CN118141777A - Preparation method of hydroxychloroquine sulfate tablet - Google Patents
Preparation method of hydroxychloroquine sulfate tablet Download PDFInfo
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- CN118141777A CN118141777A CN202410566708.7A CN202410566708A CN118141777A CN 118141777 A CN118141777 A CN 118141777A CN 202410566708 A CN202410566708 A CN 202410566708A CN 118141777 A CN118141777 A CN 118141777A
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- ZAVJTSLIGAGALR-UHFFFAOYSA-N 2-(2,2,2-trifluoroacetyl)cyclooctan-1-one Chemical compound FC(F)(F)C(=O)C1CCCCCCC1=O ZAVJTSLIGAGALR-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960002927 hydroxychloroquine sulfate Drugs 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
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- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 5
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- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of hydroxychloroquine sulfate tablets, and belongs to the technical field of pharmaceutical preparations. The preparation method comprises mixing the raw materials, filler, disintegrating agent, binder and lubricant, tabletting, and coating; the particle size D90 of the raw material medicine is 300-360 mu m, and the method improves the fluidity of the raw material medicine by controlling the particle size of the raw material medicine, and has the advantages of simple process, good dissolution of the obtained hydroxychloroquine sulfate tablet, small batch-to-batch difference, stable quality, easy scale-up production and small corrosion to equipment.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of hydroxychloroquine sulfate tablets.
Background
Chloroquine is a medicine widely applied to resisting malaria and autoimmune diseases and has broad-spectrum antiviral effect. Has a role in inhibiting replication of dengue virus, zika virus, HIV and other viruses. In 2005, vincent et al found that chloroquine was effective in blocking SARS-Cov infection in cell lines. Hydroxychloroquine belongs to 4-aminoquinoline antimalarial and consists of two aromatic rings. The two are different in that one ethyl group in chloroquine is replaced by one hydroxyethyl group in hydroxychloroquine, so that the water solubility is increased, the absorption of the medicine in a human body is promoted, the distribution is wider, and the occurrence rate of adverse reactions is lower. The hydroxychloroquine has obviously reduced toxic and side effects compared with chloroquine while retaining the original chloroquine drug effect.
Hydroxychloroquine sulfate tablet (HCQ) was developed by the company cinnoliavanet, approved for sale in the united states in 1976 under the trade name Plaquenil. Early hydroxychloroquine sulfate is an antimalarial consisting of two aromatic rings belonging to the class of 4-aminoquinolines, one ethyl group of its chloroquine being replaced by one hydroxyethyl group. The therapeutic effect of hydroxychloroquine sulfate for the treatment of rheumatic diseases was confirmed with the use of antimalarial drugs in the treatment of Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) in the 50 s of the 20 th century. Hydroxychloroquine sulfate has unique action mechanism and better safety, is widely applied in the field of clinical rheumatism, and more than 90% of clinical rheumatism treatment adopts hydroxychloroquine sulfate after the 90 th century, so that the hydroxychloroquine sulfate is the basic medicament for treating rheumatoid arthritis and lupus erythematosus at present.
The hydroxychloroquine sulfate bulk drug is white or white-like crystalline powder, has a polycrystalline form and different crystal forms and has different hygroscopicity, and is easy to dissolve in water. Some crystal forms have extremely strong hygroscopicity, and the weight of the crystal forms is increased by 20% after being placed for 24 hours in a relative humidity environment of 75%. Hydroxychloroquine sulfate is easy to dissociate into hydroxychloroquine and sulfuric acid after absorbing water, and sulfuric acid has extremely strong corrosiveness to metal equipment, and the hygroscopicity and dissociability of hydroxychloroquine sulfate bring great challenges to preparation production; meanwhile, due to the high hygroscopicity of hydroxychloroquine sulfate bulk drugs, the hydroxychloroquine sulfate tablet is easy to form a ball by material agglomeration in the wet granulation process, the soft material granulation state is very uneven, the prepared particles are very uneven in size, and the dissolution curve difference in tablet batch is large.
The patent CN 113116840A adopts corn starch slurry as an adhesive for wet granulation, and the hygroscopicity and the dissociability of hydroxychloroquine sulfate are easy to cause rusting and welding death of a pot body and a stirring paddle of a wet granulator in the production process, thereby causing the 'locking' of the wet granulator and causing granulation failure; and the preparation process is complex. The patent CN102920674A carries out wet granulation pretreatment on the bulk drug through absolute ethyl alcohol, and solves the problem of locking of a wet granulator caused by the traditional wet granulation process, but the addition of the ethyl alcohol introduces residual solvent into a finished product, thereby increasing the detection and central control cost. CN102525969a proposes that buffer solution is added to carry out wet granulation, and the dissolution rate and stability of the preparation are both obviously improved, but the problems of different sizes of wet granulation granules and large inter-batch and intra-batch differences of the product are not solved yet.
In the prior art, wet granulation is mostly reported, and mixed powder direct compression is freshly reported, so that a mixed powder direct compression method capable of overcoming the technological difficulty brought by the strong hygroscopicity of hydroxychloroquine sulfate bulk drugs, reducing the difference between dissolution curves and in-batch, and improving the stability of the dissolution curves of hydroxychloroquine sulfate is required to be developed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for preparing hydroxychloroquine sulfate tablets by directly tabletting mixed powder. The hydroxychloroquine sulfate tablet disclosed by the invention has the advantages of simple preparation process, good dissolution, small batch-to-batch difference, stable quality, easiness in large-scale production, small corrosion to equipment and the like.
In order to achieve the above purpose, the following technical scheme is adopted:
a hydroxychloroquine sulfate tablet is prepared from raw materials, filler, disintegrant, adhesive and lubricant through mixing, granulating, tabletting and coating. The particle size D90 of the crude drug is 300-360 mu m, and the preparation method has simple process and is beneficial to mass production. In addition, the hydroxychloroquine sulfate tablet obtained by the preparation method has the advantages of good dissolution, small batch-to-batch difference, stable quality, easiness in large-scale production, small corrosion to equipment and the like, and has good commercial value.
The preparation method of hydroxychloroquine sulfate tablet specifically comprises the following steps:
(1) Weighing: weighing the raw materials and the auxiliary materials according to the formula amount;
(2) Premixing: adding the raw materials, filler, adhesive and disintegrating agent into a mixer, and uniformly mixing;
(3) Total mixing: uniformly mixing the materials obtained in the step (2) with a lubricant;
(4) Tabletting: tabletting the granules prepared in the step (3);
(5) Coating: and (3) preparing the tablet prepared in the step (4) into a coated tablet by using a gastric soluble coating material.
Wherein,
The bulk drug and the auxiliary materials in the step (1) comprise the following components in parts by weight: 66.67 parts of hydroxychloroquine sulfate, 26-31 parts of filler, 1-4 parts of disintegrating agent, 0.67-2.67 parts of adhesive and 0.67 part of lubricant.
In some specific embodiments, the drug substance hydroxychloroquine sulfate has a particle size D90 of 300-360 μm.
In some embodiments, the filler is selected from one or more of lactose, microcrystalline cellulose, and combinations thereof.
In some embodiments, the disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, and combinations thereof.
In some embodiments, the binder is one or more of povidone, hydroxypropyl cellulose, and combinations thereof.
In some embodiments, the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate.
The gastric soluble coating material is a coating material conventional in the art.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention obviously improves the dissolution and stability of the obtained hydroxychloroquine sulfate tablet by controlling the grain diameter D90 of the bulk drug to be 300-360 mu m.
(2) The preparation process is simple, easy to enlarge production and small in corrosion to equipment; the obtained hydroxychloroquine sulfate tablet has good dissolution, small batch-to-batch difference and stable quality.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the invention as it is claimed and many variations and modifications of the invention will be apparent to those skilled in the art in light of the disclosure, which should be construed to fall within the scope of the invention as claimed.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. 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.
The invention is further illustrated by means of the following specific examples. The various chemical reagents used in the examples of the present invention were obtained by conventional commercial means unless otherwise specified.
Example 1 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulfate (d90=308 μm), 10 parts lactose, 21 parts microcrystalline cellulose, 1 part crospovidone, and 0.67 parts povidone K25 are added to a mixer and mixed; then adding 0.67 parts of magnesium stearate into a mixer for total mixing, tabletting and coating.
Example 2 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulfate (d90=352 μm), 10 parts lactose, 21 parts microcrystalline cellulose, 1 part crospovidone, and 0.67 parts povidone K25 are added to a mixer and mixed; then adding 0.67 parts of magnesium stearate into a mixer for total mixing, tabletting and coating.
Example 3 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulfate (d90=317 μm), 30 parts microcrystalline cellulose, 2 parts crospovidone, and 0.67 parts povidone K25 are added to a mixer and mixed; then adding 0.67 parts of magnesium stearate into a mixer for total mixing, tabletting and coating.
Example 4 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulfate (d90=317 μm), 10 parts lactose, 21 parts microcrystalline cellulose, 1 part crospovidone, and 0.67 parts povidone K25 are added to a mixer and mixed; then adding 0.67 parts of sodium stearyl fumarate into a mixer for total mixing, tabletting and coating.
Example 5 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulfate (d90=317 μm), 10 parts lactose, 16 parts microcrystalline cellulose, 4 parts sodium carboxymethyl starch and 2.67 parts povidone K30 are added to a mixer and mixed; then adding 0.67 parts of magnesium stearate into a mixer for total mixing, tabletting and coating.
Example 6 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulfate (d90=317 μm), 10 parts lactose, 19.67 parts microcrystalline cellulose, 2 parts crospovidone, 1 part hydroxypropyl cellulose were added to the mixer and mixed; then adding 0.67 parts of magnesium stearate into a mixer for total mixing, tabletting and coating.
Comparative example 1 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulfate (d90=308 μm), 10 parts lactose, 21 parts microcrystalline cellulose, 1 part crospovidone, and 0.67 parts povidone K25 are added to a wet granulator and mixed; adding purified water into a granulator for granulating, drying a soft material by using a fluidized bed, stopping drying when the drying weight loss of the granules is below 2.0%, and granulating the dried granules by using a granulating machine; then adding 0.67 parts of magnesium stearate into a mixer for total mixing, tabletting and coating.
Comparative example 2 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulphate (d90=189 μm), 10 parts lactose, 21 parts microcrystalline cellulose, 1 part crospovidone and 0.67 parts povidone K25 are added to a wet granulator and mixed; adding purified water into a granulator for granulating, drying a soft material by using a fluidized bed, stopping drying when the drying weight loss of the granules is below 2.0%, and granulating the dried granules by using a granulating machine; then, 0.67 parts of magnesium stearate was added to the mixer for total mixing, and the mixture was tabletted.
In fact, in the tabletting process, the raw materials have large proportion and small particle size, so that the flowability and the compressibility of the materials after total mixing are poor, the tabletting is stopped, and the subsequent detection is not performed.
Comparative example 3 preparation method of hydroxychloroquine sulfate tablet
The method comprises the following steps:
66.67 parts hydroxychloroquine sulfate (d90=393 μm), 10 parts lactose, 21 parts microcrystalline cellulose, 1 part crospovidone, and 0.67 parts povidone K25 are added to a wet granulator and mixed; adding purified water into a granulator for granulating, drying a soft material by using a fluidized bed, stopping drying when the drying weight loss of the granules is below 2.0%, and granulating the dried granules by using a granulating machine; then 0.67 parts of magnesium stearate was added to the mixer for total mixing.
In fact, the materials are obviously layered after total mixing due to the overlarge particle size of the raw materials, and the uniformity of total mixing is not satisfactory, so that tabletting is not carried out.
Comparative example 4:
The preparation can be made into the solid form by using a commercial reference preparation.
The tablets obtained in examples 1 to 6 and comparative examples 1 and 4 were subjected to dissolution profile test, the test method was carried out by referring to the second method of dissolution rate and release rate measurement of four parts 0931 of the chinese pharmacopoeia, the dissolution rate was measured at 75rpm using dissolution medium as aqueous medium, the test results were shown in table 1, and the samples were placed under high humidity (25 ℃/75% rh) conditions for 10 days, and the test results were shown in table 2.
Table 1: examples 1 to 6 and comparative examples 1 and 4 were examined for elution of samples
Table 2: examples 1 to 6 and comparative examples 1 and 2 were subjected to high-humidity elution test
As can be seen from the above test results in tables 1 and 2, the use of the powder blend direct compression tablet (examples 1 to 6) can significantly improve the problem of large difference in RSD of the dissolution curves in the self-developed formulation lot compared with the use of wet granulation (comparative example 1) and the commercially available reference formulation (comparative example 4), and the stability of the self-developed formulation sample using the powder blend direct compression tablet is significantly better than that of the sample using the wet granulation during the stability period by the influence factor examination.
From the results of the tablets of examples 1 to 6, comparative example 2 and comparative example 3, it is understood that the hydroxychloroquine sulfate tablet which is simple in preparation process, good in dissolution, small in batch-to-batch difference, stable in quality, easy to scale-up and less corrosive to equipment is successfully prepared by controlling the particle size range of the crude drug, mixing the crude drug, the filler, the disintegrating agent, the binder and the lubricant together, then compressing the granules into tablets and coating.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. A preparation method of hydroxychloroquine sulfate tablets is characterized by comprising the following steps: the preparation method comprises mixing the raw materials, filler, disintegrating agent, binder and lubricant, tabletting, and coating; the grain diameter D90 of the bulk drug is 300-360 mu m.
2. The method of manufacturing according to claim 1, characterized in that: the filler is selected from one or more of lactose and microcrystalline cellulose.
3. The method of manufacturing according to claim 1, characterized in that: the filler is microcrystalline cellulose.
4. The method of manufacturing according to claim 1, characterized in that: the filler is a mixture of lactose and microcrystalline cellulose.
5. The method of manufacturing according to claim 1, characterized in that: the disintegrating agent is selected from one or a combination of more of crospovidone and sodium carboxymethyl starch.
6. The method of manufacturing according to claim 1, characterized in that: the adhesive is one or a combination of more of povidone and hydroxypropyl cellulose.
7. The method of manufacturing according to claim 1, characterized in that: the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate.
8. A process for the preparation of hydroxychloroquine sulphate tablets according to any one of claims 1 to 7, characterized in that: the method comprises the following steps:
(1) Weighing: weighing the raw materials and the auxiliary materials according to the formula amount;
(2) Premixing: adding the raw materials, filler, adhesive and disintegrating agent into a mixer, and uniformly mixing;
(3) Total mixing: uniformly mixing the materials obtained in the step (2) with a lubricant;
(4) Tabletting: tabletting the granules prepared in the step (3);
(5) Coating: and (3) preparing the tablet prepared in the step (4) into a coated tablet by using a gastric soluble coating material.
9. The method of manufacturing according to claim 8, wherein: the bulk drugs and auxiliary materials in the step (1) comprise the following components in parts by weight: 66.67 parts of hydroxychloroquine sulfate, 26-31 parts of filler, 1-4 parts of disintegrating agent, 0.67-2.67 parts of adhesive and 0.67 part of lubricant.
10. Hydroxychloroquine sulphate tablet prepared by the preparation method of any one of claims 1 to 9.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102349877A (en) * | 2011-10-24 | 2012-02-15 | 高戈 | Hydroxychloroquine sulfate capsule, hydroxychloroquine sulfate dispersible tablet and application thereof |
| RU2580656C1 (en) * | 2014-11-20 | 2016-04-10 | Закрытое Акционерное Общество "БИОКОМ" | Immediate-release solid dosage form of hydroxychloroquine and method for producing it |
| CN112494437A (en) * | 2019-10-21 | 2021-03-16 | 上海上药中西制药有限公司 | Hydroxychloroquine compound-containing pharmaceutical composition, tablet and preparation method thereof |
| CN113116840A (en) * | 2021-04-14 | 2021-07-16 | 福建海西新药创制有限公司 | Preparation method of hydroxychloroquine sulfate tablet |
-
2024
- 2024-05-09 CN CN202410566708.7A patent/CN118141777A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102349877A (en) * | 2011-10-24 | 2012-02-15 | 高戈 | Hydroxychloroquine sulfate capsule, hydroxychloroquine sulfate dispersible tablet and application thereof |
| RU2580656C1 (en) * | 2014-11-20 | 2016-04-10 | Закрытое Акционерное Общество "БИОКОМ" | Immediate-release solid dosage form of hydroxychloroquine and method for producing it |
| CN112494437A (en) * | 2019-10-21 | 2021-03-16 | 上海上药中西制药有限公司 | Hydroxychloroquine compound-containing pharmaceutical composition, tablet and preparation method thereof |
| CN113116840A (en) * | 2021-04-14 | 2021-07-16 | 福建海西新药创制有限公司 | Preparation method of hydroxychloroquine sulfate tablet |
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