Spray drying of supersaturated solutions of APIs containing acetic acid.

Abstract

The present invention discloses a process for the preparation of a spray-dried solid dispersion (SDD) comprising an active pharmaceutical ingredient (API) and a dispersion polymer (DISPPOL), wherein the spray drying is carried out on a supersaturated solution of the API in a solvent mixture comprising two solvents, one of which is acetic acid, and the supersaturated solution further comprises DISPPOL.

Description

Technical Field

[0001] The present invention discloses a method for the preparation of a spray-dried solid dispersion (SDD) comprising an active pharmaceutical ingredient (API) and a dispersion polymer (DISPPOL), wherein the spray drying is carried out with a supersaturated solution of the API in a solvent mixture comprising two solvents, one of which is acetic acid, and the supersaturated solution further comprises DISPPOL.

Background Art

[0002] Spray-dried solid dispersions (SDDs) comprising an active pharmaceutical ingredient (API) and a dispersion polymer (DISPPOL) are typically produced by dissolving the dispersion polymer and the API in a volatile solvent such as methanol or acetone, or in a mixture of solvents, followed by spray drying. If the API has a limited solubility of <1 wt% in, for example, the spray drying solvent, the API suspension can be heated to a temperature below or above the atmospheric boiling point of the solvent, which is known as a "high temperature spray drying process" and results in a higher dissolved concentration of the API. In some cases, even at higher temperatures, an appropriate API concentration that is economical as a spray drying process is not provided, or other problems such as chemical degradation of the API, or the potential for incomplete API dissolution in the heat exchanger are caused. Alternative less desirable volatile solvents can provide an increased solubility of the API, but these solvents have other disadvantages that make them less desirable, such as high cost, toxicity, low equipment compatibility, low commercial availability, high disposal costs, and difficulty in removing them to a sufficiently low level.

[0003] Spray drying of suspensions is usually avoided because it can lead to clogging of the nozzles of the spray dryer. Furthermore, when the intention of the spray drying is to provide an amorphous solid dispersion (ASD) of the API in the dispersion polymer, this goal is best achieved when both the API and the dispersion polymer are dissolved in the spray drying solvent so that neither of them is present in the spray drying mixture in their commercial form, thereby best obtaining the desired intimate, homogeneous, and amorphous mixture of the ASD with the dispersion polymer.

[0004] WO2019 / 220282A1 discloses, in Example 1, the spray drying of a solution of erlotinib and a dispersion polymer (PMMAMA or hydroxypropyl methylcellulose acetate succinate H grade) in methanol to provide a spray-dried dispersion.

[0005] US2020 / 261449A1 discloses amorphous solid dispersions of nilotinib fumarate or nilotinib tartrate. In Example 13, "the required amounts of nilotinib fumarate, fumaric acid, and HPMC-AS were dissolved in methanol solvent to prepare a solution containing 3% solids. The prepared solution was sprayed on a spray dryer." The solution contained 60.77 mg of nilotinib fumarate, 182.3 mg of HPMC-ASMF, 50 mg of fumaric acid, and 9,000 mg of methanol, according to Table 19, giving a total weight of 9,293.07 mg. The term "3% solids" refers to the amount of solids dissolved in the solution, which is [60.77 mg of nilotinib fumarate + 182.3 mg of HPMC-ASMF = 243.078 mg] ÷ 9,293.07 mg = 3%.

[0006] Therefore, conventional solutions were used for spray drying, in which case all solids were dissolved. US2020 / 261449A1 does not disclose supersaturated feed solutions for spray drying.

[0007] US2009 / 247468A1, in

[0007] , discloses the effect of non-volatile solvents or high-boiling point solvents as components in the feed solution for spray drying on the properties of the resulting spray-dried particles, such as increased size, density, or fluidity. Claim 2 specifies that the mixture used as the feed material for spray drying is a solution or a suspension. A supersaturated solution of a compound is thermodynamically metastable. Nucleation and subsequent precipitation are kinetically inhibited. However, a suspension of a compound in a solvent cannot be or contain a supersaturated solution at the same time, because any solid particles of the compound in the suspension cause crystallization of any amount of the compound dissolved beyond the maximum solubility of the compound in the solvent; that is, any solid particles of the compound present in a supersaturated solution act as nucleating factors, overcoming the kinetic barrier and causing nucleation and precipitation of any amount of the compound dissolved beyond the maximum solubility, thereby leading to a thermodynamically stable state, a suspension. Therefore, a suspension of a compound in a solvent can be a mixture of solid compounds suspended together with a solvent containing the compound in an amount equivalent to that a saturated solution can contain.

[0008]

[0164] Related to

[0165] This study examines the possible solubility properties of compounds in gastric juice, where a supersaturated state may temporarily pass through during the dissolution of the compound in the stomach. However, this clearly refers to the dissolution behavior of ASD in the stomach, not spray drying.

[0009] For these reasons, US2009 / 247468A1 does not disclose supersaturated feed solutions for spray drying.

[0010] WO2019 / 220282A1 discloses oral pharmaceutical compositions comprising solid dosage forms (SDFs). Supersaturation is disclosed abstractly, on page 6, line 29, or on page 12, line 39, and elsewhere, only in relation to the SDF itself and in the environment of use, i.e., in the patient, in relation to the rapid degradation of the SDF. Example 1 discloses a spray solution having a solid content of 3%, but again, the term “solid content” refers to the amount of solid dissolved in the solution.

[0011] Therefore, WO2019 / 220282A1 does not disclose a supersaturated feed solution for spray drying.

[0012] Paudel et al., INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, 2021, 453, 253-284, discloses supersaturation of APIs in a carrier matrix, i.e., supersaturated solid dispersions in solid mixtures obtained by spray drying; see Section 1, Part 3, Introduction: "...very rapid solvent evaporation during spray drying leads to a rapid increase in viscosity, enabling kinetic capture of APIs in the carrier matrix. Often, (supersaturated) molecular dispersions are a result of this process..." The same result, i.e., the possibility of supersaturation of drugs in a carrier matrix, is implied under the second sentence of the first section of Section 5.1.1, “Supply Compositions”: "...differences in solubility between the drugs, carriers, and other additives in the supply solution (solvent) lead to different degrees of saturation / supersaturation of these components..."; the term “leads” clearly indicates that any possible supersaturation may occur in the solid dispersions resulting from spray drying.

[0013] Similar to WO2019 / 220282A1, it is mentioned that supersaturation can occur and be maintained during in vitro lysis in the gastrointestinal tract; see, in particular, the second sentence of the first paragraph of section 4.1: "...supersaturation that occurs during in vitro lysis and after oral administration in the gastrointestinal environment..."

[0014] Therefore, Paudel et al. also do not disclose supersaturation in the feed solution for spray drying.

[0015] Supersolvents such as acetic acid can dissolve APIs to high concentrations. However, preparing such SDDs from pure acetic acid may be disadvantageous due to the high viscosity of the solution containing high concentrations of dissolved dispersed polymers, the low solubility of the desired excipient in acetic acid, poor atomization / drying properties, or safety concerns of acetic acid.

[0016] There was a need for a method to prepare spray-dried solid dispersions of APIs and dispersed polymers that would allow APIs to be dissolved in an easily processable spray-drying solvent at a moderate temperature, i.e., below the boiling point at atmospheric pressure, at a concentration high enough to enable economical throughput of SDD.

[0017] A solvent shift method has been discovered, which involves dissolving the API in acetic acid at a high concentration to provide a relatively high-viscosity solution of the API in acetic acid, and then diluting this API solution with a preferred spray-drying solvent having a relatively low viscosity, such as methanol, ethanol, or acetone, to obtain a metastable supersaturated solution of the API in a solvent mixture having a fairly low viscosity and containing a dispersion polymer, in a ratio that allows for efficient spray drying. A metastable supersaturated solution of the API in a solvent mixture means that the API is present in the solvent mixture in a dissolved state and no solid API is present. In the supersaturated solution, the API is present at a concentration above the thermodynamic equilibrium concentration.

[0018] Such supersaturated solutions cannot be prepared by simply adding the API to a solvent mixture, but must be produced by mixing two solvents, each containing the dissolved API and the dispersion polymer. An advantage is that by diluting the solution of the API in acetic acid with a preferred spray-drying solvent, the viscosity of the resulting metastable supersaturated solution can be selected to be as low as that of the pure preferred spray-drying solvent. Another advantage of the solvent shift method is that it allows for higher concentrations of dissolved API in the spray-drying solution compared to the thermodynamic maximum solubility of the API in the spray-drying solution, giving higher spray-drying efficiency and higher throughput for the production of SDDs of APIs, especially for such APIs that have fairly low solubility in typical spray-drying solvents. Higher concentrations of API and dispersion polymer in the spray-drying solution can also allow for larger particles, which give advantages for improved properties of the spray-dried particles, e.g., for dosage form production or product recovery.

[0019] Abbreviations and definitions used herein AA Activator API Active Pharmaceutical Ingredients DISPPOL Dispersed Polymer Glacial acetic acid, anhydrous acetic acid, 100% acetic acid HPMCAS Hydroxypropyl Methylcellulose Acetate Succinate, Hypromellose Acetate Succinate, CAS 71138-97-1 MIXSOL2DISPPOL: A mixture of DISPPOL and a second solvent, SOL2. The pKa of the basic site of an organic Brønsted base is the pH at which half of these basic sites are protonated. Below this basic pKa, more than half of these basic sites are protonated, i.e., ionized. This pKa of the basic site is also called the basic pKa.

[0020] In contrast, the pKa of the acidic site of an organic Bronsted acid is the pH at which half of these acidic sites are protonated, i.e., ionized. At pH higher than this acidic pKa, more than half of these acidic sites are deprotonated. This pKa of the acidic site is also called the acidic pKa.

[0021] pKa values are available on the Internet and they can also be calculated, for example, by ADMET predictor® software, Simulations Plus, Inc. (Nasdaq: SLP), or measured in the laboratory.

[0022] PPO Polypropylene Oxide Room temperature Approximately 20 °C PXRD Powder X-ray Diffraction SDD Spray-dried Solid Dispersion SOL1 First Solvent SOL2 Second Solvent SOLUTION1 Solution of AA in the first solvent SOL1, optionally further containing DISPPOL SUPSATSOL Supersaturated solution of the active agent AA in the solvent mixture SOLMIX further containing DISPPOL SOLMIX Solvent mixture of SOL1 and SOL2 obtained when SOLUTION1 and MIXSOL2 DISPPOL or SOL2 are mixed Vitamin E TPGS Tocopheryl polyethylene glycol succinate (INN), Vitamin E D-α-tocopheryl polyethylene glycol succinate wt% Unless otherwise explicitly stated, any wt% in this specification is based on the weight of the solution or mixture

Summary of the Invention

[0023] The subject of the present invention is a method SPRAYDRY for preparing a spray-dried solid dispersion SDD comprising an active agent AA and a dispersion polymer DISPPOL, The method SPRAYDRY is, To provide a solution 1 of AA in a first solvent SOL1, • Mixing SOLUTION1 with the second solvent SOL2 provides the solution SUPSATSOL. This includes spray-drying SUPSATSOL in a spray dryer, AA is a drug, medication, pharmaceutical, therapeutic agent, nutritional supplement, or active pharmaceutical ingredient. SUPSATSOL contains a solvent mixture SOLMIX and AA, where SOLMIX is a mixture of SOL1 and SOL2. SUPSATSOL is a supersaturated solution of AA in SOLMIX. SUPSATSOL does not contain AA in solid form. DISPPOL is contained in SOLUTION1, SOL2, or both before mixing SOLUTION1 with SOL2. SOL1 contains 90-100 wt% acetic acid, where wt% is based on the weight of SOL1. AA is stable in SOL1, SOL2, and SOLMIX. [Modes for carrying out the invention]

[0024] In the sense of the present invention, supersaturation means that at a given temperature, particularly at the temperature of SUPSATSOL when SUPSATSOL is supplied into the spray dryer, the concentration of AA in SOLMIX exceeds the concentration of a saturated solution of AA in SOLMIX, and therefore the concentration of AA in SOLMIX exceeds the respective thermodynamic equilibrium concentrations of AA in SOLMIX. SUPSATSOL is a metastable supersaturated solution of AA in SOLMIX. In the sense of the present invention, metastable means that AA does not precipitate from SUPSATSOL between the preparation of SUPSATSOL and its spray drying.

[0025] Therefore, AA exists in SUPSATSOL in a completely dissolved state. SUPSATSOL does not contain AA in solid form.

[0026] SUPSATSOL preferably has only one liquid phase.

[0027] The amounts of AA, SOLMIX, and DISPPOL can be selected, respectively. Supersaturation of AA in SUPSATSOL can also be observed compared to the solubility of AA in SOLMIX, and the concentration of AA in SUPSATSOL may be at least 1.1 times, preferably at least 1.5 times, more preferably at least 2 times, even more preferably at least 5 times, and particularly at least 10 times, the concentration of a saturated solution of AA in SOLMIX at a given temperature, especially at the temperature of SUPSATSOL when it is supplied into the spray dryer.

[0028] The possible amount of AA in SUPSATSOL can be 0.5 wt% to 10 wt%, preferably 1 wt% to 7.5 wt%, and more preferably 1 wt% to 5 wt%, where wt% is based on the weight of SUPSATSOL.

[0029] When DISPPOL is present in SOL2 before mixing with SOLUTION1, this mixing of DISPPOL with SOL2 is referred to herein as MIXSOL2DISPPOL.

[0030] therefore, In one embodiment, SUPSATSOL is prepared by mixing SOLUTION1, which is a solution of AA in SOL1, with MIXSOL2DISPPOL. In another embodiment, SUPSATSOL is prepared by mixing SOLUTION1, which is a solution of AA in SOL1 containing DISPPOL, with SOL2. In yet another embodiment, SUPSATSOL is prepared by mixing SOLUTION1, which is a solution of AA in SOL1 containing DISPPOL, with MIXSOL2DISPPOL. Preferably, SUPSATSOL is prepared by mixing SOLUTION1, which is a solution of AA in SOL1, with MIXSOL2DISPPOL.

[0031] Mixing of SOLUTION 1 with MIXSOL2DISPPOL or SOL2 for the preparation of SUPSATSOL can be carried out by any method known to those skilled in the art for mixing liquids, such as continuous mixing using an inline mixer such as a T-shaped mixer, or by batch mixing in a container.

[0032] In the case of continuous mixing, the mixing and spray drying of SUPSATSOL can be carried out continuously and without interruption, i.e., without any isolation or retention of SUPSATSOL between mixing and spray drying. This allows the time between mixing and spray drying of SUPSATSOL to be short, which may be as short as a few milliseconds to a few seconds, which may be advantageous when the metastability of SUPSATSOL is only for a short duration.

[0033] Mixing SOLUTION1 with MIXSOL2DISPPOL or SOL2 to prepare SUPSATSOL is SOLUTION1 has a boiling point of SOLUTION1 at 4°C to atmospheric pressure, preferably a temperature below the boiling point of SOLUTION1 at 4°C to atmospheric pressure, and MIXSOL2DISPPOL or SOL2 is in a state where it has a temperature below the boiling point of MIXSOL2DISPPOL at 4°C to atmospheric pressure, preferably below the boiling point of MIXSOL2DISPPOL at 4°C to atmospheric pressure. Preferably, SOLUTION1 has a temperature of 4 to 60°C, preferably room temperature to 60°C, and MIXSOL2DISPPOL or SOL2 can be performed at a temperature of 4 to 60°C, preferably room temperature to 60°C.

[0034] SOLMIX is a solvent mixture of SOL1 and SOL2 obtained when SOLUTION1 is mixed with MIXSOL2DISPPOL or SOL2.

[0035] SDD is a spray-dried solid dispersion of AA in DISPPOL. AA and DISPPOL are preferably homogeneously mixed in the SDD.

[0036] In a solid dispersion of AA in DISPPOL, AA can be homogeneously, preferably molecularly, dispersed in DISPPOL. AA and DISPPOL can form a solid solution in SDD.

[0037] AA is amorphous or substantially amorphous in SDD, meaning substantially at least 80 wt%, preferably at least 90 wt%, more preferably at least 95 wt%, even more preferably at least 98 wt%, and especially at least 99 wt%, of the AA is amorphous, where wt% is based on the total weight of AA in the SDD. Thus, the SDD can be amorphous SDD. The amorphous nature of AA can be demonstrated by the absence of sharp Bragg diffraction peaks in the X-ray pattern when the SDD is analyzed by powder X-ray diffraction (PXRD). Possible parameters and settings for the X-ray diffractometer are an instrument with a Cu-Kalpha source, a parallel beam geometry modified by 2θ from 3 to 40°, and a scan rate of 2° / min with a step size of 0.0°. Another piece of evidence for the amorphous nature of AA in SDD may be a single glass transition temperature (Tg). A single Tg is also evidence of a homogeneous mixture of amorphous AA and polymer. Samples without any further sample preparation may be used for Tg determination, and the determination may be performed in modes that vary, for example, a scan speed of 2.5°C / min, a variation of ±1.5°C / min, and a scan range of 0 to 180°C. The amorphous nature of AA indicates a Tg that is equal to that of neat DSISPPOL or is between the Tg of the polymer and the Tg of AA. The Tg of SDD is often similar to the weighted average of the Tg of AA and the Tg of DSISPPOL. SDD is amorphous or substantially amorphous, and SDD may also be called ASD.

[0038] The concentration of DISPPOL in SUPSATSOL may be above or below, preferably below, the saturation concentration of DISPPOL in SOLMIX, at a given temperature, particularly at the temperature of SUPSATSOL when it is supplied into the spray dryer.

[0039] In one embodiment, DISPPOL is present in SUPSATSOL in a dissolved state, and the amounts of DISPPOL and SOLMIX are selected, respectively.

[0040] The amount of DISPPOL in SUPSATSOL may be 0.5 wt% to 20 wt%, preferably 1 wt% to 20 wt%, more preferably 2.5 wt% to 15 wt%, and even more preferably 5 wt% to 10 wt%, where wt% is based on the weight of SUPSATSOL.

[0041] SDD may contain 1 to 99 wt%, preferably 10 to 95 wt%, more preferably 10 to 80 wt%, and even more preferably 20 to 60 wt%, where wt% is based on the weight of SDD.

[0042] SDD may contain 1 to 99 wt%, preferably 20 to 90 wt%, more preferably 40 to 80 wt%, of DISPPOL, where wt% is based on the weight of SDD.

[0043] The combined content of AA and DISPPOL in SDD is 65-100 wt%, more preferably 67.5-100 wt%, even more preferably 80-100 wt%, particularly 90-100 wt%, and more specifically 95-100 wt%. wt% is based on the weight of the SSD. In one embodiment, the SDD consists of AA and DISPPOL.

[0044] The relative amounts of AA:DISPPOL in SDD can be 50:1 to 1:50, preferably 25:1 to 1:25, and more preferably 10:1 to 1:10 (w / w).

[0045] AA can be any bioactive compound. The bioactive compound may be desired for administration to patients who require the activator.

[0046] AA may be a drug, pharmaceutical, medicinal product, therapeutic agent, dietary supplement, or active pharmaceutical ingredient (API).

[0047] AA can generally be a "low molecular weight" with a molecular weight of 2000 daltons or less.

[0048] AA has at least 5 basic pK A It may be a Brønsted base having [a certain characteristic]. Preferably, when AA is a Brønsted base, AA is combined with acetic acid in its free base form. AA may exist in SUPSATSOL in its free base form or its protonated form. When AA is combined with acetic acid in its free base form, AA is again obtained in its free base form after spray drying.

[0049] AA may have a solubility of 40 mg / ml or less in SOL2 at a given temperature, particularly at the temperature of SUPSATSOL when it is supplied into the spray dryer.

[0050] AA may be nilotinib.

[0051] AA may be one or more activators, and SDD may contain one or more AAs.

[0052] DISPPOL may comprise one or more dispersion polymers, preferably one, two, three, or four, more preferably one, two, or three, and even more preferably one or two dispersion polymers.

[0053] DISPPOL may be a pharmaceutically acceptable dispersion polymer.

[0054] Suitable DISPPOLs include, but are not limited to, hydroxypropyl methylcellulose succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), cellulose phthalate acetate (CAP), carboxymethyl ethylcellulose (CMEC), polyvinylpyrrolidone (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA), poly(co-methyl methacrylate methacrylate) (PMMAMAA), poly(co-ethyl acrylate methacrylate), or any combination thereof.

[0055] Suitable PMMAA polymers include, but are not limited to, poly(methacrylate-comethyl methacrylate) 1:1 (e.g., Eudragit® L100) and poly(methacrylate-comethyl methacrylate) 1:2 (e.g., Eudragit® S100). Eudragit® is a polymer product of Evonik Industries AG, 45128 Essen, Germany.

[0056] Poly(methacrylate-coethyl acrylate) can be poly(methacrylate-coethyl acrylate) in a 1:1 ratio.

[0057] In some embodiments, DISPPOL is HPMCAS or PVP-VA.

[0058] SOL1 has only one liquid phase.

[0059] SOL1 may contain 90-100 wt%, preferably 95-100 wt%, more preferably 97.5-100 wt%, even more preferably 98-100 wt%, and particularly 99-100 wt% of acetic acid, where wt% is based on the weight of SOL1.

[0060] Preferably, SOL1 is acetic acid. SOL1 may be glacial acetic acid.

[0061] When SOL1 contains less than 100 wt% acetic acid, SOL1 may also contain water, methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, THF, methyl acetate, ethyl acetate, dichloromethane, 1,3-dioxolane, or mixtures thereof. Preferably, water, methanol, acetone, or a mixture thereof. More preferably, it may contain an additional solvent such as water.

[0062] SOLUTION1 is prepared by dissolving AA in SOL1 and optionally adding any DISPPOL.

[0063] SOLUTION 1 can be prepared by dissolving AA in SOL 1 and optionally adding any DISPPOL at a temperature below the boiling point of SOL 1 at 4°C to atmospheric pressure, preferably below the boiling point of SOL 1 at 4°C to atmospheric pressure, and more preferably at a temperature between room temperature and 60°C.

[0064] The AA in SOLUTION1 is dissolved in SOLUTION1, and the amounts of AA and SOL1 are selected, respectively.

[0065] The concentration of AA in SOLUTION1 is below the saturation concentration of AA in SOL1 at a given temperature, particularly at the temperature of SOLUTION1 when SOLUTION1 is mixed with MIXSOL2DISPPOL or SOL2, respectively, to provide SUPSATSOL.

[0066] In one embodiment, DISPPOL is present in SOLUTION1 in a dissolved state, and the amount of DISPPOL is selected accordingly.

[0067] The concentration of DISPPOL in SOLUTION1 is preferably below the saturation concentration of DISPPOL in SOL1 at a given temperature, particularly at the temperature of SOLUTION1 when SOLUTION1 is mixed with MIXSOL2DISPPOL or SOL2, respectively, to provide SUPSATSOL.

[0068] The typical solubility of AA in SOL1 may be at least 1 wt%, preferably at least 2 wt%, more preferably at least 5 wt%, even more preferably at least 10 wt%, and particularly at least 20 wt%, where wt% is based on the weight of SOLUTION1, and the solubility of AA in SOL1 is preferably at a temperature below the boiling point of SOL1 at 4°C to atmospheric pressure, more preferably at room temperature to 60°C. SOL1 can be selected from each of the above.

[0069] The lower limit of the amount of AA in SOLUTION 1 may be at least 0.5 wt%, preferably at least 1 wt%, more preferably at least 2.5 wt%, even more preferably at least 5 wt%, particularly at least 7.5 wt%, more specifically at least 10 wt%, even more specifically at least 20 wt%, particularly at least 30 wt%, where wt% is based on the weight of SOLUTION 1.

[0070] The amount of AA in SOLUTION 1 may be up to 50 wt%, preferably up to 40 wt%, and more preferably up to 35 wt%, where wt% is based on the weight of SOLUTION 1.

[0071] Any of the lower limits of the amount of AA in SOLUTION1 can be combined with any of the upper limits of the amount of AA in SOLUTION1.

[0072] For example, the amount of AA in SOLUTION 1 may be 0.5 to 50 wt%, preferably 0.5 to 40 wt%, and more preferably 0.5 to 35 wt%, where wt% is based on the weight of SOLUTION 1.

[0073] SOL2 has only one liquid phase.

[0074] SOL2 is a solvent commonly used for spray drying.

[0075] SOL2 may contain methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, THF, methyl acetate, ethyl acetate, dichloromethane, 1,3-dioxolane, or mixtures thereof.

[0076] SOL2 may contain an amount of water such that SOL2 remains in only one liquid phase. The solubility of water in possible non-aqueous solvents of SOL2 is known. Depending on the possible non-aqueous solvent SOL2, SOL2 may contain up to 25 wt% water, where wt% is based on the weight of SOL2.

[0077] Preferably, SOL2 comprises methanol, ethanol, acetone, or a mixture thereof, and preferably, SOL2 comprises 0 to 25 wt% water, where wt% is based on the weight of SOL2.

[0078] More preferably, SOL2 comprises methanol, acetone, or a mixture thereof, and preferably, SOL2 comprises 0 to 25 wt% water, where wt% is based on the weight of SOL2.

[0079] More preferably, SOL2 is methanol, and preferably SOL2 contains 0 to 25 wt% water, where wt% is based on the weight of SOL2.

[0080] MIXSOL2DISPPOL is prepared by mixing DISPPOL with SOL2.

[0081] MIXSOL2DISPPOL can be prepared by mixing DISPPOL with SOL2 at a temperature below the boiling point of SOL2 at 4°C to atmospheric pressure, preferably below the boiling point of SOL2 at 4°C to atmospheric pressure, and more preferably at a temperature between room temperature and 60°C.

[0082] In one embodiment, DISPPOL is present in a dissolved state in MIXSOL2DISPPOL, and the amount of DISPPOL is selected accordingly.

[0083] The concentration of DISPPOL in MIXSOL2DISPPOL is preferably below the saturation concentration of DISPPOL in SOL2 at a given temperature, particularly at the temperature of MIXSOL2DISPPOL when it is mixed with SOLUTION1 to provide SUPSATSOL.

[0084] SOL2 may have a boiling point at atmospheric pressure below 115°C.

[0085] The amount of dispol in MIXSOL2DISPPOL or SOLUTION1 may be 0.5 wt% to 20 wt%, preferably 1 wt% to 20 wt%, more preferably 2.5 wt% to 15 wt%, and even more preferably 5 wt% to 10 wt%, where wt% is based on the weight of MIXSOL2DISPPOL or SOLUTION1, respectively.

[0086] AA may have a solubility in SOL1 at a given temperature, in particular at the temperature of SOLUTION1 when SOLUTION1 is mixed with MIXSOL2DISPPOL or SOL2 to provide SUPSATSOL, at least 5 times, preferably at least 10 times, more preferably at least 50 times, and even more preferably at least 100 times higher than the solubility of AA in SOL2 at SOLUTION1 when SOLUTION1 is mixed with MIXSOL2DISPPOL or SOL2, and SOL1 and SOL2 may be selected from each other.

[0087] The ratio of SOL1 to SOL2 (w:w) can be 1:1 to 1:20, preferably 1:2 to 1:20, more preferably 1:5 to 1:20, even more preferably 1:8 to 1:20, particularly 1:8 to 1:15, and more specifically 1:8 to 1:10, when SUPSATSOL is prepared by mixing SOLUTION1 with MIXSOL2DISPPOL or SOL2.

[0088] The lower limit of the amount of SOL1 in SOLMIX may be 5 wt%, preferably 6 wt%, and more preferably 7.5 wt%, where wt% is based on the weight of SOLMIX.

[0089] The upper limit of the amount of SOL1 in SOLMIX may be 50 wt%, preferably 33 wt%, more preferably 25 wt%, even more preferably 20 wt%, particularly 15 wt%, and more specifically 10 wt%, where wt% is based on the weight of SOLMIX.

[0090] The range of the amount of SOL1 in SOLMIX is such that any of the lower limits may be combined with any of the upper limits. For example, the amount of SOL1 in SOLMIX may be 5-50 wt%, preferably 5-33 wt%, more preferably 5-25 wt%, even more preferably 5-20 wt%, particularly 5-15 wt%, and more specifically 5-10 wt%, where wt% is based on the weight of SOLMIX.

[0091] SUPSATSOL can be supplied to a spray dryer at a temperature of SUPSATSOL up to its boiling point at atmospheric pressure, preferably 4°C to the boiling point of SUPSATSOL at atmospheric pressure, preferably 4°C to a temperature below the boiling point of SUPSATSOL at atmospheric pressure, more preferably room temperature to 60°C. In the context of the present invention, the phrase "SUPSATSOL can be supplied to a spray dryer at the temperature of SUPSATSOL" means "SUPSATSOL is spray-dried at the temperature of SUPSATSOL".

[0092] Spray drying of SUPSATSOL in a spray dryer evaporates both SOL1 and SOL2.

[0093] • Temperature for preparing SOLUTION 1, • Temperature for preparing MIXSOL2DISPPOL • Temperature for preparing SUPSATSOL, • Temperature for supplying SUPSATSOL into the spray dryer These can be the same temperature among different temperatures, and they can be room temperature to 60°C. Preferably, The temperature for preparing SOLUTION 1 can be room temperature to 60°C. The temperature for preparing MIXSOL2DISPPOL can be room temperature. The temperature for preparing SUPSATSOL can be room temperature to 60°C. The temperature at which SUPSATSOL is supplied into the spray dryer can be room temperature to 60°C.

[0094] Spray drying can be performed at an inlet temperature of 80-165°C.

[0095] Spray drying can be performed at an outlet temperature below the boiling point of the solvent in SOLMIX, which has the highest boiling point.

[0096] Spray drying can be carried out using any inert gas commonly used for spray drying, such as nitrogen.

[0097] SUPSATSOL may further contain the surfactant SURF.

[0098] SURF may be mixed with SUPSATSOL, or SURF may be mixed with SOLUTION1, MIXSOL2DISPPOL, SOL1, or SOL2 before the preparation of SUPSATSOL.

[0099] SURF can be natural surfactants such as fatty acids and alkyl sulfonates, sodium doxate (available from Mallinckrodt Spec. Chern., St. Louis, Mo.), and polyoxyethylene sorbitan fatty acid esters (Tween® available from ICI Americas Inc., Wilmington, Del., Liposorb® P-20 available from Lipochem Inc., Patterson, NJ, and Capmul® POE-0 available from Abitec Corp., Janesville, Wis.), for example, sodium taurocholate, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, other phospholipids, mono and diglycerides, vitamin E TPGS, PEO, PEO-PPO-PEO triblock copolymer (known by trade name Pluronics), and PEO (PEO is also called PEG, polyethylene glycol (PEG)).

[0100] The amount of SURF can be up to 10 wt%, where wt% is based on the weight of SDD.

[0101] SUPSATSOL may further contain pharmaceutically acceptable excipients such as fillers, disintegrants, pigments, binders, lubricants, and fragrances, which can be used for customary purposes and in typical amounts known to those skilled in the art.

[0102] The viscosity of SUPSATSOL may be at least twice, preferably at least three times, lower than the viscosity of a mixture of DISPPOL in SOL1 having the same concentration of DISPPOL as the concentration of DISPPOL in SUPSATSOL.

[0103] The viscosity of SUPSATSOL can be at least twice, preferably at least three times, lower than the viscosity of SOLUTION1.

[0104] After spray drying of SUPSATSOL, the SDD may undergo a second drying to reduce any residual SOL1 or SOL2 in the SDD. The second drying may be carried out using a tray dryer or any agitator dryer known to those skilled in the art for drying solids.

[0105] Preferably, the final SDD may have a SOL1 content of 5000 ppm or less, preferably 500 ppm or less, and more preferably 100 ppm or less.

[0106] Preferably, the final SDD may have a SOL2 content of 5000 ppm or less, preferably 500 ppm or less, and more preferably 100 ppm or less.

[0107] A further subject of the present invention is a spray-dried solid dispersion SDD, wherein the SDD is obtainable by the method SPRAYDRY. SDD and SPRAYDRY are spray-dried solid dispersion SDDs as defined herein, including all their embodiments. [Examples]

[0108] Materials and Abbreviations cP centipoise; centipoise is equal to the SI millipascal second (mPa·s). HPMCAS in the form of HPMCAS-MG AQOAT(registered trademark)MG (also called AS-MG) was purchased from Shin-Etsu Chemical Co.,Ltd. (Tokyo, Japan). The letter M specifies the grade and distinguishes the content of acetyl and succinoyl groups. Other grades are specified by the letters L (HPMCAS-L) and H (HPMCAS-H). The letter G represents a particle size with an average particle size of 1 mm, and the letter F instead of G represents a fine particle size with an average particle size of 5 micrometers. The various content and parameters of these grades are given in Table 3. [Table 1] (a) Viscosity of 2 w / w% sodium hydroxide aqueous solution at 20°C (b) The Tg of HPMCAS was determined by DSC experiment under the following test conditions. Equipment: DSC Q2000 (TA Instruments.Japan) Heating rate: 10℃ / min Please refer to the second heating operation. N2 gas atmosphere Sample size: 3 mg (c) wt% is based on HPMCAS weight

[0109] Nilotinib CAS641571-10-0, nilotinib, free base, >99% was purchased from LC Laboratories, Woburn, MA01801, USA. The term "nilotinib" refers to the free base form throughout the examples unless otherwise explicitly stated.

[0110] Nilotinib has a basic pK of 2.1. A , and the basic pK of 5.4 A The two basic pKs A It holds.

[0111] These basic pK A In each of these, half of the basic site is protonated. [ka]

[0112] PVP-VA64 Kollidon (Registered Trademark) VA64, Vinylpyrrolidone-Vinyl Acetate Copolymer, CAS 25086-89-9, PVP / VA Copolymer, BASF, Ludwigshafen, Germany

[0113] method Determining the solubility of nilotinib Saturated solutions of nilotinib were prepared with excess crystalline nilotinib at different temperatures in different solvents, allowing for stirring for 24 hours to obtain a suspension of nilotinib in a nilotinib-saturated solvent. The suspension was filtered through a 1-micrometer glass filter. Crystal solubility was determined by gravimetric analysis of the saturated solution filtrate.

[0114] Details and results are given in Table 1. [Table 2] (1) Solubility is given as follows • mg of nilotinib per 1 ml of saturated solution • wt% of nilotinib based on the weight of saturated solution

[0115] The wt% and mg / mL values ​​are not precisely consistent because they were measured separately. In case of doubt, the wt% value takes precedence.

[0116] Viscosity of polymer solution in solvent The viscosity of polymer solutions in solvent was measured by adding 400 g of solvent to a 500 mL jacketed container set to 20°C, stirring the polymer into the solvent until it reached a few-weight percentage of 0–20 wt%, and measuring the viscosity at each weight percentage using a Hydramotion ReactaVisc viscometer, Hydramotion Ltd., York, UK. The viscosity at 9 wt% of the polymer was interpolated based on the weight of the polymer solution in solvent.

[0117] Table 2 shows the interpolated viscosity [cP] of the polymer at 9 wt% in each solvent. [Table 3]

[0118] Example 1 - Nilotinib concentration enhancement in methanol: Acetic acid using solvent shift The solvent shift method was performed as follows. A 19.9 wt% nilotinib solution in glacial acetic acid was prepared at 40°C by dissolving 0.521 g of nilotinib in 2.10 g of acetic acid. 0.218 g of this solution was added to 1.80 g of methanol at 40°C to obtain a supersaturated solution of 2.15 wt% nilotinib in methanol:acetic acid at a ratio of 91.2:8.8 (w:w). The final supersaturated solution of nilotinib in SOLMIX using this solvent shift procedure remained visibly clear for at least 4 hours without any solid precipitation. Visible solids were observed for 7.5 hours.

[0119] As a control, a mixture of 2.06 wt% nilotinib in 89.5:10.5 (w:w) methanol:acetic acid was also prepared, and nilotinib was directly weighed into 89.5:10.5 (w:w) methanol:acetic acid at 40°C. The control mixture resulted in a visible slurry, i.e., a suspension of undissolved nilotinib, whereas the final supersaturated solution prepared via the solvent shift method remained visibly clear for up to 4 hours without any undissolved solids.

[0120] • SOL1: Glacial acetic acid ·SOL2: Methanol SOLMIX: A mixture of acetic acid and methanol, with approximately 9 wt% acetic acid by weight based on SOLMIX.

[0121] Example 2 - Nilotinib concentration enhancement in methanol: Acetic acid in the presence of HPMCAS-MG polymer using solvent shift The solvent shift method was performed as follows. A 19.9 wt% nilotinib solution in glacial acetic acid was prepared at 40°C by dissolving 0.521 g of nilotinib in 2.10 g of acetic acid.

[0122] A 6.77 wt% HPMCAS-MG solution in methanol was prepared at room temperature by dissolving 0.643 g of HPMCAS-MG in 8.86 g of methanol. This solution was then heated to 40°C.

[0123] A solution of 0.217 g of nilotinib in acetic acid at 40°C was added to a solution of 1.81 g of HPMCAS-MG in methanol at 40°C, resulting in a final supersaturated solution of 2.13 wt% nilotinib in methanol:acetic acid:HPMCAS-MG at 40°C in a ratio of 85.0:8.8:6.2 (w:w:w). The final supersaturated solution of nilotinib in SOLMIX remained visibly clear for at least 22 hours without any solid precipitate.

[0124] • SOL1: Glacial acetic acid ·SOL2: Methanol SOLMIX: A mixture of acetic acid and methanol, with approximately 9 wt% acetic acid by weight based on SOLMIX.

[0125] Example 3 - Nilotinib concentration enhancement in methanol: Acetic acid in the presence of PVP-VA64 polymer using solvent shift The solvent shift method was performed as follows. A 19.9 wt% nilotinib solution in glacial acetic acid was prepared at 40°C by dissolving 0.521 g of nilotinib in 2.10 g of acetic acid. A 6.58 wt% PVP-VA64 solution in methanol was prepared at room temperature by dissolving 0.651 g of polymer in 9.24 g of methanol, and then heated to 40°C.

[0126] A 0.223 g solution of nilotinib in acetic acid at 40°C was added to a 1.80 g solution of PVP-VA64 in methanol at 40°C, resulting in a final supersaturated solution of 2.19 wt% nilotinib in methanol:acetic acid:PVP-VA64 at 40°C in a ratio of 85.0:9.0:6.0 (w:w:w). The final supersaturated solution of nilotinib in SOLMIX remained visibly clear for at least 2 hours without any solid precipitate. Visible solids were observed for 4 hours.

[0127] • SOL1: Glacial acetic acid ·SOL2: Methanol SOLMIX: A mixture of acetic acid and methanol, with approximately 10 wt% acetic acid based on the weight of SOLMIX.

[0128] Example 4 - Nilotinib / HPMCAS SDD using solvent shift The solvent shift method was performed as follows. 7.5 g of HPMCAS-MG was mixed in 90 g of methanol at room temperature to obtain a 7.7 wt% solution.

[0129] 2.5 g of nilotinib was dissolved in 10 g of glacial acetic acid at 50°C, resulting in a 20 wt% solution.

[0130] A solution of nilotinib in glacial acetic acid at a temperature of 50°C was added in methanol while stirring for 2 minutes at room temperature, providing a final supersaturated solution of nilotinib in SOLMIX, SUPSATSOL, in methanol:acetic acid in a 9:1 (w:w) ratio. The final supersaturated solution had a nilotinib concentration of 2.27 wt% and an HPMCAS-MG concentration of 6.82 wt%. The supersaturated solution was continued to stir for about 10 minutes before spraying, and it contained no nilotinib in solid form; instead, it contained nilotinib in a completely dissolved state and had only one liquid phase.

[0131] For spraying, a supersaturated solution at room temperature was pumped at room temperature using a peristaltic pump into a laboratory-scale 0.3 m diameter stainless steel spray drying chamber. The flow rate of the supersaturated solution was 20 g / min, and spraying was performed through a two-fluid nozzle 1 / 4 J series with 1650 air caps and 54 liquid caps, manufactured by Spraying Systems Company, Glendale Heights, IL 60187-7901, United States. Heated nitrogen gas was introduced into the 0.3 m diameter stainless steel spray drying chamber at a temperature of 130°C and a flow rate of 500 g / min. The gas outlet temperature from the chamber was 45–48°C. Spray drying provided solid-state decomposition (SDD) collected using a cyclone to separate solid particles from the gas flow.

[0132] • SOL1: Glacial acetic acid ·SOL2: Methanol SOLMIX: A mixture of acetic acid and methanol, with approximately 10 wt% acetic acid based on the weight of SOLMIX.

[0133] The SDD was amorphous.

Claims

1. A method for preparing a spray-dried solid dispersion SDD comprising an activator AA and a dispersion polymer DISPPOL, The aforementioned method SPRAYDRY - To provide a solution SOLUTION 1 of AA in a first solvent SOL1, - Mixing SOLUTION 1 with the second solvent SOL2 to provide the solution SUPSATSOL, This includes spray-drying SUPSATSOL in a spray dryer, AA is a Brønsted base having at least one basic pKa of 5 or more, which is a drug, pharmaceutical, medicinal product, therapeutic agent, nutritional supplement, or active pharmaceutical ingredient, and has a solubility of 40 mg / ml or less in SOL2 at the temperature of SUPSATSOL when SUPSATSOL is supplied into the spray dryer. SUPSATSOL contains a solvent mixture SOLMIX and AA, where SOLMIX is a mixture of SOL1 and SOL2. SUPSATSOL is a supersaturated solution of AA in SOLMIX, SUPSATSOL does not contain AA in solid form. DISPPOL is contained in SOLUTION 1, SOL 2, or both before the mixing of SOLUTION 1 with SOL 2. SOL1 contains 90-100 wt% acetic acid, where wt% is based on the weight of SOL1. AA is stable in SOL1, SOL2, and SOLMIX. SOL2 is selected from methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, THF, methyl acetate, ethyl acetate, dichloromethane, 1,3-dioxolane, or a mixture thereof. Method SPRAYDRY.

2. The method according to claim 1, wherein DISPPOL is a pharmaceutically acceptable dispersion polymer.

3. DISPPOL contains hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, and hydroxypropyl The method according to claim 1 or 2, comprising cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co-ethyl acrylate), or any combination thereof.

4. The method according to any one of claims 1 to 3, wherein DISPPOL is HPMCAS or PVP-VA.

5. The method according to any one of claims 1 to 4, wherein SOL1 is acetic acid.

6. The method according to any one of claims 1 to 5, wherein SOL2 comprises methanol, ethanol, acetone, or a mixture thereof.

7. The method according to any one of claims 1 to 6, wherein the ratio of amounts of SOL1 to SOL2 (w:w) is 1:1 to 1:20 when SUPSATSOL is prepared by mixing SOLUTION1 with MIXSOL2DISPPOL or SOL2.

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