WO2021069345A1

WO2021069345A1 - Process for producing nanoparticulate rivaroxaban

Info

Publication number: WO2021069345A1
Application number: PCT/EP2020/077777
Authority: WO
Inventors: Matthias Christian ERBER; Werner Hoheisel; Leslaw Mleczko; Rubi ROMEIS; Marcel KOKOTT
Original assignee: Bayer Aktiengesellschaft
Priority date: 2019-10-10
Filing date: 2020-10-05
Publication date: 2021-04-15
Also published as: EP3804704A1; TW202128181A

Abstract

The present invention relates to a process for producing nanoparticulate rivaroxaban comprising the following steps: a) providing a solution of rivaroxaban in a solvent, providing an antisolvent for the rivaroxaban and providing at least one stabilizer, with the stabilizer present in dissolved form in the solvent and/or the antisolvent, and b) mixing the rivaroxaban solution in the solvent, the antisolvent and the stabilizer in a micromixer to afford a suspension comprising precipitated rivaroxaban, the solvent and the antisolvent, wherein the precipitated rivaroxaban is in the form of nanoparticles. Step b) is followed by the performance of step c): c) removing the solvent and the antisolvent to afford aggregates comprising nanoparticulate rivaroxaban.

Description

Process for producing nanoparticulate rivaroxaban

The present invention relates to a process for producing nanoparticulate rivaroxaban, to nanoparticulate rivaroxaban and to an active substance formulation comprising nanoparticulate rivaroxaban.

A high pharmaceutical active substance content of over 40% is to be assigned to class 2 or 4 in the Biopharmaceutics Classification System (BCS). The active substances in this class respectively have poor solubility and high bioavailability and poor solubility and poor bioavailability. A generally accepted method of improving the poor solubility is to reduce the particle size of the active substances, thereby achieving a high surface-to-volume ratio. In accordance with the Noyes-Whitney equation, this achieves high solubility of the particle boundary layer.

Known top-down methods such as nanomilling or high-pressure homogenization are used as standard in the production of active substance microparticles and nanoparticles. However, these methods have some limitations, such as a high energy input, low yields, contamination by abrasion, and poorly controllable particle sizes and surface properties, which make their use and further commercialization difficult.

The precipitation process (bottom-up method) underlying this invention is a standard method for producing micro- and nanoparticles known to those skilled in the art. From previous work by other scientists, it is known that a reactor with excellent mixing quality is critical for the uniform production of active substance nanoparticles. A microchannel reactor offers a defined reaction volume and a defined channel, which results in better reaction control as regards concentration (mass transfer) and temperature (heat transfer). The precipitation step itself is controlled in the microchannel reactor by rapid mixing, which results in rapid supersaturation. The supersaturation in turn determines the particle size and the distribution thereof, for example the rate of nucleation and growth therefrom.

The combination of precipitation and microchannel reactor to produce micro- and nanoparticles has been described in numerous publications and patents. Particle sizes here range from 100 nm to 80 pm.

US 2013/0012551 A1 describes a method for producing micro- and nanoparticles from water-soluble and water-insoluble substances by precipitation in a microjet reactor. In this method, jets of solvent containing the product to be precipitated and of an antisolvent are mixed in a microjet reactor at defined pressures and volume flows in order to influence rapid precipitation, co-precipitation or a chemical reaction that result in the formation of micro- or nanoparticles. The particle size is controlled via the temperature in the system and via the volume flows of the solvent and antisolvent and/or of the gas. Smaller particle sizes are achieved at low temperatures, at high solvent and antisolvent volume flows and/or in the complete absence of gas flow. The method uses only a microjet reactor for precipitation. Particle sizes are in the range between 141.2-358 nm. A disadvantage with this method is that the particle size stability, in particular the long-term stability, is not addressed. Hong Zhao et al. in Ind. Eng. Chem. Res. 2007, 46, 8229-8235 describes a solvent-antisolvent precipitation (LSAP) in a microchannel reactor. The particle size was reduced here from 55 pm to 364 nm. A disadvantage with this method is the filtration of the sample after precipitation using a 0.45 pm filter. A further disadvantage with this method is that the particle size stability, in particular the long-term stability, is not addressed.

Yuancai Dong et al. in Powder Technology 2014, 268, 424-428, combine antisolvent precipitation in a microchannel reactor with spray-drying. Particle sizes between 196-296 nm are achieved. The maximum total volume flows are 4 ml/min. A disadvantage is that the process is not suitable for industrial scale-up. Another disadvantage is that, although redispersion was carried out in a water-SDS solution, it is not possible to achieve near-complete redispersion. The redispersed suspension has average particle sizes of around 350 nm.

Jiahui Hu et al. in European Journal of Pharmaceutical Sciences 2003, 20, 295-303, developed spray- freezing in liquids (SFL technology) to obtain micronized powders. In this process, an active substance solution is sprayed directly into a cryogenic liquid to obtain frozen nanostructured particles. These are then freeze-dried. In the particle size distribution, a D(10) value of 0.14 pm, a D(50) value of 0.68 pm and a D(90) value of 15.89 pm are achieved. A disadvantage is that the polydispersity ofthe particles produced in this process is very broad. Moreover, critical solvents such as acetonitrile or THF must be used to dissolve the active substance. The maximum active substance content in the original solution is 2.2% by weight.

Niva et al. (2013) combine wet milling with spray-freeze -drying. PVP (polymer) and SLS (surfactant) are used as stabilizers. Particle sizes after milling are between 170-180 nm. A disadvantage is that the redispersed particles are in the 1-100 pm range.

Mahesh V. in Chaubal Pharmaceutical Research, 2008, 25, 10, reports redispersible powders containing nanoparticles and the importance of charged surfactants in relation to the stability of particles during drying. A disadvantage in this method is that the average particle size of the suspensions after redispersion is always 10-20% greater than in the original suspensions before drying. Moreover, in addition to the stabilizing additives (poloxamer 188 and sodium deoxycholate), matrix-forming agents such as lactose, sucrose and mannitol are used. The particles are also much coarser (99% < 1 pm), even before drying (99% < 0.8 pm).

Andrej Dolenc et al. in International Journal of Pharmaceutics, 2009, 376, 204-212 produces nanosuspensions with PVP and SDS as additives and dries them by spray-drying. A disadvantage of this method is that, although the powders are redispersible, there are clear differences in the D(90) value (30%) between the original and redispersed suspensions. The possible benefits of ionic surfactants for the stability of the nanoparticles during drying are not described. SDS serves only as an additive for the formation of stable nanoparticles by precipitation. In addition, much coarser particles in the D(90) range (> 1 pm) are present.

Xu Xue et al. in AAPS PharmSciTech, 2018, 19, 4 describe the production and optimization of rivaroxaban release by self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced oral bioavailability. Droplet sizes < 100 nm are achieved here.

US 2015/0335753 Al describes the production of poorly soluble active substances having average particle sizes of < 1 pm to < 500 nm. The formulation here contains an active substance, a water-soluble surfactant and a water-soluble polymer and is characterized by a fixed geometry as promoted by the “Microfluidizer” from Microfluidics Corporation ofNewton, Mass. USA. The “Microfluidizer” forces the suspension under high pressure through microchannels into a chamber, wherein two opposite flows of suspension collide with one other and then exit the chamber perpendicular to the collision plane. The outlet flow can be recirculated until the desired particle size is attained. The invention also includes the further processing of the suspension through removal of the aqueous solvent to obtain the active substance as a dried powder.

Michael E. Matteucci et al. in Langmuir, 2006, 22, 8951-8959 precipitate the practically insoluble active substance itraconazole through solvent-antisolvent precipitation to D(90) values of 370 nm. The solvent solution here consists of itraconazole and poloxamer 407 in tetrahydrofuran (THF). THF is a hazardous substance, being a presumed carcinogen.

Rivaroxaban is a pharmaceutical active substance with poor solubility. It is used as an blood coagulation inhibitor (anticoagulant) and is also known under the chemical name (S)-5-chloro-N-{2-oxo-3-[4-(3- oxomorpholin-4 -yl)phenyl] -1,3 -oxazolidin-5 -ylmethyl (thiophene -2 -carbamide . Rivaroxaban is contained as a drug substance in the medicament Xarelto.

The object of the present invention is to provide a process for producing highly redispersible, nanoparticulate rivaroxaban. It should also provide highly redispersible, nanoparticulate rivaroxaban and an active substance formulation comprising highly redispersible, nanoparticulate rivaroxaban.

This object is achieved in accordance with the invention by a process according to Claim 1, the particles according to Claim 14 and the formulation according to Claim 15. Advantageous developments are specified in the dependent claims. They may be freely combined unless the opposite is clear from the context.

The invention proposes a process for producing nanoparticulate rivaroxaban.

The process comprises the steps of: a) providing a solution of rivaroxaban in a solvent, providing an antisolvent for the rivaroxaban and providing at least one stabilizer, with the stabilizer present in dissolved form in the solvent and/or the antisolvent and b) mixing the rivaroxaban solution in the solvent, the antisolvent and the stabilizer in a micromixer to afford a suspension comprising precipitated rivaroxaban, the solvent and the antisolvent, wherein the precipitated rivaroxaban is in the form of nanoparticles, wherein step b) is followed by the performance of step c): c) removing the solvent and the antisolvent to afford aggregates comprising nanoparticulate rivaroxaban wherein the volume flow of the solvent containing the dissolved active substance and the volume flow of the antisolvent are in a volume ratio of solvent to antisolvent within the range from > 1:200 to < 2: 1 and wherein step c) is a spray-freeze-drying step.

This process was surprisingly shown to afford a suspension containing precipitated rivaroxaban in the form of nanoparticles having a small particle size and narrow particle size distribution. Moreover, the particle size may be stabilized directly after the precipitation, the long-term stability of the rivaroxaban particles may be improved and there may be improved handling of aggregates comprising the nanoparticulate rivaroxaban for further processing into oral and parenteral dosage forms.

A feature of microstructured components such as micromixers is the small dimensions of the fluid channels, which are typically located in the range between 10 and 5000 pm. This means that multi lamination mixers, for example, may be used to produce fine fluid lamellae, between which, by virtue of their thinness, rapid mass transfer by diffusion can take place. The micromixer mixing plates preferably have nominal slit diameters between 100 and 400 pm.

Micromixers in the process according to the invention are mixers for mixing at least two fluid streams in which internal conduits have diameters of less than one millimetre. One or more centrifugal pumps, an in line homogenizer, an ultrasonic mixer, a micromixer and other combinations of such mixers may also be used, particularly when an increased residence time in the mixing zone is desired. Preferred mixers are microchannel reactors such as valve micromixers, cascade micromixers and LHtype micromixers. These microchannel reactors offer improved micromixing effects and accordingly a narrow particle size distribution and smaller particle sizes. In one embodiment of the process, the micromixer is a valve mixer or a cascade mixer.

In a valve mixer, a nonreturn valve can prevent backflow of the mixture into supply lines almost completely or altogether. Preferred valve micromixers are those having a first channel for the supply of a first partial flow and having a second channel for the supply of a second partial flow, which emerge in shallow inflow slits into a mixing and reaction zone and leave the mixing and reaction zone via an outlet channel, there being a nonreturn valve positioned between the mixing and reaction zone and at least one channel supplying a partial flow. One of the supply channels advantageously has a nonreturn valve in the section in which the supply channel widens to the mixing and reaction zone. Such micromixers are described inter alia in WO 2005/079964 Al.

The mixing principle of cascade mixers is based on the so-called split-and-recombine operation. Preference is given here to a static micromixer having supply chambers for at least two fluids to be mixed, from which microchannels lead to a mixing chamber, the microchannels being arranged in at least two adjoining supply elements, the supply elements being wedge-shaped plates that may together form at least one ring sector surrounding the mixing chamber in an arc shape, and with the microchannels provided for each fluid forming a symmetrical bifurcation cascade comprising at least two stages. Such micromixers are described inter alia in WO 2001/043857 Al.

The process according to the invention is preferably executed as a continuous process. It then has the advantage of being a single-step continuous process based on the homogeneous nucleation mechanism. This delivers a more uniform product and a smaller particle size in an efficient process. It also permits adjustment of the particle size by altering a few parameters, such as the solvent to antisolvent ratio.

The process according to the invention may be executed with short residence times in the micromixer without further energy input and at atmospheric pressure. Residence times may, for example, be within the range from > 0.01 seconds to < 0.4 seconds.

In the process according to the invention, nanoparticulate rivaroxaban may be produced by means of a continuous precipitation method via microreaction technology. In this method, the rivaroxaban to be precipitated is dissolved in a solvent in which it is readily soluble. Another solvent that is preferably completely miscible with the solvent is mixed with the solvent. This is referred to as the antisolvent. The rivaroxaban to be precipitated is poorly soluble in the antisolvent and is forced into nucleation by local oversaturation. The nuclei grow into particles.

The rivaroxaban concentration in the solution is preferably close to the practical solubility limit of the solvent.

Such concentrations depend on the solvent selected, but are typically within the range from 0.1% to 20% by weight. The rivaroxaban concentration in the solution is preferably within the range from > 1% to < 8% by weight, more preferably from > 4% to < 5% by weight.

In a preferred embodiment of the invention, it may be the case that the nanoparticles precipitated in step b) have an average particle size, determined by laser diffractometry (LD) or dynamic light scattering (DLS) in accordance with ISO 13320, of > 20 nm to < 900 nm.

Particularly preferably, the nanoparticles precipitated in step b) have an average particle size, determined by laser diffractometry (LD) or dynamic light scattering (DLS) in accordance with ISO 13320, of > 50 nm to < 700 nm, even more preferably of > 50 nm to < 400 nm.

This advantageously ensures good handling for further processing into oral and parenteral dosage forms.

The precipitated nanoparticles preferably have a D(v)90 value of < 800 nm, more preferably of < 700 nm, in particular < 650 nm. The D(v)90 value is understood here as meaning that particles having a diameter smaller than or equal to the D(v)90 value make up 90% of the particle volume.

The precipitated nanoparticles preferably have a D(v)50 value of < 500 nm, more preferably of < 400 nm, in particular < 350 nm. The D(v)50 value is understood here as meaning that particles having a diameter smaller than or equal to the D(v)50 value make up 50% of the particle volume.

The precipitated nanoparticles preferably have a D(v)10 value of > 20 nm, more preferably of > 50 nm, in particular < 150 nm. The D(v)10 value is understood here as meaning that particles having a diameter smaller than or equal to the D(v) 10 value make up 10% of the particle volume.

In an embodiment of the invention, it may be the case that the volume flow of the solvent containing the dissolved active substance and the volume flow of the antisolvent are in a volume ratio of solvent to antisolvent within a range from > 1:200 to < 2: 1

The volume ratio of solvent to antisolvent is preferably within the range from > 1:100 to < 1: 1, more preferably from > 1:90 to < 1:5, for example 1:80, and particularly preferably from > 1:50 to < 1:5.

The stabilizer consists of one or more additives that, for example, inhibit particle growth, suppress aggregation of the nanoparticles or, as a matrix-forming agent, improve the redispersibility of the nanoparticles. The stabilizer may preferably be added to the solvent and/or to the antisolvent. The choice of stabilizer(s) depends on the stabilizer-solvent or stabilizer-antisolvent interaction. Examples of stabilizers include polymers, copolymers, polyelectrolytes, metal salts and ionic and nonionic surfactants, and also strong ions. Particular preferably, small stabilizer molecules having a high rate of diffusion or mobility are preferred in order to stabilize the surfaces of particles precipitated by the rapid mixing of solvent and antisolvent. The concentration of the stabilizers depends on the rivaroxaban concentration or on the ratio by weight of rivaroxaban to stabilizer in the suspension. The ratio by weight of rivaroxaban to stabilizer in the suspension is preferably within a range from > 1: 100 to < 100: 1, preferably from > 1:10 to < 10: 1, more preferably from > 1: 1.1 to < 1.1: 1, for example 1:1.

In a preferred embodiment of the invention, it may be the case that the stabilizer comprises at least one ionic surfactant.

The ionic surfactant reduces surface tension and permits rapid mixing of solvent and antisolvent, while at the same time also reducing Ostwald ripening.

This can improve the redispersibility of the aggregates after step c).

The ionic surfactant may be an anionic, cationic or zwitterionic (amphoteric) surfactant.

In a further embodiment, the ionic surfactant is selected from: acylamino acids (and salts thereof), such as: acylglutamates, for example sodium acylglutamate, di-TEA- palmitoyl aspartate and sodium capryl glutamate; acyl peptides, for example palmitoyl-hydrolysed milk protein, sodium cocoyl-hydrolysed soy protein and sodium/potassium cocoyl-hydrolysed collagen; sarcosinates, for example myristoyl sarcosinate, TEA-lauroyl sarcosinate, sodium lauroyl sarcosinate and sodium cocoyl sarcosinate; taurates, for example sodium lauroyl taurate and sodium methyl cocoyl taurate; acyl lactylates, lauroyl lactylate, caproyl lactylate, alaninates; carboxylic acids and derivatives, such as: carboxylic acids, for example lauric acid, aluminium stearate, magnesium alkanolate and zinc undecylenate, ester carboxylic acids, for example calcium stearoyl lactylate and sodium PEG lauramide carboxylate, ether carboxylic acids, for example sodium laureth carboxylate and sodium PEG cocamide carboxylate; phosphoric esters and phosphate salts, such as DEA oleth phosphate and dilaureth phosphate; sulfonic acids and sulfonate salts, such as acyl isethionates, for example sodium/ammonium cocoyl isethionate, alkyl aryl sulfonates, alkyl sulfonates, for example sodium coco monoglyceride sulfate, sodium C -olefin sulfonate, sodium lauryl sulfoacetate and magnesium PEG cocamide sulfate, sulfosuccinates, for example dioctyl sodium sulfosuccinate, disodium laureth sulfosuccinate, disodium lauryl sulfosuccinate and disodium undecylenamido MEA-sulfosuccinate; and also sulfuric esters, such as alkyl ether sulfates, for example sodium laureth sulfate, ammonium laureth sulfate, magnesium laureth sulfate, MIPA laureth sulfate, TIPA laureth sulfate, sodium myreth sulfate and sodium C-pareth sulfate, alkyl sulfates, for example sodium lauryl sulfate, ammonium lauryl sulfate and TEA lauryl sulfate.

In accordance with the invention, ionic surfactant(s) may additionally be advantageously selected from the group of cationic surfactants. Cationic surfactants that may be used advantageously are alkylamines, alkylimidazoles, ethoxylated amines, quaternary surfactants and esterquats. Quaternary surfactants contain at least one N atom that is covalently bonded to 4 alkyl or aryl groups. This results in a positive charge, irrespective of pH. Alkyl betaine, alkyl amidopropyl betaine and alkyl amidopropyl hydroxysultaine are advantageous. Cationic surfactants used according to the invention may additionally be preferably selected from the group of quaternary ammonium compounds, in particular benzyltrialkylammonium chlorides or bromides, for example benzyldimethylstearylammonium chloride, and also alkyltrialkylammonium salts, for example cetyltrimethylammonium chloride or bromide, alkyldimethylhydroxyethylammonium chlorides or bromides, dialkyldimethylammonium chlorides or bromides, alkylamidoethyltrimethylammonium ether sulfates, alkylpyridinium salts, for example laurylpyridinium or cetylpyridinium chloride, imidazoline derivatives and compounds having a cationic character such as amine oxides, for example alkyldimethylamine oxides or alkylaminoethyldimethylamine oxides. The use of cetyltrimethylammonium salts is particularly advantageous.

In accordance with the invention, ionic surfactant(s) may be advantageously selected from the group of amphoteric surfactants.

Amphoteric surfactants that may be used advantageously are: acylethylenediamines or dialkylethylenediamines, for example sodium acylamphoacetates, disodium acylamphodipropionate s, disodium alkylamphodiacetate s, sodium acylamphohydroxypropylsulfonates, disodium acylamphodiacetates and sodium acylamphopropionates, and also N-alkylamino acids, for example aminopropylalkylglutamides, alkylaminopropionic acids, sodium alkylimidodipropionates and lauroamphocarboxyglycinate .

Preference as surfactant is given to sodium dodecyl sulfate (SDS), sodium docusate (dioctyl sodium sulfosuccinate), sodium oleate and/or sodium deoxycholate.

The surfactant is preferably dissolved in the antisolvent, with the chosen concentration of the surfactant in the antisolvent being such that the ratio by weight of the surfactant in the suspension from step b) to the rivaroxaban in the suspension from step b) is within a range from > 1: 100 to < 100: 1, preferably from > 1:10 to < 10: 1, more preferably from > 1: 1.1 to < 1.1: 1, for example 1: 1.

The concentration by weight of the surfactant in the suspension from step b) depends on the concentration of the surfactant in the antisolvent and on the volume ratio of solvent to antisolvent.

The surfactant is for example dissolved in the antisolvent in a concentration within the range from > 0.2 mg/ml to < 2 mg/ml.

In a preferred embodiment of the invention, it may be the case that the ionic surfactant is dissolved in the antisolvent and largely comprises dioctyl sodium sulfosuccinate, with the chosen concentration of dioctyl sodium sulfosuccinate in the antisolvent being such that the ratio by weight of the surfactant in the suspension from step b) to the rivaroxaban in the suspension from step b) is within a range from > 1: 100 to < 100: 1, preferably from > 1: 10 to < 10: 1, more preferably from > 1:1.1 to < 1.1: 1, for example 1: 1.

In a preferred embodiment of the invention, it may be the case that the ionic surfactant largely comprises dioctyl sodium sulfosuccinate and preferably is present dissolved in the antisolvent in a concentration within the range from > 0.2 mg/ml to < 2 mg/ml.

Particularly preferably, the surfactant is dissolved in the antisolvent in a concentration within the range from > 0.2 mg/ml to < 1 mg/ml, in particular > 0.5 mg/ml to < 0.6 mg/ml.

In a preferred embodiment of the invention, it may be the case that the stabilizer comprises a water-soluble polymer.

“Water-soluble” is understood here as meaning that at 20°C, at least 0.5 g, preferably at least 2 g, of the polymer dissolves in 100 g of water or dissolves with the formation of a gel.

The polymer may be selected from the following group: alkyl celluloses, hydroxyalkyl celluloses, hydroxyalkyl alkyl celluloses, carboxyalkyl celluloses, alkali metal salts of carboxyalkyl celluloses, carboxyalkyl alkyl celluloses, carboxyalkyl cellulose esters, starches, pectins, chitin derivatives, polysaccharides, polyacrylic acid and salts thereof, polymethacrylic acid and salts thereof, polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene oxides or a mixture of at least two of the abovementioned polymers.

The polymer is preferably selected from: methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, carboxyalkyl cellulose esters, starches, sodium carboxymethyl amylopectin, chitosan, dextran sulfate sodium salt, alginic acid, alkali metal salts and ammonium salts of alginic acid, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum, xanthan gum, polyacrylic acid and salts thereof, polymethacrylic acid and salts thereof, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide and propylene oxide, N-vinylpyrrolidone -vinyl acetate copolymers or a mixture of at least two of the abovementioned polymers. Particular preference is given to polyvinylpyrrolidones (in particular K12 and K30 types) and N-vinylpyrrolidone -vinyl acetate copolymers. The polymer may preferably be a copolymer of ethylene oxide and propylene oxide, in particular a poloxamer, or a polyvinylpyrrolidone, in particular PVPK30.

The polymer is preferably dissolved in the solvent, with the chosen concentration of the polymer in the solvent being such that the ratio by weight of the polymer in the solvent to the rivaroxaban in the solvent is within a range from > 1 : 100 to < 100: 1, preferably from > 1: 10 to < 10: 1, more preferably from > 1: 1.1 to < 1.1: 1, for example 1: 1.

The polymer is for example dissolved in the solvent in a concentration within the range from > 10 mg/ml up to the solubility limit.

In a preferred embodiment of the invention, it may be the case that the water-soluble polymer is dissolved in the solvent and largely comprises poloxamer 188 or PVPK30, with the chosen concentration of the polymer in the solvent being such that the ratio by weight of the polymer in the solvent to the rivaroxaban in the solvent is within a range from > 1: 100 to < 100: 1, preferably from > 1: 10 to < 10: 1, more preferably from > 1: 1.1 to < 1.1: 1, for example 1: 1.

In a preferred embodiment of the invention, it may be the case that the water-soluble polymer largely comprises poloxamer 188 or PVPK30 and preferably is present dissolved in the solvent in a concentration within the range from > 10 mg/ml to < 100 mg/ml.

Particularly preferably, the polymer is dissolved in the solvent in a concentration within the range from > 40 mg/ml to < 50 mg/ml.

The polymer may preferably be dissolved in the solvent and in the antisolvent, with the chosen concentration of the polymer in the solvent being such that the ratio by weight of the polymer in the solvent to the rivaroxaban in the solvent is within a range from > 1: 100 to < 100:1, preferably from > 1: 10 to

< 10: 1, more preferably from > 1: 1.1 to < 1.1: 1, for example 1: 1, and the chosen concentration of the polymer in the antisolvent being such that the ratio by weight of the polymer in the antisolvent to the rivaroxaban in the solvent is within a range from > 1:100 to < 100: 1, preferably from > 1:50 to < 50: 1, more preferably from > 1: 10 to < 10: 1, for example 1:5.

The polymer is for example dissolved in the antisolvent in a concentration within the range from 1 mg/ml( ... ) up to the solubility limit.

In a preferred embodiment of the invention, it may be the case that the water-soluble polymer is dissolved in the solvent and in the antisolvent and largely comprises poloxamer 188 or PVPK30, with the chosen concentration of the polymer in the solvent being such that the ratio by weight of the polymer in the solvent to the rivaroxaban in the solvent is within a range from > 1: 100 to < 100:1, preferably from > 1: 10 to

In a preferred embodiment of the invention, it may be the case that the water-soluble polymer largely comprises poloxamer 188 or PVPK30 and preferably is present dissolved in the solvent in a concentration within the range from > 10 mg/ml to < 100 mg/ml and dissolved in the antisolvent in a concentration from 1 mg/ml to 10 mg/ml.

Particularly preferably, the polymer is dissolved in the solvent in a concentration within the range from

> 40 mg/ml to < 50 mg/ml and in the antisolvent in a concentration from 1 mg/ml to 10 mg/ml.

In a preferred embodiment of the invention, it may be the case that the stabilizer comprises a surfactant and a polymer.

Without being bound to any particular theory, it is assumed that the ionic surfactant, particularly in combination with a polymer, has a beneficial effect on the stability of the rivaroxaban particles during step c). The combination of electrostatic and steric stabilization makes the particles accordingly easier to redisperse.

Preferably, the ratio by weight of rivaroxaban : polymer : surfactant present in the suspension from step b) may be > 0.1 to < 5 : 1 : > 0.1 to < 5, preferably > 0.5 to < 1.5 : 1 : > 0.5 to < 1.5.

In a preferred embodiment of the invention, it may be the case that an anti-flocculant is additionally provided in step a), with the anti-flocculant present in dissolved form in the solvent and/or the antisolvent.

Anti-flocculants are to be understood as meaning strongly charged ions, for example from the water- soluble salts potassium tartrate, sodium oxalate, calcium citrate, sodium pyrophosphate and sodium citrate, which contribute to a high particle charge.

The anti-flocculant is preferably dissolved in the antisolvent, with the chosen concentration of the anti- flocculant in the antisolvent being such that the ratio by weight of the anti-flocculant in the suspension from step b) to the rivaroxaban in the suspension from step b) is within a range from > 1: 100 to < 100: 1, preferably from > 1: 10 to < 10: 1, more preferably from > 2: 1.1 to < 2.1: 1, for example 2: 1.

The concentration by weight of the anti-flocculant in the suspension from step b) depends on the concentration of the anti-flocculant in the antisolvent and on the volume ratio of solvent to antisolvent.

The anti-flocculant is for example dissolved in the antisolvent in a concentration within the range from > 0.4 mg/ml to < 4 mg/ml.

In an embodiment of the invention, it may be the case that the anti-flocculant is dissolved in the antisolvent and largely comprises sodium citrate, with the chosen concentration of the anti-flocculant in the antisolvent being such that the ratio by weight of the anti-flocculant in the suspension from step b) to the rivaroxaban in the suspension from step b) is within a range from > 1: 100 to < 100: 1, preferably from

> 1 : 10 to < 10: 1, more preferably > 2: 1.1 to < 2.1:1, for example 2: 1. In an embodiment of the invention, it may be the case that the anti-flocculant largely comprises sodium citrate and preferably is present dissolved in the antisolvent in a concentration within the range from > 0.4 mg/ml to < 4 mg/ml.

Particularly preferably, the anti-flocculant is dissolved in the antisolvent in a concentration within the range from > 0.4 mg/ml to < 4 mg/ml, in particular > 1 mg/ml to < 1.2 mg/ml.

Preferably, the ratio by weight of rivaroxaban : polymer : surfactant : anti-flocculant present in the suspension in step b) may be > 0.5 to < 2 : 1 : > 0.5 to < 2 : > 1 to < 4, preferably > 0.9 to < 1.1 : 1 : > 0.9 to < 1.1 : > 1.8 to < 2.2, for example 1: 1: 1:2.

In an embodiment of the invention, the solvent may be any organic solvent that dissolves rivaroxaban adequately. The solvent should be miscible with the antisolvent. The selected solvent should preferably show ideal mixing behaviour with the antisolvent, so that distribution of the solution in the particle suspension occurs instantaneously.

In a further embodiment of the process, the solvent may be protic, for example an alkanol. Examples of alkanols are methanol, ethanol, isopropanol, n-propanol. In a further embodiment of the process, the solvent may be aprotic. Examples of aprotic solvents are THF, DMSO, DMF and NMP. The solvent may also comprise mixtures of at least two of the above-named substances.

In an embodiment of the invention, it may be the case that the solvent is dimethylformamide .

In a preferred embodiment of the invention, it may be the case that the antisolvent is water.

In a particularly preferred embodiment of the invention, it may be the case that the solvent is dimethylformamide and the antisolvent is water.

It may additionally be the case that the temperature of the solvent and/or the antisolvent is adjusted.

The solvent may preferably be adjusted to a temperature that allows the solubility of the rivaroxaban in the solvent to be increased. The solvent preferably has a temperature within the range from > 15°C to < 30°C, more preferably from > 18°C to < 25°C, in particular from > 19°C to < 21°C.

The antisolvent may preferably be adjusted to a temperature that allows the solubility of the rivaroxaban in the antisolvent to be reduced. The antisolvent preferably has a temperature within the range from > 0°C to < 15°C, more preferably from > 1°C to < 10°C, in particular from > 1°C to < 5°C.

In a preferred embodiment of the invention, it may be the case that the micromixer comprises an ultrasonic mixer. In an alternative embodiment of the invention, it may be the case that the suspension from step b) is sonicated, preferably in an ultrasound bath, prior to step c).

Sonication in an ultrasound bath may take place at a temperature within a range from > 0°C to < 5°C, in particular at < 2°C, for a period within a range from > 15 s to < 10 min, preferably from > 30 s to < 5 min, in particular from > 1 min to < 3 min.

This allows particularly small particle sizes to be advantageously achieved.

In an embodiment of the invention, it may be the case that, to suppress particle growth in solution and to stabilize the particle size, step c) is preferably carried out directly after the precipitation. The removal of the solvent and of the antisolvent may also offer improved handling as regards the pourability and flowability of the solids containing active substance particles for further processing into oral and parenteral dosage forms.

In a preferred embodiment of the invention, it may be the case that step c) is a spray-drying step, a spray - freeze-drying step, a freeze-drying step, a vacuum-drying step or a falling-film-evaporation step.

In a further embodiment of the process, after step b) the suspension is introduced from the mixer directly into a spray nozzle and sprayed and dried there in step c).

In another embodiment of the process, the mixer may be fitted directly in a spray dryer, in the spray head.

The nanoparticulate rivaroxaban aggregates obtained after step c) may also be partly or completely present in the form of nanoparticulate rivaroxaban aggregates embedded in a matrix of the stabilizer.

In an embodiment of the process, step c) includes providing droplets of the suspension, with the droplets in step c) having a diameter of > 0.001 mm to < 3 mm immediately after they have been provided. The droplet diameter is preferably from > 0.001 mm to < 0.12 mm, more preferably from > 0.001 mm to < 0.03 mm.

In a further embodiment of the process, the nanoparticulate rivaroxaban aggregates obtained have a maximum diameter of > 0.001 mm to < 1 mm. The diameter is preferably from > 0.001 mm to < 0.1 mm, more preferably from > 0.001 mm to < 0.025 mm.

Optionally, matrix-forming agents may be used in the solvent or antisolvent in order that the aggregates in step c) do not collapse, particularly during freeze-drying. It is preferable to add the matrix-forming agent to the antisolvent. The choice of matrix-forming agent depends on the matrix-forming agent- stabilizer-solvent or matrix-forming agent-stabilizer-antisolvent interaction. Crystalline matrix-forming agents, such as mannitol or glycine, and amorphous matrix-forming agents, such as trehalose, lactose, sucrose or HPbCD, known to those skilled in the art are generally used. The matrix-forming agent allows fillable and manageable processing of the dried material.

In the production of a pharmaceutical dosage form, the nanoparticulate active substance aggregates obtained after step c) may be redispersed again in an antisolvent. For the purposes of influencing the redispersion behaviour, combinations of polymers and ionic surfactants in varying concentration ratios may be used to maintain the particle size distribution (PSD) of the original suspension.

It is preferable if the average particle size (determined by laser difffactometry (LD) or dynamic light scattering (DLS) in accordance with ISO 13320) does not deviate by more than 500% from the original average particle size of the precipitated nanosuspension; any such deviation is preferably < 100%, more preferably < 50% and most preferably < 10%. In particular, long-term stability of the redispersed nanoparticle suspension is made possible in the process according to the invention. The D(90) value of the particle size distribution for the redispersed particles, determined by dynamic light scattering, is preferably below 900 nm, more preferably below 600 nm and even more preferably below 400 nm.

The percent content by weight of rivaroxaban in the total solids content after redispersion in water may be up to 70%. The percent content by weight of rivaroxaban in the total solids content may be within the range from 10 to 60%, for example from 15 to 25%.

The invention further proposes nanoparticulate rivaroxaban, which has an average particle size, determined by laser diffractometry (LD) or dynamic light scattering (DLS) in accordance with ISO 13320, of > 20 nm to < 900 nm.

The nanoparticulate rivaroxaban particularly preferably has an average particle size, determined by laser diffractometry (LD) or dynamic light scattering (DLS) in accordance with ISO 13320, of > 50 nm to < 700 nm, even more preferably of > 100 nm to < 400 nm.

The nanoparticulate rivaroxaban may in particular here be present in a suspension that includes a stabilizer and optionally an anti-flocculant.

The invention further proposes an active substance formulation that comprises at least nanoparticulate rivaroxaban, sodium citrate and dioctyl sodium sulfosuccinate.

The active substance formulation may preferably be obtained by the process described above after step c). The active substance formulation may be suitable for being redispersed in an antisolvent, with this permitting long-term stability in particular. The invention is further elucidated hereinbelow below with reference to figures and examples.

Fig. 1 is a schematic representation of the process in the present invention and depicts a continuous solvent-antisolvent precipitation process. The process includes the solvent feed 1 and antisolvent feed 2, which are ideally mixed in the micromixer 4, after which the mixture flows into the microchannel reactor 5, in which nucleation and growth into micro- or nanoparticles takes place. The particle suspensions are collected in the sample container 7 in order to measure the particle size, this being continued until the particle size or quality meets the requirements; if the requirements are not met, the suspension is fed into the waste container 6. The suspensions are then treated according to different methods depending on the dosage form of the active substance.

For example, if the dosage form requires the rivaroxaban to be in powder form, the nanoparticle suspension is fed into a post-treatment step such as freeze-drying, spray-drying, spray-freeze-drying, rotary evaporation or falling-film evaporation, so as to remove the solvent and obtain the dried nanoparticle powder, with spray-freeze-drying resulting in improved flowability/pourability.

If the active substance is delivered in the form of a nanoparticle suspension, the original particle suspension is further diluted or concentrated so as to obtain the appropriate concentration of active substance in the suspension. Optionally, cleaning solvent feed 3 may be included as a means of dissolving active substance particles in the process if the particles cause blockages of the microchannel reactor 5 or of equipment subunits.

Examples: Precipitation of rivaroxaban nanoparticles Example 1 (fig. 21:

Ultrapure water (resistance > 18.2 MOhm cm) was used as antisolvent in the process. The solvent used was dimethylformamide (DMF). The solvent and antisolvent solution were fed in using HPLC pumps at a constant volume flow. The solvent feed was thermally equilibrated at 20°C and the antisolvent feed at < 5°C, so that the product temperature was < 5°C. Dissolved in the solvent were rivaroxaban as the active substance and poloxamer 188 as stabilizer. The active substance concentration and the stabilizer concentration were 45 mg/ml and were therefore present in a 1: 1 mixture. 1.12 mg/ml of sodium citrate and 0.56 mg/ml of sodium dioctyl sulfosuccinate (docusate sodium) were used in the antisolvent. The antisolvent feed was fed in at 80 ml/min, whereas the solvent feed was at 1 ml/min. A nanoparticle suspension formed in the mixer. The nanosuspension contains 0.56 mg/ml of rivaroxaban, 0.56 mg/ml of poloxamer 188, 0.56 mg/ml of docusate sodium and 1.12 mg/ml of sodium citrate. Immediately after precipitation, the nanosuspension was sonicated for 2 min in a cold (2°C) ice bath. The particle size was determined by dynamic light scattering (Malvern Nano series) without filtration (see example 1, El, fig. 2). The D(v)10 value was 149 nm, the D(v)50 value was 338 nm and the D(v)90 value was 626 nm.

For comparison purposes, the docusate sodium (comparative example 2, CE2) or the sodium citrate (comparative example 3, CE3) in the formulation was taken out and precipitation carried out under the same conditions as in example 1. The D(v)90 value was accordingly 2350 nm (CE2) and 5590 nm (CE3). By way of further comparison, a nanosuspension containing 0.56 mg/ml of rivaroxaban, 0.56 mg/ml of poloxamer 188, 0.56 mg/ml of docusate sodium and 1.12 mg/ml of sodium citrate was measured without subsequent sonication (comparative example 4, CE4) and had a D(v)90 value of 3310 nm. Particle sizes close to the resolution limit of 5000 nm (Malvern Nano series) point to strong polydispersity and a broad particle size distribution.

Fig. 2 shows the measured values for particulate rivaroxaban with poloxamer 188, docusate sodium and sodium citrate (El) compared with the particles obtained after omitting docusate sodium (CE2) or sodium citrate (CE3), and without subsequent sonication (CE4).

Example 2 (fig. 3):

The nanosuspension was prepared in analogous manner to example 1. The solvent used was dimethylformamide (DMF). The solvent and antisolvent solution were fed in using HPLC pumps at a constant volume flow. The solvent feed was thermally equilibrated at 20°C and the antisolvent feed at < 5°C, so that the product temperature was < 5°C. Dissolved in the solvent were rivaroxaban as the active substance and poloxamer 188 as stabilizer. The active substance concentration and the stabilizer concentration were 45 mg/ml and were therefore present in a 1: 1 mixture. 1.12 mg/ml of sodium citrate and 0.56 mg/ml of sodium dioctyl sulfosuccinate (docusate sodium), or 1.12 mg/ml of sodium citrate with 2.3 mg/ml of SDS or 0.56 mg/ml of SDS, were used in the antisolvent.

Example 3 (fig. 41:

The nanosuspension was prepared in analogous manner to example 1. Dissolved in the solvent were rivaroxaban as the active substance and poloxamer 188 as stabilizer. The active substance concentration and the stabilizer concentration were 45 mg/ml and were therefore present in a 1: 1 mixture. As anti- flocculant, either 2.24 mg/ml of sodium citrate or 2.24 mg/ml of tartrate or 2.24 mg/ml of EDTA (basic conditions, pH 12) and 0.56 mg/ml of sodium dioctyl sulfosuccinate (docusate sodium) was prepared in antisolvent. The antisolvent feed was fed in at 80 ml/min, whereas the solvent feed was at 2 ml/min. A nanoparticle suspension forms in the mixer. The nanosuspension contains 1.12 mg/ml of rivaroxaban, 1.12 mg/ml of poloxamer 188, 1.12 mg/ml of docusate sodium and 2.24 mg/ml of anti-flocculant. Immediately after precipitation, the nanosuspension was sonicated for 2 min in a cold (2°C) ice bath. The particle size was determined by dynamic light scattering (Malvern Nano series) without filtration (see fig. 4). For the formulation with citrate, the D(v)10 value was 192 nm, the D(v)50 value was 435 nm and the D(v)90 value was 724 nm. The active substance content could be successfully increased to twice the concentration (see example 1). For the formulation with tartrate, the D(v) 10 value was 246 nm, the D(v)50 value was 639 nm and the D(v)90 value was 2105 nm. For the formulation with EDTA, the D(v)10 value was 436 nm, the D(v)50 value was 779 nm and the D(v)90 value was 2000 nm.

Example 4 (fig. 5):

The nanosuspension was prepared in analogous manner to example 1. Dissolved in the solvent were rivaroxaban as the active substance and PVP K30 as stabilizer. The active substance concentration and stabilizer concentration in the solvent were 45 mg/ml and thus present in a 1:1 mixture. 2.24 mg/ml of sodium citrate, 1.12 mg/ml of sodium dioctyl sulfosuccinate (docusate sodium) and 5.6 mg/ml of PVP K30 were used in the antisolvent. The antisolvent feed was fed in at 80 ml/min, whereas the solvent feed was at 2 ml/min. A nanoparticle suspension forms in the mixer. The nanosuspension contains 1.12 mg/ml of rivaroxaban, 6.72 mg/ml of PVP K30, 1.12 mg/ml of docusate sodium and 2.24 mg/ml of sodium citrate. Immediately after precipitation, the nanosuspension was sonicated for 2 min in a cold (2°C) ice bath. The particle size was determined by dynamic light scattering (Malvern Nano series) without filtration. The D(v) 10 value was 162 nm, the D(v)50 value was 330 nm and the D(v)90 value was 572 nm.

Example 5 (fig 61:

The nanosuspension from example 4, which contains 1.12 mg/ml of rivaroxaban, 6.72 mg/ml of PVP K30, 1.12 mg/ml of docusate sodium and 2.24 mg/ml of sodium citrate, was examined in a transmission electron microscope. Present in the suspension here were agglomerate sizes of 200 nm, but above all primary particle sizes of below 100 nm (fig. 6A). The numerical distribution from dynamic light scattering (Malvern Nano series) provides additional confirmation of the result (fig. 6B).

Claims

1. Process for producing nanoparticulate rivaroxaban, comprising the steps of: a) providing a solution of rivaroxaban in a solvent, providing an antisolvent for the rivaroxaban and providing at least one stabilizer, with the stabilizer present in dissolved form in the solvent and/or the antisolvent and b) mixing the rivaroxaban solution in the solvent, the antisolvent and the stabilizer in a micromixer to afford a suspension comprising precipitated rivaroxaban, the solvent and the antisolvent, wherein the precipitated rivaroxaban is in the form of nanoparticles, characterized in that step b) is followed by the performance of step c): c) removing the solvent and the antisolvent, in particular to afford aggregates comprising nanoparticulate rivaroxaban wherein

• the volume flow of the solvent containing the dissolved active substance and the volume flow of the antisolvent are in a volume ratio of solvent to antisolvent within the range from > 1:200 to < 2: 1 and wherein step c) is a spray-freeze-drying step.

2. Process according to Claim 1, wherein the stabilizer comprises at least one ionic surfactant that is dissolved in the antisolvent and largely comprises dioctyl sodium sulfosuccinate, with the chosen concentration of dioctyl sodium sulfosuccinate in the antisolvent being such that the ratio by weight of the surfactant in the suspension from step b) to the rivaroxaban in the suspension from step b) is within a range from > 1 : 100 to < 100: 1

• wherein the stabilizer comprises a water-soluble polymer that is dissolved in the solvent and largely comprises poloxamer 188 or PVPK30, with the chosen concentration of the polymer in the solvent being such that the ratio by weight of the polymer in the solvent to the rivaroxaban in the solvent is within a range from > 1: 100 to < 100: 1 wherein, in step a), an anti-flocculant is additionally provided, the anti-flocculant being dissolved in the antisolvent and largely comprising sodium citrate, with the chosen concentration of the anti- flocculant in the antisolvent being such that the ratio by weight of the anti-flocculant in the suspension from step b) to the rivaroxaban in the suspension from step b) is within a range from > 1:100 to < 100:1

3. Process according to Claim 1 or 2, wherein the solvent is dimethylformamide and the antisolvent is water.

4. Process according to Claim 1 or 2, wherein the nanoparticles precipitated in step b) have an average particle size, determined by laser diffractometry or dynamic light scattering in accordance with ISO 13320, of > 20 nm to < 900 nm.

5. Nanoparticulate rivaroxaban, characterized in that the nanoparticulate rivaroxaban has an average particle size, determined by laser diffractometry or dynamic light scattering in accordance with ISO 13320, of > 20 nm to < 900 nm.

6. Active substance formulation at least comprising nanoparticulate rivaroxaban, sodium citrate and dioctyl sodium sulfosuccinate.