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WO2019129100A1 - 一种Valbenazine二对甲苯磺酸盐的晶型及其制备方法和用途 - Google Patents

一种Valbenazine二对甲苯磺酸盐的晶型及其制备方法和用途 Download PDF

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WO2019129100A1
WO2019129100A1 PCT/CN2018/124039 CN2018124039W WO2019129100A1 WO 2019129100 A1 WO2019129100 A1 WO 2019129100A1 CN 2018124039 W CN2018124039 W CN 2018124039W WO 2019129100 A1 WO2019129100 A1 WO 2019129100A1
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Prior art keywords
crystal form
crystal
preparation
drug
present
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PCT/CN2018/124039
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English (en)
French (fr)
Inventor
陈敏华
张炎锋
杨朝惠
黄春香
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苏州科睿思制药有限公司
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Priority to CN201880031290.2A priority Critical patent/CN110621674B/zh
Priority to CA3086611A priority patent/CA3086611C/en
Priority to US16/771,799 priority patent/US11339158B2/en
Priority to KR1020207021772A priority patent/KR102447769B1/ko
Priority to JP2020535177A priority patent/JP7212958B2/ja
Priority to EP18895304.6A priority patent/EP3733666B1/en
Publication of WO2019129100A1 publication Critical patent/WO2019129100A1/zh
Priority to US17/738,534 priority patent/US20220267326A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • 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

Definitions

  • the invention relates to the field of medicinal chemistry.
  • it relates to the crystalline form of Valbenazine di-p-toluenesulfonate and its preparation and use.
  • Tardive Dyskinesia is a neurological condition characterized by involuntary movements in the oral and facial regions (ie, tongue, lips, jaw, face) and dance-like acrometic movements of the extremities and trunk. Patients with mild TD are often unaware of involuntary movements, so they do not actively seek treatment. As the severity of the symptoms increases, hyperkinetic motor movements begin to disrupt normal speech, chewing, breathing, facial expressions, limb movements, walking, and balance. In the most severe cases, TD can cause self-injury, bruises, lacerations, clothing, eating or drinking disorders.
  • VMAT2 transporter vesicle monoamine transporter 2
  • VMAT2 plays an important role in presynaptic dopamine release, regulating the storage and release of monoamines from the cytoplasm to synaptic vesicles.
  • VMAT2 inhibitors have shown efficacy in the treatment of various motor disorders, including tardive dyskinesia.
  • Valbenazine is targeted at VMAT2 and was approved by the FDA on April 11, 2017 for the treatment of adult patients with tardive dyskinesia in the form of di-p-toluenesulfonate. This is the first drug approved by the FDA for the treatment of tardive dyskinesia, and the FDA has granted the drug a quick-track review eligibility, priority review qualification, and breakthrough therapy eligibility.
  • Valbenazine (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4, 6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester (hereinafter referred to as "compound I") having the following structural formula:
  • a crystal form is a solid in which a compound molecule is orderedly arranged in a microstructure to form a crystal lattice, and a drug polymorphism phenomenon means that two or more different crystal forms of a drug exist. Because of the different physical and chemical properties, different crystal forms of drugs may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent; especially for poorly soluble solid drugs, the influence of crystal form will be greater. Therefore, the drug crystal form is inevitably an important part of drug research and an important part of drug quality control.
  • Patent WO2017075340A1 discloses six crystal forms of Valbenazine di-p-toluenesulfonate, which are Form I, Form II, Form III, Form IV, Form V, Form VI, and the stability data of Form I is described in detail in the text. It is also clearly pointed out that the stability of Form I is far superior to Form II and Form IV, and the wettability is also superior to other crystal forms. Further, this Patent Example 17 describes that Valbenazine di-p-toluenesulfonate is added to 24 different organic solvents, and more than half of the experimentally obtained crystals are Form I, and the remainder is not crystallized or amorphous or formed. Other unknown forms, it can be seen that Form I is WO2017075340A1, which discloses the most superior crystalline form in the crystalline form.
  • the inventors of the present application have unexpectedly discovered the di-toluenesulfonate crystal form A of the compound I provided by the present invention, which has advantages in physical and chemical properties, processing properties and bioavailability of the preparation, For example, there is an advantage in at least one of melting point, solubility, wettability, purification, stability, adhesion, compressibility, fluidity, dissolution in vitro and in vivo, and bioavailability.
  • the crystal form A of the invention has good physical and chemical stability, and the yield of the crystal form prepared by the same starting material is obviously improved compared with the form I, and the solubility, the wettability, the fluidity, the compressibility and the adhesion are compared with the form I. It has obvious advantages and provides a new and better choice for the development of drugs containing Valbenazine, which is very important.
  • the main object of the present invention is to provide a novel crystalline form of the di-p-toluenesulfonate of Compound I, a process for its preparation and its use.
  • Form A of Compound I di-p-toluenesulfonate (hereinafter referred to as "Form A").
  • the X-ray powder diffraction of the Form A has characteristic peaks at diffraction angles 2 ⁇ of 5.9° ⁇ 0.2°, 13.3° ⁇ 0.2°, and 19.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form A has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 11.0° ⁇ 0.2°, 8.7° ⁇ 0.2°, and 15.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form A has a characteristic peak at a diffraction angle 2 ⁇ of 11.0° ⁇ 0.2°, 8.7° ⁇ 0.2°, and 15.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a diffraction angle 2 ⁇ values of 5.9° ⁇ 0.2°, 13.3° ⁇ 0.2°, 19.8° ⁇ 0.2°, 11.0° ⁇ 0.2°, There are characteristic peaks at any 3, or 4, or 5, or 6 of 8.7 ° ⁇ 0.2 ° and 15.8 ° ⁇ 0.2 °.
  • Form A is a hydrate having an X-ray powder diffraction pattern substantially as shown in FIG.
  • the infrared spectrum of the crystal form A of the present invention is as shown in Fig. 7, and includes 621.81 cm -1 (w), 682.24 cm -1 (s), 710.21 cm -1 (w), 773.12 cm -1 (w), and 786.44 cm.
  • the present invention also provides a method for preparing the crystal form A, the preparation method comprising:
  • the solvate is preferably a cosolvate of 2-MeTHF and water.
  • the solvate is Compound II di-p-toluenesulfonate cosolvate Form CSIII (hereinafter referred to as "Form CSIII"), the XRPD pattern of which is shown in FIG.
  • the ether solvent is preferably anisole.
  • the temperature is preferably 4 °C.
  • crystal form N4 The solid obtained by the filtration was a crystal (hereinafter referred to as "crystal form N4"), and its XRPD pattern is shown in FIG.
  • the crystal form A of the present invention has a higher yield than the prior art.
  • the yield of the crude product obtained by preparing the free base is 69%
  • the third embodiment is further subjected to recrystallization treatment, and the yield is 72%-88%, that is, prepared from the free base.
  • the yield of Form I final product is only 50%-61%.
  • the yield of the crystalline form A final product obtained by preparing the crystalline form A of the present invention from the free base can reach 84%, which is 23%-34% higher than the prior art yield. Increasing the yield of drug preparation can greatly reduce the production cost and has strong social and economic benefits.
  • the crystal form A of the present invention has higher solubility than the prior art. Particularly in FeSSIF (simulated feeding state intestinal juice), the solubility is 1.23 times that of the prior art WO 2017075340A1 Form I.
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated feeding intestinal fluid
  • the solubility measured in such media is The solubility in the human environment is closer. Higher solubility in biologically relevant media is beneficial to improve the absorption of drugs in the human body, improve bioavailability, and enable drugs to exert better therapeutic effects. In addition, higher solubility can lower the drug while ensuring the efficacy of the drug. The dose, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the crystal form A of the present invention has lower wettability than the prior art.
  • the wettability was determined by the pharmacopoeia drug wettability test guidelines, and the test results showed that the wettability of the crystalline form A of the present invention was only 3/5 of the prior art crystal form.
  • the wet weight gain of Form A is 0.24%, while the wet weight gain of the prior art Form I is as high as 0.40%, and the wettability is significantly higher than that of Form A of the present invention.
  • the hygroscopicity directly affects the physicochemical stability of the drug, and the high wettability tends to cause chemical degradation and crystal transformation.
  • high moisture permeability will reduce the fluidity of the drug, thereby affecting the processing of the drug.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which imposes higher requirements on production and requires high costs.
  • high moisture permeability is likely to cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the low moisture absorbing crystal form is not demanding on the environment, which reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form A of the present invention has a good purification effect.
  • the purity of the crystal form of the invention is significantly improved by the preparation of the free base material.
  • the purity of the raw material used in the present invention is 99.09%.
  • the purity is increased to 99.38%, the purity is improved by 0.29%, and more importantly, the raw material is prepared into the crystalline form A. After that, the amount of detected impurities was significantly reduced, and the original eight impurities were reduced to five.
  • the chemical purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions. If the drug contains more than a limited amount of impurities, it is possible to change the physicochemical constant, the appearance traits will mutate, and affect the stability of the drug; the increase in impurities also makes the drug content significantly lower or the activity is reduced, the toxic side effects are significantly increased, therefore, different
  • the pharmaceutical regulations have strict requirements on the impurity content.
  • the crystal form with good purification effect can exhibit extremely strong impurity elimination ability in the crystallization process, so that the raw material medicine with higher purity can be obtained by crystallization, and the drug stability with low drug purity is low, and the curative effect is poor. , high toxicity and other shortcomings.
  • the crystalline form A drug substance and the preparation provided by the present invention all have good stability.
  • Form A drug substance is placed in a closed position at 25 ° C / 60% relative humidity.
  • the crystal form and chemical purity have not changed for at least 3 months. It is placed open at 25 ° C / 60% relative humidity for at least 3 months.
  • the type did not change, and the chemical purity was only reduced by 0.03%, and the purity remained basically unchanged during storage.
  • the crystal form A was mixed with the auxiliary material to form a pharmaceutical preparation, the crystal form did not change, and it was left at 25 ° C / 60% relative humidity, and the crystal form did not change for at least 3 months. It is indicated that the crystalline form A drug substance and the preparation have good stability under long-term conditions and are favorable for drug storage.
  • the crystal form A drug substance did not change under the condition of 40 ° C / 75% relative humidity for at least 3 months, and the chemical purity was only reduced by 0.09%, and the purity remained basically unchanged during storage.
  • the crystal form did not change at 60 ° C / 75% relative humidity for at least 1 week, and the chemical purity was only reduced by 0.08%, and the purity remained basically unchanged during storage.
  • the crystal form A is mixed with the auxiliary material to form a pharmaceutical preparation, it is left at 40 ° C / 75% relative humidity, and the crystal form does not change for at least 3 months. It is indicated that the crystalline form A drug substance and preparation have better stability under accelerated conditions and more severe conditions.
  • the stability of drug substances and preparations under accelerated conditions and under more severe conditions is critical to the drug.
  • APIs and preparations will encounter high temperature and high humidity conditions caused by weather and seasonal differences, climate differences in different regions.
  • the crystalline form A drug substance and preparation have better stability under severe conditions, and are beneficial to avoid the influence of the storage conditions on the label from the label on the quality of the drug.
  • Form A has good mechanical stability. After the crystal form A raw material is pressed into a sheet by pressure at 15kN, the crystal form remains unchanged, and has good physical stability, which is favorable for maintaining crystal form stability in the dry granulation and tableting process of the preparation.
  • Form A has good physicochemical stability, ensuring consistent controllable quality of the drug substance and preparation, and minimizing changes in drug quality and bioavailability due to changes in crystal form or impurities.
  • the crystalline form A of the present invention has superior in vitro dissolution and dissolution rate.
  • the Form A preparation has a dissolution rate of 89.7% in a 0.1 N hydrochloric acid medium at 30 minutes, which meets the requirements for rapid dissolution.
  • Dissolution and dissolution rates are important prerequisites for drug absorption.
  • Good in vitro dissolution indicates that the drug has a higher level of absorption in the body, better exposure characteristics in the body, thereby improving bioavailability and improving the efficacy of the drug; a high dissolution rate enables the drug to reach the highest concentration in plasma quickly after administration. Value, which in turn ensures that the drug works quickly.
  • crystal form A provided by the present invention has the following beneficial effects:
  • the crystal form A provided by the present invention has superior compressibility.
  • the good compressibility of the crystal form A can effectively improve the hardness/friability degree, cracking and the like in the tableting process, and make the preparation process more reliable, improve the appearance of the product, and improve the product quality.
  • Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
  • the crystal form A of the present invention has better fluidity than the prior art.
  • the fluidity evaluation results show that the crystal form A is significantly better than the prior art crystal form.
  • Better fluidity can avoid clogging production equipment and improve production efficiency; crystal A has better flow performance to ensure uniformity and content uniformity of the preparation, reduce the weight difference of the preparation, and improve product quality.
  • the crystal form A of the present invention has superior adhesion.
  • the results of adhesion evaluation showed that the adsorption amount of Form A was much lower than that of the prior art crystal form.
  • the low adhesion of the crystal form A can effectively improve or avoid the phenomenon of sticking and sticking caused by dry granulation and tablet tableting, and is beneficial to improving the appearance and weight difference of the product.
  • the low adhesion of Form A can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the final product. Content uniformity.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form A of the present invention together with a pharmaceutically acceptable carrier, diluent or adjuvant.
  • the "stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, mechanical stirring. It is preferably from 100 to 300 rpm.
  • the "drying” can be carried out at room temperature or higher.
  • the drying temperature is from room temperature to about 60 ° C, or to 50 ° C, or to 40 ° C. Drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
  • crystal or “polymorph” means confirmed by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction patterns typically vary with instrumental conditions. It should be particularly noted that the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also vary with experimental conditions, so the order of the intensity of the diffraction peaks cannot be the sole or decisive factor.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the intensity of the diffraction peaks shown herein is illustrative and not for absolute comparison.
  • the experimental error of the diffraction peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the diffraction peak angle is caused, and a certain offset is usually allowed.
  • the X-ray powder diffraction pattern of one crystal form in the present invention does not have to be exactly identical to the X-ray powder diffraction pattern in the examples referred to herein, and any having characteristic peaks in these patterns Crystal forms of the same or similar X-ray powder diffraction patterns are within the scope of the present invention.
  • Those skilled in the art will be able to compare the X-ray powder diffraction pattern listed herein with an X-ray powder diffraction pattern of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • Form A of the present invention is pure, substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Figure 8 XRPD comparison chart before and after crystal form A stability test (from top to bottom: XRPD pattern before placement, XRPD pattern after placement at 25 ° C / 60% relative humidity for 3 months, at 25 ° C / 60 XRPD pattern after 3 months of relative humidity closed for 3 months, XRPD pattern after 3 months of closed position at 40 °C / 75% relative humidity, XRPD pattern after being closed for 1 week at 60 °C / 75% relative humidity)
  • Figure 9 is a comparison of the XRPD of the crystal form A before and after the sheet pressure by 15kN (the above picture shows the XRPD pattern before tableting, and the figure below shows the XRPD pattern after tableting)
  • Figure 10 is a comparison of XRPD before and after preparation of Form A (from top to bottom: XRPD pattern of excipients, XRPD pattern of Form A prepared into capsules, and XRPD pattern of Form A)
  • Figure 11 XRPD comparison chart before and after the stability test of Form A preparation (from top to bottom: XRPD pattern before placement, XRPD pattern after 3 months of closure at 25 ° C / 60% relative humidity, and at 40 ° C / 75 XRPD pattern after 3 months of relative humidity closure
  • the X-ray powder diffraction pattern described in the examples of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the infrared spectrum (IR) pattern of the present invention was collected on a VERTEX 70 infrared spectrometer manufactured by Bruker, and the method parameters of the Fourier infrared spectrometer were as follows:
  • HPLC high performance liquid chromatography
  • HPLC method parameters are as follows:
  • the elution gradient is as follows:
  • HPLC high performance liquid chromatography
  • HPLC method parameters are as follows:
  • the elution gradient is as follows:
  • the compound I and/or its salt as a raw material is in the form of a solid (crystalline or amorphous), semi-solid, wax or oil.
  • the compound I and/or its salt as a raw material is in the form of a solid powder.
  • Valbenazine free base solids used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2008058261 A1, and the p-toluenesulfonic acid used may be a hydrate of p-toluenesulfonic acid.
  • the solid was transferred to a 100 mL vial, and about 45 mL of anisole solvent was added and stirred at -20 ° C for a period of time. Then, about 0.5 mL of a seed suspension of Form N4 was added and stirring was continued, and the obtained solid was protected with nitrogen. Filtration under the conditions, and vacuum drying at room temperature overnight gave 795.8 mg of crystal form A (yield after seed crystals: 84%).
  • the XRPD diagram is shown in Figure 4, and the XRPD data is shown in Table 2. As shown in Figure 5, the TGA was heated to 150 ° C with a mass loss of about 2.61%. As shown in Fig. 6, the DSC showed an endothermic peak near 139.1 ° C, which is a melting endothermic peak.
  • the crystal form A of the present invention is 621.81 cm -1 (w), 682.24 cm -1 (s), 710.21 cm -1 (w), 773.12 cm -1 (w), 786.44 cm - 1 (m), 813.86cm -1 (w), 866.03cm -1 (w), 893.90cm -1 (w), 940.44cm -1 (w), 969.18cm -1 (w), 1011.74cm -1 ( s), 1036.51cm -1 (s), 1062.25cm -1 (w), 1123.24cm -1 (s), 1192.18cm -1 (s), 1208.69cm -1 (s), 1268.51cm -1 (m) , 1356.58 cm -1 (w), 1385.50 cm -1 (w), 1466.67 cm -1 (w), 1522.01 cm -1 (m), 1614.23 cm -1 (w), 17
  • Simulated intestinal fluids such as FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant mediators that better reflect the effects of the gastrointestinal physiology on drug release, in such The solubility tested in the medium is closer to the solubility in the human environment.
  • the crystalline form A of the present invention and 20 mg of the prior art form I were respectively dissolved in 1.5 mL of FaSSIF and 1.5 mL of FeSSIF to prepare a saturated solution, and equilibrated for 15 minutes, and tested by high performance liquid chromatography for 30 minutes and 1 hour, respectively.
  • the content of the sample in the saturated solution (mg/mL), and the results are shown in Table 3.
  • Example 6 Form A wettability
  • the thickness of the test sample is generally about 1 m, and the weight is accurately weighed (m 2 ).
  • Form A is only 0.24% under the guiding principle of the Chinese Pharmacopoeia 2015 General Principles 9103 Drug Humidity Test, while the wet weight gain of the prior art Form I under the same conditions is 0.40%, Form A wettability Better than the prior art.
  • the crystalline form A of the present invention was prepared by a free base, and the chemical purity of the starting material and the crystalline form A of the present invention was measured by HPLC. The test results are shown in Table 5.
  • the crystal form A capsule was packaged in a HDPE bottle, placed under the conditions of 25 ° C / 60% RH and 40 ° C / 75% RH and sampled and examined for crystal form after 3 months, and the formulation stability of the form A was examined.
  • the XRPD comparison chart is shown in Figure 11. The results showed that the Form A formulation was stable for at least 3 months at 25 ° C / 60% RH and 40 ° C / 75% RH.
  • Example 10 The capsule containing Form A obtained in Example 10 was tested for in vitro dissolution under the following conditions:
  • Dissolution medium 0.1 mol/L HCl solution
  • Dissolution method paddle method + sedimentation basket
  • the in vitro dissolution of the Form A preparation is shown in the following table. As shown in Fig. 12, it is shown that the capsule having the crystalline form A of the present invention as an active ingredient can be dissolved at 80% or more at 30 minutes, which meets the requirements of rapid dissolution and has good dissolution. degree.
  • the tablet is pressed by a manual tableting machine, and when the tablet is pressed, a circular flush (which ensures the isotropy of the tablet) which can be pressed into a cylindrical tablet is selected, and a certain amount of the prior art form I and the crystal form of the invention are added.
  • the compressibility index or the Carr Index is usually used to evaluate the fluidity of the powder or the intermediate particles by measuring a certain amount of the powder into the measuring cylinder.

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Abstract

一种Valbenazine 二对甲苯磺酸盐的晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备囊泡单胺转运蛋白2 抑制剂和治疗迟发性运动障碍药物制剂中的用途。

Description

一种Valbenazine二对甲苯磺酸盐的晶型及其制备方法和用途 技术领域
本发明涉及药物化学领域。具体而言，涉及Valbenazine二对甲苯磺酸盐的晶型及其制备方法和用途。
背景技术
迟发性运动障碍(Tardive Dyskinesia，TD)是以口面部区域(即舌、嘴唇、颌、脸)的不自主运动以及四肢和躯干的舞蹈性手足徐动症样运动为特征的神经性病况。轻度TD患者通常意识不到不自主运动，因此他们不主动寻求治疗。随着症状严重性增加，运动机能亢进性运动开始扰乱正常的讲话、咀嚼、呼吸、面部表情、肢体运动、走路和平衡。在最严重的情况中，TD可能导致自我损伤、擦伤、撕裂伤，穿衣、进食或饮水障碍。
多巴胺能系统的失调是几个中枢神经系统紊乱的一部分，包括超动能运动障碍(如:迟发性运动障碍(TD))，以及精神分裂症和双相情感障碍等疾病。转运蛋白囊泡单胺转运蛋白2(VMAT2)在突触前多巴胺释放中扮演重要角色，调节单胺从细胞质到突触小泡的储存和释放。VMAT2抑制剂已经在各种运动病症(包括迟发性运动障碍)的治疗中显示出效果。
Valbenazine由Neurocrine生物科学公司研发，以VMAT2为作用靶点，于2017年4月11日被FDA批准用于治疗迟发性运动障碍成年患者，上市形态为二对甲苯磺酸盐。这是FDA批准治疗迟发性运动障碍的首款药物，FDA授予了该药物上市申请快速通道审评资格、优先审评资格及突破性疗法资格。
Valbenazine的化学名称为：(S)-2-氨基-3-甲基-丁酸(2R,3R,11bR)-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-基酯(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2018124039-appb-000001
晶型是化合物分子在微观结构中有序排列而形成晶格的固体，药物多晶型现象是指药物存在两种或两种以上的不同晶型。因为理化性质不同，药物的不同晶型可能在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效和安全性；特别是对难溶性固体药物，晶型的影响会更大。因此，药物晶型必然是药物研究的重要内容，也是药物质量控制的重要内容。
专利WO2017075340A1公开了Valbenazine二对甲苯磺酸盐的6个晶型，分别是形式I、形式II、形式III、形式IV、形式V、形式VI，其文本中详细记载了形式I的稳定性数据，且明确指出形式I的稳定性远远优于形式II和形式IV，引湿性也优于其他晶型。此外，该专利实施例17记载，将Valbenazine二对甲苯磺酸盐加入到24种不同的有机溶剂中温育，超过一半的实验获得的结晶为形式I，其余部分并未结晶或成无定形或成其他未知形式，由此可见，形式I为WO2017075340A1公开晶型中性质最为优越的晶型。
然而本申请发明人经研究发现，现有技术形式I的获得对原料药的损耗较大，收率低，如WO2017075340A1实施例2记载，其收率仅为69％，此外，经研究发现形式I还存在溶解度、引湿性、粉体学的问题。
为克服现有技术的缺点，本申请的发明人意外发现了本发明提供的化合物I的二对甲苯磺酸盐晶型A，其在理化性质，制剂加工性能及生物利用度等方面具有优势，例如在熔点，溶解度，引湿性，提纯作用，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势。本发明的晶型A自身物理、化学稳定性好，以相同起始物制备得到晶型其收率较形式I明显提升，且溶解度、引湿性、流动性、可压性和黏附性较形式I具有明显优势，为含Valbenazine的药物开发提供了新的更好的选择，具有非常重要的意义。
发明内容
本发明的主要目的是提供化合物I的二对甲苯磺酸盐的新晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物I二对甲苯磺酸盐的晶型A(以下称作“晶型A”)。
一方面，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在衍射角2θ为5.9°±0.2°、13.3°±0.2°、19.8°±0.2°处有特征峰。
进一步地，所述晶型A的X射线粉末衍射在衍射角2θ为11.0°±0.2°、8.7°±0.2°、15.8°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型A的X射线粉末衍射在衍射角2θ为11.0°±0.2°、8.7°±0.2°、15.8°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在衍射角2θ值为5.9°±0.2°、13.3°±0.2°、19.8°±0.2°、11.0°±0.2°、8.7°±0.2°、15.8°±0.2°中的任意3处、或4处、或5处、或6处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型A为水合物，其X射线粉末衍射图基本如图3所示。
本发明的晶型A的红外光谱如图7所示，包括621.81cm -1(w)、682.24cm -1(s)、710.21cm -1(w)、773.12cm -1(w)、786.44cm -1(m)、813.86cm -1(w)、866.03cm -1(w)、 893.90cm -1(w)、940.44cm -1(w)、969.18cm -1(w)、1011.74cm -1(s)、1036.51cm -1(s)、1062.25cm -1(w)、1123.24cm -1(s)、1192.18cm -1(s)、1208.69cm -1(s)、1264.51cm -1(m)、1356.58cm -1(w)、1385.50cm -1(w)、1466.67cm -1(w)、1522.01cm -1(m)、1614.23cm -1(w)、1748.34cm -1(m)(±2cm -1)中的一处或多处的吸收峰。
根据本发明的目的，本发明还提供所述晶型A的制备方法，所述制备方法包括:
将化合物I二对甲苯磺酸盐的溶剂合物置于醚类溶剂中，悬浮搅拌，过滤固体，干燥得到晶型A。
在本发明的晶型A的制备方法中：
所述溶剂合物优选为2-MeTHF和水的共溶剂合物。
在一个具体的实施例中，所述溶剂合物为化合物I二对甲苯磺酸盐共溶剂合物晶型CSIII(以下称作“晶型CSIII”)，其XRPD图如图1所示。
所述醚类溶剂优选为苯甲醚。
所述温度优选为4℃。
所述过滤得到的固体为晶体(以下称作“晶型N4”)，其XRPD图如图2所示。
本发明提供的晶型A具有以下有益效果：
(1)与现有技术相比，本发明晶型A具有更高的收率。现有技术WO2017075340A1实施例2中记载，游离碱制备得到形式I粗产品的收率为69％，实施例3进一步将其重结晶处理，收率为72％-88％，即从游离碱制备得到形式I终产品的收率仅为50％-61％。而本发明晶型A从游离碱制备得到晶型A终产品的收率可达84％，与现有技术收率相比，提升了23％-34％。提高药物制备收率可大大降低生产成本，具有很强的社会经济效益。
(2)与现有技术相比，本发明晶型A具有更高的溶解度。特别是在FeSSIF(模拟进食状态肠液)中，溶解度是现有技术WO 2017075340A1形式I的1.23倍。
FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟进食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。在生物相关介质中具有更高的溶解度有利于提高药物在人体内的吸收，提高生物利用度，使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(3)与现有技术相比，本发明晶型A具有更低的引湿性。通过药典药物引湿性试验指导原则测定引湿性，测试结果表明，本发明晶型A的引湿性仅仅为现有技术晶型的3/5。晶型A引湿性增重为0.24％，而现有技术形式I引湿性增重高达0.40％，引湿性明显高于本发明晶型A。
引湿性直接影响药物的物理化学稳定性，引湿性高易引起化学降解和晶型转变。此外，引湿性高会降低药物的流动性，从而影响药物的加工工艺。不仅如此，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。低引湿性晶型对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。
(4)本发明的晶型A具有良好的提纯作用。由游离碱原料制备成本发明晶型后纯度显著提高。在具体的实施例中，本发明使用的原料纯度为99.09％，经制备得到晶型A后，纯度提升至99.38％，纯度提升达0.29％，更重要的一点是，将原料制备成晶型A后，检出杂质数量显著减少，由原来的8个杂质减少为5个。
药物的化学纯度对于保证药物的疗效和安全性，防止药物不良反应的发生具有重要意义。如药物中含有超过限量的杂质，就有可能使理化常数变化，外观性状产生变异，并影响药物的稳定性；杂质增多也使药物含量明显偏低或活性降低，毒副作用显著增加,因此，不同的药物法规都对杂质含量有严格的要求。提纯作用好的晶型在结晶工艺中能够体现出极强的杂质排除能力，使得通过结晶就能得到纯度较高的原料药，有效的克服了药物纯度低带来的药物稳定性低、疗效差、毒性高等缺点。
(5)本发明提供的晶型A原料药和制剂均具有良好的稳定性。晶型A原料药在25℃/60％相对湿度条件下闭口放置，至少3个月晶型及化学纯度未发生变化，在25℃/60％相对湿度条件下敞口放置，至少3个月晶型未发生变化，且化学纯度仅降低0.03％，储存过程中纯度基本保持不变。晶型A与辅料混合做成药物制剂后，晶型未发生变化，在25℃/60％相对湿度条件下放置，至少3个月晶型未发生变化。说明晶型A原料药和制剂在长期条件下具有较好的稳定性，有利于药物的储存。
同时，晶型A原料药在40℃/75％相对湿度条件下放置至少3个月晶型未发生变化，且化学纯度仅降低0.09％，储存过程中纯度基本保持不变。在60℃/75％相对湿度条件下至少1周晶型未发生变化，且化学纯度仅降低0.08％，储存过程中纯度基本保持不变。晶型A与辅料混合做成药物制剂后，在40℃/75％相对湿度条件下放置，至少3个月晶型未发生变化。说明晶型A原料药和制剂在加速条件及更严苛的条件下，具有较好的稳定性。原料药和制剂在加速条件及更严苛的条件下的稳定性对于药物至关重要。原料药和制剂在储存、运输、生产过程中会遇到天气和季节差异、不同地区气候差异等带来的高温和高湿条件。晶型A原料药和制剂在苛刻的条件下具有较好的稳定性，有利于避免偏离标签上的贮藏条件对药物质量的影响。
同时，晶型A具有良好的机械稳定性。晶型A原料药经15kN压力压制成片后，晶型保持不变，具有良好的物理稳定性，有利于在制剂干法制粒和压片工艺中保持晶型稳定。
晶型的转变会导致药物的吸收发生变化，影响生物利用度，甚至引起药物的毒副作用。良好的化学稳定性可以确保在储存过程中基本没有杂质产生。晶型A具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，最大程度地减少药物由于晶型改变或杂质产生引起的药物质量变化、生物利用度改变。
(6)本发明晶型A具有优越的体外溶出度与溶出速率。晶型A制剂在0.1N盐酸介质中，30分钟时的溶出度达89.7％，符合快速溶出的要求。
不同的晶型可能导致制剂在体内有不同的溶出速率，直接影响制剂在体内的吸收、分布、代谢、排泄，最终因其生物利用度不同而导致临床药效的差异。溶出度和溶出速率是药物被吸收的重要前提。良好的体外溶出度预示药物的体内吸收程度较高，在体内暴露特性更好，从而提高生物利用度，提高药物的疗效；高的溶出速率使得给药后药物在血浆中能够很快达到最高浓度值，进而确保药物快速起效。
进一步地，本发明提供的晶型A还具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型A具有更优的可压性。晶型A好的可压性可以有效改善压片工艺中的硬度/脆碎度不合格、裂片等问题，使制剂工艺更为可靠，改善产品外观，提升产品质量。更优的可压性亦可提升压片速度进而提升生产效率，同时可减少用于改善可压性的辅料的成本支出。
(2)与现有技术相比，本发明晶型A具有更好的流动性。流动性评价结果表明，晶型A流动性明显优于现有技术晶型。更好的流动性可以避免堵塞生产设备，提升生产效率；晶型A更好的流动性能保证制剂的混合均匀度及含量均匀度、降低制剂的重量差异，提升产品质量。
(3)与现有技术相比，本发明晶型A具有更优的黏附性。黏附性评价结果表明，晶型A的吸附量远低于现有技术晶型的吸附量。晶型A的黏附性低可有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于改善产品外观、重量差异等。此外，晶型A的低黏附性还能有效减少原料的团聚现象，减少物料和器具之间的吸附，利于原料的分散及与其他辅料的混合，增加物料混合时的混合均匀度及最终产品的含量均匀度。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的本发明的晶型A及药学上可接受的载体、稀释剂或辅料。
进一步地，本发明提的晶型A在制备囊泡单胺转运蛋白2抑制剂药物制剂中的用途。
更进一步地，本发明提供的晶型A在制备治疗迟发性运动障碍药物制剂中的用途。
本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
所述“干燥”可以在室温或更高的温度下进行。干燥温度为室温到约60℃，或者到50℃,或者到40℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
本发明中，“晶体”或“多晶型”指被X射线粉末衍射图表征证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线粉末衍射图通常会随着仪器条件的不同而有所改变。特别需要指出的是，X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度的顺序不能作为唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本文所示的衍射峰强度为说明性而非用于绝对比较。另外，衍射峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成衍射峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型A是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
本发明中术语“约”，当用来指可测量的数值时，例如化合物和制剂的质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
附图说明
图1晶型CSIII的XRPD图
图2晶型N4的XRPD图
图3晶型A的XRPD图
图4晶型A的XRPD图
图5晶型A的TGA图
图6晶型A的DSC图
图7晶型A的IR图
图8晶型A稳定性实验前后XRPD对比图(从上至下依次为：放置前的XRPD图，在25℃/60％相对湿度敞口放置3个月后的XRPD图，在25℃/60％相对湿度闭口放置3个月后的XRPD图，在40℃/75％相对湿度闭口放置3个月后的XRPD图，在60℃/75％相对湿度闭口放置1周后的XRPD图)
图9晶型A经15kN的压力压制成片前后XRPD对比图(上图为压片前的XRPD图，下图为压片后的XRPD图)
图10晶型A制备成制剂前后XRPD对比图(从上到下依次为：辅料的XRPD图、晶型A制备成胶囊剂后的XRPD图及晶型A的XRPD图)
图11晶型A制剂稳定性实验前后XRPD对比图(从上至下依次为：放置前的XRPD图、在25℃/60％相对湿度闭口放置3个月后的XRPD图以及在40℃/75％相对湿度闭口放置3个月后的XRPD图)
图12晶型A制剂的溶出曲线图
具体实施方式
本发明进一步参考以下实施例说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热
TGA：热重分析
IR:红外光谱
采集数据所用的仪器及方法：
本发明实施例所述的X射线粉末衍射图在Bruker D2 PHASER X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2018124039-appb-000002
1.54060；Kα2
Figure PCTCN2018124039-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的红外光谱(IR)图在Bruker公司生产的VERTEX 70红外光谱仪上采集，所述的傅立叶红外光谱仪的方法参数如下：
光源:中红外光源
检测器:DLATGS
样品扫描次数:16
分辨率:4.0
干涉仪：Rock-Solid TM
本发明所述的测试纯度的高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)。
HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18 150×4.6mm,5μm
2、流动相：A：5mM磷酸二氢钾+5mM磷酸二氢钠+0.1％三乙胺水溶液，pH＝8.5
B：乙腈
洗脱梯度如下：
时间(min) ％B
0.0 25
30.0 60
35.0 80
37.0 80
37.1 25
42.0 25
3、流速：1.0mL/min
4、进样量：10μL
5、检测波长：230nm
6、柱温：40℃
7、稀释剂：乙腈:水(v:v)＝50:50
本发明所述的测试溶解度、溶出的高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)。
HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18 150×4.6mm,5μm
2、流动相：A：0.1％三氟乙酸水溶液
B：0.1％三氟乙酸乙腈溶液
洗脱梯度如下：
时间(min) ％B
0 8
10.0 50
12.0 90
12.1 8
17.0 8
3、流速：1.0mL/min
4、进样量：10μL
5、检测波长：230nm
6、柱温：40℃
7、稀释剂：乙腈:水(v:v)＝50:50
根据本发明，作为原料的所述化合物I和/或其盐为固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物I和/或其盐为固体粉末形式。
以下实施例中所使用的Valbenazine游离碱固体可根据现有技术制备得到，例如根据WO2008058261A1文献所记载的方法制备获得，使用的对甲苯磺酸可以是对甲苯磺酸的水合物。
具体实施方式
实施例1晶型CSIII的制备方法
称取432.1mg的游离碱于玻璃小瓶中，加入390.8mg的对甲苯磺酸，再加入1mL的2-MeTHF到该小瓶中，在室温下搅拌3分钟后，加入1mL的2-MeTHF和200μL的水，在-20℃下搅拌，分离固体即得晶型CSIII。晶型CSIII为2-MeTHF和水的共溶剂合物，其XRPD图如图1所示。
实施例2晶型A的制备方法
将46.2mg的晶型CSIII置于2.3mL苯甲醚溶剂中，4℃下悬浮搅拌，分离固体，此时所得固体为晶型N4，其XRPD图如图2所示。将晶型N4室温下真空干燥，得白色的固体。经检测，所得结晶固体为本发明晶型A，其X射线粉末衍射数据如表1，其XRPD图如图3。
表1
衍射角2θ d值 强度％
5.88 15.03 100.00
7.06 12.52 3.97
8.68 10.18 4.82
10.98 8.05 5.50
13.29 6.66 14.80
14.27 6.21 3.81
15.75 5.63 10.38
16.26 5.45 4.06
16.96 5.23 2.53
18.15 4.89 5.91
19.00 4.67 5.70
19.76 4.49 17.66
21.58 4.12 4.90
22.88 3.89 3.61
26.98 3.30 2.41
29.40 3.04 1.21
30.00 2.98 1.14
36.01 2.49 0.31
实施例3晶型A的制备方法
称取500.1mg的游离碱以及476.1mg的对甲苯磺酸于20mL的玻璃小瓶中，加入4.0mL的2-MeTHF，于-20℃搅拌约1.5h后，继续加入6.0mL的2-MeTHF，搅拌约1.5h后，离心，室温真空干燥约1.5h后得到固体。
将该固体转移至100mL小瓶，并加入约45mL的苯甲醚溶剂于-20℃搅拌一段时间，然后再加入约0.5mL晶型N4的晶种悬浊液后继续搅拌，得到的固体在氮气保护条件下过滤，室温真空干燥过夜后得到795.8mg的晶型A(扣除晶种后的收率：84％)。其XRPD图如图4所示，XRPD数据如表2所示。TGA如图5所示，将其加热至150℃约有2.61％的质量损失。DSC如图6所示，其在在139.1℃附近出现一个吸热峰，该吸热峰为熔化吸热峰。
表2
Figure PCTCN2018124039-appb-000004
Figure PCTCN2018124039-appb-000005
实施例4晶型A的IR测定
取适量的晶型A，测试其红外数据，红外谱图如图7所示。
由红外谱图可以看出，本发明的晶型A在621.81cm -1(w)、682.24cm -1(s)、710.21cm -1(w)、773.12cm -1(w)、786.44cm -1(m)、813.86cm -1(w)、866.03cm -1(w)、893.90cm -1(w)、940.44cm -1(w)、969.18cm -1(w)、1011.74cm -1(s)、1036.51cm -1(s)、1062.25cm -1(w)、1123.24cm -1(s)、1192.18cm -1(s)、1208.69cm -1(s)、1264.51cm -1(m)、1356.58cm -1(w)、1385.50cm -1(w)、1466.67cm -1(w)、1522.01cm -1(m)、1614.23cm -1(w)、1748.34cm -1(m)(±2cm -1)处有吸收峰。
实施例5晶型A的动态溶解度
模拟肠道液体，例如FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟进食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。
取本发明的晶型A及现有技术形式I各20mg分别溶于1.5mL的FaSSIF、1.5mL的FeSSIF配制成饱和溶液，平衡15分钟，30分钟、1小时后分别用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表3所示。
表3
Figure PCTCN2018124039-appb-000006
结果表明本发明晶型A较现有技术晶型具有更高的溶解度。
实施例6晶型A引湿性
按照中国药典2015年版通则9103药物引湿性试验指导原则，进行引湿性实验，实验方法如下：
1.取干燥的具塞玻璃称量瓶(外径为50mm，髙为15mm),于试验前一天置于适宜的25℃±1℃恒温干燥器(下部放置氯化铵或硫酸铵饱和溶液)或人工气候箱(设定温度为25℃±1℃，相对湿度为80％±2％)内，精密称定重量(m 1)。
2.取供试品适量，平铺于上述称量瓶中，供试品厚度一般约为1m m，精密称定重量(m 2)。
3.将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下24小时。
4.盖好称量瓶盖子，精密称定重量(m 3)。
Figure PCTCN2018124039-appb-000007
分别测试本发明晶型A和现有技术形式I的引湿性，测试结果如表4所示。
表4
Figure PCTCN2018124039-appb-000008
晶型A在中国药典2015年版通则9103药物引湿性试验指导原则条件下引湿性增重仅为0.24％，而现有技术形式I在相同条件下引湿性增重为0.40％，晶型A引湿性优于现有技术。
实施例7晶型A的提纯效果
通过游离碱制备得到本发明晶型A，采用HPLC测定起始物、本发明的晶型A的化学纯度，测试结果如表5所示。
表5
晶型 化学纯度 杂质个数 纯度提升
起始原料 99.09％ 8 ——
晶型A 99.38％ 5 0.29％
结果表明，通过起始物料制备得到晶型A后纯度有较为明显提升，纯度由原来的99.09％提升至99.38％，可检出杂质个数由原来的8个减少至5个，说明本发明晶型A具有很好的提纯效果。
实施例8晶型A的稳定性
取本发明的晶型A四份样品于25℃/60％相对湿度敞口和闭口放置3个月，40℃/75％相对湿度闭口放置3个月，60℃/75％相对湿度闭口放置1周后取样，采用XRPD和HPLC法测定晶型与纯度的变化。结果如下表所示：
表6
Figure PCTCN2018124039-appb-000009
结果表明，本发明的晶型A在25℃/60％相对湿度闭口条件下至少3个月晶型保持不变且杂质含量不变，在25℃/60％相对湿度敞口以及40℃/75％相对湿度闭口条件下至少可稳定3个月，可见，晶型A在长期和加速条件下均可保持良好的稳定性。60℃/75％相对湿度条件下闭口至少可稳定1周，可见本发明晶型A在更严苛的条件下稳定性也很好。
实施例9晶型A的机械稳定性
称取晶型A约0.1g至压片模具中，使用15KN压力进行压片，并保持压力1分钟后，卸下压力，取出模具中的样品，进行XRPD检测。结果表明压片前后晶型保持不变，XRPD图如图9所示。
实施例10晶型A的制剂制备
制剂处方如表7所示。
表7
Figure PCTCN2018124039-appb-000010
制剂工艺如表8所示。
表8
Figure PCTCN2018124039-appb-000011
将晶型A制备成胶囊剂后，采用XRPD检测其晶型，结果表明晶型A未发生变化，制剂处方工艺前后晶型保持稳定，其XRPD图如图10所示。
实施例11晶型A在制剂中的稳定性
将晶型A胶囊剂用HDPE瓶封装，放置于25℃/60％RH和40℃/75％RH的条件下并于3个月后进行取样检测晶型，考察晶型A的制剂稳定性，XRPD对比图如图11所示。结果表明，晶型A制剂在25℃/60％RH和40℃/75％RH条件下至少可以保持3个月稳定。
实施例12晶型A制剂的体外溶出度
对实施例10获得的含晶型A的胶囊测试体外溶出情况，条件如下：
溶出介质：0.1mol/L的HCl溶液
溶出方法：桨法+沉降篮
介质体积：900mL
转速：50rpm
介质温度：37℃
晶型A制剂的体外溶出情况如下表，图12所示，表明以本发明晶型A为活性成分的胶囊剂在30min时溶出即可达到80％以上，符合快速溶出的要求，具有良好的溶出度。
表9
时间(min) 累积溶出度(％)
0 0.0
5 18.2
10 44.5
15 62.2
20 73.4
30 89.7
实施例13晶型A的可压性
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲(保证片剂的各向同性)，加入一定量的现有技术形式I和本发明晶型A样品，分别采用一定的压力压制成圆形片剂，室温放置24h，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好。样品量较少时，采用下表中的推荐参数进行测试。
表10抗张强度测试推荐参数
模具 样品量 压力
Φ6mm圆形平冲 80mg 10kN
现有技术形式I和本发明晶型A的实验测定结果如表11所示。
表11
Figure PCTCN2018124039-appb-000012
结果表明，晶型A的抗张强度为1.36MPa，而形式I的抗张强度为0.86MPa，本发明晶型A的可压性相较于形式I具有明显的优势。
实施例14晶型A的流动性
制剂工艺过程中，通常可采用可压性系数(Compressibility index)或卡尔系数(Carr Index)来评价粉体或中间体颗粒的流动性，测定方法为将一定量的粉体轻轻装入量筒后测量最初松体积；采用轻敲法使粉体处于最紧状态，测量最终的体积；计算松密度ρ 0与振实密度ρ f；根据公式c＝(ρ f－ρ 0)/ρ f计算可压性系数。
可压性系数对粉体流动性的界定标准参考ICH Q4B附录13，详见表12。
表12
可压性系数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型A和现有技术形式I的流动性评价结果见表13，结果表明晶型A的流动性明显优于现有技术晶型。
表13
Figure PCTCN2018124039-appb-000013
实施例15晶型A的黏附性
分别将30mg晶型A和现有技术形式I加入到8mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续压制数次后，记录冲头累计的最终黏附量、压制过程中的最高黏附量和平均黏附量。具体的实验结果见表14。
表14
晶型 累计最终吸附量(mg) 最高吸附量(mg)
形式I 0.21 7.58
晶型A 0.06 0.17
实验结果表明，现有技术晶型的累计吸附量是晶型A的3倍多，晶型A的黏附性优于现有技术晶型。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (8)

  1. 一种Valbenazine二对甲苯磺酸盐的晶型A，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为5.9°±0.2°、13.3°±0.2°、19.8°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型A，其特征还在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为11.0°±0.2°、8.7°±0.2°、15.8°±0.2°中的1处或2处或3处具有特征峰。
  3. 一种权利要求1所述的Valbenazine二对甲苯磺酸盐晶型A的制备方法，其特征在于：将Valbenazine二对甲苯磺酸盐的溶剂合物置于醚类溶剂中，在-20℃-25℃温度下悬浮搅拌，过滤固体，干燥得到晶型A。
  4. 根据权利要求3所述的制备方法，所述Valbenazine二对甲苯磺酸盐的溶剂合物为2-MeTHF和水的共溶剂合物，所述醚类溶剂为苯甲醚。
  5. 根据权利要求4所述的制备方法，其特征在于，所述2-MeTHF和水的共溶剂合物为晶体形式，使用Cu-Kα辐射，其X射线粉末衍射图与图1一致。
  6. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1中所述的晶型A及药学上可接受的载体、稀释剂或辅料。
  7. 权利要求1中所述的晶型A在制备囊泡单胺转运蛋白2抑制剂药物中的用途。
  8. 权利要求1中所述的晶型A在制备治疗迟发性运动障碍药物中的用途。
PCT/CN2018/124039 2017-12-26 2018-12-26 一种Valbenazine二对甲苯磺酸盐的晶型及其制备方法和用途 WO2019129100A1 (zh)

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