrations in HMPCAS and HPMCP.

Example 11: Analytical Methods

(50) The solid state, and in particular amorphous nature of the resulting solid dispersions can be assessed by X-ray diffractometric measurements and/or by DSC measurements, with suitable methods employed for analysis of the preceding examples described in the following. It will be apparent to the skilled person that for certain embodiments, modifications of the analytical methods may be necessary or advantageous. Such modifications, such as adaptation of the heating ramp rate, will be readily identifiable by the skilled person.

(51) XRD:

(52) Measurements were performed in transmission geometry with Cu-Kα.sub.1 radiation on a Stoe StadiP 611 diffractometer equipped with Mythen1K Si-strip detector (PSD) by setting following parameters: preparation between amorphous films angular range: 1 °2θ-41 °2θ angular resolution: 0.03 °2θ PSD stepwith: 0.09 °2θ measurement time: 60 s/PSD-step generator settings: 40 mA, 40 kV

(53) DSC:

(54) DSC studies were performed on a DSC 1 (Mettler Toledo, Switzerland). 20 mg solid dispersion, for instance milled extrudate, were weighed into a 100 μL DSC aluminum crucible and sealed with a lid, which was punctured manually before the measurement. Three heating cycles were carried out: from 25 to 180° C. at a ramp rate of 5 K/min, then maintain at 180° C. for 5 minutes, and then cool down from 180° C. to 25° C. at −5 K/min. During the fourth heating cycle, heating from 25 to 180° C. was effected at a ramp rate of only 10 K/min. Glass transition temperatures Tg were determined in the second, third and fourth heating cycles.

(55) A single glass transition temperature is indicative of an one-phase amorphous system.

(56) HPLC:

(57) Integrity of the drug substance, in particular with regard to possible degradation products, can be assessed by HPLC as follows: System: Agilent Technologies (USA) 1260 HPLC System Method: 10 μL of sample were injected and quantified by a diode array detector working at 298 nm. The eluents used were binary mixtures of 95:5 and 5:95 (v/v) MilliQ water with 0.1% trifluoric acid and ACN. The linear gradient ran from 90% phase A to 100% B within 13 min. A YMC Triart reverse phase column (4.6×50 mm with 3 μm packing) was used, constantly heated up to 35° C.

(58) The degree of enantiomeric impurity can be assessed using quantitative chiral HPLC as follows: System: Agilent Technologies (USA) 1260 HPLC System Method: 5 μL of sample were injected and quantified by a diode array detector working at 273 nm. The eluents used were n-Hexane with 0.1% formic acid (phase A) and Isopropanol with 0.1% formic acid (phase B). The isocratic gradient with 80% phase A and 20% phase B ran within 40 min. A Lux Cellulose-1 column (4.6×150 mm with 5 μm packing) was used, constantly heated up to 20° C.