CN112540099A - Differential scanning calorimetry - Google Patents
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- 238000000113 differential scanning calorimetry Methods 0.000 title abstract description 6
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229960004372 aripiprazole Drugs 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 37
- 238000002347 injection Methods 0.000 claims abstract description 15
- 239000007924 injection Substances 0.000 claims abstract description 15
- 238000002844 melting Methods 0.000 claims abstract description 13
- 230000008018 melting Effects 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 5
- 238000001514 detection method Methods 0.000 claims description 23
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 15
- 229910052782 aluminium Inorganic materials 0.000 claims description 15
- 210000004907 gland Anatomy 0.000 claims description 7
- 230000007704 transition Effects 0.000 claims description 7
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 4
- 229940088679 drug related substance Drugs 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000000155 melt Substances 0.000 claims 1
- 239000013078 crystal Substances 0.000 abstract description 21
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000009466 transformation Effects 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 229940090044 injection Drugs 0.000 description 13
- UXQBDXJXIVDBTF-UHFFFAOYSA-N 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1h-quinolin-2-one;hydrate Chemical compound O.ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl UXQBDXJXIVDBTF-UHFFFAOYSA-N 0.000 description 10
- 229940025916 aripiprazole injection Drugs 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 238000000227 grinding Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 238000012417 linear regression Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- -1 2, 3-dichlorophenyl Chemical group 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Images
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N25/00—Investigating or analyzing materials by the use of thermal means
- G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a differential scanning calorimetry method for measuring the amorphous content of a raw material medicament in an aripiprazole long-acting injection, belonging to the technical field of analytical chemistry; the method selects the enthalpy value of the aripiprazole amorphous bulk drug in the melting and crystal transformation process as a quantitative parameter, establishes a standard curve and determines the amorphous content of the aripiprazole bulk drug. The method has the advantages of specificity, good repeatability and high sensitivity.
Description
Technical Field
The invention belongs to the technical field of analytical chemistry, and particularly relates to a differential scanning calorimetry method for determining the amorphous content of a raw material medicament in an aripiprazole long-acting injection.
Background
Aripiprazole, chemical name: 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] -3, 4-dihydro-2 (1H) -carbostyril or 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] -3, 4-dihydrocarbostyril, the structure of which is shown in formula (I), and the aripiprazole carbostyril derivative is an atypical psychotropic drug for treating schizophrenia. US patents 4734416 and US 5006528 first disclosed the structure of aripiprazole and the use for treating schizophrenia;
the aripiprazole bulk drug has various crystal forms such as a monohydrate crystal form, a crystal form A, a crystal form B, a crystal form C, a crystal form D, a crystal form E, an amorphous form and the like. Aripiprazole long-acting intramuscular injection original manufacturers take aripiprazole monohydrate as a starting material, and obtain a finished product after grinding and freeze-drying, wherein the raw material medicine in the preparation mainly exists in the form of monohydrate, but the monohydrate crystal form can generate amorphous form in the grinding and freeze-drying processes, and the amorphous form in the preparation has important influence on the absorption rate of an aripiprazole intramuscular injection part.
The aripiprazole long-acting intramuscular injection is an aqueous suspension prepared from insoluble drug particles, and the drug is slowly dissolved at the injection part to achieve the long-acting slow release effect. Therefore, the physicochemical properties of the raw material drug particles in the preparation are particularly critical to the quality of the product, including particle size, particle size distribution, crystal form, and the like.
At present, no patent and literature at home and abroad reports a method for monitoring the amorphous content in the bulk drug of the aripiprazole long-acting injection, so that a method for quickly and accurately detecting the amorphous content in the bulk drug of the aripiprazole long-acting injection needs to be developed.
Disclosure of Invention
Summary of The Invention
The invention provides a method for rapidly, accurately and sensitively measuring the amorphous content of a raw material medicament in an aripiprazole long-acting injection. The method has the advantages of strong specificity, good repeatability and high sensitivity, and the detection limit of the method is 1 percent and the quantification limit is 3 percent.
Definition of terms
The term "DSC" refers to differential scanning calorimetry.
The term "enthalpy" is an important state variable in thermodynamics that characterizes the energy of a matter system, and is generally denoted by the symbol H. For a mass of a substance, the enthalpy is defined as H ═ U + pV, where U is the internal energy of the substance, p is the pressure, and V is the volume. The enthalpy per mass of substance is called the specific enthalpy and is expressed as h ═ u + pv.
The term "about" in the present invention means within ± 5% of the numerical value concerned.
In the present invention, mL/min represents mL/min, mg represents mg, DEG C represents centigrade, DEG C/min represents centigrade/min, and J/g represents Joule/gram.
Detailed Description
The invention provides a differential scanning calorimeter method for measuring amorphous content in bulk drugs of an aripiprazole long-acting injection, which is characterized by comprising the following steps: the enthalpy value of the aripiprazole amorphous bulk drug in the melting and crystal transformation process is selected as a quantitative parameter, a standard curve is established, and the amorphous content of the aripiprazole bulk drug is measured.
The analysis method comprises the steps of selecting detection conditions, selecting a crystal transformation peak and establishing a standard curve.
In some embodiments, the differential scanning calorimetry method for determining the amorphous content in the bulk drug of the aripiprazole long-acting injection of the present invention comprises the following detection conditions:
sample disc type: an aluminum crucible (gland);
gas atmosphere: n is a radical of2；
Gas rate: 50 mL/min;
temperature rise range: 0-200 ℃;
the heating rate is as follows: 10 ℃/min.
In some embodiments, the melting transcrystallization peak at 65 ℃ to 85 ℃ is an amorphous quantitative detection peak in the aripiprazole drug substance.
In some embodiments, the standard curve is established as follows:
precisely weighing the components according to the table 1, fully and uniformly mixing to obtain experimental mixed samples with amorphous mass fractions of aripiprazole of 4%, 12%, 24%, 40%, 56% and 80%, and respectively carrying out DSC detection; and selecting a melting and crystal transformation peak of the aripiprazole at 70-85 ℃, and performing linear fitting on the enthalpy value of the amorphous melting and crystal transformation peak by taking the actual mass fraction of the amorphous in the experimental mixed sample as the abscissa to obtain a linear equation y, wherein the x and the b are respectively the maximum value and the minimum value of the enthalpy value of the amorphous melting and crystal transformation peak.
In the formula: y is the enthalpy value of the amorphous melting crystal transition peak;
a is the slope of the linear regression equation;
x is the mass fraction of the amorphous content;
b is the y-axis intercept of the linear regression equation.
TABLE 1 Standard Curve quality preparation Table
In some embodiments, the aripiprazole long acting injection blank adjuvant composition is as in table 2:
TABLE 2 Aripiprazole injection blank adjuvant composition Table
| Name of auxiliary Material | Mass fraction |
| Sodium carboxymethylcellulose | 4.0％ |
| Mannitol | 15.7％ |
| Monobasic sodium phosphate monohydrate | 0.5％ |
In some embodiments, the detection method is linear well in the range of 4% to 80%.
In some embodiments, the detection limit of the detection method is 1%.
In some embodiments, the limit of quantitation for this detection method is 3%.
In some embodiments, the temperature rise rate of the detection method is 1-20 ℃/min.
Drawings
FIG. 1 is a comparison graph of aripiprazole amorphous form, aripiprazole long-acting injection blank adjuvant, aripiprazole monohydrate;
FIG. 2 is a graph of a standard curve linear regression equation;
figure 3 is a comparison graph of aripiprazole long-acting injection before and after grinding.
Detailed Description
For a further understanding of the present invention, reference will now be made in detail to the following examples.
Example 1
Specificity experiments
Taking the amorphous aripiprazole, aripiprazole monohydrate and the blank auxiliary material of the long-acting aripiprazole injection, namely about 10mg of the blank auxiliary material, in an aluminum crucible, and covering the aluminum crucible with a cover. Detection was performed using a TA Q2000 differential scanning calorimeter (TA in usa) under the following conditions:
the detection result is shown in figure 1, the amorphous aripiprazole has a melting and crystal transition peak at the temperature of about 73 ℃, the blank auxiliary material and the aripiprazole monohydrate have no melting and crystal transition peak at the position, the detection of the amorphous aripiprazole is free from interference, and the result shows that the specificity of the method is good.
Linearity and range
The aripiprazole amorphous form, the aripiprazole monohydrate and the blank auxiliary materials of the aripiprazole long-acting injection are precisely weighed according to the following table and fully and uniformly mixed. Mixed samples for experiments containing amorphous mass fractions of aripiprazole of 4%, 12%, 24%, 40%, 56%, and 80% were obtained.
About 10mg of the 6 uniformly mixed samples were placed in an aluminum crucible and covered.
Detection was performed using a TA Q2000 differential scanning calorimeter (TA in usa) under the following conditions:
| sample disc type | Aluminum crucible (gland) |
| Atmosphere of gas | N2 |
| Rate of gas flow | 50mL/min |
| Temperature range of |
0～200℃ |
| Rate of temperature rise | 10℃/min |
The experimental results are shown in table 3, the results are shown in fig. 2, the linear regression equation is that y is 40.2881x-1.2425, the correlation coefficient r is 0.9995, and the results show that the method has good linearity in the range of 4% to 80%.
TABLE 3 results of the Linear experiment
| Mass fraction | 4％ | 12％ | 24％ | 40％ | 56％ | 80％ |
| Enthalpy (J/g) | 0.7433J/g | 3.517J/g | 8.057J/g | 14.74J/g | 21.43J/g | 31.08J/g |
Repeatability of
Accurately weighing 40mg of amorphous aripiprazole, 40mg of aripiprazole monohydrate and 20mg of blank auxiliary material of the long-acting aripiprazole injection respectively, and fully and uniformly mixing. Samples were prepared in parallel in 6 portions.
About 10mg of the 6 uniformly mixed samples were placed in an aluminum crucible and covered.
Detection was performed using a TA Q2000 differential scanning calorimeter (TA in usa) under the following conditions:
| sample disc type | Aluminum crucible (gland) |
| Atmosphere of gas | N2 |
| Rate of gas flow | 50mL/min |
| Temperature range of |
0～200℃ |
| Rate of temperature rise | 10℃/min |
The experimental results are shown in Table 4, the RSD of the enthalpy value of the amorphous melting and crystal transition peak of 6 parts of samples is calculated, the RSD of the 6 parts of results is 1.6%, and the results show that the method has good repeatability.
TABLE 4 results of repeated experiments
| Sample numbering | 1 | 2 | 3 | 4 | 5 | 6 | RSD |
| Enthalpy (J/g) | 14.74J/g | 15.06J/g | 15.40J/g | 15.23J/g | 15.48J/g | 15.19J/g | 1.6％ |
Limit of quantification
3mg of aripiprazole amorphous form, 77mg of aripiprazole monohydrate and 20mg of aripiprazole long-acting injection blank auxiliary material are precisely weighed respectively and fully and uniformly mixed. Samples were prepared in parallel in 3 portions.
About 10mg of the 3 uniformly mixed samples were placed in an aluminum crucible and pressed.
Detection was performed using a TA Q2000 differential scanning calorimeter (TA in usa) under the following conditions:
the results are shown in Table 5, with a limit of quantitation of 3.0%.
TABLE 5 quantitative limit test results
| Sample numbering | 1 | 2 | 3 |
| Enthalpy (J/g) | 0.5248J/g | 0.5227J/g | 0.5240J/g |
Detection limit
Accurately weighing 1mg of aripiprazole amorphous form, 79mg of aripiprazole monohydrate and 20mg of blank auxiliary material of the aripiprazole long-acting injection respectively, and fully and uniformly mixing. Samples were prepared in parallel in 3 portions.
About 10mg of the 3 uniformly mixed samples were placed in an aluminum crucible and pressed.
Detection was performed using a TA Q2000 differential scanning calorimeter (TA in usa) under the following conditions:
| sample disc type | Aluminum crucible (gland) |
| Atmosphere of gas | N2 |
| Rate of gas flow | 50mL/min |
| Temperature range of |
0～200℃ |
| Rate of temperature rise | 10℃/min |
The results are shown in Table 6, with a quantitative limit of 1.0%.
TABLE 6 detection limit test results
| Sample numbering | 1 | 2 | 3 |
| Enthalpy (J/g) | 0.1822J/g | 0.1706J/g | 0.1670J/g |
Example 2
Investigation of rate of temperature rise
Accurately weighing 40mg of amorphous aripiprazole, 40mg of aripiprazole monohydrate and 20mg of blank auxiliary material of the long-acting aripiprazole injection respectively, and fully and uniformly mixing.
About 10mg of the uniformly mixed sample is put in an aluminum crucible, and a cover is pressed, and 3 parts of the sample are prepared in parallel.
The detection is carried out by using a TA Q2000 differential scanning calorimeter (American TA) according to the conditions of 5 ℃/min, 10 ℃/min and 15 ℃/min respectively, and other conditions are as follows:
| sample disc type | Aluminum crucible (gland) |
| Atmosphere of gas | N2 |
| Rate of gas flow | 50mL/min |
| Temperature range of |
0～200℃ |
The experimental results are shown in Table 7, and the RSD of the enthalpy value of the amorphous melting and crystal transition peak of 3 parts of samples is calculated, and the RSD of the 3 parts of results is 2.1 percent, so that the change of the temperature rising rate has small influence on the enthalpy value of the amorphous melting and crystal transition peak.
TABLE 7 repeatability results
| Rate of temperature rise | 5℃/ |
10℃/min | 15℃/min | RSD |
| Enthalpy (J/g) | 13.27J/g | 13.97J/g | 13.61J/g | 2.1％ |
Example 3
Sample amorphous content determination investigation
About 10mg of the unmilled aripiprazole injection and the aripiprazole injection after milling for 10min were separately sampled in an aluminum crucible and capped.
Detection was performed using a TA Q2000 differential scanning calorimeter (TA in usa) under the following conditions:
| sample disc type | Aluminum crucible (gland) |
| Atmosphere of gas | N2 |
| Rate of gas flow | 50mL/min |
| Temperature range of |
0～200℃ |
The results are shown in Table 8, and the spectrum obtained in the experiment is shown in FIG. 3. The amorphous content of aripiprazole injection after 10min of grinding was calculated by combining the linear equation in example 1, no amorphous content was detected in the unmilled aripiprazole injection, and 26.0% of aripiprazole monohydrate was converted into amorphous content of aripiprazole after 10min of grinding, indicating that the method can detect the amorphous content of aripiprazole injection.
TABLE 8 results of amorphous content of aripiprazole injection before and after milling
| Grinding time (min) | Enthalpy (J/g) | Amorphous content (%) |
| 0 | 0J/ |
0 |
| 10 | 9.233J/g | 26％ |
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (9)
1. A method for measuring the amorphous content of aripiprazole in an aripiprazole long-acting injection is characterized by using a differential scanning calorimeter.
2. The method of claim 1, wherein the enthalpy value of the aripiprazole amorphous drug substance during the melting and transcrystalization process is selected as a quantitative parameter, a standard curve is established, and the amorphous content of the aripiprazole drug substance is determined.
3. The method according to claim 2, wherein the aripiprazole amorphous drug substance has a melt transition peak at 65 ℃ to 85 ℃.
4. The method of claim 2, wherein the detection condition is:
sample disc type: an aluminum crucible (gland);
gas atmosphere: n is a radical of2；
Gas rate: 50 mL/min;
temperature rise range: 0-200 ℃;
the heating rate is as follows: 10 ℃/min.
5. The method according to claim 2, characterized in that the standard curve of the method is: y is 40.2881x-1.2425 and the correlation coefficient r is 0.9995.
6. The method of claim 2, wherein the method has a linear range of 4% to 80%.
7. The method according to claim 2, wherein the temperature rise rate of the method is 1-20 ℃/min.
8. The method of any one of claims 1 to 7, wherein the method has a detection limit of 1%.
9. The method of any one of claims 1 to 7, wherein the method has a quantitation limit of 3%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850268A (en) * | 2011-06-27 | 2013-01-02 | 上海中西制药有限公司 | Aripiprazole I-type crystallite, aripiprazole solid preparation and preparation methods thereof |
| CN106632291A (en) * | 2016-10-09 | 2017-05-10 | 瑞阳制药有限公司 | Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850268A (en) * | 2011-06-27 | 2013-01-02 | 上海中西制药有限公司 | Aripiprazole I-type crystallite, aripiprazole solid preparation and preparation methods thereof |
| CN106632291A (en) * | 2016-10-09 | 2017-05-10 | 瑞阳制药有限公司 | Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal |
Non-Patent Citations (1)
| Title |
|---|
| JUSTYNA KNAPIK-KOWALCZUK等: "Influence of polymeric additive on the physical stability and viscoelastic properties of aripiprazole", MOLECULAR PHARMACEUTICS, 10 March 2019 (2019-03-10), pages 1 - 24 * |
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