LIQUISOLID PHARMACEUTICAL FORMULATION AND PROCESS FOR MANUFACTURING

Abstract

The present invention relates to a liquisolid pharmaceutical formulation comprising a porous carrier and an active pharmaceutical ingredient loaded onto a surface of the porous carrier, wherein the active pharmaceutical ingredient is dispersed in propylene carbonate or a mixture of propylene carbonate and a further solvent and the dispersion of the active pharmaceutical ingredient and propylene carbonate or a mixture of propylene carbonate and a further solvent is loaded onto the external surface and the internal surface located inside the pores of the porous carrier thereby forming a liquisolid system, and to a process for manufacturing such a liquisolid pharmaceutical formulation.

Claims

1. A liquisolid pharmaceutical formulation comprising a porous carrier and an active pharmaceutical ingredient loaded onto a surface of the porous carrier, wherein the active pharmaceutical ingredient is dispersed in propylene carbonate or a mixture of propylene carbonate and a further solvent and the dispersion of the active pharmaceutical ingredient and propylene carbonate or a mixture of propylene carbonate and a further solvent is loaded onto the external surface and the internal surface located inside the pores of the porous carrier thereby forming a liquisolid system.

2. The liquisolid pharmaceutical formulation according to claim 1, wherein the porous carrier is selected from the group consisting of porous silica, polyorganosiloxanes, pharmaceutical clays, silicon dioxide nanotubes, silica gel, magnesium aluminosilicate, anhydrous calcium phosphate, and calcium carbonate.

3. The liquisolid pharmaceutical formulation according to claim 2, wherein the porous carrier is mesoporous silica.

4. The liquisolid pharmaceutical formulation according to claim 1 , wherein the further solvent is selected from the group consisting of dimethyl sulfoxide, ethanol, methanol, isopropanol, dichloromethane, acetone, tert-butanol, and a polymer which is liquid at ambient temperature .

5. The liquisolid pharmaceutical formulation according to claim 1, wherein the active pharmaceutical ingredient is a poorly water-soluble or water-insoluble compound.

6. The liquisolid pharmaceutical formulation according to claim 1 , wherein the active pharmaceutical ingredient is loaded to the porous carrier in an amount in a range of ≥ 5 weight% to ≤ 70 weight%, based on a weight of 100 weight% of the liquisolid pharmaceutical formulation comprising the porous carrier, the active pharmaceutical ingredient and propylene carbonate.

7. The liquisolid pharmaceutical formulation according to any one of the preceding claims, wherein propylene carbonate is comprised in an amount in a range of ≥ 10 weight% to ≤ 60 weight%, based on a weight of 100 weight% of the porous carrier and propylene carbonate.

8. A pharmaceutical solid dosage form, comprising the liquisolid pharmaceutical formulation according to claims 1.

9. The pharmaceutical solid dosage form according to claim 8, wherein the compound is selected from the group consisting of a capsule, a tablet, granules, pills, pellets and micro-tablets.

10. A process for manufacturing a liquisolid pharmaceutical formulation, the process comprising the steps of: a) dispersing, dissolving or otherwise introducing an active pharmaceutical ingredient into propylene carbonate or a mixture of propylene carbonate and a further solvent to form a liquid mixture, b) selecting a porous carrier, and c) admixing the liquid mixture of step a) and the porous carrier of step b) to form a liquisolid formulation.

11. The process according to claim 10, wherein in a further step d) the liquisolid formulation is formed into capsules, tablets, granules, pills, pellets or micro-tablets.

12. The process according to claims 10, wherein the admixing in step c) is performed at a temperature in a range from ≥ 10° C. to ≤ 50° C.

13. The process according to claim 10, wherein in step a) the dispersing, dissolving or otherwise introducing an active pharmaceutical ingredient into propylene carbonate or a mixture of propylene carbonate and a further solvent is performed by ultrasonic dissolving, vortexing, or mixing using magnetic mixers or blade agitators.

14. A liquisolid pharmaceutical formulation or a pharmaceutical solid dosage form obtained by the process according to claims 10 .

15. The method of claim 4, wherein the further solvent is polyethylene glycol.

16. The method of claim 5, wherein the active pharmaceutical ingredient is selected from the group consisting of nimodipine, celecoxib, fenofibrate, naproxen, loratadine, imipramine, bisacodyl, gliclazide, furosemide, clozapine and mixtures thereof.

17. The method of claim 6, wherein the active pharmaceutical ingredient is loaded to the porous carrier in an amount in a range of ≥ 20 weight% to ≤ 50 weight%, based on a weight of 100 weight% of the liquisolid pharmaceutical formulation comprising the porous carrier, the active pharmaceutical ingredient and propylene carbonate.

18. The method of claim 7, wherein propylene carbonate is comprised in an amount in a range of ≥ 30 weight% to ≤ 50 weight%, based on a weight of 100 weight% of the porous carrier and propylene carbonate.

19. The method of claim 12, wherein the admixing in step c) is performed at a temperature in a range from ≥ 15° C. to ≤ 30° C.

Description

[0030] The figures show:

[0031] FIG. 1 The maximum deliverable dose of various poorly water-soluble active pharmaceutical ingredients in propylene carbonate (PC).

[0032] FIG. 2 The biphasic dissolution profiles of a liquisolid pharmaceutical formulation of Nimodipine compared to a Nimodipine market formulation.

[0033] FIG. 3 The biphasic dissolution profiles of a liquisolid pharmaceutical formulation of Celecoxib compared to a Celecoxib market formulation.

[0034] FIG. 4 The biphasic dissolution profiles of a liquisolid pharmaceutical formulation of Fenofibrate compared to a Fenofibrate market formulation.

[0035] FIG. 5 The biphasic dissolution profiles of a liquisolid pharmaceutical formulation of Naproxen compared to a Naproxen market formulation.

[0036] FIG. 6 The biphasic dissolution profiles of a liquisolid pharmaceutical formulation of Loratadine compared to a Loratadine market formulation.

EXAMPLE 1: SOLUBILITY ANALYSIS OF POORLY WATER-SOLUBLE DRUGS IN PROPYLENE CARBONATE

[0037] To determine suitable drug candidates, the solubility of various poorly water-soluble active pharmaceutical ingredients (API) in propylene carbonate was tested. For a preliminary analysis, 1-2 mg of each compound was weighted in an Eppendorf tube and 1 ml propylene carbonate was added. The mixture was mixed with a metal spatula for 10 min each. The solubility of compounds, which were fully dissolved in the preliminary tests where than further analyzed. About 20 mg of each compound were used and under stirring with a metal spatula propylene carbonate was added in 10 .Math.l steps. The following table 1 shows the results of the solubility tests.

TABLE-US-00001 Solubility of poorly water-soluble active pharmaceutical ingredients (API) in propylene carbonate Active Pharmaceutical Ingredient Sample [mg] Solvent [mL] Mean Solubility [mg/mL] Bisacodyl (Sigma- Aldrich Chemie GmbH, Steinheim, Germany) 22.40 0.25 91.55 22.30 0.24 20.30 0.22 Celecoxib (Kekule Pharma Limited, Hyderabad, India) 21.90 0.10 266.67 21.20 0.07 20.90 0.07 Clozapine (Swapnroop Drugs and Pharmaceuticals, Aurangabad, India) 20.60 4.30 4.79 20.50 4.30 21.20 4.40 Fenofibrate (≥ 99%, Sigma-Aldrich Chemie GmbH, Steinheim, Germany) 21.20 0.12 222.86 20.30 0.08 20.90 0.08 Furosemide (Sigma-Aldrich Chemie GmbH, Traufstein, Germany) 20.30 1.04 19.55 20.00 1.07 20.50 1.00 Gliclazide (≥ 98%, Sigma-Aldrich Chemie GmbH, Steinheim, Germany) 23.60 0.74 32.27 24.30 0.76 23.10 0.70 Griseofulvin (97%, Alfa Aesar GmbH & Co KG, Karlsruhe, Germany) 20.10 1.20 16.81 22.40 1.32 20.70 1.24 Imipramine hydrochloride (≥ 99%, Sigma-Aldrich Chemie GmbH, Steinheim, Germany) 9.70 0.06 167.00 19.90 0.11 20.50 0.13 Indomethacin (98%, Alfa Aesar GmbH & Co KG, Karlsruhe, Germany) 11.40 0.70 17.22 10.50 0.60 10.30 0.57 Loratadine (Sris Pharmaceuticals, Hyderabad, India) 20.20 0.35 60.19 21.80 0.35 20.60 0.35 Naproxen (Sigma-Aldrich Chemie GmbH, Steinheim, Germany) 19.80 0.46 41.52 23.50 0.58 22.30 0.54 Nimodipine (≥ 98%, Tokyo Chemical Industrie, Zwijndrecht, Belgium) 23.10 0.16 144.40 25.70 0.18 23.40 0.16 (+)-Verapamil hydrochloride (≥ 99%, Sigma-Aldrich Chemie GmbH, Steinheim, Germany) 19.40 0.34 56.34 22.30 0.40 21.40 0.38

[0038] FIG. 1 shows the maximum deliverable dose of the active pharmaceutical ingredients (table 1) in propylene carbonate (PC) which can be administered in a single capsule (Size 0). Nimodipine, celecoxib, fenofibrate, naproxen and loratadine were elected for the manufacture of liquisolid pharmaceutical formulations and further testing.

Example 2: Manufacture of Liquisolid Pharmaceutical Formulations by Adsorption to Mesoporous Silica

[0039] The respective active pharmaceutical ingredient and propylene carbonate (≥ 99.7%, Carl Roth GmbH + Co. KG, Karlsruhe, Germany) in the amounts as given in the following table were mixed in a 5 mL glass vial and solved by using an ultrasonic bath for 20 min at a temperature of 25° C. The mesoporous silica Silsol® (Grace GmbH, Worms, Germany) was added and mixed with a metal spatula until the solution was adsorbed by the silica. The liquisolid pharmaceutical formulations were used immediately for biphasic dissolutions tests.

TABLE-US-00002 Compositions of liquisolid formulations Compounds Dissolution 1 Amounts Dissolution 2 Amounts Dissolution 3 Amounts Nimodipine Propylene Carbonate Silsol® 10.9 mg mg 10.0 mg 11.0 mg 125 .Math.L 125 .Math.L 125 .Math.L 187.3 188.2 mg 189.4 mg Celecoxib Propylene Carbonate Silsol® 10.9 mg 10.3 mg 10.9 mg 50 .Math.L 50 .Math.L 50 .Math.L 74.0 mg 75.1 mg 75.0 mg Fenofibrate Propylene Carbonate Silsol® 10.1 mg 10.0 mg 10.5 mg 75 .Math.L 75 .Math.L 75 .Math.L 113.9 mg 113.2 mg 113.8 mg Naproxen Propylene Carbonate Silsol® 10.4 mg 10.1 mg 10.0 mg 325 .Math.L 325 .Math.L 325 .Math.L 488.2 mg 488.5 mg 489.2 mg Loratadine Propylene Parbonate Silsol® 10.0 mg 10.3 mg 11.0 mg 175 .Math.L 175 .Math.L 175 .Math.L 263.2 mg 263.9 mg 263.4 mg

Example 3: Biphasic Dissolution Tests

[0040] The in vivo performance of the liquisolid formulations of poorly water-soluble drugs as prepared in example 2 were investigated by the biphasic dissolution apparatus (BiPHa+) and setup. This approach was chosen to simulate the gastrointestinal properties to obtain in vivo predictive results.

3.1 Method

[0041] Biphasic release is a process in which, in addition to solubility in an aqueous medium, adsorption into the intestinal wall is demonstrated using an organic phase. The transition to the organic phase can be understood as absorption of active substances into the blood. The biphasic release experiments were investigated using a fully automated biphasic dissolution apparatus (BiPHa+) as described in A. Denninger et al., Pharmaceutics 2020, 12, 237.

[0042] To simulate the gastrointestinal properties to obtain in vivo predictive results, the pH-profile, bile salt concentration and gastrointestinal passage time were adjusted in the aqueous phase to mimic human gut conditions. An organic phase of 1-decanol above the aqueous phase imitated the fraction absorbed from the gut. As a test model, the profile of a person without prior food intake was chosen. Therefore, FaSSIF-V2 medium, which represents the bile salts concentration of a fasted human was used. FaSSIF-V2 medium is a mixture of a phosphate and a citrate buffer system, which facilitates comparable in vivo buffer capacities. To generate an in-situ biorelevant aqueous medium for the fasted state, biorelevant surfactants, namely sodium-taurocholate (3 mM) and lecithin (0.2 mM), were added.

[0043] Prior to the start of the experiments, both phases, 1-decanol and the acidic aqueous phase, were saturated with each other. First, the respective formulation was added (Table 2) to 50 mL HC1 (0.1 M), simulating the stomach. During the first 30 min the formulation disintegrated / dispersed in 50 ml of 0.1 M HC1. After 30 min FaSSIF-V2 concentrate (sodium-taurocholate and lecithin) was added simultaneously to the addition of citrate-phosphate buffer (tri-potassium phosphate and potassium citrate) resulting in a first pH-shift from pH 1 to pH 5.5, simulating the duodenum. Thereafter, 50 mL 1-decanol was added. The last pH-shift from 5.5 to 6.8 after 90 minutes was gradually adjusted by adding more citrate-phosphate buffer, representing the jejunum and ileum (final concentrations: 3 mM sodium-taurocholate, 0.2 mM lecithin, 525 mM tri-potassium phosphate and 225 M potassium citrate). The adjusted buffers were titrated by 0.1 M NaOH and 0.1 M HC1 (pH 5.5-6.8). The whole dissolution took 4.5 hours.

[0044] The concentration profiles of the aqueous and organic phase were measured online continuously with an Agilent 8454 UV-Vis spectrometer (Waldbronn, Germany) and quantified on the compound-specific wavelength.

[0045] For each compound, the biphasic dissolution test was performed in triplicate. In order to evaluate the liquisolid formulations in terms of their performance, each liquisolid formulation was compared to a respective commercially available formulation.

3.2 Nimodipine

[0046] The liquisolid formulation of nimodipine, as described in example 2, was compared to the commercially available market formulation Nimotop® (Bayer Vital GmbH, Leverkusen, Germany).

[0047] The FIG. 2 illustrates the pH profile and the biphasic dissolution profiles of the liquisolid formulation of nimodipine in propylene carbonate on Silsol®(PC-Silsol) and the nimodipine market formulation (Market Formulation) during the 270 min dissolution test. As can be taken from FIG. 2, the nimodipine market formulation Nimotop® provided 38% predicted absorption, while the liquisolid formulation of nimodipine provided 46% predicted absorption. Further, the liquisolid formulation of nimodipine showed a different kinetic profile, providing a faster onset of action.

3.3 Celecoxib

[0048] The liquisolid formulation of celecoxib, as described in example 2, was compared to the commercially available market formulation Celebrex® (Pfizer Pharma GmbH, Berlin, Germany).

[0049] FIG. 3 illustrates the biphasic dissolution profiles of the liquisolid formulation of celecoxib in propylene carbonate on Silsol®(PC-Silsol) and the celecoxib market formulation (Market Formulation) during the 270 min dissolution test. As can be taken from FIG. 3, the celecoxib market formulation Celebrex® provided 41% predicted absorption, while the liquisolid formulation of celecoxib provided 54% predicted absorption. Further, the liquisolid formulation of celecoxib showed a different kinetic profile, providing a faster onset of action.

3.4 Fenofibrate

[0050] The liquisolid formulation of fenofibrate, as described in example 2, was compared to the commercially available market formulation Lipidil® (Mylan Healthcare GmbH, Bad Homburg, Germany).

[0051] FIG. 4 illustrates the biphasic dissolution profiles of the liquisolid formulation of fenofibrate in propylene carbonate on Silsol®(PC-Silsol) and the fenofibrate market formulation (Market Formulation) during the 270 min dissolution test. As can be taken from FIG. 3, both, the fenofibrate market formulation Lipidil® and the liquisolid formulation of fenofibrate provided 45% predicted absorption. Further, both formulations of fenofibrate showed a kinetic profile, providing a fast onset of action.

3.5 Naproxen

[0052] The liquisolid formulation of naproxen, as described in example 2, was compared to the commercially available market formulation Dolormin GS® (Johnson & Johnson GmbH, Neuss, Germany).

[0053] FIG. 5 illustrates the biphasic dissolution profiles of the liquisolid formulation of naproxen in propylene carbonate on Silsol®(PC-Silsol) and the naproxen market formulation (Market Formulation) during the 270 min dissolution test. As can be taken from FIG. 5, the naproxen market formulation Dolormin GS® provided 89% predicted absorption, while the liquisolid formulation of naproxen provided 94% predicted absorption. Further, the liquisolid formulation of naproxen showed a kinetic profile, providing a fast onset of action.

3.6 Loratadine

[0054] The liquisolid formulation of loratadine, as described in example 2, was compared to the commercially available market formulation Lorano® akut (Hexal AG, Holzkirchen, Germany).

[0055] FIG. 6 illustrates the biphasic dissolution profiles of the liquisolid formulation of loratadine in propylene carbonate on Silsol®(PC-Silsol) and the loratadine market formulation (Market Formulation) during the 270 min dissolution test. As can be taken from FIG. 6, the loratadine market formulation Lorano® provided 34% predicted absorption, while the liquisolid formulation of loratadine provided 42% predicted absorption. Further, the liquisolid formulation of loratadine showed a steeper curve in the second half of the biphasic dissolution.

[0056] As can be seen from FIGS. 2 to 6, the liquisolid pharmaceutical formulations of poorly water-soluble drugs in propylene carbonate adsorbed onto mesoporous silica provided improved absorption of the active ingredient compared to the available market formulations.

Example for Comparison 4: Testing of Liquisolid Formulation Manufactured Using Various Non-Volatile Solvents

4.1 Solubility Screening

[0057] The solubility of the poorly water-soluble APIs celecoxib, fenofibrate, naproxen, loratadine, and nimodipine in tetraglycole (TEG), polyethylene glycol 400 (PEG 400) propylene glycol (PG) and glycerol was evaluated as described in Example 1. Therefore, 1 mg of each compound was weighted in an Eppendorf tube and 1 ml of solvent was added. The mixture was mixed with a metal spatula for 10 min each. The solubility of compounds, which were fully dissolved in the preliminary tests where than further analyzed. About 20 mg of each compound were used and under stirring with a metal spatula the solvent was added in 10 .Math.l steps. The used APIs are listed in table 3. The used solvents are summarised in Table 4.

TABLE-US-00003 Active pharmaceutical ingredients (API) API Supplier Celecoxib Kekule Pharma Limited, Hyderabad, India Fenofibrate Sigma-Aldrich Chemie GmbH, Steinheim, Germany Naproxen Sigma-Aldrich Chemie GmbH, Steinheim, Germany Loratadine Sris Pharmaceuticals, Hyderabad, India Nimodipine Tokyo Chemical Industrie, Zwijndrecht, Belgium

TABLE-US-00004 Non-volatile solvents non-volatile solvent Supplier tetraglycole (TEG) Sigma-Aldrich Chemie GmbH (Taufkirchen, Germany) polyethylene glycol 400 (PEG 400) Carl Roth GmbH + Co. KG propylene glycol (PG) Carl Roth GmbH + Co. KG glycerol Caesar & Loretz GmbH (Hilden, Germany)

[0058] The following table 5 shows the results of the solubility tests.

TABLE-US-00005 Solubility of poorly water-soluble active pharmaceutical ingredients (API) in non-volatile solvents Solubilitv (mg/mL) API TEG PEG 400 PG Glycerol Celecoxib 244.31 230.12 60.29 < 1 Fenofibrate 212.34 150.14 12.13 < 1 Naproxen 285.21 102.34 31.24 < 1 Loratadine 105.29 60.98 59.14 < 1 Nimodipine 140.13 96.31 25.45 < 1

[0059] As can be taken from Table 5, also tetraglycole (TEG) has been found to dissolve the APIs sufficiently to prepare liquisolid formulations. Furthermore, polyethylene glycol 400 (PEG 400) dissolved the APIs sufficiently. Propylene glycol (PG) dissolved only loratadine sufficiently to prepare a comparable liquisolid formulation. Glycerol was found to be not suitable due a solubility of less than 1 mg/mL.

4.2: Manufacture of Liquisolid Pharmaceutical Formulations by Adsorption to Mesoporous Silica Using Various Non-Volatile Solvents

[0060] Mesoporous silica based formulations with poorly aqueous soluble APIs as summarised in Table 3 and the non-volatile solvents tetraethylene glycol (TEG), polyethylene glycol 400 (PEG 400) and propylene glycol (PG) were prepared as described in Example 2.

[0061] The active pharmaceutical ingredient and the respective amount of non-volatile solvent in the amounts as given in the following Tables 6, 7, 8, 9 and 10 were mixed in a 10 mL screw lid glass vial and solved by using an ultrasonic bath for 20 min at a temperature of 25° C. The mesoporous silica Silsol® (Lot. 1000306729; W. R. Grace & Co.-Conn. Europe, Worms, Germany) was added and mixed with a metal spatula until the solution was adsorbed by the silica. The liquisolid pharmaceutical formulations were used immediately for biphasic dissolutions tests.

TABLE-US-00006 Composition of liquisolid celecoxib formulations Compounds Dissolution 1 Amounts Dissolution 2 Amounts Dissolution 3 Amounts Celecoxib 10.6 mg 10.0 mg 10.1 mg TEG 50 .Math.L 50 .Math.L 50 .Math.L Silsol® 75.2 mg 75.1 mg 76.1 mg Celecoxib 10.1 mg 10.4 mg 10.1 mg PEG 400 50 .Math.L 50 .Math.L 50 .Math.L Silsol® 74.3 mg 76.1 mg 75.9 mg

TABLE-US-00007 Composition of liquisolid fenofibrate formulations Compounds Dissolution 1 Amounts Dissolution 2 Amounts Dissolution 3 Amounts Fenofibrate 10.6 mg 9.4 mg 9.9 mg TEG 75 .Math.L 75 .Math.L 75 .Math.L Silsol® 111.4 mg 115.0 mg 113.8 mg Fenofibrate 10.3 mg 10.3 mg 10.6 mg PEG 400 75 .Math.L 75 .Math.L 75 .Math.L Silsol® 114.3 mg 114.0 mg 113.9 mg

TABLE-US-00008 Composition of liquisolid naproxen formulations Compounds Dissolution 1 Amounts Dissolution 2 Amounts Dissolution 3 Amounts Naproxen 10.5 mg 10.6 mg 11.0 mg TEG 325 .Math.L 325 .Math.L 325 .Math.L Silsol® 486.6 mg 484.0 mg 486.8 mg Naproxen 10.2 mg 10.2 mg 10.6 mg PEG 400 325 .Math.L 325 .Math.L 325 .Math.L Silsol® 489.3 mg 487.9 mg 487.1 mg

TABLE-US-00009 Composition of liquisolid loratadine formulations Compounds Dissolution 1 Amounts Dissolution 2 Amounts Dissolution 3 Amounts Loratadine 9.8 mg 10.7 mg 10.6 mg TEG 175 .Math.L 175 .Math.L 175 .Math.L Silsol® 264.4 mg 260.2 mg 263.9 mg Loratadine 9.6 mg 10.0 mg 10.0 mg PEG 400 175 .Math.L 175 .Math.L 175 .Math.L Silsol® 266.8 mg 261.2 mg 263.9 mg Loratadine 9.9 mg 10.0 mg 10.0 mg PG 175 .Math.L 175 .Math.L 175 .Math.L Silsol® 286.2 mg 261.4 mg 265.2 mg

TABLE-US-00010 Composition of liquisolid nimodipine formulations Compounds Dissolution 1 Amounts Dissolution 2 Amounts Dissolution 3 Amounts Nimodipine 10.4 mg 10.2 mg 10.3 mg TEG 125 .Math.L 125 .Math.L 125 .Math.L Silsol® 187.0 mg 190.5 mg 191.2 mg Nimodipine 10.9 mg 9.4 mg 9.3 mg PEG 400 125 .Math.L 125 .Math.L 125 .Math.L Silsol® 186.6 mg 190.5 mg 186.3 mg

4.3: Biphasic Dissolution Tests of Liquisolid Formulation Manufactured Using Various Non-Volatile Solvents

[0062] To evaluate the performance of the prepared formulations in vitro biphasic dissolution tests were performed via the BiPHa+ as described in Example 3. The maximum partitioned drug in the organic phase in vitro has the ability to estimate the fraction absorbed in vivo, due to the selected biorelevant method setup simulating human GIT conditions. The market formulations (Originator) of the selected APIs were tested additionally to compare the performance against established marked products. The market formulations (Originator) as summarised in the following table 11 were used:

TABLE-US-00011 Used market formulations of the active pharmaceutical ingredients (APIs) API Market Formulation Supplier Celecoxib Celebrex® Pfizer Pharma GmbH (Berlin, Germany) Fenofibrate Lipidil® Mylan Healthcare GmbH (Bad Homburg, Germany Naproxen Dolormin GS® Johnson & Johnson GmbH (Neuss, Germany) Loratadine Lorano® akut Hexal AG (Holzkirchen, Germany) Nimodipine Nimotop® Bayer Vital GmbH (Leverkusen, Germany)

[0063] The results of the biphasic dissolutions represented by the maximum partitioned drug (%) in the organic phase are summarised in the following table 12 and compared to the results for propylene carbonate (PC) as determined in examples 3.2 to 3.6.

TABLE-US-00012 Biphasic dissolution results: maximum partitioned drug in the organic phase Maximum Partitioned Drug in the Organic Phase (%) API PC Silsol® Formulation TEG Silsol® Formulation PEG 400 Silsol® Formulation PG Silsol® Formulation Market Formulation Celecoxib 54 53 46 * 41 Fenofibrate 45 28 32 * 45 Naproxen 94 86 69 * 89 Loratadine 42 38 23 38 34 Nimodipine 46 38 32 * 38 *Poor solubility of the API in the solvent, therefore, not feasible for formulation.

[0064] As can be taken from the table 12, the formulations where the API was dissolved in propylene carbonate demonstrated the best performance regarding the dissolution and solubility properties for all tested APIs.

[0065] The corresponding marked formulations were also analyzed under the same in vitro conditions and revealed that the formulations using propylene carbonate were comparable for fenofibrate, and for the further APIs celecoxib, naproxen, loratadine, and nimodipine showed even better results than the commercially available formulations.