WO2015035817A1

WO2015035817A1 - An inositol crystal as well as preparation method and use thereof

Info

Publication number: WO2015035817A1
Application number: PCT/CN2014/080912
Authority: WO
Inventors: 朱理平; 梅雪峰
Original assignee: 诸城市浩天药业有限公司
Priority date: 2013-09-10
Filing date: 2014-06-27
Publication date: 2015-03-19
Also published as: CN103408400A; CN103408400B

Abstract

Disclosed are an inositol crystal, preparation method therefor and use thereof. The X-ray powder diffraction (XRPD) pattern of crystal form C has characteristic peaks at the following angles of 2θ±0.2°： 14.86°, 17.82°, 20.38°, 25.32°, 26.42°, 28.39°, 31.28° and 34.33°.

Description

Inositol crystal and preparation method and use thereof

Technical field

The present invention relates to the field of chemical pharmaceuticals, and in particular to a novel inositol crystal, a preparation method thereof and use thereof. Background technique

The polymorphism phenomenon refers to a phenomenon in which a solid substance is arranged in two or more different spatial manners to form a solid state having different physicochemical properties. In the field of pharmaceutical research, polymorphs include multicomponent crystalline forms such as organic solvates and hydrates. Drug polymorphism is widespread in drug development and is an inherent property of organic small molecule compounds. Different crystal forms have different colors, melting points, solubility, dissolution properties, chemical stability, mechanical stability, reactivity, etc. These physicochemical properties and processability sometimes directly affect the safe and effective performance of the drug. Therefore, crystal form research has become an important part of the drug research process.

In theory, small molecule drugs can have an infinite number of crystal packing methods—polymorphs. Studies have shown that the number of drug polymorphs found is directly proportional to the time and resources of the research they are investigating. The main means of crystal discovery are solution volatilization, melt crystallization, rapid cooling and suspension, etc., which affect the external conditions of drug crystallization by changing the crystallization conditions such as solvent, temperature, speed, and ratio of suspended solvent. High-throughput sample preparation platforms were used to prepare hundreds of crystallization experiments simultaneously, and new crystal forms were prepared and discovered using micro sample preparation techniques and analytical testing methods.

Inositol can promote fat metabolism in the liver and is used to treat liver cirrhosis, fatty liver, hepatitis and other diseases. Inositol also has the effect of lowering blood cholesterol, treating fat and cholesterol catabolism disorders; inositol and its derivatives It can also be used to treat depression and obsessive-compulsive disorder. Four single crystal structures for inositol can be found in the Cambridge Crystal Database (CCD): MYIINOL (ActaCrystallogr. ( 1964 ) , 17, 159 ) , MYINOL01 ( ActaCrystallogr. , Sect. E: Struct.Rep. Online (2007), 63, 0530), MYTOLD (ActaCrystallogr. (1963), 16,264) and MYTOLDO 1 (ActaCrystallogr., Sect. E: Struct. Rep. Online (2006), 62, 02902). Among them, MYTOLD and MYTOLD01 are the same crystal form, both of which are dihydrate crystal forms. MYIINOL is a monoclinic system and MYINOL01 is an orthorhombic system.

There is an urgent need in the art to provide a crystalline form with better properties, such as a new crystalline form that increases the bioavailability of the drug. Summary of the invention

The present invention aims to provide a novel inositol crystal.

Another object of the present invention is to provide a process for the preparation of the novel inositol crystals.

A further object of the invention is to provide the use of said novel inositol crystals.

A fourth object of the present invention is to provide a pharmaceutical composition containing novel inositol crystals. In a first aspect of the invention, there is provided an inositol crystal form C having a structure as shown in Formula I, wherein said Form C has an X-ray powder diffraction (XRPD) pattern at the following 2 Θ ± 0.2° angle Characteristic peaks: 14.86°, 17.82°, 20.38°, 2 8°, 34.33°;

Preferably, the X-ray powder diffraction (XRPD) pattern of the Form C is at the following 2 Θ ± 0.2° angle and has a characteristic purlin: 12.53. , 18.04. , 22.06°, 24.04. , 25.78. , 27.80. , 29.50. 30.05°, 31.81°, 32.72°, 33.13°, 35.68°, 36.17°; more preferably, the X-ray powder diffraction (XRPD) pattern of the Form C has a characteristic peak at the following 2Θ ± 0.2° angle : 5.96°, 6.26°, 6.74°, 8.07°, 14.59°, 18.35°, 19.99°, 24.74°, 30.92°, 33.62°, 36.69°, 38.42. .

In another preferred embodiment, the crystal C has an X-ray powder diffraction (XRPD) pattern as shown in FIG.

In another preferred embodiment, the Form C differential scanning calorimetry has a characteristic exothermic peak at about 208.2 °C and a characteristic endothermic peak at about 227.4 °C. In a second aspect of the present invention, there is provided a process for the preparation of inositol Form C provided by the present invention as described above, the method comprising the steps of: cooling 230 to C to molten mentitol to room temperature to obtain the above The inositol crystal form C provided by the present invention is described.

In another preferred embodiment, it is cooled to room temperature at a rate of 10-100 ° C / minute; more preferably, 50-100 Cool at a rate of °C/min.

In another preferred embodiment, the method includes the steps of:

(1) heating the inositol to 230 ° C to melt;

(2) The inositol crystal form C provided by the present invention as described above is obtained by cooling 230 ° C to molten inositol at a rate of 10-100 ° C /min to room temperature.

In another preferred embodiment, the inositol is heated to 240 ° C to melt and cooled to room temperature at a rate of 50-100 ° C /min. In a third aspect of the invention, there is provided a pharmaceutical composition comprising the inositol crystalline form C of the invention as described above and a pharmaceutically acceptable carrier. In a fourth aspect of the invention, there is provided a use of the inositol crystal form C provided by the invention as described above for the preparation of a medicament for the treatment of hypercholesterolemia and fatty liver. Accordingly, the present invention provides a better inositol crystal form. DRAWINGS

Fig. 1 is an X-ray powder diffraction (XRPD) pattern of the inositol C crystal form obtained in the examples.

Fig. 2 is an infrared spectrum (IR) chart of the inositol C crystal form obtained in the examples.

Fig. 3 is a Raman spectrum diagram of the inositol C crystal form obtained in the examples.

Fig. 4 is a graph showing the thermogravimetric analysis (TG) of the inositol C crystal form obtained in the examples.

Fig. 5 is a differential scanning calorimetry (DSC) chart of the inositol C crystal form obtained in the examples.

Fig. 6 is a dynamic water vapor adsorption (DFS) diagram of the inositol C crystal form obtained in the examples. detailed description

After several attempts by the inventors, a new inositol crystal form, crystal form C, was discovered, and a simple preparation method for obtaining such a crystal form was found. On the basis of this, the present invention has been completed. As used herein, "compounds of formula I", "compounds of formula 1" or "myo-inositol" are used interchangeably and refer to cis-1,2,3,5-trans-4,6-ring. Hexahexanol has the following structure:

As used herein, "room temperature" means 15-30 ° C, preferably 20-25 ° C.

As used herein, the term "treatment or treating" includes prophylactic (gp, prophylactic), curative or palliative treatment which results in a desired pharmaceutical and/or physiological effect. In addition, the term "treatment" is used herein to mean one or more symptoms based on partial or complete mitigation, delayed onset, inhibition of progression, reduction in severity, and/or reduction in a particular disease, disorder, and/or medical condition. The purpose of the probability, and for the individual (or patient) to be tested, especially a medical condition, a symptom of the medical condition, a disease or condition caused by the medical condition, or a The compounds of the present disclosure are administered or applied to an individual in an advanced condition in which the medical condition develops. Individuals who have not developed a significant condition for a particular disease, abnormality, and/or medical condition, and/or individuals who have an early onset of the particular disease, abnormality, and/or medical condition may be treated to reduce the occurrence of the particular disease, abnormality And/or the risk of pathology associated with medical conditions. Reducing one or more signs or clinical indicators means that the treatment is "effective."

The words "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to when applied to a body. (Human or animal) A compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

The numerical values and parameters used to define the broader scope of the invention are approximated, and the relevant values in the specific embodiments are presented as precisely as possible herein. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the average, depending on the considerations of those skilled in the art. Except for the experimental examples, or unless otherwise explicitly stated, all ranges, quantities, values, and percentages used herein are understood (eg, to describe the amount of material used, the length of time, the temperature, the operating conditions, the quantity ratio, and the like. )) are all modified by "about". Therefore, unless otherwise Rather, the numerical parameters disclosed in the specification and the appended claims are intended to be At a minimum, these numerical parameters should be understood as the number of significant digits indicated and the values obtained by applying the general carry method. Identification and properties of inositol crystal form C

The present inventors further studied the properties of the inositol crystal form C by various means and instruments.

"X-ray powder diffraction", also known as "X-ray polycrystalline diffraction (XRPD)", is a commonly used test method for determining crystal structure (ie, crystal form;). An X-ray powder diffractometer is used to generate a series of diffraction patterns when X-rays are transmitted through the crystal. The different diffraction lines and their intensities in the spectrum are determined by the atomic groups of a certain structure, thereby determining the specific crystal structure of the crystal.

Methods for determining X-ray powder diffraction of crystals are known in the art. For example, using a Bmker DS Advanced model X-ray powder diffractometer, a copper radiation target is used to acquire the spectrum at a scan rate of 2° per minute.

The inositol crystal form C of the present invention has a specific crystal form and has a specific characteristic peak in an X-ray powder diffraction (XRPD) chart. Specifically, the X-ray powder diffraction (XRPD) pattern of the inositol crystal form C of the present invention has a characteristic peak at the following 2 Θ ± 0.2° angle: 14.86. , 17.82. , 20.38. 25.32°, 26.42°, 28.39°, 31.28°, 34.33°; Preferably, the spectrum has a characteristic peak at the following 2 Θ ± 0.2° angle: 12.53. , 14.86. , 17.82. , 18.04. , 20.38. , 22.06°, 24.04. , 25.32°, 25.78. , 26.42°, 27.80°, 28.39°, 29.50°, 30.05°, 31.28°, 31.81°, 32.72°, 33.13°, 34.33°, 35.68°, 36.17°; more preferably, the map is 2 Θ ± 0.2° below The corners have characteristic peaks: 5.96°, 6.26°, 6.74°, 8.07°, 12.53°, 14.59°, 14.86. , 17.82°, 18.04°, 18.35. , 19.99°, 20.38°, 22.06°, 24.04°, 24.74°, 25.32°, 25.78°, 26.42°, 27.80°, 28.39°, 29.50°, 30.05°, 30.92°, 31.28°, 31.81. , 32.72°, 33.13. , 33.62. , 34.33. , 35.68. , 36.17. , 36.69. , 38.42. . In a preferred embodiment of the invention, the inositol form C has an X-ray powder diffraction (XRPD) pattern substantially identical to that of Figure 1.

"Differential scanning calorimetry", also known as "differential calorimetric scanning analysis" (DSC), is a technique for measuring the relationship between the energy difference between a test substance and a reference material and temperature during heating. The position, shape and number of peaks on the DSC map are related to the nature of the material and can therefore be used qualitatively to identify the substance. This method is commonly used in the art to detect various parameters such as phase transition temperature, glass transition temperature, and heat of reaction of a substance. DSC assay methods are known in the art. For example, a DSC Q20 scan of the crystal can be obtained by using a DSC Q20 differential scanning calorimeter at a temperature increase rate of 10 ° C per minute from 25 ° C to 300 ° C.

In one embodiment of the present invention, the inositol Form C obtained by the method of the present invention has a characteristic exothermic peak at about 208.2 ° C and a characteristic endothermic peak at about 227.4 ° C, preferably the present invention. Inositol Form C has a DSC pattern substantially consistent with Figure 5.

Infrared profiling (IR) can also be employed to determine the type of crystal, the method of which is known in the art. For example, PE Spectrum One B can be used, which is compressed in KBr: sample = 200:1, and scanned in the range of 400 OOcnT ¹ . The infrared spectrum of the inositol crystal form C of the present invention shows characteristic peaks of the following wave numbers: 3384.46 cm" ¹ , 3255.25 cm" ¹ , 2933.20 cm" ¹ , 1359.57 cm" ¹ , 1141.65 cm" ¹ , 1039.44 cm" ¹ , 881.31 cm " ¹ , 725.10 cm^ preferably has an infrared spectrum substantially identical to that of Fig. 2. Raman's characteristic map (Raman) can also be used to determine the crystal type, and the measurement method is known in the art. For example, Raman measurement can be employed. Different crystal forms of ranitidine hydrochloride and diclofenac sodium. The Raman characteristic map of the inositol crystal form C of the present invention shows characteristic peaks of the following wave numbers: 3409.08 cm" ¹ , 2949.24 cm" ¹ , 2936.35 cm" ¹ , 2913.12 cm " ¹ , 1422.16 cm" ¹ , 1260.87 cm" ¹ , 1147.70 cm" ¹ , 1112.93 cm" ¹ , 1088.95 cm" ¹ , 1060.58 cm" ¹ , 1014.21 cm" ¹ , 886.30 cm" ¹ , 512.64 cm" ¹ , 420.63 cm " ^{1. It} is preferable to have a Raman characteristic map substantially consistent with FIG.

The inositol crystal form C of the present invention has a specific stability and is advantageous for preservation. The inventors showed by the DVS spectrum that in the conventional storage environment (40%-80% RH), Form C has no or almost no hygroscopicity. In a preferred embodiment, the DVS profile of the resulting inositol Form C is substantially identical to that of Figure 6. Inositol crystal form C preparation method

The inventors have found through intensive studies that it is possible to cool the inositol from 230 ° C to room temperature to obtain inositol crystal form C.

The present invention provides a method of preparing the inositol crystal form C, the method comprising the steps of:

In the first step, the inositol as shown in Formula I is heated to 230 ° C to melt;

In the second step, the inositol crystal form c provided by the present invention is obtained by cooling 230 ° C to molten inositol at a rate of 10-100 ° C / minute to room temperature. In the first step of the above method, the inositol can be heated to 230 ° C in a blast oven to melt; preferably heated to 240 ° C to melt.

In the second step of the above method, the cooling rate may be 50 - 100 ° C / min. Use of inositol crystal form C and composition thereof

The inositol crystal form C produced by the present invention has better stability, is easy to store and use, and has high purity, and thus can be provided as a drug substance or used for the preparation of a medicament for treating hypercholesterolemia and fatty liver.

Accordingly, the present invention is also directed to a composition comprising the inositol Form C of the present invention, the composition comprising an effective amount of inositol Form c, and a pharmaceutically acceptable carrier.

As used herein, the term "containing" or "including" includes "comprising", "consisting essentially of", and "consisting of". The term "effective amount" refers to an amount which is functional or active against a human and/or animal and which is acceptable to humans and/or animals.

As used herein, the term "pharmaceutically acceptable" means a substance that is suitable for use in humans and/or animals without excessive adverse side effects (eg, toxicity, irritability, and allergies; ie, a reasonable benefit/risk ratio) . The term "pharmaceutically acceptable carrier" refers to a carrier for the administration of a therapeutic agent, including various excipients and diluents. The term refers to pharmaceutical carriers which are not themselves essential active ingredients and which are not excessively toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. A full discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences, Mack Pub. Co., N.J. 1991.

Preferably, the "pharmaceutically acceptable carrier" is selected from the group consisting of: a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, a coating material, an excipient, or a gentle/ Controlled release agent. In the compositions, the pharmaceutically acceptable carrier can contain liquids such as water, saline, glycerol and ethanol. In addition, auxiliary substances such as fillers, disintegrants, lubricants, glidants, effervescent agents, wetting or emulsifying agents, flavoring agents, pH buffering substances and the like may also be present in these carriers. Generally, these materials can be formulated in a non-toxic, inert, andpharmaceutically acceptable aqueous carrier medium wherein the pH is usually from about 5 to about 8, preferably, the pH is from about 6 to about 8. The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, may be arbitrarily combined. All of the features disclosed in the present specification can be used in combination with any of the compositions, and the various features disclosed in the specification can be substituted for any alternative feature that provides the same, equal or similar purpose. Therefore, there is a special It should be noted that the disclosed features are merely general examples of equal or similar features. The main advantages of the invention are:

1. The novel crystal form provided by the invention has high crystallinity, low hygroscopicity and high solubility, and can improve the bioavailability of inositol.

2. The method for preparing new inositol crystals provided by the invention is simple and easy to industrialize. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in which the specific conditions are not indicated in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

The unit of weight percent by volume in the present invention is well known to those skilled in the art and, for example, refers to the weight of the solute in a 100 ml solution.

Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only. Experimental conditions:

XRPD: All XRPD spectra of this patent are detected by the D8advance X-ray diffractometer from Bruker, Germany. The target is Cu Κα (40 kV, 40 mA), and the scanning range is from 3° to 40°. Is 0.1 s / step.

It should be noted that in the X-ray diffraction pattern of a powder sample, the relative intensity of the band may vary due to the dominant orientation effect due to the difference in crystallization conditions, particle size, relative content of the mixture, and other test conditions. Therefore, the crystal to which the relative intensity of the diffraction peak is directed is not characteristic. When judging whether it is the same as the known crystal form, more attention should be paid to the position of the peaks rather than their relative intensities. In addition, care should be taken to maintain the overall concept when determining whether the crystal form is the same, because not a diffraction line represents a phase, but a specific set of "relative intensity can i" data represents a phase. It should also be noted that in the identification of the mixture, some of the diffraction lines are missing due to factors such as a decrease in content. At this time, it is not necessary to rely on all the bands observed in the high-purity sample, and even one band may be given. The crystals are characteristic.

IR: All infrared spectra of this patent are made by Nicolet-Magna FT-IR 750 of Nikola The infrared spectrometer is detected at room temperature, and the detection range is: the wave number of 4000-350 cm.

Raman: All Raman spectra of this patent are detected by the American Thermoelectric Company's DXR Raman microscope at room temperature. The detection range is: 3500-50 cm ^-1 Raman shift.

DSC: All DSC spectra of this patent were measured by a DSC 8500 differential scanning calorimeter from Elmer, Inc., Platinum, USA, with an atmosphere of nitrogen and a heating rate of 10 degrees Celsius per minute.

DVS: All DVS spectra of this patent were tested by the British SMS company's DVS Intrinsic Dynamic Water Vapor Detector and tested in the humidity range of 0-95% RH.

Inositol is from Shandong Zhucheng Haotian Pharmaceutical Co., Ltd., which belongs to granular crystals. Example 1

Preparation of inositol crystal form c crystal

The inositol is heated to 230 ° C to melt, and cooled to room temperature at a cooling rate of 10 ° C /min to obtain crystal form C crystals of inositol. Example 2

Preparation of inositol crystal form C crystal

The inositol is heated to 230 ° C to melt, and cooled to room temperature at a cooling rate of 100 ° C /min to obtain a crystalline form C crystal of inositol. Example 3

Preparation of inositol crystal form C crystal

The inositol is heated to 240 ° C to melt, and cooled to room temperature at a cooling rate of 10 ° C /min to obtain a crystalline form C crystal of inositol. Example 4

Preparation of inositol crystal form C crystal

The inositol was heated to 240 degrees Celsius to melt, and cooled to room temperature at a cooling rate of 50 degrees Celsius/minute to obtain crystal form C crystals of inositol. Example 5

Preparation of inositol crystal form c crystal

The inositol is heated to 240 ° C to melt, and cooled to room temperature at a cooling rate of 100 ° C /min to obtain a crystalline form C crystal of inositol. The inositol crystal form C prepared in Example 1 was transmitted by X-rays, and the X-ray powder diffraction peak positions obtained are shown in Table 1.

Table 1 X-ray powder derivative data of Form C prepared in Example 1

2 d angle d ( A ) intensity (%)

12.561 7.0412 6.6

14.593 6.0643 77.6

14.867 5.9539 15.2

17.820 4.9734 100.0

18.055 4.9092 67.3

20.385 4.3530 77.4

22.080 4.0225 14.7

24.040 3.6988 4.8

25.355 3.5098 80.8

25.814 3.4485 13.2

26.421 3.3706 66.0

27.804 3.2060 12.0

28.406 3. 1394 38.9

29.51 1 3.0243 9.7

3 1.294 2.8559 78.8

3 1.834 2.8087 16.0

32.739 2.7332 20.6

33.154 2.6999 2.3

34.343 2.6090 39.7

35.680 2.5143 6.5

36.165 2.4817 4.8 The inositol crystal form C prepared in the above examples was subjected to other tests, and the obtained infrared spectrum, Raman spectrum and DSC thermogram were basically as shown in Figs. 2, 3 and 5. The above is only the preferred embodiment of the present invention, and is not intended to limit the scope of the technical scope of the present invention. The technical content of the present invention is broadly defined in the scope of the claims of the application, any technical entity completed by others. The method or method, if it is identical to the scope of the claims, or equivalents, is considered to be within the scope of the claims.

Claims

3⁄4 ^

An inositol crystal form C having a structure as shown in Formula I, wherein the Form C has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at the following 2 Θ ± 0.2° angle: 14.86. , 17.82. , 20.38. , 25.32°, 26.42° , 28.39°, 3

2. The inositol crystal form C according to claim 1, wherein the crystal form C has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at the following 2 Θ ± 0.2° angle: 12.53°, 18.04°, 22.06°, 24.04. , 25.78. , 27.80. , 29.50. , 30.05. , 31.81. , 32.72°, 33.13. , 35.68. , 36.17. .

The inositol crystal form C according to claim 2, wherein the crystal form C has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at the following 2 Θ ± 0.2° angle: 5.96°, 6.26°, 6.74°, 8.07°, 14.59°, 18.35°, 19.99°, 24.74°, 30.92°, 33.62°, 36.69°, 38.42. .

The inositol crystal form C according to claim 1, wherein the crystal C has an X-ray powder diffraction (XRPD) pattern as shown in Fig. 1.

5. The inositol crystal form C of claim 1 wherein said Form C differential scanning calorimetry has a characteristic exothermic peak at about 208.2 ° C and a characteristic endotherm at about 227.4 ° C. peak.

6. The method for preparing inositol crystal form C according to any one of claims 1 to 5, wherein the method comprises the steps of: cooling the molten inositol from 230 ° C to room temperature to obtain a right Requires any of 1-5 Inositol Form C as described.

The process according to claim 6, wherein it is cooled to room temperature at a rate of from 10 to 100 ° C / minute; preferably at a rate of from 50 to 100 ° C / minute.

8. The method according to claim 6, wherein the method comprises the steps of:

(1) heating the inositol to 230 ° C to melt;

(2) The inositol crystal form C according to any one of claims 1 to 5 is obtained by cooling 230 ° C to molten inositol at a rate of 10 to 100 ° C / minute to room temperature.

A pharmaceutical composition comprising the inositol crystal form C according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

Use of the inositol crystal form C according to any one of claims 1 to 5, which is for use in the preparation of a medicament for treating hypercholesterolemia and fatty liver.