JP3174818B2 - Method for producing crystal with improved dissolution rate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a crystal having an improved dissolution rate. The present invention particularly relates to a method for increasing the dissolution rate of crystals of a physiologically active substance having poor solubility.

[0002]

2. Description of the Related Art One of the most important factors affecting the gastrointestinal absorption of a physiologically active substance such as a drug is the dissolution rate of the drug. That is, in order to enhance gastrointestinal absorption, a technique for improving the dissolution rate of the drug is used. In particular, poorly soluble drugs such as aspirin (acetylsalicylic acid), nifedipine, nicardipine, diazepam, furosemide,
With regard to digitoxin, indomethacin, phenytoin, testosterone, cinnarizine, etc., some measures have been taken to increase the dissolution rate in order to increase the rate of gastrointestinal absorption.

[0003] As a technique for improving the dissolution rate of a drug, there is known a method in which drug particles are finely pulverized using a fine pulverizing device such as a pin mill or a zet mill to increase the surface area of the drug particles. However, this method has a drawback that the bulk of the drug is increased, making it difficult to handle in a later step. There is also known a method in which a drug is once dissolved in an appropriate solvent such as an organic solvent, and the solution is coated with an inert carrier particle so that the drug is adsorbed on the surface of the carrier particle. In addition, the activity per volume of the drug tends to be insufficient, and there is a problem in removing the residual solvent from the carrier particles, which is disadvantageous as an industrial method. Alternatively, it is also known to increase the solubility by changing the drug to a metastable form or an amorphous state, but the metastable form of the crystal tends to change to a less soluble stable form during storage. There is a problem that it is difficult to maintain its metastable form, and to convert it to non-quality, a method of applying heat to the drug or treating it with a solvent is used. Therefore, there is a problem that the medicinal effect of the drug tends to decrease, and there is also a problem that the processing cost increases.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for easily producing a crystal having an improved dissolution rate. An object of the present invention is to provide a method for increasing the dissolution rate of a crystal of a sparingly soluble drug and converting the crystal into a drug crystal having high solubility.

[0005]

SUMMARY OF THE INVENTION According to the present invention, a crystal face having a relatively high solubility has a difference in solubility and a dissolution rate depending on a crystal face, and a crystal face having a relatively high solubility is different from a crystal face having a relatively high dissolution rate. A crystal of the matching substance is placed in a solution of the substance adjusted to a concentration between the solubility of one crystal plane and the solubility of the other crystal plane, thereby giving priority to the crystal plane exhibiting its high solubility. Production of crystals having an improved dissolution rate characterized by increasing the ratio of crystal planes having a high dissolution rate to the total crystal surface area by increasing the ratio of the crystal planes to the total crystal surface area by realizing an effective dissolution. In the way.

Next, the present invention will be described in detail by taking aspirin (acetylsalicylic acid), which is famous as a hardly soluble substance, as an example.

It is already known that aspirin crystals have three types of crystal planes named (011), (100) and (001) according to the Miller index, and that there is a difference in dissolution rate between the respective crystal planes. Have been. The inventor has
Further studies on the behavior of the solubility of aspirin crystals showed that the solubility with respect to each crystal plane was different in each crystal plane, and that the crystal plane having relatively high solubility was relatively high. Was found to be consistent with a crystal plane having a high dissolution rate. That is, the solubility and dissolution rate of aspirin in water at 20 ° C. are as follows for each crystal plane.

[0008] crystal plane Solubility in dissolution rate (ratio) (011) 0.33g / 100ml 0.26 (100) 0.21g / 100ml 0.19 (001) 0.11g / 100ml 0.12

The solubility and dissolution rate at each crystal face are measured by preparing a single crystal of aspirin, placing a fixed volume of purified water on each crystal face of the single crystal, and examining the amount and rate of dissolution. can do.

The present inventor has invented a method for producing a crystal having an improved dissolution rate by utilizing this phenomenon. That is, for example, for aspirin exhibiting the above dissolution behavior, the concentration of aspirin is 0.33 g / 10
When an aspirin aqueous solution between 0 ml and 0.21 g / 100 ml is prepared and aspirin crystals are placed in this aspirin aqueous solution, dissolution of aspirin hardly occurs on the (100) plane and the (001) plane. On the other hand, (0
On the 11) plane, since the solubility is higher than the concentration of the aqueous solution, aspirin is preferentially dissolved until the concentration of the aqueous solution reaches the solubility of the (011) plane.
FIG. 1 attached schematically shows the progress of this dissolution. That is, the surface of the crystal having a high solubility (= the crystal surface having a high dissolution rate) is preferentially dissolved, so that the area of the crystal surface having a high dissolution rate does not change. (Low crystal plane). Thus, looking at the crystals, the proportion of surfaces with relatively high dissolution rates will increase. For this reason,
The dissolution rate of the entire crystal increases at a higher rate than the rate of the increase of the surface area per volume, not in proportion to the rate of the decrease of the surface area due to the decrease of the volume of the crystal (= increase of the surface area per volume). Will do.

[0011]

According to the present invention, there is provided a method of producing a crystal having an improved dissolution rate by using the above-mentioned method, without reducing the risk of deterioration of the activity (medicine effect, etc.) of the physiologically active substance and deterioration. By utilizing this method, not only aspirin, but also the production of easily soluble crystals of poorly soluble drugs such as nifedipine, nicardipine, diazepam, furosemide, digitoxin, indomethacin, phenytoin, testosterone, cinnarizine, etc. It becomes possible.

[0012]

EXAMPLE A single crystal of aspirin was produced and its (01)
When the solubility and dissolution rate of the (1), (100) and (001) planes in water at 20 ° C. were measured, the following numerical values were obtained. Crystal plane Solubility in dissolution rate (ratio) (011) 0.33g / 100ml 0.26 (100) 0.21g / 100ml 0.19 (001) 0.11g / 100ml 0.12 of the above single crystal, aspirin Concentration of 0.26 g / 10
After placing in a 0 ml aqueous solution (aqueous solution temperature: 20 ° C.) and leaving at the aqueous solution temperature, a single crystal was taken out and the surface area of each crystal plane was examined for fluctuation. Although the surface area of the surface hardly changed, it was confirmed that the surface area of the (100) surface and the (001) surface of the hardly soluble surface decreased. Therefore, it was found that the solubility per volume of the single crystal was increased.

Separately, a phenytoin single crystal recrystallized from acetone was prepared. FIG. 2 shows a schematic diagram of the shape of this phenytoin crystal and each crystal axis. A ring is adhered and fixed on a slide glass to prepare a cell, and ethanol (liquid temperature: 20-
(25 ° C.) slowly (liquid sending rate: 0.5 mL / min) and simultaneously discharging the liquid at the same rate from the other side, so that the solution concentration inside the cell can be adjusted to be constant. A crystal melting device was assembled. A phenytoin single crystal was allowed to stand in the cell, and while the ethanol was being supplied and the internal solution was being discharged, a photograph of the dissolved state of the crystal was taken at regular intervals using a polarizing microscope. The length of the crystal in each direction of the a-axis, b-axis and c-axis of the crystal was measured from the obtained photograph, and the amount of the crystal is shown in FIG. 3 as a graph. From the results of FIG. 3, it can be seen that, when the phenytoin single crystal was treated with ethanol, the rate of decrease in the surface with a relatively high dissolution rate (the surface perpendicular to the a-axis) was relatively low. It can be seen that the ratio of the surface having a high dissolution rate (surface perpendicular to the a-axis) to the total surface area of the phenytoin crystal after treatment is high, since the ratio decreases with decreasing ratio of the surface perpendicular to the axis). That is, phenytoin crystals having high solubility can be obtained by such a treatment.

[Brief description of the drawings]

FIG. 1 is a diagram schematically showing the progress of dissolution of an aspirin single crystal in an aspirin aqueous solution.

FIG. 2 shows a schematic diagram of the shape of a phenytoin single crystal used in Examples and each crystal axis thereof.

FIG. 3 shows a-axis and b-axis of phenytoin single crystal in Examples.
It is a graph which shows the amount of decrease of each direction of an axis and a c-axis.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 29/00 A61P 29/00 C07C 67/52 C07C 67/52 69/157 69/157

Claims (1)

(57) [Claims] Claims 1. A crystal having a difference in solubility and dissolution rate depending on a crystal face, and a crystal face having a relatively high solubility corresponds to a crystal face having a crystal face having a relatively high dissolution rate. Placed in a solution of the substance adjusted to a concentration between the solubility of the crystal plane of and the solubility of another crystal plane, thereby realizing preferential dissolution of the crystal plane showing its high solubility, A method for producing a crystal having an improved dissolution rate, characterized by increasing the ratio of the crystal face having a high dissolution rate to the total crystal surface area by increasing the ratio of the crystal face to the total crystal surface area.