CN117396192A - Spray drying of API in supersaturated solutions comprising formic acid - Google Patents

Abstract

The present invention discloses a process for preparing a spray dried solid dispersion (SDD) comprising an Active Pharmaceutical Ingredient (API) and a dispersion polymer (DISPPOL), wherein spray drying is performed with a supersaturated solution of the API in a solvent mixture comprising two solvents, the supersaturated solution further comprising DISPPOL.

Description

Spray drying of API in supersaturated solutions comprising formic acid

The present invention discloses a process for preparing a spray dried solid dispersion (SDD) comprising an Active Pharmaceutical Ingredient (API) and a dispersion polymer (DISPPOL), wherein spray drying is performed with a supersaturated solution of the API in a solvent mixture comprising two solvents, one of which is formic acid, the supersaturated solution further comprising DISPPOL.

Background

Solid dispersions (SDDs) comprising an Active Pharmaceutical Ingredient (API) and a dispersion polymer (DISPPOL) are typically prepared by dissolving the dispersion polymer and API in a volatile solvent, such as methanol or acetone, or a mixture of solvents, followed by spray drying. In the case of APIs with limited solubility in the spray-drying solvent (e.g., <4wt% at room temperature), the API suspension may be heated to a temperature below or above the ambient pressure boiling point of the solvent, which is referred to as "thermal spray-drying process," resulting in a higher dissolution concentration of the API. In some cases, even higher temperatures do not result in sufficient API concentrations for economy as a spray drying process, or cause other problems such as chemical degradation of the API, or the possibility of incomplete dissolution of the API in the heat exchanger. Alternative, non-preferred volatile solvents can provide increased API solubility, but these solvents have other drawbacks that make them less desirable, such as high cost, toxicity, poor equipment compatibility, poor commercial availability, high processing costs, elimination of challenges to sufficiently low levels.

Spray drying of the suspension is generally avoided, as the suspension may cause clogging of the spray dryer nozzle. Furthermore, when the purpose of spray drying is to provide an Amorphous Solid Dispersion (ASD) of API in a dispersion polymer, this objective can be best achieved where both the API and the dispersion polymer are dissolved in a spray drying solvent such that neither is present in a solid form in the spray drying mixture; so that the desired intimate, homogeneous and amorphous mixture of ASD and dispersion polymer is best obtained.

WO 2019/220282 A1 discloses in example 1 spray drying of solutions of erlotinib and a dispersion polymer (PMMAMA or hypromellose acetate succinate H grade) in methanol to provide a spray dried dispersion.

US2020/0261449 A1 discloses spray drying of a mixture of nilotinib tartrate, HPMC-AS and tartaric acid in methanol.

US2019/0083629 A1 discloses spray drying of a mixture of vitamin Mo Feini or Itraconazolan (as API), BSA (as excipient), methanol and formic acid.

There is a need for a process for preparing spray-dried solid dispersions of API and dispersion polymers that allows dissolving the API in a readily processable spray-drying solvent at a sufficiently high concentration at moderate temperatures (i.e., temperatures below the ambient pressure boiling point) to achieve economic yields of SDD. The SDD should remain stable for a longer period of time.

A solvent shift route was discovered that involved dissolving an API in formic acid to a high concentration, thereby providing a solution of the API in formic acid having a relatively high viscosity, then diluting the API solution with a preferred spray drying solvent (e.g., methanol, ethanol or acetone) having a relatively low viscosity, and containing the desired dispersion polymer in a ratio such that a metastable supersaturated solution of the API is formed in the solvent mixture containing the dispersion polymer, and having a relatively low viscosity and being capable of being spray dried with high efficiency. A metastable supersaturated solution of API in a solvent mixture means that the API is present in the solvent mixture in a dissolved state, with no solid API present; in supersaturated solutions, the API is present at a concentration above the thermodynamic equilibrium concentration.

Such supersaturated solutions cannot be prepared by simply adding the API to the mixed solvent; it must be produced by mixing two solvents containing the dissolved API and dispersion polymer, respectively. One advantage is that by diluting a solution of API in formic acid with a preferred spray-drying solvent, the viscosity of the resulting metastable supersaturated solution can be chosen to be significantly lower than the viscosity of a solution of API in formic acid, meaning that the viscosity is within the viscosity range of a solution in a pure preferred spray-drying solvent. Another advantage of the solvent shift route is that it allows higher concentrations of dissolved API in the spray-dried solution relative to the thermodynamic maximum solubility of the API in the spray-dried solution, thereby providing higher spray-drying efficiency and higher yields for SDDs that make the API (especially for such APIs that have relatively low solubility in typical spray-dried solvents). Higher API and dispersion polymer concentrations in the spray-dried solution may also allow for enhanced spray-dried particle characteristics, e.g., larger particles provide advantages in dosage form manufacture or product recovery.

Abbreviations and definitions used in the present specification

AA active agent. As used herein, the term "active agent" refers to a component that exerts a desired physiological effect on a mammal (including, but not limited to, humans). Synonymous terms include "active ingredient", "active substance", "active ingredient", "active pharmaceutical ingredient" and "drug".

The amorphous form is substantially amorphous. Amorphous solids lack a definite crystal structure and a distinct and sharp melting point; instead, amorphous solids gradually melt over a range of temperatures.

API active pharmaceutical ingredient

Dispersion: a system in which the particles are distributed in the continuous phase of different compositions. A solid dispersion is a system in which at least one solid component is distributed in another solid component.

DISPPOL Dispersion Polymer

HPMCAS hydroxypropyl methylcellulose acetate succinate (Hydroxypropyl Methylcellulose Acetate Succinate/Hypromellose Acetate Succinate), CAS 71138-97-1

Mixture of MIXSOL2DISPPOL DISPPOL and second solvent SOL2

The pKa of the basic sites of pKa organic bronsted bases is the pH at which half of these basic sites are protonated. At a pH below the basic pKa, more than half of these basic sites are protonated, i.e., ionized. This pKa of the basic site is also known as basic pKa.

In contrast, the pKa of the acidic sites of organic bronsted acids is the pH at which half of these acidic sites are deprotonated, i.e. ionized. At a pH above the acidic pKa, more than half of these acidic sites are deprotonated. This pKa of the acidic site is also referred to as acidic pKa.

pKa values are available on the Internet, they can also be obtained, for example, by ADMETSoftware (solutions Plus, inc.; naswak: SLP) calculated or measured in the laboratory.

PPO polypropylene oxide

RT room temperature, for the purposes of the present invention, RT means a temperature from 20℃to 25 ℃

PXRD powder X-ray diffraction

SDD spray-dried solid dispersion

SOL1 first solvent

SOL2 second solvent

Solubility the solubility referred to herein in wt% means the weight of a substance dissolved per weight of solvent;

the solubility in mg/ml or mg/g herein means milligrams of a substance dissolved per milliliter or per milligram of solvent;

any solubility herein is determined at a given temperature (such as room temperature to 60 ℃, particularly the given temperature that substsol has when it is fed into a spray dryer);

if not explicitly stated otherwise.

Solubilization makes it soluble or increases solubility.

The solution is a homogeneous mixture of two or more substances. The solute (minor component) is dissolved in the solvent (major component). In contrast to suspensions, light passes through the solution without being scattered by solute particles.

SOLUTION of SOLUTION1 AA in first solvent SOL1 (optionally further comprising DISPPOL)

Supersaturated solution of the sustsol active agent AA in solvent mixture SOLMIX further comprising DISPPOL. SUPSASSOL is a spray solution that is sprayed to provide a spray dried solid dispersion SDD comprising active agent AA and dispersion polymer DISPPOL. As used herein, the term "spray solution," i.e., substsol, refers to a fluid formed by dissolving an active agent and a dispersion polymer in a solvent and an amount of ammonia. The term "dissolved" has a conventional meaning with respect to an active agent, indicating that the active agent has entered into solution when combined with a solvent and an amount of ammonia. The term "dissolution" may be used in a broader definition with respect to the dispersion polymer. For some dispersion polymers, the term "dissolved" may mean that the dispersion polymer has entered the solution and has dissolved in the conventional sense, or it may mean that the dispersion polymer is dispersed or highly swollen by the solvent such that it behaves as if it were "in solution", or it may mean that a portion of the dispersion polymer molecules are in solution and the remaining dispersion polymer molecules are dispersed or highly swollen by the solvent. Any suitable technique may be used to determine whether the active agent and dispersion polymer are dissolved. Examples include dynamic or static light scattering analysis, turbidity analysis, and visual observation.

SOLMIX solvent mixture of SOL1 and SOL2 obtained by mixing SOLUTION1 with MIXSOL2DISPPOL or SOL2

Vitamin E TPGS Tocopolase (INN), vitamin E D-alpha-tocopheryl polyethylene glycol succinate

wt% any wt% value herein is based on the weight of the solution or mixture, unless explicitly stated otherwise

Disclosure of Invention

The subject of the invention is a process SPRAYRY for preparing a spray-dried solid dispersion SDD comprising an active agent AA and a dispersion polymer DISPPOL;

the method SPRAYRY comprises the following steps:

providing a SOLUTION of AA in a first solvent SOL1,

mixing the SOLUTION1 with a second solvent SOL2 to provide a SOLUTION susattsol,

spray drying susatasol in a spray dryer;

wherein the method comprises the steps of

AA is a drug, medicament, pharmaceutical, therapeutic agent, nutraceutical or active pharmaceutical ingredient;

SUPSASSOL comprises solvent mixtures SOLMIX and AA, where SOLMIX is a mixture of SOL1 and SOL 2;

SUPSASSOL is a supersaturated solution of AA in SOLMIX;

SUPSASSOL does not contain AA in solid form;

prior to mixing the SOLUTION1 with SOL2, DISPPOL is included in SOLUTION1, SOL2, or both,

SOL1 comprises 90wt% to 100wt% formic acid, wherein wt% is by weight of SOL 1;

AA is stable in SOL1, SOL2 and SOLMIX.

Drawings

Fig. 1: shows a PXRD diffractogram of the amorphous nature of the SDD, which represents the nilotinib dispersion in HPMCAS-MG.

Fig. 2: viscosity of HPMCAS-M solution in various mixtures of formic acid and methanol.

Detailed Description

Supersaturation in the sense of the present invention means that the concentration of AA in the SOLMIX is higher than the concentration of AA in the saturated solution of SOLMIX at a given temperature (particularly at the temperature of substsol when it is fed into the spray dryer); the concentration of AA in SOLMIX is thus higher than the corresponding thermodynamic equilibrium concentration of AA in SOLMIX. SUPSASSOL is a metastable supersaturated solution of AA in SOLMIX. Metastable in the sense of the present invention means that AA does not precipitate out of the susatasol between its preparation and its spray drying.

Thus, AA is present in the substraffic in a fully dissolved state. The substsol does not contain AA in solid form.

The substsol has only one liquid phase.

AA. The amounts of SOLMIX and DISPPOL may be selected separately. Supersaturation of AA in subsol can also be expressed relative to AA solubility in SOLMIX; the concentration of AA dissolved in the susatasol may be at least 1.1 times, preferably at least 1.25 times, more preferably at least 1.5 times, even more preferably at least 1.75 times, especially at least 2 times, more especially at least 2.5 times, even more especially at least 3 times, especially at least 4 times, more especially at least 5 times, even in more particular cases even at least 10 times the concentration of AA in the saturated solution of AA in SOLMIX at a given temperature (especially at the temperature of the susatasol when the susatasol is fed into the spray dryer).

Possible amounts of AA in the sustsol may be from 0.5wt% to 10wt%, preferably from 1wt% to 7.5wt%, more preferably from 1wt% to 5wt%, wherein wt% is by weight of the sustsol.

When DISPPOL is included in SOL2 prior to mixing SOLUTION1 with SOL2, then the mixture of DISPPOL and SOL2 is referred to herein as MIXSOL2DISPPOL.

Thus, the first and second substrates are bonded together,

in one embodiment, SUPSATSOL is prepared by mixing SOLUTION1 (which is a SOLUTION of AA in SOL 1) with MIXSOL2 DISPPOL;

in another embodiment, SUPSATSOL is prepared by mixing SOLUTION1 (which is a SOLUTION of AA in SOL1 comprising DISPPOL) with SOL 2;

in yet another embodiment, SUPSATSOL is prepared by mixing SOLUTION1 (which is a SOLUTION of AA in SOL1 comprising DISPPOL) with MIXSOL2 DISPPOL;

preferably, the substsol is prepared by mixing SOLUTION1 (which is a SOLUTION of AA in SOL 1) with MIXSOL2DISPPOL.

Mixing the SOLUTION1 with MIXSOL2 DISPPOOL or with SOL2 to prepare SUPSATSOL may be performed by any means known to those skilled in the art for mixing liquids, such as by continuous mixing (e.g., by using an in-line mixer such as a T-blender) or by batch mixing (e.g., in a vessel).

In the case of continuous mixing, the mixing and spray drying of the susatasol may be performed continuously, i.e. there is no separation or retention of the susatasol between mixing and spray drying. Thus, the time between mixing and spray drying of the subsol can be very short, which can be as short as a few milliseconds to a few seconds; this may be advantageous if the metastability duration of the substsol is short.

The mixing of SOLUTION1 with MIXSOL2 DISPPOOL or SOL2 to prepare SUPSASSOL may be performed under the following conditions

Wherein the SOLUTION1 has a temperature from 4 ℃ to the boiling point of the SOLUTION1 at ambient pressure, preferably from 4 ℃ to a temperature below the boiling point of the SOLUTION1 at ambient pressure, in particular the given temperature of the SOLUTION as it is fed into the spray dryer, and

wherein MIXSOL2 DISPPOOL or SOL2 has a temperature from 4 ℃ to the boiling point of MIXSOL2 DISPPOOL at ambient pressure, preferably from 4 ℃ to a temperature below the boiling point of MIXSOL2 DISPPOOL at ambient pressure, in particular a given temperature of SUPSATSOL when SUPSATSOL is fed into the spray dryer;

preferably

Wherein the SOLUTION1 has a temperature of from 4 ℃ to 60 ℃, preferably from room temperature to 60 ℃, especially a given temperature of SUPSATSOL when it is fed into the spray dryer, and

wherein MIXSOL2 DISPPOOL or SOL2 has a temperature of from 4 ℃ to 60 ℃, preferably from room temperature to 60 ℃, especially the given temperature of SUPSATSOL when it is fed into the spray dryer.

SOLMIX is a solvent mixture of SOL1 and SOL2, which is obtained when SOLUTION1 is mixed with MIXSOL2DISPPOL or SOL2.

In one embodiment, the substsol consists of AA, DISPPOL, SOL1 and SOL2, with AA, DISPPOL, SOL and SOL2 being as defined herein, as are their embodiments.

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

In solid dispersions of AA in DISPPOL, AA may be uniformly and preferably also molecularly dispersed in DISPPOL. AA and DISPPOL can form solid solutions in SDD.

AA is amorphous or substantially amorphous in the SDD; by substantially is meant that at least 80wt%, preferably at least 90wt%, more preferably at least 95wt%, even more preferably at least 98wt%, especially at least 99wt% of the AA is amorphous; the wt% is based on the total weight of AA in the SDD. Thus, the SDD may be an amorphous SDD. When the SDD is analyzed by X-ray powder diffraction (PXRD), the amorphous nature of AA can be demonstrated by the lack of sharp bragg diffraction peaks in the X-ray pattern. Possible parameters and settings of the x-ray diffractometer are a device with a Cu-Kalpha source, set between 3 and 40 ° 2θ in a modified parallel beam geometry, scan rate of 2 °/min, step size of 0.0 °. Another evidence of the amorphous nature of AA in SDD may be a single glass transition temperature (Tg). The single Tg is also evidence of a homogeneous mixture of amorphous AA and polymer. Such samples without any further sample preparation may be used to determine Tg, which determination may be run, for example, in a 2.5 ℃/min scan rate, ±1.5 ℃/min modulation, and a modulation mode in the scan range of 0 ℃ to 180 ℃. The amorphous nature of AA shows a Tg equal to that of pure DISPPOL or between that of polymer and AA. The Tg of the SDD is generally similar to the weighted average of the Tg of the AA and the Tg of the DISPPOL. The SDD may be amorphous or substantially amorphous, and the SDD may also be referred to as an ASD.

The concentration of DISPPOL in the sustsol may be higher or lower, preferably lower than the saturation concentration of DISPPOL in the SOLMIX at a given temperature, in particular at the temperature of the sustsol when it is fed into the spray dryer.

In one embodiment, DISPPOL is present in the substsol in a dissolved state, the amounts of DISPPOL and SOLMIX being selected, respectively.

The amount of DISPPOL in the sustsol may be from 0.5wt% to 25wt%, preferably from 1wt% to 20wt%, more preferably from 2.5wt% to 15wt%, even more preferably from 5wt% to 10wt%, wherein wt% is by weight of the sustsol.

The amounts of DISPPOL and AA in the substsol are selected so as to provide a predetermined amount of DISPPOL and AA in the SDD.

The SDD may comprise from 1wt% to 99wt%, preferably from 10wt% to 95wt%, more preferably from 10wt% to 80wt%, even more preferably from 20wt% to 60wt% AA, the wt% being by weight of the SDD.

The SDD may comprise from 1wt% to 99wt%, preferably from 20wt% to 90wt%, more preferably from 40wt% to 80wt% of DISPPOL, the wt% being by weight of the SDD.

Preferably, the combined AA and DISPPOL content in the SDD is 65wt% to 100wt%, more preferably 67.5wt% to 100wt%, even more preferably 80wt% to 100wt%; in particular from 90 to 100% by weight; more particularly from 95wt% to 100wt%;

wt% is based on the weight of the SDD;

in one embodiment, the SDD consists of AA and DISPPOL.

The relative amounts of AA and DISPPOL in the SDD may be from 50:1 to 1:50, preferably from 25:1 to 1:25, more preferably from 10:1 to 1:10 (w/w).

AA may be any bioactive compound. The bioactive compound may need to be administered to a patient in need of the active agent.

AA may be a drug, medicament, pharmaceutical, therapeutic agent, nutraceutical, fertilizer, insecticide, herbicide, nutrient, or Active Pharmaceutical Ingredient (API); preferably an API.

AA may be a "small molecule," typically having a molecular weight of 2000 daltons or less.

AA may be at least 3 or greater, preferably 4 or greater, more preferablyAn alkaline pK of optionally 5 or more _A Is a Bronsted base. Preferably, when AA is a bronsted base, then AA in the free base form is combined with formic acid. AA may be present in the substsol in its free base form or in protonated form. When AA is combined in its free base form with formic acid in its free base form, then AA in its free base form is again obtained after spray drying, so sprayry is recovered and provided with AA in its free base form, thus obtaining substantially all AA and it is present in its free base form in the SDD.

AA may be nilotinib.

AA may be one or more active agents; the SDD may comprise one or more AA.

The DISPPOL may comprise one or more dispersion polymers, preferably 1,2, 3 or 4, more preferably 1,2 or 3, even more preferably 1 or 2 dispersion polymers.

The DISPPOL may be a pharmaceutically acceptable dispersion polymer.

Suitable DISPPOL include, but are not limited to: hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), cellulose Acetate Phthalate (CAP), carboxymethyl ethylcellulose (CMEC), polyvinylpyrrolidone (PVP), poly (vinylpyrrolidone-co-vinyl acetate) (PVP-VA), poly (methacrylic acid-co-methyl methacrylate) (PMMAMA), poly (methacrylic acid-co-ethyl acrylate), [ vinyl acetate, comprising 1-vinylhexahydro-2H-azaPolymers of-2-one and alpha-hydro-omega-hydroxy poly (oxy-1, 2-ethanediyl), grafted]Or any combination thereof.

Suitable PMMAMA polymers include, but are not limited to, poly (methacrylic acid-co-methyl methacrylate) 1:1 (e.g.(Eudragit) L100) and poly (methyl methacrylate-co-methyl methacrylate) 1:2 (e.g.)> S100)。/>Is a polymer product of the winning industry group (Evonik Industries AG,45128Essen,Germany) of Eisen (post code 45128) of Germany.

The poly (ethyl methacrylate-co-acrylate) may be poly (ethyl methacrylate-co-acrylate) 1:1.

[ vinyl acetate comprising 1-vinylhexahydro-2H-aza ]Polymers of-2-one and alpha-hydro-omega-hydroxy poly (oxy-1, 2-ethanediyl), grafted]Is a polymethacrylate and can be used as +.>Obtained from basf (ludwigiko, germany, postal code 67056).

In a preferred embodiment, the dispersion polymer is selected from HPMCAS, HPMC, PVP-VA, PVP, polymethacrylate, HPMCP, CMEC, CAP.

In another preferred embodiment, the dispersion polymer is selected from HPMCAS, HPMC, PVP-VA, PVP, polymethacrylate, HPMCP, CMEC, CAP, [ vinyl acetate, and 1-vinylhexahydro-2H-aza-containingPolymers of-2-one and alpha-hydro-omega-hydroxy poly (oxy-1, 2-ethanediyl), grafted]。

In another more preferred embodiment, the dispersion polymer is selected from HPMCAS, PVP-VA, polymethacrylate, HPMCP, CMEC, CAP.

In another preferred embodiment, the dispersion polymer is selected from HPMCAS, PVP-VA, polymethacrylate, HPMCP, CMEC, CAP, [ vinyl acetate, and containing 1-vinylhexahydro-2H-azaPolymers of-2-one and alpha-hydro-omega-hydroxy poly (oxy-1, 2-ethanediyl), grafted]。

In one embodiment, the dispersion polymer is PMMAMA, HPMCAS, HPMC, PVP-VA or PVP;

in another embodiment, the dispersion polymer is HPMC;

in another embodiment, the dispersion polymer is PMMAMA, HPMCAS, PVP-VA or PVP;

in another embodiment, the dispersion polymer is PMMAMA, HPMCAS or PVP-VA;

in another embodiment, the DISPPOL is HPMCAS or PVP-VA;

in another embodiment, the dispersion polymer is PVP-VA;

in another embodiment, the dispersion polymer is PVP;

in another embodiment, the dispersion polymer is HPMCAS.

Preferred embodiments of HPMCAS are

HPMCAS in which the acetyl content is from 5 to 9% by weight and the succinyl content is from 14 to 18% by weight,

HPMCAS wherein the acetyl content is from 7 to 11wt% and the succinyl content is from 10 to 14wt%, or

HPMCAS, wherein the acetyl content is from 10wt% to 14wt% and the succinyl content is from 4wt% to 8wt%;

more preferably

HPMCAS in which the acetyl content is from 5 to 7% by weight and the succinyl content is from 14 to 16% by weight,

HPMCAS wherein the acetyl content is from 7 to 9wt% and the succinyl content is from 10 to 12wt%, or

HPMCAS, wherein the acetyl content is from 11wt% to 13wt% and the succinyl content is from 5wt% to 7wt%;

wherein wt% is based on the weight of HPMCAS.

SOL1 has only one liquid phase.

SOL1 may comprise from 90wt% to 100wt%, preferably from 95wt% to 100wt%, more preferably from 97.5wt% to 100wt%, even more preferably from 98wt% to 100wt%, especially from 99wt% to 100wt% formic acid, wherein wt% is by weight of SOL1.

Preferably, SOL1 consists of formic acid. In the sense of the present invention, the term "consisting of formic acid" encompasses common technical grade formic acid which is commercially available, such as formic acid having a purity of 98%.

When SOL1 comprises less than 100wt% formic acid, then SOL1 may comprise additional solvents in addition to formic acid, such as 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 mixtures thereof;

more preferably, water.

The SOLUTION1 is prepared by dissolving AA in SOL1 and optionally adding any DISPPOL.

The SOLUTION1 may be prepared by the following method: AA is dissolved in SOL1 at a temperature of 4 ℃ to the boiling point of SOL1 at ambient pressure, preferably 4 ℃ to a temperature below the boiling point of SOL1 at ambient pressure, more preferably at a temperature from room temperature to 60 ℃, especially at the given temperature of substsol when it is fed into the spray dryer, and optionally any DISPPOL is added.

AA in the SOLUTION1 is in a dissolved state in the SOLUTION1, and the amounts of AA and SOL1 are selected, respectively.

The concentration of AA in SOLUTION1 is lower than the saturation concentration of AA in SOL1 at a given temperature (particularly at the temperature of SOLUTION1 when SOLUTION1 is mixed with MIXSOL2 disppoint or with SOL2 to provide SUPSASSOL, respectively).

In one embodiment, DISPPOL is present in dissolved state in SOLUTION1, and the amount of DISPPOL is selected separately.

The concentration of DISPPOL in SOLUTION1 is preferably lower than the saturation concentration of DISPPOL in SOL1 at a given temperature (especially at the temperature of SOLUTION1 when SOLUTION1 is mixed with MIXSOL2DISPPOL or with SOL2 to provide substsol, respectively).

Typical solubility of AA in SOL1 may be at least 1wt%, preferably at least 2wt%, more preferably at least 5wt%, even more preferably at least 10wt%, especially at least 20wt% AA; wherein wt% is by weight of SOLUTION 1; the solubility of AA in SOL1 is preferably at the following given temperature: at a temperature from 4 ℃ to the boiling point of SOL1 at ambient pressure, preferably from 4 ℃ to a temperature below the boiling point of SOL1 at ambient pressure, more preferably from room temperature to 60 ℃, especially at the given temperature that susattol has when it is fed to the spray dryer. SOL1 may be selected separately.

The lower limit of the amount of AA in the SOLUTION1 may be at least 0.5wt%, preferably at least 1wt%, more preferably at least 2.5wt%, even more preferably at least 5wt%, especially at least 7.5wt%, more especially at least 10wt%, even more especially at least 20wt%, especially at least 30wt%, wherein the wt% is based on the weight of the SOLUTION 1.

The amount of AA in the SOLUTION1 may be up to 50wt%, preferably up to 40wt%, even more preferably up to 35wt%, where wt% is based on the weight of the SOLUTION 1.

Any lower limit on the amount of AA in the SOLUTION1 may be combined with any upper limit on the amount of AA in the SOLUTION 1.

For example, the amount of AA in SOLUTION1 may be from 0.5wt% to 50wt%, preferably from 0.5wt% to 40wt%, more preferably from 0.5wt% to 35wt%, where wt% is by weight of SOLUTION 1.

SOL2 has only one liquid phase.

SOL2 is a solvent commonly used in spray drying.

SOL2 may comprise methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, THF, methyl acetate, ethyl acetate, methylene chloride, 1, 3-dioxolane, or mixtures thereof.

SOL2 may contain water in an amount selected so that SOL2 remains in only one liquid phase. The solubility of water in possible nonaqueous solvents for SOL2 is known. Depending on the possible non-aqueous solvents of SOL2, SOL2 may comprise 30wt% or less, preferably 27.5wt% or less, more preferably 25wt% or less, even more preferably 22.5wt% or less, especially 20wt% or less, more especially 15wt% or less, even more especially 10wt% or less, especially 5wt% or less, of water, the wt% being based on the weight of SOL 2;

in one embodiment, SOL2 consists of methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, THF, methyl acetate, ethyl acetate, dichloromethane, 1, 3-dioxolane, water, or mixtures thereof;

preferably, SOL2 comprises methanol, ethanol, acetone or mixtures thereof, optionally further comprising water, preferably wherein SOL2 comprises from 0wt% to 25wt% water, the wt% being based on the weight of SOL 2;

more preferably, SOL2 consists of methanol, acetone, water or mixtures thereof, preferably wherein SOL2 comprises 0wt% to 25wt% water, the wt% being based on the weight of SOL 2;

even more preferably, SOL2 consists of methanol or a mixture of methanol and water, preferably wherein SOL2 comprises 0wt% to 25wt% water, the wt% being based on the weight of SOL2.

When the dispersion polymer is HPMC, preferably SOL2 comprises water; wherein the amount of water and all embodiments thereof as described herein, for example, is from 10wt% to 30wt%, or 15wt% to 30wt%, or 20wt% to 30wt%; the wt% is based on the weight of SOL2.

Preferably, AA has a low solubility in SOL2 (such as in methanol, ethanol, acetone, especially in methanol) at a given temperature (such as room temperature to 60 ℃, especially a given temperature that sustsol has when it is fed into a spray dryer), e.g. has a solubility in SOL2 of, e.g., 40mg/ml or less, or less than 30mg/ml, or less than 20mg/l, or less than 15mg/ml, or less than 10mg/ml, or less than 7.5mg/ml, or less than 5mg/ml, or less than 4mg/ml, or less than 3mg/ml, or less than 2mg/ml, or less than 1mg/ml, or less than 0.5mg/ml, or less than 0.25 mg/ml.

MIXSOL2DISPPOL is prepared by mixing DISPPOL with SOL2.

MIXSOL2DISPPOL can be prepared by the following method: the DISPPOL is mixed with SOL 2at a temperature of 4 ℃ to the boiling point of SOL 2at ambient pressure, preferably from 4 ℃ to a temperature below the boiling point of SOL 2at ambient pressure, more preferably from room temperature to 60 ℃, especially at the given temperature of substsol when it is fed into the spray dryer.

In one embodiment, DISPPOL is present in the MIXSOL2DISPPOL in a dissolved state, the amount of DISPPOL being selected separately.

The concentration of DISPPOL in MIXSOL2DISPPOL is preferably lower than the saturation concentration of DISPPOL in SOL 2at a given temperature, respectively, in particular at the temperature of MIXSOL2DISPPOL when MIXSOL2DISPPOL is mixed with SOLUTION1 to provide SUPSASSOL.

SOL2 may have a boiling point of 115 ℃ or less at ambient pressure.

The amount of DISPPOL in MIXSOL2DISPPOL or in SOLUTION1 may be from 0.5 to 20wt%, preferably from 1 to 20wt%, more preferably from 2.5 to 15wt%, even more preferably from 5 to 10wt%, wherein wt% is based on the weight of MIXSOL2DISPPOL or SOLUTION1, respectively.

The solubility of AA in SOL1 may be at least 5 times, preferably at least 10 times, more preferably at least 50 times, even more preferably at least 100 times the solubility of AA in SOL 2at a given temperature (especially at the temperature of the SOLUTION1 when mixed with MIXSOL2DISPPOL or with SOL2 to provide substsol); SOL1 and SOL2 may be selected separately.

When SUPSASSOL is prepared by mixing SOLUTION1 with MIXSOL2DISPPOL or with SOL2, the ratio of the amount of SOL1 to SOL2 (w: w) may be from 1:1 to 1:20, preferably from 1:2 to 1:20, more preferably from 1:5 to 1:20, even more preferably from 1:8 to 1:20, especially from 1:8 to 1:16, more especially from 1:8 to 1:15, in one particular embodiment from 1:8 to 1:10, in another particular embodiment from 1:13 to 1:15.

The lower limit of the amount of SOL1 in the SOLMIX may be 5wt%, preferably 6wt%, more preferably 7.5wt%, the wt% being based on the weight of the SOLMIX.

The upper limit of the amount of SOL1 in the SOLMIX may be 50wt%, preferably 33wt%, more preferably 25wt%, even more preferably 20wt%, especially 15wt%, more especially 10wt%, the wt% being based on the weight of the SOLMIX.

For the range of the amount of SOL1 in the SOLMIX, any lower limit may be combined with any upper limit, e.g. the amount of SOL1 in the SOLMIX may be 5wt% to 50wt%, preferably 5wt% to 33wt%, more preferably 5wt% to 25wt%, even more preferably 5wt% to 20wt%, especially 5wt% to 15wt%, more especially 5wt% to 10wt%, the wt% being based on the weight of the SOLMIX.

The susattsol may be fed into the spray dryer at a given temperature of the susattsol up to the boiling point of the susattsol at ambient pressure; preferably at a given temperature of 4 ℃ to the boiling point of substsol at ambient pressure, preferably from 4 ℃ to a temperature below the boiling point of substsol at ambient pressure, more preferably from room temperature to 60 ℃. In the context of the present invention, the term "sustsol may be fed into the spray dryer at a temperature of sustsol" means "spray drying of sustsol at a temperature of sustsol".

Spray drying of susatasol in a spray dryer evaporates both SOL1 and SOL2.

For use in

A temperature at which SOLUTION1 is prepared,

Temperature for preparing MIXSOL2DISPPOL,

Temperature for preparing SUPSASSOL

Temperature for feeding SUPSASSOL into a spray dryer

Which may be the same or different, and which may be a given temperature from room temperature to 60 ℃;

preferably for

The temperature at which the SOLUTION1 is prepared may be from room temperature to 60 c,

the temperature used to prepare MIXSOL2DISPPOL may be room temperature,

the temperature for preparing SUPSATSOL may be from room temperature to 60deg.C, and

the temperature for feeding the susatasol into the spray dryer may be from room temperature to 60 ℃.

Spray drying may be performed at an inlet temperature of from 60 ℃ to 165 ℃, preferably from 80 ℃ to 165 ℃, more preferably from 80 ℃ to 140 ℃.

The spray drying may be performed at an outlet temperature equal to or lower than the boiling point of the solvent with the highest boiling point in the SOLMIX (such as at an outlet temperature from 20 ℃ to 10 ℃ lower than the boiling point of the solvent with the highest boiling point in the SOLMIX).

The spray drying may be carried out with any inert gas commonly used for spray drying, such as nitrogen.

In one embodiment, the susattsol does not contain Bovine Serum Albumin (BSA).

The SUPSASSOL may further comprise the surfactant SURF.

SURF may be mixed with SUPSASSOL, or SURF may be mixed with SOLUTION1, with MIXSOL2DISPPOL, with SOL1 or with SOL2 prior to preparing SUPSASSOL.

SURF may be, for example, fatty acids and alkyl sulfonates; docusate sodium (available from the company of specialty chemicals, velopmental, holy lewis, missouce, mallinckrodt Spec.Chern., st.Louis, mo.), and polyoxyethylene sorbitan fatty acid esters @ICI Americas Inc (ICI Americas Inc, wilmington, del.) available from Wilmington, telangiectasia, usa; />P-20, available from Lipochem Inc. (Patterson, N.J.); and +.>POE-0, available from Jian Siwei mol, wisconsin, USAAbitec Corp., janesville, wis.); and natural surfactants such as sodium taurocholate, 1-palmitoyl-2-oleoyl-tin-glycero-3-phosphorylcholine, lecithin, other phospholipids and monoglycerides and diglycerides, vitamin E TPGS, PEO-PPO-PEO triblock copolymers (known under the trade name pramipexole (pluronics)), and PEO (PEO also known as PEG, polyethylene glycol (PEG)).

The amount of SURF may be up to 10wt%, wt% based on the weight of the SDD.

The sustsol may further comprise pharmaceutically acceptable excipients such as fillers, disintegrants, pigments, binders, lubricants, flavoring agents, which may be used for conventional purposes and in typical amounts known to those skilled in the art.

The viscosity of the sustsol may be at least 2 times, preferably at least 3 times lower than the viscosity of a mixture of DISPPOL in SOL1 having the same concentration of DISPPOL as in sustsol.

The viscosity of the subsol may be at least 2 times, preferably at least 3 times lower than the viscosity of the SOLUTION 1.

After spray drying the susatasol, the SDD may be subjected to a second drying in order to reduce the amount of any residual SOL1 or SOL2 in the SDD. The secondary drying may be carried out using a tray dryer or any agitated dryer known to those skilled in the art for drying solids.

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

Preferably, the final SDD can have a SOL2 content of 5000ppm or less, preferably 500ppm or less, more preferably 100ppm or less.

Another subject of the invention is a spray-dried solid dispersion SDD, wherein the SDD is obtainable by a spray-drying (SPRAYRY) process;

SDD and spray drying (sprayry) are as defined herein, as are all their examples.

Examples

Materials and abbreviations

cP centipoise, centipoise equal to SI millipascal seconds (mPa.s)

Formic acid 98%, merck-Merck company (EMD Millipore Corporation), merck group (Merck KGaA) subsidiaries, damshitata, germany

HPMCAS-MG presentationHPMCAS in the form of MG (also referred to AS AS-MG) is available from Shin-Etsu Chemical Co., ltd.) (Tokyo, japan). Letter M designates the scale and distinguishes between acetyl and succinyl groups content. The other grades are designated by letters L (HPMCAS-L) and H (HPMCAS-H). Letter G represents a particle size grade having an average particle size of 1mm, and when letter F is substituted for G, it will represent a micronization grade having an average particle size of 5 microns. The various levels and parameters of these grades are shown in table 3. />

(a) Viscosity of 2w/w% solution in aqueous sodium hydroxide solution at 20 ℃C

(b) Tg of HPMCAS was determined by DSC experiments under the following test conditions:

the device comprises: DSC Q2000 (TA Instruments, japan)

Heating rate: 10 ℃/min

With reference to a second heating run

N ₂ Atmosphere of

Sample size 3mg

(c) Wt% by weight of HPMCAS

NA not available

Nilotinib CAS 641571-10-0; MW 529.5g/mol, nilotinib, free base, >99%, available from LC Laboratories, inc. of Wobbe (post code 01801) of Massachusetts, U.S.A. The term "nilotinib" refers to the free base form throughout the examples, unless explicitly stated otherwise.

Nilotinib has two basic pks _A : basic pK _A 2.1 and basic pK _A 5.4 (according to https:// go. Drug bank. Com/drugs/DB04868, the strongest basic pKa is 5.92).

At these basic pKs _A Half of the corresponding basic sites are protonated.

PVP-VA64 VA64, vinylpyrrolidone-vinyl acetate copolymer, CAS25086-89-9, PVP/VA copolymer, basoff (Lede Vischolar, germany)

Method

Viscosity of a solution of a polymer in a solvent

Table 2 shows the viscosity of a 7.4wt% solution of HPMCAS-M in a mixture of formic acid and methanol. The amount of formic acid to MeOH exceeding about 50:50w:w shows a non-linear increase in viscosity.

Fig. 2 graphically shows the data in table 2, i.e., viscosity of HPMCAS-M solutions in various mixtures of formic acid and methanol.

Example 1: SDD-25:75 nilotinib: HPMCAS-MG using formic acid with methanol for solvent conversion

4.0g of formic acid was weighed into flask 1 as SOL1, and 36.0g of methanol was weighed into flask 2 as SOL2. 1.0055g of nilotinib free base was added to flask 1 containing formic acid and stirred with a magnetic stirring bar (20 ℃ C.) to give a 20wt% solution. 3.0040g of HPMCAS-MG was added to flask 2 containing methanol and stirred in the same manner as flask 1 to give a 7.7wt% solution. Once the two solutions were completely dissolved, the contents of flask 1 were slowly poured into flask 2 while stirring to provide a supersaturated solution of nilotinib in SOLMIX (which is 9:1 (w: w) methanol: formic acid) sustsol. The supersaturated solution had a nilotinib concentration of 2.28wt% in SOLMIX and an HPMCAS-MG concentration of 6.83wt%.

The supersaturated solution, which does not contain nilotinib in solid form but rather contains nilotinib in a fully dissolved state and which has only one liquid phase, is stirred for 6 minutes prior to spray drying.

The supersaturated solution at a temperature of 20 ℃ was spray dried using a custom spray dryer. The supersaturated solution was pumped using peristaltic pumps into a laboratory scale 0.3m diameter stainless steel spray drying chamber to feed the solution to the nozzle at a flow rate of 15 g/min. A two-fluid nozzle 1/4J series with 1650 liquid body and 64 air cap was manufactured by spray systems company (Spraying Systems Company) of Greenland, ill., (post code 6087-7901) Grandel. The solution was atomized using nitrogen as the sheath gas at a pressure of 20 psi. The granules were dried using heated nitrogen (inlet 115 ℃, outlet 45 ℃ to 50 ℃,500 g/min). The resulting SDD was collected using a cyclone separator to separate solids from the gas stream.

The collected SDD was placed in a vacuum tray dryer at 40℃and twice dried at a pressure of 0.2atm with a nitrogen purge of 3.5slpm (standard liters per minute) for 24 hours.

Fig. 1 shows PXRD of the collected SDD, which represents nilotinib dispersion in HPMCAS-MG, and which confirms the amorphous nature of the SDD.

Comparative example A

A mixture having the same composition as in example 1 was prepared without using a solvent shift method. In a 20ml glass bottle containing a magnetic stir bar, 0.100g of nilotinib free base was combined with 0.301g of HPMCAS-MG. To this mixture was added 3.99g of premixed 9:1 methanol: formic acid. The mixture was stirred at 25℃for 24h. The sample did not dissolve but was still heterogeneous with a large amount of solids present. The composition (in wt%) of the mixture was: 2.28% nilotinib, 6.83% HPMCAS, and the remainder solvent.

Claims (8)

1. A process sprayry for preparing a spray-dried solid dispersion SDD comprising an active agent AA and a dispersion polymer DISPPOL;

the method SPRAYRY comprises the following steps:

providing a SOLUTION of AA in a first solvent SOL1,

mixing the SOLUTION1 with a second solvent SOL2 to provide a SOLUTION susattsol,

spray drying susatasol in a spray dryer;

wherein the method comprises the steps of

AA is a drug, medicament, pharmaceutical, therapeutic agent, nutraceutical or active pharmaceutical ingredient;

SUPSASSOL comprises solvent mixtures SOLMIX and AA, where SOLMIX is a mixture of SOL1 and SOL 2;

SUPSASSOL is a supersaturated solution of AA in SOLMIX;

SUPSASSOL does not contain AA in solid form;

prior to mixing the SOLUTION1 with SOL2, DISPPOL is included in SOLUTION1, SOL2, or both,

SOL1 comprises from 90wt% to 100wt% formic acid, wherein the wt% is by weight of SOL 1;

AA is stable in SOL1, SOL2 and SOLMIX.

2. The method of claim 1, wherein

DISPPOL is a pharmaceutically acceptable dispersion polymer.

3. The method according to claim 1 or 2, wherein

The DISPPOL includes hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate phthalate, carboxymethyl ethylcellulose, polyvinylpyrrolidone, poly (vinylpyrrolidone-co-vinyl acetate), poly (methacrylic acid-co-methyl methacrylate), poly (methacrylic acid-co-ethyl acrylate), or any combination thereof.

4. A method according to one or more of claims 1 to 3, wherein

DISPPOL is HPMCAS or PVP-VA.

5. The method according to one or more of claims 1 to 4, wherein

SOL1 consists of formic acid.

6. The method according to one or more of claims 1 to 5, wherein

SOL2 comprises methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, THF, methyl acetate, ethyl acetate, methylene chloride, 1, 3-dioxolane, or mixtures thereof.

7. The method according to one or more of claims 1 to 6, wherein

SOL2 comprises methanol, ethanol, acetone, or mixtures thereof.

8. The method according to one or more of claims 1 to 7, wherein

When SUPSASSOL is prepared by mixing SOLUTION1 with MIXSOL2DISPPOL or with SOL2, the ratio of the amount of SOL1 to SOL2 (w: w) is 1:1 to 1:20.