NANO-DRY MELTING

Abstract

Disclosed herein is a method for the preparation of an amorphous solid dispersion (ASD) comprising the steps of providing an aqueous suspension comprising nano-particles having a solubility in the aqueous suspension of less than 10 g/1, water and at least one polymer, nano-dry-melting of the aqueous suspension comprising nano-particles for a time span between 0.1 seconds and 300 seconds, at a temperature between a) 20 K below the glass transition temperature as determined with DSC according to DIN EN ISO 11357-2 at a heating rate of 10 K/min of the solid components of the aqueous suspension comprising nano-particles or 20 K below the glass transition temperature of the at least one polymer, depending on what is higher, b) the decomposition temperature of the at least one polymer or the decomposition temperature of the nano-particles, depending which is lowerto form the amorphous solid dispersion.

Claims

1. A method for preparation of an amorphous solid dispersion (ASD) comprising providing an aqueous suspension at a temperature between 253 K and 323 K comprising nano-particles having a solubility in the aqueous suspension of less than 10 g/I, water and at least one polymer, nano-dry-melting of the aqueous suspension comprising nano-particles for a time span between 0.1 seconds and 300 seconds , at a temperature between a) 20 K below the glass transition temperature as determine with DSC according to DIN EN ISO 11357-2 at a heating rate of 10 K/min of the solid components of the aqueous suspension comprising nano-particles or 20 K below the glass transition temperature of the at least one polymer, depending on what is higher, b) the decomposition temperature of the at least one polymer or the decomposition temperature of the nano-particles, depending which is lower, to form the amorphous solid dispersion.

2. The method according to claim 1 wherein the nano-particles are active ingredient nano -particles.

3. The method according to claim 1, wherein the aqueous suspension comprises nano-particles only having a solubility of less than 10 g/I, water and at least one polymer.

4. The method according to claim 1, wherein the aqueous suspension further comprises one or more surfactants.

5. The method according to claim 1 wherein the nano-dry-melting temperature lies between a) the glass transition temperature as determined with DSC according to DIN EN ISO 11357-2 at a heating rate of 10 K/min of the solid components of the aqueous suspension comprising nano-particles or the glass transition temperature of the at least one polymer, depending on what is higher, b) the decomposition temperature of the at least one polymer or the decomposition temperature of the nano-particles, depending which is lower.

6. The method according to claim 1 wherein the nano-dry-melting temperature lies between a) 20 K above the glass transition temperature as determined with DSC according to DIN EN ISO 11357-2 at a heating rate of 10 K/min of the solid components of the aqueous suspension comprising nano-particles or 20 K above the glass transition temperature of the at least one polymer, depending on what is higher, b) the decomposition temperature of the at least one polymer or the decomposition temperature of the nano-particles, depending which is lower.

7. The method according to claim 1 wherein the nano-dry-melting of the aqueous suspension comprising nano-particles occurs for a time span between 0.1 seconds and 180 seconds.

8. The method according to claim 1 wherein the process starts with nanogrinding the particles to form nano-particles.

9. The method according to claim 8 wherein the nano-grinding is carried out at a temperature between 273 K and 303 K.

10. The method according to claim 1 wherein the nano-melt-drying is carried out via a process selected from the group consisting of spray drying, spray granulation, fluidized bed drying systems, contact drying, extrusion processes and drying by electromagnetic radiation.

11. The method according to claim 1 wherein the generated ASD is further processed via tempering.

12. The method according to claim 8 wherein the method is carried out continuously.

Description

FIGURES

[0117] FIG. 1: XRPD-measurements of different Indomethacine-PVPK12 powders, produced with different drying temperatures.

[0118] FIG. 2: XRPD-measurements of samples resulting from and suspensions comprising micro- (two upper curves) and nanoparticles (two lower curves processed at different temperature zones on Kofler bench.

EXAMPLES

Example 1: Preparation of an Aqueous Suspension Comprising Nano-Particles

[0119] The aqueous suspension comprising nano-particles was produced by means of a planetary ball mill (Fritsch Pulverisette 5). For this purpose, ~7 wt% indomethacin was stabilized with ~13 wt% PVP K12 and 0.2 wt% SDS. The polymer surfactant solution was prepared and dissolved separately in distilled water. Indomethacin powder was then added to the solution and the resulting suspension was homogenized on a stirring plate. The grinding chambers were filled to 60% (volume) with 0.4-0.6 mm (SiLibeads, zirconium oxide, yttrium stabilized) grinding media and the remaining volume with suspension, free of air bubbles. After 1 h 30 min grinding time at 400 rpm, a suspension comprising nanoparticles with particles d90 < 500 nm (Malvern, Mastersizer 2000) was available for production of ASD (drug load ~35 wt%) via nano melt drying.

Example 2: Nano Melt Drying Via Spray Drying

[0120] The aqueous suspension comprising nano-particles generated in example 1 was spray dried at two different temperatures to produce ASDs. For this process a Büchi B-290 labspray dryer was used. Two different inlet temperatures were chosen which were 200° C. and 220° C. The resulting outlet temperatures during the process were 100° C. and 115° C. Relative aspirator power and pump speed were fixed at 1 and 0.20. In FIG. 1 the XRPD-graphs of both resulting powders is visible. By processing the suspension with an outlet temperature of 115° C. it was possible to produce a completely X-ray amorphous ASD. For processing with 100° C. outlet temperature the residence time was not sufficient to produce a completely X-ray amorphous ASD.

Example 3: Comparison of Suspensions Comprising Micro- and Nanoparticles on Kofler-Bench

[0121] To compare the suspensions comprising microparticles used to produce the aqueous suspension comprising nano-particles with the resulting aqueous suspension comprising nano-particles a Kofler bench was used. There a film was extracted from the respective suspension and treated with different temperatures. The films were dried on Kofler bench for several minutes. Then samples of different temperature areas were taken and measured in XRPD-device. FIG. 2 shows the different XPRD-graphs. It can be seen that in case of suspensions comprising nanoparticles fully amorphous ASD-films were produced. Films resulting from suspensions comprising microparticles are still crystalline. In addition, the films resulting from suspensions comprising nanoparticles were visually much more homogeneous than those from suspensions comprising microparticles.