An amorphous solid dispersion and a method of preparation thereof and a pharmaceutical composition

Abstract

An amorphous solid dispersion, its preparation method, and a pharmaceutical composition thereof are disclosed. The amorphous solid dispersion comprises a compound I named 1-((2S,5R)-5-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and a polymer matrix selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, or copovidone, wherein the mass ratio of compound I to the polymer matrix is ​​1:3 to 1:5. The preparation method comprises dissolving compound I and the polymer matrix together in a mixed solvent of dichloromethane and methanol, followed by spray drying. This invention is the first to discover that combining the free base of compound I with a specific polymer in the above-mentioned ratio to form an amorphous solid dispersion unexpectedly and significantly inhibits its inherent dimerization / oligomerization degradation tendency, exhibits chemical stability far exceeding that of existing crystalline formulations, and maintains good dissolution performance.

Description

Technical Field

[0001] This invention relates to an amorphous solid dispersion, its preparation method, and a pharmaceutical composition thereof, particularly to an amorphous solid dispersion comprising 1-((2S,5R)-5-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one, its preparation method, and a pharmaceutical composition thereof, belonging to the field of pharmaceutical formulation technology. Background Technology

[0002] 1-((2S,5R)-5-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one is a compound having the structure of formula I (hereinafter referred to as "Compound I"):

[0003] ;

[0004] This is the free base form of the drug rituximab (development code: PF-06651600), a highly selective, irreversible JAK3 inhibitor developed by Pfizer Inc. Its oral formulation (trade name: LITFULO™) has been approved for the treatment of severe alopecia areata. However, the acrylamide structure of the active pharmaceutical ingredient in this formulation makes it highly susceptible to intermolecular Michael addition reactions during production and storage, generating dimerization and oligomerization degradation impurities including formulas a, b, c, and d (chemical structural formulas below):

[0005] , , , ;

[0006] Furthermore, significant changes can be observed in the appearance of the tablets, namely, a change from white to yellow / brown or the appearance of strong localized color changes.

[0007] This inherent chemical instability poses a serious challenge to the quality control and long-term storage of pharmaceuticals.

[0008] To address this issue, existing technologies primarily employ two strategies: First, compound I is prepared into a specific crystal form of p-toluenesulfonate, as described in the invention patent "Pyrrolo[2,3-d]pyrimidine toluenesulfonate, its crystalline form and related preparation methods and intermediates" (authorization announcement number: CN112888691B), utilizing the ordered arrangement of molecules in the crystal lattice to raise the reaction energy barrier; second, commercial formulation formulations are optimized, as described in the invention patent "Stable immediate-release tablets and capsules of 1-((2S,5R)-5-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one" (authorization announcement number: CN115023221B), by adjusting excipients to improve the drug microenvironment.

[0009] Although these methods can control dimer impurities and total impurities to certain limits in the short term, such as no more than 0.7 wt% and 1.2 wt% respectively, the degradation process is not eradicated.

[0010] Stability data for the commercially available capsule formulation (LITFULO™) showed that after 12 months of storage at 30°C and 65% relative humidity, the content of dimer impurities increased from the initial 0.04 wt% to 0.1 wt%, an increase of over 100%. This indicates that existing crystalline formulations still exhibit significant quality degradation when stored for extended periods or deviating from recommended storage conditions, posing a safety risk to patients.

[0011] On the other hand, preparing poorly soluble drugs into amorphous solid dispersions (ASDs) is a common strategy to improve their solubility and bioavailability.

[0012] Amorphous drugs exist in a thermodynamic high-energy state, which can provide higher apparent solubility, but their physical instability (such as recrystallization) and chemical instability are also common challenges faced by this technology.

[0013] Conventional ASD technology mainly focuses on how to inhibit the physical crystallization of drugs to maintain dissolution advantage. However, for specific drugs like Compound I, which have high chemical reactivity and are prone to intermolecular degradation, existing technologies have not provided clear guidance or successful insights on how to achieve excellent chemical stability through ASD technology at the same time.

[0014] Although studies have indicated that selecting suitable polymers, such as hydroxypropyl methylcellulose (HPMC), and optimizing processes, such as spray drying, can produce ASDs with high drug loading and physical stability, and HPMC is often chosen as a preferred matrix due to its good interaction with drugs, existing knowledge does not address, nor can it predict, whether these methods can effectively inhibit the chemical degradation reactions of specific molecular structures like Compound I. Therefore, there is an urgent need to develop a novel drug formulation that can fundamentally and significantly improve the chemical stability of Compound I. Summary of the Invention

[0015] The present invention aims to overcome the shortcomings of existing p-toluenesulfonate crystal form formulations containing compound I in terms of insufficient chemical stability. Specifically, it provides a novel formulation of compound I that, under normal long-term storage conditions, such as 25°C and 60% relative humidity, can control the growth of key degradation impurities dimers and total degradation products of compound I to extremely low levels and maintain excellent chemical stability for at least 24 months. This reduces product quality risks, simplifies storage and transportation conditions, and ensures patient medication safety.

[0016] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0017] An amorphous solid dispersion of compound I, comprising compound I and a polymer matrix, wherein the mass ratio of compound I to the polymer matrix is ​​1:3 to 1:5, and the polymer matrix is ​​selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (such as HPMCS-MG or HPMCS-HG), or copovidone (PVP VA).

[0018] Surprisingly, the solid dispersion composed of this specific combination exhibits unexpected chemical stability: after being stored for 24 months at (25±2) °C and (60±5)% relative humidity, the compound I dimer impurity in the amorphous solid dispersion does not exceed 0.3 wt%, and the total degradation products do not exceed 1.0 wt%.

[0019] In a preferred embodiment, the polymer matrix is ​​hydroxypropyl methylcellulose (HPMC) traded under the name Methocelᵀᴹ E3 Premium LV, and the mass ratio of compound I to Methocelᵀᴹ E3 Premium LV is 1:4. This preferred embodiment exhibits the best overall performance in both accelerated and long-term stability tests.

[0020] A method for preparing the aforementioned amorphous solid dispersion includes the following steps:

[0021] Compound I and the polymer matrix were dissolved together in a mixed solvent of dichloromethane and methanol at a mass ratio of 1:3 to 1:5 to form a solution with a solid content of 5 g / 100 mL to 15 g / 100 mL, wherein the volume ratio of dichloromethane to methanol was 1:1 to 1.5:1; the polymer matrix was hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, or copovidone.

[0022] The solution obtained in the above steps is spray-dried at an inlet temperature of 75°C to 105°C and an outlet temperature of 35°C to 55°C.

[0023] In a preferred embodiment, the solution in the above steps has a solid content of 10 g / 100 mL, and the spray drying preferably uses a dual-fluid nozzle with an orifice diameter of 0.7 mm or 1.0 mm.

[0024] In a preferred embodiment, the spray-dried product is further subjected to a secondary drying process, which is carried out under vacuum conditions at 30°C to 50°C for at least 6 hours.

[0025] A pharmaceutical composition comprising an amorphous solid dispersion of compound I as described in any of the preceding claims and one or more pharmaceutically acceptable excipients.

[0026] Preferably, the pharmaceutical composition is an oral solid dosage form, such as capsules or tablets, comprising 50% to 70% of the above-mentioned amorphous solid dispersion by weight of the total composition, and excipients such as microcrystalline cellulose, lactose, crospovidone and glyceryl disorbate. Compared with the prior art, the outstanding beneficial effects and significant progress of the present invention are as follows:

[0027] First, the present invention provides an amorphous solid dispersion composed of compound I and hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (such as HPMCS-MG or HPMCS-HG) or copovidone (PVP VA) as a polymer matrix, which has a revolutionary improvement in chemical stability;

[0028] This invention is the first to discover that by combining the free alkaline form of compound I with a specific polymer (such as HPMC, HPMCAS-MG, HPMCAS-HG, or PVP VA) at a specific narrow range of mass ratios (1:3 to 5) to form an amorphous solid dispersion, it is possible to unexpectedly and significantly suppress its inherent dimerization / oligomerization degradation trend. Experimental data show that the solid dispersion provided by this invention, under accelerated conditions of 40°C / 75%RH for 6 months, or under long-term conditions of 25°C / 60%RH for 24 months, has a dimer impurity content that is far lower than that of commercially available crystalline capsules, achieving a qualitative leap.

[0029] It can be seen that this invention is not a simple application of known ASD technology. Its improved stability stems from a synergistic mechanism, namely: on the one hand, the polymer solid solution formed by spray drying highly disperses and "isolates" compound I in the polymer chain at the molecular level, greatly reducing the probability of Michael addition reaction between drug molecules; on the other hand, the intermolecular interactions (such as hydrogen bonds) that may form between the selected specific polymer (especially HPMC) and compound I further restrict the mobility (migration rate) of drug molecules, thereby significantly reducing the degradation reaction rate from a kinetic perspective, forming a clear and synergistic anti-aggregation mechanism.

[0030] Secondly, the amorphous form also gives the drug higher apparent solubility and dissolution rate;

[0031] The solid dispersion prepared by this invention exhibits significantly better dissolution behavior than the p-toluenesulfonate crystalline form of compound I in in vitro simulated physiological media SGF or FaSSIF, ensuring good oral bioavailability and achieving excellent stability while also possessing superior dissolution performance.

[0032] Furthermore, the technical solution provided by this invention has good prospects for industrialization;

[0033] As can be seen, the preparation method provided by this invention is based on mature spray drying technology, with clear and scalable process parameters. The resulting dispersion powder can be directly used for capsule filling or tableting. The process route is simple and reliable, and has great value for promotion and application.

[0034] In conclusion, it can be seen that:

[0035] Through ingenious formulation design and process control, this invention successfully transforms the amorphous solid dispersion technology, which is usually used to improve solubility, into a disruptive solution to the problem of chemical stability of specific drug molecules, providing Compound I with an ideal formulation form that is far more stable than existing technologies, more competitive in the market, and easier to produce. Attached Figure Description

[0036] Figure 1 This is a superimposed image of representative powder X-ray diffraction (XRPD) spectra of amorphous solid dispersions (SDD-0 to SDD-8) with different polymer matrices;

[0037] Figure 2 This is a superimposed image of representative powder X-ray diffraction (XRPD) spectra of amorphous solid dispersions (SDD-9 to SDD-11) with different drug loadings based on Methocel® E3 Premium LV.

[0038] Figure 3This is a superimposed image of X-ray diffraction (XRPD) spectra of representative powders of the wet product obtained by spray drying and the dry product obtained by secondary drying during the scale-up preparation of ASD-I, an amorphous solid dispersion with a drug loading of 20 wt% based on Methocel E3 Premium LV.

[0039] Figure 4 The image shows a representative modulated differential scanning calorimetry (mDSC) curve of a sample (ASD-I) prepared by scale-up of an amorphous solid dispersion with a drug loading of 20 wt% using Methocel® E3 Premium LV as the matrix.

[0040] Figure 5 Typical images of an amorphous solid dispersion (ASD-I) prepared by amplification using Methocel® E3 Premium LV as the matrix and loaded with 20 wt% drug under a polarizing microscope (PLM).

[0041] Figure 6 The stability test results are shown in the figure for the amorphous solid dispersion (ASD-I) prepared by scale-up of Methocel® E3 Premium LV as matrix and with a drug loading of 20 wt%, which is an embodiment of the present invention.

[0042] Figure 7 Dissolution-time comparison curves of the scale-up preparation sample (ASD-I) containing the amorphous solid dispersion of compound I prepared for the embodiments of the present invention and the capsules containing the crystalline form of compound I-p-toluenesulfonate (Ritlecitinib) (LITFULO™). Detailed Implementation

[0043] To make the technical solution, beneficial effects and significant progress of the present invention clearer and more comprehensive, the technical solution provided by the present invention will be clearly and completely described below through specific embodiments and their effects. Obviously, all embodiments and their effects described below are only some embodiments and effects of the present invention, and not all of them.

[0044] Based on the embodiments and effects provided by this invention, all other embodiments and effects obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0045] In addition, all instruments, equipment, raw materials, reagents and standards involved in the following specific embodiments are commercially available unless otherwise specified.

[0046] The technical solution of the present invention will now be described in detail with reference to specific embodiments. Example 1

[0047] This embodiment provides an amorphous solid dispersion containing 1-((2S,5R)-5-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one.

[0048] An amorphous solid dispersion (ASD) comprising 1-((2S,5R)-5-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (abbreviated as: Compound I), comprising Compound I and a polymer matrix, wherein the mass ratio of Compound I to the polymer matrix is ​​1:3 to 1:5, and the polymer matrix is ​​selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (such as HPMCS-MG or HPMCS-HG), or copovidone (PVP VA); and

[0049] After being stored for 24 months at (25±2)℃ and (60±5)% relative humidity, the compound I dimer impurity in the amorphous solid dispersion does not exceed 0.3wt%, and the total degradation products do not exceed 1.0wt%.

[0050] In a preferred embodiment, the polymer matrix is ​​Methocelᵀᴹ E3 Premium LV, and the mass ratio of compound I to Methocelᵀᴹ E3 Premium LV is 1:4.

[0051] The following experimental results demonstrate a surprising finding:

[0052] The solid dispersions composed of this specific combination exhibit unexpected chemical stability, and the amorphous solid dispersions obtained from the preferred embodiment show the best overall performance in both accelerated and long-term stability tests.

[0053] The pharmaceutical preparation obtained by reacting compound I with the crystalline form of p-toluenesulfonate (Ritlecitinib) is called Litfulo. TM In contrast, the amorphous solid dispersions composed of different mass ratios of compound I to polymer matrix provided in this embodiment, and the solid dosage forms of pharmaceutical compositions containing such amorphous solid dispersions, are storage stable, with no signs of X-ray diffraction (XRPD) identifiable transition to crystalline form observed under typical storage conditions, and can remain stable for at least 2 years at a stability level of 0.3 wt% or less of compound I dimer and 1.0 wt% or less of total degradation products.

[0054] It is worth noting that in this embodiment:

[0055] In addition to the aforementioned hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (such as HPMCAS-MG or HPMCAS-HG), or copovidone (PVP VA), the polymer matrix may also be selected from any one or more of the following: methacrylic acid and methyl methacrylate copolymers (such as Eudragit® L100), polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam graft copolymers (such as Soluplus®), povidone (such as Kollidon® 30 (PVP K30)), hydroxypropyl methylcellulose acetate succinate (such as HPMCAS-MG or HPMCAS-HG), poloxamer 188, hydroxypropyl methylcellulose phthalate (such as HPMCP), or hydroxypropyl cellulose (such as HPC-SSL);

[0056] The screening of polymer matrices is mainly based on the solubility and stability of the solid dispersions, including chemical and physical stability;

[0057] The weight percentage range of compound I to the polymer matrix can even be extended to 1:1 to 1:19.

[0058] In addition, unless otherwise limited in specific circumstances, the following terms have the following meanings in this specification.

[0059] The term "solid dispersion" (SDD) refers to a dispersion system in which a drug is highly dispersed in a solid carrier, and the drug particle size in the carrier is between 0.001 and 0.1 mm. It is mainly used to accelerate and increase the dissolution of poorly soluble drugs and improve their bioavailability.

[0060] The term "amorphous solid dispersion" (ASD) refers to a solid product containing at least two different components. These two different components are typically a polymer matrix or carrier and an amorphous (non-crystalline) drug. For the purposes of this specification, the amorphous (non-crystalline) drug specifically refers to non-crystalline compound I. This amorphous solid dispersion is a molecular mixture or a solid solution. For the purposes of this specification, it is a solid solution of non-crystalline compound I.

[0061] The term "amorphous compound I" refers to a solid compound I that is substantially free of crystalline form, which can be assessed by XRPD analysis and / or scanning electron microscopy to determine whether a crystalline form of compound I is present.

[0062] The term "matrix polymer" refers to a pharmaceutically acceptable component in a solid dispersion that is not an API (Active Pharmaceutical Ingredient). It may contain one or more polymers and one or more surfactants. Excipients added after the solid dispersion is formed are not components of the solid dispersion itself, but can form a portion of the pharmaceutical composition containing the solid dispersion. For the purposes of this specification, the matrix polymer, once co-treated with compound I, serves to maintain compound I in an amorphous form.

[0063] "wt%" (abbreviated as "wt%" or "w / w%)" refers to the percentage by mass of a specific component in the mixture, based on the dry weight of the total mixture.

[0064] "Mass ratio": refers to the mass ratio of two or more components in a mixture relative to each other.

[0065] "Solid dosage form" refers to a pharmaceutical product containing compound I that is delivered in a solid form, such as capsules or tablets, suitable for individual consumption, to provide a defined dose.

[0066] As can be seen from the technical solution provided in this embodiment:

[0067] The core objective of this invention is to develop a solid dispersion of compound I to improve the inherent chemical stability of compound I, and to further construct novel pharmaceutical compositions to prepare new highly stable formulations, thereby reducing product quality risks, simplifying storage and transportation conditions, and ensuring patient medication safety.

[0068] Therefore, this embodiment utilizes the high glass transition temperature (Tg), high affinity, high compatibility, and high dispersibility of the polymer matrix to disperse compound I at the molecular level in the matrix. This dispersion process allows each compound I molecule to form hydrogen bonds or van der Waals forces with hydrogen bond donors and acceptors on the polymer, which greatly reduces or increases the intermolecular distance of compound I molecules, thereby greatly reducing Michael addition and other interactions between compound I molecules, and suppressing the occurrence of dimerization and oligomerization degradation.

[0069] As can be seen from the following effect example, the solid dispersion provided in this embodiment maintains good chemical stability. After being stored at room temperature (25°C) and 60% RH for 6 months, high performance liquid chromatography (HPLC) detection showed only an increase of 0.01 wt% of compound I dimer impurity. This indicates that the solid dispersion containing compound I provided in this embodiment is chemically stable for at least 6 months at room temperature (25°C) and 60% RH, and is fully suitable as a formulation for commercially available pharmaceuticals. Example 2

[0070] This embodiment provides a method for preparing an amorphous solid dispersion containing compound I.

[0071] A method for preparing an amorphous solid dispersion containing compound I includes the following steps:

[0072] Compound I and the polymer matrix were dissolved together in a mixed solvent of dichloromethane and methanol at a mass ratio of 1:3 to 1:5 to form a solution with a solid content of 5 g / 100 mL to 15 g / 100 mL, wherein the volume ratio of dichloromethane to methanol was 1:1 to 1.5:1; the polymer matrix was hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, or copovidone.

[0073] The solution obtained in the above steps is spray-dried at an inlet temperature of 75°C to 105°C and an outlet temperature of 35°C to 55°C.

[0074] In a preferred embodiment, the solution in the above steps has a solid content of 10 g / 100 mL, and the spray drying preferably uses a dual-fluid nozzle with an orifice diameter of 0.7 mm or 1.0 mm.

[0075] In a preferred embodiment, the spray-dried product is further subjected to a secondary drying process, which is carried out under vacuum conditions at 30°C to 50°C for at least 6 hours.

[0076] It should be noted that:

[0077] In the above preparation method, in addition to the mixed solvent composed of dichloromethane and methanol, a single solvent or mixed solvent composed of one or more of methanol, ethanol, n-propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, or water can also be used, as long as the single solvent or mixed solvent can simultaneously dissolve compound I and the polymer matrix and can be rapidly evaporated by spray drying process;

[0078] Generally, the boiling point of a single solvent or a mixture of solvents should be 150°C or lower; in addition, the solvent should preferably have relatively low toxicity and be removable from the dispersion to a level acceptable to the International Council for Harmonisation (ICH) guidelines.

[0079] In addition, the volume ratio of dichloromethane to methanol can be extended from 1:1 to 1.5:1 to 9:1, and the solid content in the solution can be extended from 5 g / 100 mL to 15 g / 100 mL to 1 g / 100 mL to 20% g / 100 mL.

[0080] It should also be noted that:

[0081] In this embodiment, compound I, as a raw material, should be a free base. The raw material compound I used in this embodiment to prepare the amorphous solid dispersion should have a purity greater than 70 wt%, preferably greater than 90 wt%, by weight, HPLC area, or both, and can be in solid form, solution, suspension, or other forms.

[0082] Compound I in its free base form can be obtained by neutralizing its commercially available p-toluenesulfonate salt.

[0083] The organic solvent used to neutralize free compound I-p-toluenesulfonate may be one or more mixed solvents selected from ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether, or isopropyl ether.

[0084] The base used for neutralization and release can be an aqueous solution of one of the following: sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, triethylamine, potassium carbonate, and sodium carbonate.

[0085] The specific implementation method is as follows:

[0086] Compound I-p-toluenesulfonate (trade name: Ritlecitinib) is dissolved or suspended in the above-mentioned organic solvent (e.g., ethyl acetate) to form a drug-containing solution or drug-containing suspension;

[0087] Slowly add a dilute alkaline solution (e.g., a 1N sodium hydroxide aqueous solution) dropwise to the obtained drug-containing solution or drug-containing suspension until the pH reaches 6-7, making it an alkaline solution;

[0088] The resulting alkaline solution was separated into layers, and the organic phase was the solution of compound I.

[0089] The resulting compound I solution (e.g., compound I-ethyl acetate solution) can be directly used in this embodiment to prepare a solution mixed with the polymer matrix, and then the solid dispersion can be prepared according to the remaining steps and methods of this embodiment;

[0090] In addition, the above-mentioned compound I solution (e.g., compound I-ethyl acetate solution) can also be concentrated under reduced pressure to obtain compound I in solid form for later use.

[0091] In this embodiment, the solid dispersion is formed by rapidly removing the solvent that dissolves compound I and the polymer matrix in a spray drying device through evaporation using a spray drying method, thereby forming a uniform or substantially uniform solid dispersion, while compound I is uniformly dispersed throughout the polymer and becomes a solid solution in the polymer.

[0092] The spray drying equipment applicable to this embodiment has a nozzle that is a dual-fluid atomizing nozzle or a pressure atomizing nozzle. Generally, the principle of nozzle design is to generate droplets with a required size range when the spray solution is pumped through the nozzle at the required rate.

[0093] The following spray drying equipment and operating parameters are available for reference:

[0094] BUCHI B290 spray dryer: 0.7mm nozzle, pump speed 50 rpm, feed rate approximately 18 mL / min, inlet temperature set according to solvent system, outlet temperature maintained between approximately 35~55℃; or

[0095] 0.7mm nozzle, pump speed 50 rpm, feed rate approximately 18 mL / min, inlet temperature approximately 80℃, outlet temperature maintained at approximately 36~44℃; or

[0096] Using a GEA PSD-1 spray dryer with a 1.0 mm dual-fluid nozzle, the circulating gas flow rate is 100 kg / h, the inlet temperature is 75℃ to 105℃, the outlet temperature is 35℃ to 55℃, the atomizing gas flow rate is (40~130) NI / min, the atomizing pressure is (0.3~2.0) bar, and the condenser outlet temperature is (-12~-15)℃ to 0℃; or

[0097] The Buhlar SD-2 spray dryer was used with a 1.0 mm dual-fluid nozzle, a circulating gas flow rate of 0.5 m³ / min, an inlet temperature of 75°C to 105°C, an outlet temperature of 35°C to 55°C, an atomizing gas flow rate of (8–25) L / min, an atomizing pressure of (0.3–2.5) bar, and a condenser outlet temperature of -15°C or 0°C.

[0098] In the preferred embodiment described above, the spray-dried product is further subjected to secondary drying, which is carried out under vacuum, typically at a pressure below approximately -0.085 MPa.

[0099] To further aid in understanding the technical solution provided in this embodiment, as well as the specific operation process and technical effects achievable, the preparation method provided in this embodiment will be further explained below through specific preparation examples.

[0100] Of course, those skilled in the art should understand that:

[0101] The preparation examples described below are illustrative only and not restrictive, and should not be construed as limiting the scope of protection claimed by this invention; and

[0102] The following preparation examples only use some of the preferred proportioning parameters and operating parameters in this embodiment as examples. In fact, the same results can be obtained within the control range of all optional materials, proportioning parameters and operating parameters provided in this embodiment. This embodiment is only for the sake of simplicity and will not be described in detail. Preparation Example 1: Preparation of amorphous solid dispersion (ASD) of compound I

[0103] Weigh 10.0 g of compound I (free base) and 0.0 g of Methocelᵀᴹ E3 Premium LV4 (mass ratio 1:4), and add them together to a mixed solvent consisting of 500 mL of dichloromethane and 500 mL of methanol (volume ratio 1:1). Stir at room temperature until completely dissolved to form a clear and transparent solution with a solid content of 10.0 g / 100 mL (or expressed as 10% (w / v)).

[0104] The above solution was dried using a spray dryer (model BUCHI B290), with the following process parameters set:

[0105] A dual-fluid nozzle (0.7 mm orifice) was used, with a feed rate of 18 mL / min, atomizing gas pressure controlled at (0.6–0.8) bar, an inlet temperature of 80 °C, and an outlet temperature maintained between 36 °C and 44 °C. A light white to off-white fluffy powder was collected, with a yield of 88%.

[0106] The obtained spray-dried powder was placed in a vacuum drying oven for secondary drying under the following conditions:

[0107] The temperature was 40℃, the vacuum degree was below -0.09MPa, and the drying time was 12 hours. After drying, an amorphous solid dispersion of compound I, Methocelᵀᴹ E3 Premium LV (labeled ASD-1), was obtained. Differential scanning calorimetry (DSC or preferably mDSC) and powder X-ray diffraction (XRPD) confirmed that compound I was highly dispersed in the polymer matrix in an amorphous form. Preparation Example 2: Preparation of ASD with Different Polymer Matrices

[0108] Following the same steps as in Preparation Example 1, except that the polymer matrix was replaced with an equal mass of copovidone 64 (PVPVA64, trade name Kollidon® VA64), and the mass ratio of compound I to PVP VA64 remained 1:4, ASD-2 was prepared.

[0109] DSC and PXRD analysis confirmed that the ASD-2 formed an amorphous solid dispersion. Preparation Example 3: Preparation of ASD with different mass ratios

[0110] Following the same steps as in Preparation Example 1, by changing the mass ratio of compound I to Methocelᵀᴹ E3 Premium LV, the following compounds can be prepared:

[0111] ASD-3: The mass ratio of compound I to Methocel® E3 Premium LV is 1:3;

[0112] ASD-4: The mass ratio of compound I to Methocel® E3 Premium LV is 1:5.

[0113] Testing revealed that both successfully formed amorphous solid dispersions. Preparation Example 4: Preparation of ASD with Different Process Parameters

[0114] By changing the spray drying process parameters according to the formulation of Example 1, the following products can be prepared respectively:

[0115] The preparation process parameters for ASD-5 are as follows: the inlet temperature is adjusted to 75℃ and the outlet temperature is 35℃.

[0116] ASD-6, its preparation process parameters are: inlet temperature adjusted to 105℃, outlet temperature approximately 55℃;

[0117] ASD-7: Its preparation process parameters are as follows: a dual-fluid nozzle with an orifice diameter of 0.7 mm is used, and other parameters are the same as in Example 1;

[0118] By collecting the spray-dried products of the above products and subjecting them to secondary drying (under the same conditions as in Preparation Example 1), ASD-5, ASD-6 and ASD-7 dried products can be obtained respectively.

[0119] Tests showed that all samples formed amorphous solid dispersions.

[0120] The following section further illustrates the technical effects that the technical solution provided by this invention can achieve by characterizing and evaluating the key quality indicators of the amorphous solid dispersion (ASD) prepared by the technical solution provided in this embodiment.

[0121] It should be noted that:

[0122] The test and control samples involved in the evaluation process may not be entirely amorphous solid dispersions (ASDs), but may only be solid dispersions (SDDs).

[0123] Therefore, to distinguish the amorphous solid dispersion (ASD) in the above preparation examples, the following evaluation indicators and the test and control samples involved in the evaluation and analysis process are uniformly numbered with "SDD-X" without distinguishing between amorphous solid dispersion and solid dispersion. However, those skilled in the art should be able to easily distinguish that the solid dispersion sample containing compound I in this specification is the amorphous solid dispersion (ASD) to be provided by this invention. Evaluation indicators and evaluation analysis methods:

[0124] 1) Morphological and crystallinity analysis:

[0125] Polarizing microscopy (PLM) observation: Using a Leica DM4P microscope, the sample dispersed in silicone oil was observed under cross-polarized light (10X eyepiece, 20X objective) to determine whether birefringence was present, in order to determine the crystallization characteristics of compound I in the sample.

[0126] Powder X-ray diffraction (XRPD) detection: The test was performed using a Bruker D8 Advance diffractometer (Cu / K-Alpha1 radioactive source, λ=1.5406Å, 40kV, 40mA) with a scanning range of 3° to 40°2θ and a step size of 0.02° to confirm the crystalline or amorphous state of the sample.

[0127] 2) Thermodynamic property analysis:

[0128] Modulated differential scanning calorimetry (mDSC) analysis: Using a TADiscovery Q2000 thermal analyzer, the sample was placed in a perforated sealed Tzero disk and scanned from 0℃ to 250℃ (or decomposition temperature) at a rate of 2℃ / min under a nitrogen flow of 50mL / min, with a modulation amplitude of ±1℃ / min and a period of 60 seconds. This was used to determine the glass transition temperature (Tg) of the sample and detect residual crystals.

[0129] Thermogravimetric analysis (TGA): Using a TADiscovery 5500 or Q5000IR thermogravimetric analyzer, the sample is heated from room temperature to the set endpoint at a rate of 10°C / min in a sealed aluminum pan to assess the thermal stability and moisture / solvent residue of the sample.

[0130] 3) Chemical and residual solvent analysis:

[0131] Ultra-high performance liquid chromatography (UPLC) detection:

[0132] A Waters HSST3 column (column temperature 45℃) was used for detection at a flow rate of 0.65 mL / min under UV 210 nm. The mobile phase consisted of 0.1% methanesulfonic acid aqueous solution (A) and acetonitrile (B). The gradient elution program was as follows: 0–8.20 min, B increased from 2% to 50%; 8.20–9.00 min, B increased from 50% to 100%; 9.00–9.50 min, B remained at 100%; 9.50–9.51 min, B decreased to 2%; 9.51–12.00 min, A remained at 2%, to determine related substances (such as dimer impurities) and their content.

[0133] Gas chromatography (GC) detection:

[0134] A DB-624 column (25m × 200μm, 1.12μm) was used with nitrogen as the carrier gas (flow rate 1.2mL / min); the injection port temperature was 240℃, the split ratio was 20:1; the FID detector temperature was 260℃, and the hydrogen flow rate was 40mL / min; the temperature program was: 45℃ held for 0.20min, increased to 50℃ at 2℃ / min, then increased to 250℃ at 35℃ / min and held for 3.30min; this was used to determine the residual organic solvents in the sample.

[0135] 4) Dissolution test:

[0136] The USPII method (paddle method) was used with a settling basket at 50 rpm and 37°C, with 500 mL of 0.1 N hydrochloric acid at pH 1.2 as the dissolution medium. A Waters HSST3 column (column temperature 45°C) was used with a flow rate of 1.0 mL / min and detection at UV 260 nm. The mobile phase was 0.1% methanesulfonic acid aqueous solution: acetonitrile = 40:60 (v / v) isocratic elution, and the run time was 3 min. This method was used to evaluate the dissolution behavior of the formulation.

[0137] To more accurately predict the behavior of formulations in vivo, some experiments were conducted using biologically relevant media, including:

[0138] FaSSIF media:

[0139] Fasted State Simulated Intestinal Fluid (FaSSIF) is a medium used to simulate the small intestinal environment of a person in a fasting state. Its formula and preparation method can be found in references (e.g., J Dressman et al., Pharm Res., 1998, 15(1), 11-22). The pH value of the FaSSIF medium used in this instruction manual is approximately 6.5.

[0140] SGF medium: Simulated Gastric Fluid (SGF) is usually a hydrochloric acid solution with pH=1.2 or an enzyme-containing buffer solution used to simulate the gastric environment.

[0141] cFaSSIF media:

[0142] This refers to concentrated or adjusted FaSSIF media used for specific dissolution transfer experiments.

[0143] For detailed evaluation and analysis, please refer to the specific effect examples below. Example 1: Preliminary evaluation of polymer screening and ASD

[0144] This example uses a spray-dried solid dispersion (SDD) sample with a drug loading of 20 wt% of compound I to evaluate the physicochemical properties, dissolution, and preliminary stability of the product obtained by the technical solution provided in this embodiment.

[0145] 1.1) Preparation of SDD series samples:

[0146] Compound I was dissolved in a dichloromethane:methanol (1:1, v / v) mixture with different polymers (mass ratio 1:4) to prepare the solution (compound I concentration 10 mg / mL). The solution was then prepared using a BUCHIB290 spray dryer (nozzle 0.7 mm, feed rate ~18 mL / min, inlet temperature 80 °C, outlet temperature 36 °C to 44 °C). The resulting powder was then subjected to secondary drying under vacuum at 40 °C and stored at 2 °C to 8 °C. The specific formulations of the SDD samples are shown in Table 1. Table 1 Formulation of spray-dried dispersion samples (SDD-X)

[0147]

[0148] 1.2) Physicochemical characterization:

[0149] The surface powder X-ray diffraction (XRPD) results for the different formulations of spray-dried dispersions (SDD-X) listed in Table 1 are shown below. Figure 1 The superimposed images show representative powder X-ray diffraction (XRPD) spectra of amorphous solid dispersions (SDD-0 to SDD-8) with different polymer matrices.

[0150] All SDD samples (SDD-0 to SDD-8) were confirmed to be amorphous using PLM, XRPD, and mDSC.

[0151] Initial related material analysis showed that, compared with pure compound I spray-dried powder (SDD-0), all polymer-containing SDDs were more effective in suppressing the formation of dimer impurities (<0.05wt% vs. 0.09wt%) and had lower total impurities (0.34–0.50wt% vs. 0.6wt5%), as detailed in Table 2. Table 2 Initial characterization results of SDD-X related substances

[0152]

[0153] 1.3) Evaluation of dissolution performance:

[0154] 1.3.1) Kinetic solubility in FaSSIF: The sample was placed in a fasting simulated intestinal fluid (FaSSIF) medium according to the solubility detection method described above to detect the dissolution of compound I in SDD. Detailed detection data are shown in Table 3.

[0155] Table 3 shows the following:

[0156] All SDD-X samples showed superior solubility compared to the active pharmaceutical ingredient Ritlecitinib, with SDD-2 (PVP VA64) and SDD-4 (Methocel) showing the best solubility. TM E3 Premium LV), SDD-6 (HPMCP), and SDD-7 (HPC) exhibited high solubility and good retention. Table 3. Kinetic solubility of SDD-X in FaSSIF medium

[0157]

[0158] 1.3.2) Two-step dissolution test:

[0159] The screened SDD-2, 4, 5, 6, and 7 underwent a two-step dissolution test simulating the gastrointestinal tract (first SGF pH 1.3, then transferred to cFaSSIF). The specific method is as follows:

[0160] Weigh appropriate amounts of SDD-2, SDD-4, SDD-5, SDD-6, and SDD-7 (containing 1200 mg of compound I) into 100 mL glass bottles, then add 9 mL of SGF (pH 1.3). Stir magnetically at 150 rpm for 30 min at 37 °C. Take 1 mL of the suspension and centrifuge (14000 rpm, 2 min) to separate the supernatant. Dilute with diluent for UPLC analysis. Immediately afterward, add 16 mL of cFaSSIF (pH 12.1) to a concentration of 50 mg / mL for target compound I. Continue stirring. At each time point of 15 min, 30 min, 60 min, and 120 min, take 500 µL of the suspension and centrifuge (14000 rpm, 2 min) to separate the supernatant. Dilute with diluent for UPLC analysis. Finally, measure the pH value of the solution with a pH meter. The relevant detection data are shown in Table 4. Table 4. Two-step dissolution results of the preferred SDD-X

[0161]

[0162] Table 4 shows the results:

[0163] SDD-2 (PVP VA64), SDD-4 (Methocel® E3 Premium LV), and SDD-5 (HPMCAS-MG) all exhibited excellent dissolution and retention in both media.

[0164] 1.4) Preliminary stability evaluation:

[0165] The above-mentioned preferred SDD samples and the active pharmaceutical ingredient Ritlecitinib were subjected to an 8-week stability study at 60°C (open) and 40°C / 75%RH (open / closed). The accelerated stability comparison results of the preferred SDD and the active pharmaceutical ingredient, represented by the dimer impurities (wt%) contained in the samples, can be obtained as shown in Table 5. Table 5. Comparison of accelerated stability between the preferred SDD-X and the active pharmaceutical ingredient.

[0166]

[0167] Table 5 shows the results:

[0168] All SDDs significantly outperformed Ritlecitinib API in inhibiting the growth of dimer impurities. In particular, after 8 weeks of storage at 40°C / 75%RH in a closed container, the dimer impurities of SDD-4 (Methocelᵀᴹ E3 Premium LV) and SDD-5 (HPMCAS-MG) were still controlled below 0.10%, demonstrating the best chemical stability.

[0169] Example 2: Optimization and Evaluation of Drug Loading

[0170] This effect study used Methocel® E3 Premium LV as the matrix to investigate the effect of different drug loadings (20%, 30%, 40%, 50%) on the properties of ASD.

[0171] 2.1) Preparation and basic characterization: Test samples SDD-X (SDD-4, 9, 10, 11) with different drug loadings were prepared according to the method in Example 1. Then, they were characterized and detected by PLM, XRPD, mDSC, GC and UPLC respectively. The specific detection data are shown in Table 6. Table 6 Characterization data of Methocel® E3 Premium LV test samples with different drug loadings

[0172]

[0173] Among them, the superimposed powder X-ray diffraction (XRPD) spectra of representative amorphous solid dispersions (SDD-9 to SDD-11) with different drug loadings based on Methocelᵀᴹ E3 Premium LV are shown in the figure below. Figure 2 As shown.

[0174] Table 6 shows the following:

[0175] PLM and XRPD confirmed that all samples were amorphous; and

[0176] As the drug loading increased from 20% to 50%, the glass transition temperature (Tg) of the system decreased (from 126.2℃ to 121.5℃), the initial dimer impurities increased slightly (from <0.05% to 0.07%), and the solvent residue met the requirements.

[0177] 2.2) Dissolution performance:

[0178] Similar to Example 1, a two-step dissolution test was performed on SDD-9, SDD-10, and SDD-11, and compared in parallel with SDD-4. Specifically:

[0179] Approximately 1.2 g of SDD-4 (6 g), SDD-9 (4 g), SDD-10 (3 g), and SDD-11 (2.4 g) corresponding to compound I were weighed into 100 mL glass bottles. Then, 9 mL of SGF (pH 1.3) was added, and the mixture was magnetically stirred at 150 rpm for 30 min at 37 °C. 1 mL of the suspension was aspirated and centrifuged (14000 rpm, 2 min) to separate the supernatant, which was then diluted with diluent for UPLC analysis. Immediately afterwards, 16 mL of cFaSSIF (pH 12.1) was added to bring the concentration of target compound I to approximately 50 mg / mL. The mixture was then stirred continuously. At each time point of 15 min, 30 min, 60 min, and 120 min, 500 μL of the suspension was aspirated and centrifuged (14000 rpm, 2 min) to separate the supernatant, which was then diluted with diluent for UPLC analysis. Finally, the pH value of the solution was measured using a pH meter, and the results are shown in Table 7.

[0180] The data in Table 7 shows that:

[0181] As the drug loading increased, the drug's ability to maintain concentration in FaSSIF medium decreased. However, the dissolution of all drug loadings was still significantly better than that of the active pharmaceutical ingredient Ritlecitinib (see Table 3). Furthermore, the data in Table 7 show that SDD-4 (20% drug loading) exhibited the best dissolution maintenance effect. Table 7. Two-step dissolution results of test samples with different drug loadings

[0182]

[0183] 2.3) Stability evaluation:

[0184] Appropriate amounts of each SDD-X were placed in 40 mL vials and placed under the conditions of 60℃ (open), 40℃ / 75% RH (sealed), and 40℃ / 75% RH (open) for 2, 4, and 8 weeks, respectively. The stability, represented by dimer impurities (wt%), was evaluated by detecting XRPD, mDSC, moisture, and HPLC.

[0185] The results of the 8-week stability test under different acceleration conditions are shown in Table 8.

[0186] Table 8 shows the results:

[0187] The higher the drug loading, the faster the growth rate of dimer impurities. Under the closed-cell conditions of 40°C / 75%RH, which simulates conventional drug storage, SDD-4 (20% drug loading) had only 0.08% dimer impurities after 8 weeks, which was significantly lower than that of the sample with higher drug loading (SDD-11 was 0.67%), indicating that the test sample with 20% drug loading has the best chemical stability. Table 8. Stability data of test samples with different drug loading (dimer impurities wt%)

[0188]

[0189] Example 3: Screening of solid content in spray-dried solutions

[0190] This example uses a test sample obtained from Methocel® E3 Premium LV with a 20% drug loading to investigate the effect of the solid content of the spray-dried solution on the solution properties. The specific method is as follows:

[0191] Different amounts of compound I and Methocel® E3 Premium LV were dissolved in 10 mL of dichloromethane:methanol (1:1, v / v), and the viscosity of the solution was tested. The relevant results are shown in Table 9. Table 9 Viscosity test of spray-dried solution

[0192]

[0193] Table 9 shows that:

[0194] As the solid content in the 10 mL dichloromethane:methanol = (1 / 1, v / v) mixed solvent increases, the solution gradually becomes more viscous.

[0195] Solutions with a pressure of no more than 30 mPa·s are generally suitable for spray drying operations. Therefore, Methocel® E3 Premium LV solid dispersion with 20% Compound I loading is preferred in a dichloromethane:methanol = (1 / 1, v / v) solution with a solid content of 10%.

[0196] When the solid content reaches 10% (w / v), the solution viscosity is approximately 21.3 mPa·s, which is still suitable for spray drying.

[0197] Since further increasing the solid content may lead to excessively high viscosity, affecting the atomization effect, it is preferable to use a solid content of 10% for subsequent preparation. Example 4: Preparation and characterization of ASD-I, a scale-up preparation of the preferred test sample.

[0198] Based on the aforementioned screening results, the preferred formulation (20% drug loading, Methocel® E3 Premium LV, 10% solids solution) was scaled up (5L solution scale) to obtain the scaled-up preparation ASD-I of the selected test sample. The specific method is as follows:

[0199] Using a BUCHIB290 spray dryer with the same process parameters as in Example 2, powdered ASD-I was obtained with a yield of approximately 88%.

[0200] Comprehensive characterization using XRPD, PLM, mDSC, UPLC, GC, and moisture determination confirmed that ASD-I is a high-quality amorphous solid dispersion.

[0201] in:

[0202] Figure 3 This image shows a comparison and overlay of X-ray diffraction (XRPD) spectra of representative powders from the wet product obtained by spray drying and the dry product obtained by secondary drying during the scale-up preparation of an amorphous solid dispersion (ASD-I) with Methocel® E3 Premium LV as the matrix and a drug loading of 20 wt%.

[0203] Figure 4 The representative modulation differential scanning calorimetry (mDSC) curves of the amorphous solid dispersion prepared by scale-up (ASD-I) with Methocel® E3 Premium LV as matrix and a drug loading of 20 wt% are shown.

[0204] Figure 5 Typical images of an amorphous solid dispersion (ASD-I) prepared by scale-up microscopy (PLM) with Methocel® E3 Premium LV as the matrix and a drug loading of 20 wt% are shown.

[0205] The specific test results (amorphous form, Tg, low impurities, low solvent residue) of the amorphous solid dispersion prepared by scale-up of Methocel® E3 Premium LV with a drug loading of 20 wt% are shown in Table 10. Table 10 Characterization results of the scaled-up test samples (ASD-I)

[0206]

[0207] The data listed in Table 10 show that:

[0208] The scaled-up test sample (ASD-I) exhibited amorphous morphology, Tg, low impurities, and low solvent residue, demonstrating the scalability and reproducibility of the process. Example 3

[0209] This embodiment provides a pharmaceutical composition and an oral solid dosage form prepared from the pharmaceutical composition. Preparation Example 5: Preparation of Capsules

[0210] Using the test sample (ASD-I) prepared in Effect Example 4, 50mg capsules were prepared according to the formulation in Table 11, specifically as follows:

[0211] After the ASD-I obtained from Effect Example 4 was mixed evenly with microcrystalline cellulose, anhydrous lactose, and crospovidone, glyceryl disorbate was added for lubrication. After sieving and mixing, the mixture was filled into No. 0 hydroxypropyl methylcellulose capsules. Each capsule was filled with 400 mg of the mixture (containing 250 mg of ASD-I obtained from Effect Example 4, i.e., containing 50 mg of compound I). The specific capsule formulation is shown in Table 11.

[0212] Table 11 Capsule Prescription

[0213]

[0214] The examination and testing showed that the preparation process of the above-mentioned capsules was stable and the contents of the capsules were mixed evenly. Preparation Example 6: Preparation of Tablets

[0215] The test sample (ASD-I) prepared using Effect Example 4 was used to prepare 50mg tablets according to the formulation in Table 12 via dry granulation. The specific method is as follows:

[0216] The ASD-I prepared in Example 4 was mixed with internal excipients, dry granulated, and then external disintegrants and lubricants were added and mixed. Finally, tablets were compressed to obtain tablets with a core weight of 400 mg. Table 12 50 mg tablet prescription (mg)

[0217] Example 5: Stability Study of the Pharmaceutical Functional Ingredient (ASD-I)

[0218] The stability of ASD-I prepared in Example 4 was studied under accelerated conditions (40℃±2℃ / 75%RH±5%RH) and long-term conditions (25℃±2℃ / 60%RH±5%RH), and the results are listed in Tables 13 and 14, respectively: Table 13 ASD-I Accelerated Stability Data

[0219] Table 14 Long-term stability data of ASD-I

[0220]

[0221] The data listed in Tables 13 and 14 show that:

[0222] After 6 months of accelerated storage and 6 months of long-term storage, ASD-I maintained its amorphous state and unchanged appearance, with a slight increase in moisture content within acceptable limits. Most importantly, the growth of dimer impurities and total impurities was extremely slow; after 6 months of accelerated storage, dimer impurities were only 0.08%, and after 6 months of long-term storage, they were 0.06%, far below the preset standard (0.3%), demonstrating its excellent chemical stability.

[0223] In other words, the amorphous solid dispersion ASD-I, based on polymer HPMC E3 and with a drug loading of 20 wt% of compound I, can maintain stability for at least 6 months under normal storage conditions. During this period, its solid form remains amorphous and the related substances remain stable. Example 6: Stability Study of Capsules Containing ASD-I

[0224] The stability of the capsules prepared in Preparation Example 3.1 was studied under accelerated conditions (40℃±2℃ / 75%RH±5%RH) and long-term conditions (25℃±2℃ / 60%RH±5%RH), and the results are shown in Tables 15 and 16. Table 15 Accelerated stability data for ASD-I capsules

[0225] Table 16 contains long-term stability data for ASD-I capsules.

[0226]

[0227] From Tables 15 and 16, we can see that:

[0228] After 6 months of accelerated storage at 40℃±2℃ / 75%RH±5%RH and 24 months of long-term storage at 25℃±2℃ / 60%RH±5%RH, the appearance, content, and dissolution of the contents of the capsules containing ASD-I remained stable. Furthermore, the dimer impurities were only 0.11% and the total impurities were 0.73% at the end of 24 months, demonstrating excellent long-term stability. Example 7: Stability comparison between capsules containing ASD-I and commercially available formulations.

[0229] Control capsules were prepared according to the publicly available formulation of the commercially available formulation LITFULO™ (based on the crystal form of compound I-p-toluenesulfonate) (Table 17), and their stability was compared with that of capsules containing ASD-I under the same long-term conditions. Table 17 Prescriptions for commercially available LITFULO™ capsules

[0230]

[0231] Table 18 shows the results of a long-term stability comparison between capsules containing ASD-I and crystalline capsules (LITFULO™) prepared based on the crystalline form of compound I-p-toluenesulfonate (based on dimer impurities (wt%)). Table 18

[0232]

[0233] The results in Table 18 clearly show:

[0234] The capsules containing ASD-I provided by the present invention have significant advantages in inhibiting the growth of dimer impurities. After 24 months, the ASD-I-containing capsules have a dimer impurity content of only 0.11 wt%, which is much lower than the 0.19 wt% of the control crystalline capsules. This demonstrates the outstanding effect of the present invention in solving the chemical instability problem of compound I.

[0235] Figure 6 The graph shows the long-term stability comparison between capsules containing ASD-I and crystalline capsules (LITFULO™) prepared based on the crystalline form of compound I-p-toluenesulfonate (based on dimer impurities (wt%)).

[0236] from Figure 6 In the study, it can be more clearly seen that capsules containing ASD-I have better stability than crystalline capsules based on the I-p-toluenesulfonate crystal form (LITFULO™). Example 8: Comparison of dissolution rates between capsules containing ASD-I and commercially available formulations.

[0237] Following the kinetic solubility detection method in 1.3.1-FaSSIF described above, the above-mentioned capsules containing ASD-I and the crystalline capsules based on the I-p-toluenesulfonate crystal form (LITFULO™) were respectively placed in a fasting simulated intestinal fluid (FaSSIF) medium for dissolution testing, and the results were as follows: Figure 7 The dissolution-time curves shown are for a scaled-up sample (ASD-I) containing compound I amorphous solid dispersion and a capsule containing compound I-p-toluenesulfonate (Ritlecitinib) (LITFULO™).

[0238] from Figure 7 It can be seen from this:

[0239] Capsules made from the amorphous solid dispersion prepared using this invention not only have extremely high stability, but also exhibit dissolution behavior no less than that of capsules made from the active pharmaceutical ingredient of compound I-p-toluenesulfonate, thus ensuring good oral bioavailability. They achieve both superior stability and excellent dissolution performance.

[0240] It should be reiterated that although the above-mentioned effect examples are mainly limited experiments conducted on products prepared using the preferred technical solutions provided in this embodiment, it is fully understandable to those skilled in the art that all products prepared using all technical solutions provided in this embodiment, including all optional materials and their proportions, and all operating parameter ranges, can achieve the same or similar technical effects, although they may fluctuate within a reasonable range. Therefore, this specification only provides a more detailed description of the effects of the products prepared using the optimized method, and does not provide a detailed description of the corresponding technical effects of products obtained by other possible preparation schemes.

[0241] In summary, the above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it.

[0242] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features, and such modifications or substitutions do not cause the corresponding technical solutions to deviate from the spirit and scope of the technical solutions given in the embodiments of the present invention.

Claims

1. An amorphous solid dispersion comprising 1-((2S,5R)-5-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one, with the structural formula […]. The compound I and the polymer matrix are characterized by: The polymer matrix is ​​selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate or copovidone. The mass ratio of compound I to the polymer matrix is ​​1:3 to 1:

5. After being stored for 24 months at a temperature of (25±2)℃ and a relative humidity of (60±5)%, the dimer impurities of compound I in the amorphous solid dispersion do not exceed 0.3wt%, and the total degradation products do not exceed 1.0wt%.

2. The amorphous solid dispersion according to claim 1, characterized in that, The polymer matrix is ​​hydroxypropyl methylcellulose with the trade name Methocelᵀᴹ E3 Premium LV.

3. The amorphous solid dispersion according to claim 2, characterized in that, The mass ratio of compound I to Methocel® E3 Premium LV is 1:

4.

4. The amorphous solid dispersion according to claim 1, characterized in that, The amorphous solid dispersion was prepared by spray drying.

5. The amorphous solid dispersion according to claim 4, characterized in that, In the spray drying step for preparing the amorphous solid dispersion, the inlet temperature is 75°C to 105°C and the outlet temperature is 35°C to 55°C.

6. A method for preparing the amorphous solid dispersion as described in claim 1, characterized in that, Includes the following steps: Compound I and the polymer matrix are dissolved together in a mixed solvent of dichloromethane and methanol at a mass ratio of 1:3 to 1:5 to form a solution with a solid content of 5 g / 100 mL to 15 g / 100 mL. The polymer matrix is ​​selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, or copovidone. The resulting solution was spray-dried.

7. The method according to claim 6, characterized in that: The solution has a solid content of 10 g / 100 mL, the volume ratio of dichloromethane to methanol is 1:1 to 1.5:1, and the spray drying uses a dual-fluid nozzle with an orifice diameter of 0.7 mm or 1.0 mm.

8. The method according to claim 6 or 7, characterized in that, Also includes: The spray-dried product is subjected to a secondary drying process, which is carried out under vacuum conditions at 30°C to 50°C for at least 6 hours.

9. A pharmaceutical composition, characterized in that, It comprises an amorphous solid dispersion as described in any one of claims 1 to 5 and one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition is an oral solid dosage form comprising: The composition comprises 50% to 70% by weight of the amorphous solid dispersion as described in any one of claims 1 to 5, microcrystalline cellulose, lactose, crospovidone, and glyceryl disorbate.

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