CN116617406A - A kind of microcrystalline mannitol pharmaceutical excipient, hard capsule and preparation method thereof - Google Patents

Abstract

The invention provides a microcrystalline mannitol pharmaceutical auxiliary material, a hard capsule and a preparation method thereof, belongs to the field of pharmaceutical auxiliary materials, and can solve the technical problem that mannitol auxiliary materials which can be widely applied to various mannitol pharmaceutical preparations are lacking in the prior art. Wherein the microcrystalline mannitol pharmaceutical auxiliary material is a compound mannitol polycrystal composed of alpha-mannitol and delta-mannitol, the mass ratio of the alpha-mannitol is 50-80%, and the mass ratio of the delta-mannitol is 20-50%. The preparation method of the microcrystalline mannitol pharmaceutical excipients comprises the steps of preparing mannitol aqueous solution, heating and dissolving, mixing the dissolved mannitol aqueous solution with ethanol to separate out solid, drying the solid and the like. The invention can be applied to the preparation of pharmaceutical excipients.

Description

A kind of microcrystalline mannitol pharmaceutical excipient, hard capsule and preparation method thereof

technical field

The invention belongs to the field of pharmaceutical excipients, and in particular relates to a microcrystalline mannitol pharmaceutical excipient, a hard capsule and a preparation method thereof.

Background technique

The molecular formula of mannitol is C ₆ H ₁₄ O ₆ , the molecular weight is 182, and it is easily soluble in water. agent etc. Due to its low hygroscopicity and high inertness, mannitol has been widely used in pharmaceuticals in recent years. In order to study the physical form and crystal form of mannitol, mannitol is divided into α-mannitol, β-mannitol and δ-mannitol, all of which are in the shape of strips, blocks or rods with sharp edges and corners, and α-mannitol The most slender. Mannitol is recrystallized in a mixed solution of ethanol and water (ethanol to water is 100:0, 95:5, 90:10 or 85:15), and different mannitol forms and crystal forms can be obtained, and the obtained product form is also All are angular strips, blocks or rods.

The physical and chemical properties of the mannitol prepared by the prior art are established, and the mannitol often needs to be mixed with other pharmaceutical excipients to meet the preparation requirements. Composite pharmaceutical excipients are obtained by mixing mannitol, lactose and crospovidone. Mannitol has good fluidity, disintegration, taste and physical strength, and can be used in various oral solid preparations.

Therefore, the creation of new mannitol pharmaceutical excipients, so that mannitol can obtain improved, practical and novel physical and chemical properties, has a positive significance for the innovation of pharmaceutical preparations. Develop an improved mannitol excipient, which can be applied to tens of thousands of pharmaceutical preparations using mannitol, upgrading them across the board.

Contents of the invention

The present invention aims at the technical problem of the lack of mannitol excipients that can be widely used in various mannitol pharmaceutical preparations in the prior art, and proposes a microcrystalline mannitol pharmaceutical excipient, hard capsules and the like with good stability and wide application range. Preparation.

In order to achieve the above object, the technical scheme adopted in the present invention is:

A pharmaceutical excipient for microcrystalline mannitol, the pharmaceutical excipient for microcrystalline mannitol is a composite mannitol polycrystal composed of α-mannitol and δ-mannitol, wherein the mass ratio of the α-mannitol is 50 -80%, the mass proportion of the δ-mannitol is 20-50%.

In one embodiment, the microscopic shape of the composite mannitol polycrystalline solid powder is fibrous or filamentous, and the composite mannitol polycrystalline solid powder is a porous structure material.

In one embodiment, the nitrogen adsorption specific surface area of the porous structural material is 2-9 m ² /g.

In one embodiment, the organic solvent adsorption capacity of the porous structure material under the action of capillary phenomenon is 300 mL/g, and the DSC melting point peak is 167±1 degree.

The present invention also provides a preparation method of microcrystalline mannitol pharmaceutical excipients, comprising the following steps:

Configure mannitol aqueous solution and heat until completely dissolved;

The dissolved mannitol aqueous solution and ethanol are mixed according to a certain ratio, left to stand for 15-30 minutes, filtered, and then the filtered solid is dried to obtain the microcrystalline mannitol pharmaceutical excipient.

In one embodiment, the concentration of the aqueous mannitol solution is 0.5-1.0 g/mL.

In one embodiment, the concentration of the aqueous mannitol solution is 0.6 g/mL.

In one embodiment, the dissolved mannitol aqueous solution and ethanol are mixed in a ratio of 1:(50-300).

The present invention provides a kind of preparation method of microcrystalline mannitol hard capsule again, comprises the following steps:

Dissolve the microcrystalline mannitol pharmaceutical excipient described in any of the above embodiments and pour it into a capsule shell, and then put another capsule shell at the mouth of the capsule shell that has been filled with the microcrystalline mannitol pharmaceutical excipient , to seal the capsule to obtain the microcrystalline mannitol hard capsule.

The present invention further provides a microcrystalline mannitol hard capsule, which is prepared by the above-mentioned method.

Compared with prior art, advantage and positive effect of the present invention are:

1. The present invention provides a pharmaceutical excipient of microcrystalline mannitol and a preparation method thereof, wherein the pharmaceutical excipient of microcrystalline mannitol is a composite mannitol polycrystal composed of α-mannitol and δ-mannitol. The ratio of α-mannitol and δ-mannitol in polycrystalline, optimize the preparation process of microcrystalline mannitol pharmaceutical excipients, so as to obtain microcrystalline mannitol pharmaceutical excipients with good stability and wide application range, so as to solve the problem of existing technology The lack of mannitol excipients that can be widely applied to various pharmaceutical preparations using mannitol;

2. The present invention provides a preparation method of microcrystalline mannitol hard capsules, which are obtained by dissolving microcrystalline mannitol pharmaceutical excipients and then pouring them into the capsule shell and sealing them. The hard capsules have good stability and can be taken for a long time. There is no damage, no toxicity and no side effects.

Description of drawings

Fig. 1 is a schematic flow chart of the preparation process of the microcrystalline mannitol pharmaceutical excipient provided by the embodiment of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present invention, but not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

The embodiment of the present invention provides a pharmaceutical excipient of microcrystalline mannitol. The pharmaceutical excipient of microcrystalline mannitol is a composite mannitol polycrystal composed of α-mannitol and δ-mannitol, wherein the α-mannitol The mass proportion of alcohol is 50-80%, and the mass proportion of the δ-mannitol is 20-50%.

In the above-mentioned embodiments, the present invention provides a pharmaceutical excipient of microcrystalline mannitol, wherein the pharmaceutical excipient of microcrystalline mannitol is a compound mannitol polycrystal composed of α-mannitol and δ-mannitol. The ratio of α-mannitol and δ-mannitol in the crystal, and then optimize the preparation process of microcrystalline mannitol pharmaceutical excipients, so as to obtain microcrystalline mannitol pharmaceutical excipients with good stability and wide application range, to solve the existing problems There is a lack of technical problems in mannitol excipients that can be widely used in various mannitol pharmaceutical preparations.

Further, the mass ratio of α-mannitol can specifically be selected as 50%, 60%, 70%, 80%, or any value within the above-mentioned limited range selected by those skilled in the art according to actual needs, which falls within the protection scope of the present invention Within the range, the mass ratio of δ-mannitol can be specifically selected as 20%, 30%, 40%, 50%, or any value within the above-mentioned limited range selected by those skilled in the art according to actual needs, all fall within the protection scope of the present invention .

In a specific embodiment, the microscopic shape of the composite mannitol polycrystalline solid powder is fibrous or filamentous, and the composite mannitol polycrystalline solid powder is a porous structure material.

In a specific embodiment, the nitrogen adsorption specific surface area of the porous structure material is 2-9m ² /g, and the specific nitrogen adsorption specific surface area can be selected from 2m ² /g, 3m ² /g, 4m ² /g, 5m ² /g, 6m ² /g, 7m ² /g, 8m ² /g, 9m ² /g or any value within the above-mentioned limited range selected by those skilled in the art according to actual needs falls within the protection scope of the present invention.

In a specific embodiment, the organic solvent adsorption capacity of the porous structure material under the action of capillary phenomenon is 300 mL/g, and the DSC melting point peak is 167±1 degree.

The present invention also provides a preparation method of the microcrystalline mannitol pharmaceutical excipient described in any one of the above embodiments, comprising the following steps:

S1, configure the mannitol aqueous solution, and heat until completely dissolved;

In the above S1 step, the concentration of the aqueous mannitol solution is 0.5-1.0 g/mL, specifically, 0.5 g/mL, 0.6 g/mL, 0.7 g/mL, 0.8 g/mL, 0.9 g/mL, 1.0 g/mL can be selected. g/mL or any value selected by those skilled in the art according to actual needs within the above-mentioned limited range falls within the protection scope of the present invention, and the concentration of the mannitol aqueous solution is preferably 0.6 g/mL.

Further, the concentration of the mannitol aqueous solution can be appropriately increased, but should not exceed 0.5g/mL too much (that is, an increase of no more than 0.5g/mL on the basis of 0.5g/mL, preferably 0.6g/mL), otherwise it needs to be heated to Only when the water is close to boiling can all mannitol solutes be completely dissolved, and boiling will cause too much water loss, and the amount of loss is uncertain; at the same time, the concentration of mannitol aqueous solution can be reduced, but too much water molecules brought in will affect the subsequent mixing with ethanol The process has adverse effects on crystallization and subsequent ethanol recovery and purification. The mixing ratio of the configured mannitol aqueous solution and ethanol is particularly important for the crystallization process. If it is lower or higher than this ratio, it will be difficult to obtain the target mannitol product in the form of fibers or filaments, because the crystallization speed affects the α-mannose Transformation and co-crystallization between alcohol and delta-mannitol. The time for static filtration can also be adjusted according to the actual situation. It should not be too short, otherwise the crystals will not form stably, and it should not be too long, otherwise α-mannitol and δ-mannitol may be slowly converted into more stable β-mannitol.

S2. Mix the dissolved mannitol aqueous solution and ethanol according to a certain ratio, let stand for 15-30 minutes, filter, and then dry the filtered solid to obtain the microcrystalline mannitol pharmaceutical excipient.

In a specific embodiment, the dissolved mannitol aqueous solution and ethanol are mixed in a ratio of 1:(50-300).

In the above embodiment, the ratio of the dissolved mannitol aqueous solution to ethanol can be selected as 1:50, 1:100, 1:150, 1:200, 1:250, 1:300 or selected by those skilled in the art according to actual needs. Any numerical value within the above limited range falls within the protection scope of the present invention.

The present invention also provides a preparation method of microcrystalline mannitol hard capsules, comprising the following steps:

Dissolve the microcrystalline mannitol pharmaceutical excipient described in any of the above embodiments and pour it into a capsule shell, and then put another capsule shell at the mouth of the capsule shell that has been filled with the microcrystalline mannitol pharmaceutical excipient , to seal the capsule to obtain the microcrystalline mannitol hard capsule.

The present invention further provides a microcrystalline mannitol hard capsule, which is prepared by the above-mentioned preparation method.

In order to introduce the microcrystalline mannitol pharmaceutical excipient provided in the examples of the present invention and its preparation method in more detail, the following will be described in conjunction with specific examples.

Example 1

This embodiment provides a preparation method of microcrystalline mannitol pharmaceutical excipients, comprising the following steps:

(1) Prepare a mannitol aqueous solution with a concentration of 0.5g/mL and heat until completely dissolved;

(2) Mix the dissolved mannitol aqueous solution and ethanol at a ratio of 1:50; let stand for 15-30 minutes, filter, and then dry the filtered solid to obtain microcrystalline mannitol pharmaceutical excipients.

Example 2

This embodiment provides a preparation method of microcrystalline mannitol pharmaceutical excipients, comprising the following steps:

(1) Prepare a mannitol aqueous solution with a concentration of 0.5g/mL and heat until completely dissolved;

(2) Mix the dissolved mannitol aqueous solution and ethanol at a ratio of 1:300; let stand for 15-30 minutes, filter, and then dry the filtered solid to obtain microcrystalline mannitol pharmaceutical excipients.

Example 3

This embodiment provides a preparation method of microcrystalline mannitol pharmaceutical excipients, comprising the following steps:

(1) Prepare a mannitol aqueous solution with a concentration of 0.6g/mL and heat until completely dissolved;

(2) Mix the dissolved mannitol aqueous solution and ethanol at a ratio of 1:50; let stand for 15-30 minutes, filter, and then dry the filtered solid to obtain microcrystalline mannitol pharmaceutical excipients.

Example 4

This embodiment provides a preparation method of microcrystalline mannitol pharmaceutical excipients, comprising the following steps:

(1) Prepare a mannitol aqueous solution with a concentration of 0.6g/mL and heat until completely dissolved;

(2) Mix the dissolved mannitol aqueous solution and ethanol at a ratio of 1:300; let stand for 15-30 minutes, filter, and then dry the filtered solid to obtain microcrystalline mannitol pharmaceutical excipients.

Example 5

This embodiment provides a preparation method of microcrystalline mannitol pharmaceutical excipients, comprising the following steps:

(1) Prepare a mannitol aqueous solution with a concentration of 1.0g/mL and heat until completely dissolved;

(2) Mix the dissolved mannitol aqueous solution and ethanol at a ratio of 1:50; let stand for 15-30 minutes, filter, and then dry the filtered solid to obtain microcrystalline mannitol pharmaceutical excipients.

Example 6

This embodiment provides a preparation method of microcrystalline mannitol pharmaceutical excipients, comprising the following steps:

(1) Prepare a mannitol aqueous solution with a concentration of 1.0g/mL and heat until completely dissolved;

(2) Mix the dissolved mannitol aqueous solution and ethanol at a ratio of 1:300; let stand for 15-30 minutes, filter, and then dry the filtered solid to obtain microcrystalline mannitol pharmaceutical excipients.

Example 7

The present embodiment provides a preparation method of microcrystalline mannitol hard capsules, comprising the following steps:

The microcrystalline mannitol pharmaceutical adjuvant prepared in any of the above-mentioned examples (Example 1-6) is dissolved and poured into a capsule shell, and then another capsule shell is wrapped in the microcrystalline mannitol that has been poured into it. The mouth of the capsule shell of the pharmaceutical auxiliary material is used to seal the capsule to obtain the microcrystalline mannitol hard capsule.

Claims (10)

1. The microcrystalline mannitol pharmaceutical auxiliary material is characterized by being a compound mannitol polycrystal composed of alpha-mannitol and delta-mannitol, wherein the mass ratio of the alpha-mannitol is 50-80%, and the mass ratio of the delta-mannitol is 20-50%.

2. The microcrystalline mannitol pharmaceutical adjuvant according to claim 1, wherein the micro morphology of the composite mannitol polycrystalline solid powder is fibrous or filiform, and the composite mannitol polycrystalline solid powder is a porous structure material.

3. The microcrystalline mannitol pharmaceutical adjuvant according to claim 2, wherein the nitrogen adsorption specific surface area of the porous structure material is 2-9m ² /g。

4. The microcrystalline mannitol pharmaceutical adjuvant according to claim 2, wherein the porous structure material has an adsorption capacity of 300mL/g for organic solvents under capillary action, and a DSC melting point peak of 167±1 degree.

5. A method for preparing the microcrystalline mannitol pharmaceutical adjuvant according to any one of claims 1-4, comprising the steps of:

preparing mannitol aqueous solution, and heating until the mannitol aqueous solution is completely dissolved;

mixing the dissolved mannitol aqueous solution with ethanol according to a certain proportion, standing for 15-30 minutes, filtering, and drying the solid obtained by filtering to obtain the microcrystalline mannitol pharmaceutical adjuvant.

6. The method for preparing microcrystalline mannitol pharmaceutical excipients according to claim 5, wherein the concentration of mannitol aqueous solution is 0.5-1.0g/mL.

7. The method for preparing microcrystalline mannitol pharmaceutical excipients according to claim 6, wherein the concentration of mannitol aqueous solution is 0.6g/mL.

8. The method for preparing microcrystalline mannitol pharmaceutical excipients according to claim 5, wherein the dissolved mannitol aqueous solution and ethanol are mixed according to the following ratio 1: (50-300) in a proportion.

9. The preparation method of the microcrystalline mannitol hard capsule is characterized by comprising the following steps:

dissolving microcrystalline mannitol pharmaceutical excipients according to any one of claims 1-4, filling into a capsule shell, and sleeving the other capsule shell on the mouth of the capsule shell filled with the microcrystalline mannitol pharmaceutical excipients to seal the capsule, thereby obtaining the microcrystalline mannitol hard capsule.

10. A microcrystalline mannitol hard capsule prepared by the method of claim 9.