CN115322150B

CN115322150B - Solid of deuterated dextromethorphan hydrobromide, preparation method and medical application thereof

Info

Publication number: CN115322150B
Application number: CN202210504226.XA
Authority: CN
Inventors: 许文杰; 李松; 肖瑛; 李亲泽; 连小磊; 华怀杰
Original assignee: Shenzhen Salubris Pharmaceuticals Co Ltd
Current assignee: Shenzhen Salubris Pharmaceuticals Co Ltd
Priority date: 2021-05-11
Filing date: 2022-05-10
Publication date: 2024-05-28
Anticipated expiration: 2042-05-10
Also published as: CN115322150A

Abstract

The invention belongs to the technical field of chemical medicines, and provides a solid of deuterated dextromethorphan hydrobromide, a preparation method and medical application thereof, in particular to a crystal form, an amorphous form, a preparation method and medical application thereof.

Description

Solid of deuterated dextromethorphan hydrobromide, preparation method and medical application thereof

Technical Field

Background

Dextromethorphan (CAS: 125-71-3), with the English name: dextromethorphan, which is known by the chemical name (+) -3-methoxy-17-methyl- (9α,13α,14α) -morphinans, are used clinically in most pharmaceutical applications, such as dextromethorphan hydrobromide monohydrate, with the following chemical structure:

Dextromethorphan compounds that have been marketed include solid (e.g., tablets) and liquid (e.g., oral liquids) formulations that can be administered orally for dry cough without sputum, including frequent, severe cough.

Deuteration can be obtained by prior art CN101687868a, etc., in addition, deuterated dextromethorphan compound hydrobromide monohydrate can be prepared by other known methods including: CN109641849a. The structural formula is as follows:

Recently, the combined application of dextromethorphan and quinidine (deuterated or non-deuterated) is currently in clinical research stage, and is used for new indications such as false bulbar emotion, depression, surging behavior in dementia, hot flushes caused by hormone changes, night sweat symptoms and the like. Therefore, the method has important significance for further research on the stable solid form of the deuterated dextromethorphan.

Disclosure of Invention

In view of the prior art, the invention provides a series of crystalline forms and amorphous forms of deuterated dextromethorphan hydrobromide for better application of the drug. And its application in medicines for treating cough and other diseases.

Specifically, the invention provides a deuterated dextromethorphan hydrobromide crystal form B, which is characterized in that the deuterated dextromethorphan hydrobromide has a structure shown as a formula I,

The XRPD of form B has strong characteristic peaks at 11.68, 14.93, 15.43, 19.03, 21.57, 24.29 in terms of 2θ angles (°), with an error of ±0.2°.

As a preferred embodiment of the present invention, the XRPD of form B has characteristic peaks, expressed in terms of 2θ angles (°), at 11.68, 14.93, 15.43, 19.03, 21.57, 24.29 and at 14.60, 16.89, 23.43, 24.72, 26.41, 27.11, 28.98, with an error of ±0.2 °.

As a preferred embodiment of the present invention, the XRPD of form B has characteristic peaks, expressed in terms of 2θ degrees (°), at 11.68, 14.93, 15.43, 19.03, 21.57, 24.29, 14.60, 16.89, 23.43, 24.72, 26.41, 27.11, 28.98, and 7.83、9.51、15.81、16.13、17.92、19.57、20.97、22.63、25.91、28.01、28.51、29.94、30.40、31.25、31.90、32.35、32.83、35.05、35.94、36.88、38.20、39.45, with an error of ±0.2 °.

As a preferred embodiment of the present invention, the XRPD pattern of form B is shown in fig. 5 or fig. 8.

As a preferred embodiment of the present invention, DSC of form B has a maximum absorption peak at 202 ℃ + -5 ℃.

As a preferred embodiment of the present invention, the DSC chart of the crystal form B is shown in FIG. 6 or 9.

As a preferred embodiment of the present invention, the TG pattern of the crystal form B is shown in FIG. 7.

As a preferable technical scheme of the invention, the TG pattern of the crystal form B is shown in figure 10

As a preferred embodiment of the present invention, there is no distinct characteristic peak in the amorphous XRPD pattern.

As a preferred embodiment of the present invention, the amorphous XRPD is as shown in figure 11.

The invention further provides a pharmaceutical composition characterized by comprising the aforementioned deuterated dextromethorphan hydrobromide form B, or deuterated dextromethorphan hydrobromide amorphous form, and one or more pharmaceutically acceptable carriers.

The invention further provides the application of the deuterated dextromethorphan hydrobromide crystal form B or the deuterated dextromethorphan hydrobromide amorphous form in preparing medicaments for treating cough and other diseases.

The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active agents of the present invention, which does not interfere with the biological activity of the active agents and which does not have toxic or side effects to the host or patient, representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference may be made to Remington THE SCIENCE AND PRACTICE of Pharmacy,21st Ed, lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.

For a drug or pharmacologically active agent to be present in an effective or therapeutically effective amount, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "treatment" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The compound crystal form and amorphous form of the invention have the following beneficial effects compared with the crystal form in the prior art:

(1) The crystal form of the invention has better bioavailability through animal experiments, and is expected to have better clinical treatment effect.

(2) The crystal form of the invention has obviously improved stability property, and can be expected to be better used as a medicine.

(3) The preparation of the crystal forms has certain difficulty, and the applicant tries various methods, and other methods are difficult to obtain.

(4) The amorphous preparation of the invention has certain difficulty, and the amorphous preparation is required to be prepared by adopting the novel crystal form B, so that the amorphous preparation is also difficult to expect.

Drawings

FIG. 1, a schematic structural diagram of deuterated dextromethorphan hydrobromide;

FIG. 2, XRPD patterns for form A of deuterated dextromethorphan hydrobromide monohydrate of example 1;

fig. 3, DSC profile of crystalline form a of deuterated dextromethorphan hydrobromide monohydrate of example 1;

fig. 4, TG profile of crystalline form a of deuterated dextromethorphan hydrobromide monohydrate of example 1;

fig. 5, XRPD pattern of crystalline form B of deuterated dextromethorphan hydrobromide of example 2;

FIG. 6, DSC plot of form B of deuterated dextromethorphan hydrobromide of example 2;

Fig. 7, TG profile of crystalline form B of deuterated dextromethorphan hydrobromide of example 2;

FIG. 8, XRPD patterns for form B of deuterated dextromethorphan hydrobromide of example 3;

Fig. 9, DSC profile of form B of deuterated dextromethorphan hydrobromide of example 3;

fig. 10, TG profile of form B of deuterated dextromethorphan hydrobromide of example 3;

fig. 11, amorphous XRPD pattern of deuterated dextromethorphan hydrobromide of example 4.

Detailed Description

The present invention will be described in further detail with reference to examples and drawings, but embodiments of the invention are not limited thereto.

The X-ray powder diffraction (XRD) spectrum shown in the invention is obtained by detecting with a Panakey sharp (Empyrean) X-ray diffractometer, and the detection conditions are as follows: cu-K alpha radiation, wavelengthThe divergence slit is 1/4 degree, the anti-scattering slit is 1 degree, the cable-stayed slit is 0.04rad, the shading plate is 4mm, the voltage of the X-ray light tube is 45kV, the current of the X-ray light tube is 40mA, the scanning range is 3-40 degrees (2 theta), the step length is 0.026 degree, and the scanning time of each step is 30.09s.

The DSC spectrogram is obtained by adopting a Netzsch DSC-204F1 synchronous thermal analyzer of German resistant company, and the detection conditions are as follows: an aluminum sample pan was used under a nitrogen atmosphere at a temperature rising rate of 10℃per minute and at a temperature rising from room temperature to a specific temperature at 20 ml/min.

The TG spectrum is obtained by detecting Netzsch TG-209F1 of German resistant company under the following detection conditions: an air atmosphere, 20ml/min, a heating rate of 10 ℃/min, was heated from room temperature to the highest detection temperature using a platinum sample tray.

Example 1 preparation method of deuterated dextromethorphan hydrobromide monohydrate form A

The preparation method of the crystal form A comprises the following steps: YMSF-D6 (1.0 eq) was added to 48% HBr (0.42 v/w,1.05eq, d=1.5) and water (5 v/w), warmed to 65-75 ℃, stirred for 0.5h, slowly cooled to 20-30 ℃, stirred for 0.5h above, filtered, washed with water (2 v/w), dried in vacuo for 10h, and the XRPD characteristic absorption peaks for the resulting form A are shown in the following table:

specifically, XRPD patterns, DSC patterns, and TG patterns of the crystal form a containing water of crystallization, calculated from karl fischer test results, were shown in fig. 2,3, and 4, respectively, and the mole number of the water of crystallization was 1.

Example 2 preparation method of deuterated dextromethorphan hydrobromide Crystal form B

3.5G of deuterated dextromethorphan hydrobromide monohydrate crystal form A is weighed, added into 10ml of methanol, stirred and dissolved, dripped into 200ml of methyl tertiary butyl ether, stirred for 5 hours, filtered under the protection of nitrogen, and the solid is dried in vacuum at 40 ℃ for one day to obtain 3g (crystal form B) of solid, and the weight yield is 85.7%.

XRPD of the obtained crystal form B had strong characteristic peaks at 11.66, 14.89, 15.40, 18.99, 21.54, 24.26 with an error of ± 0.2 °; further preferred XRPD data are shown in the table below; more preferably, the XRPD is as shown in fig. 5, the DSC is as shown in fig. 6, the maximum absorption peak is at 202.2 ℃, the TG is as shown in fig. 7, and the crystal form does not contain crystal water and is an anhydrous crystal form as seen from the TG results.

Example 3 preparation method of deuterated dextromethorphan hydrobromide Crystal form B

1G of deuterated dextromethorphan hydrobromide monohydrate crystal form A is weighed, 20ml of chloroform or toluene is added, the mixture is concentrated to dryness at 40 ℃, then 20ml of isopropyl acetate is added for ultrasound for 30min, suction filtration is carried out under the protection of nitrogen, and the solid is dried for one day at 40 ℃ in vacuum, thus obtaining 1.8g of solid with the weight yield of 90.0%.

XRPD of the obtained crystal form B has stronger characteristic peaks at 11.71, 14.96, 15.47, 19.06, 21.60 and 24.33, and the error is +/-0.2 degrees; further preferred XRPD data are shown in the table below; more preferably, the XRPD is as shown in fig. 8, the DSC is as shown in fig. 9, the maximum absorption peak is at 202.1 ℃, the TG is as shown in fig. 10, and the crystal form does not contain crystal water and is an anhydrous crystal form as seen from the TG results.

Combining examples 2 and 3, the XRPD of the resulting form B, as an average, has strong characteristic peaks at 11.68, 14.93, 15.43, 19.03, 21.57, 24.29, in terms of 2θ angles (°), with an error of ± 0.2 °; preferably, the strong characteristic peaks are also arranged at 14.60, 16.89, 23.43, 24.72, 26.41, 27.11 and 28.98, and the error is +/-0.2 degrees; it is further preferred that there is also a characteristic peak at 7.83、9.51、15.81、16.13、17.92、19.57、20.97、22.63、25.91、28.01、28.51、29.94、30.40、31.25、31.90、32.35、32.83、35.05、35.94、36.88、38.20、39.45 with an error of + -0.2 °; more preferably the XRPD is as shown in figure 5 or figure 8.

Example 4 preparation of deuterated dextromethorphan hydrobromide amorphous form

After grinding form B of example 2 (using a ball mill of lez MM400, frequency: 20H _Z, time 30 min), an amorphous form was prepared, which had no distinct characteristic peaks in the XRPD pattern. The amorphous XRPD is shown in figure 11.

Example 5

1. Experimental materials

SD rats: male, 250-300g, purchased from Beijing Vietnam laboratory animal technologies Co.

Reagent: physiological saline, EDTA-K ₂, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.

Instrument: siemens flight LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometry).

2. Experimental method

The solid powder of the compound of the crystal form A of the example 1 and the solid powder of the compound of the crystal form B of the example 2 are respectively weighed, about 3.5mg is filled in ToRPAC capsules of No. 9 for oral administration, 200 mu L of venous blood is collected in EDTA.K ₂ anticoagulation EP tubes at 15min, 30min, 1h, 2h, 5h, 7h and 24h, and centrifuged at 10000rpm for 2min, and blood plasma is taken for frozen storage at-80 ℃ to be tested. A certain amount of test sample was precisely weighed and dissolved to 2mg/mL with DMSO to be used as a stock solution. Accurately sucking a proper amount of compound stock solution, and adding acetonitrile-water (v/v, 1:1) to dilute to prepare a standard series of solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, mixing uniformly by vortex, preparing into plasma samples with the plasma concentrations of 0.3, 1,3, 10, 30, 100, 300, 1000 and 3000ng/mL, carrying out double-sample analysis on each concentration, and establishing a standard curve. 30. Mu.L of plasma was taken, 150. Mu.L of acetonitrile solution of internal standard propranolol (50 ng/mL) was added, after vortexing and mixing, 80. Mu.L of purified water was added, vortexing and mixing again, centrifugation at 4000rpm for 5min, and the supernatant was taken for LC-MS/MS analysis. LC-MS/MS detection conditions were as follows:

Chromatographic column: the Siemens flight HyperSIL GOLD C-18UPLC column, 100 x 2.1mm,1.7 μm.

Mobile phase: gradient elution with water (0.1% formic acid) -acetonitrile was performed as follows

Time (min)	Water (0.1% formic acid)	Acetonitrile
			0	90％	10％
0.6	90％	10％
			1	10％	90％
2.6	10％	90％
			2.61	90％	10％
4	90％	10％

3. Data processing

After LC-MS/MS detection of blood concentration, the pharmacokinetic parameters were calculated using WinNonlin 6.1 software, non-compartmental model method, the results are shown in the following table.

Analyte(s)	Parameters (parameters)	Unit (B)	Results
				EXAMPLE 1 form A	AUClast	h*ng/ml	41.4
EXAMPLE 2 form B	AUClast	h*ng/ml	47.1

Example 6 stability experiment

Form a of example 1 and form B of example 2 were placed at 80 ℃ and sampled at different times to determine the following:

Time of	Purity of	Time of	Purity of
				EXAMPLE 1 form A	0h	99.58％	EXAMPLE 2 form B	0h	99.67％
24h	99.55％	24h	99.67
					48h	99.48％		48h	99.66％

Comparative experiment 1

The product was prepared using a variety of crystallization methods, with the following results:

1.1 cycle temperature increase and decrease method: stirring in a single solvent at 50 ℃ for 5.5h, stirring at room temperature for 16h, then stirring at 50 ℃ for 8h, stirring at room temperature for 15.5h, and filtering under nitrogen protection.

Solvent(s)	Results
		Ethanol	Solution cleaner
Isopropyl alcohol	Crystal form A
		Acetone (acetone)	Crystal form A
Acetonitrile	Crystal form A
		Tetrahydrofuran (THF)	Crystal form A
1, 4-Dioxahexacyclic ring	Crystal form A
		N-hexane	Crystal form A
Acetic acid ethyl ester	Crystal form A
		Acetic acid isopropyl ester	Crystal form A
Methyl tert-butyl ether	Crystal form A
		Isopropyl ether	Crystal form A
N, N-dimethylformamide	Solution cleaner
		Dichloromethane (dichloromethane)	Crystal form A
Sec-butanol	Crystal form A

1.2 Ball milling method: a ball mill of lez MM400 was used.

Solvent(s)	Frequency of	Time of	Results
				Without any means for	25Hz	30min	Crystal form A
Methanol	25Hz	30min	Crystal form A
				Water and its preparation method	20Hz	30min	Crystal form A
Isopropyl alcohol	20Hz	30min	Crystal form A
				Acetone (acetone)	20Hz	30min	Crystal form A
Acetic acid ethyl ester	20Hz	30min	Crystal form A
				N-hexane	20Hz	30min	Crystal form A
Tetrahydrofuran (THF)	20Hz	30min	Crystal form A
				Sec-butanol	20Hz	30min	Crystal form A

1.3 Antisolvent method: after dissolution in the good solvent, the poor solvent is added.

1.4 Anti-solvent method, API is dissolved in good solvent, then dropping into anti-solvent and stirring.

As can be seen from the results of comparative experiment 1, the crystal forms obtained by various methods are all the crystal form a, and it is fully explained that the crystal form B obtained by the foregoing method is more difficult to obtain by the conventional method.

Comparative experiment 2

With form a of example 1, which could not be processed by the grinding of example 4, the obtained form was still crystalline form a, and it was difficult to obtain the amorphous form of example 4, which showed that it was difficult to obtain it by conventional means.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. The deuterated dextromethorphan hydrobromide crystal form B is characterized in that the deuterated dextromethorphan hydrobromide has the structure shown in the following formula,

XRPD of form B having characteristic peaks at 11.68, 14.93, 15.43, 19.03, 21.57, 24.29 in terms of 2θ degrees (°), error being ± 0.2 °.

2. Deuterated dextromethorphan hydrobromide form B according to claim 1 characterized by XRPD of form B having characteristic peaks expressed in 2Θ angles (°) at 11.68, 14.93, 15.43, 19.03, 21.57, 24.29 and 14.60, 16.89, 23.43, 24.72, 26.41, 27.11, 28.98 with an error of ± 0.2 °.

3. Deuterated dextromethorphan hydrobromide form B according to claim 1 characterized by an XRPD of form B having characteristic peaks expressed in degrees 2Θ (°) at 11.68, 14.93, 15.43, 19.03, 21.57, 24.29, 14.60, 16.89, 23.43, 24.72, 26.41, 27.11, 28.98, and 7.83、9.51、15.81、16.13、17.92、19.57、20.97、22.63、25.91、28.01、28.51、29.94、30.40、31.25、31.90、32.35、32.83、35.05、35.94、36.88、38.20、39.45 with an error of ± 0.2 °.

4. The deuterated dextromethorphan hydrobromide form B of claim 1, wherein the XRPD pattern of form B is as shown in fig. 5 or fig. 8.

5. The deuterated dextromethorphan hydrobromide form B according to any of claims 1-4 wherein the DSC of form B has a maximum absorption peak at 202 ℃ ± 5 ℃.

6. The deuterated dextromethorphan hydrobromide form B according to any of claims 1-4 wherein the DSC profile of form B is shown in figure 6 or 9.

7. The deuterated dextromethorphan hydrobromide form B according to any of claims 1-4 wherein the TG profile of form B is as depicted in figure 7.

8. The deuterated dextromethorphan hydrobromide form B according to any of claims 1-4 wherein the TG profile of form B is as depicted in figure 10.

9. A pharmaceutical composition comprising deuterated dextromethorphan hydrobromide form B according to any one of claims 1-8 and one or more pharmaceutically acceptable carriers.

10. Use of deuterated dextromethorphan hydrobromide form B according to any one of claims 1-8 for the preparation of a medicament for treating cough.