CN117964552A - Crystal form of bedaquiline sugar refined salt and preparation method and application thereof - Google Patents

Crystal form of bedaquiline sugar refined salt and preparation method and application thereof Download PDF

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Publication number
CN117964552A
CN117964552A CN202410127449.8A CN202410127449A CN117964552A CN 117964552 A CN117964552 A CN 117964552A CN 202410127449 A CN202410127449 A CN 202410127449A CN 117964552 A CN117964552 A CN 117964552A
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bedaquiline
salt
crystalline form
sugar
crystal form
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刘育
张晓雯
边静
徐智儒
孟冬朔
陈瑶
崔慧昕
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China Pharmaceutical Industry Research Institute Co ltd
Shanghai Pharmaceutical Industry Research Institute Co ltd
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China Pharmaceutical Industry Research Institute Co ltd
Shanghai Pharmaceutical Industry Research Institute Co ltd
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Abstract

The invention belongs to the technical field of pharmaceutical chemistry and crystallization technology. The invention provides a crystal form of a beta-quinoline sugar refined salt and a preparation method thereof. The crystal form is comprehensively characterized by means of X-ray powder diffraction analysis, thermogravimetric analysis, differential scanning calorimetric analysis and the like, and the crystal form is found to have better physicochemical and patent drug properties. The preparation method of the crystal form of the bedaquiline sugar refined salt is simple, easy to control, good in reproducibility and capable of stably obtaining a target crystal form.

Description

Crystal form of bedaquiline sugar refined salt and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and crystallization processes, and particularly relates to a crystal form of a bedaquiline sugar refined salt, a preparation method and application thereof.
Background
The chemical name of Bedaquiline (Bedaquiline) is: (1R, 2S) -1- (6-bromo-2-methoxy-3-quinolinyl) -4- (dimethylamino) -2- (1-naphthyl) -1-phenyl-2-butanol, having the chemical structural formula:
Bedaquinoline is a diaryl quinoline antimycobacterial drug, is clinically combined with other antitubercular drugs to treat adult multi-drug resistant tuberculosis, and is currently marketed in the form of fumarate. Due to the poor solubility of bedaquiline in water, it has low in vivo bioavailability.
Thus, there is a need in the art to develop a crystalline form of a salt of bedaquiline with good stability, solubility and bioavailability.
Disclosure of Invention
The invention aims to provide a crystal form of a salt of bedaquiline with good stability, solubility and bioavailability. In particular to a crystal form of salt of bedaquiline, a preparation method and application thereof.
In a first aspect of the present invention, there is provided a crystalline form of a bedaquiline sugar salt, the X-ray powder diffraction pattern of crystalline form a of bedaquiline sugar salt comprising 3 or more 2 theta values selected from the group consisting of: 5.19.+ -. 0.02 °, 7.09.+ -. 0.02 °, 14.091.+ -. 0.02 °, 17.72.+ -. 0.02 °, 22.13.+ -. 0.02 °, 23.86.+ -. 0.02 °, 26.50.+ -. 0.02 °.
In another preferred embodiment, the X-ray powder diffraction pattern of crystalline form a of the fine salt of bedaquiline comprises the following 2θ values: 5.19 + -0.02 deg., 7.09 + -0.02 deg., 22.13 + -0.02 deg..
In another preferred embodiment, the crystalline form a of the bedaquiline salt further has 3 or more 2θ values selected from the group consisting of: 7.65.+ -. 0.02 °, 13.78.+ -. 0.02 °, 19.75.+ -. 0.02 °, 21.08.+ -. 0.02 °, 21.36.+ -. 0.02 °, 21.71.+ -. 0.02 °, 25.60.+ -. 0.02 °, 27.67.+ -. 0.02 °.
In another preferred embodiment, the crystalline form a of the bedaquiline salt has an XRPD pattern diffraction angle 2θ value with a characteristic peak at ：5.19±0.02°、7.09±0.02°、7.65±0.02°、11.86±0.02°、12.80±0.02°、13.08±0.02°、13.78±0.02°、14.09±0.02°、15.28±0.02°、15.45±0.02°、15.77±0.02°、17.45±0.02°、17.72±0.02°、18.64±0.02°、18.92±0.02°、19.75±0.02°、20.56±0.02°、21.08±0.02°、21.36±0.02°、21.71±0.02°、22.13±0.02°、22.45±0.02°、23.13±0.02°、23.86±0.02°、25.60±0.02°、26.26±0.02°、26.50±0.02°、27.67±0.02°、30.50±0.02°、30.84±0.02°、31.73±0.02°、32.60±0.02°、33.46±0.02°、34.76±0.02°、35.20±0.02°、37.73±0.02°、38.23±0.02°.
In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form of the salt of bedaquiline is substantially as shown in figure 1.
In another preferred embodiment, the thermogravimetric analysis of the crystalline form of the salt of bedaquiline is substantially as shown in figure 2, said crystalline form having a weight loss of 1.1±0.5% at 120-130 ℃ and losing water of crystallization.
In another preferred embodiment, the differential scanning pattern of the crystalline form of the fine salt of bedaquiline sugar has a melting endotherm at 120-145 ℃.
In a second aspect of the present invention, there is provided a process for the preparation of a crystalline form of a fine salt of bedaquiline sugar as described in the first aspect, comprising the steps of:
(i) Adding the bedaquiline and saccharin into an organic solvent, dissolving and clearing by ultrasonic, slowly volatilizing and crystallizing the organic solvent, filtering and drying to obtain the crystal form;
Or alternatively
(Ii) Adding the bedaquiline and saccharin into an organic solvent, heating, stirring and dissolving, filtering the hot reaction solution, cooling the filtrate, stirring and crystallizing, filtering, and drying to obtain the crystal form.
In another preferred embodiment, the stirring speed of process (ii) is 60-600rpm.
In another preferred embodiment, the drying is selected from: vacuum drying and freeze drying.
In another preferred embodiment, the organic solvent is selected from the group consisting of: methanol, ethanol, acetonitrile, acetone, isopropanol, tetrahydrofuran, or combinations thereof.
In another preferred embodiment, the mass ratio of the bedaquiline to the saccharin is 2-3:1.
In another preferred embodiment, the molar ratio of bedaquiline to saccharin is 1:1-1.5.
In another preferred embodiment, the volume to mass ratio of the organic solvent to the bedaquiline in process (ii) is 15-30ml/1g.
In another preferred embodiment, the organic solvent described in method (ii) is selected from the group consisting of: a mixture of methanol and isopropanol, a mixture of methanol and ethanol, a mixture of methanol and acetonitrile, and a mixture of methanol and acetone.
In another preferred embodiment, the volume ratio of methanol to isopropanol=2-5:1.
In another preferred embodiment, the volume ratio of methanol to ethanol is = 2-5:1.
In another preferred embodiment, the volume ratio of methanol to acetonitrile=2-5:1.
In another preferred embodiment, the volume ratio of methanol to acetone is = 2-5:1.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising:
(a) An active ingredient which is a crystalline form of a fine salt of bedaquiline sugar as described in the first aspect, and (b) a pharmaceutically acceptable carrier.
In another preferred embodiment, the crystalline form of the salt of bedaquiline in the active ingredient is 50-100wt%, preferably 80-99.99wt%; more preferably 90-99.5wt%.
In another preferred embodiment, the crystalline form of the salt of bedaquiline in the active ingredient is 50-100wt%, preferably 80-99.99wt%; more preferably 90-99.5wt%.
In another preferred embodiment, the pharmaceutical composition is an oral formulation.
In another preferred embodiment, the oral formulation is a solid formulation or a liquid formulation.
In another preferred embodiment, the solid formulation is selected from: capsules, tablets, pills, powders, or granules.
In a fourth aspect of the present invention there is provided the use of a crystalline form of a salt of bedaquiline as defined in the first aspect or a pharmaceutical composition as defined in the third aspect for the manufacture of a medicament or formulation for the prophylaxis and/or treatment of tuberculosis.
In another preferred embodiment, the tuberculosis is selected from the group consisting of: adult multi-drug resistant tuberculosis and teenagers multi-drug resistant tuberculosis.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
Figure 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline form a of the fine salt of bedaquiline sugar of example 2.
Figure 2 shows a thermogravimetric analysis (TG) of the crystalline form of the fine salt of bedaquiline sugar of example 2.
Figure 3 shows a Differential Scanning Calorimetric (DSC) profile of a crystalline form of the bedaquiline sugar salt of example 2.
Figure 4 shows an infrared spectrum (IR) diagram of the crystalline form of the fine salt of bedaquiline sugar of example 2.
Fig. 5 shows an X-ray powder diffraction (XRPD) contrast pattern of the bedaquiline and nicotinamide co-form of example 1.
FIG. 6 shows a contrast image of the X-ray powder diffraction (XRPD) of the bedaquiline and oxalic acid co-form of example 1.
FIG. 7 shows a contrast image of the X-ray powder diffraction (XRPD) of the co-form of bedaquiline and L-glutamic acid of example 1.
FIG. 8 shows a contrast image of the X-ray powder diffraction (XRPD) of the bedaquiline and L-malic acid co-former of example 1.
Detailed Description
The inventor provides a crystal form of the beta-quinoline sugar refined salt and a preparation method thereof through extensive and intensive research and a large number of experimental screening. The invention adopts the means of X-ray powder diffraction analysis, thermogravimetric analysis, differential scanning calorimetric analysis and the like to comprehensively characterize the crystal form, and discovers that the crystal form A of the invention has better physicochemical and patent drug properties. The preparation method of the crystal form of the bedaquiline sugar refined salt is simple, easy to control, good in reproducibility and capable of stably obtaining a target crystal form. The present invention has been completed on the basis of this finding.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …", or "consisting of …".
In another preferred example, the term "inert solvent" refers to a solvent that does not react with the dissolved compound, including (but not limited to): water, ethanol, acetone, isopropanol, methanol, N-propanol, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, benzyl alcohol, N-butanol, or a combination thereof.
The term "room temperature" or "normal temperature" refers to a temperature of 4-32 ℃, preferably 25±5 ℃, unless otherwise specified.
As used herein, the term "n or more" is meant to include n as well as any positive integer greater than n (e.g., n, n+1, …), where the upper limit Nup is the number of all values in the set. For example, "1 or more" includes not only each positive integer of the upper limit Nup of 1,2, 3,4, 5, 6, 7, 8, 9, 10 …, but also ranges of "2 or more", "3 or more", "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more", and the like.
Crystal forms of beta-quinoline sugar refined salt
As used herein, the terms "crystalline form of the invention", "crystalline form of the salt of bedaquiline of the invention", "crystalline form a of the bedaquiline sugar refined salt" are used interchangeably and refer to crystalline forms of the salt of bedaquiline prepared by the process of the invention.
In one embodiment of the present invention, the inventors reacted bedaquiline with saccharin, nicotinamide, oxalic acid, L-glutamic acid and L-malic acid, respectively, and compared the XRPD diffraction patterns, so that the bedaquiline and the product formed by nicotinamide, oxalic acid, L-glutamic acid and L-malic acid all have no new diffraction peak, so no corresponding crystal form is formed, and the crystallized product of bedaquiline and saccharin has new diffraction peak (as shown in fig. 1), which indicates that the product formed by bedaquiline and saccharin is in crystal form.
Further, according to the guidelines for pharmaceutical co-crystal regulatory classification (2018) issued by the U.S. Food and Drug Administration (FDA), if Δpka (pKa (conjugate acid of base) -pKa (acid)) between the drug and the ligand is greater than 1, then the compound formed by both is judged as a salt; a drug is classified as co-crystal if its Δpka (pKa (conjugate acid of base) -pKa (acid)) between the ligand is less than 1. The Δpka of bedaquiline and saccharin is 11.7, and the compound formed by the bedaquiline and saccharin is salt.
Thus, the bedaquiline of the invention successfully forms a crystalline product of the salt with saccharin.
In the present invention, the X-ray powder diffraction pattern of the crystalline form a of the fine salt of bedaquiline comprises 3 or more 2 theta values selected from the group consisting of: 5.19.+ -. 0.02 °, 7.09.+ -. 0.02 °, 14.091.+ -. 0.02 °, 17.72.+ -. 0.02 °, 22.13.+ -. 0.02 °, 23.86.+ -. 0.02 °, 26.50.+ -. 0.02 °.
In another preferred embodiment, the X-ray powder diffraction pattern of crystalline form a of the fine salt of bedaquiline comprises the following 2θ values: 5.19 + -0.02 deg., 7.09 + -0.02 deg., 22.13 + -0.02 deg..
In another preferred embodiment, the crystalline form a of the bedaquiline salt further has 3 or more 2θ values selected from the group consisting of: 7.65.+ -. 0.02 °, 13.78.+ -. 0.02 °, 19.75.+ -. 0.02 °, 21.08.+ -. 0.02 °, 21.36.+ -. 0.02 °, 21.71.+ -. 0.02 °, 25.60.+ -. 0.02 °, 27.67.+ -. 0.02 °.
In another preferred embodiment, the crystalline form a of the bedaquiline salt has an XRPD pattern diffraction angle 2θ value with a characteristic peak at ：5.19±0.02°、7.09±0.02°、7.65±0.02°、11.86±0.02°、12.80±0.02°、13.08±0.02°、13.78±0.02°、14.09±0.02°、15.28±0.02°、15.45±0.02°、15.77±0.02°、17.45±0.02°、17.72±0.02°、18.64±0.02°、18.92±0.02°、19.75±0.02°、20.56±0.02°、21.08±0.02°、21.36±0.02°、21.71±0.02°、22.13±0.02°、22.45±0.02°、23.13±0.02°、23.86±0.02°、25.60±0.02°、26.26±0.02°、26.50±0.02°、27.67±0.02°、30.50±0.02°、30.84±0.02°、31.73±0.02°、32.60±0.02°、33.46±0.02°、34.76±0.02°、35.20±0.02°、37.73±0.02°、38.23±0.02°.
In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form of the salt of bedaquiline is substantially as shown in figure 1.
In another preferred embodiment, the thermogravimetric analysis of the crystalline form of the salt of bedaquiline is substantially as shown in figure 2, said crystalline form having a weight loss of 1.1±0.5% at 120-130 ℃ and losing water of crystallization.
In another preferred embodiment, the differential scanning pattern of the crystalline form of the fine salt of bedaquiline sugar has a melting endotherm at 120-145 ℃.
In one embodiment of the present invention, the preparation method of the crystal form of the fine salt of bedaquiline sugar comprises the steps of:
(i) Adding the bedaquiline and saccharin into an organic solvent, dissolving and clearing by ultrasonic, slowly volatilizing and crystallizing the organic solvent, filtering and drying to obtain the crystal form;
Or alternatively
(Ii) Adding the bedaquiline and saccharin into an organic solvent, heating, stirring and dissolving, filtering the hot reaction solution, cooling the filtrate, stirring and crystallizing, filtering, and drying to obtain the crystal form.
Pharmaceutical composition and use
The pharmaceutical composition of the invention comprises the pharmaceutical crystalline form of the invention and a pharmaceutically acceptable carrier within a safe and effective amount range.
The pharmaceutical composition of the invention can be used for preventing and/or treating tuberculosis. The tuberculosis includes (but is not limited to): adult multi-drug resistant tuberculosis and teenagers multi-drug resistant tuberculosis.
Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of the pharmaceutical form/dose of the invention, more preferably 10-500mg of the pharmaceutical form/dose of the invention. Preferably, the "one dose" is a capsule or tablet.
"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the drug crystalline forms of the present invention without significantly reducing the efficacy of the drug crystalline forms. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the pharmaceutical crystalline form or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
The crystalline form of the salt of bedaquiline of the invention has better stability in gastrointestinal fluids than bedaquiline, so the pharmaceutical composition of the invention is particularly preferably an oral formulation.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the pharmaceutical forms of the invention are admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the pharmaceutical crystalline form or active compound of the present invention in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The pharmaceutical forms of the invention may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the pharmaceutical crystalline forms of the invention, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
In addition to the pharmaceutical crystalline forms of the invention, suspensions may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the pharmaceutical forms of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The pharmaceutical forms of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. Such as anticancer agents. In certain embodiments, the pharmaceutical forms of the invention are administered in combination with other conventional cancer therapies, e.g., radiation therapy or surgery, to a subject suffering from cancer. Radiation therapy is well known in the art and includes X-ray therapies, such as gamma radiation, and radiopharmaceutical therapy.
The general range of therapeutically effective doses for the pharmaceutical forms of the invention will be: about 1 to 2000 mg/day, about 10 to about 1000 mg/day, about 10 to about 500 mg/day, about 10 to about 250 mg/day, about 10 to about 100 mg/day, or about 10 to about 50 mg/day. Or the amount of lobaplatin contained in the pharmaceutical crystalline form according to the present invention. A therapeutically effective dose will be administered in one or more doses. However, it will be appreciated that the particular dosage of the pharmaceutical form of the invention for any particular patient will depend on a variety of factors, such as the age, sex, weight, general health, diet, individual response of the patient to be treated, the time of administration, the severity of the disease to be treated, the activity of the particular pharmaceutical form administered, the dosage form, the mode of application and concomitant medication. The therapeutically effective amount for a given situation can be determined by routine experimentation and is within the ability and judgment of a clinician or physician. In any event, the pharmaceutical form or composition will be administered in multiple doses based on the individual condition of the patient and in a manner that allows for the delivery of a therapeutically effective amount.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In this document, each abbreviation is in a conventional sense as understood by those skilled in the art unless otherwise indicated.
Compared with the prior art, the invention has the following beneficial effects:
(1) The crystalline form of the fine salt of bedaquiline sugar of the present invention has advantages in at least one of stability, solubility, bioavailability, hygroscopicity, water content, and the like.
(2) The preparation method of the crystal form of the bedaquiline sugar refined salt is simple, has the advantages of amplified feasibility, simple and easy operation and low cost, and is suitable for drug research and development and industrial production.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
EXAMPLE 1 screening of the crystalline forms of the salt of Beda quinoline
In this experiment, 0.2g of bedaquiline was added to 10ml of methanol, ethanol, acetonitrile, isopropanol, ethyl acetate, dichloromethane or a combination thereof, respectively, and an acceptable co-former selected from saccharin, nicotinamide, oxalic acid, L-glutamic acid and L-malic acid was further added, the molar ratio of bedaquiline to co-former being 1:1, ultrasonic clearing, and slowly volatilizing and crystallizing the organic solvent after complete dissolution. If solid is precipitated, the solid is filtered and dried. The XRPD diffraction patterns of the above products, as shown in figures 5, 6, 7 and 8, compare with those of bedaquiline and the corresponding coformulants, and as shown in figures 5, 6, 7 and 8, the bedaquiline forms with nicotinamide, oxalic acid, L-glutamic acid and L-malic acid without new diffraction peaks, and thus the corresponding crystalline forms are not formed, whereas the devitrified product of bedaquiline and saccharin has new diffraction peaks (as shown in figure 1), indicating that the product formed by bedaquiline and saccharin is crystalline.
Further, according to the guidelines for pharmaceutical co-crystal regulatory classification (2018) issued by the U.S. Food and Drug Administration (FDA), if Δpka (pKa (conjugate acid of base) -pKa (acid)) between the drug and the ligand is greater than 1, then the compound formed by both is judged as a salt; a drug is classified as co-crystal if its Δpka (pKa (conjugate acid of base) -pKa (acid)) between the ligand is less than 1. The Δpka of bedaquiline and saccharin is 11.7, and the compound formed by the bedaquiline and saccharin is salt.
Thus, from the above results, it can be seen that bedaquiline forms a crystalline product of salt with saccharin.
EXAMPLE 2 preparation of crystalline forms of the salt of Beda quinoline
Adding 2.0g of bedaquiline into 40ml of isopropanol, heating to 80-90 ℃, stirring to dissolve, slowly adding 1.0g of saccharin (the molar ratio of bedaquiline to saccharin is 1:1.5), filtering the hot reaction solution after stirring to dissolve, transferring the filtrate into a reaction kettle, cooling to 0-10 ℃, stirring to crystallize for 1 hour, filtering, and drying to obtain 2.5g of solid with the yield of 83%. The XRPD diffraction pattern is shown in figure 1, and the infrared spectrum (IR) pattern of the crystal form of the fine salt of bedaquiline sugar is shown in figure 4. The diffraction peaks for the XRPD pattern of form a of the fine salt of bedaquiline sugar are listed in table 1.
Table 1: XRPD data for form a of the fine salt of bedaquiline
Thermal weight loss analysis (TG) was performed on the crystalline form a of the bedaquiline salt, and the results are shown in fig. 2, from which it can be seen that 1.1% of water molecules lost in weight before the pharmaceutical crystalline form was 130 ℃ and then decomposed.
Differential scanning calorimetric analysis (DSC) of form A of the fine salt of bedaquiline sugar is shown in FIG. 3, wherein the endothermic peak corresponds to the melting process and has a maximum peak at 130.54 ℃.
EXAMPLE 3 preparation of crystalline forms of the salt of Beda quinoline
Adding 2.0g of bedaquiline into 30ml of mixed solution of methanol and acetonitrile (4:1), heating to 80-90 ℃, stirring to dissolve, slowly adding 1.0g of saccharin, stirring to dissolve, filtering the hot reaction solution, transferring the filtrate into a reaction kettle, cooling to 0-10 ℃, stirring to crystallize for 1 hour, filtering, drying to obtain 2.6g of solid, and obtaining the yield of 87%. The XRPD diffraction results are consistent with inventive example 2, belonging to crystalline form a of the fine salt of bedaquiline sugar.
EXAMPLE 4 preparation of crystalline forms of the salt of Beda quinoline
Adding 2.0g of bedaquiline into 35ml of mixed solution of methanol and ethanol (2:1), heating to 80-90 ℃, stirring to dissolve, slowly adding 1.0g of saccharin, stirring to dissolve, filtering the hot reaction solution, transferring the filtrate into a reaction kettle, cooling to 0-10 ℃, stirring to crystallize for 1 hour, filtering, drying to obtain 2.4g of solid, and obtaining the yield of 80%. The XRPD diffraction results are consistent with inventive example 2, belonging to crystalline form a of the fine salt of bedaquiline sugar.
EXAMPLE 5 preparation of crystalline forms of the salt of Beda quinoline
1.0G of bedaquiline and 0.5g of saccharin are added into 30ml of mixed solution of methanol and isopropanol (2:1), ultrasonic clearing is carried out, after complete dissolution, the organic solvent is slowly volatilized for crystallization, suction filtration and drying are carried out, and 1.3g of solid is obtained, and the yield is 89%. The XRPD diffraction results are consistent with inventive example 2, belonging to crystalline form a of the fine salt of bedaquiline sugar.
Effect examples
1. Stability investigation
In this experiment, a sample of the crystalline form a of the fine salt of bedaquiline sugar of the present invention was placed at 60 ℃,25 ℃/92.5% rh and 45 ℃/75% rh, respectively, and the placed samples were sampled at different times and tested for XRPD and content, and the results are shown in table 2.
Table 2: form a stability data
From the above examples, it was found that the crystalline form A of the fine salt of bedaquiline sugar of the present invention has good stability and chemical stability under the conditions of 60 ℃, 25 ℃/92.5% RH and 45 ℃/75% RH.
2. Investigation of hygroscopicity
And carrying out a hygroscopicity test on the crystal form A of the fine salt of the bedaquiline sugar according to the method of Chinese pharmacopoeia. The method comprises the following specific steps:
1. The dried glass weighing bottle with plug (outer diameter: 50mm, height: 15 mm) was placed in a climatic chamber (set temperature: 25 ℃ + -1 ℃ C., relative humidity: 80% + -2%) one day before the test, and precisely weighed (m 1).
2. The crystal form solids are respectively taken and are spread in a weighing bottle, the thickness is about 1mm, and the weight (m 2) is precisely weighed.
3. The weighing bottle is opened and placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.
4. The lid of the weighing flask was closed, and the weighing flask was precisely weighed (m 3).
Percentage weight gain due to moisture = (m 3-m 2)/(m 2-m 1) ×100%.
The results are shown in Table 3.
Table 3: hygroscopicity data for form a
From the above examples, it can be found that the crystalline form a of the fine salt of bedaquiline sugar of the present invention has no or almost no hygroscopicity.
3. Solubility investigation
The solubility comparison was performed for crystalline form a of the fine salt of bedaquiline of the invention and bedaquiline in the form of the commercially available fumarate salt. The crystalline form a of the fine salt of bedaquiline of the present invention and the commercial sample of bedaquiline in the form of fumarate salt were placed in buffers ph1.0, ph2.0, ph4.5 and ph6.8, respectively, and the solubility was determined by shake flask method. The results are shown in Table 4.
Table 4: solubility data
From the above examples, it was found that the crystalline form A of the fine salt of bedaquiline sugar of the present invention has better solubility in buffers of pH1.0, pH2.0, pH4.5 and pH6.8 than bedaquiline in the form of commercial fumarate salt, and has advantages in drug preparation and drug absorption.
4. Non-clinical trial
Non-clinical trials of beagle dogs were performed on crystalline form a of the fine salt of bedaquiline of the invention and bedaquiline in the form of the commercially available fumarate salt. The pharmacokinetic parameters were compared for fasting gastric administration in 8 beagle dogs. The results are shown in Table 5.
Table 5: non-clinical trial data
From the above examples, it can be found that the crystalline form a of the fine salt of bedaquiline sugar of the present invention has an advantage in drug absorption that the area under the curve (AUC 0-t) is about 2.4 times that of commercially available bedaquiline fumarate in a non-clinical test of the fasting gastric administration of beagle dogs, and a high therapeutic effect of oral administration can be expected.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. A crystalline form of a fine salt of bedaquiline, characterized in that the X-ray powder diffraction pattern of crystalline form a of the fine salt of bedaquiline comprises 3 or more 2-theta values selected from the group consisting of: 5.19.+ -. 0.02 °, 7.09.+ -. 0.02 °, 14.091.+ -. 0.02 °, 17.72.+ -. 0.02 °, 22.13.+ -. 0.02 °, 23.86.+ -. 0.02 °, 26.50.+ -. 0.02 °.
2. Form a of the fine salt of bedaquiline sugar according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form of the salt of bedaquiline is substantially as shown in figure 1.
3. Form a of the fine salt of bedaquiline as claimed in claim 1, wherein the thermogravimetric analysis of the crystalline form of the salt of bedaquiline is substantially as shown in figure 2, said crystalline form having a 1.1 ± 0.5% loss of weight, losing water of crystallization at 120-130 ℃.
4. Form a of the fine salt of bedaquiline according to claim 1, wherein the differential scanning profile of the fine salt of bedaquiline has a melting endotherm at 120-145 ℃.
5. A process for the preparation of a crystalline form of a fine salt of bedaquiline sugar as claimed in claim 1, comprising the steps of:
(i) Adding the bedaquiline and saccharin into an organic solvent, dissolving and clearing by ultrasonic, slowly volatilizing and crystallizing the organic solvent, filtering and drying to obtain the crystal form;
Or alternatively
(Ii) Adding the bedaquiline and saccharin into an organic solvent, heating, stirring and dissolving, filtering the hot reaction solution, cooling the filtrate, stirring and crystallizing, filtering, and drying to obtain the crystal form.
6. The method of claim 5, wherein the organic solvent is selected from the group consisting of: methanol, ethanol, acetonitrile, acetone, isopropanol, tetrahydrofuran, or combinations thereof.
7. The process of claim 5, wherein the organic solvent in process (ii) is selected from the group consisting of: a mixture of methanol and isopropanol, a mixture of methanol and ethanol, a mixture of methanol and acetonitrile, and a mixture of methanol and acetone.
8. A pharmaceutical composition comprising:
(a) An active ingredient which is a crystalline form of the fine salt of bedaquiline sugar as defined in claim 1, and (b) a pharmaceutically acceptable carrier.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is an oral formulation.
10. Use of a crystalline form of a salt of bedaquiline as defined in any one of claims 1 to 7 or a pharmaceutical composition as defined in claim 8 for the preparation of a medicament or formulation for the prophylaxis and/or treatment of tuberculosis.
CN202410127449.8A 2024-01-30 2024-01-30 Crystal form of bedaquiline sugar refined salt and preparation method and application thereof Pending CN117964552A (en)

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