JPS6144846B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing crystalline lactose with a high beta-lactose content useful as an excipient. Conventionally, α-lactose monohydrate, α-lactose anhydride, β-lactose
It is known to use lactose, such as lactose, as an excipient. However, α-lactose monohydrate has poor compression moldability, and α-lactose anhydride has superior compression moldability compared to α-lactose monohydrate, but the volume increase due to moisture absorption is large. It has the disadvantage of causing cracks, etc. Also β
Lactose has excellent compression moldability and a small increase in volume due to moisture absorption, making it an excellent excipient, but it is difficult to manufacture and difficult to supply in large quantities. However, as a result of extensive research into lactose, which has excellent compression moldability, a small increase in volume due to moisture absorption, is excellent as an excipient, and is easy to produce, the present inventor has developed a method using amorphous lactose as a starting material. We have discovered the new fact that by processing this under specific conditions, crystalline lactose with a high β-lactose content can be obtained very easily, and that this crystalline lactose is excellent as an excipient, and has developed the present invention. It was about to be completed. That is, in the present invention, amorphous lactose is exposed to a humidity atmosphere of 65% RH or higher at a temperature of 30 to 50°C, and once the X-ray diffraction angle 2 is
This invention relates to a method for producing crystalline lactose with a high β-lactose content, which is characterized by bringing the peak to a maximum at θ=10.5° and then drying it. Next, the method for producing crystalline lactose having a high β-lactose content according to the present invention will be explained with reference to the drawings. The figure shows how the water content of total lactose (including adsorbed water and hydration water) and the amount of β-lactose produced change with processing time when amorphous lactose is exposed to a humid atmosphere and dried. It is an explanatory diagram.
In the drawings, curve A is a curve showing changes in the water content of total lactose, and curve B is a curve showing changes in the amount of β-lactose produced. The X mark on curve B indicates that the amount of β-lactose produced is at its maximum here. The dashed line indicates the water content corresponding to lactose monohydrate. When amorphous lactose is exposed to a humid atmosphere of 65% or higher, it absorbs more and more water as shown in curve A, finally reaching saturation. Amorphous lactose is microscopically dissolved in the adsorbed water, and from this point β-lactose begins to crystallize as shown by curve B. Since β-lactose is an anhydrous substance that does not easily absorb moisture, the water content of the entire system decreases as amorphous lactose converts to β-lactose crystals. A part of the generated β-lactose crystals is dissolved in the adsorbed water, and α-lactose monohydrate is generated from this. Therefore, the amount of β-lactose crystals produced decreases after a certain point. For this reason, the amount of β-lactose crystals produced is tracked by X-ray diffraction, and when the amount of β-lactose crystals produced reaches the maximum, the humidity treatment is stopped and the next drying step is started. The drying step is a step in which water adsorbed on β-lactose and α-lactose monohydrate is removed, leaving only the hydration water of partially produced α-lactose monohydrate. The amorphous lactose used as a starting material in the present invention can be obtained, for example, by preparing a saturated aqueous solution of α-lactose monohydrate at room temperature and spray-drying it with a spray dryer.
At that time, it is preferable that the drying humidity does not fall below 160°C. If the drying temperature is lower than 160°C, α-lactose anhydride will be produced, which is not preferable. Humidity treatment is performed at a humidity of 65% RH or higher. In particular, a humidity close to 100% RH is preferable because the production rate is high. The temperature condition during humidity treatment is 30
Temperatures in the range ~50°C are employed. The humidity treatment is usually carried out by leaving the amorphous lactose under the above-mentioned humidity conditions, but it may also be stirred as appropriate. To confirm the point at which the amount of β-lactose crystals produced reaches its maximum, sample the sample at appropriate time intervals during humidity treatment, and apply it to an X-ray diffraction device to obtain a diffraction angle of 2θ = 10.5° corresponding to the 110 planes of the β-lactose crystal. This is done by determining the point in time when the peak of When the amount of β-lactose crystals produced reaches the maximum, the humidity treatment is stopped and the next drying step is started. As the drying means, any means such as natural leaving under atmospheric conditions, heat drying, leaving under low humidity, reduced pressure drying, etc. may be employed, and a combination of these means may be used. When drying by heating, the drying temperature is 90℃.
The following are preferred. If the drying temperature exceeds 90°C, there is a risk that α-lactose anhydride will be regenerated. Note that during drying, it may be appropriately stirred. In this way, the crystalline lactose of the present invention with a high β-lactose content can be obtained. The β-lactose content in the crystalline lactose of the present invention is usually 55% (weight %, the same applies hereinafter) or more, and the remainder is substantially α-lactose monohydrate. The crystalline lactose of the present invention is comparable to β-lactose, has excellent compression moldability, and has a small increase in volume due to moisture absorption, making it excellent as an excipient. Furthermore, it has the advantage that it is easier to produce and can be supplied in large quantities compared to β-lactose. The crystalline lactose of the present invention can be suitably used as an excipient for tabletting any substance used in tablet form, such as medicines and foods. In tabletting, it is usually used in an amount of about 1 to 10 parts per 1 part (by weight, the same applies hereinafter) of the substance to be tabletted. The method and conditions for tabletting using the excipient of the present invention are not particularly limited, and conventional methods and conditions may be employed as they are. Next, the method for producing crystalline lactose having a high β-lactose content according to the present invention will be explained with reference to Examples, Application Examples, and Comparative Examples. Example 1 Humidify 100 parts of amorphous lactose powder (100 mesh)
The mixture was gently stirred under conditions of 100% RH and a temperature of 40°C. Sampling samples at regular intervals,
Cu using an X-ray diffraction device (JDX-7S model manufactured by JEOL Ltd.)
The intensity of the peak at a diffraction angle of 2θ=10.5° was measured using -Kα radiation. The diffraction angle 2θ changes about 1 hour after the start of the reaction.
The intensity of the peak at =10.5° was the maximum. It was then dried at 90° C. for 6 hours under atmospheric conditions to yield 95 parts of crystalline lactose. The β-lactose content in the crystalline lactose obtained was 55%. The β-lactose content was measured as follows. The sample was dried over phosphorus pentoxide under reduced pressure at 80°C, and a certain amount of the sample was taken to determine the water content by Karl Fischer method. This water content is estimated to be the hydration water of α-lactose monohydrate (because β-lactose is anhydrous), the content of α-lactose monohydrate is determined, and the remaining
The β-lactose content was determined by assuming that it was lactose. Example 2 An experiment was conducted in the same manner as in Example 1 except that the humidity during the humidity treatment was changed to 75% RH. In this case, the intensity of the peak at an X-ray diffraction angle of 2θ=10.5° reached its maximum 2 hours after the start of the reaction. The yield of crystalline lactose was 97 parts, and the β-lactose content was 55%. Comparative Example 1 An experiment was conducted in the same manner as in Example 1 except that the humidity during the humidity treatment was changed to 45% RH. In this case, the intensity of the peak at an X-ray diffraction angle of 2θ=10.5° reached its maximum 4 hours after the start of the reaction. The yield of crystalline lactose is
97 parts, and the β-lactose content was as low as 40%. Application Examples 1 to 2 and Comparative Examples 2 to 4 100 parts of each crystalline lactose obtained in Examples 1 to 2 were thoroughly mixed with 50 parts of starch, and 0.5 g of the mixture was accurately weighed.
Tablets were obtained by static compression to a diameter of 16 mm and a thickness of 1.92 mm at a compression pressure of 1 ton/cm ² . The tablet hardness of the obtained tablets was measured. Furthermore, the moisture absorption rate and volume increase rate of the tablets left at room temperature and humidity of 63% RH for 7 days were measured, and the presence or absence of abnormalities was observed. Tablet hardness was measured using an Instron type material testing machine according to the deflection tensile test method. The results are shown in the table below. For comparison, experiments similar to those described above were conducted using α-lactose monohydrate, α-lactose anhydride, and β-lactose. The results are also listed in the table below. 【table】

[Brief explanation of the drawing]

The drawing is an explanatory diagram showing the relationship between the water content of total lactose, the amount of β-lactose produced, and the processing time when amorphous lactose is exposed to a humid atmosphere and dried. (Symbols in drawings), A: Curve showing changes in water content of total lactose, B: Curve showing production amount of β-lactose.

Claims (1)

[Claims] 1. Amorphous lactose at a temperature of 30 to 50°C and a humidity of 65% RH.
Once exposed to the above humidity atmosphere, the β-lactose crystals
A method for producing crystalline lactose with a high β-lactose content, which is characterized by bringing the crystalline lactose to a state where the peak at an X-ray diffraction angle of 2θ = 10.5°, which indicates the growth of 110 planes, is maximum, and then drying the state. 2 Claim 1 in which drying is carried out at 90°C or lower
A method for producing crystalline lactose with a high β-lactose content as described in . 3. The method for producing crystalline lactose with a high β-lactose content according to claim 1, wherein the β-lactose content is 55% by weight or more.