WO2023191666A1 - Forme cristalline de 1-(2-(1н-imidazol-4-yl)éthyl)pipéridine-2,6-dione, et utilisation de celle-ci - Google Patents

Forme cristalline de 1-(2-(1н-imidazol-4-yl)éthyl)pipéridine-2,6-dione, et utilisation de celle-ci Download PDF

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Publication number
WO2023191666A1
WO2023191666A1 PCT/RU2023/050067 RU2023050067W WO2023191666A1 WO 2023191666 A1 WO2023191666 A1 WO 2023191666A1 RU 2023050067 W RU2023050067 W RU 2023050067W WO 2023191666 A1 WO2023191666 A1 WO 2023191666A1
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Prior art keywords
ethyl
dione
imidazol
crystalline form
piperidin
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PCT/RU2023/050067
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English (en)
Russian (ru)
Inventor
Владимир Евгеньевич НЕБОЛЬСИН
Наталья Александровна ГОЛУБЕВА
Антон Петрович ПЕРЕВЕРЗЕВ
Original Assignee
Общество С Ограниченной Ответственностью "Валента-Интеллект"
Владимир Евгеньевич НЕБОЛЬСИН
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Priority claimed from RU2022108213A external-priority patent/RU2812541C1/ru
Application filed by Общество С Ограниченной Ответственностью "Валента-Интеллект", Владимир Евгеньевич НЕБОЛЬСИН filed Critical Общество С Ограниченной Ответственностью "Валента-Интеллект"
Publication of WO2023191666A1 publication Critical patent/WO2023191666A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to the field of medicine, pharmacology and the chemical-pharmaceutical industry, namely to a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione, containing its pharmaceutical composition and dosage form, which may be used for the treatment and/or prevention of cough.
  • Cough is one of the patient complaints with which patients often seek medical help. Usually the reason is the nature of the cough, which interferes with the patient’s quality of life. It is generally accepted to evaluate cough as a symptom of diseases associated with damage to the human respiratory system. However, during a severe cough, intrathoracic pressure and air flow speed increase, which can lead to a variety of complications. These include, in particular, neurological diseases, for example, depression, headaches, fear of a dangerous disease, etc. (P.V.DICPINIGAITIS et al., Prevalence of depressive symptoms among patients with chronic cough, CHEST, 2006, V.130, N.6, pp.1839-1843, doi: 10.1378/chest.130.6.1839).
  • a technical problem that has not been solved is the insufficient stability, therapeutic efficacy and pharmacokinetic parameters (rate of development of therapeutic effect and bioavailability) of dosage forms of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6- diona.
  • the objective of the present invention is to develop a storage-stable, non-hygroscopic new form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione, which has an optimal set of physicochemical and pharmacokinetic parameters.
  • the inventors unexpectedly discovered that a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione, previously unknown from the prior art, has reduced hygroscopicity and increased storage stability while maintaining good solubility.
  • the active pharmaceutical substance containing the specified new crystalline form has improved compressibility with good flowability without noticeable electrostatic phenomena, while maintaining its therapeutic effectiveness.
  • the new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione also has improved bioavailability, which, in particular, is reflected in the rapid development of the therapeutic effect.
  • Stability refers to the ability of the form of a substance, active pharmaceutical substance, pharmaceutical composition and drug to maintain chemical, physical, microbiological and biopharmaceutical properties within certain limits for a selected period.
  • Hygroscopicity refers to the ability of a substance to absorb water vapor (moisture) from the air. The degree and intensity of absorption of water vapor depend on the chemical composition of the substance, the form of the substance and the content of water vapor in the air.
  • Compressibility refers to the ability of powder particles to cohere under pressure to form a stable solid dosage form.
  • the flowability of a dosage form characterizes the ability of a powder to uniformly fill a given form.
  • Therapeutic efficacy refers to the ability of a drug to provide a pharmacological effect.
  • the therapeutic effectiveness of any particular drug can be determined by assessing the response of the patient or animal after administration of the drug; in this case, a drug with high therapeutic efficacy will provide greater relief of symptoms and/or their disappearance than a drug with low therapeutic efficacy.
  • Different crystalline and amorphous forms of a particular active substance may have different properties, such as dissolution profile, melting point, stability, hygroscopicity, particle shape, density, bioavailability, electrification, compressibility, flowability, etc. These properties must be taken into account in the manufacture of medicines.
  • strong electrification and low compressibility do not allow obtaining a dosage form such as a tablet.
  • Drug compounds must be able to dissolve well and be stored for long periods of time without exhibiting significant changes in physicochemical properties, for example, not becoming waterlogged, which can lead to both a change in the chemical composition of the drug and to loosening and disintegration of the dosage form, for example , pills.
  • 1-(2-(1H-Imidazol-4-yl)ethyl)piperidin-2,6-dione can be presented in the form of mesomeric structures.
  • Crystalline forms of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione are included in the present invention regardless of the method of depicting the mesomeric structure.
  • Mesomeric structures include:
  • a mesomer (mesomeric structure) is understood as a structure in the theory of chemical resonance that arises due to the conjugation of multiple bonds and/or lone electron pairs in a molecule.
  • 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione a mesomeric effect is possible at the imidazole group.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by the peak positions in X-ray powder diffraction obtained using Cu(K0) radiation, 2D, deg: 16.3 ⁇ 0.2, 23.8 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by peak positions in an X-ray powder diffraction pattern obtained using Cu(K0) radiation, 2D, deg: 16.3 ⁇ 0.2, 23.4 ⁇ 0.2, 23.7 ⁇ 0.2, 23.8 ⁇ 0.2, 24.5 ⁇ 0.2, 26.6 ⁇ 0.2, 27.0 ⁇ 0.2.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by the positions of peaks in an X-ray powder diffraction pattern obtained using Cu(CL) radiation, 2D, deg: 11.9 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 23.0 ⁇ 0.2, 23.4 ⁇ 0.2, 23.7 ⁇ 0.2, 23.8 ⁇ 0.2, 24.5 ⁇ 0.2, 26.6 ⁇ 0.2, 27.0 ⁇ 0.2, 28.3 ⁇ 0.2, 35.9 ⁇ 0.2 and 47.1 ⁇ 0.2.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by the X-ray powder diffraction pattern shown in FIG. 1.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by lattice syngony and crystal unit cell parameters.
  • a crystal cell is a parallelepiped built on the nodes of a crystal lattice, parallel transfers (translations) of which in three dimensions make it possible to construct the entire crystal lattice.
  • the parameters of the crystal lattice are the sizes of the edges (a, b and c) and the values of the angles between them (a, P and y).
  • the crystal lattice system of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention is orthorhombic system.
  • the parameters of the crystal lattice of the rhombic system are the sizes of the edges.
  • the edge values at room temperature (296.15 K) are (in angstroms, A) 9.5 ⁇ 0.3, 15.0 ⁇ 0.3 and 15.0 ⁇ 0.3, and preferably 9.4835, 15.0520 and 14.9745. It should be taken into account that the observed parameters of the crystal cell depend on the measurement temperature.
  • crystalline form in the context of the present invention refers to a substance in solid form in which the molecules occupy an ordered position in space and form a crystal lattice. Ordered position of molecules in a crystal lattice is called long-range order.
  • the structure of a certain chemical composition as a result of any physical and chemical influence can greatly change its properties. For the most part, this is caused by a change in the crystal structure or distortion of this structure under the influence of external forces or internal stresses.
  • Some pharmaceutically active substances can form more than one type of crystal structure. Crystal forms that differ in crystal structure and properties are called polymorphs.
  • the pharmaceutical substance may also exist in an amorphous phase. The amorphous state of a substance differs from the crystalline state by the lack of order in the mutual arrangement of atoms or molecules in the substance (long-range order in the relative arrangement of molecules), intermolecular distance and higher internal energy.
  • Powder X-ray diffraction is usually used to study crystalline forms.
  • the powder X-ray diffractometry method makes it possible to identify even small changes in the state of the atomic lattice of a crystal that are not detected by other methods.
  • X-ray diffraction of polycrystalline samples makes it possible to determine the state of a solid (crystalline, its various forms, amorphous, or combinations thereof).
  • the importance of structural studies is very great. Determining the relationship between the atomic structure and the properties of a substance allows us to establish rational control over technological processes, reveal the reasons for changes in these properties under the influence of one or another factor, and makes it possible to more consciously manage the technological process of creating pharmaceutical substances and change it in the right direction.
  • the powder X-ray diffraction method is based on the acquisition and subsequent analysis of the diffraction pattern resulting from the diffraction of X-rays on a powder or polycrystalline sample of the material under study.
  • a crystal can be represented as a series of planes onto which an X-ray beam is directed at an angle of 9. Diffracted rays are recorded using a detector or photographic film.
  • compositions for the treatment and/or prevention of cough containing the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione of the present invention and at least one pharmaceutically acceptable excipient.
  • composition a composition (mixture, composition, etc.) suitable for use in humans or animals, including an active pharmaceutical substance.
  • the active pharmaceutical substance in the pharmaceutical composition includes the active substance - the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione of the present invention.
  • the pharmaceutical composition of the present invention will also include compositions containing one or more other active pharmaceutical ingredients.
  • the pharmaceutical composition is in solid form.
  • solid dosage forms are powders, granules, briquettes, capsules, tablets, dragees, etc.
  • the pharmaceutical composition of the present invention can be in any other form that ensures the preservation of the positive properties of the active pharmaceutical substance.
  • the solid form is a powder, granule, capsule or tablet.
  • Powder is a solid, non-dosed dosage form consisting of solid individual dry particles of varying dispersion, possessing the property of flowability.
  • a capsule is a solid dosage or non-dosage dosage form, including a hard (usually gelatinous) shell, inside which is an encapsulate containing one or more active substances with or without the addition of excipients.
  • a granule is a solid dosage form in the form of grains (aggregates of powder particles) of round, cylindrical or irregular shape, containing one or more active ingredients with the addition of excipients.
  • a tablet is a solid dosage form, most often obtained by compressing powders or granules containing one or more active ingredients with or without the addition of excipients.
  • the quantitative content of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione in the pharmaceutical composition is selected from the range from 0.01 to 99.99 wt.%, preferably from 1.00 to 80.00 wt. %, more preferably from 10.00 to 60.00 wt.%, for example, 5.00 wt.%, 10.00 wt.%, 15.00 wt.%, 20.00 wt.%, 25.00 wt.%, 30.00 wt.%, 35.00 wt.%, 40.00 wt.%, 45.00 wt.%, 50.00 wt.%, 55.00 wt.%, 60.00 wt.%.
  • the pharmaceutical composition includes a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione of the present invention in an effective amount.
  • an effective amount in the context of the present invention refers to an amount of a pharmaceutical composition or drug that, when administered to a subject, is sufficient to effect such treatment on the disease, disorder or symptom.
  • the "effective amount” may vary, for example, depending on the form in which the substance is present, the nature of the disease, disorder and/or symptoms of the disease or disorder, the severity of the disease, disorder and/or symptoms of the disease or disorder, the age of the subject, to be treated, and/or on the weight of the subject to be treated. The appropriate amount in any particular case will be apparent to one skilled in the art or can be determined by standard experimentation.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione is contained in a pharmaceutical composition or drug and is used in a specific dosage.
  • Dosage of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione according to according to the present invention may be in the range from 1 mg to 1000 mg per day, preferably from 60 mg to 500 mg.
  • 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione is present in an amount corresponding to the recommended dosage.
  • dosage characterizes the content of one or more active substances in quantitative terms per unit dose, or unit volume, or unit mass in accordance with the dosage form, or for some types of dosage forms, the amount of active substance released from the dosage form per unit time.
  • the pharmaceutical composition of the present invention includes at least one pharmaceutically acceptable excipient, which is a carrier of active substances, providing the required volume/weight and the necessary characteristics of the drug in a particular dosage form.
  • the pharmaceutical composition includes a pharmaceutically acceptable excipient that is selected from the group consisting of a filler, a binder, a lubricant, a disintegrant, a glidant, a preservative, a flavoring agent and a coloring agent.
  • excipient or "diluent” means excipients used to give solid dosage forms a given volume or weight.
  • binder means substances included in the tablet mass to give it the necessary viscosity.
  • Water, ethyl alcohol, starch paste, sugar syrup, solutions of carboxymethylcellulose (CMC), hydroxyethylcellulose (OEC), hydroxypropylmethylcellulose (OPMC) are used as binders; polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, gelatin, etc. The group is not limited to this list.
  • the term "glidant” refers to auxiliary substances used in the tablet manufacturing process at the compression stage to improve the flow of granules or powder by reducing friction between particles.
  • the sliding substance can be represented by one or more of starch, talc, polyethylene oxide-4000, stearic acid, calcium and magnesium stearate, etc. The group is not limited to this list.
  • lubricant or “lubricant” means auxiliary substances that help reduce the friction force between the surface of the tablet and the walls of the punch cuvette in which the tablet is formed, used in the technological process of producing tablets at the pressing stage.
  • the lubricant can be represented by one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol (with a molecular weight greater than 3350), sodium lauryl sulfate, talc, mineral oil, leucine and poloxamer, etc. The group is not limited to this list.
  • the term "disintegrant” means substances used to improve disintegration or dissolution, providing mechanical destruction of tablets in a liquid medium, which is necessary for the rapid release of the active substance.
  • the baking powder can be one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, starch, pectin, gelatin, amylopectin, ultraamylopectin, agar-agar, alginic acid, potassium and sodium alginate, Tween-80, etc. The group is not limited to this list.
  • flavoring agents are used to improve taste (sweetener) and smell (flavor). These include, for example, sugar, cocoa, vanillin.
  • Dyes pigments are used to improve the appearance of pharmaceutical compositions and dosage forms. Examples of dyes are titanium dioxide, indigo carmine.
  • the amount, composition and form of the pharmaceutically acceptable excipient can be selected by one skilled in the art as long as the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione is retained completely or partially.
  • the pharmaceutical composition according to the invention includes (wt.%):
  • the pharmaceutical composition according to the invention includes (wt.%):
  • the pharmaceutical composition according to the invention includes:
  • Routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, oral, inhalation, topical, transdermal, sublingual and rectal routes.
  • the pharmaceutical composition is administered orally or sublingually.
  • the pharmaceutical composition of the present invention can be prepared using known conventional methods in the pharmaceutical field.
  • the present technical problem is solved, and the specified technical results are also achieved thanks to a medicinal product for the treatment and/or prevention of cough containing a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione or pharmaceutical the composition of the present invention.
  • a medicinal product means an active pharmaceutical substance or pharmaceutical composition in the form of a dosage form suitable for use in humans or animals.
  • the present invention relates to a drug in solid dosage form.
  • the dosage forms of the present invention include, but are not limited to: tablets, in particular buccal tablets, effervescent tablets, film-coated tablets, sustained release tablets, regular tablets, controlled release tablets, orally dispersible tablets, lyophilized instant tablets and so on.; capsules such as hard capsules, soft capsules, gelatin capsules and the like; injection powders such as lyophilized injection powders, regular injection powders and the like; solutions, aerosols, sprays, transdermal medicinal products such as patches, granules, suppositories and other dosage forms.
  • the drug of the present invention can be in any form that ensures the preservation of the positive properties of the active pharmaceutical substance.
  • the solid form is a powder, granule, capsule or tablet.
  • the medicinal product of the present invention may be an active pharmaceutical substance and a pharmaceutical composition comprising a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione.
  • the medicament also includes at least one pharmaceutically acceptable excipient, however, its presence is not required.
  • the quantitative content of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione in the drug is selected from the range from 0.01 to 100 May. %, preferably from 1.00 to 80.00 May. %, more preferably from 10.00 to 60.00 wt.%, for example, 5.00 wt.%, 10.00 wt.%, 15.00 wt.%, 20.00 wt.%, 25.00 wt.%, 30.00 wt.%, 35.00 wt.%, 40.00 wt.%, 45.00 wt.%, 50.00 wt.%, 55.00 wt.%, 60.00 wt.%.
  • the medicinal product of the present invention is a tablet and includes a pharmaceutical composition according to the proposed invention (wt.%):
  • the medicinal product of the present invention is a tablet and includes a pharmaceutical composition according to the proposed invention (wt.%):
  • Lactose anhydrous up to 100% and also dispersed film coating.
  • the pharmaceutical composition according to the present invention includes Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-40.00 mg dione
  • the drugs of the present invention can be administered (but not limited to) orally, parenterally, inhalation, subcutaneously, intraperitoneally, topically, rectally.
  • Therapeutic dosage of a medicinal product containing a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione or an active pharmaceutical substance or a pharmaceutical composition of the present invention or a pharmaceutical composition for the treatment of cough which contains in a therapeutically effective amount the new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the present invention, may be adjusted in patients depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, the rate of their metabolism and excretion from the body, as well as depending on the age, gender and stage of the patient’s disease.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, the active pharmaceutical substance containing it, the pharmaceutical composition and the drug of the present invention can be used for the treatment of cough.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, the active pharmaceutical substance containing it, the pharmaceutical composition of the present invention can be used for the manufacture of the drug of the present invention.
  • the cough for the treatment and/or prevention of which the present invention is aimed may refer to a dry cough, refractory cough, chronic cough of unknown etiology, cough due to diseases of the respiratory tract caused by bronchial asthma, COPD, idiopathic pulmonary fibrosis, lung cancer.
  • the cough that the present invention is intended to treat and/or prevent is a dry cough.
  • the cough that the present invention is intended to treat and/or prevent may be a cough caused by viral infections.
  • the cough may be caused by an acute respiratory viral infection (ARVI).
  • ARVI acute respiratory viral infections refer to infectious diseases that affect the mucous membranes of the upper respiratory tract.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione in the pharmaceutical composition or medicinal product of the present invention is administered in an amount of from 5 mg to 200 mg per day, for example, from 5 to 20 mg 1-3 times a day.
  • the most preferred dosage options may be determined based on the age and/or body weight of the patient, as well as the nature of the symptoms exhibited.
  • treatment of cough involves symptomatic treatment, that is, treatment aimed at eliminating the symptom of cough, regardless of the etiopathogenesis of other possible diseases.
  • Figure 1 Powder X-ray diffraction pattern of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione of the present invention
  • Figure 2 Powder X-ray diffraction pattern of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione of the present invention and its comparison with the calculated one.
  • the blue curve is the experiment, the red one is the calculation, the gray one is the difference between them;
  • Fig.3 General view of the 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione molecule in the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine -2,6-dione of the present invention.
  • the structure was established according to X-ray diffraction analysis (XRD).
  • Figure 1 shows the X-ray powder diffraction pattern of the resulting crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione. Table 1 lists the positions of the 29 angles and their relative intensities.
  • the crystal structure of the resulting phase was determined using single-crystal X-ray diffraction and full-profile refinement of the powder diffraction data array (“Rietveld method”). The measurements were carried out at room temperature (296.15K). A general view of the diffraction patterns of samples of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione and their comparison with the calculated ones is shown in Figure 2. The blue curve is the experiment, the red one is the calculation, the gray one is the difference between them. The parameters of the crystal cell are determined in Table 2.
  • the values of the cell edges obtained in the study of a single crystal differ by 1-3% from those calculated on the basis of powder X-ray diffraction data. This is due to the fact that the study of the single crystal was carried out at a temperature of 100 K, and the study of the powder phase at room temperature.
  • the resulting crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione was used to obtain the active pharmaceutical substance (API) through an additional drying step (drying in a CO2 stream, spray drying method, drying under vacuum, etc.) to constant mass.
  • the output was a fine white powder.
  • the finished pharmaceutical substance was placed in a hermetically sealed bottle.
  • the stability of the active pharmaceutical substance which is a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione, was assessed by the accelerated aging method in accordance with GPM.1.1.0009.15 Shelf life of medicines, the state pharmacopoeia RF.
  • the physicochemical processes occurring in medicines are accelerated, leading over time to undesirable changes in quality.
  • the period of time during which controlled quality indicators of the medicinal product are maintained within acceptable limits (experimental shelf life), artificially reduced.
  • the shelf life ( ⁇ ) at storage temperature (/ ⁇ mon) is related to the experimental shelf life ( ⁇ réelle) at an elevated experimental storage temperature (/ réelle ) by the Van't Hoff equation: where is the temperature coefficient, which is taken equal to 2.5.
  • the storage conditions chosen for the accelerated aging experiment were 28 days at 65°C.
  • a sample of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione was left in a climate chamber for 28 days at a temperature of 65°C.
  • an X-ray diffraction pattern of the resulting sample was recorded. There were no additional reflections in the resulting picture, which indicates the purity of the form and the preservation of the crystal structure.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione remains stable under the selected storage conditions.
  • the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione was placed in a climate chamber at 80% relative humidity and 25°C for 24 hours. Next, a sample of the resulting substance was placed in a bottle brought to a constant weight. Drying was carried out in a desiccator over phosphorus oxide (V) for 12 hours. After this, the bottle was removed from the desiccator, covered with a lid and weighed.
  • V phosphorus oxide
  • Weight loss upon drying was calculated using the formula: mi is the mass of the bottle with a lid, m2 is the mass of the substance together with the bottle before drying; tz - the mass of the substance with the bottle after drying.
  • the pharmaceutical substance of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione obtained in Example 1 was used for the preparation of pharmaceutical compositions according to the compositions disclosed in Table 2.
  • the pharmaceutical substance was mixed with the excipients listed in Table 5, and the final mixture was thoroughly mixed.
  • the pharmaceutical composition obtained in example 5 was tableted on a tablet machine consisting of a steel matrix with holes with a diameter of 10 mm and two chrome-plated rods located one above the other - upper and lower punches.
  • the lower punch fixes the space in the matrix into which the pharmaceutical composition is poured.
  • the upper punch compresses the composition.
  • the upper and lower punches are then removed sequentially from the die, ejecting the tablet.
  • the first composition of the composition described in example 5 was chosen for tableting.
  • a drug containing the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2, 6-dione was obtained in the form of a tablet with a diameter of 10 mm and a height of 3 mm.
  • the tablet was additionally coated with Opadry II.
  • composition of the tablet is a composition of the tablet:

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte au domaine de la médecine, de la pharmacologie et de l'industrie chimique et pharmaceutique, et concerne notamment une nouvelle forme cristalline de 1-(2-(1Н-imidazol-4-yl)éthyl)pipéridine-2,6-dione, sa composition pharmaceutique et une forme médicamenteuse, qui peuvent être utilisées pour le traitement et/ou la prévention de la toux.
PCT/RU2023/050067 2022-03-29 2023-03-28 Forme cristalline de 1-(2-(1н-imidazol-4-yl)éthyl)pipéridine-2,6-dione, et utilisation de celle-ci WO2023191666A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2022108213A RU2812541C1 (ru) 2022-03-29 Новая кристаллическая форма 1-(2-(1н-имидазол-4-ил)этил)пиперидин-2,6-диона и ее фармацевтическое применение
RU2022108213 2022-03-29

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014168522A1 (fr) * 2013-04-12 2014-10-16 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Dérivés de glutarimides, leur utilisation, composition pharmaceutique sur leur base et procédés de fabrication
WO2020106191A1 (fr) * 2018-11-23 2020-05-28 Общество С Ограниченной Ответственностью "Хемиммьюн Терапьютикс" Production de glutarimide pour vaincre la résistance aux stéroïdes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014168522A1 (fr) * 2013-04-12 2014-10-16 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Dérivés de glutarimides, leur utilisation, composition pharmaceutique sur leur base et procédés de fabrication
WO2020106191A1 (fr) * 2018-11-23 2020-05-28 Общество С Ограниченной Ответственностью "Хемиммьюн Терапьютикс" Production de glutarimide pour vaincre la résistance aux stéroïdes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Supramolecular Chemistry II", 1 January 2017, ELSEVIER, ISBN: 9780128031995, article THAKURIA, THAKUR, GOKEL GEORGE W.: "Crystal Polymorphism in Pharmaceutical Science", pages: 283 - 309, XP009550613, DOI: 10.1016/B978-0-12-409547-2.12570-3 *
"Klinicheskaya farmakokinetika: teoreticheskiye, prikladnyye i analiticheskiye aspekty: rukovodstvo [Clinical pharmacokinetics: theoretical, applied and analytical aspects: a guide]", vol. 432, 30 November 2008, GEOTAR-MEDIA, Russia, ISBN: 978-5-9704-0972-5, article V.G. KUKESA: "11.2. Vzaimosvyaz' kristallicheskoy struktury substantsii veshchestva, farmakokinetiki i effektivnosti lekarstvennogo sredstva. [Chapter 11.2. The relationship between the crystal structure of the substance, pharmacokinetics and effectiveness of the drug]", pages: 235 - 248, XP009550317 *

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