CN114105994A - Preparation method of allopurinol - Google Patents
Preparation method of allopurinol Download PDFInfo
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- CN114105994A CN114105994A CN202111358964.XA CN202111358964A CN114105994A CN 114105994 A CN114105994 A CN 114105994A CN 202111358964 A CN202111358964 A CN 202111358964A CN 114105994 A CN114105994 A CN 114105994A
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- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 229960003459 allopurinol Drugs 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001694 spray drying Methods 0.000 claims abstract description 9
- 239000003463 adsorbent Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000012467 final product Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 28
- 238000004090 dissolution Methods 0.000 claims description 16
- 239000000843 powder Substances 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000007670 refining Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 claims description 2
- 229940102253 isopropanolamine Drugs 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- NGPZWOOKVNRELB-UHFFFAOYSA-N ethane-1,2-diol;methanol Chemical compound OC.OCCO NGPZWOOKVNRELB-UHFFFAOYSA-N 0.000 claims 1
- 239000006199 nebulizer Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 20
- 238000000746 purification Methods 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000004965 Silica aerogel Substances 0.000 description 7
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 7
- 229940116269 uric acid Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010046337 Urate nephropathy Diseases 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
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- 238000005406 washing Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010093894 Xanthine oxidase Proteins 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009690 centrifugal atomisation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides an allopurinol preparation process, which comprises the steps of placing a crude allopurinol product in one or more organic solvents, and dissolving the crude allopurinol product; adding water mixed with adsorbent, and filtering; spray drying to obtain the final product; the organic solvent is selected from ethanol, isopropanol, N-dimethylformamide, 1-methyl-2-pyrrolidone and/or dimethyl sulfoxide.
Description
Technical Field
The invention relates to the field of preparation methods of allopurinol, in particular to allopurinol powder with improved performance obtained by refining.
Background
Allopurinol has the chemical name of 1H-pyrazolo [3.4-d ] pyrimidine-4 alcohol and the molecular weight of 136.11. Allopurinol (Allopurinol) and its metabolite can inhibit xanthine oxidase, prevent hypoxanthine and xanthine from being converted into uric acid, reduce uric acid synthesis, reduce uric acid concentration in blood, reduce deposition of urate on bone, joint and kidney, and inhibit uric acid synthesis. The product can inhibit the activity of liver drug enzyme. The clinical application is: 1. primary and secondary hyperuricemia, especially hyperuricemia with overproduction of uric acid, also for renal insufficiency; 2. can be used for treating gout, and is suitable for patients with recurrent or chronic gout. Can be used for treating gouty nephropathy, and can relieve symptoms and reduce formation of uric acid calculus in kidney; 3. tophus; 4. can be used for treating uric acid renal calculus and/or uric acid nephropathy. The synthetic route is shown in FIG. 3.
CN103965197 discloses a preparation method of allopurinol crystal, adding allopurinol seed crystal into allopurinol alkaline solution, acidifying, precipitating crystal, the obtained crystal is large, has better fluidity, and is easy to tabletting, the method needs to add seed crystal, has higher requirement on acidifying dropping speed, does not belong to simple solvent refining method, is complicated to operate, causes more irregular crystallization, is difficult to control uniformity, and has poor solubility and bioavailability.
At present, the water or ethanol is adopted for dissolution and refining, but the solubility is extremely low, a large amount of solvent is required for hot melting and decoloring, and a large amount of cooling water is required for cooling and crystallizing.
CN103896944 discloses an allopurinol purification method, which comprises heating and dissolving an organic solvent, decolorizing, cooling and crystallizing, separating, washing and purifying to obtain high-purity allopurinol crystal. However, the decoloring time and the crystallization time are too long, the efficiency is low, and as a crystallization product, the supersaturation thereof results in no improvement in the solubility and bioavailability of allopurinol.
Allopurinol has poor water solubility, and low dissolution rate not only causes the reduction of bioavailability, but also causes larger individual pharmacokinetic difference, and dose and side effect control are difficult to determine in the process of pharmacy and medication. In the prior art, the method for transforming the compound into salt or co-crystallizing the compound with other medicines is used for increasing the medicine dissolution, so that not only are the fussy transformation steps increased, but also the medicine effect structure of the product is easy to damage in the transformation process.
In conclusion, in the purification and refining in the prior art, heating is needed to promote dissolution, and then cooling and crystallization are carried out, or acid and alkali are added for dropwise adding operation; the method has the advantages of complicated steps, easy reduction of yield in high-temperature or acid-base environments, damage to a compound structure to generate byproducts, long time consumption in the operation process, different crystal performances and no improved solubility improvement.
Disclosure of Invention
In view of the defects of the prior art, the invention provides an allopurinol purification product which is simple in process, high in yield and directly used for medicament preparation by repeatedly testing and continuously searching by adopting a plurality of organic solvents.
By changing the purification process, the method adopts cosolvent, adds silica aerogel micropowder and combines a drying method to obtain purer allopurinol powder with improved solubility on the basis of not changing the chemical structure, and can directly prepare an allopurinol liquid solid preparation.
The allopurinol powder obtained by the invention is in an amorphous state, has better bioavailability than allopurinol crystals, and has obviously improved solubility.
The present invention also finds a novel application for the silica aerogel, improving yield and simplifying the heating, cooling and decolorizing steps in the purification process of allopurinol.
The invention uses a spray drying method, the spray head uses a piezoelectric technology, preferably ultrasonic waves are carried, organic solvent and water are effectively separated in the centrifugal process, the obtained product has uniform and loose particle size, the purified product can be directly used as pharmaceutical raw materials, and the product has good compressibility and fluidity.
The method comprises the following specific steps:
putting the crude allopurinol in one or more organic solvents, and dissolving the crude allopurinol; adding water mixed with adsorbent, and filtering; spray drying to obtain the final product; the organic solvent is selected from ethanol, isopropanol, ethylene glycol, methanol, isopropanolamine, N, N-dimethylformamide, 1-methyl-2-pyrrolidone and/or dimethyl sulfoxide.
The mass ratio of the crude allopurinol to the organic solvent is 1: 2 to 16; preferably 1: 4-5; the weight ratio of the organic solvent to the adsorbent is 50-500: 1, preferably 50 to 400: 1, more preferably 180-: 1.
the organic solvent is preferably multi-solvent blending, more preferably isopropanol/N, N-dimethylformamide blending solvent, and the mass ratio of 1-2: 3-8, preferably 1: 2.5-3;
the adsorbent is silicon dioxide gas-condensing agent micro powder, and the mass ratio of the adsorbent to water is 1: 800-: 1000-4000, more preferably 1: 2000-3000;
stirring at room temperature for dissolution, or heating at low temperature below 100 deg.C for promoting dissolution; or room temperature ultrasonic method, wherein the ultrasonic treatment is performed by Branson digital ultrasonic instrument with frequency of 20-50KHZ and power of 150W.
Preferably, the spray drying is carried out by using an ion ultrasonic spray instrument, and the high-speed centrifugal atomizer is provided with an ultrasonic atomization nozzle. The inlet air temperature is controlled between 160 ℃ and 250 ℃, and the outlet air temperature is controlled between 140 ℃ and 180 ℃.
The silica aerogel is mainly used in the fields of heat insulation, electric light transmission and the like, and the silica aerogel adopted by the invention is originally used for heat preservation, and the dissolving efficiency is improved in the heating and dissolving process, but the silica aerogel is unexpectedly found to simplify the purification process and adsorb impurities in the using process, and the selection of the temperature becomes an unnecessary condition.
The allopurinol powder obtained by purification is in an amorphous state, the purity is more than or equal to 99.8 percent, and the content of single impurities is less than 0.01 percent.
Compared with the existing purification method, the purification process of the invention determines the purity and the characteristics of allopurinol, not only simplifies the crystallization process, but also simplifies the decoloring and high-temperature steps by adding the silica aerogel, so that the product is refined and purified under relatively stable conditions, the yield and the purification degree are increased, and the obtained product has better industrial practicability. The method is different from the conventional refining method of single solvent or non-solvent precipitation and high-temperature dissolution and low-temperature crystallization, and a purified product is obtained by using a cosolvent and a decolorizing agent under the stable temperature state.
Drawings
FIG. 1: allopurinol product and impurity mass spectrometric detection (MS).
FIG. 2: and (3) detecting the spectrum of allopurinol product powder.
FIG. 3: synthetic roadmaps in the background art.
These general terms used in the present specification adopt the following definitions, whether appearing alone or in combination. It is noted that, unless the context indicates otherwise, the word "the" is used in this specification and the appended claims to include the plural forms. The invention dissolves crude products by multiple solvents, blends a plurality of organic solvents, and the dissolution and blending include but are not limited to suspension or miscible state; the amorphous state is not a crystalline state.
Detailed Description
Example 1:
the crude allopurinol product is put into various organic solvents to study the dissolution and precipitation state, and is specifically shown in table 1:
example 2:
taking 100g of crude allopurinol, putting the crude allopurinol in a mixed solvent of 400g of isopropanol/N, N-dimethylformamide, and stirring overnight at room temperature to dissolve the allopurinol; or using ultrasonic method at room temperature to accelerate dissolution (ultrasonic wave is performed by Branson digital ultrasonic instrument, frequency is 20-50KHZ, and power is 150W); the weight ratio of isopropanol to N, N-dimethylformamide is 1: 3;
adding 2g of silica aerogel micropowder into 4kg of water to obtain micropowder-water mixed solution, slowly adding the organic mixed solution dissolved with the crude allopurinol into the micropowder-water mixed solution in batches (the dropping speed is 10 ml/min-100 ml/min), and stirring while dropping; after the dropwise addition is finished, continuously stirring until turbidity just appears, and standing overnight; separating the upper gel layer, filtering the precipitate, adding water for cleaning, performing spray drying by using an ion ultrasonic spray instrument, and performing spray drying by using a centrifugal atomizer with an ultrasonic spray nozzle at the temperature of 160-202 ℃. The obtained powder is detected to be amorphous allopurinol powder, the purity is 99.8% (HPLC), the content of single impurity is less than 0.01%, and the detection result is shown in figure 1/figure 2.
Example 3:
taking 100g of crude allopurinol, putting the crude allopurinol in a mixed solvent of 400g of isopropanol/N, N-dimethylformamide, and stirring overnight at room temperature to dissolve the allopurinol; or using ultrasonic method at room temperature to accelerate dissolution (ultrasonic wave is performed by Branson digital ultrasonic instrument, frequency is 20-50KHZ, and power is 150W); the weight ratio of isopropanol to N, N-dimethylformamide is 1: 3;
slowly adding the organic mixed solution dissolved with the crude allopurinol into purified water in batches (the dropping speed is 10 ml/min-100 ml/min), and stirring while dropping; no precipitation was observed.
Example 4:
taking 100g of crude allopurinol, putting the crude allopurinol in a mixed solvent of 400g of isopropanol/N, N-dimethylformamide, heating to 150 ℃, and dissolving the crude allopurinol; the weight ratio of isopropanol to N, N-dimethylformamide is 1: 3; adding 4kg of purified water into an organic solvent, adding activated carbon for decolorization, rapidly cooling to room temperature, separating out a precipitate, filtering the precipitate, adding water for cleaning, performing spray drying by using an ion ultrasonic spray instrument, and performing high-speed centrifugal atomization by using a high-speed centrifugal atomizer with an ultrasonic atomization nozzle at the temperature of 160-202 ℃. The product obtained by detection is allopurinol crystal, the purity is 97.8%, and the content of single impurity is less than 0.08%.
Example 5:
taking 100g of crude allopurinol, putting the crude allopurinol in 400g of 1-methyl-2-pyrrolidone/dimethyl sulfoxide solvent, heating to 170 ℃, and gradually dissolving allopurinol; the weight ratio of 1-methyl-2-pyrrolidone/dimethyl sulfoxide is 1: 4; gradually cooling to 100 deg.C, slowly adding purified water, slowly cooling to room temperature, cooling for crystallizing, filtering, washing precipitate with water, and vacuum drying to obtain allopurinol crystal with purity of 98.9% and single impurity content of less than 0.08%.
The results show that the product of the embodiment 2 has higher purity, the heating and cooling crystallization steps are not needed in the purification process, and no precipitate is separated out in the embodiment 3; examples 4 to 5 were dissolved by heating and then cooled to precipitate crystals.
Test 1: physical Property measurements (see Table 2 for results)
Tabletting by a conventional process, adding the pure allopurinol, adding 20% of an excipient, 10% of a filler and 5% of a lubricant, mixing, and tabletting by a tabletting machine, wherein the excipient is microcrystalline cellulose, the filler is starch, and the lubricant is magnesium stearate.
1) Solubility Using a Distek dissolution apparatus (DISTEK corporation, 2100A), the dissolution rate of the pellets of the product of examples in a phosphoric acid buffer solution of sodium lauryl sulfate at room temperature was measured, and the dissolution surface area was 1cm2。
2) Hygroscopicity 1g of each example powder was taken using a moisture adsorption analyzer from disk corporation, and the equilibrium time of the weight change (0.01%) under a humidity increasing condition (10% to 90%) was evaluated at room temperature.
3) Physical stability, the powder state and weight change of the examples were examined by storing the powder indoors for 2 months under the conditions of 40 ℃ and 70% humidity.
4) Compressibility: friability of the pellets was tested using a Vankel, cary US apparatus
5) Powder flowability detection: by using angle of repose
TABLE 2
As can be seen from the results shown in Table 2 of experiment 1, the purified allopurinol powder obtained by the invention can be directly used for tabletting, the solubility of the allopurinol pure product in example 2 is obviously improved, and the dissolution rate is obviously increased. Since the powder particle size is more uniform, both the compactability and flowability are superior to the other examples.
In general, the prior art uses crystallization or salt-forming purification, and stable products can be obtained, but the pure amorphous product of the invention of example 2 is not expected to be obtained, the improvement of solubility and compression type is difficult to estimate in advance, the physical property change is probably due to the change of the dissolving solvent in the crude product refining step and the stability of temperature, and the obtained product has high industrial utility value.
The above-described embodiments are not intended to limit the scope of the present invention, and those skilled in the art can make various modifications and applications of the present invention based on the above-described description.
Claims (5)
1. A refining method of allopurinol comprises the following steps: putting the crude allopurinol in one or more organic solvents, and dissolving the crude allopurinol; adding water mixed with adsorbent, and filtering; spray drying to obtain the final product; the organic solvent is selected from ethanol, isopropanol, ethylene glycol methanol, isopropanolamine, N-dimethylformamide, 1-methyl-2-pyrrolidone and/or dimethyl sulfoxide; wherein the mass ratio of the crude allopurinol to the organic solvent is 1: 2-16, the weight ratio of the organic solvent to the adsorbent is 50-500: 1.
2. the method of claim 1, wherein: the adsorbent is silicon dioxide gas condensing agent micro powder.
3. The method of claim 1, wherein: heating may be selected to promote dissolution at temperatures below 100 ℃.
4. The method of claim 1, wherein: two organic solvents are used for co-dissolving, and the operation is carried out at room temperature.
5. The method of claim 1, wherein the spray drying is performed using an ion ultrasonic nebulizer.
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| CN110372709A (en) * | 2019-09-05 | 2019-10-25 | 江苏红豆杉药业有限公司 | A kind of preparation method of Allopurinol crystal |
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| CN104447754A (en) * | 2014-11-04 | 2015-03-25 | 重庆康乐制药有限公司 | Method for carrying out solvent-out crystallization on allopurinol |
| CN107698596A (en) * | 2017-11-15 | 2018-02-16 | 双鹤药业（商丘）有限责任公司 | A kind of synthetic method of Allopurinol |
| CN110372709A (en) * | 2019-09-05 | 2019-10-25 | 江苏红豆杉药业有限公司 | A kind of preparation method of Allopurinol crystal |
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