Paracetamol- amantadine hydrochloride pharmaceutical co-crystal form a, process for its preparation and use

Abstract

This invention discloses a paracetamol-amantadine hydrochloride cocrystal, its preparation method, and its uses. The active components of the cocrystal, paracetamol and amantadine hydrochloride, are the main components responsible for the antipyretic, analgesic, and antiviral effects of the over-the-counter compound paracetamol and amantadine tablets / capsules; this cocrystal can also be used to treat movement disorders in Parkinson's syndrome. The cocrystal can be obtained by water-assisted milling of raw materials or by suspending raw materials in an organic solvent with poor water content. The process is simple, environmentally friendly, stable, and has a high yield, making it suitable for industrial development. The tableting performance of the cocrystal is significantly improved compared to paracetamol crystal form I and amantadine hydrochloride, allowing for direct tableting, thereby reducing formulation costs and improving patient compliance.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to the crystal form of a acetaminophen-amantadine hydrochloride dual-drug cocrystal, its preparation method, and its uses. Background Technology

[0002] The solid-state form of drugs plays a crucial role in formulation development. Common solid-state forms include polymorphs, salts, cocrystals, and hydrates / solvates. Among these, cocrystals, a rapidly developing solid-state control strategy in recent years, utilize two or more different molecules in the same crystal lattice at a fixed stoichiometric ratio to form a solid form. These molecules are assembled through non-covalent interactions (such as hydrogen bonds, van der Waals forces, and π-π stacking), rather than being dominated by covalent or ionic bonds. When both components in the cocrystal are active pharmaceutical ingredients, it is called a drug-drug cocrystal. Studies have shown that drug-drug cocrystals, when used in combination with other drugs, have potential advantages such as improved drug molecule stability, bioavailability, and mechanical properties, making them more promising than compound formulations.

[0003] Acetaminophen (paracetamol), also known as paracetamol, is a common antipyretic and analgesic drug. Its chemical name is N-acetyl-p-aminophenol, and its molecular formula is C8H9NO2. Its structural formula is shown in formula (Ⅰ).

[0004]

[0005] Equation (I)

[0006] Acetaminophen is a common antipyretic and analgesic. Commercially available products use the thermodynamically stable crystal form I, which has poor tableting properties (Pharmaceutical Research, 2011, Vol. 28, pp. 3248-3255). For tablet production of this compound, a large amount of binder is typically required to prevent tablet breakage.

[0007] Amantadine hydrochloride, chemically named tricyclic [3,3,1,13,7]decane-1-amine hydrochloride, has the molecular formula: C 10 H 18 ClN, with the structural formula shown in formula (II):

[0008]

[0009] Formula (II)

[0010] Amantadine hydrochloride was initially developed in the 1960s and is widely used to treat influenza, Parkinson's disease, and depression due to its versatility and low cost. No polymorphism has been reported with amantadine hydrochloride, and studies have found that its tableting performance is critical in the absence of excipients. Commercially available amantadine hydrochloride tablets also contain binding excipients to improve product stability.

[0011] Acetaminophen and amantadine hydrochloride are the main active pharmaceutical ingredients in the Chinese over-the-counter drug compound acetaminophen and amantadine tablets / capsules. They exert antipyretic and analgesic effects, and antiviral effects, respectively, and are primarily used to treat symptoms caused by the common cold or influenza. Due to the aforementioned tableting defects, the formulation of compound acetaminophen and amantadine tablets typically includes high-molecular-weight excipients such as hydroxypropyl methylcellulose and microcrystalline cellulose, which act as binders. The use of a large number and variety of excipients increases the complexity and cost of the formulation process, and also increases the tablet weight, leading to swallowing difficulties for some patients.

[0012] Furthermore, literature reports that acetaminophen can protect brain dopaminergic neurons in animal models of Parkinson's syndrome through its antioxidant properties (Pharmacological Research, 2016, Vol. 109, pp. 119–131). Combining the dopaminergic and anti-glutamatergic properties of amantadine hydrochloride, the two have the potential to treat motor disorders and other neurological diseases associated with Parkinson's syndrome.

[0013] Currently, there are no reports on the preparation of cocrystals of acetaminophen and amantadine hydrochloride, two active pharmaceutical ingredients. Based on pharmacological synergies of existing compound drugs, we discovered cocrystal form A of acetaminophen–amantadine hydrochloride. This cocrystal form A exhibits unexpected direct compression properties, providing a new option for the preparation of pharmaceutical formulations for the prevention and / or treatment of colds and Parkinson's syndrome. Summary of the Invention

[0014] The present invention provides a eutectic form A of acetaminophen-amymantaline hydrochloride, wherein the molar ratio of acetaminophen to amymantaline hydrochloride in eutectic form A is 1:1.

[0015] Furthermore, the acetaminophen-amylamidine hydrochloride eutectic crystal form A is a hydrate.

[0016] Non-limiting, the molar ratio of lattice water in the acetaminophen-amylamidine hydrochloride eutectic crystal form A is between 0.5 and 1.0; preferably, the molar ratio of lattice water is between 0.5 and 0.8; preferably, the molar ratio of lattice water is 0.75, as shown in Formula III.

[0017]

[0018] Formula (III)

[0019] Using Cu-Kα radiation, the powder X-ray diffraction pattern of the acetaminophen-amylamidine hydrochloride eutectic crystal form A of the present invention has characteristic peaks at diffraction angles 2θ of 15.6±0.2°, 16.5±0.2°, 17.2±0.2°, 17.5±0.2° and 21.4±0.2°.

[0020] Furthermore, using Cu-Kα radiation, the powder X-ray diffraction pattern of the acetaminophen-amylamidine hydrochloride eutectic form A exhibits characteristic peaks at diffraction angles 2θ of 8.0±0.2°, 12.8±0.2°, 16.1±0.2°, 18.0±0.2°, 20.9±0.2°, 22.1±0.2°, 24.6±0.2°, 26.1±0.2°, 28.0±0.2°, and 28.7±0.2°.

[0021] Non-limiting, using Cu-Kα radiation, the powder X-ray diffraction pattern of eutectic form A is basically as follows: Figure 1 As shown.

[0022] The acetaminophen-amylamidine hydrochloride eutectic crystal form A of the present invention has the following unit cell parameters when the single crystal sample is tested at a temperature of 150 K: a=24.97±0.2 Å, b=12.40±0.2 Å, c=11.92±0.2 Å, α=90°, β=98.89±1°, γ=90°, and the space group is C2 / c.

[0023] The acetaminophen-amylamidine hydrochloride eutectic crystal form A of this invention is characterized by perforation in the sample crucible lid and a heating rate of 5 °C·min. −1 N2 flow rate 50 mL·min −1 Under these conditions, its differential scanning calorimetry curves show endothermic peaks at peak values ​​of 108.8±5 °C, 137.8±5 °C, and 318.6±5 °C.

[0024] This invention also relates to a mechanochemical method (also known as a milling method) for preparing acetaminophen-adamantane hydrochloride eutectic crystal form A, specifically: a small amount of solvent is added to a powder in which acetaminophen and adamantane hydrochloride are mixed at a certain molar ratio, and the mixture is mechanically or manually milled for a certain period of time, followed by drying. The resulting powder sample is acetaminophen-adamantane hydrochloride eutectic crystal form A.

[0025] Furthermore, the molar ratio of acetaminophen to amantadine hydrochloride is 1:1.

[0026] Furthermore, the solvent is one or more of water, methanol, ethanol, isopropanol, isobutanol, acetonitrile, acetone, acetic acid, dimethyl sulfoxide, tetrahydrofuran, n-propanol, and ethylene glycol; pure water is preferred as the solvent; aqueous mixed solvents may be selected; when using anhydrous organic solvents to assist milling, it should be ensured that the system is exposed to a water-containing gas environment.

[0027] Non-limiting, the ratio of solvent used to assist milling to raw material solids is 0.05~0.5 μL·mg. −1

[0028] Furthermore, the drying temperature is 25~65 °C.

[0029] This invention also relates to a solvent suspension method for preparing acetaminophen-amymantaline hydrochloride eutectic form A, specifically: acetaminophen and amymantaline hydrochloride are added to a poor organic solvent containing water in a molar ratio of 1:1, the suspension is stirred and pulped, and after filtration and drying, eutectic form A is obtained.

[0030] Furthermore, the undesirable solvent is one or more of the following: hexane, cyclohexane, heptane, pentane, petroleum ether, dichloromethane, toluene, and xylene.

[0031] Non-limiting, the ratio of water to unsuitable solvent is 0.01 to 5:100.

[0032] This invention relates to the paracetamol-amantadine hydrochloride co-crystalline form A, which can be used to relieve symptoms such as fever, headache, nasal congestion, and sore throat caused by the common cold or influenza, and can also be used for the prevention and treatment of influenza. This invention also relates to the paracetamol-amantadine hydrochloride co-crystalline form A, which can be used for the treatment of motor disorders in Parkinson's syndrome.

[0033] The beneficial effects of this invention are as follows:

[0034] 1. This invention is the first to form a cocrystalline form A of acetaminophen and amantadine hydrochloride, which effectively improves tablet compressibility compared to commercial acetaminophen form I and amantadine hydrochloride. This unexpected effect benefits both the simplification of formulation and production, and reduces the difficulty of swallowing for patients by decreasing tablet weight.

[0035] 2. The acetaminophen-amylamidine hydrochloride eutectic crystal form A disclosed in this invention can be synthesized using mechanochemical methods to obtain a highly crystalline sample, indicating that it possesses good physical stability.

[0036] 3. The acetaminophen-amylamidine hydrochloride eutectic crystal form A disclosed in this invention can be prepared by one-step milling or suspension in poor solvents. The process is simple and easy to scale up. It does not require the use of organic solvents, is green and environmentally friendly, and has no risk of solvent residue. Attached Figure Description

[0037] Figure 1 The image shows the powder X-ray diffraction pattern of the acetaminophen-amylamidine hydrochloride eutectic crystal form A prepared in Example 1.

[0038] Figure 2 Differential scanning calorimetry (DSC) of the acetaminophen-amantadine hydrochloride eutectic crystal form A prepared in Example 1.

[0039] Figure 3 This is a diagram of the asymmetric unit cell of the single crystal structure of the acetaminophen-amylamidine hydrochloride eutectic crystal form A prepared in Example 6.

[0040] Figure 4 Tensile strength diagrams for commercially available acetaminophen crystal form I, adamantane hydrochloride, and the acetaminophen-adamantane hydrochloride eutectic crystal form A prepared in Example 1.

[0041] Figure 5 Optical photographs of tablets prepared under the conditions of Experimental Example 1 for commercially available acetaminophen crystal form I, amantadine hydrochloride, and the acetaminophen-amantadine hydrochloride co-crystal form A prepared in Example 1. Detailed Implementation

[0042] The following detailed description of the present application is provided in conjunction with embodiments, but is not intended to limit the present application. Any equivalent substitutions made in the art based on the disclosure of the present application shall fall within the protection scope of the present application.

[0043] Example 1

[0044] 302.3 mg of acetaminophen and 375.4 mg of adamantane hydrochloride powder were mixed in a 10 mL stainless steel ball mill jar, 100 μL of water and three 8 mm stainless steel grinding balls were added, and the mixture was ball milled at 40 Hz for 15 min. The resulting solid was dried at 50 °C for 15 min to obtain 692.6 mg of acetaminophen-adamantane hydrochloride eutectic powder, crystal form A. Its powder X-ray diffraction pattern is shown below. Figure 1 As shown, the differential scanning calorimetry curve is as follows: Figure 2 As shown.

[0045] Example 2

[0046] 302.3 mg of acetaminophen and 375.4 mg of adamantane hydrochloride powder were mixed, and 200 μL of ethanol was added. The mixture was manually ground in an agate mortar for 15 min at room temperature. The resulting solid was dried at 50 °C for 1 h to obtain 675.1 mg of acetaminophen-adamantane hydrochloride eutectic powder, crystal form A. Its powder X-ray diffraction pattern is similar to... Figure 1 They are roughly the same.

[0047] Example 3

[0048] 302.3 mg of acetaminophen and 375.4 mg of adamantane hydrochloride powder were mixed in a 10 mL stainless steel ball mill jar, and 200 μL of a water-acetonitrile (9:1 volume ratio) mixed solvent was added. The mixture was ball-milled for 15 min at room temperature using three 8 mm stainless steel grinding balls. The resulting solid was dried at 50 °C for 2 h to obtain 679.8 mg of acetaminophen-adamantane hydrochloride eutectic powder, crystal form A. Its powder X-ray diffraction pattern is similar to... Figure 1 They are roughly the same.

[0049] Example 4

[0050] 75.6 mg of acetaminophen and 93.9 mg of adamantane hydrochloride were added to 5 mL of n-heptane, followed by 50 μL of water. The mixture was suspended at room temperature for 48 h to obtain a acetaminophen-adamantane hydrochloride co-crystalline suspension (form A). The suspension was filtered, and the resulting solid was dried at 40 °C for 6 h to obtain 159.4 mg of acetaminophen-adamantane hydrochloride co-crystalline powder (form A). Its powder X-ray diffraction pattern is similar to... Figure 1 They are roughly the same.

[0051] Example 5

[0052] 75.6 mg of acetaminophen and 93.9 mg of adamantane hydrochloride were added to 5 mL of dichloromethane, followed by 50 μL of water. The suspension was magnetically stirred at room temperature for 48 h. The suspension was then filtered, and the resulting solid was dried at 40 °C for 1 h to obtain 142.7 mg of acetaminophen-adamantane hydrochloride eutectic powder, crystal form A. Its powder X-ray diffraction pattern is similar to... Figure 1 They are roughly the same.

[0053] Example 6

[0054] 37.8 mg of acetaminophen and 46.9 mg of amantadine hydrochloride were added to a container containing 5 mL of water and stirred until the powder was completely dissolved. The solution was filtered through a 0.22 μm polytetrafluoroethylene membrane filter and allowed to stand at 50 °C for slow evaporation. After about 3 days, blocky crystals precipitated, yielding a single crystal of the acetaminophen-amantadine hydrochloride eutectic, crystal type A. The obtained crystal was subjected to single crystal testing at 150 K.

[0055] The powder sample of acetaminophen-amymantaline hydrochloride eutectic crystal form A obtained in Example 1 and the single crystal sample of acetaminophen-amymantaline hydrochloride eutectic crystal form A obtained in Example 6 were subjected to physicochemical and structural characteristic tests, specifically including the following aspects:

[0056] 1. Powder X-ray diffraction

[0057] Powder X-ray diffraction (PXRD) of the acetaminophen-amylamidine hydrochloride eutectic crystal form A prepared in Example 1 was performed using a Bruker D8 Advance diffractometer. The measurement conditions were as follows: Cu-Kα radiation source, tube current of 40 mA, tube voltage of 40 kV, scan rate of 10° / min, and range of 3°–40°. The resulting powder X-ray diffraction pattern is shown below. Figure 1 As shown in the figure, its spectrum exhibits characteristic diffraction angles and relative intensities as shown in Table 1. The sharp diffraction peaks indicate high crystallinity.

[0058] Table 1. Characteristic diffraction angles and relative intensities of acetaminophen-amantadine hydrochloride eutectic crystal form A

[0059] 1 8.0 19.6 2 12.8 35.7 3 14.0 6.2 4 14.2 10.5 5 15.6 85.5 6 16.1 33.3 7 16.5 48.7 8 17.2 79.7 9 17.5 50.5 10 18.0 35.9 11 18.5 10.1 12 20.9 32.0 13 21.4 100.0 14 22.1 15.2 15 24.6 12.3 16 26.0 26.9 17 28.0 48.7 18 28.3 11.7 19 28.7 18.6 20 31.0 7.9 21 31.8 9.0 22 32.8 7.9 23 33.2 8.3 24 34.4 10.2 25 34.7 11.5

[0060] 2. Differential scanning calorimetry analysis

[0061] The powder from Example 1 was measured using a Mettler Toledo DSC 3 differential scanning calorimeter under the following conditions: ~5 mg of powder was encapsulated in an aluminum dish with perforations; the heating temperature range was 25 °C to 375 °C; the heating rate was 5.0 °C / min; and a nitrogen gas flow rate of 50 mL / min was used. The results were as follows: Figure 2 The differential scanning calorimetry (DSC) curves are shown. Under these test conditions, the DSC curves of the acetaminophen-amantadine hydrochloride eutectic crystal form A show endothermic peaks at 108.8±5 °C, 137.8±5 °C, and 318.6±5 °C. The 108.8±5 °C peak is a dehydration peak; the high dehydration temperature indicates good thermal stability.

[0062] 3. Single crystal structure determination

[0063] Using a Bruker D8 VENTURE X-ray single-crystal diffractometer, data were collected at 150 K using enhanced Cu-Kα radiation (λ = 1.54186 Å) on the single-crystal sample of acetaminophen-adamantaneamine hydrochloride eutectic form A prepared in Example 6. The obtained data were solved directly in the OLEX2 program. The structure was determined to be a eutectic of acetaminophen-adamantaneamine hydrochloride dual active components, with the molar ratio of acetaminophen, adamantaneamine hydrochloride, and water set at 1:1:0.75. The crystallographic data and structural refinement parameters of eutectic form A are shown in Table 2, and the asymmetric unit cell structure diagram is shown below. Figure 3 As shown. The cell parameters are: a=24.9659(5) Å, b=12.4043(3) Å, c=11.9232(3) Å, α=90°, β=98.8900(1)°, γ=90°, and the space group is C2 / c.

[0064] Table 2. Crystallographic data and structural refinement parameters of acetaminophen-amantadine hydrochloride eutectic crystal form A

[0065] Empirical formula <![CDATA[C8H9NO2·C 10 H 18 ClN·0.75H2O]]> Formula weight 352.38 Temperature / K 150 Crystal system monoclinic Space group C2 / c a / Å 24.9659 (5) b / Å 12.4043 (3) c / Å 11.9232 (3) α / ° 90 β / ° 98.8900 (1) γ / ° 90 <![CDATA[V / Å 3 ]]> 3648.07 (15) Z 8 / 1 <![CDATA[Calculated density (g / cm 3 )]]> 1.283 <![CDATA[Absorption coefficient (mm -1 )]]> 1.987 F (000) 1516 <![CDATA[R int ]]> 0.0207 Independent reflections 3578 GOF 1.087 Final R indexes [I ≥ 2σ (I)] <![CDATA[R1= 0.0397, wR2= 0.1042]]> Final R indexes [all data] <![CDATA[R1= 0.0403, wR2= 0.1046]]>

[0066] Test Example 1: Tensile Strength Test

[0067] To demonstrate that the compressibility of the acetaminophen-amantadine hydrochloride co-crystal form A of this invention is significantly superior to that of acetaminophen and amantadine hydrochloride, tableting was performed using a manual tablet press within a pressure range of 50 to 350 MPa. To ensure the repeatability of the results, each tableting experiment was repeated three times. During tableting, a circular flat punch with a diameter (D) of 8 mm was selected, and approximately 100 mg of acetaminophen-amantadine hydrochloride co-crystal form A was added and compressed into circular tablets. After being left at room temperature for 24 hours to allow for complete elastic recovery, the crushing force (F) was tested using a YPD-200C tablet hardness tester, and the tablet thickness was measured using vernier calipers. Acetaminophen (crystal form I) and amantadine hydrochloride were used as controls, and tests were conducted under the same conditions. The formula was used... 2F / The tensile strengths of acetaminophen crystal form I, amantadine hydrochloride, and the acetaminophen-amantadine hydrochloride eutectic form A of this invention were calculated under different pressures. Under a given pressure, a higher tensile strength indicates better compressibility. Generally, a tensile strength higher than 1.7 to 2.0 MPa is considered sufficient to maintain tablet integrity during production (Journal of Drug Delivery Science and Technology, 2018, Vol. 46, pp. 1–6); otherwise, a large amount of binder excipients is required to prevent breakage. For example... Figure 4 and Figure 5 As shown, acetaminophen crystal form I is consistently difficult to compress into tablets within a pressure range of 50 to 350 MPa, while amantadine hydrochloride, although it can form tablets, only barely meets the tensile strength requirement at 150 MPa. Surprisingly, the acetaminophen-amantadine hydrochloride co-crystal form A exhibits excellent mechanical properties. Within a compression pressure range of 150 to 350 MPa, the tensile strength of the co-crystal formulation consistently exceeds 1.9 MPa, and particularly reaches 2.66 MPa at 200 MPa. These results indicate that the acetaminophen-amantadine hydrochloride co-crystal form A can be produced via direct compression over a wide range of process parameters. Given that the combination formulation of acetaminophen crystal form I and amantadine hydrochloride is a high-dose product, the excellent direct compression performance of the co-crystal promises to avoid the use of binder excipients, thereby reducing production costs and tablet weight.

[0068] Furthermore, the inventors of this case also conducted corresponding experiments and verifications based on the above embodiments, using other raw materials, process operations, and process conditions mentioned in this specification. The experimental results show that all of them can achieve relatively ideal results.

[0069] It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds and their preparation methods without departing from the spirit or scope of this application. Therefore, the scope of protection of this application covers various modifications and variations made to this application, as long as the modifications or variations are within the scope covered by the claims and their equivalent embodiments.

Claims

1. A eutectic crystal form A of acetaminophen-amantadine hydrochloride, characterized in that, Acetaminophen and amantadine hydrochloride, two pharmacologically active compounds, crystallize in the same crystalline phase at a molar ratio of 1:

1.

2. The acetaminophen-amymantaline hydrochloride eutectic crystal form A according to claim 1, characterized in that, Using Cu-Kα radiation, the powder XRD pattern of crystal form A, expressed at a 2θ angle, has characteristic peaks at 15.6±0.2°, 16.5±0.2°, 17.2±0.2°, 17.5±0.2°, and 21.4±0.2°.

3. The acetaminophen-amymantaline hydrochloride eutectic crystal form A according to claim 1, characterized in that, Using Cu-Kα radiation, the powder XRD pattern of crystal form A, expressed at 2θ angles, exhibits characteristic peaks at 8.0±0.2°, 12.8±0.2°, 16.1±0.2°, 18.0±0.2°, 20.9±0.2°, 22.1±0.2°, 24.6±0.2°, 26.1±0.2°, 28.0±0.2°, and 28.7±0.2°.

4. The acetaminophen-amymantaline hydrochloride eutectic crystal form A according to claim 1, characterized in that, When the test temperature is 150 K, the single crystal cell parameters are: a=24.97±0.2 Å, b=12.40±0.2 Å, c=11.92±0.2 Å, α=90°, β=98.89±1°, γ=90°, and the space group is C2 / c.

5. The acetaminophen-amymantaline hydrochloride eutectic crystal form A according to claim 1, characterized in that, Its differential scanning calorimetry curve has endothermic peaks at peak values ​​of 108.8±5 °C, 137.8±5 °C and 318.6±5 °C.

6. The acetaminophen-amylamidine hydrochloride eutectic crystal form A according to claim 1 is a hydrate.

7. The method for preparing the acetaminophen-amymantaline hydrochloride eutectic crystal form A according to any one of claims 1 to 6 is a milling method. It is characterized in that... Add an appropriate amount of solvent to the powder of acetaminophen and adamantane hydrochloride mixed in a molar ratio of 1:1, and grind for a certain period of time to obtain eutectic crystal form A.

8. The method for preparing acetaminophen-amymantaline hydrochloride eutectic crystal form A as described in claim 7, characterized in that, The solvent is water or an aqueous solvent; or the operating system is exposed to a water-containing gas environment.

9. The method for preparing the acetaminophen-amymantaline hydrochloride eutectic crystal form A according to any one of claims 1 to 6 is a solvent suspension method, characterized in that, Acetaminophen and adamantane hydrochloride were added to a poor organic solvent containing water at a molar ratio of 1:

1. The suspension was stirred and pulped, and after filtration and drying, eutectic crystal form A was obtained.

10. The method for preparing acetaminophen-amymantaline hydrochloride eutectic crystal form A as described in claim 9, characterized in that, The undesirable solvent is one or more of the following: hexane, cyclohexane, heptane, pentane, petroleum ether, dichloromethane, toluene, and xylene.

11. The use of the acetaminophen-amantadine hydrochloride co-crystal A according to any one of claims 1 to 9 in the preparation of a pharmaceutical formulation for the prevention and / or treatment of colds and Parkinson's syndrome.

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