阅读说明：本技术 一种磺丁基-β-环糊精的制备方法 (Preparation method of sulfobutyl-beta-cyclodextrin ) 是由 罗志豪 肖劲鹏 陈勇 吴鹏辉 于 2020-05-07 设计创作，主要内容包括：本发明提供一种磺丁基-β-环糊精的制备方法,方法包括将磺丁基-β-环糊精溶解于水中,采用喷雾干燥,获得粒径D-(50)大于70μm的磺丁基-β-环糊精。本发明的方法通过控制样品固含量和喷雾干燥参数,能够获得粒径较大,含水量较低,符合药用辅料质量标准的产品；且工艺简单、易于操作、可控性强、重复稳定性好,可以用于工业化生产。(The invention provides a preparation method of sulfobutyl-beta-cyclodextrin, which comprises the steps of dissolving sulfobutyl-beta-cyclodextrin in water, and obtaining particle size D by adopting spray drying 50 Sulfobutyl-beta-cyclodextrin of greater than 70 μm. According to the method, by controlling the solid content of the sample and spray drying parameters, a product which is large in particle size, low in water content and in accordance with the quality standard of pharmaceutic adjuvants can be obtained; and the method has the advantages of simple process, easy operation, strong controllability and good repeated stability, and can be used for industrial production.)

1. A method for preparing sulfobutyl-beta-cyclodextrin, comprising: dissolving sulfobutyl-beta-cyclodextrin in water, and spray drying to obtain particle diameter D₅₀Sulfobutyl-beta-cyclodextrin of greater than 70 μm.

2. The method of claim 1, wherein the sulfobutyl- β -cyclodextrin is dissolved in water to provide a sulfobutyl- β -cyclodextrin solid content ranging from 20% to 60% by weight of the sulfobutyl- β -cyclodextrin relative to the weight of water.

3. The method according to claim 1 or 2, the atomizer frequency of the spray drying is 5Hz-15 Hz.

4. The method according to any one of claims 1 to 3, wherein the inlet air temperature for spray drying is 210 ℃ to 250 ℃.

5. The method according to any one of claims 1 to 3, wherein the outlet air temperature of the spray drying is 120 ℃ to 160 ℃.

6. The method according to any one of claims 1 to 3, wherein the frequency of the induced draft fan for spray drying is 25Hz-50 Hz.

7. The method according to any one of claims 1 to 3, wherein the spray drying is carried out at a feed rate of from 10rpm to 25 rpm.

8. The method according to any one of claims 1 to 7, wherein the solid content of the sulfobutyl-beta-cyclodextrin is 20 to 60 percent, the air inlet temperature of spray drying is 210 to 250 ℃, the air outlet temperature is 120 to 160 ℃, the frequency of an induced draft fan is 25 to 50Hz, the frequency of an atomizer is 5 to 15Hz, and the sample injection rate is 10 to 25rpm according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water.

9. The method according to any one of claims 1-7, comprising: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 40%, the air inlet temperature of spray drying is 230 ℃, the air outlet temperature is 140 ℃, the frequency of an induced draft fan is 50Hz, the frequency of an atomizer is 5Hz, and the sample injection rate is 15 rpm.

10. The process according to any one of claims 1 to 9, wherein the sulfobutyl- β -cyclodextrin obtained has a particle size D₅₀Greater than 100 μm or 130 μm; and/or the obtained sulfobutyl-beta-cyclodextrin has a water content of less than 2.0%.

Technical Field

The invention relates to a preparation method of sulfobutyl-beta-cyclodextrin, in particular to a preparation method of sulfobutyl-beta-cyclodextrin with large particle size, belonging to the technical field of pharmacy.

Background

Sulfobutyl-beta-cyclodextrin (Betadex Sulfobutyl Ether Sodium, CAS number: 182410-00-0), formula: c₄₂H_70-nO₃₅·(C₄H₈SO₃Na)_nMolecular weight: 2163 (degree of substitution n ═ 6.5), the structural formula is shown below:

the sulfobutyl-beta-cyclodextrin is an anionic high-water-solubility cyclodextrin derivative, and can be well included with drug molecules to form a non-covalent compound, so that the stability, water solubility and safety of the drug are improved, the nephrotoxicity is reduced, the hemolysis of the drug is alleviated, the release rate of the drug is controlled, the unpleasant odor is covered, and the like; the nitrogen-containing compound has been applied to injection, oral administration, nasal administration and ophthalmic administration, and has special affinity and inclusion property for nitrogen-containing medicines.

Currently, the production flow of sulfobutyl-beta-cyclodextrin is generally as follows: the beta-cyclodextrin reacts with butyl sultone under the catalytic action of sodium hydroxide, and the finished product is obtained through further decolorization, ultrafiltration and spray drying. The product prepared by the conventional spray drying method has smaller particle size and relatively higher water content, and the fine powder has very strong hygroscopicity due to larger surface area, so that the water content of the material is rapidly increased, the material is difficult to weigh and feed or transfer and store, the stability, impurity content and the like of active ingredients of the medicament are easily influenced in the process of preparing the medicinal preparation, the product is easy to absorb moisture and become damp, the control and storage are very difficult, the stability of the medicinal preparation is influenced, and the difficulty of preparing the preparation is increased.

If the sulfobutyl-beta-cyclodextrin with larger particle size and lower water content can be prepared, the operation and control in the preparation process of the sulfobutyl-beta-cyclodextrin and the application of the sulfobutyl-beta-cyclodextrin in the preparation of pharmaceutical preparations and the quality control of pharmaceutical preparation products are facilitated. The invention develops a preparation method through research, and the sulfobutyl-beta-cyclodextrin product with large particle size can be prepared and obtained through spray drying and controlling and adjusting various parameters of the spray drying; the product prepared by the method has good powder fluidity, larger particle size of particles and relatively smaller moisture absorption performance, and is beneficial to being used for pharmaceutical preparations.

Disclosure of Invention

The invention provides a preparation method of large-particle-size sulfobutyl-beta-cyclodextrin, which can obtain a product which has good powder fluidity, uniform and non-agglomerated particles, larger particle size, lower water content and hygroscopicity, meets the quality standard of pharmaceutic adjuvants and meets the requirements of preparations; the method has the advantages of simple process, easy operation, strong controllability and good repeated stability, and can be used for industrial production.

A method for preparing sulfobutyl-beta-cyclodextrin, comprising: dissolving sulfobutyl-beta-cyclodextrin in water, and spray drying to obtain particle diameter D₅₀Sulfobutyl-beta-cyclodextrin of greater than 65 μm.

A method for preparing sulfobutyl-beta-cyclodextrin, comprising: dissolving sulfobutyl-beta-cyclodextrin in water, and spray drying to obtain particle diameter D₅₀Sulfobutyl-beta-cyclodextrin of greater than 70 μm.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: spray drying with sulfobutyl-beta-cyclodextrin water solution with certain solid content, setting air inlet temperature, air outlet temperature, frequency of induced draft fan, atomizer frequency and sample introduction rate to obtain particle diameter D₅₀Sulfobutyl-beta-cyclodextrin of greater than 70 μm.

The preparation method of the invention has the advantages that the obtained product has low water content which is lower than 2.0 percent. In some embodiments, the process of the present invention, the product obtained has a moisture content of less than 1.8% or less than 1.5% or less than 1.4% or less than 1.3%. In the present invention, the water content can be measured by a Karl Fischer moisture meter.

The method can obtain the particle diameter D of the product particles by controlling various parameter conditions in the spray drying process₅₀The product with the water content of more than 70 mu m and less than 2.0 percent has uniform product particles, larger particle size, smaller hygroscopicity and lower water content.

The inventors have found that a relatively large particle size, e.g. D, can be achieved with a frequency of the atomizer which has a greater effect on the particle size of the product, with a corresponding decrease in particle size as the frequency of the atomizer increases, and a frequency of the atomizer which is less than 20Hz₅₀Products larger than 65 μm or larger than 70 μm. In some embodiments, the atomizer frequency is 5Hz to 15Hz, more preferably 5Hz, which is advantageous for obtaining a product with a larger particle size.

The inventors have also found that the solid content has a large influence on the particle size of the product, the water content, and the like. The solid content of the sample is that after the sulfobutyl-beta-cyclodextrin is dissolved in water, the solid content of the sulfobutyl-beta-cyclodextrin can be 20% -60% (W/W) calculated according to the weight ratio (W/W) of the sulfobutyl-beta-cyclodextrin to the water. In some embodiments, the sulfobutyl- β -cyclodextrin has a solids content ranging from 30% to 50% (W/W), more preferably 40% (W/W), as calculated on the weight of sulfobutyl- β -cyclodextrin to water (W/W), which facilitates process control and yields a desirable product.

The air inlet temperature of the spray drying can be 210-250 ℃, and is preferably 230 ℃, which is beneficial to operation control and obtaining of products meeting the requirements.

The air outlet temperature of the spray drying can be 120-160 ℃, and is preferably 140 ℃, which is beneficial to operation control and obtaining of products meeting requirements.

The frequency of the induced draft fan for spray drying can be 25Hz-50Hz, preferably 50Hz, and the induced draft fan is favorable for obtaining products meeting the requirements.

The injection rate of the spray drying can be 10rpm-25rpm, preferably 15rpm, and the product meeting the requirements can be obtained.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 20-60% (W/W), the air inlet temperature of spray drying is 210-250 ℃, the air outlet temperature is 120-160 ℃, the frequency of an induced draft fan is 25-50 Hz, the frequency of an atomizer is 5-15 Hz, and the sample injection rate is 10-25 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm and less than 2.0%.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 20-60% (W/W), the air inlet temperature of spray drying is 210-250 ℃, the air outlet temperature is 120-160 ℃, the frequency of an induced draft fan is 25-50 Hz, the frequency of an atomizer is 5-15 Hz, and the sample injection speed is 5-15 HzThe rate is 10rpm-25 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm and less than 2.0%. In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 20-60% (W/W), the air inlet temperature of spray drying is 210-250 ℃, the air outlet temperature is 120-160 ℃, the frequency of an induced draft fan is 25-50 Hz, the frequency of an atomizer is 5-10 Hz, and the sample injection rate is 10-25 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm and less than 2.0%. In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 30-50% (W/W), the air inlet temperature of spray drying is 210-250 ℃, the air outlet temperature is 120-160 ℃, the frequency of an induced draft fan is 25Hz-50Hz, the frequency of an atomizer is 5Hz-15Hz, and the sample injection rate is 10-25 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm and less than 2.0%. In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 30-50% (W/W), the air inlet temperature of spray drying is 210-250 ℃, the air outlet temperature is 120-160 ℃, the frequency of an induced draft fan is 25Hz-50Hz, the frequency of an atomizer is 5Hz-10Hz, and the sample injection rate is 10-25 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm and less than 2.0%.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 30-50% (W/W), the air inlet temperature of spray drying is 220-240 ℃, the air outlet temperature is 130-150 ℃, the frequency of an induced draft fan is 40-50 Hz, the frequency of an atomizer is 5-15 Hz, and the sample injection rate is 10-20 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm and less than 2.0%. In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight of sulfobutyl-beta-cyclodextrin and the weight of waterIn comparison, the solid content of the sulfobutyl-beta-cyclodextrin is 30-50% (W/W), the air inlet temperature of spray drying is 220-240 ℃, the air outlet temperature is 130-150 ℃, the frequency of an induced draft fan is 40Hz-50Hz, the frequency of an atomizer is 5Hz-15Hz, and the sample introduction speed is 10-20 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 100 μm and less than 2.0%. In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 30-50% (W/W), the air inlet temperature of spray drying is 220-240 ℃, the air outlet temperature is 130-150 ℃, the frequency of an induced draft fan is 40-50 Hz, the frequency of an atomizer is 5-15 Hz, and the sample injection rate is 10-20 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 130 μm and less than 2.0%.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 40% (W/W), the air inlet temperature of spray drying is 230 ℃, the air outlet temperature is 140 ℃, the frequency of an induced draft fan is 50Hz, the frequency of an atomizer is 5Hz, and the sample introduction speed is 15 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm and less than 2.0%. In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 40% (W/W), the air inlet temperature of spray drying is 230 ℃, the air outlet temperature is 140 ℃, the frequency of an induced draft fan is 50Hz, the frequency of an atomizer is 5Hz, and the sample introduction speed is 15 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 100 μm and less than 2.0%. In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin, comprises: according to the weight ratio of the sulfobutyl-beta-cyclodextrin to the water, the solid content of the sulfobutyl-beta-cyclodextrin is 40% (W/W), the air inlet temperature of spray drying is 230 ℃, the air outlet temperature is 140 ℃, the frequency of an induced draft fan is 50Hz, the frequency of an atomizer is 5Hz, and the sample introduction speed is 15 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 130 μm and less than 2.0%.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin comprises: the solid content of the sample is 60% (W/W), the air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of an induced draft fan is 50Hz, the frequency of an atomizer is 15Hz, and the sample injection rate is 15 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm, more than 100 μm or more than 130 μm and water content of less than 2.0%.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin comprises: the solid content of the sample is 40% (W/W), the air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of an induced draft fan is 50Hz, the frequency of an atomizer is 10Hz, and the sample introduction speed is 15 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm, more than 100 μm or more than 130 μm and water content of less than 2.0%.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin comprises: the solid content of the sample is 40% (W/W), the air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of an induced draft fan is 50Hz, the frequency of an atomizer is 15Hz, and the sample injection rate is 15 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm, more than 100 μm or more than 130 μm and water content of less than 2.0%.

In some embodiments, a method of preparing sulfobutyl- β -cyclodextrin comprises: the solid content of the sample is 20% (W/W), the air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of an induced draft fan is 50Hz, the frequency of an atomizer is 15Hz, and the sample injection rate is 15 rpm; obtaining D₅₀Sulfobutyl-beta-cyclodextrin with water content of more than 70 μm, more than 100 μm or more than 130 μm and water content of less than 2.0%.

In some embodiments, the particle size D of the product produced by the process of the present invention₅₀Greater than 100 μm, or greater than 130 μm, and a water content of less than 1.8%, or 1.5%, or 1.4%, or 1.3%.

The sulfobutyl-beta-cyclodextrin powder obtained by the preparation method has good fluidity, uniform particles, no agglomeration, larger particle size, lower water content and hygroscopicity, can meet the quality requirements of pharmaceutical excipients, and can be used for preparing pharmaceutical preparations; the preparation method has the advantages of simple process, strong controllability and good repeated stability in the industrial amplification process.

Drawings

FIG. 1: particle size distribution profile of the product of example 1.

FIG. 2: particle size distribution profile of the product of example 2.

FIG. 3: particle size distribution profile of the product of example 3.

FIG. 4: particle size distribution profile of the product of example 4.

FIG. 5: particle size distribution profile of the product of example 5.

FIG. 6: particle size distribution profile of the product of example 6.

FIG. 7: particle size distribution profile of the product of example 7.

FIG. 8: particle size distribution profile of the product of example 8.

FIG. 9: particle size distribution profile of the product of example 9.

FIG. 10: particle size distribution profile of the product of example 10.

FIG. 11: particle size distribution profile of the product of example 11.

FIG. 12: particle size distribution profile of the product of example 12.

FIG. 13: particle size distribution profile of the product of example 13.

FIG. 14: particle size distribution profile of the product of example 14.

FIG. 15: particle size distribution profile of the product of example 15.

Definition of terms

The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

In the present invention, "optionally" means that a certain component may or may not be contained, and for example, "optionally containing other auxiliary materials" means that other auxiliary materials may or may not be contained.

In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.

The term "fan frequency" is the same as "induced fan frequency".

The term "sample rate" is the same as "pump speed".

The term "D₅₀"refers to the particle size corresponding to a cumulative percent particle size volume distribution of 50% for a sample.

The term "solids content" refers to the mass ratio of solids to solvent used (W/W).

The term "titer" refers to the mass (g/mL) of the drug to be measured per 1mL of a titration solution (standard solution) at a certain molar concentration, and is denoted by F.

DEG C means centigrade, Hz means hertz, rpm means rotational speed, μm means micron, g/mL means gram/mL, RH means relative humidity, bar means pressure unit bar, s means second, RSD means relative standard deviation.

Detailed Description

For a further understanding of the present invention, reference will now be made in detail to the following examples.

Example 1

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 15Hz, and the sample introduction speed is 15 rpm. The sample solids content was 60% (W/W). Spray drying to obtain powder product. The resulting product had a particle size of 70.805 μm (D)₅₀) The particle size distribution is shown in FIG. 1, and the water content is less than 2.0%.

Example 2

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 5Hz, and the sample introduction speed is 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain powder product. The resulting product had a particle size of 138.880 μm (D)₅₀) The particle size distribution is shown in FIG. 2, and the water content is less than 2.0%.

Example 3

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 10Hz, and the sample introduction speed is 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain powder product. The resulting product had a particle size of 95.643 μm (D)₅₀) The particle size distribution is shown in FIG. 3, and the water content is less than 2.0%.

Example 4

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 15Hz, and the sample introduction speed is 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain powder product. The resulting product had a particle size of 75.850 μm (D)₅₀) The particle size distribution is shown in FIG. 4, and the water content is less than 2.0%.

Example 5

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 20Hz, and the sample introduction speed is 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain powder product. The resulting product had a particle size of 45.428 μm (D)₅₀) The particle size distribution is shown in FIG. 5, and the water content is less than 2.0%.

Example 6

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 25Hz, and the sample introduction speed is 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain powder product. The resulting product had a particle size of 37.620 μm (D)₅₀) The particle size distribution is shown in FIG. 6, and the water content is less than 2.0%.

Example 7

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 35Hz, and the sample introduction speed is 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain powder product. The resulting product had a particle size of 29.239 μm (D)₅₀) The particle size distribution is shown in FIG. 7, and the water content is less than 2.0%.

Example 8

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 15Hz, and the sample introduction speed is 15 rpm. The sample solids content was 20% (W/W). Spray drying to obtain powder product. The resulting product had a particle size of 67.278 μm (D)₅₀) The particle size distribution is shown in FIG. 8, and the water content is less than 2.0%.

Example 9

The air inlet temperature is set to be 210 ℃, the air outlet temperature is set to be 120 ℃, the frequency of a draught fan is set to be 50Hz, the frequency of an atomizer is set to be 5Hz, and the feeding speed is set to be 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain a powder product having a particle size of 114.888 μm (D)₅₀) The particle size distribution is shown in FIG. 9, and the water content is less than 2.0%.

Example 10

The air inlet temperature is set to be 250 ℃, the air outlet temperature is set to be 160 ℃, the frequency of a draught fan is set to be 50Hz, the frequency of an atomizer is set to be 5Hz, and the sample injection speed is set to be 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain a powder product having a particle size of 122.619 μm (D)₅₀) The particle size distribution is shown in FIG. 10, and the water content is less than 2.0%.

Example 11

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 40Hz, the frequency of an atomizer is 25Hz, and the sample introduction speed is 15 rpm. Sample (A)The solid content of the product is 40 percent (W/W). Spray drying to obtain a powder product having a particle size of 37.938 μm (D)₅₀) The particle size distribution is shown in FIG. 11.

Example 12

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 30Hz, the frequency of an atomizer is 25Hz, and the sample introduction speed is 15 rpm. The sample solids content was 40% (W/W). Spray drying to obtain a powder product having a particle size of 40.847 μm (D)₅₀) The particle size distribution is shown in FIG. 12.

Example 13

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 25Hz, and the sample introduction speed is 10 rpm. The sample solids content was 40% (W/W). Spray drying to obtain a powder product having a particle size of 34.903 μm (D)₅₀) The particle size distribution is shown in FIG. 13.

Example 14

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 25Hz, and the sample introduction speed is 20 rpm. The sample solids content was 40% (W/W). Spray drying to obtain a powder product having a particle size of 39.615 μm (D)₅₀) The particle size distribution is shown in FIG. 14.

Example 15

The air inlet temperature is 230 ℃, the air outlet temperature is 140 ℃, the frequency of a draught fan is 50Hz, the frequency of an atomizer is 25Hz, and the sample introduction speed is 25 rpm. The sample solids content was 40% (W/W). Spray drying to obtain a powder product having a particle size of 41.565 μm (D)₅₀) The particle size distribution is shown in FIG. 15.

Example 16

The products obtained in example 2, example 3, example 4, example 5, example 6 and example 7 were placed at room temperature (25 ℃) in RH 75% + -5% and the moisture was absorbed in a desiccator, and after 1 hour, a sample was taken and the moisture was measured by Karl Fischer. The results are as follows:

sample name	0h moisture content	1h of water content	1h moisture absorption and weight increment	Particle size of the product (D)50)	Frequency of atomizer
						Example 2	1.280％	2.690％	1.410％	138.880μm	5Hz
Example 3	1.260％	3.209％	1.949％	95.643μm	10Hz
						Example 4	1.210％	3.331％	2.121％	75.850μm	15Hz
Example 5	1.259％	3.532％	2.273％	45.428μm	20Hz
						Example 6	1.283％	3.623％	2.340％	37.620μm	25Hz
Example 7	1.304％	3.827％	2.523％	29.239μm	35Hz

As shown in the table above, as the atomizer frequency increases, the particle size of the product decreases, and as the particle size of the product increases, the moisture absorption of the product decreases.

Example 17

The products of example 1, example 4 and example 8 were placed at room temperature (25 ℃) in RH 75% + -5% and desiccator to absorb moisture, and after 1 hour, samples were taken and the moisture was measured by a Karl Fischer moisture meter. The results are as follows:

sample name	0h moisture content	1h of water content	1h moisture absorption and weight increment	Particle size of the product (D)50)	Solid content of sample
						Example 1	1.076％	3.321％	2.245％	70.805μm	60％(W/W)
Example 4	1.210％	3.331％	2.121％	75.850μm	40％(W/W)
						Example 8	1.086％	3.335％	2.249％	67.278μm	20％(W/W)

As shown in the above table, the particle size of the product was large at a sample solid content of 40% (W/W), and the hygroscopicity was low. The solid content of the sample is more than or equal to 60 percent (W/W), and the material viscosity is too high to block the atomizer.

Example 18

The product of example 2, example 3, example 4, example 5, example 6, and example 7 was used to conduct an angle of repose test using a powder flowability tester. The results are as follows:

as shown in the above table, as the atomizer frequency increases, the product angle of repose gradually increases and the product flowability becomes worse.

Example 19

The products of example 1, example 4 and example 8 were used for angle of repose test using a powder flowability tester. The results are as follows:

sample name	Example 1	Example 4	Example 8
				Sample solid content (W/W)	60％	40％	20％
Angle of repose	52.54°	49.60°	55.64°

As shown in the above table, the angle of repose was small and the fluidity was good at a sample solid content of 40% (W/W).

Example 20

Taking a proper amount of sulfobutyl-beta-cyclodextrin aqueous solution in a single-mouth bottle, and carrying out decompression rotary steaming in a water bath at the temperature of 80 ℃. The obtained product is completely stuck on the wall of the bottle, and powder cannot be obtained. The lumps are different in size after being scraped by the scraper, the particle size cannot be detected, and the moisture test cannot be carried out.

Example 21

The moisture content of the appropriate amount of the product of example 9, example 4, and example 10 was measured by a Karl Fischer moisture meter, and the results were as follows:

sample name	Example 9	Example 2	Example 10
				Temperature of inlet air	210℃	230℃	250℃
Temperature of outlet air	120℃	140℃	160℃
				Product(s)Particle size (D)50)	114.888μm	138.880μm	122.619μm
0h moisture content	1.842％	1.280％	1.047％

As the temperature increases, the product moisture content decreases. However, the air inlet temperature of 250 ℃ reaches the limit value of the instrument, the equipment is easy to damage, and the wall adhesion phenomenon occurs at 250 ℃. Therefore, the inlet air temperature is 230 ℃ and the outlet air temperature is 140 ℃ more suitable.

Example 22

The products of example 6, example 11 and example 12 were weighed and the yield was calculated as follows:

numbering	Example 6	Example 11	Example 12
				Frequency of induced draft fan	50Hz	40Hz	30Hz
Particle size of the product (D)50)	37.620μm	37.938μm	40.847μm
				Yield of	89.20％	69.43％	81.72％

From the results, the particle size tends to increase with the decrease of the fan frequency, but the particle size is not very different, and the product yield is highest when the fan frequency is 50 Hz.

Example 23

The products of example 13, example 6, example 14 and example 15 were weighed, and the yield was calculated as follows:

numbering	Example 13	Example 6	Example 14	Example 15
					Speed of pump	10rpm	15rpm	20rpm	25rpm
Particle size of the product (D)50)	34.903μm	37.620μm	39.615μm	41.565μm
					Yield of	75.98％	89.20％	81.77％	86.98％

From the results, the product particle size increases with increasing pump speed, but the product particle size is not very different; and the pump speed is 15rpm, the product yield is highest, and the pump speed is preferably 15 rpm.

Relevant instrument parameters, test conditions and characterization results

Instrument information:

1) shanghai Dachuan original SCL-12 type spray drying instrument

2) Malvern particle analyzer 2000

3) Karl Fischer tester

The detection method comprises the following steps:

1. malvern particle analyzer 2000

Selecting dry method to measure particle diameter, setting air pressure at 2.0bar, sample introduction amount at 50%, sample introduction/background time at 10s/10s, adding appropriate amount of sample to be tested, parallel measuring for three times, and averaging.

2. Karl Fischer moisture tester

Precisely weighing a sample to be tested, wherein the solvent is absolute ethyl alcohol. Directly using a Karl Fischer moisture tester for testing, carrying out parallel determination for three times, and then taking an average value. Wherein the Karl droplet definite degree F value is 4.9308g/mL, and the RSD is 0.51%.

In the description of the present specification, reference to the terms "some embodiments," "one specific example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.