CN116082346A - High-fluidity sitagliptin phosphate monohydrate crystal and preparation method thereof - Google Patents
High-fluidity sitagliptin phosphate monohydrate crystal and preparation method thereof Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K9/2004—Excipients; Inactive ingredients
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- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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Abstract
The invention provides a high-fluidity sitagliptin phosphate monohydrate crystal and a preparation method thereof. Specifically, the sitagliptin phosphate monohydrate crystals have the following characteristics: d (50) is 112-115 μm, D (90) is 330-350 μm; the repose angle is 36-40 degrees; and a flow factor of 13.1-14.7. The crystal of the invention has good fluidity and is matched with two main auxiliary materials (anhydrous calcium hydrophosphate and microcrystalline cellulose) in the aspects of granularity distribution, flow factor and the like, thereby being very beneficial to preparing the sitagliptin tablet with good uniformity.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a high-fluidity sitagliptin phosphate monohydrate crystal and a preparation method thereof.
Background
The sitagliptin tablet is prepared by adopting a powder direct compression process, and the bulk drug accounts for 32 weight percent of the tablet core and needs to have good fluidity. The other two main auxiliary materials of the tablet core are anhydrous calcium hydrophosphate and microcrystalline cellulose which respectively account for 31 weight percent of the tablet core (shown according to prescription information published by the sitagliptin phosphate tablet of the original grinding of Argentina). This requires that the drug substance, anhydrous dibasic calcium phosphate and microcrystalline cellulose contained in the drug formulation have good miscibility, that is, that the crystallography parameters of the sitagliptin phosphate drug substance are close to those of the excipients to ensure uniformity and flowability during mixing and tabletting. However, the crystal obtained by the simple crystallization process has smaller particle size, larger parameter difference with the crystal of anhydrous calcium hydrophosphate and microcrystalline cellulose auxiliary material and low uniformity, and the crystal is needle-shaped particles, so that the fluidity of the crystal is further reduced.
Therefore, the preparation method of the sitagliptin bulk drug with high compatibility with auxiliary materials has important significance in the field.
Disclosure of Invention
The invention aims to provide a sitagliptin crystal bulk drug with high compatibility with auxiliary materials and a preparation method thereof.
In a first aspect of the present invention, there is provided a crystal of sitagliptin phosphate monohydrate, wherein,
sitagliptin phosphate monohydrate exists in crystalline form and has an XRPD pattern with diffraction peaks at 2θ as follows: 13.884 + -0.2 °, 15.0981 + -0.2 ° and 18.497 + -0.2 °; and is also provided with
The crystal has the following characteristics: d (50) is 112-115 μm, D (90) is 330-350 μm; the repose angle is 36-40 degrees; and a flow factor of 13.1-14.7.
In another preferred embodiment, the crystals have a D (50) of 113-114 μm and a D (90) of 338-348. Mu.m.
In another preferred embodiment, the D (10) of the crystals is 29-33. Mu.m, preferably 31-32. Mu.m.
In another preferred embodiment, the angle of repose of the crystal is 37-38 °.
In another preferred embodiment, the flow factor of the crystals is 13.4-14.3.
In another preferred embodiment, the crystals have a D (50) of 113.5 μm and a D (90) of 343 μm and a flow factor of 14.2.
In another preferred embodiment, the crystal has an XRPD pattern substantially as shown in figure 4.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising:
crystalline, anhydrous dibasic calcium phosphate, and microcrystalline cellulose as described in the first aspect of the invention.
In another preferred embodiment, the pharmaceutical composition is in the form of a tablet.
In another preferred embodiment, the anhydrous dibasic calcium phosphate has the following characteristics: d (50): (138.5+ -3%) μm, D (90): (229+ -3%) μm, angle of repose of 37.1°+ -3% and flow factor of 201+ -3%; preferably, optionally ± 2% or ± 1%.
In another preferred embodiment, the microcrystalline cellulose has the following characteristics: d (50): (115+ -3%) μm, D (90): (236+ -3%) μm, angle of repose of 38.5°+ -3% and flow factor of 14.4+ -3%; preferably, optionally ± 2% or ± 1%.
In another preferred embodiment, anhydrous dibasic calcium phosphate is purchased from Huzhou observance under the product numbers D425, D (10): 50.6 μm, D (50): 138.5 μm, D (90): 229 μm, angle of repose 37.1, flow factor 201; microcrystalline cellulose was purchased from Chamchina, cat No. 302, D (10): 34.6 μm, D (50): 115 μm, D (90): 236 μm, angle of repose 38.5, flow factor 14.4.
In a third aspect of the present invention, there is provided a method for preparing a crystal according to the first aspect of the present invention, comprising the steps of:
(1) Providing a mixture of sitagliptin phosphate, water and isopropanol;
in the mixture, the weight ratio of the sitagliptin phosphate to the water is 1: (1.4-1.9); and the weight ratio of water to isopropanol is 1: (1.11-1.35);
(2) Heating the mixture to 55-79 ℃ for the first time under stirring to completely dissolve the solids;
(3) Cooling water is started, the temperature is reduced to 50-59 ℃, and after stirring is carried out for 20-40min, the temperature is continuously reduced to 3-10 ℃ with the cooling rate of 4-8 ℃/h;
(4) Heating to 35-45deg.C for the second time, dissolving part of the solid, maintaining the temperature for 20-40min, cooling to 3-10deg.C, cooling at 4-8deg.C/h, maintaining the temperature at 3-10deg.C, and stirring for 50-80min;
(5) Continuously repeating the step (4) for 7-14 times;
in the steps 1-5, the stirring speed is optionally 200-500r/min;
(6) Filtering and washing a filter cake;
(7) And (3) drying under reduced pressure at 41-48 ℃ for 4-8h, wherein the vacuum degree is < -0.09Mpa in the reduced pressure drying process until the water content of the product is 3.3-3.55wt%, thereby obtaining the sitagliptin phosphate monohydrate crystal.
In another preferred embodiment, in steps (1) - (5), the speed of each stirrer is the same.
In a fourth aspect, the present invention provides the use of a crystal according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention in the manufacture of a medicament for the prophylaxis or treatment of type 2 diabetes.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 is a photomicrograph of the product of example 1;
FIG. 2 is a photomicrograph of the product of example 5;
FIG. 3 is a photomicrograph of the product of example 6;
fig. 4 is a crystalline XRPD pattern of the product sitagliptin phosphate monohydrate obtained in example 1, crystalline form being consistent with CN1832949 a.
Fig. 5 is a crystalline XRPD pattern of the product sitagliptin phosphate monohydrate obtained in example 3, crystalline form being consistent with CN1832949 a.
Fig. 6 is a crystalline XRPD pattern of the product sitagliptin phosphate monohydrate obtained in example 5, crystalline form being consistent with CN1832949 a.
Detailed Description
Through extensive and intensive studies, the present inventors have provided a high-fluidity sitagliptin phosphate monohydrate crystal and a method for preparing the same, through a large number of screening and testing. According to the invention, in the process of preparing the sitagliptin phosphate monohydrate crystal, the cyclic process of increasing the temperature and reducing the temperature can greatly improve the crystallographic properties, and the obtained sitagliptin phosphate crystal has good mobile phase, is matched with two main auxiliary materials in the aspects of particle size distribution, flow factors and the like, and is very beneficial to preparing the sitagliptin tablet with good uniformity. The present invention has been completed on the basis of this finding.
Terminology
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.
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4 to 40 o C, preferably 25.+ -.5 o C。
As used herein, the term "D10" refers to the particle size corresponding to when the cumulative particle size distribution of a sample reaches 10%. Its physical meaning is that the particles with a particle size smaller than that of it account for 10%. Similarly, the term "D50" refers to the particle size corresponding to a sample having a cumulative particle size distribution percentage of 50%; its physical meaning is that the particle size is greater than 50% of its particles and less than 50% of its particles, also called median or median particle size, D50. The term "D90" refers to the particle size corresponding to a sample having a cumulative particle size distribution of 90%. Its physical meaning is that its particle size is less than 90% of its particle size.
Sitagliptin phosphate monohydrate
As used in the present invention, the sitagliptin phosphate monohydrate has the structural formula:
sitagliptin phosphate monohydrate is an active ingredient of sitagliptin phosphate tablets and can be used for treating type 2 diabetes.
Crystal body
The invention provides a sitagliptin phosphate monohydrate crystal with specific crystal parameters, which is more convenient for preparation process and has better compatibility with pharmaceutical excipients when being used for preparing sitagliptin phosphate tablets, so that the sitagliptin phosphate monohydrate crystal is more uniformly distributed in the tablets (such as having better dissolution curve).
As used herein, the term "crystalline" refers to aggregates of sitagliptin phosphate monohydrate having a particular crystalline form.
Specifically, the XRPD pattern of the crystal has diffraction peaks at 2θ:13.884 ±0.2°, 15.0981 ±0.2° and 18.497 ±0.2°. More specifically, the crystals have an XRPD pattern substantially as shown in figure 4 (each peak may have an error of ± 0.2 °).
In the present invention, the D (50) of the crystal is 112-115 μm and the D (90) is 330-350 μm.
Further, the angle of repose of the crystal is 36-40 degrees; and a flow factor of 13.1-14.7.
Preferably, the crystals D (50): 113.5 μm, D (90): 343 μm, angle of repose of 37.8℃and flow factor 14.2.
From the micrograph, the individual particles of the crystals are spheroid or cylinder-like in shape.
Pharmaceutical composition and use
The pharmaceutical composition of the present invention comprises the above-mentioned sitagliptin phosphate monohydrate crystals as an active ingredient.
It will be appreciated by those skilled in the art that the crystals of the present invention and pharmaceutical compositions comprising the same have the biological activity of sitagliptin phosphate, for example as a medicament for the treatment of type 2 diabetes.
Further preferably, when the sitagliptin phosphate monohydrate crystal is used for sitagliptin phosphate tablets, the sitagliptin phosphate monohydrate crystal further comprises a pharmaceutic adjuvant, wherein the pharmaceutic adjuvant comprises anhydrous calcium hydrophosphate and microcrystalline cellulose.
In another preferred embodiment, the anhydrous dibasic calcium phosphate has the following characteristics: d (50): (138.5 ± 3%) μm, D (90): (229 ± 3%) μm, angle of repose (37.1 ± 3%), flow factor (201 ± 3%), preferably, optionally ± 2% or ± 1%.
In another preferred embodiment, the microcrystalline cellulose has the following characteristics: d (50): (115±3%) μm, D (90): (236±3%) μm, angle of repose (38.5±3%) and flow factor (14.4±3%) preferably, optionally ±2% or ±1%.
Even more preferably, anhydrous dibasic calcium phosphate is purchased from Huzhou observers under the product numbers D425, D (10): 50.6 μm, D (50): 138.5 μm, D (90): 229 μm, angle of repose 37.1, flow factor 201; microcrystalline cellulose was purchased from Chamchina, cat No. 302, D (10): 34.6 μm, D (50): 115 μm, D (90): 236 μm, angle of repose 38.5, flow factor 14.4.
Preparation method
The invention also provides a preparation method of the crystal, which comprises the following steps:
(1) Providing a mixture of sitagliptin phosphate, water and isopropanol;
in the mixture, the weight ratio of the sitagliptin phosphate to the water is 1: (1.4-1.9); and the weight ratio of water to isopropanol is 1: (1.11-1.35);
(2) Heating the mixture to 55-79 ℃ for the first time under stirring to completely dissolve the solids;
(3) Opening cooling water (the cooling water is arranged in a jacket, other cooling can be used in the invention), cooling to 50-59 ℃, stirring for 20-40min, continuing cooling to 3-10 ℃ and cooling at a speed of 4-8 ℃/h;
(4) Heating to 35-45deg.C for the second time, dissolving part of the solid, maintaining the temperature for 20-40min, cooling to 3-10deg.C, cooling at 4-8deg.C/h, maintaining the temperature at 3-10deg.C, and stirring for 50-80min;
(5) Continuously repeating the step (4) for 7-14 times;
in the steps 1-5, the stirring speed is optionally 200-500r/min;
(6) Filtering and washing a filter cake;
(7) And (3) drying under reduced pressure at 41-48 ℃ for 4-8h, wherein the vacuum degree is < -0.09Mpa in the reduced pressure drying process until the water content of the product is 3.3-3.55wt%, thereby obtaining the sitagliptin phosphate monohydrate crystal.
In another preferred embodiment, in steps 1-5, the speed of each agitation is the same.
At the drying temperature of the step (7), the water of crystallization in the crystal is not lost, and the water outside the crystal is dried.
The main advantages of the invention include:
the invention provides a sitagliptin monohydrate crystal bulk drug which has good fluidity and is matched with two main auxiliary materials (anhydrous calcium hydrophosphate and microcrystalline cellulose) in the aspects of granularity distribution, flow factor and the like, thereby being very beneficial to preparing a sitagliptin tablet with good uniformity.
In addition, the invention also provides a method for preparing the sitagliptin monohydrate crystal.
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1
(1) 70g of sitagliptin phosphate is added into a mixed solvent of 126g of water and 154g of isopropanol, and stirring is started;
(2) Heating to 68 ℃ for one time to completely dissolve the solid;
(3) Starting cooling water, cooling to 55 ℃, stirring for 30min, and continuously cooling to 5 ℃ (cooling rate 5 ℃/h);
(4) Raising the temperature to 40 ℃ for the second time, dissolving part of the solid, preserving the heat for 30 minutes, reducing the temperature to 5 ℃ (the temperature reduction rate is 5 ℃/h), and preserving the heat and stirring for 60 minutes at 5 ℃;
(5) Repeating the step (4) for 9 times;
in the step 1-5, the stirring speed is kept unchanged, and the stirring speed is 400r/min;
(6) Filtering, and cleaning a filter cake by using 14g of isopropanol;
(7) Drying under reduced pressure at 45deg.C for 6h, and maintaining vacuum degree of < -0.09Mpa during the drying process to obtain sitagliptin phosphate monohydrate.
Example 2
Unlike example 1, step 1 was to add 70g of sitagliptin phosphate to a mixed solvent of 112g of water and 144g of isopropanol, and stirring was started.
Example 3
Unlike example 1, in step 3 and step 4, the cooling rate was 7 ℃/h. In the step 1-5, the stirring speed is kept unchanged, and the stirring speed is 500r/min.
Example 4
Unlike example 1, step (5) was repeated 11 times further to step (4). In the step 1-5, the stirring speed is kept unchanged, and the stirring speed is 300r/min.
Example 5
Unlike example 4, step (5) was repeated 4 times further to step (4). In the step 1-5, the stirring speed is kept unchanged, and the stirring speed is 500r/min.
Example 6
(1) 70g of sitagliptin phosphate is added into a mixed solvent of 126g of water and 154g of isopropanol, and stirring is started;
(2) Heating to 68 ℃ for one time to completely dissolve the solid;
(3) Starting cooling water, cooling to 55 ℃, stirring for 30min, and continuously cooling to 5 ℃ (cooling rate 5 ℃/h);
(4) Preserving heat at 5 ℃ and stirring for 70min;
in the step 1-4, the stirring speed is kept unchanged, and the stirring speed is 400r/min;
(5) Filtering, and cleaning a filter cake by using 14g of isopropanol;
(6) Drying under reduced pressure at 46 ℃ for 6h, and keeping vacuum degree < -0.09Mpa in the process of drying under reduced pressure to obtain sitagliptin phosphate monohydrate.
Example 7
Unlike example 1, the cooling rates in both step 3 and step 4 were 2 ℃/h.
Example 8
Unlike example 1, the cooling rates in both step 3 and step 4 were 10 ℃/h.
Example 9
Unlike example 1, step 1 was to add 73g of sitagliptin phosphate to a mixed solvent of 127g of water and 178g of isopropyl alcohol (the ratio of isopropyl alcohol to the mixed solvent of water and isopropyl alcohol was 58.36 wt%), and stirring was started. Step 2 is to raise the temperature to 76 ℃ once so as to completely dissolve the solid.
Example 10
Unlike example 1, step 1 was to add 65g of sitagliptin phosphate to a mixed solvent of 122g of water and 133g of isopropyl alcohol, and stirring was started (the ratio of isopropyl alcohol to the mixed solvent of water and isopropyl alcohol was 52.16 wt%). Step 2 is to raise the temperature to 58 ℃ once so as to completely dissolve the solid.
Example 11
Unlike example 1, step 1 was to add 67g of sitagliptin phosphate to a mixed solvent of 105g of water and 154g of isopropyl alcohol (the ratio of isopropyl alcohol to the mixed solvent of water and isopropyl alcohol was 59.46 wt%), and stirring was started. Step 2 is to raise the temperature to 78 ℃ once, and the solid is not completely dissolved. The final product has slightly lower moisture and may have some non-transcrystalline sitagliptin phosphate present.
Example 12
Unlike example 1, step 1 was to add 70g of sitagliptin phosphate to a mixed solvent of 147g of water and 164g of isopropyl alcohol (the ratio of isopropyl alcohol to the mixed solvent of water and isopropyl alcohol was 52.73 wt%), and stirring was started. Step 2 is to raise the temperature to 62 ℃ once so as to completely dissolve the solid. The solid yield was significantly reduced compared to example 1.
Example 13
Unlike example 1, step 1 was to add 70g of sitagliptin phosphate to a mixed solvent of 131g of water and 113g of isopropyl alcohol (the ratio of isopropyl alcohol to the mixed solvent of water and isopropyl alcohol was 46.31 wt%), and stirring was started. Step 2 is to raise the temperature to 60 ℃ once so as to completely dissolve the solid.
Example 14, performance test
The results of the performance tests of the products prepared in examples 1 to 13 are shown in Table 1 below:
TABLE 1
* The moisture content was determined by a mertelecher fischer moisture meter;
the particle size distribution was determined by a malvern MS3000 particle sizer;
the angle of repose is determined according to GB 11986-89;
the flow factor is measured by a Memerorelix FT4 crystal rheometer according to the standard draft of the crystal flowability measurement guidelines issued by the national formulary Committee at month 12 of 2022;
the photomicrographs were determined by a biological microscope from the Shanghai national instruments, BM-44 X.9F.
According to the standard draft of the crystal flowability measurement guidelines issued by the national formulary committee at 2022, month 12, the repose angle is between 36 and 40 degrees, which shows that the flowability is better-no help is needed; the angle of repose is between 41-45 deg., indicating that flowability is still probable; the angle of repose is between 46-55 deg. indicating poor flowability, and must be agitated and vibrated.
According to the standard draft of the crystal flowability measurement guidelines issued by the national formulary committee at 2022, month 12, the Flowability Factor (FF) is greater than 10, which indicates good flowability and free flowability; the Flow Factor (FF) is 4-10, which indicates poor flowability, and only can flow; the Flow Factor (FF) was 2-4, indicating poor flowability and manifesting as sticking.
From the above experimental results, it can be seen that the sitagliptin phosphate monohydrate obtained in examples 1 to 4 is more matched with two main excipients anhydrous dicalcium phosphate, microcrystalline cellulose and better in fluidity, and the anhydrous dicalcium phosphate is spherical, so that more non-spherical microcrystalline cellulose is considered in view of flow suitability. The invention controls the growth and coalescence of crystals by controlling the proportion among sitagliptin phosphate, water and isopropanol and matching with a specific temperature raising and lowering process, thereby affecting the nucleation of the crystals and unexpectedly obtaining the specific crystals of the invention.
In example 7, however, the decrease in the cooling rate not only resulted in the change in the particle size distribution, angle of repose, flow factor, etc., but also prolonged the experimental time, resulting in a significant decrease in the production efficiency; in example 8, the rate of cooling was too fast and the moisture content of the resulting product was significantly reduced, suggesting that there was some non-seeding behavior of sitagliptin phosphate, i.e. the product tended to form anhydrous sitagliptin phosphate under the conditions described.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. A crystal of sitagliptin phosphate monohydrate, characterized in that, in the crystal,
sitagliptin phosphate monohydrate exists in crystalline form and has an XRPD pattern with diffraction peaks at 2θ as follows: 13.884 + -0.2 °, 15.0981 + -0.2 ° and 18.497 + -0.2 °; and is also provided with
The crystal has the following characteristics: d (50) is 112-115 μm, D (90) is 330-350 μm; the repose angle is 36-40 degrees; and a flow factor of 13.1-14.7.
2. The crystal of claim 1, wherein the crystal has a D (50) of 113-114 μm and a D (90) of 338-348 μm.
3. The crystal according to claim 1, wherein the angle of repose of the crystal is 37-38 °.
4. The crystal of claim 1, wherein the crystal has a flow factor of 13.4 to 14.3.
5. A pharmaceutical composition comprising:
the crystalline, anhydrous dibasic calcium phosphate, and microcrystalline cellulose of claim 1.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in the form of a tablet.
7. The pharmaceutical composition of claim 5, wherein the anhydrous dibasic calcium phosphate has the following characteristics: d (50): (138.5+ -3%) μm, D (90): (229+ -3%) μm, angle of repose of 37.1°+ -3% and flow factor of 201+ -3%; and is also provided with
The microcrystalline cellulose has the following characteristics: d (50): (115.+ -. 3%) μm, D (90): (236.+ -. 3%) μm, angle of repose of 38.5.+ -. 3%, and flow factor of 14.4.+ -. 3%.
8. A method for producing a crystal according to claim 1, comprising the steps of:
(1) Providing a mixture of sitagliptin phosphate, water and isopropanol;
in the mixture, the weight ratio of the sitagliptin phosphate to the water is 1: (1.4-1.9); the weight ratio of water to isopropanol is 1: (1.11-1.35);
(2) Heating the mixture to 55-79 ℃ for the first time under stirring to completely dissolve the solids;
(3) Cooling water is started, the temperature is reduced to 50-59 ℃, and after stirring is carried out for 20-40min, the temperature is continuously reduced to 3-10 ℃ with the cooling rate of 4-8 ℃/h;
(4) Heating to 35-45deg.C for the second time, dissolving part of the solid, maintaining the temperature for 20-40min, cooling to 3-10deg.C, cooling at 4-8deg.C/h, maintaining the temperature at 3-10deg.C, and stirring for 50-80min;
(5) Continuously repeating the step (4) for 7-14 times;
in the steps 1-5, the stirring speed is optionally 200-500r/min;
(6) Filtering and washing a filter cake; and
(7) And (3) drying under reduced pressure at 41-48 ℃ for 4-8h, wherein the vacuum degree is < -0.09Mpa in the reduced pressure drying process until the water content of the product is 3.3-3.55wt%, thereby obtaining the sitagliptin phosphate monohydrate crystal.
9. The method of claim 8, wherein in steps (1) to (5), the stirring speeds are the same.
10. Use of the crystal of claim 1 or the pharmaceutical composition of claim 5 for the preparation of a medicament for preventing or treating type 2 diabetes.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310383880.4A CN116082346A (en) | 2023-04-12 | 2023-04-12 | High-fluidity sitagliptin phosphate monohydrate crystal and preparation method thereof |
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| CN116459227A (en) * | 2023-05-11 | 2023-07-21 | 宙晟智维生命科学(上海)有限公司 | Sitagliptin tablet and preparation method thereof |
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