JP2011174904A - Method for quickly predicting hydrolysis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for heating gas to a high temperature of 80°C, preferably 100°C or higher to perform hydrolytic reaction because evaluation under a high temperature is needed for quickly evaluating hydrolytic reaction. <P>SOLUTION: Gas having passed through water of a temperature from a room temperature to 35°C is introduced to the reactor of a thermal decomposition apparatus to superheat, which enables the gas to heat to a high temperature around 130°C to quickly evaluate the hydrolytic reaction. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

    The present invention relates to a method for rapidly evaluating the stability of chemical substances in a preparation.

  In general, the stability test of pharmaceuticals has been conducted for a very long period of 6 months under accelerated conditions (40 ° C./75% RH) and 24 months under long-term storage conditions (25 ° C./60% RH). In addition, when several types of candidate formulations are studied along with the improvement and scale-up of the formulation, many stability tests will be conducted in parallel, resulting in significant development costs. It is important to predict stability at an early stage.

  As a method that can be applied to the stability prediction in the initial stage of formulation formulation development, a stability prediction method using a thermal measurement device has been reported (Patent Documents 1 and 2). In general, when a hydrolysis reaction is evaluated using a heat measurement device, it is known to use a humidity control device to heat while controlling the humidity in the heating furnace of the heat measurement device. .

JP-A-8-145918 JP 2000-074809 A

One problem to be solved by the present invention is to establish a method for allowing a hydrolysis reaction to be performed at a high temperature and for quickly evaluating the stability of a chemical substance.
In the case of measuring the stability using a heat measuring device while controlling the humidity using a humidity control device, which has been reported in the past, the temperature could only be raised to about 80 ° C. due to condensation on the exhaust part. However, in order to evaluate the hydrolysis reaction more quickly, it was necessary to evaluate at a higher temperature. Therefore, it has been a problem to establish a method capable of performing the hydrolysis reaction by raising the temperature at a higher temperature, preferably higher than 100 ° C.

In order to perform the hydrolysis reaction at a higher temperature, the present inventors examined a stability prediction method using a heat measurement device. As a result, without using a humidity control device, by introducing a gas through which water having a water temperature of room temperature to 35 ° C. has been passed into a heating furnace of the heat measurement device and heating it, the temperature can be made higher than 100 ° C., The present inventors have found that the hydrolysis reaction can be evaluated more quickly and completed the present invention.

That is, the present invention includes the following inventions.
[1] A method for measuring a hydrolysis reaction at a temperature higher than 100 ° C., comprising the following steps.
(Step 1) Gas through which water having a water temperature of 35 ° C. from room temperature is passed is introduced into the reactor of the heat measuring device.
(Step 2) A composition containing a compound in which the amount of decomposition product in the composition when decomposed for 24 hours under the conditions of 80 ° C. and 90% RH is less than 3% is used in a heating furnace of a heat measuring device. It is installed, and the temperature inside the heating furnace of the heat measuring device is heated to a set temperature higher than 100 ° C. to cause a decomposition reaction.
(Step 3) A sample is taken out from the heating furnace, and the amount of decomposition product is quantified.

[2] The method according to [1], wherein the gas in step 1 is nitrogen gas.
[3] The method according to [1] or [2], wherein the water temperature in Step 1 is 25 ° C. to 35 ° C.

[4] The method according to any one of [1] to [3], wherein the composition in step 2 is a composition consisting only of the drug substance and additives.
[5] The method according to [4], wherein the weight ratio between the drug substance and the additive is 1: 1 to 1:50.

[6] A method for predicting the residual ratio of a compound, the method comprising the following steps.
(Step 1) Gas through which water having a water temperature of 35 ° C. from room temperature is passed is introduced into the reactor of the heat measuring device.
(Step 2) A composition containing a compound having a decomposition amount of less than 3% when decomposed for 24 hours under the conditions of 80 ° C. and 90% RH is placed in a heating furnace of a thermal analyzer, and subjected to thermal analysis. The temperature in the furnace of the apparatus is heated to a set temperature higher than 100 ° C. to cause a decomposition reaction.
(Step 3) A sample is taken out from the heating furnace, and the residual rate is calculated by quantifying the amount of decomposition products.
(Step 4) Steps 2 and 3 are repeated three or more times at different furnace temperatures.
(Step 5) A reaction rate equation and / or a reaction rate constant is calculated using the obtained plurality of remaining rates.
(Step 6) A regression line and / or regression line equation is obtained from the Arrhenius plot, and the residual rate is predicted.

[7] The method according to [6], wherein the gas in step 1 is nitrogen gas.
[8] The method according to [6] or [7], wherein the water temperature in step 1 is 25 ° C to 35 ° C.
[9] The method according to any one of [6] to [8], wherein the remaining rate predicted in step 6 is a remaining rate under accelerated conditions or long-term storage conditions.

[10] The method according to any one of [6] to [9], wherein the composition in step 2 is a composition consisting only of the drug substance and an additive.
[11] The method according to [10], wherein the weight ratio of the drug substance and the additive is 1: 1 to 1:50.

  According to the present invention, the temperature inside the heating furnace of the heat measuring device can be increased under humidification, and the chemical hydrolysis can be evaluated more rapidly. Further, no special device such as a humidity control device is required, and the operation is simple. In the method of the present invention, the relative humidity at high temperature is low, but surprisingly, the hydrolysis reaction can be evaluated without depending on the relative humidity. Therefore, according to the method of the present invention, the stability of the drug substance in the composition can be quickly evaluated, and the compounding eligibility of the additive at the early stage of development of the pharmaceutical composition can be determined.

Schematic diagram of the device according to the invention Results of thermal analysis in Reference Example 1 Regression line created in Example 4

  In this specification, “atmosphere gas” means an inert gas such as nitrogen gas or argon gas, or air. Since the present invention is a method for measuring a decomposition product by a hydrolysis reaction, from the viewpoint of preventing side reactions, an inert gas such as nitrogen gas or argon gas is preferable, and nitrogen gas is more preferable.

  In the present specification, the “thermal measurement device” means a device that can accurately measure the function of keeping a sample at a desired temperature, the temperature of the sample, changes in heat absorption / release of the sample, and changes in weight. Furthermore, it is more preferable if a desired atmospheric gas such as water vapor or nitrogen gas can be allowed to flow through the heating furnace so that thermal analysis measurement can be performed with high accuracy. Specifically, for example, a differential scanning calorimeter, a calorimeter, a microcalorimeter, a differential calorimeter, a differential thermal-thermogravimetric measuring device, a thermogravimetric analyzer, a thermomechanical measuring device, a dynamic thermomechanical measuring device, etc. I can give you.

In this specification, the “heating furnace of the heat measuring device” refers to a furnace that heats a sample, and means a furnace that can flow an arbitrary atmospheric gas.
In the present specification, “a compound in which the amount of decomposition product in the composition when decomposed for 24 hours under the conditions of 80 ° C. and 90% RH is less than 3%” means the upper limit of an existing heat measuring apparatus capable of conditioning the humidity. It means a compound that cannot be decomposed to the lower limit of the optimal decomposition rate for stability prediction when decomposed at temperature and humidity.

  In this specification, “set temperature” of “set temperature higher than 100 ° C.” has an upper limit temperature depending on the sample. It can be arbitrarily set up to the upper limit temperature. Considering the simplicity of operation, it is preferable to set every 10 ° C. or every 5 ° C. In addition, about an upper limit temperature, it measures for every sample with the following method.

In the present specification, the “accelerated condition” means a condition of 40 ° C./75% RH, which is widely used for the stability test of pharmaceutical products.
As used herein, “long-term storage conditions” means conditions of 25 ° C./60% RH, which are widely used for stability testing of pharmaceutical products.

In the present specification, the “reaction rate equation” and “reaction rate constant” mean a mathematical expression in which the decomposition rate is expressed as a function of time.
In the present specification, the “Arrhenius plot” means a temperature plotted as an absolute temperature T and its reciprocal taken on the X axis and the natural logarithm of the reaction rate constant plotted on the Y axis.

In this specification, “regression line” and “regression line expression” mean an approximation to a linear expression by the least square method, and the regression line expression means an expression representing the approximated line.
In the present specification, the “active drug substance” means an active ingredient of a pharmaceutical product.

(Determination of upper limit of heating temperature)
The heating temperature in the present invention needs to be a temperature at which the same decomposition reaction as the temperature to be extrapolated occurs. That is, one of the objects of the present invention is to predict the residual ratio in the composition under accelerated conditions and long-term storage conditions, so it is necessary to avoid decomposition reactions that occur only at high temperatures and do not occur near room temperature. There is. Therefore, it is necessary to confirm the temperature at which sudden increase or decrease in TG (thermogravimetric analysis) and rapid exotherm or endotherm occur in DTA (differential thermal analysis), and to decompose below that temperature.

(Measurement method of degradation amount)
The method for measuring the amount of decomposition product by hydrolysis at a temperature higher than 100 ° C. in the present invention comprises the following steps.

(Step 1) Gas through which water having a water temperature of 35 ° C. from room temperature is passed is introduced into a heating furnace of a heat measuring device.
(Step 2) A composition containing a compound in which the amount of decomposition product in the composition when decomposed for 24 hours under the conditions of 80 ° C. and 90% RH is less than 3% is used in a heating furnace of a heat measuring device. It is installed, and the temperature inside the heating furnace of the heat measuring device is heated to a set temperature higher than 100 ° C. to cause a decomposition reaction.
(Step 3) A sample is taken out from the heating furnace, and the amount of decomposition product is quantified.

Step 1 is a step of introducing a gas containing moisture into the heating furnace of the heat measuring device.
In this step, a gas cleaning bottle or the like is incorporated into a normal atmosphere gas flow path, and humidification is performed by passing the atmosphere gas through water. The gas washing bottle is heated from room temperature to 35 ° C. in a water bath and kept at a constant temperature. The temperature of the water bath is preferably 25 ° C. to 35 ° C., more preferably 30 ° C.

Step 2 is a step of decomposing the sample in the heating furnace of the thermal decomposition apparatus.
The material of the sample container used when the sample is kept warm in the heat measuring apparatus should be a material that does not chemically react with the sample and does not change within the temperature range to be measured. For example, metal, glass, Teflon (registered trademark) And graphite. A material having high thermal conductivity is preferable, for example, an aluminum sample container is preferable. If the sample has high reactivity, for example, a platinum sample container may be used. The shape of the sample container may be any shape that can be used in a heat measurement device used for keeping a sample warm. The amount of sample to be weighed into the sample container depends on the size of the sample container of the heat measuring device to be used, but is usually 1 mg to 100 mg in consideration of operability, and is preferably 5 mg to 20 mg in consideration of errors in thermal conductivity. .

In the method of the present invention, first, the sample container as described above in which a sample is weighed is placed in a heat measurement apparatus, and the sample is kept warm while measuring the temperature of the sample. In addition to the temperature of the sample, it is preferable to keep the temperature while measuring changes in the heat absorption / release, weight, etc. of the sample over time by a thermometer.

The incubation time of the sample at each temperature is set so that the decomposition rate Y (%) is in the range of 3% <Y <50%. Specifically, in consideration of the time until the condition in the heat measurement apparatus reaches equilibrium and the sample reaches a constant temperature, measurement error of the heat retention time, etc., the heat retention time is preferably 2 hours or more. When it is necessary to keep the heat retention time at 2 hours or less, the heating furnace of the heat measuring device is preferably held at the heat retention temperature in advance, and the sample container containing the sample is put into the heating furnace.

Step 3 is a step of measuring the amount of decomposition products.
After the sample is kept warm in this way, the target substance in the sample is quantified. Any quantitative and quantitative method may be used as long as it is accurate and accurate, and can be appropriately selected depending on the properties of the sample. Specific examples include various chromatographic methods, electrophoresis methods, spectroscopic analysis methods, and titration methods.

(Method for predicting the residual ratio of compounds)
A method for predicting the residual ratio of a compound under accelerated conditions or long-term storage conditions includes the following steps.

(Step 1) Gas through which water having a water temperature of 35 ° C. from room temperature is passed into the heating furnace of the heat measuring device (Step 2) Decomposed product when decomposed for 24 hours at 80 ° C. and 90% RH A composition containing a compound having an amount of less than 3% is placed in a heating furnace of a heat measuring device, and the temperature in the heating furnace of the heat measuring device is heated to a set temperature higher than 100 ° C. to cause a decomposition reaction ( Step 3) Taking out a sample and quantifying the amount of decomposition product to calculate the residual rate (Step 4) Repeating Step 2 and Step 3 three or more times at a constant temperature at different furnace temperatures. Repeat the temperature at a constant temperature of 3 or more points.
(Step 5) A reaction rate equation is selected using the obtained plurality of remaining rates, and a reaction rate constant is calculated. (Step 6) A regression line and / or regression line equation is obtained from the Arrhenius plot, and the remaining rate is predicted. To do.

Steps 1 to 3 are substantially the same as the above-described “method for measuring the amount of decomposition product”. In step 3, the only difference is that the residual rate is calculated from the amount of decomposition products.
In addition, since it is necessary to measure a plurality of compound residual ratios at different temperatures when predicting the compound residual ratio, it is necessary to repeat Step 2 and Step 3 while changing the temperature (Step 4). Such measurement can increase the accuracy of the prediction of the remaining rate as the temperature range is widened and the temperature is increased. Such measurement of the temperature and temperature of the sample is performed at least once for each decomposition time at each temperature, and when repeated, the accuracy of prediction of the remaining rate can be further increased.

Step 5 is a step of calculating a reaction rate equation and a reaction rate constant.
Examples of reaction rate equations include nth order reaction rate equation (n is a real number greater than or equal to 0), Jander equation, Weibull equation, diffusion rate equation, Avrami equation, Prout-Tompkins rate equation, etc. The formula that best suits the decomposition of the target substance in the sample can be selected. The reaction rate constant at each temperature is calculated from the selected rate equation.

Step 6 is a step of obtaining a regression linear equation and predicting the remaining rate.
Each temperature is plotted by converting the temperature of the sample being kept into an absolute temperature T and taking the reciprocal on the horizontal axis and taking the natural logarithm of the reaction rate constant k at that temperature on the vertical axis. From this plot, regression analysis is performed by the least square method or the like to obtain a regression line.
Extrapolate from the obtained regression linear equation to the temperature to be predicted (for example, 40 ° C. for acceleration conditions and 25 ° C. for long-term storage conditions) to determine the reaction rate constant at the target temperature. After that, the reaction rate constant, the target decomposition rate, or the storage period is substituted into the reaction rate equation selected in Step 6 for prediction.

(Method for evaluating compounding eligibility)
When evaluating the compounding eligibility of the drug substance and additives, evaluate the mixture consisting only of the drug substance and additives according to the above (Method for measuring the amount of degradation products) and (Method for predicting the residual ratio of compounds). .
In this step, the amount of the additive can be appropriately selected depending on the drug substance, and the weight ratio of the drug substance and the additive is preferably 1: 1 to 1:50.

(Example)
Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited thereto.

(Reference Example 1)
A gas cleaning bottle was installed between the flow meter in the atmospheric gas flow path of the thermal measurement device (TG-DTA, Seiko Instruments, TG / DTA6200) and the TG-DTA device, and water was put in the gas cleaning bottle. . This gas washing bottle was kept at 30 ° C. in a water bath (FIG. 1).

Famotidine and crystalline cellulose were mixed at a ratio of 1: 9 and used as a sample. The sample was heated by the above-described heat measurement apparatus under the condition of measurement condition 1 every 10 ° C. for 3 hours in the range of 100 ° C. to 150 ° C. The results are shown in FIG. In this temperature range, no endothermic or exothermic reaction was observed on the DTA curve, but a decreasing trend was observed on the TG curve at 150 ° C. Although this is thought to be due to a rapid decomposition reaction, there is a possibility of a reaction that cannot occur in the normal temperature range, so the upper limit of the temperature at which the sample is decomposed was set to 140 ° C.

<Measurement condition 1>
Sample container: Open type aluminum pan atmosphere gas: Humidified nitrogen atmosphere Gas flow rate: 100 mL / min Temperature program: Stepwise temperature rising method (holding the sample temperature at 100 ° C. for 3 hours, then increasing the temperature by 10 ° C. at 50 ° C./min) In this case, the step of keeping the temperature at a constant temperature for 3 hours was repeated until reaching 150 ° C., then the temperature was lowered to 100 ° C. and kept for 3 hours.

A gas cleaning bottle was installed between the flow meter in the ambient gas flow path of the thermal analyzer (TG-DTA, Seiko Instruments, TG / DTA6200) and the TG-DTA device, and water was put in the gas cleaning bottle. . This gas washing bottle was kept at 30 ° C. in a water bath (FIG. 1).
Famotidine and crystalline cellulose were mixed at a ratio of 1: 9 and used as a sample. The sample was heated to 120 ° C. under the measurement condition 2 by the thermal analyzer according to the present invention. The heating time was 15, 20, and 25 hours. There was no significant change in TG or DTA during warming. The heated sample was quantified by high performance liquid chromatography under the condition of measurement condition 3. The results are shown in Table 2.

<Measurement condition 2>
Sample container: Open type aluminum pan atmosphere gas: Humidified nitrogen atmosphere Gas flow rate: 100 mL / min Temperature program: Temperature was raised from room temperature to 120 ° C. at 50 ° C./min, and 120 ° C. was maintained for the heating time.

<Measurement condition 3>
Mobile phase A: 20 mM sodium dihydrogen phosphate solution Mobile phase B: Methanol mobile phase for liquid chromatography Liquid feed: Mixing ratio of mobile phases A and B was changed as shown in Table 1, and the concentration gradient was controlled.

Using the same thermal analyzer as that used in Example 1, the same sample as that used in Example 1 was used, and the sample was heated to 130 ° C. under the measurement condition 4. The heating time was 10, 15, and 20 hours. There was no significant change in TG or DTA during warming. Thereafter, the amount was quantified by high performance liquid chromatography in the same manner as in Example 1. The results are shown in Table 2.

<Measurement condition 4>
Sample container: open type aluminum pan atmosphere gas: humidified nitrogen atmosphere gas flow rate: 100 mL / min Temperature program: The temperature was raised from room temperature to 130 ° C. at 50 ° C./min, and 130 ° C. was maintained for the heating time.

Using the same thermal analyzer as that used in Example 1, a sample similar to that used in Example 1 was used and heated to 140 ° C. under the condition of measurement condition 5. The heating time was 3, 4.5 and 6 hours. There was no significant change in TG or DTA during warming. Thereafter, the amount was quantified by high performance liquid chromatography in the same manner as in Example 1. The results are shown in Table 2.

<Measurement condition 4>
Sample container: Open type aluminum pan atmosphere gas: humidified nitrogen atmosphere gas flow rate: 100 mL / min Temperature program: Temperature was raised from room temperature to 140 ° C. at 50 ° C./min, and 140 ° C. was maintained for the heating time.

The residual rate determined by high performance liquid chromatography was substituted into each reaction rate equation, and a first order reaction equation with a correlation coefficient closest to 1 and a y-intercept close to 0 was adopted as the reaction rate equation. The reaction rate constant was calculated from the first-order reaction equation, and the regression line was obtained by the Arrhenius plot (the value obtained by multiplying the reciprocal of the absolute temperature T by 1000 on the horizontal axis and the natural logarithm 1nk of the reaction rate constant at each temperature on the vertical axis). (FIG. 3) and a regression line equation (formula 1: y = −7.51x + 6.1367) were obtained. The reaction rate formula at 40 ° C. was calculated from the obtained formula 1, and the residual ratio when stored for 4 weeks was 95.6%.

(Comparative Example 1)

The sample was placed in a brown glass bottle and stored at 40 ° C./75% RH for 4 weeks without a lid. Thereafter, the amount was quantified by high performance liquid chromatography in the same manner as in Example 1. As a result, the residual rate was 95.7%.

The result of Comparative Example 1 was substantially the same as the numerical value obtained in Example 4, and it was found that the hydrolysis reaction can be predicted in a short time by the method of the present invention.

(Comparative Example 2)
Potassium chloride saturation support solution was placed in the bottom of the desiccator, and the sample was placed in the desiccator and stored at 80 ° C. The potassium chloride saturation aid is 90% relative humidity. The storage time was 24, 48, 72 hours, and quantified by high performance liquid chromatography in the same manner as in Example 1. The results are shown in Table 3.

From the results of Comparative Example 2, the hydrolysis reaction at 80 ° C. did not progress so much, and it took a considerable time to achieve an appropriate decomposition rate of 3% or more, and the decomposition under accelerated conditions was rapid. Could not be predicted.

The present invention is a method for quickly and simply evaluating the stability of a compound in a pharmaceutical preparation, and is industrially useful.

Claims (11)

A method for measuring a hydrolysis reaction at a temperature higher than 100 ° C., comprising the following steps.
(Step 1) Gas through which water having a water temperature from room temperature to 35 ° C. has been passed is introduced into the reaction furnace of the heat measuring device (Step 2) Composition when decomposed for 24 hours at 80 ° C. and 90% RH A composition containing a compound whose decomposition product is less than 3% is placed in a heating furnace of a heat measuring device, and the temperature in the heating furnace of the heat measuring device is heated to a set temperature higher than 100 ° C. Perform decomposition reaction (Step 3) Remove the sample from the furnace and quantify the amount of decomposition product The method of claim 1, wherein the gas in step 1 is nitrogen gas. The method according to claim 1 or 2, wherein the water temperature in step 1 is 25 ° C to 35 ° C. The method according to any one of claims 1 to 3, wherein the composition in step 2 is a composition consisting only of an active ingredient and an additive. 5. The method of claim 4, wherein the weight ratio of drug substance to additive is from 1: 1 to 1:50. A method for predicting the residual ratio of a compound, comprising the following steps.
(Step 1) Gas through which water having a temperature of 35 ° C. through room temperature is introduced into the reactor of the heat measuring device (Step 2) Decomposed product when decomposed for 24 hours at 80 ° C. and 90% RH A composition containing a compound with an amount of less than 3% is placed in a heating furnace of a thermal analyzer, and the temperature in the heating furnace of the thermal analyzer is heated to a set temperature higher than 100 ° C. to cause a decomposition reaction ( Step 3) A sample is taken out from the heating furnace, and the residual rate is calculated by quantifying the amount of decomposition products (Step 4). Steps 2 and 3 are repeated three or more times at different heating furnace temperatures.
(Step 5) A reaction rate equation and / or reaction rate constant is calculated using the obtained plurality of remaining rates. (Step 6) A regression line and / or regression line equation is obtained from the Arrhenius plot, and the remaining rate is predicted. . The method of claim 6, wherein the gas in step 1 is nitrogen gas. The method according to claim 6 or 7, wherein the water temperature in step 1 is 25 ° C to 35 ° C. The method according to any one of claims 6 to 8, wherein the survival rate predicted in step 6 is a survival rate under accelerated conditions or long-term storage conditions. The method according to any one of claims 6 to 9, wherein the composition in Step 2 is a composition consisting only of an active ingredient and an additive. 11. The method of claim 10, wherein the weight ratio of drug substance to additive is 1: 1 to 1:50.

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