PROCESS FOR THE PREPARATION OF A NANOPARTICULATE ACTIVE INGREDIENT

Abstract

A process for the preparation of a nanoparticulate active ingredient comprises the steps of: a) providing a solvent, a pharmaceutical active ingredient dissolved in the solvent, a liquid antisolvent and a stabilizer which is dissolved in the solvent or in the antisolvent and wherein the antisolvent is miscible in the solvent; b) mixing the solvent, the active ingredient, the antisolvent and the stabilizer in a micromixer, thereby obtaining a suspension comprising a precipitate of the active ingredient, the solvent and the antisolvent. The active ingredient precipitate is present in the form of nanoparticles having an average particle size of ≥10 nm to ≤999 nm and a particle size distribution, determined by dynamic light scattering (DLS) according to ISO 22412:2017, having a polydispersity index of ≤0.2.

Claims

1. A process for preparation of a nanoparticulate active ingredient comprising: a) providing a solvent, a pharmaceutical active ingredient dissolved in the solvent, a liquid antisolvent and a stabilizer which is dissolved in the solvent or in the antisolvent and wherein the antisolvent is miscible in the solvent, b) mixing the solvent, the active ingredient, the antisolvent and the stabilizer in a micromixer, thereby obtaining a suspension comprising a precipitate of the active ingredient, the solvent and the antisolvent, wherein the active ingredient precipitate is present in the form of nanoparticles having an average particle size of ≥10 nm to ≤999 nm and a particle size distribution, determined by dynamic light scattering (DLS) according to ISO 22412:2017, having a polydispersity index of ≤0.2.

2. The process according to claim 1, wherein the nanoparticulate active ingredient has an average particle size, determined by dynamic light scattering (DLS) according to ISO 22412:2017, of ≥20 to ≤300 nm.

3. The process according to claim 1, wherein the nanoparticulate active ingredient has a spherical or nearly spherical shape with an aspect ratio of ≤2:1.

4. The process according to claim 1, wherein the flow in the micromixer is turbulent and the Reynold number Re is ≥2300.

5. The process according to claim 1, wherein in the micromixer the segregation index Xs is ≤0.1.

6. The process according to claim 1, wherein the micromixer is a valve-assisted mixer or a cascade mixer.

7. The process according to claim 1, wherein the active ingredient has a solubility in the mixture of solvent, antisolvent and stabilizer of ≤1% by weight based on the total mass.

8. The process according to claim 1, wherein the antisolvent is water.

9. The process according to claim 8, wherein the water has a temperature of >0 to ≤30° C.

10. The process according to claim 1, wherein the solvent is an alkanol.

11. The process according to claim 1, wherein the ratio of the solvent to the antisolvent is ≥1:100.

12. The process according to claim 1, wherein the flow rate of the solvent with the dissolved active ingredient and the flow rate of the antisolvent are in a ratio of ≥1:100 to ≤1:1.

13. The process according to claim 1, wherein the concentration ratio of stabilizer to active ingredient in the mixture is ≤10:1.

14. The process according to claim 1, wherein the stabilizer is polyvinylpyrrolidone.

15. The process according to claim 1, wherein the weight ratio of active ingredient to stabilizer is in a range of ≥1:1 to ≤5:1.

Description

[0050] The present invention will be further described with reference to the following examples and figures without wishing to be limited by them.

[0051] FIG. 1 shows a configuration for carrying out the method according to the invention. Depicted are a drug solvent infeed 1, an anti-solvent infeed 2, a cleaning solvent infeed 3, a mixer 4 for mixing the solvent and the antisolvent, a microchannel reactor 5 for nucleation and particle growth, a waste vessel 6, a sample vessel 7, a post-treatment device 8, temperature sensors T and pressure sensors P.

[0052] The solvent infeed 1 and the anti-solvent infeed 2 are preferably ideally mixed with each other in the mixer 4. Then the mixture flows into the microchannel reactor 5 where the nucleation and particle growth occurs. The particle suspension can then be fed into sample vessel 7 to measure the target particle size to check whether the particle size or other quality parameters are met. If not, the suspension will be discarded into the waste vessel 6. The obtained suspension can be treated according to the drug dosage requirement. For example, if the delivery system needs a powdered drug, the nanoparticle suspension will flow into the post-treatment device 8 such as a freeze-dryer, spray dryer, film evaporator, and the like in order to remove the solvents and to obtain the dry nanoparticle powder. If the dosage form is a nanoparticle suspension the original suspension would be diluted or concentrated to obtain the proper concentration of the drug suspension. Optionally, the cleaning solvent infeed 3 is designed to dissolve any drug particles which may block the mixer 4, the reactor 5 or any other auxiliary facilities.

Example 1

[0053] A continuous liquid antisolvent precipitation process as outlined in FIG. 1 was used. The micromixer, a valve mixer, was a Modular MicroReaction System by Ehrfeld Mikrotechnik GmbH, Germany. Deionized water was used as an antisolvent in the process and ethanol as a solvent. Firstly, deionized water continuously flowed in the system at a flow rate of 80 ml/min at a constant temperature of 20° C. by means of an HPLC constant-flow pump. 50.0 grams of a solvent solution of 5.0 weight-% naproxen and 2.5 weight-% polyvinylpyrrolidone (PVP) K30 in ethanol were pumped at a volume flow rate of 1 ml/min at a temperature of 1° C. by an HPLC constant-flow pump. A nanoparticle suspension was formed by mixing the solvent and the antisolvent in the valve mixer used in the example. The particle size distribution of the particles in suspension was measured without filtration using a Malvern Nano series ZSP analyzer (dynamic light scattering) and is given in FIG. 2 (“Nap”: naproxen particles). The particle suspension was then introduced into a freezing dryer at a temperature of −50° C. to −60° C. The precipitation experiment was repeated several times. The particle sizes dp (arithmetic mean particle diameter) after freeze drying were 109.2 nm (without ultrasonic treatment) and 106.3 nm (with ultrasonic treatment), respectively. As the example shows, the particle size did not change after ultrasonic treatment of the sample. The PDI value after precipitation was around 0.18. The PDI value after freeze drying without ultrasonication was around 0.16 and with ultrasonication 0.15.

Example 2

[0054] The stabilizer PVP K30 was added to the anti-solvent water (0.03125 weight-%) with the same weight ratio of drug to stabilizer (2:1) as in example 1. The other experimental conditions were also the same. The mean particle size in nanosuspension without filtration was about 225.0 nm (Malvern Nano series ZSP) and the particle size distribution is depicted in FIG. 3 (“Nap”: naproxen particles).

Example 3

[0055] The concentration of the stabilizer PVP K30 added into the water was changed from 0.03125 weight-% to 2.5 weight-%. The other conditions were the same as in example 2. The mean particle size in nanosuspension without filtration was about 122.4 nm and the particle size distribution is depicted in FIG. 4 (“Nap”: naproxen particles).