CN112110795A - Mannitol calcium bromide eutectic compound and preparation method and application thereof - Google Patents
Mannitol calcium bromide eutectic compound and preparation method and application thereof Download PDFInfo
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- CN112110795A CN112110795A CN202011000371.1A CN202011000371A CN112110795A CN 112110795 A CN112110795 A CN 112110795A CN 202011000371 A CN202011000371 A CN 202011000371A CN 112110795 A CN112110795 A CN 112110795A
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Abstract
The invention discloses a mannitol calcium bromide eutectic compound and a preparation method and application thereof, belonging to the technical field of medicines. Compared with the original mannitol crystal, the eutectic compound obviously improves the tabletting property of the mannitol and the tensile strength of the prepared tablet, and is expected to be a better tablet filler for replacing beta-mannitol.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a mannitol calcium bromide eutectic compound and a preparation method and application thereof.
Background
Mannitol is a common pharmaceutical adjuvant, has low hygroscopicity and good chemical stability, has refreshing feeling in mouth, and can improve compliance of patients. Mannitol is widely used as a diluent or filler in tablets. Mannitol coexists in alpha, beta and three crystal forms, wherein beta-mannitol is the most thermodynamically stable under normal circumstances, so commercially available mannitol is usually in the beta crystal form. However, beta-mannitol has a drawback of poor tabletability as a tablet filler, and is likely to cause problems such as insufficient tablet strength and cracking.
Eutectic is a crystal formed by two or more molecules bonded in a fixed stoichiometric ratio in the same crystal lattice through non-covalent bonds (hydrogen bonds, pi-pi stacking action, van der waals force, etc.), and the crystal structure, lattice energy, surface properties, etc. of the eutectic can be greatly changed, so that the physicochemical properties of the eutectic can be changed to different degrees compared with those of the original crystal.
Disclosure of Invention
Aiming at the problems of poor tabletting property of mannitol and insufficient strength of prepared tablets, the invention provides a mannitol calcium bromide eutectic compound which can obviously improve the tabletting property of mannitol and the tensile strength of prepared tablets compared with the original mannitol crystals.
In order to achieve the purpose, the invention adopts the following technical scheme:
a mannitol calcium bromide eutectic compound is shown in the general formula (mannitol)x·(CaBr2)y·(H2O)zX, y and z are each independently a molar number, x: y: z is 1:1: 2;
the unit cell parameters are as follows:
the class is that of tetragonal system,
space group P43212；
Length of unit cell
b＝8.6251，c＝18.1877；
Unit cell angle (°) α is 90 °, β is 90 °, γ is 90 °;
volume of
Rwp(％)＝13.45。
Further, the eutectic compound has characteristic diffraction peaks at 11.3, 17.5, 21.2, 22.1, 23.6, 24.4, 25.0, 25.3, 26.5, 36.1 and 38.9 in a diffraction spectrum 2 θ (°) by powder X-ray diffraction.
Further, the infrared absorption spectrum of the co-crystal was measured at 3482cm by KBr pellet-1、3384cm-1、3339cm-1And 3207cm-1There is a characteristic absorption peak.
The preparation method of the mannitol calcium bromide eutectic compound comprises the following steps of mixing mannitol and calcium bromide according to a molar ratio of 1:1, dissolving in water, adding an organic reagent into the obtained solution to generate white solid precipitate, stirring until the solid precipitate becomes hard blocky particles, filtering, and drying in vacuum to obtain the mannitol calcium bromide eutectic compound.
Further, the organic reagent is isopropanol.
Further, the volume ratio of the water to the organic reagent is 1: 30-1: 70, preferably 1: 50.
further, the temperature of the vacuum drying is 20-40 ℃, preferably 25 ℃.
By measuring the tensile strength of the tablets prepared from the mannitol calcium bromide eutectic and the beta-mannitol, the inventor finds that the tensile strength of the mannitol calcium bromide eutectic monotonically increases in a nearly linear trend along with the increase of the tabletting pressure in a pressure range of 50-400MPa and is always larger than that of the beta-mannitol, wherein the tensile strength of the tablets prepared by compressing the mannitol calcium bromide eutectic is 1.24 times that of the mannitol at the lowest (under 150MPa pressure) and 10 times that of the mannitol at the highest (under 400MPa pressure), and proves that the tabletting performance of the mannitol calcium bromide eutectic is better than that of the mannitol.
The tensile strength of the tablet is closely related to the tabletting property of the auxiliary materials, a cocrystal product formed by mannitol and calcium bromide belongs to a cocrystal salt, and compared with a common molecular crystal material, the cocrystal salt has higher internal porosity and extremely large specific surface area, and the auxiliary materials with high porosity and specific surface area are often excellent in tabletting property, so that the compressed tablet has higher tensile strength.
Has the advantages that:
1. the powder X-ray spectrum characteristic diffraction peaks and infrared spectrograms of the physical mixture of the mannitol calcium bromide eutectic, the mannitol, the calcium bromide and the mannitol calcium bromide disclosed by the invention are different, and the DSC spectrogram and the TGA spectrogram of the mannitol calcium bromide eutectic and the mannitol are different, so that the mannitol calcium bromide eutectic is a new form completely different from the physical mixture of the mannitol, the calcium bromide and the mannitol calcium bromide.
2. According to the invention, mannitol and calcium bromide are prepared into a eutectic compound, the tabletting property is good, and the eutectic compound is expected to be a better tablet filler instead of beta-mannitol.
3. The invention provides a brand-new strategy for developing novel auxiliary materials (eutectic auxiliary materials), and has certain referential significance for the development of other novel auxiliary materials.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of mannitol;
FIG. 2 is a powder X-ray diffraction pattern of calcium bromide;
FIG. 3 is a powder X-ray diffraction pattern of a physical mixture of mannitol calcium bromide;
FIG. 4 is a powder X-ray diffraction pattern of a mannitol calcium bromide cocrystal;
FIG. 5 is a DSC of mannitol;
FIG. 6 is a DSC of mannitol calcium bromide cocrystals;
FIG. 7 is a TGA profile of mannitol;
FIG. 8 is a TGA profile of mannitol calcium bromide
FIG. 9 is an infrared spectrum of mannitol;
FIG. 10 is an infrared spectrum of calcium bromide;
FIG. 11 is a chart of the infrared spectrum of a physical mixture of mannitol calcium bromide;
FIG. 12 is an infrared spectrum of a mannitol calcium bromide eutectic;
fig. 13 is a graph comparing the tensile strength of mannitol calcium bromide cocrystals and mannitol at pressures of 50-400MPa (n-3).
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples. The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention. The experimental procedures, in which specific conditions are not specified in the examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Example 1
Mannitol calcium bromide eutectic
72.84g of mannitol (0.5mol) and 80g of anhydrous calcium bromide (0.5mol) were weighed into a 4L beaker, 60mL of water was added and heated in a 50 ℃ water bath until completely dissolved, followed by the addition of 3L of isopropanol with stirring, resulting in a large amount of white solid precipitate which rapidly agglomerated into a relatively sticky dough-like solid mass and adhered to the bottom of the beaker. Stirring was continued for 24 hours, whereupon the dough-like solid at the bottom of the beaker was converted into a hard lump-like solid which was filtered off with suction and the resulting lump-like white solid was dried in a vacuum oven at 25 ℃ for 24 hours.
The raw materials mannitol, calcium bromide, the physical mixture of mannitol and calcium bromide used in example 1, and the prepared mannitol calcium bromide eutectic compound were tested, specifically as follows:
1. stoichiometric ratio
And (3) measuring the content of mannitol: the content of mannitol is measured according to the content measuring method in mannitol variety in the second part of Chinese pharmacopoeia 2015 edition. A proper amount of sample powder is precisely weighed, placed in a 250mL measuring flask, dissolved and diluted to scale by adding water, and shaken uniformly; precisely measuring 5mL, placing in an iodine bottle, precisely adding 25mL of sodium periodate solution [ prepared by mixing 90mL of sulfuric acid solution (1 → 20) and 110mL of sodium periodate solution (2.3 → 1000) ] placing on a water bath for heating for 15 minutes, cooling, adding 5mL of potassium iodide test solution, sealing a plug, placing for 5 minutes, titrating with sodium thiosulfate titration solution (0.05mol/L), adding 0.5mL of starch indicator solution when the end point is reached, continuing to titrate until the blue color disappears, and correcting the titration result by using a blank test. Each 1mL of sodium thiosulfate titration solution (0.05mol/L) corresponds to 0.9109mg of mannitol.
And (3) measuring the content of calcium bromide: the content of calcium bromide is obtained by converting the content of calcium ions, and the content of calcium ions is measured according to a content measuring method in a calcium chloride variety in the second part of Chinese pharmacopoeia 2015 edition. Taking a proper amount of the product, placing the product in a weighing bottle with the weight of about 10ml of water, precisely weighing, transferring the product to a 100ml weighing bottle, diluting the product to a scale with water, and shaking up; precisely measuring 10ml, placing in a conical flask, adding 90ml of water, 15ml of sodium hydroxide test solution and about 0.1g of calcium purpurin indicator, and titrating with disodium ethylenediamine tetraacetic acid titration solution (0.05mol/L) until the solution is changed from purple to pure blue. Each 1mL of disodium EDTA titration solution (0.05mol/L) corresponds to 10mg of anhydrous calcium bromide.
And (3) moisture determination:
the instrument comprises the following steps: karl Fischer moisture meter model V20 Mettler Toledo, Switzerland
The sample (about 100mg) was weighed and quickly transferred to a titration vessel containing anhydrous methanol for titration.
And (3) measuring results: the mass fractions of mannitol, calcium bromide and water in the mannitol calcium bromide eutectic compound are respectively 43.54%, 47.85% and 8.61%, and the mass fractions are converted into mole numbers, and the molar ratio of the mannitol to the calcium bromide eutectic compound to the water is 1:1: 2.
2. Powder X-ray diffraction
The instrument comprises the following steps: d8 Advance X-ray diffractometer (Bruker, Germany)
Target: Cu-Kalpha radiation
Wavelength:
pipe pressure: 40KV
Pipe flow: 40mA
Step length: 0.02 degree
Scanning speed: 2 °/min
Scanning the range; 2 theta, 5-40 deg
As shown in fig. 1 to 4, mannitol has characteristic diffraction peaks at 10.4, 14.4, 16.6, 18.6, 20.3, 20.9, 21.5, 23.2, 24.5, 25.7, 28.1, 29.3, 33.3, 35.9 and 38.5 in 2 θ (°), calcium bromide has characteristic diffraction peaks at 18.8, 20.8, 23.8, 27.6, 29.7, 31.3, 38.0 and 39.7 in 2 θ (°), and mannitol calcium bromide eutectic has characteristic diffraction peaks at 11.3, 17.5, 21.2, 22.1, 23.6, 24.4, 25.0, 25.3, 26.5, 36.1 and 38.9 in 2 θ (°). It can be found that the characteristic diffraction peaks in the PXRD pattern of the mannitol calcium bromide eutectic do not appear in the PXRD pattern of the starting materials mannitol and calcium bromide, and the characteristic diffraction peaks of mannitol and calcium bromide almost completely disappear, indicating that the mannitol calcium bromide eutectic is a novel crystal completely different from mannitol and calcium bromide.
3. Differential Scanning Calorimetry (DSC)
The instrument comprises the following steps: netzsch DSC 204F1 Phoenix differential scanning thermal analyzer (Netzsch, Germany)
The range is as follows: 40-200 deg.C
Temperature rise rate: 10 ℃/min
As shown in fig. 5 and 6, a DSC spectrum of mannitol has a unique sharp endothermic peak at 169 ℃, and a DSC spectrum of the mannitol calcium bromide eutectic compound has a unique sharp endothermic peak at 152 ℃, which indicates that the mannitol calcium bromide eutectic compound and the mannitol calcium bromide eutectic compound are two different crystalline products, and the mannitol calcium bromide eutectic compound is a single-phase crystal, further proving that the mannitol calcium bromide is co-crystallized.
4. Thermogravimetric analysis (TGA)
The instrument comprises the following steps: netzsch, TG 209C thermogravimetric analyzer (Netzsch, Germany)
The range is as follows: 40-200 deg.C
Temperature rise rate: 10 ℃/min
As shown in fig. 7 and 8, the TGA profile of the mannitol calcium bromide cocrystal shows a weight loss of about 8.6% at around 152 ℃, which is consistent with the melting temperature in DSC. Indicating endothermic melting of the mannitol calcium bromide cocrystals at 152 ℃ with concomitant loss of water of crystallization.
5. Infrared spectroscopy
The instrument comprises the following steps: shimadzu IRAffinity-1S Fourier transform infrared spectrometer
The range is as follows: 4000-400cm-1
The scanning times are as follows: 32 times (twice)
As shown in FIGS. 9-12, the physical mixture of mannitol and calcium bromide, and calcium bromide were all 3000cm-1There is a broad peak, mannose in the above rangeAlcohol content at 3400cm-1And 3290cm-1There is sharp hydroxyl (-OH) stretching vibration, and mannitol calcium bromide eutectic is at 3000cm-1There are 4 distinct absorption peaks in the above range, each at 3482cm-1、3384cm-1、3339cm-1And 3207cm-1To (3).
6. Tabletability study
To compare the tabletability of the mannitol calcium bromide cocrystal and the mannitol powder, it was separately compressed into tablets and the tablet tensile strength was measured.
The tabletting conditions were as follows:
the instrument comprises the following steps: hydraulic press (Carver, 4235.L)
Punch head, plane round punch head (diameter d 13mm)
Pressure: 50-400MPa
Pressure residence time: 5 seconds
Piece weight: 500mg of
Under the above tabletting conditions, 3 tablets were compressed in parallel, and to avoid potential sticking risks, the punches and dies were lubricated with a small amount of magnesium stearate prior to tabletting. The resulting tablets were left to stand at room temperature for 48 hours to relieve residual stress.
The tensile strength of the tablets was determined as follows:
the tablets after standing for 48 hours were taken, the mass (m) of each tablet was measured, and the diameter (d) and thickness (h) of each tablet were measured with a micrometer (Chengdu mass tools group Co., Ltd.), followed by measuring the hardness (F) of each tablet using a texture analyzer (Stable Micro Systems, model TA XT Plus). The Tensile Strength (TS) of each sheet was calculated using the hardness, thickness and diameter data using the following formula.
As shown in fig. 13, the tensile strength of the mannitol calcium bromide eutectic compound increases monotonically with increasing tableting pressure in a nearly linear trend, and is consistently greater than mannitol, over the pressure range of 50-400 MPa. The tensile strength group of tablets formed by pressing the mannitol calcium bromide eutectic compound is 1.24 times (under the pressure of 150 MPa) as low as that of mannitol and 10 times (under the pressure of 400 MPa) as high as that of mannitol, and the tabletting performance of the mannitol calcium bromide eutectic compound is better than that of mannitol.
7. Determination of Crystal Structure
The crystal obtained in example 1 was cut into 0.220mm X0.190 mm X0.170 mm size for single crystal X-ray diffraction analysis testing, and the crystal structure was simulated by Materials Studio8.0 software. Firstly, performing diffraction peak Indexing through a Reflex Powder Indexing module to determine crystal system and unit cell parameters; subsequently, selecting a Pseudo-Voigt peak shape function, and performing Pawley fine modification on the cell parameters; correcting preferred orientation by applying a Reflex Powder solution module; constructing a possible space group by applying a Reflex Powder Indexing module; followed by Rietveld refinement according to the weighting factor RwpValue determination accuracy (R) of simulated crystal structurewpLess than or equal to 15 percent). The crystal surface attachment of the eutectic of the beta-mannitol and the mannitol calcium bromide can be calculated by using a Morphology module in Materials studio8.0 software, the calculation parameters are Dreiding 2.21 force field and Gasteiger electric field, the maximum value of (h k l) is set as (333), the calculation is carried out under the Fine grade, and the crystal structure is geometrically optimized before the calculation.
Table 1 crystal structure of mannitol calcium bromide cocrystal
TABLE 2 attachment energies and amounts of different crystal faces of mannitol and mannitol calcium bromide eutectic
From the above results, the mannitol calcium bromide eutectic compound provided by the invention can significantly improve the tabletting property of mannitol and the tensile strength of the prepared tablet compared with the original mannitol crystal.
Claims (9)
1. Mannitol calcium bromide eutecticAn article, characterized in that: the general formula of the eutectic compound is (mannitol)x·(CaBr2)y·(H2O)zX, y and z are each independently a molar number, x: y: z is 1:1: 2;
the unit cell parameters of the eutectic are as follows:
class = the crystal system of tetragonal system,
space group = P43212；
Unit cell length (a) a =8.6251, b =8.6251, c = 18.1877;
unit cell angle (°) α = 90 °, β = 90 °, γ = 90 °;
volume (a 3) = 1353.03;
Rwp（%）= 13.45。
2. the co-crystal of claim 1, wherein: the eutectic compound is obtained by powder X-ray diffraction and diffraction spectrum 2 theta (o) Characteristic diffraction peaks at 11.3, 17.5, 21.2, 22.1, 23.6, 24.4, 25.0, 25.3, 26.5, 36.1 and 38.9.
3. The co-crystal of claim 1, wherein: the infrared absorption spectrum of the eutectic compound measured by a KBr pellet is 3482cm-1、3384cm-1、3339 cm-1And 3207cm-1There is a characteristic absorption peak.
4. The method for preparing the mannitol calcium bromide eutectic compound as claimed in claim 1, wherein the method comprises the following steps: dissolving mannitol and calcium bromide in water, adding an organic reagent into the obtained solution to generate white solid precipitate, stirring until the solid precipitate becomes hard blocky particles, performing suction filtration, and performing vacuum drying to obtain the mannitol calcium bromide eutectic compound.
5. The method of claim 4, wherein: the molar ratio of mannitol to calcium bromide is 1: 1.
6. the method of claim 4, wherein: the organic reagent is isopropanol.
7. The method of claim 6, wherein: the volume ratio of the water to the organic reagent is 1: 30-1: 70.
8. the method of claim 4, wherein: the temperature of the vacuum drying is 20-40 DEG CoC。
9. Use of the mannitol calcium bromide co-crystals of claim 1 as a tablet filler.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113788849A (en) * | 2021-10-20 | 2021-12-14 | 中国药科大学 | Preparation method of mannitol eutectic auxiliary material suitable for industrial amplification production |
-
2020
- 2020-09-22 CN CN202011000371.1A patent/CN112110795A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| HAO CHENG等: "Improving Tabletability of Excipients by Metal-Organic Framework-Based Cocrystallization: a Study of Mannitol and CaCl2", 《PHARM RES》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113788849A (en) * | 2021-10-20 | 2021-12-14 | 中国药科大学 | Preparation method of mannitol eutectic auxiliary material suitable for industrial amplification production |
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