CN117105923A - Lurasidone salt with high bioavailability as well as preparation method and application thereof - Google Patents

Lurasidone salt with high bioavailability as well as preparation method and application thereof Download PDF

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Publication number
CN117105923A
CN117105923A CN202210530902.0A CN202210530902A CN117105923A CN 117105923 A CN117105923 A CN 117105923A CN 202210530902 A CN202210530902 A CN 202210530902A CN 117105923 A CN117105923 A CN 117105923A
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lurasidone
salt
alpha
trans
aconitic acid
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任国宾
郭春阳
齐明辉
洪鸣凰
朱彬
谢俊毅
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East China University of Science and Technology
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East China University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/347—Saturated compounds containing more than one carboxyl group containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The application relates to a lurasidone salt, a preparation method thereof, a pharmaceutical composition and application thereof. The lurasidone salt comprises a counter ion selected from alpha-ketoglutaric acid and trans aconitic acid, and the stoichiometric ratio of lurasidone to the counter ion is 1:1. The application also relates to a pharmaceutical composition containing the lurasidone salt and application of the lurasidone salt and the pharmaceutical composition in preparing medicines for treating major depressive episode diseases related to schizophrenia and type I bipolar disorder.

Description

Lurasidone salt with high bioavailability as well as preparation method and application thereof
Technical Field
The application relates to the technical field of pharmaceutical chemistry and crystallization processes, in particular to lurasidone salt, a preparation method thereof, a pharmaceutical composition and application thereof.
Background
Lurasidone (lurasidone) has the chemical name: (3 aR,4S,7R,7 aS) -2- [ [ (1R, 2R) -2- [ [4- (1, 2-Benzisothiazol-3-yl) -1-piperazinyl ] methyl ] cyclohexyl ] methyl ] hexa hydro-4, 7-methano-1H-isoinondole-1, 3 (2H) -dione, its chemical structural formula is as follows:
lurasidone is an atypical antipsychotic developed by the japanese Sumitomo pharmaceutical company with a high affinity for both the 5-hydroxytryptamine receptor and the dopamine D2 receptor for the treatment of major depressive episodes associated with adolescents (13-17 years) and schizophrenia in adults as well as bipolar I disorders. Lurasidone has a lower tendency to gain weight and adverse metabolic effects than other drugs. However, the lurasidone has poor water solubility and poor oral absorption, so that the clinical application of lurasidone is greatly limited.
For ionizable free base or free acid molecules, the corresponding salt forms have the potential to improve the physicochemical properties of the compound, such as solubility, crystallinity, hygroscopicity, melting point, stability, bioavailability, and the like.
U.S. patent publication No. US8853395 discloses a process for the preparation of lurasidone hydrochloride, which is also the salt form currently employed for lurasidone marketed drugs. Even though lurasidone hydrochloride is somewhat improved over the free base, it is still at a lower level. There is a need in the art to provide a new pharmaceutical form of lurasidone that is stable, has greater solubility and bioavailability.
Disclosure of Invention
The application aims to provide a novel lurasidone salt with high solubility, high dissolution rate and high bioavailability, a preparation method, a pharmaceutical composition and application thereof.
In a first aspect of the application, the application provides two lurasidone salts, wherein the molar ratio of lurasidone to counterion is 1:1, a step of; wherein the counterion is selected from the group consisting of: alpha-ketoglutaric acid and trans aconitic acid.
The structures of the alpha-ketoglutaric acid and the trans aconitic acid are shown as follows:
the X-ray powder diffraction pattern of the salt of lurasidone and alpha-ketoglutaric acid has characteristic peaks at diffraction angles 2 theta of 6.8 degrees, 8.3 degrees, 10.2 degrees, 10.7 degrees, 11.3 degrees, 12.9 degrees, 13.9 degrees, 15.1 degrees, 15.9 degrees, 16.9 degrees, 17.5 degrees, 18.6 degrees, 19.1 degrees, 20.2 degrees, 20.7 degrees, 22.1 degrees, 22.5 degrees, 24.7 degrees, 26.1 degrees and 29.0 degrees, and the error is +/-0.2 degrees.
In certain embodiments, the salt of lurasidone with alpha-ketoglutarate has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 1.
In certain embodiments, the salt of lurasidone with alpha-ketoglutarate has a thermogravimetric analysis (TGA) profile substantially as shown in figure 2.
In certain embodiments, the differential scanning calorimetric profile of the salt of lurasidone and alpha-ketoglutarate has a characteristic melting peak at 172±2 ℃, preferably the salt of lurasidone and alpha-ketoglutarate has a Differential Scanning Calorimetric (DSC) profile substantially as shown in fig. 3.
In certain embodiments, the salt of lurasidone and alpha-ketoglutarate has an infrared spectrum of at least 3435cm -1 、2937cm -1 、2875cm -1 、1764cm -1 、1691cm -1 、1601cm -1 、1561cm -1 、1495cm -1 、1395cm -1 、1333cm -1 、1301cm -1 、1204cm -1 、1184cm -1 Having characteristic peaks, preferably the salt of lurasidone with alpha-ketoglutaric acid has an infrared spectrum (IR) pattern substantially as shown in fig. 4.
In certain embodiments, the salt of lurasidone and alpha-ketoglutarate is in an orthorhombic system and the space group is P2 1 2 1 2 1 The unit cell parameters are:α=90°; beta = 90 °; gamma = 90 ° unit cell volume +.>The asymmetric unit structure of the crystal is shown in fig. 5.
In another preferred example, the X-ray powder diffraction pattern of the salt of lurasidone and trans-aconitic acid has characteristic peaks at diffraction angles 2θ of 5.4 °, 9.9 °, 10.9 °, 13.76 °, 16.74 °, 17.9 °, 18.5 °, 19.3 °, 19.8 °, 22.0 °, 23.6 °, 24.7 ° with an error of ±0.2 °.
In certain embodiments, the salt of lurasidone with trans-aconitic acid has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 6.
In a specific embodiment, the salt of lurasidone with mesaconic acid has a thermogravimetric analysis (TGA) profile substantially as shown in fig. 7.
In a specific embodiment, the differential scanning calorimetric profile of the salt of lurasidone and trans aconitic acid has a characteristic melting peak at 179±2 ℃, preferably the salt of lurasidone and trans aconitic acid has a Differential Scanning Calorimetric (DSC) profile substantially as shown in fig. 8.
In a specific embodiment, the infrared spectrum of the salt of lurasidone and trans-aconitic acid is at least 3421cm -1 、2499cm -1 、1701cm -1 、1590cm -1 、1560cm -1 、1490cm -1 、1382cm -1 、1292cm -1 、1269cm -1 、1184cm -1 、1028cm -1 、968cm -1 、869cm -1 With characteristic peaks atPreferably, the salt of lurasidone with trans-aconitic acid has an infrared spectrum (IR) profile substantially as shown in fig. 9.
In a specific embodiment, the salt of lurasidone and trans-aconitic acid is monoclinic, and the space group is P2 1 The unit cell parameters are:α=90°; β= 101.804 (2) °; gamma = 90 ° unit cell volume +.>The asymmetric unit of the crystal is shown in fig. 10.
In a second aspect of the present application, the present application provides a method for preparing lurasidone salt according to the first aspect of the present application, the method comprising the steps of:
a. dissolving lurasidone and a counter ion in an organic solvent to form a lurasidone and counter ion solution;
b. crystallizing the lurasidone and a counter ion solution;
c. and separating from the solution system to obtain the salt of lurasidone and counter ions.
In a specific embodiment, in step a, the lurasidone and the counter ion are mixed in a molar ratio of 2:1 to 1:2 in said organic solvent.
In a specific embodiment, in the step a, the organic solvent is selected from any one of methanol, ethanol, acetone, ethyl acetate, acetonitrile, dichloromethane and nitromethane, or a mixed solvent of any two of the solvents.
In a specific embodiment, in step b, the crystallization treatment comprises removing the organic solvent by evaporation and reacting crystallization with stirring.
In a specific embodiment, in step b, the crystallization treatment comprises being performed at any temperature in the temperature range of 20 ℃ to 50 ℃.
In a specific embodiment, the step c includes one of the following steps:
c1, filtering the solution system to obtain a salt of lurasidone and counter ions;
c2, centrifuging the solution system to obtain a salt of lurasidone and counter ions;
it is understood that within the scope of the present application, the above-described technical features of the present application 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
Fig. 1 is an x-ray powder diffraction (XRPD) pattern of a salt of lurasidone with alpha-ketoglutaric acid provided in example 1 of the application.
Fig. 2 is a thermogravimetric analysis (TGA) plot of a salt of lurasidone with α -ketoglutaric acid provided in example 1 of the application.
Fig. 3 is a Differential Scanning Calorimetric (DSC) plot of a salt of lurasidone with alpha-ketoglutaric acid provided in example 1 of the application.
Fig. 4 is an infrared spectrum (IR) diagram of a salt of lurasidone with α -ketoglutarate provided in example 1 of the present application.
Fig. 5 is a diagram showing the asymmetric unit structure of a single crystal of a salt of lurasidone and α -ketoglutaric acid provided in example 1 of the present application.
Fig. 6 is an X-ray powder diffraction (XRPD) pattern of a salt of lurasidone with trans-aconitic acid provided in example 8 of the present application.
Fig. 7 is a thermogravimetric analysis (TGA) plot of a salt of lurasidone with trans-aconitic acid provided in example 8 of the present application.
Fig. 8 is a Differential Scanning Calorimetric (DSC) diagram of a salt of lurasidone and trans-aconitic acid provided in example 8 of the present application.
Fig. 9 is an infrared spectrum (IR) diagram of a salt of lurasidone and trans-aconitic acid provided in example 8 of the present application.
Fig. 10 is an asymmetric unit structure diagram of a single crystal of a salt of lurasidone and trans-aconitic acid provided in example 8 of the present application.
Fig. 11 is a graph comparing the dissolution rates of lurasidone and alpha-ketoglutaric acid salt and lurasidone hydrochloride powder in dissolution medium at ph2.0 provided in example 1 of the present application.
Fig. 12 is a graph showing drug concentration in blood at various times after oral administration of lurasidone and alpha-ketoglutarate of example 1 of the present application to rats (n=3) lurasidone hydrochloride (10 mg/kg).
Fig. 13 is a graph showing comparison of powder dissolution rates of lurasidone and trans-aconitic acid salts and lurasidone hydrochloride in a dissolution medium at pH2.0 provided in example 8 of the present application.
Fig. 14 is a graph showing the drug concentration in blood at various times after oral administration of lurasidone and trans-aconitic acid salt of example 8 of the present application to rats (n=3) (10 mg/kg).
Detailed Description
The present inventors have conducted extensive and intensive studies and, through extensive screening, developed for the first time a series of novel salts of lurasidone and crystalline forms thereof. Unexpectedly, these salts and their particular crystalline forms have significant advantages in terms of solubility, hygroscopicity, dissolution rate, and bioavailability. The present application has been completed on the basis of this finding.
Terminology
In this document, each abbreviation is in a conventional sense as understood by those skilled in the art unless otherwise indicated.
As used herein, unless otherwise indicated, the solvent or solution is added by direct pouring, constant velocity addition, or slow dropping, etc.
Polymorphs
The solid is present either in amorphous form or in crystalline form. In the case of the crystalline form, the molecules are positioned within the three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it may crystallize in a different spatial lattice arrangement (this property is known as "polymorphism") to form crystals having different crystalline forms, which are known as "polymorphs". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, bulk density, habit, mode of stacking, flowability and/or solid state stability.
Crystallization
The process of precipitating crystalline solids from a vapor, solution or molten species may be operated such that a supersaturated state of the target compound is achieved. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature, and then cooling the solution to a supersaturated state; reducing the liquid volume by heating boiling, atmospheric evaporation, vacuum drying, or by some other method; reducing the solubility of the target compound in the solvent system by adding a poor solvent; in addition, the solubility can be reduced by adjusting the pH of the solution. For a detailed description of Crystallization see crystal, third edition, J W Mullens, butterworth-Heineman Ltd.,1993, ISBN0750611294.
If salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble in the reaction medium than the starting material, then the addition of an appropriate acid or base can effect direct crystallization of the desired salt. As used herein, the term "room temperature" generally refers to 4-30 ℃, preferably 20±5 ℃.
Identification and Properties of polymorphs
After the lurasidone salt is prepared, the properties of the lurasidone salt are researched in the following various modes and instruments.
Powder diffraction by X-rays
Methods for determining X-ray powder diffraction of crystalline forms are known in the art. For example, using a Rigaku D/max 2550VB/PC model X-ray powder diffractometer, a profile is obtained using a copper radiation target at a scan rate of 2℃per minute.
The lurasidone salts of the present application have a specific crystalline form and have specific characteristic peaks in an X-ray powder diffraction (XRPD) pattern.
Differential scanning calorimeter analysis
Also known as "differential thermal scanning analysis" (DSC), is a technique that measures the relationship between the energy difference between a substance being measured and a reference substance and temperature during heating. The position, shape and number of peaks on a DSC profile are related to the nature of the substance and can therefore be used qualitatively to identify the substance. The method is commonly used in the art to detect various parameters such as the phase transition temperature, the glass transition temperature, the reaction heat and the like of a substance.
DSC measurement methods are known in the art. For example, a TA Q2000 differential scanning calorimeter (TA Instruments) from 25℃to 300℃at a rate of 10℃per minute may be used
And obtaining a DSC scanning spectrum of the crystal form.
The lurasidone salts of the present application have specific characteristic peaks in a Differential Scanning Calorimetric (DSC) plot.
Pharmaceutical compositions and methods of administration
Since the lurasidone salt of the present application has excellent therapeutic effects on major depressive episode diseases associated with schizophrenia and bipolar i disorder, the lurasidone salt of the present application and a pharmaceutical composition containing the crystalline form of the present application or the lurasidone salt of the present application as a main active ingredient can be used for treating major depressive episode diseases associated with schizophrenia and bipolar i disorder.
The pharmaceutical composition of the present application comprises the lurasidone salt of the present application in a safe and effective amount range, and a pharmaceutically acceptable excipient or carrier.
Wherein, "safe and effective amount" means: the amount of the compound (either crystalline or amorphous) is sufficient to significantly improve the condition without serious side effects. Typically, the pharmaceutical composition contains 1 to 2000mg of the salt of the application per dose, more preferably 2.5 to 200mg of the salt of the application per dose. 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. "compatibility" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present application without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween(, wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the lurasidone salt or pharmaceutical composition of the present application is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is 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 active ingredient 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 active ingredient 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 active ingredient, the 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.
Suspensions, in addition to the active ingredient, may contain suspending agents as, 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.
The dosage forms of lurasidone salts of the present application 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 lurasidone salts of the application may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of the lurasidone salt of the present application is suitable for use in a mammal (e.g., a human) in need of treatment, wherein the dosage at the time of administration is a pharmaceutically effective dosage, and the daily dosage is usually 1 to 2000mg, preferably 2.5 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The main advantages of the application include:
(1) Compared with the prior art, the lurasidone salt provided by the application has larger solubility, is beneficial to improving the bioavailability, and further improves the clinical treatment effect.
(2) Compared with the prior art, the lurasidone salt provided by the application has higher dissolution rate, is beneficial to improving the bioavailability, and further improves the clinical treatment effect.
(3) Compared with the prior art, the lurasidone salt provided by the application has lower hygroscopicity. The low hygroscopicity indicates that the lurasidone salt has no harsh requirements on packaging and storage conditions, no special drying conditions are needed in the preparation process, the preparation and post-treatment processes of the medicine are simplified, the industrial production is facilitated, and the cost of medicine production, transportation and storage is obviously reduced.
General method
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. 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 weight percentages and parts unless otherwise indicated.
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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
Experimental materials: lurasidone is purchased from Shanghai Baishikai chemical technology Co., ltd and has a purity of more than 98%. Alpha-ketoglutarate was purchased from Shanghai Ara Ding Shenghua technologies Co., ltd and had a purity of greater than 98%. Trans aconitic acid was purchased from Shanghai A Ding Shenghua technologies Co., ltd and had a purity of greater than 98%.
Preparation examples: preparation of salts of lurasidone with alpha-ketoglutaric acid
Example 1
0.1mmol of lurasidone and 0.1mmol of alpha-ketoglutarate are added into 1.5 ml of methanol according to the stoichiometric ratio of 1:1, and after complete dissolution, the lurasidone and the alpha-ketoglutarate are slowly volatilized under the room temperature condition to obtain the salt of lurasidone and the alpha-ketoglutarate.
Example 2
0.1mmol of lurasidone and 0.1mmol of alpha-ketoglutarate are added into 1ml of ethanol according to the stoichiometric ratio of 1:1, and after complete dissolution, the lurasidone and the alpha-ketoglutarate are slowly volatilized at the temperature of 30 ℃ to obtain the salt of lurasidone and the alpha-ketoglutarate.
Example 3
0.2mmol of lurasidone and 0.4mmol of alpha-ketoglutarate are added into 1ml of acetone according to a stoichiometric ratio of 1:2, stirred for about 12 hours at room temperature, and filtered and separated to obtain the salt of lurasidone and alpha-ketoglutarate.
Example 4
And adding 0.2mmol of lurasidone and 0.1mmol of alpha-ketoglutaric acid into 2 ml of mixed solvent of ethyl acetate and ethanol (volume ratio is 3:1) according to a stoichiometric ratio of 2:1, slowly volatilizing at room temperature after complete dissolution, filtering and drying after solid precipitation to obtain the salt of lurasidone and alpha-ketoglutaric acid.
Example 5
And adding 0.1mmol of lurasidone and 0.1mmol of alpha-ketoglutarate into 1ml of acetonitrile according to a stoichiometric ratio of 1:1, and slowly volatilizing at room temperature after complete dissolution to obtain the salt of lurasidone and alpha-ketoglutarate.
Example 6
0.1mmol of lurasidone and 0.1mmol of alpha-ketoglutarate are added into 1ml of dichloromethane according to the stoichiometric ratio of 1:1, and after complete dissolution, the lurasidone and the alpha-ketoglutarate are slowly volatilized under the room temperature condition, so as to obtain the salt of lurasidone and the alpha-ketoglutarate.
Example 7
0.1mmol of lurasidone and 0.1mmol of alpha-ketoglutarate are added into 1ml of nitromethane according to the stoichiometric ratio of 1:1, and after complete dissolution, the lurasidone and the alpha-ketoglutarate are placed under the volatilizing condition of 50 ℃ to obtain the salt of lurasidone and the alpha-ketoglutarate.
Experimental example 1:
the salt of lurasidone and alpha-ketoglutaric acid provided by the application is characterized by solid-state analysis methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetric analysis (DSC) and Infrared (IR).
Single crystal X-ray diffraction analysis was performed on single crystals of the salt of lurasidone and α -ketoglutaric acid prepared in example 1, using a Bruker Smart Apex II type X-ray single crystal diffractometer under the following measurement conditions: graphite monochromator, cu-K alpha rayThe voltage was 50kV, the current was 30mA, and the temperature was 298K. The salt of lurasidone and alpha-ketoglutaric acid of example 1 was measured by single crystal X-ray diffractometer as orthorhombic system and the space group was P2 1 2 1 2 1 The unit cell parameters are:α=90°; beta = 90 °; gamma = 90 ° unit cell volumeThe molar ratio of lurasidone to alpha-ketoglutaric acid is 1:1, and the single crystal asymmetric unit structure is shown in figure 5.
The salt solid sample of lurasidone and alpha-ketoglutaric acid obtained in example 1 was subjected to X-ray powder diffraction analysis using a Ultima IV diffractometer from Physics electric enterprise instruments (Beijing) Co., ltd., cu-K alpha rayThe voltage is 40KV, the current is 40mA, and the step diameter is as follows: 0.02 degrees, 0.1 seconds per step.
The analysis results are shown in FIG. 1.
As can be seen from fig. 1, the salt has characteristic peaks at diffraction angles 2θ of 6.8 °, 8.2 °, 10.2 °, 10.7 °, 11.23 °, 12.89 °, 13.89 °, 15.01 °, 15.9 °, 16.89 °, 17.5 °, 18.56 °, 19.1 °, 20.2 °, 20.67 °, 22.1 °, 22.4 °, 24.72 °, 26.1 °, 29.0 ° with an error of ±0.2 °.
The salt solid samples of lurasidone and alpha-ketoglutarate prepared in examples 2-7 were subjected to X-ray powder diffraction analysis as above, and the diffraction peaks were similar to those of FIG. 1, i.e., the salts prepared in examples 2-7 should be the same phase as the salt prepared in example 1.
The solid sample of the salt of lurasidone with alpha-ketoglutaric acid obtained in example 1 was subjected to thermogravimetric analysis using a thermal gravimetric analyzer model Q500, TA instruments ltd in the united states, under nitrogen, at a temperature rise rate of 10 ℃/min. The analysis results are shown in FIG. 2.
A differential scanning calorimetric analysis was performed on a solid sample of the salt of lurasidone and alpha-ketoglutaric acid obtained in example 1, using a Q2000 differential scanning calorimeter from TA instruments, america, under nitrogen at a heating rate of 10℃per minute. The analysis results are shown in FIG. 3.
The salt solid sample of lurasidone and alpha-ketoglutaric acid prepared in example 1 was subjected to infrared analysis, and was detected at room temperature using a Cary 630FTIR infrared spectrometer from agilent technologies, america, in the following detection range: 4000-350cm -1 Wavenumber. The analysis results are shown in FIG. 4.
Experimental example 2: comparison of the dissolution rates of the powder of lurasidone and alpha-ketoglutarate and lurasidone hydrochloride
Sample source: the lurasidone bulk drug is purchased from Shanghai Baishikai chemical technology Co., ltd, and the purity is more than 98%; the salt of lurasidone with alpha-ketoglutarate is prepared by the method provided in preparation example 1 of the present application; lurasidone hydrochloride was prepared according to the procedure of example 5 described in patent US 8853395.
The experimental method comprises the following steps: and sieving the prepared lurasidone hydrochloride and lurasidone trans-aconitate by using a 100-mesh screen. Accurately weighing 20mg of lurasidone hydrochloride and 25 mg of lurasidone and alpha-ketoglutaric acid salt with corresponding contents, respectively magnetically stirring in 10 ml of dissolution medium, taking 0.1 ml of solution at intervals, filtering by a water phase microporous filter membrane, and measuring the concentration of lurasidone in the solution at each time point by using a high-efficiency liquid phase to finally obtain the powder dissolution rates of the two salts.
Dissolution medium: glycine-hydrochloric acid aqueous solution at pH 2.0.
Magnetic rotation speed: 200 revolutions per minute
Dissolution temperature: 37 DEG C
Sampling time: 5. 10, 15, 20, 40, 60, 90, 120 minutes
Liquid phase conditions: instrument: agilent Infinity1260
Mobile phase: 0.5% phosphoric acid-triethylamine solution (pH 2.2), methanol and acetonitrile (volume ratio 30/15/55).
Column temperature: 35 DEG C
Flow rate: 1mL/min
Sample injection amount: 10 mu L
Ultraviolet detection wavelength of 230nm
Experimental results:
as shown in fig. 11, the dissolution rate of the salt of lurasidone and α -ketoglutarate in glycine-hydrochloric acid aqueous solution at pH2.0 of the present application is significantly improved compared to lurasidone hydrochloride. The highest concentration of the dissolved alpha-ketoglutarate is about 5.4 times that of the hydrochloride. And the concentration of alpha-ketoglutarate is still higher than that of the hydrochloride when equilibrium is reached.
Experimental example 3: characteristics of blood concentration of lurasidone hydrochloride and salt of lurasidone and alpha-ketoglutarate in rats
The salt of lurasidone with alpha-ketoglutaric acid prepared according to preparation example 1 of the application and lurasidone hydrochloride prepared according to the method described in patent US8853395 were suspended in an aqueous solution containing 1% HPMC.
At a dose of 10mg/kg (based on lurasidone), two aqueous solutions containing salts were administered intragastrically to clean rats (n=3), and orbital blood from the rats was withdrawn at different time points after administration, and lurasidone content was measured using liquid chromatography-mass spectrometry.
Test conditions:
test instrument: liquid phase-agilent 1260; triple quadrupole tandem mass spectrometer of mass spectrometry-Sciex company of America
Test parameters: liquid phase method: agilent extension-C18 (1.8 μm, 2.1X150 mm); flow rate: 0.4mL/min; sample injection amount: 1 μl; column temperature: 40 ℃; detection wavelength: 230nm;
mobile phase:
a (Water, 0.1% formic acid) B (acetonitrile, 0.1% formic acid) Time (min)
80％ 20％ 1
10％ 90％ 3
80％ 20％ 3.1
80％ 20％ 6
Mass spectrometry method: ion source: ESI; flow rate: 500L/min; spray voltage 4.5KV; the temperature of the ion source is 550 ℃; collision voltage: 20.9V; the data acquisition software is analysis; mass to charge ratio: q1=493.3, q2=166.1.
As shown in fig. 12 and table 1, the results demonstrate that: under the condition of oral administration of rats with the same dosage, the salt of lurasidone and alpha-ketoglutarate has better biological absorption, wherein the peak value of blood concentration and the salt of the alpha-ketoglutarate with the bioavailability are obviously higher than those of lurasidone hydrochloride. In addition, compared with the commercially available lurasidone hydrochloride blood concentration peak time, the alpha-ketoglutarate has longer drug half-life, so that the higher blood concentration can be maintained for a longer time, thereby being beneficial to improving the curative effect of the drug and reducing the toxic and side effects caused by the short-time severe change of the blood concentration. The advantages make the salt prepared by the application have outstanding advantages in terms of the improvement of the curative effect and safety of administration compared with the hydrochloride of the application in the prior art.
TABLE 1 pharmacokinetic parameters
Experimental example 4: moisture-wicking comparison of lurasidone and alpha-ketoglutarate with lurasidone hydrochloride
The salt of lurasidone with α -ketoglutaric acid prepared according to preparation example 1 of the present application and lurasidone hydrochloride prepared according to the method described in patent US8853395 were evaluated for hygroscopicity using a dynamic water vapor adsorber.
Instrument model: intrinsic DVS dynamic steam adsorber (British surface test systems instruments Co., ltd.)
Test conditions: nitrogen purge rate 15mL min -1 The method comprises the steps of carrying out a first treatment on the surface of the The sample amount was about 20mg; the test temperature was 25 ℃. And placing under the initial temperature and humidity conditions, and taking dm/dt less than or equal to 0.001 as a mass to reach the balance judgment standard.
The results are shown in Table 2 below:
TABLE 2 hygroscopicity data of lurasidone hydrochloride and lurasidone alpha-ketoglutarate under different relative humidity conditions
From analysis of the hygroscopicity results, it is known that the salt of lurasidone and alpha-ketoglutarate of the present application has significantly improved solubility compared with lurasidone hydrochloride, and the hygroscopicity is not increased but is reduced.
Preparation examples: preparation of salt of lurasidone and trans-aconitic acid
Example 8
And adding 0.1mmol of lurasidone and 0.1mmol of trans-aconitic acid into 2 ml of methanol according to a stoichiometric ratio of 1:1, and slowly volatilizing at room temperature after complete dissolution to obtain the salt of lurasidone and trans-aconitic acid.
Example 9
And adding 0.1mmol of lurasidone and 0.1mmol of trans-aconitic acid into 1ml of ethanol according to a stoichiometric ratio of 1:1, and slowly volatilizing at 35 ℃ after complete dissolution to obtain the salt of lurasidone and trans-aconitic acid.
Example 10
And adding 0.2mmol of lurasidone and 0.4mmol of trans-aconitic acid into 1ml of acetone according to a stoichiometric ratio of 1:2, stirring at room temperature for reaction for 12 hours, and filtering and separating to obtain the salt of lurasidone and trans-aconitic acid.
Example 11
And adding 0.2mmol of lurasidone and 0.1mmol of trans-aconitic acid into 3 ml of mixed solution of ethyl acetate and acetonitrile (volume ratio is 1:1) according to a stoichiometric ratio of 2:1, slowly volatilizing at room temperature after complete dissolution, and filtering and drying after solid precipitation to obtain the salt of lurasidone and trans-aconitic acid.
Example 12
And adding 0.1mmol of lurasidone and 0.1mmol of trans-aconitic acid into 1ml of acetonitrile according to a stoichiometric ratio of 1:1, and slowly volatilizing at room temperature after complete dissolution to obtain the salt of lurasidone and trans-aconitic acid.
Example 13
And adding 0.1mmol of lurasidone and 0.1mmol of trans-aconitic acid into 1ml of dichloromethane according to a stoichiometric ratio of 1:1, and slowly volatilizing at room temperature after complete dissolution to obtain the salt of lurasidone and trans-aconitic acid.
Example 14
And adding 0.1mmol of lurasidone and 0.1mmol of trans-aconitic acid into 1ml of nitromethane according to a stoichiometric ratio of 1:1, completely dissolving, and then placing under a volatilization condition at 50 ℃ to obtain the salt of lurasidone and trans-aconitic acid.
Experimental example 5:
the salt of lurasidone and trans-aconitic acid provided by the application is characterized by solid-state analysis methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetric analysis (DSC), infrared (IR) and the like.
Single crystal X-ray diffraction analysis was performed on the single crystal of the salt of lurasidone and trans-aconitic acid prepared in example 8, using a Bruker Smart Apex II type X-ray single crystal diffractometer under the following measurement conditions: graphite monochromator, cu-K alpha rayThe voltage was 50kV, the current was 30mA, and the temperature was 298K. The salt of lurasidone and trans-aconitic acid in example 1 was monoclinic system, space group was P21, and unit cell parameters were:α=90°; β= 101.804 (2) °; gamma = 90 ° unit cell volume +.>The molar ratio of lurasidone to trans aconitic acid is 1:1, and the single crystal asymmetric unit structure is shown in figure 10.
The salt solid sample of lurasidone and trans-aconitic acid obtained in example 8 was subjected to X-ray powder diffraction analysis using a Ultima IV diffractometer from Physics electric enterprise instruments (Beijing) Co., ltd., cu-K. Alpha. RadiationThe voltage is 40KV, the current is 40mA, and the step diameter is as follows: 0.02 degrees, 0.1 seconds per step. The analysis results are shown in FIG. 1. As can be seen from fig. 1, the salt has characteristic peaks at diffraction angles 2θ of 5.4 °, 9.9 °, 10.9 °, 13.76 °, 16.74 °, 17.9 °, 18.5 °, 19.3 °, 19.8 °, 21.9 °, 23.6 °, 24.7 ° with an error of ±0.2 °.
The salt solid samples of lurasidone and trans-aconitic acid prepared in examples 9-14 were subjected to X-ray powder diffraction analysis as above, and the results showed that the diffraction peaks were similar to those of fig. 6, i.e., the salts prepared in examples 9-14 should be the same phase as the salt prepared in example 8.
The salt solid sample of lurasidone and trans-aconitic acid prepared in example 8 was subjected to thermogravimetric analysis using a U.S. TA instruments company Q500 thermogravimetric analyzer under nitrogen at a heating rate of 10 ℃/min. The analysis results are shown in FIG. 7.
The salt solid sample of lurasidone and trans-aconitic acid prepared in example 1 was subjected to differential scanning calorimetric analysis using a Q2000 differential scanning calorimeter from TA instruments, usa, in a nitrogen atmosphere at a heating rate of 10 ℃/min. The analysis results are shown in FIG. 8.
The salt solid sample of lurasidone and trans-aconitic acid prepared in example 1 was subjected to infrared analysis, and was detected at room temperature using a Cary 630FTIR infrared spectrum analyzer of agilent technologies, inc. In the united states, the detection range was: 4000-350cm -1 Wavenumber. The analysis results are shown in FIG. 9.
Experimental example 6: comparison of the dissolution rates of the salt of lurasidone and trans-aconitic acid and lurasidone hydrochloride powder
Sample source: the lurasidone bulk drug is purchased from Shanghai Baishikai chemical technology Co., ltd, and the purity is more than 98%; the salt of lurasidone and trans-aconitic acid is prepared by the method provided in preparation example 8 of the present application; the lurasidone bulk drug is purchased from Shanghai Baishikai chemical technology Co., ltd, and the purity is more than 98%. Lurasidone hydrochloride was prepared according to the procedure of example 5 described in patent US 8853395.
The experimental method comprises the following steps: and sieving the prepared lurasidone hydrochloride and lurasidone trans-aconitate by using a 100-mesh screen. Accurately weighing 20mg of lurasidone hydrochloride and about 27 mg of lurasidone and trans-aconitic acid salt with corresponding contents, respectively adding into 10 ml of dissolution medium, stirring by using a magnetic stirrer, taking 0.1 ml of solution at intervals, filtering by using a water phase microporous filter membrane, and measuring the concentration of lurasidone in the solution at each time point by using a high-efficiency liquid phase to finally obtain the powder dissolution rate of the two salts.
Dissolution medium: glycine-hydrochloric acid aqueous solution at pH 2.0.
Magnetic rotation speed: 200 revolutions per minute
Dissolution temperature: 37 DEG C
Sampling time: 5. 10, 15, 20, 40, 60, 90, 120 minutes
Experimental results:
as shown in fig. 13, the dissolution rate of the salt of lurasidone and trans-aconitic acid in glycine-hydrochloric acid aqueous solution at pH2.0 is significantly improved compared to lurasidone hydrochloride. The highest concentration of trans aconitic acid eluted is about 7 times that of hydrochloride. And the concentration of trans aconitate is still higher than that of hydrochloride when equilibrium is reached.
Experimental example 7: characteristics of blood concentration of lurasidone hydrochloride and salt of lurasidone and trans-aconitic acid in rats
The salt of lurasidone with trans-aconitic acid prepared according to preparation example 8 of the present application and lurasidone hydrochloride prepared according to the method of example 5 described in patent US8853395 were suspended in an aqueous solution containing 1% hpmc.
At a dose of 10mg/kg (based on lurasidone), two aqueous solutions containing salts were administered intragastrically to clean rats (n=3), and orbital blood from the rats was withdrawn at different time points after administration, and lurasidone content was measured using liquid chromatography-mass spectrometry.
Test conditions:
test instrument: liquid phase-agilent 1260; triple quadrupole tandem mass spectrometer of mass spectrometry-Sciex company of America
Test parameters: liquid phase method: agilent extension-C18 (1.8 μm, 2.1X150 mm); flow rate: 0.4mL/min; sample injection amount: 1 μl; column temperature: 40 ℃; detection wavelength: 230nm;
mobile phase:
a (Water, 0.1% formic acid) B (acetonitrile, 0.1% formic acid) Time (min)
80％ 20％ 1
10％ 90％ 3
80％ 20％ 3.1
80％ 20％ 6
Mass spectrometry method: ion source: ESI; flow rate: 500L/min; spray voltage 4.5KV; the temperature of the ion source is 550 ℃; collision voltage: 20.9V; the data acquisition software is analysis; mass to charge ratio: q1=493.3, q2=166.1.
As shown in fig. 14 and table 4, the results demonstrate that: under the condition that rats take the same dose orally, the time for the drug in blood to reach the peak concentration is the same, but the blood concentration and the drug half-life of the salt of lurasidone and trans-aconitic acid are obviously higher than those of lurasidone hydrochloride. In addition, the salt of lurasidone and trans-aconitic acid has higher bioavailability compared with the commercial lurasidone hydrochloride drug as a whole. The advantages make the salt prepared by the application have outstanding advantages in improving the curative effect and safety of administration compared with the hydrochloride of the application in the prior art.
TABLE 4 lurasidone hydrochloride and lurasidone trans-aconitate rat pharmacokinetic parameters
Experimental example 8: moisture-wicking comparison of lurasidone and trans-aconitic acid salts with lurasidone hydrochloride
The salt of lurasidone with trans-aconitic acid prepared according to preparation example 8 of the present application and lurasidone hydrochloride prepared according to the method of example 5 described in patent US8853395 were evaluated for hygroscopicity by using a dynamic water vapor adsorber.
Instrument model: intrinsic DVS dynamic steam adsorber (British surface test systems instruments Co., ltd.)
Test conditions: nitrogen purge rate 15mL min -1 The method comprises the steps of carrying out a first treatment on the surface of the The sample amount was about 20mg; the test temperature was 25 ℃. And placing under the initial temperature and humidity conditions, and taking dm/dt less than or equal to 0.001 as a mass to reach the balance judgment standard.
The results are shown in Table 5 below:
TABLE 5 hygroscopicity data of lurasidone hydrochloride and lurasidone trans-aconitate under different relative humidity conditions
The results of the hygroscopicity experiments show that the salt provided by the application not only has significantly improved solubility in water, but also has no improved hygroscopicity, and even has lower hygroscopicity under different relative humidities than hydrochloride.
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 salt of lurasidone comprising lurasidone and a counterion selected from the group consisting of: alpha-ketoglutaric acid and trans aconitic acid; and, in addition, the processing unit,
the stoichiometric ratio of the lurasidone to the counter ion is 1:1;
the salt is in an amorphous or crystalline state.
2. A salt according to claim 1 wherein the counterion is α -ketoglutarate and the salt is in a crystalline state having an X-ray powder diffraction with characteristic peaks at 2Θ of 8.3 ° ± 0.2 °, 12.9 ° ± 0.2 °, 15.1 ° ± 0.2 °, 17.5 ° ± 0.2 °, 18.6 ° ± 0.2 °, 22.5 ° ± 0.2 °.
3. The salt of claim 2, wherein the salt is orthorhombic and the space group is P2 1 2 1 2 1 The unit cell parameters are:α＝90°；β＝90°；γ＝90°。
4. the salt of claim 2, wherein the salt has an infrared spectrum at 3435cm -1 、2937cm -1 、2875cm -1 、1764cm -1 、1691cm -1 、1601cm -1 、1561cm -1 、1495cm -1 、1395cm -1 、1333cm -1 、1301cm -1 、1204cm -1 、1184cm -1 With characteristic peaks.
5. A salt according to claim 1 wherein the counterion is trans aconitic acid and the salt is in a crystalline state having characteristic peaks in X-ray powder diffraction at 2Θ of 5.4 ° ± 0.2 °, 9.9 ° ± 0.2 °, 13.76 ° ± 0.2 °, 19.8 ° ± 0.2 °, 23.6 ° ± 0.2 °.
6. The salt of claim 5, wherein the salt is monoclinic and the space group is P2 1 The unit cell parameters are:α＝90°；β＝101.804(2)°；γ＝90°。
7. the salt of claim 5, wherein the salt has an infrared spectrum at 3421cm -1 、2499cm -1 、1701cm -1 、1590cm -1 、1560cm -1 、1490cm -1 、1382cm -1 、1292cm -1 、1269cm -1 、1184cm -1 、1028cm -1 、968cm -1 、869cm -1 With characteristic peaks.
8. A pharmaceutical composition comprising (1) a salt according to any one of claims 1 to 7 and (2) optionally a pharmaceutically acceptable carrier.
9. Use of a salt according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment of major depressive episode disorders associated with schizophrenia and bipolar i disorder.
10. The use according to claim 9, for mammals.
In another preferred embodiment, the mammal is a rat or a human.
In another preferred embodiment, the mammal is a human.
CN202210530902.0A 2022-05-16 2022-05-16 Lurasidone salt with high bioavailability as well as preparation method and application thereof Pending CN117105923A (en)

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