A new crystal form of maropitant and its preparation method

Abstract

A new crystalline form of maropitant and its preparation method. The present invention provides an amorphous maropitant citric acid compound, its preparation method, pharmaceutical composition, and its use. The amorphous maropitant citric acid compound disclosed herein has stable properties, good water solubility, and high bioavailability, providing an effective solution for improving drug safety and efficacy. Furthermore, the preparation method of the amorphous maropitant citric acid compound disclosed herein is simple, has high yield, and high purity, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and in particular to a preparation method of a new crystal form of maropitant and uses thereof. Background Art

[0002] Maropitant's chemical name is (2S, 3S)-2-diphenylmethyl-N-(5-tert-butyl-2-methoxybenzyl)quinuclidine-3-amine. It is a type of alternative quinine drug and a receptor antagonist of neurokinin type 1 (NK1). It can act on the central nervous system by inhibiting substance P (a key neurotransmitter that causes vomiting). Therefore, maropitant can inhibit peripheral and central vomiting. Maropitant has also been developed as a citrate monohydrate with the trade name Cerenia (antiemetic), which was originally developed by Pfizer. In 2007, the FDA approved this drug for the prevention and treatment of acute vomiting in dogs and was subsequently approved for prescription use in cats. The chemical structure of the already marketed maropitant citrate monohydrate is as follows:

[0003]

[0004] Pfizer's patent CN1353711A discloses a crystalline form of maropitant citrate monohydrate and its preparation method. However, this crystalline form suffers from poor water solubility and physicochemical stability. Patent CN106977512A discloses a method for preparing maropitant free base, but this maropitant free base crystalline form suffers from poor solubility. Apart from this, there are few prior art reports on other crystalline forms of maropitant.

[0005] It is well known that different salt forms or crystal forms of drugs may exhibit different colors, melting points, stabilities, apparent solubilities, and dissolution rates. These properties directly impact the stability, solubility, hygroscopicity, and bioavailability of drug formulations, leading to differences in drug quality and clinical efficacy. The preparation and study of new crystal forms of maropitant have the potential to further improve the in vitro dissolution and in vivo absorption properties of finished drugs, thereby enhancing their clinical value, which is highly significant. Summary of the Invention

[0006] The object of the present invention is to provide an amorphous maropitant citric acid with stable properties and good water solubility, a preparation method thereof, a pharmaceutical composition and use thereof.

[0007] The present invention provides an amorphous maropitant citrate compound. The compound is subjected to X-ray powder diffraction using a Cu Ka radiation source, and the X-ray powder diffraction pattern thereof has no characteristic peaks. Preferably, the compound has substantially Figure 1 、 Figure 4 or Figure 5 The X-ray powder diffraction pattern shown is characteristic.

[0008] The present invention provides a method for preparing amorphous maropitant citric acid as shown below, which comprises the following steps:

[0009] A. Dissolve the crude product of maropitant citrate hydrate by heating with a solvent;

[0010] B. Filter, concentrate the filtrate to dryness under reduced pressure, and dry the obtained product under reduced pressure to obtain amorphous maropitant citrate.

[0011] In step A, the solvent is acetone, and the temperature range of heating and dissolving is 25°C to 60°C; the volume mass ratio of the solvent acetone to the crude maropitant citric acid is 12:1 to 2:1 mL / g, preferably 4:1 to 6:1 mL / g; in step B, the temperature range of the reduced pressure concentration is 35°C to 50°C; the temperature range of the reduced pressure drying is 60°C to 75°C.

[0012] In step A, the crude maropitant citric acid can be treated with maropitant free base to form a citrate by any conventional salt-forming method. However, considering the yield of the reaction itself and impurities, the preferred preparation method is the following method:

[0013] C. Dissolve maropitant free base and citric acid monohydrate in acetone;

[0014] D. Reflux to dissolve, filter hot, add methyl tert-butyl ether dropwise to the filtrate, let stand at room temperature for crystallization, filter, and wash the filter cake with methyl tert-butyl ether.

[0015] In step C, the mass ratio of citric acid monohydrate to maropitant free base is 0.45:1 to 0.5:1; the volume mass ratio of acetone to maropitant free base is 5:1 to 10:1 mL / g.

[0016] In step D, the volume-to-mass ratio of the methyl tert-butyl ether to the maropitant free base is 5:1 to 10:1.

[0017] The present invention also provides a pharmaceutical composition comprising the above-mentioned amorphous maropitant citrate as an active ingredient and pharmaceutically acceptable excipients or auxiliary ingredients. The composition is preferably in the form of a solution, injection, mixture, lotion, aerosol, spray, powder, pill, tablet, film, ointment, suppository, or paste.

[0018] The present invention also provides use of the amorphous maropitant citric acid in preparing medicines for treating and preventing vomiting.

[0019] The pharmaceutically acceptable excipients or auxiliary ingredients described in the present invention are commonly used excipients or excipients for preparing the above-mentioned preparations, which are well known in the art. Commonly used excipients or excipients for oral preparations or injections include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, antibacterial agents, disintegrants, etc. Adhesives such as syrup, gum arabic, gelatin, starch slurry, povidone, cellulose derivatives, etc.; fillers such as lactose, dextrin, starch and its derivatives, cellulose derivatives, inorganic calcium salts, mannitol, agar powder, etc.; lubricants such as micropowdered silica gel, stearic acid and its salts, talc, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants such as starch and its derivatives, cross-linked povidone, cellulose derivatives, etc.; wetting agents such as water, alcohols or other organic solvents, etc. Commonly used excipients or adjuvants for injections include, but are not limited to: antioxidants such as sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, etc.; antibacterial agents such as phenol, benzyl alcohol, chlorobutanol, etc.; regulators such as hydrochloric acid, citric acid, potassium hydroxide (sodium), buffers, etc.; emulsifiers such as polysorbate 80, lecithin, soy lecithin, etc.; solubilizers such as Tween 80, etc. Furthermore, the active ingredient can be combined with a pharmaceutically acceptable sustained-release carrier to prepare a sustained-release preparation according to methods for preparing sustained-release preparations well known in the art.

[0020] The composition of the present invention may be in the form of a liquid preparation, a solid preparation, or a semisolid preparation, preferably in the form of a commonly used preparation such as an oral solution, an injection, or a tablet.

[0021] The amorphous maropitant citric acid provided by the present invention has more stable properties, better water solubility, and high bioavailability compared with the existing maropitant citric acid monohydrate crystal form and maropitant free base, thereby providing an effective solution for improving the safety and effectiveness of drugs. In addition, the amorphous maropitant citric acid provided by the present invention has a simple preparation process and a high yield, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 X-ray powder diffraction pattern of the amorphous maropitant citric acid prepared in Example 1.

[0023] Figure 2 TGA spectrum of the amorphous maropitant citric acid prepared in Example 1.

[0024] Figure 3 DSC spectrum of the amorphous maropitant citric acid prepared in Example 1.

[0025] Figure 4 X-ray powder diffraction pattern of the amorphous maropitant citric acid prepared in Example 2.

[0026] Figure 5 X-ray powder diffraction pattern of the amorphous maropitant citric acid prepared in Example 3. DETAILED DESCRIPTION

[0027] All raw materials and equipment in the present invention are known products and are obtained by purchasing commercially available products.

[0028] Among them, the raw material maropitant free base (chemical name: (2S, 3S)-2-diphenylmethyl-N-(5-tert-butyl-2-methoxybenzyl alcohol) quinuclidine-3-amine) is a well-known compound and is prepared according to the method reported in existing literature.

[0029] Example 1 Preparation of Amorphous Maropitant Citrate

[0030] 500.0 g of maropitant free base (HPLC content 98.0%) and 224.0 g of citric acid monohydrate were dissolved in 3.5 L of acetone, the temperature was raised to reflux for dissolution, and the mixture was hot filtered. 3.5 L of methyl tert-butyl ether was added dropwise to the filtrate, and the mixture was allowed to stand at room temperature overnight for crystallization. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether to obtain 688.0 g of crude maropitant citric acid monohydrate with a yield of 95.0%.

[0031] 688.0 g of crude maropitant citric acid monohydrate was added to 2.8 L of acetone and heated to 50° C. for dissolution. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure at 40° C. The obtained sample was dried under reduced pressure at 70° C. for 72 hours to obtain 685.7 g of white powdered amorphous maropitant citric acid with a yield of 100%, an HPLC assay of 100.10%, and an HPLC purity of 99.91%.

[0032] Karl Fischer moisture test method:

[0033] Accurately weigh 0.2 g of this product and determine the moisture content according to the moisture determination method (Chinese Pharmacopoeia Part IV 2015 edition). The moisture content is 1.28%.

[0034] Loss on drying test:

[0035] Accurately weigh 1.0 g of this product and determine the loss on drying according to the loss on drying method (Chinese Pharmacopoeia Volume IV 2015 Edition). The loss on drying result is 2.29%.

[0036] Figure 2 Provided is a TGA spectrum of amorphous maropitant citric acid prepared by the preparation method of this example; Figure 3 A DSC spectrum of amorphous maropitant citric acid prepared by the preparation method of this embodiment is provided; at the same time, the residual solvent test shows that the residual acetone result is 0.87%, and the residual methyl tert-butyl ether result is 0.16%. Combined with the results of the moisture and solvent residual determinations, the results are consistent with the above-mentioned drying loss results and the TGA results.

[0037] Example 2 Preparation of Amorphous Maropitant Citrate

[0038] 500.0 g of maropitant free base (HPLC content 98.0%) and 250.0 g of citric acid monohydrate were dissolved in 2.5 L of acetone, and the temperature was raised to reflux for reaction for 1 hour. The mixture was filtered hot, and 5.0 L of methyl tert-butyl ether was added dropwise to the filtrate. The mixture was allowed to stand at room temperature overnight for crystallization, and filtered. The filter cake was washed with methyl tert-butyl ether to obtain 673.5 g of crude maropitant citric acid monohydrate with a yield of 93.0%.

[0039] 673.5 g of crude maropitant citric acid monohydrate was added to 4.0 L of acetone and heated to 40° C. to dissolve, filtered, and the filtrate was concentrated to dryness under reduced pressure at 50° C. The obtained sample was dried under reduced pressure at 75° C. for 65 hours to obtain 671.2 g of white powdered amorphous maropitant citric acid, with a yield of 100%, an HPLC assay of 99.95%, and an HPLC purity of 99.92%.

[0040] Karl Fischer moisture test method:

[0041] Accurately weigh 0.2 g of this product and determine the moisture content according to the moisture determination method (Chinese Pharmacopoeia Part IV 2015 edition). The moisture content is 1.29%.

[0042] Loss on drying test:

[0043] Accurately weigh 1.0 g of this product and determine the loss on drying according to the loss on drying method (Chinese Pharmacopoeia Part IV 2015 edition). The loss on drying result is 2.30%.

[0044] Figure 4 An X-ray powder diffraction pattern of the amorphous maropitant citrate is provided.

[0045] Example 3 Preparation of Amorphous Maropitant Citrate

[0046] 500.0 g of maropitant free base (HPLC content 98.0%) and 225.0 g of citric acid monohydrate were dissolved in 5 L of acetone, and the temperature was raised to reflux for reaction for 1 hour. The mixture was filtered hot, and 5 L of methyl tert-butyl ether was added dropwise to the filtrate. The mixture was allowed to stand at room temperature overnight for crystallization, and filtered. The filter cake was washed with methyl tert-butyl ether to obtain 681.0 g of crude maropitant citric acid monohydrate with a yield of 94.0%.

[0047] 681.0 g of crude maropitant citric acid monohydrate was added to 8.3 L of acetone and heated to 25° C. to dissolve, filtered, and the filtrate was concentrated to dryness under reduced pressure at 35° C. The obtained sample was dried under reduced pressure at 60° C. for 80 hours to obtain 678.7 g of white powdered amorphous maropitant citric acid, with a yield of 100%, an HPLC content of 99.92%, and an HPLC purity of 99.85%.

[0048] Karl Fischer moisture test method:

[0049] Accurately weigh 0.2 g of this product and determine the moisture content according to the moisture determination method (Chinese Pharmacopoeia Part IV 2015 edition). The moisture content is 1.30%.

[0050] Loss on drying test:

[0051] Accurately weigh 1.0 g of this product and determine the loss on drying according to the loss on drying method (Chinese Pharmacopoeia Part IV 2015 edition). The loss on drying result is 2.31%.

[0052] Figure 5 An X-ray powder diffraction pattern of the amorphous maropitant citrate is provided.

[0053] Example 4 Preparation of Amorphous Maropitant Citrate

[0054] 688.0 g of crude maropitant citric acid monohydrate was added to 1.4 L of acetone and heated to 60° C. for dissolution. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure at 40° C. The obtained sample was dried under reduced pressure at 70° C. for 72 hours to obtain 685.7 g of amorphous maropitant citric acid with a yield of 100%, an HPLC content of 99.97%, and an HPLC purity of 99.84%.

[0055] Karl Fischer moisture test method:

[0056] Accurately weigh 0.2 g of this product and determine the moisture content according to the moisture determination method (Chinese Pharmacopoeia Part IV 2015 edition). The moisture content is 1.28%.

[0057] Loss on drying test:

[0058] Accurately weigh 1.0 g of this product and determine the loss on drying according to the loss on drying method (Chinese Pharmacopoeia Volume IV 2015 Edition). The loss on drying result is 2.29%.

[0059] Example 5 Sustained-release tablets prepared from amorphous maropitant citric acid of the present invention

[0060]

[0061] The prepared amount of amorphous maropitant citric acid, hydroxypropyl methylcellulose and lactose are mixed evenly, sieved, added with 75% ethanol solution to prepare a soft material, passed through a 20-mesh sieve to prepare wet granules, dried at about 50°C, sieved through a 20-mesh sieve to prepare granules, added with magnesium stearate and talc, mixed evenly and then tableted.

[0062] Example 6 Capsules prepared from amorphous maropitant citric acid of the present invention

[0063]

[0064] The amorphous maropitant citric acid and starch in the amount to be prepared are mixed evenly by an equal amount increasing method, and then mixed evenly with microcrystalline cellulose, granulated, and filled into capsules to obtain the product.

[0065] Example 7 Sublingual tablets prepared from amorphous maropitant citric acid of the present invention

[0066]

[0067] The raw materials and auxiliary materials were sieved through a 100-mesh sieve. The amorphous maropitant citric acid and low-substituted hydroxypropyl methylcellulose to be prepared were mixed in equal and increasing amounts, and then mannitol and lactose starch were added in sequence, and finally sweet orange flavor and magnesium stearate were added. After mixing evenly, tablets were pressed.

[0068] Comparative Example:

[0069] Maropitant citrate was prepared by the following method. The different solvent types, processing conditions, and the resulting crystal types and qualities are shown in Table 1 below:

[0070] A. Dissolving the crude product of maropitant citric acid hydrate prepared by the prior art by heating with a solvent;

[0071] B. After recrystallization, dry or filter, concentrate the filtrate to dryness under reduced pressure, and dry the obtained product under reduced pressure.

[0072] Table 1 Solvent types, treatment conditions and resulting crystal forms

[0073]

[0074]

[0075] The applicant of the present invention has screened a large number of solvents, and only acetone can obtain amorphous maropitant citric acid under reduced pressure concentration. The volume mass ratio of the solvent acetone to the crude maropitant citric acid monohydrate must be 20:1 to 2:1 mL / g, and the temperature range for reduced pressure concentration must be 35°C to 50°C; the temperature range for reduced pressure drying must be 60°C to 75°C. If the solvent volume ratio, concentration temperature or drying temperature is not within the above range, mixed crystals consisting of amorphous maropitant citric acid and citric acid monohydrate crystal form will be obtained, or the solvent residue and impurity content of the obtained amorphous maropitant citric acid will be too high.

[0076] The beneficial effects of the present invention are demonstrated by experimental examples below.

[0077] Experimental Example 1: Crystalline Solubility Test

[0078] Test group 1: amorphous maropitant citric acid prepared in Example 1 of the present invention;

[0079] Control group 1: maropitant citrate monohydrate prepared according to the method disclosed in the existing literature (Example 1 of CN1353711A);

[0080] Control group 2: Maropitant free base prepared according to the method disclosed in the existing literature (Example 5 of CN106977512A).

[0081] Weigh 0.5 g of the test sample and place it in water at 25 ± 2°C. Shake vigorously for 10 seconds every 1 minute. Observe the dissolution within 3 minutes. If no dissolved particles are visible, it is considered completely dissolved. If dissolved particles are visible, add 10 times the volume of water (i.e., 5 ml of water) equal to the weight of the test sample and repeat the above steps until it is completely dissolved. Record the total amount of water used. The results are shown in Table 2.

[0082] Table 2 Solubility of different crystal forms

[0083]

[0084] The solubility test results in Table 1 show that the water solubility of the free base of maropitant is extremely poor and is almost insoluble in water. The amount of water required for the citric acid dissolution of the amorphous maropitant prepared by the present invention and the time required for complete dissolution are significantly less than those of the maropitant citric acid monohydrate crystalline form disclosed in the prior art. In other words, the citric acid solubility of the amorphous maropitant disclosed by the present invention is significantly better than that of the maropitant citric acid monohydrate crystalline form disclosed in the prior art. Generally speaking, good water solubility may improve the bioavailability and in vivo absorption of a drug, allowing it to be developed into more dosage forms and improving the efficacy of clinical medication.

[0085] Experimental Example 2: Crystal Stability Effect Test

[0086] 1. Experimental methods

[0087] (1) Preparation of test samples

[0088] Test group 1: amorphous maropitant citric acid prepared in Example 1 of the present invention;

[0089] Control group 1: maropitant citrate monohydrate prepared according to the method disclosed in the existing literature (Example 1 of CN1353711A);

[0090] Control group 2: Maropitant free base prepared according to the method disclosed in the existing literature (Example 5 of CN106977512A).

[0091] (2) Stability test conditions include: (1) Thermal degradation: approximately 200 mg of the sample was placed in a 60°C drying oven; (2) Photodegradation: approximately 200 mg of the sample was placed in an environment with an illumination of 4500 ± 500 1x; (3) High humidity degradation: approximately 200 mg of the sample was placed in a desiccator containing a saturated KNO3 solution at room temperature. The stability test results are shown in Table 3.

[0092] 2. Experimental results

[0093] Table 3 Stability test results

[0094]

[0095]

[0096] The test results in Table 2 show that the purity of the amorphous maropitant citric acid prepared by the present invention did not change significantly under conditions of high heat, high humidity, and light. However, the purity of the maropitant citric acid monohydrate in Control Group 1 and the maropitant free base in Control Group 2 decreased under conditions of high heat, high humidity, and light.

[0097] It can be seen that the amorphous maropitant citric acid prepared by the present invention has more stable and controllable quality than the maropitant citric acid monohydrate and maropitant free base disclosed in the prior art, and is suitable for the manufacture and long-term storage of pharmaceutical preparations.

[0098] Test Example 3: Bioavailability Test

[0099] Test group 1: amorphous maropitant citric acid prepared in Example 1 of the present invention;

[0100] Control group 1: maropitant citrate monohydrate prepared according to the method disclosed in the existing literature (Example 1 of CN1353711A);

[0101] Eight healthy male beagle dogs were randomly divided into two groups of four dogs each. Each group was orally administered amorphous maropitant citrate or maropitant citrate monohydrate at a dose equivalent to 8 mg / kg (calculated as maropitant free base). The test samples were prepared into an aqueous solution at a concentration of 1 mg / mL before administration. The beagle dogs fasted for 12 hours before administration and resumed feeding 4 hours after administration. Blank blood was drawn before administration, and 4 ml of blood was drawn from the forelimb vein at preset time intervals of 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 24 hours after administration. The blood was placed in a heparinized centrifuge tube and centrifuged at 4000 rpm for 10 minutes to separate the plasma. The supernatant was taken and the concentration of maropitant in the plasma was determined. The pharmacokinetic parameters were calculated. The results are shown in Table 4. The pharmacokinetic parameters of each group were compared using one-way analysis of variance (AVOVA), and P < 0.05 or P < 0.01 was considered to be a significant difference.

[0102] Table 4 Comparison results of pharmacokinetic parameters

[0103] Subjects AUC (ng·h / mL) T1 / 2(h) Tmax(h) Cmax (ng / mL) Experimental group 1 <![CDATA[9450±72.4 ## ]]> 5.2±0.1 <![CDATA[1.6±0.1 # ]]> <![CDATA[978±18.6 ## ]]> Control group 1 7760±63.2 5.4±0.1 1.7±0.1 776±17.4

[0104] Compared with the crystal form of maropitant citrate monohydrate, # P<0.05, ## P<0.01.

[0105] The test results in Table 3 show that compared with the existing product, maropitant citrate monohydrate, the average area under the plasma concentration-time curve (AUC) value of amorphous maropitant citrate increased by about 21.7%, and the peak concentration (Cmax) increased by 26%. This indicates that under the same dosage conditions, the amorphous maropitant citrate of the present invention has an approximately 21.7% increase in the amount of drug absorbed into the human circulation compared to the prior art maropitant citrate monohydrate crystal form, and the maximum blood concentration that can be achieved is 26% higher than that of the prior art maropitant citrate monohydrate crystal form, has higher bioavailability, and can better exert its medicinal effect.

[0106] In summary, compared with the maropitant citrate monohydrate crystalline form and maropitant free base disclosed in the prior art, the amorphous maropitant citrate provided by the present invention has more stable properties, better water solubility, and significantly improved bioavailability, providing an effective solution for improving the effectiveness and safety of drugs; in addition, the preparation process of the compound of the present invention is simple, the yield is higher than the preparation method of the prior art, and it is suitable for industrial production.

Claims

1. An amorphous maropitant citric acid, characterized in that: The X-ray powder diffraction pattern of the amorphous maropitant citrate is shown in FIG1 .

2. The preparation method of amorphous maropitant citric acid according to claim 1: A. Dissolve the crude product of maropitant citrate hydrate by heating with a solvent; B. Filter, concentrate the filtrate to dryness under reduced pressure, and dry the obtained product under reduced pressure; in, In step A, the solvent is acetone, and the temperature range of heating and dissolving is 25°C to 60°C; the volume mass ratio of the solvent acetone to the crude maropitant citric acid is 12:1 to 2:1 mL / g; in step B, the temperature range of the reduced pressure concentration is 35°C to 50°C; the temperature range of the reduced pressure drying is 60°C to 75°C.

3. The preparation method according to claim 2, wherein: The volume-to-mass ratio of the solvent acetone to the crude maropitant citric acid product is 4:1 to 6:1 mL / g.

4. The preparation method according to claim 2, wherein: The crude product of maropitant citrate hydrate was prepared by the following method: C. Dissolve maropitant free base and citric acid monohydrate in acetone; D. Reflux to dissolve, filter hot, add methyl tert-butyl ether dropwise to the filtrate, let stand at room temperature for crystallization, filter, and wash the filter cake with methyl tert-butyl ether.

5. The preparation method according to claim 4, characterized in that: In step C, the mass ratio of citric acid monohydrate to maropitant free base is 0.45:1 to 0.5:1; the volume mass ratio of acetone to maropitant free base is 5:1 to 10:1 mL / g.

6. The preparation method according to claim 4, characterized in that: In step D, the volume-to-mass ratio of the methyl tert-butyl ether to the maropitant free base is 5:1 to 10:

1.

7. A pharmaceutical composition, characterized in that: The pharmaceutical preparation contains the amorphous maropitant citrate as claimed in claim 1 as an active ingredient and is prepared by adding pharmaceutically acceptable excipients or auxiliary ingredients.

8. The pharmaceutical composition according to claim 7, characterized in that: The preparations are liquid preparations, gas preparations, solid preparations and semisolid preparations.

9. The pharmaceutical composition according to claim 7, characterized in that: The preparation is a solution, injection, mixture, lotion, aerosol, spray, powder, pill, tablet, film, ointment, suppository, or paste.

10. Use of the amorphous maropitant citrate according to claim 1 in the preparation of medicaments for treating and preventing vomiting.

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