Method for crystallization of active pharmaceutical ingredients

Abstract

The present disclosure relates to a method for crystallization of an active pharmaceutical ingredient (API), where the crystallization and crystal growth are controlled. According to the method, an aqueous solution comprising a solid amorphous nano-sized API and one or more polymers and / or copolymers are contacted to form a suspension comprising the nano-sized API in a crystalline form.

Description

[Technical Field]

[0001] The present disclosure relates to methods for crystallizing active pharmaceutical ingredients (APIs), and in particular to methods in which crystallization and crystal growth are controlled by an aqueous solution containing one or more polymers and / or copolymers. [Background technology]

[0002] Many active pharmaceutical ingredients (APIs) have limited bioavailability, primarily due to their insufficient dissolution rate to treat the target pathology. It is well known that the dissolution rate of an API depends on the available surface area. Reducing the particle size of an API can be used to increase the surface area and dissolution rate. In addition, nanoization can increase solubility. Therefore, reducing the particle size of an API using micronization / nanoization technology is an effective approach to improve the bioavailability of an API.

[0003] Amorphous materials are known to have significantly higher solubility than their crystalline counterparts, making amorphization an attractive option. Unfortunately, amorphous APIs tend to crystallize during processing, storage, and administration, and thus, the solubility advantage may be lost. One of the most common approaches to stabilizing amorphous drugs is to molecularly disperse the drug in a polymer matrix and form an amorphous solid dispersion (ASD). However, for stabilization, the ASD dose must contain a significant amount of polymer.

[0004] Patent Document 1 discloses a method for preparing a submicron-sized API, which includes dissolving the API in a water-miscible first solvent to form a solution, mixing the solution in a second solvent containing a surface modifier to produce a presuspension liquid, and adding energy to the presuspension liquid by homogenization, counter-current homogenization, microfluidization, or sonication.

[0005] Patent Document 2 discloses a method for crystallizing an API that includes rapidly adding an API solution in an organic solvent to an aqueous polymer solution.

[0006] Patent Document 3 discloses a method for crystallizing an API that includes dispersing an amorphous API in an aqueous solution of polyvinylpyrrolidone (PVP), and then treating it with a media mill filled with a polymeric grinding medium until the average particle size of the API becomes about 200 nm.

[0007] Patent Document 4 discloses a method for crystallizing coarse API particles by grinding them in an aqueous solution of Pluronic F127 until the particle size is reduced to about 270 nm.

[0008] Non-Patent Document 1 discloses a method for forming crystalline nitrendipine nanoparticles. In this method, nitrendipine is dissolved in a solvent of polyethylene glycol (PEG) and acetone, and then precipitated from an aqueous solution of polyvinyl alcohol, hydroxypropylmethylcellulose (HPMC) or poloxamer. The initially formed particles were amorphous. Continuing the precipitation process, these particles were converted into nano-sized crystals under conditions where the process was carried out at low temperature.

[0009] However, there is still a need for further methods for the preparation of pharmaceutical active ingredients with improved bioavailability.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

[0011] [Non-Patent Document 1] Xia et al., Pharm. Res. 2012, 29:158-169 Summary of the Invention

[0012] The present disclosure is based on the observation that when amorphous nano-sized active pharmaceutical ingredients (APIs) are contacted with an aqueous solution comprising one or more polymers and / or copolymers, a suspension is obtained comprising the nano-sized APIs in crystalline form.

[0013] It is therefore an object of the present disclosure to provide a novel method for the crystallization of an active pharmaceutical ingredient (API), the method comprising: providing an amorphous nanosized API; providing an aqueous solution comprising one or more polymers and / or copolymers; and contacting the amorphous nano-sized API with an aqueous solution comprising one or more polymers and / or copolymers to form a mixture, wherein the content of the amorphous nano-sized API in the mixture is greater than the solubility of the amorphous nano-sized API in the aqueous solution comprising the one or more polymers and / or copolymers, thereby obtaining a suspension comprising the nano-sized API in crystalline form. Includes:

[0014] Further aspects of the present disclosure are set out in the accompanying dependent claims.

[0015] Illustrative and non-limiting embodiments of the present invention, both as to organization and method of operation, together with additional objects and advantages thereof, will best be understood from the following description of specific exemplary embodiments when read in connection with the accompanying drawings.

[0016] In this specification, the verbs "to comprise" and "to include" are used as open-ended limitations that neither exclude nor require the presence of features not recited. Features recited in the appended dependent claims are combinable freely with each other unless otherwise explicitly stated. Further, it is to be understood that the use of the singular forms "a" or "an" throughout this specification does not exclude a plurality.

Brief Description of the Drawings

[0017] [Figure 1] Figure 1 is an XRD diffraction pattern of nano-sized amorphous exemestane and nano-sized amorphous budesonide. [Figure 2] Figure 2A is an SEM image of nano-sized amorphous exemestane. Figure 2B is an SEM image of nano-sized amorphous exemestane crystallized from water. Figure 2C is an SEM image of nano-sized amorphous exemestane crystallized from water containing 5 wt.-% PVPVA and 0.2 wt.-% SLS. The upper figure is an enlarged view of the region of the corresponding lower figure indicated by the dashed rectangle. [Figure 3] Figure 3 is an SEM image of a composition containing nanocrystals of ceritinib and poloxamer 407 (dry suspension; ceritinib:poloxamer ratio is 1:1; w / w). Scale bars are 1 μm and 400 nm. [Figure 4] Figure 4 is a diagram tracking the crystallization of exemestane by XRD as a function of time in a suspension containing 20 wt.-% aq. PVPVA (exemestane:PVPVA ratio is 1:1; w / w). [Figure 5] Figure 5 is a diagram showing the results of crystallization of amorphous nano-sized exemestane as a function of PVPVA concentration. The exemestane concentration was 2 mg / mL and the suspension was mixed overnight before filtration and drying for SEM. A: 1 wt.-% PVPVA + 0.2 wt.-% SLS; B: 2.5 wt.-% PVPVA + 0.2 wt.-% SLS; C: 5 wt.-% PVPVA + 0.2 wt.-% SLS. The upper figure is an enlarged view of the region of the corresponding lower figure indicated by the dashed rectangle. [Figure 6] Figure 6 shows XRD diffractograms of the ezetimibe nanocrystals (filtered and dried 25 mg / mL suspension) from Figure 5. a: 1 wt.-% PPVVA + 0.2 wt.-% SLS; b: 2.5 wt.-% PPVVA + 0.2 wt.-% SLS; c: 5 wt.-% PPVVA + 0.2 wt.-% SLS; d: bulk crystalline ezetimibe. [Figure 7] Figure 7 shows the crystallization results of amorphous nanosized budesonide as a function of HPMC concentration. The budesonide concentration was 25 mg / mL, and the suspensions were mixed overnight before filtering and drying for SEM. A: 1 wt.-% HPMC + 0.2 wt.-% SLS; B: 2.5 wt.-% HPMC + 0.2 wt.-% SLS; C: 5 wt.-% HPMC + 0.2 wt.-% SLS. The top panel is an enlargement of the corresponding area in the bottom panel, indicated by the dashed rectangle. [Figure 8] Figure 8 shows XRD diffractograms of the budesonide nanocrystals of Figure 7. a: 1 wt.-% HPMC + 0.2 wt.-% SLS; b: 2.5 wt.-% HPMC + 0.2 wt.-% SLS; c: 5 wt.-% HPMC + 0.2 wt.-% SLS. [Figure 9] Figure 9 shows XRD diffractograms of dried mixtures of PVPVA and nano-sized crystalline ezetimibe. a: Immediately after drying; b: Stored for 7 hours; c: Stored for 14 hours; d: Stored for 30 days; e: Bulk ezetimibe. t=40°C, 75% relative humidity. [Figure 10] Figure 10 shows XRD diffractograms of dried mixtures of HPMC and nano-sized crystalline budesonide. a: Immediately after drying; b: Stored for 7 hours; c: Stored for 14 hours; d: Stored for 30 days; e: Bulk budesonide. t=40°C, 75% relative humidity. [Figure 11] FIG. 11 shows SEM images of nano-sized ceritinib compositions in fresh state and after one month of storage at room temperature. [Figure 12] FIG. 12 shows A: FASSIF and B: SGF-FaSSIF dissolution of a: ezetimibe prepared according to the present disclosure and b: bulk ezetimibe. [Figure 13]FIG. 13 shows the permeability of a: ezetimibe prepared according to the present disclosure and b: bulk ezetimibe. DETAILED DESCRIPTION OF THE INVENTION

[0018] As defined herein, a nanosized API is composed of particles having a Dv90 equal to or less than 1000 nm, i.e., a nanosized API is composed of particles with a volume fraction of 90% having a diameter less than 1000 nm. The particle size of the API can be between 10 nm and 1000 nm, e.g., between 10 nm and 200 nm, between 200 nm and 500 nm, or between 500 nm and 1000 nm. The preferred size of the nanoparticles can depend on the API and application, and therefore the size distribution can be adjusted as desired.

[0019] A suspension, as used herein, is a mixture of a solid (here, the API) suspended in a liquid (here, an aqueous solution containing one or more polymers and / or copolymers).

[0020] As defined herein, an aqueous solution is water containing one or more dissolved substances. The dissolved substances in an aqueous solution may be solids, gases, or other liquids.

[0021] Unless expressly stated otherwise, the term "active pharmaceutical ingredient, API" refers to the API, its non-salt form, its physiologically acceptable salts, co-crystals, polymorphs and / or solvates.

[0022] In one aspect, the present disclosure relates to a method for crystallization of an amorphous nanosized active pharmaceutical ingredient (API), the method comprising: a) providing a solid amorphous nanosized API, preferably as a dry powder; b) providing an aqueous solution comprising one or more polymers and / or copolymers; and c) contacting the solid amorphous nano-sized API with an aqueous solution comprising one or more polymers and / or copolymers to form a mixture, wherein the content of the amorphous nano-sized API in the mixture is greater than the solubility of the amorphous nano-sized API in the aqueous solution comprising the one or more polymers and / or copolymers. Including, This results in a suspension containing the nano-sized API in crystalline form.

[0023] The grain size growth of the API is inhibited during crystallization, and the resulting particles remain nanoparticles. For example, if the average particle size of the amorphous API is about 40 nm, the average particle size of the API crystallized using the methods of the present disclosure may be about 120 nm. Thus, although the particle size of the crystalline API may be larger than the particle size of the amorphous API, the crystalline API of the present disclosure remains nanosized, and the particle size typically does not grow by more than 300%, preferably by more than 100%, more preferably by more than 50%, even more preferably by more than 25%, and most preferably by more than 10% during crystallization.

[0024] To form a suspension, the content of amorphous nano-sized API in the mixture must be, for example, at least 10 times, preferably at least 50 times, more preferably at least 100 times, and even more preferably at least 500 times higher than its solubility in an aqueous solution containing one or more polymers and / or copolymers. Therefore, the amount of amorphous API required in this method depends on its solubility. Solubility can be measured by any method known in the art.

[0025] Typically, the contacting is carried out at a temperature of 15 to 40°C, preferably 20 to 40°C, for example 30°C.

[0026] In a preferred embodiment, the contacting includes mixing the suspension. Mixing is preferably carried out for at least 10 hours, more preferably at least 16 hours, and even more preferably at least 24 hours. A relatively long mixing time is preferred to achieve complete wetting and good dispersion. Mixing can be carried out, for example, by shaking, stirring, or using a spatula. Mixing and wetting can be promoted by ultrasound. However, high-intensity ultrasound is not required. The ultrasound intensity is preferably 3 W / cm. 2 The following is the result.

[0027] If mixing is omitted, contacting is preferably carried out for at least 24 hours.

[0028] The ratio of API:polymer and / or copolymer is typically 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 5:1 to 1:1, e.g., 4:1, 3:1, 2:1, or 1:1, where the amount of API is calculated as mg / mL of suspension and the amount of polymer and / or copolymer is calculated as wt% of the suspension. For example, 25 mg / mL of amorphous nanosized ezetimibe with a 1:1 API:polymer and / or copolymer ratio produces the desired crystals in 24 hours at 20°C. The optimal API:polymer ratio depends on the polymer and API.

[0029] The one or more polymers and / or copolymers may be synthetic polymers or biopolymers. Illustrative examples of polymers and copolymers suitable for the present method include polyvinylpyrrolidone / vinyl acetate (PVPVA), polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hypromellose succinate (HPMCAS), polyacrylic acid (PAA), polyethylene glycol (PEG), polyvinylcaprolactam (PVCL), poloxamer, poly(N-vinylcaprolactam)-poly(vinyl acetate)-poly(ethylene glycol) (Soluplus®), and any copolymers thereof. Proteins, such as wheat protein, may also be used.

[0030] Too high a polymer content may lead to slow crystal formation. The optimum polymer content is polymer dependent.

[0031] A preferred copolymer is PVPVA. The content of PVPVA in the aqueous solution is typically 0.2 to 50 wt. %, for example 0.2 to 40 wt. %, preferably 10 wt.-% to 45 wt.-%.

[0032] Another preferred polymer is HPMC. The content of HPMC in the aqueous solution is typically 0.2 to 5% by weight.

[0033] Another preferred polymer is poloxamer. The content of poloxamer in the aqueous solution is typically 0.2 to 40% by weight, preferably 1 to 20% by weight. The poloxamer is preferably selected from the group consisting of poloxamer 331, poloxamer 338, poloxamer 181, poloxamer 407, poloxamer 182, poloxamer 184, poloxamer 237, poloxamer 188, and poloxamer 124, and more preferably poloxamer 407.

[0034] Preferably, the one or more polymers and / or copolymers are sufficiently hydrophilic and sufficiently lipophilic to interact with the API.

[0035] In one embodiment, the one or more polymers and / or copolymers comprise or consist essentially of a copolymer derived from a first monomer and a second monomer, where the first monomer is more hydrophilic than the second monomer. Preferably, the first monomer in its neat state has a relative dipole moment that is at least 0.1 Debye, preferably at least 0.2 Debye, more preferably at least 0.3 Debye, and even more preferably at least 0.4 Debye greater than the dipole moment of the second monomer in its neat state.

[0036] Suitable APIs for the present method are typically selected from BSC Class II APIs and BSC Class IV APIs.

[0037] Exemplary APIs suitable for the present disclosure include adefovir, dipivoxil, apalutamide, atazanavir, avacopan, deucravacitinib, doravirine, enzalutamide, elagolix, encorafenib, etravirine, everolimus, and the like. mus), etonogestrel, fenofibrate, glecaprevir, pibrentasvir, grazoprevir, pibrentasvir, griseofulvin, telmisartan, itraconazole, ivacaftor, lumacaftor, Tezacaftor, elexacaftor, lonafarnib, nabilone, olaparib, paclitaxel, posaconazole, pralsetinib, regorafenib, ripretinib, ritonavir, lopinavir, paritaprevir revir, ombitasvir, sofosbuvir, ledipasvir, suvorexant, tacrolimus, tadalafil, telaprevir, tolvaptan, vemurafenib, venetoclax, verapamil, and any combination thereof.

[0038] By selecting appropriate conditions, crystallization can be controlled and the undesirable growth of crystalline nanoparticles is prevented. Thus, by inducing crystallization under appropriate conditions, the size of the amorphous API nanoparticles is not significantly increased.

[0039] In one embodiment, the solution contains one or more surfactants. Exemplary surfactants suitable for the method are sodium lauryl sulfate (SLS), Tween 80, Tween 20, sodium dioctyl sulfosuccinate (DOSS), and tocopherol soran (TPGS). The total content of the one or more surfactants in the aqueous solution is preferably 0.0025 to 1.5% by weight. A specific surfactant is SLS. The surfactant enhances the wetting efficiency.

[0040] In an exemplary embodiment, the API is budesonide, and the polymer is HPMC, and when a surfactant is present, it is SLS.

[0041] In another exemplary embodiment, the API is ezetimibe, and the copolymer is PVPVA, and when a surfactant is present, it is SLS.

[0042] In another exemplary embodiment, the API is apalutamide, and the copolymer is PVPVA, and when a surfactant is present, it is SLS.

[0043] In yet another exemplary embodiment, the API is apalutamide, and the polymer is HPMC, and when a surfactant is present, it is SLS.

[0044] In yet another exemplary embodiment, the API is ceritinib, and the polymer is poloxamer, preferably poloxamer 407, and when a surfactant is present, it is SLS.

[0045] In one embodiment, the suspension is dried to provide a solid product comprising the crystalline nano-sized API and one or more polymers and / or copolymers. Drying can be carried out using methods well known in the art. Exemplary drying methods include heating, evaporation, vacuum drying, using a fluidized bed dryer, spray drying, and freeze drying. A specific drying method is evaporation. Grinding the solid product, for example, using a mortar, produces a powder suitable for tableting. Grinding does not affect particle size.

[0046] The API can be separated from the wet suspension, for example, by filtering using a hydrophilic filter or by centrifuging and then discarding the supernatant containing the polymer and / or copolymer solution. The material can then be washed, for example with water, and by repeating the filtering or centrifugation step. This can be repeated as many times as necessary.

[0047] In another aspect of the present disclosure, the present disclosure relates to a process for preparing a pharmaceutical dosage form, the process comprising: a) granulating, preferably wet granulating, the crystallized nano-sized API obtained by the process of the present disclosure with one or more pharmaceutical excipients; and b) Compressing the granules Includes:

[0048] The disclosed method allows the preparation of pharmaceutical compositions and oral dosage forms containing relatively high doses of API. Thus, swallowable tablets, i.e., tablets with a total weight of not more than about 1000 mg but with a high drug load, can be produced. Furthermore, since less polymer is required than in the corresponding ASD formulation, the tablet size can be reduced.

[0049] material and method Bulk crystalline ezetimibe (anhydrous, CCDC *:947148), bulk crystalline budesonide, bulk crystalline ceritinib (Form 1), and bulk crystalline apalutamide were purchased from Sinoway Industrial Co, NewChem, MSN Laboratories, and Habotech, respectively. Amorphous nanosized API was prepared from bulk API using the process disclosed in U.S. Pat. No. 10,098,842. Permeability was tested using a MicroFLUX instrument (Pion Inc.). XRD diffractograms of amorphous nanosized ezetimibe and amorphous nanosized budesonide are shown in FIG. 1 for illustrative purposes.

[0050] SEM images were taken using a Zeiss Sigma 300 VP SEM instrument. Samples were dispersed in water and filtered through a 0.1 μm filter. The filter was dried, transferred to an SEM sample holder, and coated with a 5 nm thick layer of platinum.

[0051] XRPD measurements were performed using a Malvern PANalytical Empyrean X-ray diffractometer equipped with a Cu Kα (1.54 Å) source, MultiCore optics, and a solid-state PIXcel3D detector. Samples were attached to aluminum or polycrystalline silicon sample holders using Kapton tape. Dried slurries were measured under Kapton tape without further sample preparation, and suspensions were filtered, dried, and the filter attached with double-sided tape. Samples were measured in reflection geometry with a spin measurement stage. The measurement range was 5–40° 2θ. The step size and time per step were varied depending on the number of counts per second obtained.

[0052] Dynamic light scattering (DLS) measurements were performed using a Malvern Zetasizer. Slurries or dry powders were redispersed in water or 0.1% HPMC (aq.), stirred, and measured after the sample was completely dispersed. A backscattering measurement setup was used, and the CUMULANTS algorithm was used to obtain the mean particle size (Z-average) and polydispersity index (PI).

[0053] Stability testing The solid material was weighed into individual vials (approximately 150 mg of material each) and transferred to a stability chamber. Three conditions were applied: ambient (material in sealed vials at room temperature), 25°C / 65% RH, and 40°C / 75% RH. The material was analyzed at T0 (freshly prepared), T7 (7 hours), T14 (14 hours), and T30 (30 days) after the start of the stability test. SEM, XRD, and dissolution / permeability studies were used to evaluate the material's crystallinity, particle size / morphology, and performance.

[0054] Dissolution test Dissolution profiles were measured using a Pion Rainbow R2D instrument (Pion Inc UK Ltd, Forest Row, UK). Suspensions were prepared at 5 mg / mL in a 1% PVPVA suspension vehicle loaded with 40 μg / mL (ezetimibe) or 30 μg / mL (apalutamide). Fasted simulated intestinal fluid (FaSSIF) at pH 6.5 was used for the dissolution study of ezetimibe. Dissolution studies of apalutamide were performed in a biphasic mode for 15 minutes, starting in simulated gastric fluid (SGF) (0.025 M HCl pH 1.6). The contents of the SGF were then converted to FaSSIF medium pH 6.5 by the addition of 10 mL of FaSSIF concentrated medium.

[0055] The temperature was set to 37°C and the stirring speed to 150 rpm. API concentrations were continuously monitored across the path length of a fiber-optic UV-Vis probe. UV-Vis spectra were collected at 30-second intervals using a Pion Rainbow Dynamic with either a 10-mm tip for ezetimibe or a 5-mm tip for apalutamide. API concentrations were calculated based on standard curves (5 mg / mL stock solutions of each API in ethanol) using second-derivative data transformation in the wavelength range of 293–320 nm for both ezetimibe and apalutamide.

[0056] Transmittance measurement (μFlux) A μFlux device connected to a Rainbow apparatus (Pion Inc UK Ltd, Forest Row, UK) was used to measure the passive permeability of API from different formulations. The suspension was loaded into a donor chamber containing 10 mL of SGF (0.025 M HCl, pH 1.6) and incubated for 15 minutes. The contents in the donor chamber were then converted to FaSSIF solvent pH 6.5 by adding 10 mL of FaSSIF concentrated solvent and stirring at 150 rpm. The receiver compartment contained 20 mL of PION acceptor buffer pH 7.4 at a stirring rate of 150 rpm. Permeability was assessed through a gastrointestinal PAMPA membrane (Pion Inc UK Ltd, Forest Row, UK). Suspensions were loaded at either 40 μg / mL for ezetimibe or 30 μg / mL for apalutamide, using suspensions prepared at 5 mg / mL in a 1 wt.% PVPVA suspension vehicle. The temperature was set at 37°C during measurements. UV-Vis spectra were recorded at 30-second intervals between 293 and 320 nm using either a 10 mm tip for ezetimibe or a 5 mm tip for apalutamide using a Pion Rainbow Dynamic. API concentrations were calculated using second-order derivatives based on a standard curve (5 mg / mL stock solution in ethanol) to avoid interference from undissolved suspended particles. Standard curves were generated separately for the SGF and FaSSIF solvents for the donor chamber and the acceptor solvent for the acceptor chamber, but the same stock solutions and analytical ranges were used.

[0057] Crystallization measurements The crystallization of API nanoparticles was assessed via a kinetic study of the suspension. XRD measurements were therefore performed on the suspension at different time points. Crystallization reached its thermodynamic maximum when the peak height no longer increased with time.

[0058] Calculation of the polymer and API contents in the suspension was performed as shown in Table 1.

[0059] [Table 1]

[0060] Crystallization Amorphous API nanoparticles (budesonide, ezetimibe, ceritinib, apalutamide) were added as dry powders to aqueous polymer solutions. The mixtures were either: (i) Mixed using a magnetic stirrer and sonicated until the API was completely surrounded by water (wetted). Stirring was continued for 16 to 24 hours at ambient temperature, or (ii) Blended using a metal spatula and allowed to stand at room temperature for 18-24 hours.

[0061] The resulting suspensions were analyzed after 18-24 hours. SEM and XRD samples were prepared as described above. The results are shown in Table 2.

[0062] Preparation of solid materials A suspension containing the nanosized API prepared as described above was dried overnight in a vacuum desiccator. The solid material was ground to produce a powder. The powder was analyzed by XRD and SEM. The powder containing the nanosized API was used for stability, permeability, and dissolution tests as described above. The results are shown in Table 2.

[0063] [Table 2] JPEG0007716600000003.jpg225157 JPEG0007716600000004.jpg225157 JPEG0007716600000005.jpg225157

[0064] Tableting The formulation was manufactured by using wet granulation technology. A 20% w / w API loading was used, and the tablet compression parameters (e.g., die cavity height, compression force, ejection force, strokes per minute) were kept constant in order to investigate the influence of excipients on tablet properties.

[0065] Compressed tablets can be manufactured by a process including the following steps. 1. Wet mixing 2. Wet granulation 3. Drying 4. Grinding and sieving 5. Lubrication 6. Compression 7. Dust removal and storage

[0066] Results and discussion Figure 2 shows the influence of particle size and morphology in nanosized amorphous ezetimibe (A) during crystallization from pure water (B) and from an aqueous solution (C) containing PVPVA, respectively. As can be seen from the figure, crystallization using the method of the present disclosure significantly suppresses the growth of particle size.

[0067] Figure 3 shows the SEM of a composition of a dried suspension containing ceritinib and 15 wt.-% poloxamer 407. The API:polymer ratio was 1:1. The composition exists as uniform round-like nanoclusters (size smaller than 3 μm) together with ceritinib nanocrystals of 70 - 110 nm.

[0068] Figure 4 shows the XRD diffraction pattern of a suspension containing ezetimibe in 20 wt.-% aq. PVPVA (API:polymer ratio is 1:1) as a function of time. As can be seen from the figure, crystal formation can be observed only in the diffraction pattern 9 hours after contact.

[0069] SEM images of amorphous nanosized ezetimibe crystallized from aqueous solutions containing three different PVPVA and SLS concentrations are shown in Figure 5. As can be seen, particle size growth decreased with increasing PPVVA concentration. The crystallinity of samples prepared using aqueous solutions containing 1 wt.-% PPVVA and 0.2 wt.-% SLS (a), 2.5 wt.-% PPVVA and 0.2 wt.-% SLS (b), and 5 wt.-% PPVVA and 0.2 wt.-% SLS (c) was characterized by XRD (Figure 6). Crystalline bulk ezetimibe (d) is shown as a control. This result indicates that amorphous nanoparticle crystallization occurred and that crystal size control was achieved.

[0070] When PVPVA was replaced by other polymers, the formation of desired crystalline ezetimibe nanoparticles was significantly reduced. As can be seen from Table 2, the best nanocrystals of ezetimibe were obtained when crystallization was carried out using an aqueous solution containing PVPVA, while the best nanocrystals of budesonide and ceritinib were produced using aqueous solutions containing HPMC and poloxamer, respectively.

[0071] For apalutamide, the best nanocrystals were produced using PVPVA and HPMC. The XRD patterns of the nanocrystals showed reflections that were inconsistent with the polymorphs of apalutamide known in the patent literature to date. This allows us to conclude that a specific molecular arrangement represents a novel structure for nanocrystalline apalutamide stabilized by HPMC or PVPVA.

[0072] SEM images of budesonide nanoparticles crystallized from aqueous solutions containing three HPMC+SLS concentrations are shown in Figure 7. The crystallinity of these samples was characterized by XRD (Figure 8). The results indicate that crystallization of amorphous nanoparticles occurred and that particle size control was achieved using HPMC+SLS.

[0073] The crystallization of the amorphous API can also be carried out at higher concentrations, with the limitation that the polymer concentration also needs to be increased simultaneously. This leads to practical limitations of 5 - 10 wt.-% in the case of, for example, HPMC, but is a viable option in the case of PVPVA. In fact, in the case of PVPVA, significantly higher contents, such as up to 50 wt.-%, can be applied.

[0074] As can be seen from Table 2, crystallization can be affected, in particular, by the polymer and by the ratio of API to polymer. Typically, the addition of a surfactant, such as SLS for example, promotes nanocrystallization.

[0075] The stabilities of the nanocrystalline ezetimibe and budesonide prepared according to the present disclosure are summarized in Tables 3 and 4, respectively. As can be seen from the tables, the prepared materials were stable throughout the stability tests. Crystallinity was also confirmed by XDR. The XRD diffraction patterns as a function of time for ezetimibe and budesonide stored at 40 °C / relative humidity 75% are shown as exemplary embodiments in Figures 9 and 10, respectively. SEM images of the ceritinib composition fresh and stored at room temperature for 1 month are shown in Figure 11, indicating good stability.

[0076]

Table 3

[0077]

Table 4

[0078] Figure 12 shows the FaSSIF and SGF-FaSSIF dissolution profiles of exemplary ezetimibe compositions and bulk ezetimibe compositions of the present disclosure. For the experiments, the compositions as powders were resuspended in an aqueous 1% PPVVA suspension vehicle. As clearly shown, the ezetimibe compositions of the present disclosure have superior solubility to the bulk material, as they dissolve significantly faster under both fasted and fed intestinal conditions.

[0079] Figure 13 shows a comparison of the permeability of ezetimibe compositions prepared according to the present disclosure with the corresponding bulk API. Thus, the permeability of the API of the present disclosure was significantly better than that of the corresponding bulk API.

[0080] The advantage of the present invention compared to amorphous solid dispersions is that it does not require a high polymer content to stabilize the composition. Furthermore, in contrast to solvent-antisolvent methods, the disclosed method does not involve the use of organic solvents, which may not be completely eliminated by practical manufacturing techniques. In addition, subjecting the API to significant mechanical forces to break down bulk API crystals into smaller crystals is avoided.

Claims

**Claim 1** A method for the crystallization of an active pharmaceutical ingredient (API), the method comprising providing an amorphous nano-sized API, providing an aqueous solution comprising one or more polymers and / or copolymers, and contacting the amorphous nano-sized API with the aqueous solution comprising one or more polymers and / or copolymers to form a mixture, wherein the content of the amorphous nano-sized API in the mixture is higher than the maximum content of amorphous nano-sized API in the aqueous solution comprising one or more polymers and / or copolymers calculated from the solubility of the amorphous nano-sized API comprising thereby obtaining a suspension comprising nano-sized API in crystalline form. **Claim 2** The method according to claim 1, wherein the content of the amorphous nano-sized API in the mixture is at least 10 times higher than the maximum content of amorphous nano-sized API in the aqueous solution comprising one or more polymers and / or copolymers calculated from the solubility of the amorphous nano-sized API. **Claim 3** The method according to claim 1, wherein the ratio of API: polymer and / or copolymer is from 10:1 to 1:10, wherein the amount of the API is calculated as mg / mL of the suspension, and the amount of the polymer is calculated as weight % of one or more polymers and / or copolymers of the suspension. **Claim 4** The method according to claim 1, wherein the aqueous solution comprising one or more polymers and / or copolymers comprises one or more surfactants. **Claim 5** The method according to claim 4, wherein the content of the one or more surfactants in the aqueous solution is from 0.0025 to 1.5 wt%. **Claim 6** The method according to claim 4, wherein the one or more surfactants are selected from the group consisting of sodium lauryl sulfate (SLS), Tween 80, Tween 20, sodium dioctyl sulfosuccinate (DOSS), and tocopherol soran (TPGS). **Claim 7** The method according to claim 1, wherein the one or more polymers are selected from the group consisting of polyvinylpyrrolidone / vinyl acetate (PVPVA), polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hypromellose acetate succinate (HPMCAS), polyacrylic acid (PAA), polyethylene glycol (PEG), polyvinylcaprolactam (PVCL), poloxamer, poly(N-vinylcaprolactam)-poly(vinyl acetate)-poly(ethylene glycol), and proteins.

8. The method according to claim 7, wherein the polymer is PVPVA, and the aqueous solution contains 0.2 to 50 wt.-% of PVPVA.

9. The method according to claim 7, wherein the polymer is HPMC, and the aqueous solution contains 0.2 to 5 wt.-% of HPMC.

10. The method according to claim 1, wherein the API is selected from BSC class II APIs and BSC class IV APIs.

11. The API is adefovir dipivoxil, apalutamide, atazanavir, avacopan, deucravacitinib, doravirine, enzalutamide, elagolix, encorafenib, etravirine, everolimus, etonogestrel, fenofibrate, glecaprevir, pibrentasvir, grazoprevir, pibrentasvir, griseofulvin, telmisartan, itraconazole, ivacaftor, lumacaftor, tezacaftor, elexacaftor, lonafarnib, nabilone, olaparib, paclitaxel, posaconazole, pralsetinib, regorafenib, ripretinib, ritonavir, lopinavir, paritaprevir, ombitasvir, sofosbuvir, ledipasvir, suvorexant, tacrolimus, tadalafil, telaprevir, telmisartan, tolvaptan, vemurafenib, venetoclax, verapamil,The method according to claim 1, selected from the group consisting of and any combination thereof.

12. The method according to claim 1, wherein the contacting comprises mixing the suspension.

13. The method according to claim 1, wherein the contacting comprises subjecting the suspension to ultrasonic waves.

14. The intensity of the ultrasonic wave is 3 W / cm 2 The method according to claim 13, wherein the intensity is 3 W / cm or less.

15. The method according to claim 1, wherein the contacting is carried out for at least 10 hours.

16. The method according to claim 1, comprising drying the suspension and thereby producing a solid comprising the nano-sized API in crystalline form and the one or more polymers and / or copolymers.

17. The method according to claim 16, comprising crushing the solid and thereby producing a powder comprising the nano-sized API in crystalline form and the one or more polymers and / or copolymers.

18. The method according to claim 1, comprising separating the nano-sized API in crystalline form from the suspension and optionally drying the separated nano-sized API in crystalline form.

19. The method according to claim 1, wherein the particle size of the crystalline API is not more than 300% larger than the particle size of the amorphous nano-sized API.

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