HK40099700A - Mixed solvents for spray drying for preparation of amorphous solid dispersions - Google Patents

Description

Mixed solvent for spray drying of amorphous solid dispersions

This invention discloses a method for preparing a spray-dried amorphous solid dispersion comprising an active agent (such as an active pharmaceutical ingredient API) and a dispersion polymer, wherein the spray drying is carried out with a solution of the active agent and the dispersion polymer in a solvent comprising a mixture of _C1-2 alkanols and _C1-2 carboxylic acids and _C1-2 alkyl esters, and optionally water.

Background Technology

Spray-dried amorphous solid dispersions containing an active pharmaceutical ingredient (API) and a dispersion polymer are typically prepared by dissolving the dispersion polymer and API in a volatile solvent (such as methanol or acetone) and then spray-drying. When the API has limited solubility in the spray-drying solvent (approximately <4 wt% at room temperature), the API suspension can be heated to a temperature below or above the ambient pressure boiling point of the solvent; this is known as "thermal spray drying," and higher concentrations of API can be obtained. In some cases, even higher temperatures may not yield sufficient API concentrations economically viable for spray drying, or may introduce other problems such as chemical degradation of the API, or the risk of incomplete dissolution of the API in a heat exchanger. Alternatively, less preferred volatile solvents may provide increased API solubility, but these solvents have other disadvantages that make them less desirable, such as high cost, toxicity, poor equipment compatibility, poor commercial availability, high processing costs, challenges in eliminating to sufficiently low levels, and higher viscosity.

WO 2019/220282 A1 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.

A method is needed for preparing spray-dried solid dispersions of surfactants and dispersion polymers, which allows for the dissolution of APIs in readily processable spray-drying solvents at sufficiently high concentrations at moderate temperatures (i.e., below the boiling point at ambient pressure) to achieve economical yields of spray-dried amorphous solid dispersions. The amorphous solid dispersions should remain stable over a relatively long period.

A mixture of _C1-2 alkanols and _C1-2 carboxylic acid _C1-2 alkyl esters was found to exhibit synergistic (also known as nonlinear) solubility behavior; that is, the mixture provides higher solubility than the expected solubility of the individual solvents at their respective weight averages, obtained by linear extrapolation from the solubility of the pure solvents, and can be used as a mixed solvent in such spray drying methods. This synergistic behavior was unexpected. Furthermore, while both _C1-2 alkanols and _C1-2 carboxylic acid _C1-2 alkyl esters are considered poor solvents compared to solvents such as dichloromethane (DCM), tetrahydrofuran (THF), and N-methyl-2-pyrrolidone (NMP), both are considered highly suitable for spray drying. Therefore, when these two solvents are used as a mixture, the synergistic increase in solubility allows for a higher concentration of surfactant in the spray solution. The increased surfactant solubility yields higher manufacturing yields and potentially better particle characteristics for spray drying compared to the manufacturing yields and particle characteristics achievable with spray solutions containing lower solids content.

Another advantage is that both solvents are miscible with water to provide ternary mixtures, and this aqueous ternary mixture of the two solvents and water still provides a synergistic increase in solubility, thus also allowing the use of dispersion polymers such as HPMC (which typically require the presence of some water to dissolve in organic solvents). The synergistic behavior of the ternary mixture is also unexpected, as water alone is generally considered a worse solvent than any _C1-2 alcohol and _C1-2 carboxylic acid _C1-2 alkyl ester.

Abbreviations and definitions used in this specification

As used herein, the term "active agent" refers to a component that exerts a desired physiological effect on mammals, including but not limited to humans. Synonyms include "active ingredient," "active substance," "active component," "active pharmaceutical ingredient," and "drug."

Amorphous solids are essentially non-crystalline. They lack a defined crystal structure and a defined melting point; instead, they gradually melt within a certain temperature range.

API active pharmaceutical ingredients

ASD Amorphous Solid Dispersions

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

eq equivalent

HPMCAS: Hydroxypropyl methylcellulose acetate succinate, CAS 71138-97-1

PVPVA vinylpyrrolidone-vinyl acetate copolymer

PXRD (Powder X-ray Diffraction)

RH (Relative Humidity)

RT refers to room temperature, which for the purposes of this invention is 20°C to 25°C.

Solubility: The solubility mentioned in this article, expressed in wt%, refers to the weight of the substance dissolved in a unit weight of solvent.

Solubility expressed in mg/ml or mg/g in this article refers to the number of milligrams of substance dissolved per milliliter or per milligram of solvent;

All solubility values described herein were determined at room temperature (typically 25°C) as defined herein;

Unless otherwise explicitly stated.

Dissolve; make soluble or increase solubility.

A solution is a homogeneous mixture of two or more substances. The solute (minor component) is dissolved in the solvent (major component). Unlike a suspension, light is not scattered by solute particles when it passes through a solution.

As used herein, the term "spray solution" refers to a fluid formed by dissolving an surfactant and a dispersion polymer in a solvent and a certain amount of ammonia. In the case of surfactants, the term "dissolved" has a conventional meaning, indicating that the surfactant has entered the solution when mixed with the solvent and a certain amount of ammonia. With regard to dispersion polymers, the term "dissolved" can be given a broader definition. For some dispersion polymers, the term "dissolved" can mean that the dispersion polymer has entered the solution and is dissolved in the conventional sense, or it can mean that the dispersion polymer is dispersed by the solvent or highly swollen, making it appear as if it is "in solution," or it can mean that a portion of the dispersion polymer molecules are in solution and the remaining dispersion polymer molecules are dispersed by the solvent or highly swollen. Any suitable technique can be used to determine whether the surfactant and dispersion polymer are dissolved. Examples include dynamic or static light scattering analysis, turbidity analysis, and visual observation.

wt% (weight%)

Summary of the Invention

The subject of this invention is a method for preparing an amorphous solid dispersion by spray drying a spray solution containing...

a) A mixed solvent containing

i. Solvent 1, which is selected from the group consisting of: methyl acetate, methyl formate, ethyl acetate, ethyl formate and mixtures thereof;

ii. Solvent 2, which is selected from the group consisting of: methanol, ethanol and mixtures thereof;

The ratio (w:w) of solvent 1 to solvent 2 is 10:90 to 90:10;

b) Surfactants;

c) Dispersion polymers.

Attached Figure Description

Figure 1: Graphical representation of the data in Table 1: Solubility of sulfasalazine in MeOAc/MeOH (in wt%), i.e., saturation concentration.

Figure 2: Graphical representation of the data in Table 1: Solubility of sulfasalazine in MeOAc/MeOH (in mg/ml), i.e., saturation concentration.

Figure 3: Graphical representation of the data in Table 2: Solubility of sulfasalazine in EtOAc/EtOH (in wt%), i.e., saturation concentration.

Figure 4: Graphical representation of the data in Table 2: Solubility of sulfasalazine in EtOAc/EtOH (in mg/ml), i.e., saturation concentration.

Figure 5: Graphical representation of the data in Table 3: solubility of nilotinib in MeOAc/MeOH (in wt%), i.e., saturation concentration.

Figure 6: Graphical representation of the data in Table 3: solubility of nilotinib in MeOAc/MeOH (in mg/ml), i.e., saturation concentration.

Figure 7: Graphical representation of the data in Table 4: solubility of nilotinib in EtOAc/EtOH (in wt%), i.e., saturation concentration.

Figure 8: Graphical representation of the data in Table 4: solubility of nilotinib in EtOAc/EtOH (in mg/ml), i.e., saturation concentration.

Figure 9: Graphical representation of the data in Table 5: solubility of gefitinib in MeOAc/MeOH (in wt%), i.e., saturation concentration.

Figure 10: Graphical representation of the data in Table 5: solubility of gefitinib in MeOAc/MeOH (in mg/ml), i.e., saturation concentration.

Figure 11: Graphical representation of the data in Table 6: solubility of gefitinib in EtOAc/EtOH (in wt%), i.e., saturation concentration.

Figure 12: Graphical representation of the data in Table 6: solubility of gefitinib in EtOAc/EtOH (in mg/ml), i.e., saturation concentration.

Figure 13: Graphical representation of the data in Table 7: solubility of gefitinib in MeOAc/EtOH (in wt%), i.e., saturation concentration.

Figure 14: Graphical representation of the data in Table 7: solubility of gefitinib in MeOAc/EtOH (in mg/ml), i.e., saturation concentration.

Figure 15: Graphical representation of the data in Table 8: solubility of gefitinib in EtOAc/MeOH (in wt%), i.e., saturation concentration.

Figure 16: Graphical representation of the data in Table 8: solubility of gefitinib in EtOAc/MeOH (in mg/ml), i.e., saturation concentration.

Figure 17: Graphical representation of the data in Table 9: solubility of gefitinib in ethyl formate/MeOH (in wt%), i.e., saturation concentration.

Figure 18: Graphical representation of the data in Table 9: solubility of gefitinib in ethyl formate/MeOH (in mg/ml), i.e., saturation concentration.

Figure 19: Overlay of Figures 1 and 3.

Figure 20: Overlay of Figures 2 and 4.

Figure 21: Overlay of Figures 5 and 7.

Figure 22: Overlay of Figures 6 and 8.

Figure 23: Overlay of Figures 9, 11, 13 and 15.

Figure 24: Overlay of Figures 10, 12, 14 and 16.

Figure 25: PXRD of ASD prepared according to Example 7.

Figure 26: PXRD of ASD prepared according to Example 8.

Figure 27: PXRD of ASD prepared according to Example 9.

Figure 28: PXRD of ASD prepared according to Example 10.

Figure 29: Graphical representation of the data in Table 10: solubility of gefitinib in MeOAc/MeOH containing 20% water (in wt%), i.e., saturation concentration.

Figure 30: Graphical representation of the data in Table 10: solubility of gefitinib in MeOAc/MeOH containing 20% water (in mg/ml), i.e., saturation concentration.

Figure 31: Solubility of sulfasalazine in EtOAc/MeOH and MeOAc/MeOH mixtures (in wt%), i.e., saturation concentration.

Figure 32: Solubility of nilotinib in EtOAc/MeOH and MeOAc/MeOH mixtures (in wt%), i.e., saturation concentration.

Detailed Implementation

The surfactant solution in the spray solution is a stable solution.

The spray solution has no more than one liquid phase.

The liquid in the spray solution may also contain additional solvents besides the mixed solvent.

The amount of mixed solvent in the liquid of the spray solution can be at least 50 wt%, preferably at least 60 wt%, more preferably at least 70 wt%, even more preferably 80 wt%, especially at least 90 wt%, and even more particularly at least 95 wt%; wherein wt% is based on the weight of the liquid in the spray solution;

In one embodiment, the liquid in the spray solution consists of a mixed solvent.

The active agent is a biologically active compound. Biologically active compounds may need to be administered to patients who require the active agent.

Bioactive compounds can be drugs, pharmaceuticals, medicines, therapeutic agents, nutrients, agrochemicals, fertilizers, pesticides, herbicides, nutrients, or active pharmaceutical ingredients (APIs); preferably, they are APIs.

The surfactant can be one or more surfactants; the spray-dried amorphous solid dispersion may contain one or more surfactants.

Preferably, the active agent has low solubility in solvent 1 and solvent 2 (such as in methanol or methyl acetate, especially in methanol), for example, less than 3 wt%, or even less than 2 wt%, or even less than 1 wt%, or even less than 0.5 wt%, or even less than 0.25 wt%.

Preferably, the solubility of the active agent in the mixed solvent is at least 1.1 times, more preferably at least 1.25 times, even more preferably at least 1.5 times, even more preferably at least 1.75 times, even more preferably at least 2 times, especially at least 3 times, and even more preferably at least 4 times.

Preferably, the solubility of the surfactant in the spray solution is at least 1.1 times, more preferably at least 1.25 times, even more preferably at least 1.5 times, even more preferably at least 1.75 times, even more preferably at least 2 times, especially at least 3 times, and even more preferably at least 4 times.

Preferably, the concentration of the active agent dissolved in the mixed solvent is at least 1.1 times, more preferably at least 1.25 times, even more preferably at least 1.5 times, even more preferably at least 1.75 times, even more preferably at least 2 times, especially at least 3 times, and even more preferably at least 4 times, the solubility of the active agent in solvent 1 or solvent 2 alone.

Preferably, the concentration of the surfactant dissolved in the spray solution is at least 1.1 times, more preferably at least 1.25 times, even more preferably at least 1.5 times, even more preferably at least 1.75 times, even more preferably at least 2 times, especially at least 3 times, and even more preferably at least 4 times, the solubility of the surfactant in solvent 1 or solvent 2 alone.

Preferably, the activator and the dispersion polymer are uniformly mixed in a spray-dried amorphous solid dispersion.

In a spray-dried amorphous solid dispersion containing an active agent and a dispersion polymer, the active agent can be uniformly and preferably also molecularly dispersed in the dispersion polymer. The active agent and the dispersion polymer can form a solid solution in the spray-dried amorphous solid dispersion.

The surfactant in a spray-dried amorphous solid dispersion can be amorphous or substantially amorphous; substantially means 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 surfactant is amorphous; this wt% is based on the total weight of the surfactant in the spray-dried amorphous solid dispersion. When the spray-dried amorphous solid dispersion is analyzed by X-ray powder diffraction (PXRD), the amorphous nature of the surfactant can be demonstrated by the lack of sharp Bragg diffraction peaks in the X-ray pattern. Possible parameters and settings for the X-ray diffractometer are a device with a Cu-Kalpha source, set between 3 and 40°2θ in a modified parallel beam geometry, a scan rate of 2°/min, and a step size of 0.0°. Another piece of evidence for the amorphous nature of the surfactant in a spray-dried amorphous solid dispersion can be a single glass transition temperature (Tg). A single Tg is also evidence of a homogeneous mixture of the amorphous surfactant and the dispersion polymer. Such samples, without any further sample preparation, can be used to determine Tg, which can be performed, for example, in a modulation mode with a scan rate of 2.5 °C/min, modulation of ±1.5 °C/min, and a scan range of 0 °C to 180 °C. The amorphous properties of the surfactant exhibit a Tg equal to or between the Tg of the pure dispersion polymer and the Tg of the surfactant. The Tg of spray-dried amorphous solid dispersions is generally similar to a weighted average of the Tg of the surfactant and the Tg of the dispersion polymer.

The amount of surfactant in the spray solution can be at least 0.5 wt%, preferably at least 1 wt%, wherein wt% is based on the weight of the spray solution.

The amount of surfactant in the spray solution can be up to 10 wt%, preferably up to 7.5 wt%, more preferably up to 5 wt%, wherein wt% is based on the weight of the spray solution.

Any lower limit of surfactant in a spray solution can be combined with any upper limit.

For example, the possible amount of surfactant in the spray solution can be from 0.5 wt% to 10 wt%, preferably from 1 wt% to 10 wt%, more preferably from 1 wt% to 7.5 wt%, wherein wt% is based on the weight of the spray solution.

The mixed solvent may include the following combinations: methyl acetate/methanol, methyl acetate/ethanol, ethyl acetate/methanol, ethyl acetate/ethanol, methyl formate/methanol, methyl formate/ethanol, ethyl formate/methanol, and ethyl formate/ethanol;

Preferably, the mixture consists of methyl acetate/methanol, methyl acetate/ethanol, ethyl acetate/ethanol, or ethyl formate/methanol.

More preferably, methyl acetate/methanol, methyl acetate/ethanol, and ethyl acetate/ethanol;

Even more preferably, the mixed solvent comprises the following combination: methyl acetate/methanol, or ethyl acetate/ethanol;

In one embodiment, the mixed solvent comprises a combination of methyl acetate/methanol.

In one embodiment, the mixed solvent is not methanol/ethyl acetate.

The ratio of solvent 1 to solvent 2 (w:w) can be from 10:90 to 90:10, preferably from 20:80 to 80:20, and more preferably from 30:70 to 70:30.

The combined amount of solvent 1 and solvent 2 in the mixed solvent can be at least 70 wt%, preferably at least 80 wt%;

Higher combined amounts of solvent 1 and solvent 2 in the mixed solvent can also be used, such as at least 85 wt%, or preferably at least 90 wt%, or at least 95 wt%; where wt% is based on the weight of the mixed solvent.

In one embodiment, the mixed solvent consists of a mixture of solvent 1 and solvent 2;

Preferably, solvent 1 consists of only one of the possible individual solvents 1, and solvent 2 consists of only one of the possible individual solvents 2;

Solvent 1 and solvent 2, as well as their embodiments and combinations, are as defined herein.

The mixed solvent may further contain water.

The amount of water was chosen such that the spray solution had no more than one liquid phase.

When the mixed solvent contains water, the mixed solvent contains no more than 30 wt%, preferably no more than 27.5 wt%, more preferably no more than 25 wt%, even more preferably no more than 22.5 wt%, and especially no more than 20 wt%.

Lower amounts of water may also be used, such as no more than 15 wt%, or no more than 10 wt%, or no more than 5 wt%, where wt% is based on the weight of the mixed solvent.

When the mixed solvent contains water, the mixed solvent may contain at least 0.5 wt%, preferably at least 1 wt%, more preferably at least 2 wt%, and even more preferably at least 5 wt% water, wherein wt% is based on the weight of the mixed solvent.

In one embodiment, the mixed solvent consists of a mixture of solvent 1, solvent 2, and water;

Preferably, solvent 1 consists of only one of the possible individual solvents 1, and solvent 2 consists of only one of the possible individual solvents 2.

In one embodiment, the mixed solvent consists of a mixture of solvent 1 and solvent 2;

Preferably, solvent 1 consists of only one of the possible individual solvents 1, and solvent 2 consists of only one of the possible individual solvents 2.

In one embodiment, solvent 1 consists of only one of the possible individual solvents 1, and solvent 2 consists of only one of the possible individual solvents 2.

The spray solution may contain one or more dispersion polymers, preferably one, two, three or four, more preferably one, two or three, or even more preferably one or two dispersion polymers.

The dispersion polymer can be a pharmaceutically acceptable dispersion polymer.

Suitable dispersion polymers include, but are not limited to: hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), cellulose acetate (CAP), carboxymethyl ethyl cellulose (CMEC), polyvinylpyrrolidone (PVP), poly(vinylpyrrolidone-vinyl acetate) (PVPVA), polymethacrylates such as poly(methyl methacrylate-bis(methacrylate)) (PMMAMA) or poly(ethyl methacrylate-bis(methacrylate)), [vinyl acetate, a polymer comprising 1-vinylhexahydro-2H-aza-2-one and α-hydro-ω-hydroxy poly(oxy-1,2-ethylenedimethyl) grafted], or combinations thereof.

Suitable polymethacrylates, such as PMMAMA polymers, including but not limited to poly(methyl methacrylate-p-methacrylate) 1:1 (e.g., Eudragit L100) and poly(methyl methacrylate-p-methacrylate) 1:2 (e.g., S100). These are polymer products of Evonik Industries AG (45128 Essen, Germany).

Poly(ethyl methacrylate) can be 1:1.

[Vinyl acetate, a polymer comprising 1-vinylhexahydro-2H-aza-2-one and α-hydro-ω-hydroxy poly(oxy-1,2-ethylenedimethyl), grafted] is a polymethacrylate and is available as a product of BASF, 67056 Ludwigshafen, Germany.

In a preferred embodiment, the dispersion polymer is selected from HPMCAS, HPMC, PPVVA, PVP, polymethyl methacrylate, HPMCP, CMEC, and CAP.

In another preferred embodiment, the dispersion polymer is selected from HPMCAS, HPMC, PPVVA, PVP, polymethyl methacrylate, HPMCP, CMEC, CAP, [vinyl acetate, grafted with a polymer comprising 1-vinylhexahydro-2H-aza-2-one and α-hydro-ω-hydroxy poly(oxy-1,2-ethylenedimethyl)].

In another preferred embodiment, the dispersion polymer is selected from HPMCAS, PPVVA, polymethyl methacrylate, HPMCP, CMEC, and CAP.

In another preferred embodiment, the dispersion polymer is selected from HPMCAS, PPVVA, polymethyl methacrylate, HPMCP, CMEC, CAP, [vinyl acetate, grafted with a polymer comprising 1-vinylhexahydro-2H-aza-2-one and α-hydro-ω-hydroxy poly(oxy-1,2-ethylenedimethyl)].

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

In another embodiment, the dispersion polymer is HPMC;

In another embodiment, the dispersion polymer is PMMAMA, HPMCAS, PPVVA, or PVP;

In another embodiment, the dispersion polymer is PMMAMA, HPMCAS, or PPVVA;

In another embodiment, the dispersion polymer is PVP;

In another embodiment, the dispersion polymer is HPMCAS.

The preferred embodiment of HPMCAS is

• HPMCAS, with an acetyl content of 5 wt% to 9 wt% and a succinyl content of 14 wt% to 18 wt%.

• HPMCAS, acetyl content of 7wt% to 11wt%, and succinyl content of 10wt% to 14wt%, or

• HPMCAS, with an acetyl content of 10 wt% to 14 wt% and a succinyl content of 4 wt% to 8 wt%;

More preferably is

• HPMCAS, with an acetyl content of 5 wt% to 7 wt% and a succinyl content of 14 wt% to 16 wt%.

• HPMCAS, acetyl content of 7wt% to 9wt%, and succinyl content of 10wt% to 12wt%, or

• HPMCAS, with an acetyl content of 11 wt% to 13 wt% and a succinyl content of 5 wt% to 7 wt%;

wt% is based on the weight of HPMCAS.

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

The dispersion polymer and the mixed solvent are selected such that the dispersion polymer dissolves in the mixed solvent.

The dispersion polymer is preferably present in a dissolved state in the spray solution, and the amounts of the dispersion polymer and the mixed solvent are selected respectively.

For example, the amount of the dispersion polymer in the spray solution can be from 0.5 wt% to 25 wt%, preferably from 1 wt% to 20 wt%, more preferably from 2.5 wt% to 15 wt%, and even more preferably from 3 wt% to 10 wt%, wherein wt% is based on the weight of the spray solution.

The amounts of dispersion polymer and surfactant in the spray solution are selected such that a predetermined amount of dispersion polymer and surfactant are provided in the spray-dried amorphous solid dispersion.

The spray-dried amorphous solid dispersion may contain 1 wt% to 99 wt%, preferably 10 wt% to 95 wt%, more preferably 10 wt% to 80 wt%, and even more preferably 20 wt% to 60 wt% of an active agent, wherein the wt% is based on the weight of the spray-dried amorphous solid dispersion.

The spray-dried amorphous solid dispersion may contain from 1 wt% to 99 wt%, preferably from 20 wt% to 90 wt%, more preferably from 40 wt% to 80 wt% of a dispersion polymer, where wt% is based on the weight of the spray-dried amorphous solid dispersion.

Preferably, the combined content of the active agent and the dispersion polymer in the spray-dried amorphous solid dispersion is from 65 wt% to 100 wt%, more preferably from 67.5 wt% to 100 wt%, even more preferably from 80 wt% to 100 wt%, especially from 90 wt% to 100 wt%, and even more particularly from 95 wt% to 100 wt%, where wt% is based on the weight of the spray-dried amorphous solid dispersion.

In one embodiment, the spray-dried amorphous solid dispersion consists of an active agent and a dispersion polymer.

The relative amounts (w:w) of the active agent to the dispersion polymer in the spray-dried amorphous solid dispersion can be from 50:1 to 1:50, preferably from 25:1 to 1:25, more preferably from 10:1 to 1:10, and even more preferably from 5:1 to 1:5.

One embodiment of the present invention is a method for preparing an amorphous solid dispersion by spray drying a spray solution containing...

a) A mixed solvent containing

i. Solvent 1, which is selected from the group consisting of: methyl acetate, methyl formate, ethyl acetate, ethyl formate and mixtures thereof;

ii. Solvent 2, which is selected from the group consisting of: methanol, ethanol and mixtures thereof;

The ratio (w:w) of solvent 1 to solvent 2 is 10:90 to 90:10;

b) Surfactants;

c) HPMC, as a dispersion polymer;

Preferably, the mixed solvent further comprises water; wherein the amount of water and all embodiments thereof are as described herein.

One embodiment of the present invention is a method for preparing an amorphous solid dispersion by spray drying a spray solution containing...

a) A mixed solvent containing

i. Solvent 1, which is selected from the group consisting of: methyl acetate, methyl formate, ethyl acetate, ethyl formate and mixtures thereof;

ii. Solvent 2, which is selected from the group consisting of: methanol, ethanol and mixtures thereof;

The ratio (w:w) of solvent 1 to solvent 2 is 10:90 to 90:10;

b) Surfactants;

c) PVP, which is a dispersion polymer;

The prerequisite is that the mixed solvent is not composed of methanol and ethyl acetate.

One embodiment of the present invention is a method for preparing an amorphous solid dispersion by spray drying a spray solution containing...

a) A mixed solvent containing

i. Solvent 1, which is selected from the group consisting of: methyl acetate, methyl formate, ethyl acetate, ethyl formate and mixtures thereof;

ii. Solvent 2, which is selected from the group consisting of: methanol, ethanol and mixtures thereof;

The ratio (w:w) of solvent 1 to solvent 2 is 10:90 to 90:10;

b) Surfactants;

c) A dispersion polymer selected from the group consisting of: hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), cellulose acetate (CAP), carboxymethyl ethyl cellulose (CMEC), poly(vinylpyrrolidone-vinyl acetate) (PVPVA), polymethacrylates such as poly(methyl methacrylate-p-methacrylate) (PMMAMA) or poly(ethyl methacrylate-p-acrylate), [vinyl acetate, a polymer grafted with 1-vinylhexahydro-2H-aza-2-one and α-hydro-ω-hydroxy poly(oxy-1,2-ethylenedimethyl)], or combinations thereof.

The spray solution can be fed into the spray dryer at a temperature up to the boiling point of the spray solution at ambient pressure; preferably from 4°C to the boiling point of the spray solution at ambient pressure, and more preferably from 4°C to a temperature below the boiling point of the spray solution at ambient pressure. In the context of this invention, the term "the spray solution can be fed into the spray dryer at the temperature of the spray solution" means "the spray solution is spray-dried at the temperature of the spray solution".

Spray drying can be carried out at an inlet temperature ranging from 60°C to 165°C, preferably from 80°C to 140°C.

Spray drying can be carried out at an outlet temperature equal to or lower than the boiling point of the mixed solvent (such as an outlet temperature from 20°C to 10°C below the boiling point of the mixed solvent).

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

The spray solution may further contain dissolved surfactants.

Surfactants can be, for example, fatty acids and alkyl sulfonates, sodium docusate (e.g., available from Mallinckrodt Spec. Chern., St. Louis, Mo., Missouri), polyoxyethylene sorbitan fatty acid esters (e.g., available from ICI Americas Inc., Wilmington, Del., Delaware), or P-20, available from Lipochem Inc., Patterson, New Jersey. POE-0, or POE-0, is available from Abitec Corp., Janesville, Wisconsin, a natural surfactant such as sodium taurocholate, 1-palmitoyl-2-oleoyl-tin-glycerol-3-phosphocholine, lecithin, other phospholipids and mono- and diglycerides of glycerol, vitamin E TPGS, PEO-PPO-PEO triblock copolymers (e.g., known under the trade name Pluronic), or PEO (PEO is also known as PEG, polyethylene glycol (PEG)).

The amount of surfactant in the spray solution may provide up to 10 wt% or up to 5 wt% of surfactant in the spray-dried amorphous solid dispersion, where wt% is based on the weight of the spray-dried amorphous solid dispersion.

The spray solution may further contain pharmaceutically acceptable excipients, such as fillers, disintegrants, pigments, binders, lubricants, flavoring agents, etc., which are intended for conventional purposes and used in typical amounts known to those skilled in the art.

The spray-dried amorphous solid dispersion may contain residual mixed solvents, namely residual solvent 1 or residual solvent 2 or both, and the total content of residual solvents in the spray-dried amorphous solid dispersion may be 5,000 ppm or less, preferably 3,000 ppm or less, more preferably 500 ppm or less, and even more preferably 100 ppm or less, where ppm is based on the weight of the spray-dried amorphous solid dispersion.

By subjecting the spray-dried amorphous solid dispersion to a secondary drying process, any residual solvent content in the spray-dried amorphous solid dispersion can be reduced to the desired predetermined and final solvent content. The secondary drying can be performed using a disc dryer or any stirred dryer known to those skilled in the art for drying solids.

Another subject of the present invention is a spray-dried amorphous solid dispersion, wherein the spray-dried amorphous solid dispersion can be obtained by a method for preparing an amorphous solid dispersion by spray drying a spray solution;

The methods, amorphous solid dispersions, and spray solutions are as defined herein, as are all their embodiments.

Example

Materials and Abbreviations

Gefitinib Crystalline gefitinib, free base, CAS 184475-35-2, compound of formula (1), LC Laboratories (Woburn, Massachusetts, USA, 01801)

Nilotinib Crystalline nilotinib, CAS 641571-10-0, compound of formula (2), LC Laboratories (Woburn, Massachusetts, USA, 01801)

Sulfasalazine, crystalline sulfasalazine, CAS 599-79-1, compound of formula (3), THICA Chemical Industries, Ltd. (Portland, Oregon, USA 97203)

UTEC L100 PMMAMA polymer, Evonik Industries AG (Essen, Germany 45128)

HPMCAS-MG Hydroxypropyl methylcellulose acetate succinate, Shin-Etsu Polymer Co., Ltd. (Tokyo, Japan 101-0041), such as MG (also known as AS-MG).

The letter M specifies the grade and distinguishes between the content of acetyl groups and succinyl groups. Other grades are specified by the letters L (HPMCAS-L) and H (HPMCAS-H). The letter G represents a granular grade with an average particle size of 1 mm, and the letter F replaces G to represent a micronized grade with an average particle size of 5 micrometers. The various contents and parameters of these grades are given in Table 15.

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

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

Equipment: DSC Q2000 (TA Instruments, Japan)

Heating rate: 10℃/min

Refer to the second heating operation

_N2 atmosphere

Sample volume 3mg

(c) wt% based on HPMCAS weight

HPMC E3 Hydroxypropyl Methylcellulose, trade name METHOCEL E3 Premium LV, DuPont (Wilmington, Delaware, USA)

PVPVA64 Vinylpyrrolidone-vinyl acetate, trade name Kollidon VA64, BASF (Ludwigshafen, Germany)

method

Determining the saturation concentration of a drug in a solvent.

Mixed solvents are prepared by premixing individual solvents by weight. The solvent ratio is the weight percentage of each component.

Saturated solutions were prepared by adding excess crystalline API to 2 mL of a single solvent or a mixture of solvents and stirring at 25 °C for 24 h. Each sample was then filtered through a 1 μm glass filter. 50 μL aliquots were run isothermally at 90 °C for 10 min on a TA Inc. Discovery TGA (TA Instruments, Newcastle, Delaware, 19720, USA) to remove the solvent and measure the mass of API in the solution.

The results are listed in the table. The mg/ml values are measured values, and the wt% values are calculated based on the density estimates of the mixed solvent.

Example 1: Solubility in MeOAc:MeOH

Example 1a: Sulfasalazine

Table 1 shows the saturation concentrations of sulfasalazine in MeOAc/MeOH.

Figure 1 graphically displays the data from Table 1: solubility (in wt%).

Figure 2 graphically displays the data from Table 1: solubility (in mg/ml).

Example 1b: Nilotinib

Table 3 shows the saturation concentration of nilotinib in MeOAc/MeOH.

Figure 5 graphically displays the data from Table 3: solubility (in wt%).

Figure 6 graphically displays the data from Table 3: solubility (in mg/ml).

Example 1c: Gefitinib

Table 5 shows the saturation concentration of gefitinib in MeOAc/MeOH.

Figure 9 graphically displays the data from Table 5: solubility (in wt%).

Figure 10 graphically displays the data from Table 5: solubility (in mg/ml).

Example 2: Solubility in EtOAc:EtOH

Example 2a: Sulfasalazine

Table 2 shows the saturation concentration of sulfasalazine in EtOAc/EtOH.

Figure 3 graphically displays the data from Table 2: solubility (in wt%).

Figure 4 graphically displays the data from Table 2: solubility (in mg/ml).

Example 2b: Nilotinib

Table 4 shows the saturation concentration of nilotinib in EtOAc/EtOH.

Figure 7 graphically displays the data from Table 4: solubility (in wt%).

Figure 8 graphically displays the data from Table 4: solubility (in mg/ml).

Example 2c: Gefitinib

Table 6 shows the saturation concentration of gefitinib in EtOAc/EtOH.

Figure 11 graphically displays the data from Table 6: solubility (in wt%).

Figure 12 graphically displays the data from Table 6: solubility (in mg/ml).

Example 3: Solubility in MeOAc:EtOH

Example 3a: Gefitinib

Table 7 shows the saturation concentration of gefitinib in MeOAc/EtOH.

Figure 13 graphically displays the data from Table 7: solubility (in wt%).

Figure 14 graphically displays the data from Table 7: solubility (in mg/ml).

Example 4: Solubility in EtOAc:MeOH

Example 4a: Gefitinib

Table 8 shows the saturation concentration of gefitinib in EtOAc/MeOH.

Figure 15 graphically displays the data from Table 8: solubility (in wt%).

Figure 16 graphically displays the data from Table 8: solubility (in mg/ml).

Example 5: Solubility in ethyl formate:MeOH

Example 5a: Gefitinib

Table 9 shows the saturation concentration of gefitinib in ethyl formate/MeOH.

Figure 17 graphically displays the data from Table 9: solubility (in wt%).

Figure 18 graphically displays the data from Table 9: solubility (in mg/ml).

Example 6: Solubility of MeOAc/MeOH in 20% water

Example 6a: Gefitinib

Table 10 shows the saturation concentration of gefitinib in MeOAc/MeOH containing 20% water, which is based on the weight of the mixed solvent (i.e., the combined weight of solvent 1, solvent 2, and water).

Figure 29 graphically displays the data from Table 10: solubility (in wt%).

Figure 30 graphically displays the data from Table 10: solubility (in mg/ml).

Overlay image - sulfasalazine:

Figure 19 shows an overlay of Figures 1 and 3.

Figure 20 shows an overlay of Figures 2 and 4.

Overlay image - Nilotinib:

Figure 21 shows an overlay of Figures 5 and 7.

Figure 22 shows an overlay of Figures 6 and 8.

Overlay image - Gefitinib:

Figure 23 shows an overlay of Figures 9, 11, 13, and 15.

Figure 24 shows an overlay of Figures 10, 12, 14, and 16.

Example 7: ASD-25:75 Gefitinib:PVPVA64 using a MeOAc/MeOH mixture

Weigh 71.4 g of 50/50 (w/w) methanol/methyl acetate into a flask. Add 1.01 g of gefitinib to the mixed solvent and stir with a magnetic stir bar at 20 °C until completely dissolved. Add 3.00 g of PPVVA64 and stir the mixture for at least 30 min until the polymer is dissolved.

The solution was then spray-dried using a custom-made spray dryer. The solution was pumped into a laboratory-scale, 0.3m diameter stainless steel spray drying chamber using a 120psi can top pump. The spray solution was then atomized using nozzles.

1.5 pressure swirl nozzle with 0.15mm diameter; SCHLICK hollow cone, type 121, with standard spray cone, Schlick Americas, Bluffton, South Carolina, USA.

The particles are dried using heated nitrogen gas (inlet 125°C to 130°C, outlet 48°C to 52°C, 500 g/min). The resulting ASD is collected using a cyclone separator to separate the solid particles from the gas stream.

The collected ASD was subjected to secondary drying in a disc dryer at 40°C/15% RH to remove residual solvent. The ASD was dried on the disc dryer for 24 hours. After the disc dryer treatment, the residual MeOH content, as determined by GC, was less than 50 ppm.

Figure 25 shows the PXRD of ASD after disc drying. The PXRD shows that ASD is amorphous, as indicated by the lack of sharp diffraction peaks.

Example 8: ASD-25:75 Gefitinib: Eutrich L100 using a MeOAc/MeOH mixture

Weigh 71.5 g of 50/50 (w/w) methanol/methyl acetate into a flask. Add 1.00 g of gefitinib to the mixed solvent and stir with a magnetic stir bar at 20 °C until completely dissolved. Add 3.01 g of Eutrapeptide L100 and stir the mixture for at least 30 min until the polymer is dissolved.

The solution was then spray-dried using a custom-made spray dryer. The solution was pumped into a laboratory-scale, 0.3m diameter stainless steel spray drying chamber using a 120psi can top pump. The spray solution was then atomized using nozzles.

1.5 pressure swirl nozzle with 0.15mm diameter; SCHLICK hollow cone, type 121, with standard spray cone, Schlick Americas, Bluffton, South Carolina, USA.

The particles are dried using heated nitrogen gas (inlet 125°C to 130°C, outlet 48°C to 52°C, 500 g/min). The resulting ASD is collected using a cyclone separator to separate the solid particles from the gas stream.

The collected ASD was subjected to secondary drying in a disc dryer at 40°C/15% RH to remove residual solvent. The ASD was dried on the disc dryer for 24 hours. After the disc dryer treatment, the residual MeOH content, as determined by GC, was less than 60 ppm.

Figure 26 shows the PXRD of ASD after disc drying. The PXRD shows that ASD is amorphous, as indicated by the lack of sharp diffraction peaks.

Example 9: ASD-25:75 Gefitinib:HPMCAS-MG using a MeOAc/MeOH mixture

Weigh 71.5 g of 50/50 (w/w) methanol/methyl acetate into a flask. Add 1.00 g of gefitinib to the mixed solvent and stir with a magnetic stir bar at 20 °C until completely dissolved. Add 3.00 g of HPMCAS-MG and stir the mixture for at least 30 min until the polymer is dissolved.

The solution was then spray-dried using a custom-made spray dryer. The solution was pumped into a laboratory-scale, 0.3m diameter stainless steel spray drying chamber using a 120psi can top pump. The spray solution was then atomized using nozzles.

1.5 pressure swirl nozzle with 0.15mm diameter; SCHLICK hollow cone, type 121, with standard spray cone, Schlick Americas, Bluffton, South Carolina, USA.

The particles are dried using heated nitrogen gas (inlet 125°C to 130°C, outlet 48°C to 52°C, 500 g/min). The resulting ASD is collected using a cyclone separator to separate the solid particles from the gas stream.

The collected ASD was subjected to secondary drying in a disc dryer at 40°C/15% RH to remove residual solvent. The ASD was dried on the disc dryer for 24 hours. After the disc dryer treatment, the residual MeOH concentration, as determined by GC, was less than 30 ppm.

Figure 27 shows the PXRD of ASD after disc drying. The PXRD shows that ASD is amorphous, as indicated by the lack of sharp diffraction peaks.

Example 10: ASD-25:75 Gefitinib:HPMC E3 using a MeOAc/MeOH mixture

Weigh 74.8 g of 40/40/20 (w/w/w) methanol/methyl acetate/water into a flask. Add 1.00 g of gefitinib to the mixed solvent and stir with a magnetic stir bar at 24 °C until completely dissolved. Add 3.00 g of HPMC E3 and stir the mixture for at least 30 min until the polymer is dissolved.

The solution was then spray-dried using a custom-made spray dryer. The solution was pumped into a laboratory-scale, 0.3m diameter stainless steel spray drying chamber using a 120psi can top pump. The spray solution was then atomized using nozzles.

1.5 pressure swirl nozzle with 0.15mm diameter; SCHLICK hollow cone, type 121, with standard spray cone, Schlick Americas, Bluffton, South Carolina, USA.

The particles are dried using heated nitrogen gas (inlet 145°C to 150°C, outlet 48°C to 53°C, 500 g/min). The resulting ASD is collected using a cyclone separator to separate the solid particles from the gas stream.

The collected ASD was subjected to secondary drying in a disc dryer at 40°C/15% RH to remove residual solvent. The ASD was dried on the disc dryer for 24 hours. After the disc dryer, the residual amount of MeOH, as determined by GC, was less than 10 ppm.

Figure 28 shows the PXRD of ASD after disc drying. The PXRD shows that ASD is amorphous, as indicated by the lack of sharp diffraction peaks.

Example 11: Solubility of sulfasalazine in MeOAc:MeOH and EtOAc/MeOH

Table 11 shows the solubility values (in wt%) of sulfasalazine in the EtOAc/MeOH mixture, i.e., the saturation concentration.

Table 12 shows the solubility values (in wt%) of sulfasalazine in the MeOAc/MeOH mixture, i.e., the saturation concentration.

Figure 31: A superimposed graph showing the solubility data (in wt%) of Tables 11 and 12, i.e., the saturation concentrations of sulfasalazine in EtOAc/MeOH and MeOAc/MeOH mixtures.

Example 12: Solubility of nilotinib in MeOAc:MeOH and EtOAc/MeOH

Table 13 shows the solubility values of nilotinib in the EtOAc/MeOH mixture (in wt%), i.e., the saturation concentration.

Table 14 shows the solubility values of nilotinib in the MeOAc/MeOH mixture (in wt%), i.e., the saturation concentration.

Figure 32: A superimposed graph showing the solubility data (in wt%) of Tables 13 and 14, i.e., the saturation concentrations of nilotinib in EtOAc/MeOH and MeOAc/MeOH mixtures.

Claims (22)

1. A method for preparing an amorphous solid dispersion by spray drying a spray solution, wherein the spray solution comprises d) A mixed solvent, the mixed solvent comprising i. Solvent 1, which is selected from the group consisting of: methyl acetate, methyl formate, ethyl acetate, ethyl formate and mixtures thereof; ii. Solvent 2, which is selected from the group consisting of: methanol, ethanol and mixtures thereof; The ratio (w:w) of solvent 1 to solvent 2 is 10:90 to 90:10; e) Surfactants; f) HPMC, which is a dispersion polymer. 2. A method for preparing an amorphous solid dispersion by spray drying a spray solution, wherein the spray solution comprises d) A mixed solvent, the mixed solvent comprising i. Solvent 1, which is selected from the group consisting of: methyl acetate, methyl formate, ethyl acetate, ethyl formate and mixtures thereof; ii. Solvent 2, which is selected from the group consisting of: methanol, ethanol and mixtures thereof; The ratio (w:w) of solvent 1 to solvent 2 is 10:90 to 90:10; e) Surfactants; f) PVP, as a dispersion polymer The prerequisite is that the mixed solvent is not composed of a mixture of methanol and ethyl acetate. 3. A method for preparing an amorphous solid dispersion by spray drying a spray solution, wherein the spray solution comprises d) A mixed solvent, the mixed solvent comprising i. Solvent 1, which is selected from the group consisting of: methyl acetate, methyl formate, ethyl acetate, ethyl formate and mixtures thereof; ii. Solvent 2, which is selected from the group consisting of: methanol, ethanol and mixtures thereof; The ratio (w:w) of solvent 1 to solvent 2 is 10:90 to 90:10; e) Surfactants; f) A dispersion polymer selected from the group consisting of: hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), cellulose acetate (CAP), carboxymethyl ethyl cellulose (CMEC), poly(vinylpyrrolidone-vinyl acetate) (PVPVA), polymethacrylates such as poly(methyl methacrylate-p-methacrylate) (PMMAMA) or poly(ethyl methacrylate-p-acrylate), [vinyl acetate, a polymer grafted with 1-vinylhexahydro-2H-aza-2-one and α-hydro-ω-hydroxy poly(oxy-1,2-ethylenedimethyl)], or combinations thereof. 4. The method according to one or more of claims 1 to 3, wherein The spray solution has no more than one liquid phase. 5. The method according to one or more of claims 1 to 4, wherein The amount of mixed solvent in the liquid of the spray solution is at least 50 wt%, wherein the wt% is based on the weight of the liquid in the spray solution. 6. The method according to one or more of claims 1 to 5, wherein The active agent is a bioactive compound and can be a drug, pharmaceutical preparation, medicine, therapeutic agent, nutrient, or active pharmaceutical ingredient (API). 7. The method according to one or more of claims 1 to 6, wherein The amount of the active agent in the spray solution is at least 0.5 wt%, wherein the wt% is based on the weight of the spray solution. 8. The method according to one or more of claims 1 to 6, wherein the concentration of the active agent dissolved in the mixed solvent is at least 1.1 times the solubility of the active agent in solvent 1 or solvent 2 alone. 9. The method according to one or more of claims 1 to 8, wherein The mixed solvent comprises the following combinations: methyl acetate/methanol, methyl acetate/ethanol, ethyl acetate/methanol, ethyl acetate/ethanol, methyl formate/methanol, methyl formate/ethanol, ethyl formate/methanol, and ethyl formate/ethanol. 10. The method according to one or more of claims 1 to 9, wherein The mixed solvent comprises the following combinations: methyl acetate/methanol, methyl acetate/ethanol, ethyl acetate/ethanol, and ethyl formate/methanol. 11. The method according to one or more of claims 1 to 10, wherein The mixed solvent comprises methyl acetate/methanol. 12. The method according to one or more of claims 1 to 11, wherein The ratio (w:w) of solvent 1 to solvent 2 is from 20:80 to 80:20. 13. The method according to one or more of claims 1 to 12, wherein The combined amount of solvent 1 and solvent 2 in the mixed solvent is at least 70 wt%. The wt% mentioned therein is based on the weight of the mixed solvent. 14. The method according to one or more of claims 1 to 13, wherein The mixed solvent further contains water. 15. The method of claim 14, wherein The mixed solvent contains no more than 30 wt% water, wherein the wt% is based on the weight of the mixed solvent. 16. The method according to claim 14 or 15, wherein The mixed solvent consists of a mixture of solvent 1 and solvent 2 with water. 17. The method of claim 16, wherein the dispersion polymer is HPMC. 18. The method according to one or more of claims 1 to 13, wherein The mixed solvent is composed of a mixture of solvent 1 and solvent 2. 19. The method according to one or more of claims 1 to 18, wherein Solvent 1 consists of only one of the possible individual solvents 1, and solvent 2 consists of only one of the possible individual solvents 2. 20. The method according to one or more of claims 3 to 19, wherein The dispersion polymer is selected from HPMCAS, PPVVA, polymethyl methacrylate, HPMCP, CMEC, CAP, [vinyl acetate, grafted with a polymer containing 1-vinylhexahydro-2H-aza-2-one and α-hydro-ω-hydroxy poly(oxy-1,2-ethylenedimethyl)]. 21. The method according to one or more of claims 3 to 20, wherein The dispersion polymer is PMMAMA, HPMCAS, or PPVVA. 22. The method according to one or more of claims 3 to 21, wherein The dispersion polymer is HPMCAS.