CN115671074B - Lenvatinib mesylate preparation and preparation method thereof - Google Patents
Lenvatinib mesylate preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a lenvatinib mesylate preparation and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The invention relates to a lenvatinib mesylate preparation, which comprises the following components: and (3) lenvatinib mesylate, calcium carbonate, mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and talcum powder. The C crystal form in the lenvatinib mesylate accounts for 15-30wt% and the balance is amorphous. According to the invention, the content of the C crystal form in the lenvatinib mesylate in the preparation is controlled, so that the preparation has an optimal dissolution effect, the mass difference between batches is smaller, the requirement on the particle size of raw material medicine, namely the lenvatinib mesylate is lower, and when the particle size of the lenvatinib mesylate is D90 less than or equal to 40 mu m, the preparation of the lenvatinib mesylate with uniform particle size distribution, small loading difference and good dissolution effect can be obtained.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a lenvatinib mesylate preparation and a preparation method thereof.
Background
Lenvatinib (Lenvatinib), chemical name: 4- [ 3-chloro-4- (N' -cyclopropylureido) phenoxy ] -7-methoxyquinoline-6-carboxamide having the formula:
the product of the lamivtinib on the market is a lamivtinib mesylate capsule, the preparation is approved to be on the market by FDA in 2 months 2015, the raw material is a lamivtinib mesylate C crystal form, and the auxiliary materials are as follows: calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, and talc (FDA product instructions).
201080030508.6 (Publication No. CN 102470133A) discloses a preparation of lenvatinib mesylate and a preparation method thereof, wherein the preparation method comprises the steps of wet granulation, mixing of a C crystal form of the lenvatinib mesylate, mannitol, calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and microcrystalline cellulose, adding refined water, wet granulation, particle size of less than 1mm, and then adding microcrystalline cellulose and talcum powder, and uniformly mixing.
There are also several manufacturers applying for related patents of the lenvatinib mesylate formulation, such as: combination with meglumine and/or arginine (201510179868.7), combination with potassium and calcium salts (201510357763.6), combination with dibasic calcium phosphate (201610266697.6), combination with sodium carbonate and sodium bicarbonate (201811202967.2). But the dissolution effect of the finally prepared preparation is poor.
In addition, in the preparation process of the lenvatinib mesylate preparation, because the auxiliary materials contain alkaline substances, a wet granulation process is often used. After water is added, the lamivudine mesylate is hardened, and the phenomenon is mainly caused by that the lamivudine mesylate is agglomerated when meeting water and then gelled, and once hardening occurs, the content uniformity of the preparation is directly unqualified, so that the effectiveness of a product is affected.
Therefore, research and development of a novel lenvatinib mesylate preparation are needed to be carried out, so that the novel lenvatinib mesylate preparation has the advantages of uniform particle size distribution, small loading difference, good dissolution effect and stable and controllable preparation process.
Disclosure of Invention
In view of the above, the technical problem to be solved by the invention is to provide a lenvatinib mesylate preparation and a preparation method thereof. The preparation provided by the invention has the advantages of uniform particle size distribution, small loading difference and good dissolution effect.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides a lenvatinib mesylate preparation, which comprises the following components: and (3) lenvatinib mesylate, calcium carbonate, mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and talcum powder.
Preferably, the C crystal form of the lenvatinib mesylate in the preparation accounts for 15-30wt% of the total amount of the active ingredients, and the rest is amorphous.
The hydroxypropyl cellulose is short for high-substituted hydroxypropyl cellulose.
When the C crystal form of the lenvatinib mesylate accounts for 15-30wt% of the total amount of the active ingredients in the lenvatinib mesylate preparation, the preparation has the advantages of small loading difference and good dissolution effect.
Preferably, the particle size of the lenvatinib mesylate is D90 less than or equal to 40 mu m.
Preferably, the preparation comprises the following components in parts by weight: 5 parts of lenvatinib mesylate.
Preferably, the preparation further comprises 30-35 parts of calcium carbonate; more preferably, the calcium carbonate is 31 to 33 parts; it is further preferable that the calcium carbonate is 32 to 33 parts.
Preferably, the preparation further comprises 11-16 parts of mannitol; more preferably, the mannitol is 12-15 parts; further preferably, 13 to 14 parts of mannitol.
Preferably, the preparation further comprises 25-29 parts of low-substituted hydroxypropyl cellulose; more preferably, the low-substituted hydroxypropyl cellulose is 25-28 parts; further preferably, the low-substituted hydroxypropylcellulose is 26 to 28 parts.
Preferably, the preparation further comprises 2-6 parts of hydroxypropyl cellulose; more preferably, the hydroxypropyl cellulose is 2 to 5 parts; further preferably, the amount of hydroxypropyl cellulose is 3 to 4 parts.
Preferably, the preparation further comprises 10-17 parts of microcrystalline cellulose; more preferably, 13 to 17 parts of microcrystalline cellulose; further preferably, the microcrystalline cellulose is 13 to 15 parts.
Preferably, the preparation further comprises 1-5 parts of talcum powder; more preferably, the talcum powder is 2-4 parts.
In some embodiments of the invention, the formulation comprises, in parts by weight: 5 parts of lenvatinib mesylate, 30-35 parts of calcium carbonate, 11-16 parts of mannitol, 25-29 parts of low-substituted hydroxypropyl cellulose, 2-6 parts of hydroxypropyl cellulose, 10-17 parts of microcrystalline cellulose and 1-5 parts of talcum powder.
More preferably, the components of the preparation are as follows: 5 parts of lenvatinib mesylate, 31-33 parts of calcium carbonate, 12-15 parts of mannitol, 25-28 parts of low-substituted hydroxypropyl cellulose, 2-5 parts of hydroxypropyl cellulose, 13-17 parts of microcrystalline cellulose and 2-4 parts of talcum powder.
It is further preferable that 5 parts of lenvatinib mesylate, 32-33 parts of calcium carbonate, 13-14 parts of mannitol, 25-28 parts of low-substituted hydroxypropyl cellulose, 3-4 parts of hydroxypropyl cellulose, 13-15 parts of microcrystalline cellulose and 2-4 parts of talcum powder.
Preferably, the microcrystalline cellulose is a combination of microcrystalline cellulose PH101 and microcrystalline cellulose PH 102.
Preferably, the microcrystalline cellulose PH101 is contained in an amount of 5-10 parts in the preparation; more preferably 8 to 10 parts; further preferably 10 parts.
Preferably, the microcrystalline cellulose PH102 is 5-7 parts in the preparation; more preferably 5 parts.
In some embodiments of the invention, microcrystalline cellulose PH101 is present in an amount of 10 parts and microcrystalline cellulose PH102 is present in an amount of 5 parts.
In a specific example of the invention, 1 part represents 1g.
The invention also provides a preparation method of the lenvatinib mesylate preparation, which comprises the following steps:
1) Pulverizing the raw material drug of the lenvatinib mesylate C crystal form by air flow for later use;
2) Preparing an aqueous solution of hydroxypropyl cellulose;
3) Uniformly mixing the air-flow crushed lenvatinib mesylate with the hydroxypropyl cellulose aqueous solution to obtain a bulk drug suspension;
4) Mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose PH101 and calcium carbonate are added into a fluidized bed for preheating, and then the bulk drug suspension obtained in the step 3) is sprayed into the fluidized bed for granulating to obtain material particles;
5) Mixing the above material particles with microcrystalline cellulose PH102 and talcum powder, and encapsulating to obtain the lenvatinib mesylate preparation.
Preferably, the particle size of the lenvatinib mesylate obtained in the step 1) after the air current crushing is D90 less than or equal to 40 mu m; more preferably, the particle size of the lenvatinib mesylate is D90 less than or equal to 21 mu m.
Preferably, the pressure of the jet milling is 2.5-7.0 bar; more preferably 2.5 to 3.5bar. The pressure range can ensure that the particle size of the bulk drug obtained by jet milling is D90 less than or equal to 40 mu m.
In the invention, the raw material drug of the lenvatinib C crystal form is converted into amorphous form in the preparation process of the lenvatinib mesylate preparation, and the inventor discovers that the preparation has the best dissolution effect and smaller loading difference when the amount of the remaining lenvatinib C crystal form of the methanesulfonic acid in the preparation accounts for 15-30wt% of the total amount of the active ingredient of the lenvatinib mesylate by controlling the conversion amount of the crystal form.
According to the invention, the C crystal form of the raw material drug, namely the lenvatinib mesylate, is treated in a jet milling mode, and the grain size of the lenvatinib mesylate is controlled to be D90 less than or equal to 40 mu m.
If mechanical crushing, grinding and other modes are adopted to cause local overheating to exceed 190 ℃, the raw material drug, namely the lenvatinib mesylate, is decomposed into methanesulfonic acid and lenvatinib, so that the pungent smell of the methanesulfonic acid is generated, and the drug effect of the product is reduced. In addition, mechanical crushing or grinding and other modes can cause the C crystal form of the lenvatinib mesylate to be converted into amorphous form in the crushing stage, so that the content of the C crystal form of the active ingredient of the lenvatinib mesylate in the obtained final preparation product is mostly less than 15wt%, and the dissolution of the preparation is unstable. Compared with mechanical crushing, grinding and other schemes, the method has the advantages of simplicity and controllability, stronger process stability and more contribution to controlling the conversion of the crystalline form of the lenvatinib mesylate.
And then granulating by a fluidized bed to ensure that the C crystal form of the raw material drug, namely the lenvatinib mesylate, is converted into amorphous form, the quantity of the C crystal form is most stable, the residual quantity of the C crystal form can be kept between 15 and 30 weight percent, and the tolerance to the fluctuation of process parameters is best.
Preferably, the concentration of the hydroxypropyl cellulose aqueous solution in the step 2) is 3-7 wt%; more preferably, the concentration of the hydroxypropyl cellulose aqueous solution is 4wt% to 5wt%.
Preferably, the mixing in step 3) is high shear mixing.
When the lenvatinib mesylate is mixed with a binder solution (hydroxypropyl cellulose aqueous solution), a hardening phenomenon can occur, so that high-shear mixing is adopted, and the hardening phenomenon of the prepared bulk drug suspension is avoided, so that the effectiveness of the preparation is reduced.
Preferably, the preheating temperature in the step 4) is 45-55 ℃;
Preferably, the spraying speed of the bulk drug suspension in the step 4) into the fluidized bed is 120-150 g/min.
In the granulation process of the step 4), the air inlet temperature of the fluidized bed is preferably 65-75 ℃.
Preferably, in the granulating process, the air inlet quantity is 1500-2200 m 3/h.
Preferably, in the granulating process, the temperature of the materials is 30-42 ℃.
Preferably, in the granulating process, after the spraying of the bulk drug suspension is finished, sampling is carried out, and when the water content of the material is less than 1.2wt%, the material is continuously dried for 4-7 min and then stopped for discharging.
When the air inlet temperature of the fluidized bed is controlled to be 65-75 ℃, and the air inlet quantity is 1500-2200 m 3/h, the material temperature can be well controlled to be 30-42 ℃.
When the content of the active ingredient of the lenvatinib mesylate C crystal form in the final preparation is controlled, the temperature of the material is controlled to be maintained within the range of 30-42 ℃, the moisture content of the material and the subsequent drying time are important, and when the moisture content is more than 1.2wt%, the conversion of the lenvatinib mesylate C crystal form into amorphous form is caused to be less than 70wt%; whereas when the moisture content is equal to 1.2wt% and the drying time is too long, the amount of conversion of the crystalline form C of lenvatinib mesylate to amorphous may exceed 85wt%. And when the amount of conversion of form C into amorphous form is less than 70wt% or more than 85wt%, the dissolution effect of the preparation is poor.
Therefore, the water content of the selected materials is lower than 1.2 weight percent, the drying time is reduced, the C crystal form of the lenvatinib mesylate in the obtained preparation product is controlled to be 15 to 30 weight percent, and the rest is amorphous, so that the dissolution of the preparation is more stable.
By adopting the preparation method, the purpose of crystal transformation of the C crystal form of the lenvatinib mesylate can be achieved in the preparation process, and 70-85 wt% of the C crystal form of the lenvatinib mesylate can be controlled to be transformed into amorphous, so that the prepared preparation product has the following advantages:
1) The requirement on the particle size of the raw material drug of the lenvatinib mesylate is lower (the conventional wet granulation process needs to control the particle size D90 of the raw material drug below 10 mu m), the pretreatment process of the raw material drug is simpler, and the time and the energy consumption are less.
2) The particle size distribution is more uniform, the powder fluidity is better, the control of the loading difference is more facilitated, the quality uniformity of the preparation products can be ensured, and the quality difference among preparation batches is reduced. Is more beneficial to controlling the cost of the product and greatly improves the yield of the product.
3) The preparation product has good dissolution effect and good similarity with the original preparation.
Compared with the prior art, the lenvatinib mesylate preparation provided by the invention comprises the following components: and (3) lenvatinib mesylate, calcium carbonate, mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and talcum powder. The C crystal form in the lenvatinib mesylate accounts for 15-30wt% and the balance is amorphous. According to the invention, the content of the C crystal form in the lenvatinib mesylate in the preparation is controlled, so that the preparation has an optimal dissolution effect, the mass difference between batches is smaller, the requirement on the particle size of raw material medicine, namely the lenvatinib mesylate is lower, and when the particle size of the lenvatinib mesylate is D90 less than or equal to 40 mu m, the preparation of the lenvatinib mesylate with uniform particle size distribution, small loading difference and good dissolution effect can be obtained.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline form C of lenvatinib mesylate;
FIG. 2 is an X-ray powder diffraction pattern of blank particles without lenvatinib mesylate;
FIG. 3 is an X-ray powder diffraction pattern of the amorphous form of lenvatinib mesylate;
FIG. 4 is an X-ray powder diffraction pattern of an amorphous formulation of lenvatinib mesylate containing a indicated amount of 0.7% by weight;
FIG. 5 is a quantitative standard curve of the crystalline form C of lenvatinib mesylate in a formulation of lenvatinib;
Fig. 6 is a schematic diagram of the location of the quantitative characteristic peak of the crystalline form C of lenvatinib mesylate.
Detailed Description
In order to further illustrate the present invention, the following describes in detail the preparation method of the lenvatinib mesylate formulation provided by the present invention with reference to examples.
1. Particle size detection is carried out by adopting a laser particle sizer.
2. The PXRD detection method is as follows (the method exclusive for detecting the C crystal form content of the lamvastatin mesylate):
incident light path: selecting a divergence slit 1, a Soxhlet slit 0.03rad, a light shielding frame Mask18mm and an anti-scattering slit 4;
Diffraction light path: an anti-scatter slit P7.0; the voltage of the X-ray tube is 45kV, the current of the X-ray tube is 35mA, the scanning range is 16.5-18.5 degrees (2 theta), the step length is 0.03 degrees, and the scanning speed is 3.90 multiplied by 10 -4 degrees/s.
Examples 1 to 8
Preparation of lenvatinib mesylate capsules
1. The formulation compositions and particle size ranges of examples 1 to 4 are shown in tables 1 and 2.
Table 1 formulation compositions of examples 1 to 4
| Composition of the composition | Weight (g) |
| Crystal form C of lenvatinib mesylate | 5 |
| Calcium carbonate | 33 |
| Mannitol (mannitol) | 16 |
| Low substituted hydroxypropyl cellulose | 25 |
| Hydroxypropyl cellulose | 3 |
| Microcrystalline cellulose PH101 | 10 |
| Microcrystalline cellulose PH102 | 5 |
| Talc powder | 3 |
| Totals to | 100 |
Table 2 particle size of examples 1 to 4
2. The formulation compositions and particle size ranges for examples 5-8 are shown in Table 3.
Table 3 formulation compositions and particle size of examples 5 to 8
3. The preparation method comprises the following steps:
1) Pretreatment of raw material medicines: the raw material drug, crystalline form C of lenvatinib mesylate was crushed using a jet mill at a crushing pressure of 2.5bar, with the particle size as required in examples 1 to 8.
2) Weighing: raw and auxiliary materials are weighed according to the formula proportion listed in examples 1-8 for standby.
3) Preparing a bulk drug suspension: the preparation method comprises the steps of dissolving hydroxypropyl cellulose in the formula amount in purified water to prepare an aqueous solution with the concentration of 4wt%, slowly adding the crushed crude drug into the hydroxypropyl cellulose solution in a stirring state, and uniformly dispersing the crude drug into an adhesive solution by using an HM-H020 type high-shear stirrer at the rotating speed of 2000 rpm.
4) Granulating in one step: mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose (PH 101) and calcium carbonate are added into a fluidized bed, a fan is started to enable materials to flow and mix in the fluidized bed, meanwhile, a pot body is preheated to 50 ℃, then a top spraying mode is adopted, a peristaltic pump liquid feeding mode is adopted, the spraying speed of the bulk drug suspension is controlled within the range of 120-150 g/min, and the bulk drug suspension is sprayed into the fluidized bed to be granulated with other auxiliary materials in one step, so that material particles are obtained. The granulating process needs to keep the suspension of the raw materials in a stirring state, and meanwhile, the air inlet temperature of the fluidized bed is controlled within the range of 65-75 ℃ and the air inlet quantity is controlled within the range of 1500-2200 m 3/h, so that the temperature of the materials is maintained within the range of 30-42 ℃; after the spraying of the bulk drug suspension is finished, sampling is carried out to measure the water content of the material, and when the water content of the material is 0.7wt% -1.1wt%, the material is continuously dried for 5 minutes and is stopped for discharging.
5) Total mixing: adding the granulated granules, microcrystalline cellulose (PH 102) and talcum powder into a hopper mixer, and mixing for 10min at a rotating speed of 15 rpm.
Filling: the total mixed material is filled into a No. 4 hydroxypropyl methylcellulose capsule according to the filling amount of 100mg, and the preparation is obtained.
And (3) packaging: and (5) double-aluminum packaging is carried out on the capsules by adopting aluminum foil and cold aluminum.
Comparative examples 1 to 4
Preparation of lenvatinib mesylate capsules
1. Capsules were prepared using the formulation and process of example 2 of the original developer patent (201080030508.6) as the formulation of comparative examples 1-4 of this patent. The formulation composition is shown in Table 1, and the particle size ranges are the same as those of examples 1 to 4, and are shown in Table 4.
2. Particle size: see Table 4
Table 4 particle diameters of raw materials of comparative examples 1 to 4
( The raw materials of comparative examples 1 to 4 were the same as the raw material batches used in examples 1 to 4, respectively, and thus the particle diameters were the same; comparative example 3 was similar to the raw material batches used in examples 5 to 8, and had the same particle size. )
3. The preparation process comprises the following steps:
1) Pretreatment: the raw material drug, namely the C crystal form of the lenvatinib mesylate, is subjected to jet milling, and the particle size after milling is shown in Table 4 for later use.
2) Premixing: according to Table 1, the formulated amounts of calcium carbonate, lenvatinib mesylate, mannitol, low-substituted hydroxypropylcellulose, microcrystalline cellulose (pH 101) were sequentially fed into a wet granulator, and mixed for 15 minutes at a stirring speed of 600rpm and a cutter of 1500 rpm.
3) Granulating: the hydroxypropyl cellulose was weighed according to the formula amount and prepared into a binder solution with water, and the binder solution was added to a pan at a stirring speed of 800rpm and a cutter speed of 2000rpm in a wet mixing granulator to prepare wet granules.
4) And (3) drying: preheating the fluidized bed pan body, adding wet particles into the pan when the temperature reaches 50 ℃, drying, and granulating by using a mobile granulator with a circular screen mesh to obtain dry particles.
5) Total mixing: the dry granules, microcrystalline cellulose (pH 102) and talc were added to a hopper mixer and mixed for 15 minutes at a mixing speed of 15 rpm.
6) Filling the capsule: and filling according to the target filling amount of the capsule to obtain the lenvatinib mesylate capsule.
Comparative example 5
Preparation of lenvatinib mesylate capsules
1. The formulation is shown in Table 1;
2. the preparation method is the same as in example 1, except that: and stopping discharging when the water content of the material in the fluidized bed is 1.5 wt%.
Comparative example 6
Preparation of lenvatinib mesylate capsules
1. The formulation is shown in Table 1;
2. the preparation method is the same as in example 1, except that: when the moisture of the material in the fluidized bed was 1.2wt%, and the prolonged drying time was 8min.
The formulations prepared in examples 1 to 8 and comparative examples 1 to 6 were tested for the difference in the amount of the formulation, the content of the C-form, and the dissolution profile, and the experimental results were as follows:
1. Difference in loading
1. Sample: the formulations provided in examples 1 to 8 and comparative examples 1 to 6.
2. Detection method
And (3) detecting by referring to the "difference in filling amount" under the examination item of the capsule of the four-part rule 0103 in the edition 2020 of Chinese pharmacopoeia.
3. Detection result: see tables 5-1, 5-2, 5-3
TABLE 5-1 load variation check
| Sample of | Example 1 | Example 2 | Example 3 | Example 4 |
| Difference in loading | -3.1％～+3.9％ | -2.4％～+3.1％ | -2.8％～+3.5％ | -2.2％～+2.9％ |
TABLE 5-2 load variation check
| Sample of | Example 5 | Example 6 | Example 7 | Example 8 |
| Difference in loading | -2.7％～+3.4％ | -2.5％～+3.7％ | -3.3％～+2.5％ | -2.7％～+2.9％ |
TABLE 5-3 load variation check
The results in tables 5-1, 5-2 and 5-3 show that the preparation samples (examples 1-8 and comparative examples 5-6) obtained by the one-step granulating process have less than +/-5% of loading difference, meet the quality requirements of the preparation, and have relatively high product yield with the weight meeting the requirements. The preparation samples (comparative examples 1-4) obtained by the conventional wet granulation process have large loading differences of more than +/-5%, and the quality of the preparation can be ensured to meet the requirements only by weight sorting.
2. C crystal form content detection in lenvatinib mesylate preparation
1. Sample: the formulations provided in examples 1 to 8 and comparative examples 1 to 6.
2. C crystal form content detection method
1) Standard spectrum: the C crystal form of the lenvatinib mesylate is measured by a powder X-ray diffractometer (PXRD) to obtain the XRD pattern of the C crystal form (see figure 1).
2) Establishment of a standard curve:
The method was developed with 0.7wt% (corresponding to 14.0wt% of the labeled amount of the preparation) as the limit of the amount of the present quantitative method. (the labeled amount is the content of the active ingredient in the preparation, the active ingredient in the application is 5g, accounting for 0.7wt% of the preparation)
Preparing a physical mixed sample with the blank auxiliary material and the C crystal form content of about 0.7wt% to 15wt% as a standard substance, determining a C crystal form characteristic diffraction peak in the sample according to a four 0451X-ray diffraction method of the 2020 edition of Chinese pharmacopoeia, taking the average peak height as an independent variable and the concentration of the C crystal form as a strain quantity, and establishing a linear model (see figure 5).
3) Establishment of characteristic diffraction peaks for quantification:
A. x-ray powder diffraction pattern of blank particles:
the blank particles (blank particles prepared according to the method of example 1) without lenvatinib mesylate were tested with PXRD to give a profile (see fig. 2);
B. an amorphous X-ray powder diffraction pattern of lenvatinib mesylate (see fig. 3);
C. Amorphous preparation of lenvatinib mesylate containing an indicated amount of 0.7% by weight, the X-ray powder diffraction pattern of which was determined (see FIG. 4)
D. Comparing fig. 2 with fig. 1, see fig. 6, 3 strong diffraction peaks of the C crystal form are obtained, namely, the regions (2 Theta) respectively located at 5.5-6.5 °, 16.5-18.5 ° and 19.5-20.3 °, and the three regions are shown by arrows in fig. 6.
E. comparing the figures 1, 3 and 4, the peak intensity of C-crystal form pranlukast mesylate within the interval of 16.5-18.5 degrees is highest and is not interfered by auxiliary materials after the peak within the interval is eliminated due to the auxiliary material peak interference of 19.5-20.3 degrees.
In summary, a 17.7 ° diffraction peak was selected as a characteristic diffraction peak for quantitative determination of crystalline form C of lenvatinib mesylate, as shown in fig. 6.
4) Content detection: the formulations of comparative examples 1 to 4 and examples 1 to 8 were each subjected to X-ray diffraction detection, and the measured peak heights were substituted into a linear model (standard curve see fig. 5), thereby obtaining the content of form C in the formulations.
3. Detection result: see Table 6-1, 6-2
Table 6-1 content of form C in example samples (in terms of labeled amount 100 wt.%)
Table 6-2 comparative sample contains form C (in terms of labeled amount of 100 wt.%)
| Sample of | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | Comparative example 6 |
| C crystal form content | 67.35％ | 33.47％ | 51.90％ | 14.46％ | 35.73％ | 14.18％ |
The results show that:
In the examples 1-8 of the one-step granulation method, when the grain diameter D90 of the bulk drug is smaller than 40 mu m, the moisture of the material is smaller than 1.2wt% and then the material is dried for 5 minutes, and the content of the C crystal form in the prepared preparation can be stably maintained at 15-30 wt% of the marked amount of the preparation.
The content difference of the C crystal forms of comparative examples 5-6 is still larger by adopting the method of the invention, and the comparative data show that when the water content of the material in the fluidized bed is more than 1.2wt%, the material is stopped to be discharged, so that the C crystal form of the raw material medicine is converted into an amorphous form with less than 70wt%; when the water content of the material in the fluidized bed is equal to 1.2wt%, and the prolonged drying time is more than or equal to 8min, the material is stopped for discharging, so that the conversion of the crystal form C of the bulk drug into amorphous form exceeds 85wt%.
However, the content of form C in comparative examples 1 to 4 varies greatly, and the content of form C in the sample obtained by conventional wet granulation exceeds the range of 15 to 30% by weight.
3. Dissolution curve detection in lenvatinib mesylate preparation
1. Sample: examples 1 to 8 and comparative examples 1 to 6, and commercially available products (lenvima, lot number: 132946).
2. Detection method
The dissolution rate and the release rate were measured by the dissolution rate measurement method (second method of the fourth edition of the chinese pharmacopoeia 2020 edition, rule 0931). The key medium elution conditions are shown in Table 7, and the chromatographic conditions are shown in Table 8.
TABLE 7 dissolution profile determination method
| Dissolution medium | Experimental conditions | Time of investigation (min) |
| pH4.0 | 75r/min | 10、15、30、60 |
| Water-1.0% Tween 80 | 75r/min | 10、30、60、120、240 |
Table 8 dissolution HPLC detection chromatographic conditions
| Chromatographic column | YMC-Pack Pro C18 (75X 4.6mm,3 μm) |
| Mobile phase | Water-acetonitrile-perchloric acid (70%) (800:200:1) |
| Flow rate | 1.0mL/min |
| Detection wavelength | 252nm |
| Chromatographic column temperature | 35℃ |
| Sample injection volume | 10μL |
| Acquisition time | 8min |
Test solution: and precisely measuring 10mL of the dissolution liquid at each sampling time point, filtering, and taking the subsequent filtrate as a sample solution.
Control solution: and diluting the lenvatinib mesylate reference substance with a dissolution medium to prepare a solution containing about 4.4 mug of the lenvatinib mesylate in each 1mL, and shaking uniformly.
3. Detection result
The elution profile measurement data of examples 1 to 8, comparative examples 1 to 6 and commercially available products (raw preparation) in water and pH4.0 medium are shown in tables 9, 10 and 11, respectively.
Table 9 data for elution profile measurements for examples 1 to 8
Table 10 comparative examples 1 to 6 dissolution profile measurement data
TABLE 11 dissolution profile data for crude preparation
4. Analysis and discussion
Through the combination of the dissolution detection result and the C crystal form content detection result in the lenvatinib mesylate preparation, the C crystal form conversion ratio of the samples of examples 1 to 8 is in the range of 15 to 30 weight percent, and the dissolution curves in two key dissolution media of water and pH4.0 are similar to those of the original preparation. Under the condition of controlling the moisture and the drying time at the drying end point, the adjustment of the air inlet temperature in the granulating process within the range of 65+/-5 ℃ can not cause obvious influence on the content and the dissolution of the C crystal form in the preparation.
The ratio of the bulk drugs of the C crystal form in the preparations of comparative examples 1 to 4 is not equal to 14 to 68 weight percent, the dissolution result is dissimilar to that of the original preparation, and the dissolution result is greatly influenced by the conversion of the C crystal form into the amorphous form. The ratio of the C crystal form bulk drug in the comparative examples 5 to 6 adopting one-step granulation is respectively more than 30 weight percent and less than 15 weight percent, and the dissolution result is dissimilar to that of the original grinding preparation, thus further proving that the dissolution result is greatly influenced by the conversion of the C crystal form into the amorphous form.
From the above, the preparation method of the invention has the advantages of good process robustness and parameter durability, less time consumption and lower energy consumption, and is beneficial to reducing the production cost of the preparation product and ensuring the stable quality of the product.
The dissolution curves of the lenvatinib mesylate preparation prepared by the method are measured in two key dissolution media of water and pH4.0, and the results show that the dissolution curves of the samples of comparative examples 1-4 are dissimilar to those of the original preparation. Reviewing the formulation and process, the main differences found for the 4 comparative examples were: 1) The particle sizes D90 of the raw materials are different; 2) The adding time and shearing time of the adhesive solution have slight fluctuation in the granulating process of the four groups of formulas; 3) There is a certain difference in the drying time of the wet granules. Therefore, under the condition that the grain size of the bulk drug and the process operation are not strictly controlled, when the conventional wet granulation process is used for preparing the lenvatinib mesylate preparation, the dissolution condition of the sample is extremely easily affected by the fluctuation of process parameters, and the process robustness and the parameter durability are poor.
In summary, the preparation method of the invention adopts jet milling to control the grain diameter of the raw material drug of the lenvatinib mesylate to be less than or equal to 40 mu m, and then the raw material drug is granulated by a fluidized bed in one step, so that the requirements on the grain diameter range of the raw material drug are wider, the process robustness and the controllability are better, and the dissolution condition of the obtained preparation product is more similar to that of a reference preparation.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (6)
1. The lenvatinib mesylate preparation is characterized by comprising the following components in parts by weight: 5 parts of lenvatinib mesylate, 30-35 parts of calcium carbonate, 11-16 parts of mannitol, 25-29 parts of low-substituted hydroxypropyl cellulose, 2-6 parts of high-substituted hydroxypropyl cellulose, 10-17 parts of microcrystalline cellulose and 1-5 parts of talcum powder;
The C crystal form of the lenvatinib mesylate in the preparation accounts for 15 wt-30 wt%, and the rest is amorphous;
It is prepared by the following method:
1) Pulverizing the raw material drug of the lenvatinib mesylate C crystal form by air flow for later use;
2) Preparing a high-substituted hydroxypropyl cellulose aqueous solution with the concentration of 3 wt% -7: 7 wt%;
3) Uniformly mixing the air-flow crushed lenvatinib mesylate with the high-substituted hydroxypropyl cellulose aqueous solution to obtain an original drug suspension;
4) Adding mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose PH101 and calcium carbonate into a fluidized bed for preheating, wherein the preheating temperature is 45-55 ℃, spraying the crude drug suspension obtained in the step 3) into the fluidized bed, and granulating to obtain material particles;
When granulating: the air inlet temperature of the fluidized bed is 65-75 ℃;
the air inlet quantity is 1500-2200 m/h;
The temperature of the materials is 30-42 ℃;
In the granulating process, after spraying of the bulk drug suspension, sampling and measuring that the water content of the material is less than 1.2 wt%, continuously drying for 4-7 min, and stopping discharging;
5) Mixing the above material particles with microcrystalline cellulose PH102 and talcum powder, and encapsulating to obtain the lenvatinib mesylate preparation.
2. The formulation of lenvatinib mesylate according to claim 1, characterized in that the microcrystalline cellulose is a combination of microcrystalline cellulose PH101 and microcrystalline cellulose PH 102;
The microcrystalline cellulose PH101 and the microcrystalline cellulose PH102 are respectively 5-10 parts and 5-7 parts in the preparation.
3. A method for preparing a lenvatinib mesylate formulation according to any one of claims 1-2, comprising the steps of:
1) Pulverizing the raw material drug of the lenvatinib mesylate C crystal form by air flow for later use;
2) Preparing a high-substituted hydroxypropyl cellulose aqueous solution with the concentration of 3 wt% -7: 7 wt%;
3) Uniformly mixing the air-flow crushed lenvatinib mesylate with the high-substituted hydroxypropyl cellulose aqueous solution to obtain an original drug suspension;
4) Mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose PH101 and calcium carbonate are added into a fluidized bed for preheating, the preheating temperature is 45-55 ℃, then the crude drug suspension obtained in the step 3) is sprayed into the fluidized bed for granulating, material particles are obtained,
The conditions during granulation are as follows: the air inlet temperature of the fluidized bed is 65-75 ℃;
the air inlet quantity is 1500-2200 m/h;
The temperature of the materials is 30-42 ℃;
In the granulating process, after spraying of the bulk drug suspension, sampling and measuring that the water content of the material is less than 1.2 wt%, continuously drying for 4-7 min, and stopping discharging;
5) Mixing the above material particles with microcrystalline cellulose PH102 and talcum powder, and encapsulating to obtain the lenvatinib mesylate preparation.
4. A process for the preparation of a formulation of lenvatinib mesylate according to claim 3, wherein the particle size of the as-jet milled lenvatinib mesylate in step 1) is d90.ltoreq.40 μm;
the pressure of the jet milling is 2.5-7.0 bar.
5. A process for the preparation of a formulation of lenvatinib mesylate according to claim 3, wherein the mixing in step 3) is a high shear mixing.
6. The method for preparing a lenvatinib mesylate preparation according to claim 3, wherein the spraying speed of the crude drug suspension in the step 4) into the fluidized bed is 120-150 g/min.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102470133A (en) * | 2009-08-19 | 2012-05-23 | 卫材R&D管理有限公司 | Pharmaceutical compositions containing quinoline derivatives |
| CN113831283A (en) * | 2021-11-04 | 2021-12-24 | 南京科默生物医药有限公司 | Preparation method of amorphous matter of Ranuncutinib salt |
| CN114632067A (en) * | 2020-12-15 | 2022-06-17 | 重庆药友制药有限责任公司 | Lovatinib pharmaceutical composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102470133A (en) * | 2009-08-19 | 2012-05-23 | 卫材R&D管理有限公司 | Pharmaceutical compositions containing quinoline derivatives |
| CN114632067A (en) * | 2020-12-15 | 2022-06-17 | 重庆药友制药有限责任公司 | Lovatinib pharmaceutical composition and preparation method thereof |
| CN113831283A (en) * | 2021-11-04 | 2021-12-24 | 南京科默生物医药有限公司 | Preparation method of amorphous matter of Ranuncutinib salt |
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