Production method of pharmaceutical grade magnesium oxide

Abstract

The invention provides a production method of pharmaceutical grade magnesium oxide, and relates to the field of pharmaceutical grade magnesium oxide. The production method of the pharmaceutical grade magnesium oxide comprises the following steps: a reaction-aging step, a multi-stage pulping and washing step, a drying step, a calcining step and a post-treatment step. According to the production method of the pharmaceutical grade magnesium oxide, the purity and activity requirements of the pharmaceutical grade magnesium oxide can be effectively balanced, and the influence of poor quality and structure morphology of magnesium carbonate is effectively avoided while the tablet hardness is ensured to reach 2.5-3 kg; the magnesium carbonate structure morphology affects the quality of magnesium oxide, and the content of sulfate radicals in pharmaceutical grade magnesium oxide is high.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical grade magnesium oxide, in particular to a production method of pharmaceutical grade magnesium oxide. BACKGROUND

[0002] Magnesium is an essential cationic element in the human body, ranking fourth in the cell tissue only next to potassium. Magnesium participates in all energy metabolism of the human body, activates and catalyzes enzyme systems, promotes the completion of biochemical reactions and the formation of cells. As an important raw material and auxiliary material for producing drugs, pharmaceutical grade magnesium oxide is widely used in the pharmaceutical industry. The specifications of pharmaceutical grade magnesium oxide (including the contents of calcium oxide, acid-insoluble substances, iron, sulfate radical and loss on ignition) are strictly regulated in the national pharmacopoeia; in addition to the above-mentioned specifications, the tabletting hardness as the application performance of pharmaceutical grade magnesium oxide is also crucial. On the one hand, it can ensure that the tablets are less likely to break or wear during production, packaging, transportation, storage and patient use, effectively guaranteeing the integrity and reducing the loss of active ingredients; at the same time, when the patient needs to break the tablets (such as scored tablets), high tabletting hardness can produce neat fracture during breaking, reducing the generation of irregular fragments and avoiding the problem of inaccurate dosage. On the other hand, due to the hygroscopicity of magnesium oxide, high tabletting hardness can slow down the penetration speed of external moisture into the tablet, and the overall stability and storage performance of the tablet are better.

[0003] Compared with the preparation of magnesium oxide products for other purposes, the preparation of pharmaceutical grade magnesium oxide is relatively special, which has the characteristics of sticky material, poor flowability and high process requirements. Compared with other purposes of magnesium oxide, it not only needs a certain purity content, but also needs a certain activity, which is between ordinary high-purity magnesium oxide and active magnesium oxide. The inventors found in the production practice of pharmaceutical grade magnesium oxide that the conventional calcination of heavy magnesium carbonate, light magnesium carbonate and magnesium hydroxide cannot produce pharmaceutical grade magnesium oxide meeting the tabletting hardness requirements, and the tabletting hardness cannot reach the required 2.5-3 kg.

[0004] Further, the inventors also found that due to the poor quality and structure morphology of magnesium carbonate (the morphology cannot reach spherical shape, generally irregular morphology such as needle-like, rod-like and snowflake-like), there are problems of low reaction efficiency, the structure morphology of magnesium carbonate affecting the quality of magnesium oxide and high sulfate radical content of pharmaceutical grade magnesium oxide in the existing production of pharmaceutical grade magnesium oxide. SUMMARY

[0005] To solve the technical problems in the prior art, the present application provides a production method of medical-grade magnesium oxide, which can effectively balance the purity and activity requirements of medical-grade magnesium oxide, effectively avoid the problems of low reaction efficiency, magnesium carbonate structure affecting the quality of magnesium oxide, and high sulfate content of medical-grade magnesium oxide, while ensuring that the tablet hardness reaches 2.5-3 kg, and the quality and structure of magnesium carbonate are not affected.

[0006] To solve the above technical problems, the technical solutions adopted by the present application are as follows: A production method of medical-grade magnesium oxide, comprising the following steps: reaction-aging step, multi-stage beating and washing step, drying step, calcination step, and post-treatment step. In the reaction-aging step, polyethylene glycol is added to the magnesium sulfate solution under stirring conditions, and after mixing uniformly, the first portion of sodium carbonate solution is added to the 90-95℃ magnesium sulfate solution, and the first portion of sodium carbonate solution is reacted after being added; the second portion of sodium carbonate solution is continuously added to the 90-95℃ magnesium sulfate solution, and the second portion of sodium carbonate solution is reacted after being added; then aging is carried out at a temperature not lower than 65℃, and a primary reactant is obtained. The multi-stage beating and washing step consists of the following steps: first-stage beating and washing, second-stage beating and washing, and third-stage leaching. In the first-stage beating and washing, the primary reactant is pressure-filtered to obtain a first filter cake, which is then mixed with first-stage beating water and water washing aids, and subjected to first-stage beating to obtain first-stage beating and washing material. In the second-stage beating and washing, the first-stage beating and washing material is pressure-filtered to obtain a second filter cake, which is then mixed with second-stage beating water and water washing aids, and subjected to second-stage beating to obtain second-stage beating and washing material. In the third-stage leaching, a side-washing type leaching method is adopted, and after the second-stage beating and washing material is leached by the first portion of leaching water and the second portion of leaching water, it is pressure-filtered to obtain a third-stage leaching filter cake.

[0007] Further, in the drying step, the third-stage leaching filter cake is dried at 130-150℃ to a water content of ≤3.0wt%, and magnesium carbonate dry powder is obtained. In the calcination step, the magnesium carbonate dry powder is calcined at 800-850℃, and calcined magnesium oxide semi-product is obtained. In the post-treatment step, the calcined magnesium oxide semi-product is subjected to demagnetization and sieving, and then is pulverized to an average particle size D50 of 8-10μm, and medical-grade magnesium oxide is prepared.

[0008] Preferably, in the reaction-aging step, the molar concentration of the magnesium sulfate solution is 2.0-2.5mol / L, and the molar concentration of the sodium carbonate solution is 1.0-1.5mol / L. The volume ratio of the first sodium carbonate solution to the second sodium carbonate solution is 1.9-2.1:1; The molar ratio of magnesium sulfate to all sodium carbonate in the magnesium sulfate solution, the first sodium carbonate solution and the second sodium carbonate solution is 1:1.1-1.2.

[0009] Preferably, in the reaction-aging step, the first sodium carbonate solution is added for 30-45 min; and the reaction is maintained for 20-40 min after the addition of the first sodium carbonate solution is completed. The second sodium carbonate solution is added for 30-45 min; and the reaction is maintained for 2-2.5 h after the addition of the second sodium carbonate solution is completed.

[0010] Preferably, in the reaction-aging step, the aging time is 2-3 h. The addition amount of the polyethylene glycol is 0.5-1% of the total mass of the prepared magnesium carbonate dry powder.

[0011] Preferably, in the primary beating and washing, the beating speed is controlled to be 200-250 r / min, the beating temperature is controlled to be 40-45℃, and the beating time is controlled to be 1.5-2 h. The amount of the primary beating water is 14-15 m 3 / ton of the magnesium carbonate dry powder. The washing aids are hexadecyl trimethyl ammonium bromide and ammonium bicarbonate; the addition amount of the hexadecyl trimethyl ammonium bromide is 0.5-1% of the total mass of the magnesium carbonate dry powder, and the addition amount of the ammonium bicarbonate is 5-10% of the total mass of the magnesium carbonate dry powder.

[0012] Preferably, in the secondary beating and washing, the beating speed is controlled to be 200-250 r / min, the beating temperature is controlled to be 40-45℃, and the beating time is controlled to be 1-1.5 h. The amount of the secondary beating water is 14-15 m 3 / ton of the magnesium carbonate dry powder. The washing aids are hexadecyl trimethyl ammonium bromide and ammonium bicarbonate; the addition amount of the hexadecyl trimethyl ammonium bromide is 0.5-1% of the total mass of the magnesium carbonate dry powder, and the addition amount of the ammonium bicarbonate is 2-5% of the total mass of the magnesium carbonate dry powder.

[0013] Preferably, in the tertiary leaching, the first leaching water is used to leach in a left-in-right-out mode, and the leaching time is 20-30 min. The second leaching water is used to leach in a right-in-left-out mode, and the leaching time is 20-30 min. The amount of the first leaching water is 9-10 m 3 / ton of the magnesium carbonate dry powder. The amount of the second leaching water is 9-10 m3 / ton of dry magnesium carbonate powder.

[0014] Preferably, the calcination time in the calcination step is 40-60 min. In the post-processing step, the magnetic separation is performed by using an electromagnetic powder magnetic separator, the control excitation current is 52-55 A, and the magnetic induction intensity is 19000-20000 GS.

[0015] Further, the medical-grade magnesium oxide has a magnesium oxide content of ≥96.0 wt%, an average particle size D50 of 8-10 μm, a specific surface area of 15-25 m 2 / g, a 30-degree citric acid activity of 30-50 s, and a sulfate content of ≤0.5 wt%.

[0016] Compared with the prior art, the present application has the following beneficial effects: (1) In the production method of the medical-grade magnesium oxide, in the reaction-aging step, firstly, the molar concentrations of the magnesium sulfate solution and the sodium carbonate solution are controlled as the basic conditions for synthesizing heavy magnesium carbonate with a bulk density of ≥0.5 g / mL; then, the sodium carbonate solution is added to the magnesium sulfate solution in batches, and the bulk density and particle size of the heavy magnesium carbonate are adjusted by controlling the related process parameters (such as the addition time and the reaction temperature) in the reaction and aging processes, so as to balance the purity and activity of the medical-grade magnesium oxide prepared subsequently, to avoid the adverse effects of the poor quality and structure of the magnesium carbonate on the medical-grade magnesium oxide, while ensuring that the tablet hardness reaches 2.5-3 kg; in the multi-stage beating and washing step, the sulfate attached to the primary reactant magnesium carbonate is removed by the first-stage beating and washing, the second-stage beating and washing, and the third-stage leaching; then, the medical-grade magnesium oxide is prepared through the drying step, the calcination step, and the post-processing step; the aforementioned technical means cooperate with each other and work together, which can effectively balance the purity and activity requirements of the medical-grade magnesium oxide, while ensuring that the tablet hardness reaches 2.5-3 kg, and effectively avoiding the problems of low reaction efficiency, the influence of the magnesium carbonate structure on the quality of the magnesium oxide, and high sulfate content of the medical-grade magnesium oxide, which are caused by the poor quality and structure of the magnesium carbonate.

[0017] (2) The medical-grade magnesium oxide prepared by using the production method of the medical-grade magnesium oxide has the specifications shown in the following table:

[0018] (3) The production method of the medical-grade magnesium oxide is easy to obtain raw materials, has a simple process flow, and is easy to control the reaction process, and is suitable for industrialized scale production. DETAILED DESCRIPTION

[0019] In order to have a clearer understanding of the technical features, objectives and effects of the present application, the specific embodiments of the present application are described. It should be pointed out that the following detailed description is exemplary and is intended to provide further description of the present application. Unless otherwise specified, all technical and scientific terms used in the present application have the same meaning as generally understood by those skilled in the art to which the present application belongs.

[0020] It should be noted that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, "first", "second", and the like are used to distinguish similar objects, and are not intended to describe a particular order or sequence, and it should also be understood that when the terms "comprise" and / or "include" are used in the specification, there is a feature, step, operation, device, component and / or combination thereof.

[0021] The present application provides a production method of pharmaceutical grade magnesium oxide, which is carried out by the following process flow: magnesium sulfate, sodium carbonate → preparation → reaction and aging → cooling → filtration → washing → drying → calcination → demagnetization → screening → crushing → packaging → finished product.

[0022] The production method of pharmaceutical grade magnesium oxide comprises the following steps: a preparation step, a reaction-aging step, a multi-stage beating and washing step, a drying step, a calcination step, and a post-treatment step.

[0023] The method of the preparation step is to use magnesium sulfate heptahydrate, sodium carbonate and deionized water as raw materials to prepare a magnesium sulfate solution with a molar concentration of 2.0-2.5 mol / L and a sodium carbonate solution with a molar concentration of 1.0-1.5 mol / L, respectively.

[0024] In the preparation step, the magnesium sulfate heptahydrate is a commercially available pharmaceutical grade magnesium sulfate qualified product, and the sodium carbonate is a commercially available pharmaceutical grade sodium carbonate qualified product.

[0025] The method of the reaction-aging step is as follows: heating a magnesium sulfate solution and a sodium carbonate solution to 90-95° C. respectively, and keeping them warm; adding polyethylene glycol to the magnesium sulfate solution under stirring at 100-120 r / min, stirring evenly, adding the first portion of sodium carbonate solution to the magnesium sulfate solution at 90-95° C. (note that back addition is not allowed), and controlling the addition time of the first portion of sodium carbonate solution to be 30-45 minutes; after the first portion of sodium carbonate solution is added, keeping the temperature at 90-95° C. for reaction for 20-40 minutes, adding the second portion of sodium carbonate solution while continuing stirring, and controlling the addition time of the second portion of sodium carbonate solution to be 30-45 minutes; after the second portion of sodium carbonate solution is added, adjusting the stirring speed to 150-180 r / min, keeping the temperature at 90-95° C. for reaction for 2-2.5 hours; after the reaction is completed, adjusting the stirring speed to 60-80 r / min, controlling the material temperature to be not less than 65° C. during the aging period, aging for 2-3 hours, and cooling to below 50° C. to obtain a primary reactant.

[0026] In the reaction-aging step, the volume ratio of the first sodium carbonate solution to the second sodium carbonate solution is 1.9-2.1:1; In the magnesium sulfate solution, the first sodium carbonate solution, and the second sodium carbonate solution, the molar ratio of magnesium sulfate to the total sodium carbonate (the sum of the first and second solutions) is 1:1.1-1.2; The polyethylene glycol is PEG-400, and its addition amount is 0.5-1% of the total mass of the magnesium carbonate dry powder obtained by the reaction, and is used to improve the reaction efficiency and adjust the particle size of the magnesium carbonate particles.

[0027] After a large number of experiments and studies, the inventors found that the bulk density of magnesium carbonate is too low, which will directly affect the quality of magnesium oxide produced by subsequent calcination, resulting in the tableting hardness of magnesium oxide failing to meet the predetermined requirements (tableting hardness reaches 2.5-3kg) when used in the pharmaceutical industry; and the inventors further found that even if high-purity magnesium hydroxide with activity and specific surface area that meet the requirements is used as a raw material, the tableting performance of the magnesium oxide prepared by calcination still cannot meet the predetermined requirements; and heavy magnesium carbonate with a bulk density ≥0.5g / mL must be used to produce pharmaceutical-grade magnesium oxide that meets the tableting hardness requirements. In this step, the molar concentrations of the magnesium sulfate solution and the sodium carbonate solution are first controlled as the basic conditions for the reaction synthesis of heavy magnesium carbonate with a bulk density of ≥0.5 g / mL; then the addition method is controlled to add the sodium carbonate solution to the magnesium sulfate solution in batches, and by controlling the relevant process parameters (such as addition time, reaction temperature, etc.) during the reaction and aging process, the bulk density and particle size of the heavy magnesium carbonate are adjusted in a targeted manner to balance the purity and activity of the subsequently prepared pharmaceutical-grade magnesium oxide, while ensuring that the tableting hardness reaches 2.5-3 kg, while avoiding the adverse effects of the poor quality and structural morphology of the magnesium carbonate on the pharmaceutical-grade magnesium oxide.

[0028] The multi-stage beating and washing step comprises: a first-stage beating and washing, a second-stage beating and washing, and a third-stage washing.

[0029] The method of the first-stage beating and washing is as follows: the primary reactant is introduced into a 1# filter press, and is filtered to obtain a first filter cake with a water content of ≤50wt%; the first filter cake is introduced into a 1# beater tank, and then first-stage beating water and a water washing aid are added, the first-stage beating speed is controlled to be 200-250r / min, the first-stage beating temperature is controlled to be 40-45℃, and the first-stage beating is performed for 1.5-2h to obtain a first-stage beating and washing material.

[0030] In the first-stage beating and washing, the amount of the first-stage beating water is 14-15m 3 / ton of dry magnesium carbonate powder. The water washing aid is cetyltrimethylammonium bromide CTAB and ammonium bicarbonate; the addition amount of the cetyltrimethylammonium bromide CTAB is 0.5-1% of the total mass of the dry magnesium carbonate powder, and the addition amount of the ammonium bicarbonate is 5-10% of the total mass of the dry magnesium carbonate powder.

[0031] The method of the second-stage beating and washing is as follows: the first-stage beating and washing material is introduced into a 2# filter press, and is filtered to obtain a second filter cake with a water content of ≤50wt%; the second filter cake is introduced into a 2# beater tank, and then second-stage beating water and a water washing aid are added, the second-stage beating speed is controlled to be 200-250r / min, the second-stage beating temperature is controlled to be 40-45℃, and the second-stage beating is performed for 1-1.5h to obtain a second-stage beating and washing material.

[0032] In the second-stage beating and washing, the amount of the second-stage beating water is 14-15m 3 / ton of dry magnesium carbonate powder. The water washing aid is cetyltrimethylammonium bromide CTAB and ammonium bicarbonate; the addition amount of the cetyltrimethylammonium bromide CTAB is 0.5-1% of the total mass of the dry magnesium carbonate powder, and the addition amount of the ammonium bicarbonate is 2-5% of the total mass of the dry magnesium carbonate powder.

[0033] In the first-stage beating and washing and the second-stage beating and washing, the water washing aid ammonium bicarbonate can react with magnesium sulfate attached to the magnesium carbonate to generate ammonium sulfate, and the ammonium sulfate is easily dissolved in water and dispersed into the filtrate; in combination with the added cetyltrimethylammonium bromide CTAB, the dispersibility of the magnesium carbonate in water is improved, so that the sulfate is more easily washed away, and the washing efficiency and effect of the sulfate are further improved.

[0034] The method of the third stage washing is that the secondary pulping washing material is introduced into a 3# side washing filter press, and the side washing method is used for washing; first, the left side is introduced into the right side, and the first part of normal temperature washing water is introduced for washing for 20-30 minutes, then the right side is introduced into the left side, and the second part of normal temperature washing water is introduced for washing for 20-30 minutes, and the filter cake is pressed to a water content of ≤50wt%, and the third stage washing filter cake is obtained.

[0035] In the third stage washing, the amount of the first part of washing water is 9-10m 3 / ton of dry magnesium carbonate powder; The amount of the second part of washing water is 9-10m 3 / ton of dry magnesium carbonate powder.

[0036] In this step, the sulfate attached to the primary reactant magnesium carbonate is removed by one stage pulping washing, two stage pulping washing and three stage washing; by controlling the amount of pulping water at each stage, and the composition and amount of the washing aid, the sulfate content of the product is reduced to 1-1.5wt% after one stage pulping washing, the sulfate content of the product is reduced to 0.5-1wt% after two stage pulping washing, and the sulfate content of the product is ≤0.2wt% after three stage washing.

[0037] The method of the drying step is that the third stage washing filter cake is put into the feeding hopper, and is fed into the drying furnace through the feeding auger, the drying temperature is controlled to be 130-150℃, the material moisture content is dried to ≤3.0wt%, the drying is stopped, the material is scattered, the dry magnesium carbonate powder is obtained, and is discharged to the storage bin for use.

[0038] In the drying step, the magnesium oxide content of the dry magnesium carbonate powder is ≥42.0wt%, the sulfate content is ≤0.2wt%, the moisture content is ≤3.0wt%, and the bulk density is ≥0.5g / mL.

[0039] In this step, by controlling the drying temperature at 130-150℃, the premature decomposition of part of the magnesium carbonate into magnesium oxide during the drying process is prevented, and then the morphology and structure of the magnesium carbonate are not good, which affects the quality of the magnesium oxide prepared by subsequent calcination.

[0040] The method of the calcination step is that the dry magnesium carbonate powder is put into the feeding hopper, and is fed into the rotary calcination furnace through the feeding auger, the calcination temperature is controlled to be 800-850℃, the calcination is carried out for 40-60min, the activity and specific surface area of the magnesium oxide are controlled, then the calcined magnesium oxide semi-finished product is obtained after crushing, and is discharged to the storage bin for use.

[0041] In the calcination step, the magnesium oxide semi-finished product has a magnesium oxide content of ≥96.0wt%, a weight loss on ignition ≤5.0%, a sulfate content ≤0.5%, a moisture content ≤0.5%, a citric acid activity of 40-60s at 30 degrees, and a specific surface area of ​​10-20m 2 / g.

[0042] In this step, a rotary calciner is used to precisely balance the magnesium oxide's activity, specific surface area, and ignition loss under specific calcination temperature and time conditions, thereby ensuring the tableting hardness meets the desired requirements. Furthermore, the inventors' experiments revealed that other methods, such as shuttle kilns and roller hearth kilns, were unable to produce magnesium oxide products with acceptable activity.

[0043] The post-processing step comprises the following steps: placing the calcined magnesium oxide semi-finished product into an electromagnetic powder separator, controlling the excitation current to 52-55A and the magnetic induction intensity to 19,000-20,000 GS, performing demagnetization treatment, screening with an 80-mesh sieve, and then crushing the product by impact grinding to an average particle size D50 of 8-10 μm to obtain pharmaceutical-grade magnesium oxide.

[0044] In this step, an electromagnetic powder magnetic separator is used to demagnetize (remove iron) the calcined magnesium oxide semi-finished product to remove some magnetic substances (such as iron, etc.) introduced by the calcination step. After removal by the demagnetization equipment, the iron content in the product is controlled to meet the standard, and the black spots meet the standard (10-20 black spots before demagnetization, which can be reduced to less than 5 after demagnetization); screening is to remove impurities introduced during the drying, calcination and other steps, so that the acid-insoluble matter meets the standard; an impact mill is used to pulverize the material, and the average particle size D50 must be controlled at 8-10μm. Too coarse or too fine a particle size will result in the tableting hardness not meeting the standard.

[0045] The magnesium oxide content of the pharmaceutical grade magnesium oxide is ≥96.0wt%, the CaO content is ≤0.1wt%, the acid insoluble matter content is ≤0.1wt%, the moisture content is ≤0.5wt%, and the iron (Fe 3+ ) content ≤ 0.01wt%, average particle size D50 is 8-10μm, specific surface area is 15-25m 2 / g, 30-degree citric acid activity is 30-50s, black spots (5g) ≤5, ignition loss ≤5.0wt%, sulfate content ≤0.5wt%.

[0046] The present invention will be further described below with reference to some specific embodiments.

[0047] Example 1 This embodiment provides a method for producing pharmaceutical-grade magnesium oxide, specifically: 1. Preparation steps The magnesium sulfate heptahydrate, sodium carbonate and deionized water are used as raw materials to prepare a magnesium sulfate solution with a molar concentration of 2.5 mol / L and a sodium carbonate solution with a molar concentration of 1.5 mol / L.

[0048] The magnesium sulfate heptahydrate is a commercially available pharmaceutical-grade magnesium sulfate qualified product, and the sodium carbonate is a commercially available pharmaceutical-grade sodium carbonate qualified product.

[0049] 2. Reaction and aging step The magnesium sulfate solution and the sodium carbonate solution are heated to 95℃ and kept at this temperature. Under the condition of stirring at 120 r / min, the polyethylene glycol is added to the magnesium sulfate solution, and after uniform stirring, the first portion of the sodium carbonate solution is added to the 95℃ magnesium sulfate solution (note that the sodium carbonate solution should not be added to the magnesium sulfate solution). The addition time of the first portion of the sodium carbonate solution is controlled to be 45 min. After the addition of the first portion of the sodium carbonate solution is completed, the reaction is kept at 95℃ for 30 min, and the second portion of the sodium carbonate solution is continuously added under stirring. The addition time of the second portion of the sodium carbonate solution is controlled to be 45 min. After the addition of the second portion of the sodium carbonate solution is completed, the stirring speed is adjusted to 180 r / min, and the reaction is kept at 95℃ for 2 h. After the reaction is completed, the stirring speed is adjusted to 80 r / min, the temperature of the material during the aging is controlled to be not lower than 65℃, and the aging is performed for 2 h. After the aging, the temperature is cooled to below 50℃, and the primary reaction product is obtained.

[0050] The volume ratio of the first portion of the sodium carbonate solution to the second portion of the sodium carbonate solution is 2:1.

[0051] The molar ratio of the magnesium sulfate to the total sodium carbonate (the sum of the first portion and the second portion) in the magnesium sulfate solution, the first portion of the sodium carbonate solution and the second portion of the sodium carbonate solution is 1:1.2.

[0052] The polyethylene glycol is PEG-400, and the addition amount is 1% of the total mass of the magnesium carbonate dry powder prepared by the reaction.

[0053] 3. Multi-stage beating and washing step (1) First-stage beating and washing The primary reaction product is introduced into a 1# filter press, and is filtered to obtain a first filter cake with a water content of ≤50 wt%. The first filter cake is then introduced into a 1# beater tank, and a first-stage beating water and a water washing aid are added. The first-stage beating speed is controlled to be 250 r / min, the first-stage beating temperature is controlled to be 45℃, and the first-stage beating is performed for 2 h to obtain a first-stage beating and washing material.

[0054] The amount of the first-stage beating water is 15 m 3 / ton of the magnesium carbonate dry powder.

[0055] The water washing aid is cetyltrimethylammonium bromide CTAB and ammonium bicarbonate; the addition amount of cetyltrimethylammonium bromide CTAB is 1% of the total mass of the dry magnesium carbonate powder, and the addition amount of ammonium bicarbonate is 5% of the total mass of the dry magnesium carbonate powder.

[0056] (2) Secondary pulp washing The primary pulp washing material is introduced into a 2# filter press, and is filtered to obtain a second filter cake with a water content of ≤50wt%; the second filter cake is introduced into a 2# pulp tank, and then secondary pulp water and a water washing aid are added, the secondary pulp rotation speed is controlled to be 250r / min, the secondary pulp temperature is controlled to be 45℃, and secondary pulp washing is performed for 1.5h to obtain a secondary pulp washing material.

[0057] The amount of the secondary pulp water is 15m 3 / ton of dry magnesium carbonate powder.

[0058] The water washing aid is cetyltrimethylammonium bromide CTAB and ammonium bicarbonate; the addition amount of cetyltrimethylammonium bromide CTAB is 1% of the total mass of the dry magnesium carbonate powder, and the addition amount of ammonium bicarbonate is 3% of the total mass of the dry magnesium carbonate powder.

[0059] (3) Tertiary leaching The secondary pulp washing material is introduced into a 3# side washing filter press, and is leached by using a side washing leaching mode; first, the left side is used to introduce the right side to introduce the first portion of leaching water at room temperature to leach for 30min, and then the right side is used to introduce the left side to introduce the second portion of leaching water at room temperature to leach for 30min, and the filter cake is filtered to obtain a tertiary leaching filter cake with a water content of ≤50wt%.

[0060] The amount of the first portion of leaching water is 10m 3 / ton of dry magnesium carbonate powder.

[0061] The amount of the second portion of leaching water is 10m 3 / ton of dry magnesium carbonate powder.

[0062] 4, Drying step The tertiary leaching filter cake is introduced into a feeding hopper, and is fed into a drying furnace through a feeding auger, the drying temperature is controlled to be 140℃, and the material is dried until the water content is ≤3.0wt%, and then the drying is stopped, the material is scattered, and then dry magnesium carbonate powder (the bulk density is 0.58g / mL) is obtained, and is discharged into a storage bin for use.

[0063] 5, Calcination step The dry magnesium carbonate powder is introduced into a feeding hopper, and is fed into a rotary calcination furnace through a feeding auger, the calcination temperature is controlled to be 800℃, and the calcination is performed for 60min, and then the activity and specific surface area of the magnesium oxide are controlled, and then the calcined magnesium oxide semi-finished product is obtained after being crushed, and is discharged into a storage bin for use.

[0064] 6. Post-treatment step The calcined magnesium oxide semi-product is put into an electromagnetic powder magnetic separator, the excitation current is controlled to be 55 A, the magnetic induction intensity is 20000 GS, after magnetic treatment, 80 mesh screen is used for screening, and then impact mill is used for crushing to an average particle size D50 of 9.3 μm, to obtain the pharmaceutical grade magnesium oxide.

[0065] The quality specification of the pharmaceutical grade magnesium oxide prepared in the embodiment is shown in the following table:

[0066] Example 2 The embodiment provides a production method of pharmaceutical grade magnesium oxide, in particular: 1. Preparation step Seven water magnesium sulfate, sodium carbonate and deionized water are used as raw materials to prepare a magnesium sulfate solution with a molar concentration of 2.0 mol / L and a sodium carbonate solution with a molar concentration of 1.5 mol / L.

[0067] The seven water magnesium sulfate is a commercially available pharmaceutical grade magnesium sulfate qualified product, and the sodium carbonate is a commercially available pharmaceutical grade sodium carbonate qualified product.

[0068] 2. Reaction-aging step The magnesium sulfate solution and the sodium carbonate solution are heated to 90 ℃ respectively and kept; under the condition of 120 r / min stirring, polyethylene glycol is added to the magnesium sulfate solution, after uniform stirring, the first portion of the sodium carbonate solution is added to the 90 ℃ magnesium sulfate solution (note that it cannot be added inversely), and the adding time of the first portion of the sodium carbonate solution is controlled to be 45 min; after the addition of the first portion of the sodium carbonate solution is completed, 95 ℃ is kept for 30 min of reaction, and the second portion of the sodium carbonate solution is continuously added under stirring, and the adding time of the second portion of the sodium carbonate solution is controlled to be 45 min; after the addition of the second portion of the sodium carbonate solution is completed, the stirring speed is adjusted to 180 r / min, and 90 ℃ is kept for 2 h of stirring reaction; after the reaction is completed, the stirring speed is adjusted to 80 r / min, the temperature of the material during aging is controlled to be not lower than 65 ℃, and after 2 h of aging, the temperature is cooled to below 50 ℃, to obtain a primary reactant.

[0069] The volume ratio of the first portion of the sodium carbonate solution to the second portion of the sodium carbonate solution is 2:1.

[0070] In the magnesium sulfate solution, the first portion of the sodium carbonate solution and the second portion of the sodium carbonate solution, the molar ratio of magnesium sulfate to all sodium carbonate (the sum of the first portion and the second portion) is 1:1.1.

[0071] The polyethylene glycol is PEG-400, and the adding amount is 1% of the total mass of the magnesium carbonate dry powder prepared by reaction.

[0072] 3. Multi-stage beating and washing step (1) First-stage beating and washing The primary reactant is introduced into a 1# filter press, and is filtered to a filter cake moisture content of ≤50wt%, to obtain a first filter cake; the first filter cake is introduced into a 1# beater tank, and then first-stage beating water and a water washing aid are added, the first-stage beating speed is controlled at 250r / min, the first-stage beating temperature is controlled at 45℃, and first-stage beating is performed for 2h, to obtain a first-stage beating and washing material.

[0073] The amount of first-stage beating water is 15m 3 / ton of dry magnesium carbonate powder.

[0074] The water washing aid is cetyltrimethylammonium bromide CTAB and ammonium bicarbonate; the amount of cetyltrimethylammonium bromide CTAB added is 1% of the total mass of the dry magnesium carbonate powder, and the amount of ammonium bicarbonate added is 5% of the total mass of the dry magnesium carbonate powder.

[0075] (2) Second-stage beating and washing The first-stage beating and washing material is introduced into a 2# filter press, and is filtered to a filter cake moisture content of ≤50wt%, to obtain a second filter cake; the second filter cake is introduced into a 2# beater tank, and then second-stage beating water and a water washing aid are added, the second-stage beating speed is controlled at 250r / min, the second-stage beating temperature is controlled at 45℃, and second-stage beating is performed for 1.5h, to obtain a second-stage beating and washing material.

[0076] The amount of second-stage beating water is 15m 3 / ton of dry magnesium carbonate powder.

[0077] The water washing aid is cetyltrimethylammonium bromide CTAB and ammonium bicarbonate; the amount of cetyltrimethylammonium bromide CTAB added is 1% of the total mass of the dry magnesium carbonate powder, and the amount of ammonium bicarbonate added is 3% of the total mass of the dry magnesium carbonate powder.

[0078] (3) Third-stage elution The second-stage beating and washing material is introduced into a 3# side-washing filter press, and is eluted using a side-washing elution method; first, a first portion of elution water at room temperature is introduced in a left-to-right direction, and elution is performed for 30min, then a second portion of elution water at room temperature is introduced in a right-to-left direction, and elution is performed for 30min, and the filter cake is filtered to a filter cake moisture content of ≤50wt%, to obtain a third-stage elution filter cake.

[0079] The amount of the first portion of elution water is 10m 3 / ton of dry magnesium carbonate powder.

[0080] The amount of the second portion of elution water is 10m 3 / ton of dry magnesium carbonate powder.

[0081] 4. Drying step The tertiary leaching filter cake is put into the feeding hopper, fed into the drying furnace through the feeding auger, the drying temperature is controlled at 145℃, and the material is dried to a moisture content of ≤3.0wt%, then the drying is stopped, the material is broken up, and magnesium carbonate dry powder (bulk density 0.53g / mL) is obtained, which is discharged to the storage bin for later use.

[0082] 5. Calcination step The magnesium carbonate dry powder is put into the feeding hopper, fed into the rotary calcination furnace through the feeding auger, the calcination temperature is controlled at 850℃, and the calcination is kept for 60min, so as to control the activity and specific surface area of magnesium oxide, then the calcined magnesium oxide semi-finished product is obtained after crushing, which is discharged to the storage bin for later use.

[0083] 6. Post-treatment step The calcined magnesium oxide semi-finished product is put into the electromagnetic powder magnetic separator, the excitation current is controlled at 55A, the magnetic induction intensity is 20000GS, and after the magnetic treatment, the product is sieved with an 80-mesh screen, then the impact mill is used for crushing to an average particle size D50 of 8.8μm, and the pharmaceutical-grade magnesium oxide is prepared.

[0084] The quality specifications of the pharmaceutical-grade magnesium oxide prepared in this example are shown in the following table:

[0085] Example 3 This example provides a production method of pharmaceutical-grade magnesium oxide, specifically: 1. Preparation step Seven-water magnesium sulfate, sodium carbonate and deionized water are used as raw materials to prepare a magnesium sulfate solution with a molar concentration of 2.0mol / L and a sodium carbonate solution with a molar concentration of 1.5mol / L, respectively.

[0086] Among them, the seven-water magnesium sulfate is a commercially available pharmaceutical-grade magnesium sulfate qualified product, and the sodium carbonate is a commercially available pharmaceutical-grade sodium carbonate qualified product.

[0087] 2. Reaction-aging step The magnesium sulfate solution and the sodium carbonate solution are heated to 95°C respectively and kept at the temperature; under the condition of stirring at 100 r / min, the polyethylene glycol is added to the magnesium sulfate solution, and after being stirred uniformly, the first portion of the sodium carbonate solution is added to the 95°C magnesium sulfate solution (note that the sodium carbonate solution should not be added to the magnesium sulfate solution in reverse), and the addition time of the first portion of the sodium carbonate solution is controlled to be 40 min; after the addition of the first portion of the sodium carbonate solution is completed, the reaction is kept at 95°C for 30 min, and the second portion of the sodium carbonate solution is continuously added under stirring, and the addition time of the second portion of the sodium carbonate solution is controlled to be 35 min; after the addition of the second portion of the sodium carbonate solution is completed, the stirring speed is adjusted to 150 r / min, and the reaction is kept at 95°C for 2 h under stirring; after the reaction is completed, the stirring speed is adjusted to 60 r / min, the temperature of the material during aging is controlled to be not lower than 65°C, and after aging for 2 h, the temperature is cooled to below 50°C, and a primary reactant is obtained.

[0088] The volume ratio of the first portion of the sodium carbonate solution to the second portion of the sodium carbonate solution is 2:1.

[0089] The molar ratio of magnesium sulfate to all sodium carbonate (the sum of the first portion and the second portion) in the magnesium sulfate solution, the first portion of the sodium carbonate solution and the second portion of the sodium carbonate solution is 1:1.15.

[0090] The polyethylene glycol is PEG-400, and the addition amount is 1% of the total mass of the magnesium carbonate dry powder prepared by reaction.

[0091] 3. Multi-stage beating and washing steps (1) First-stage beating and washing The primary reactant is introduced into a 1# filter press, and is filtered to obtain a first filter cake with a water content of ≤50 wt%; the first filter cake is put into a 1# beating tank, and then a first-stage beating water and a water washing aid are added, the first-stage beating speed is controlled to be 250 r / min, the first-stage beating temperature is controlled to be 45°C, and the first-stage beating is performed for 2 h to obtain a first-stage beating and washing material.

[0092] The addition amount of the first-stage beating water is 15 m 3 / ton of magnesium carbonate dry powder.

[0093] The water washing aid is cetyltrimethylammonium bromide CTAB and ammonium bicarbonate; the addition amount of the cetyltrimethylammonium bromide CTAB is 1% of the total mass of the magnesium carbonate dry powder, and the addition amount of the ammonium bicarbonate is 7.5% of the total mass of the magnesium carbonate dry powder.

[0094] (2) Second-stage beating and washing The first-stage beating and washing material is introduced into a 2# filter press, and the filter cake is filtered to a water content of ≤50wt%, to obtain a second filter cake; the second filter cake is introduced into a 2# beater tank, then secondary beating water and a water washing aid are added, the secondary beating speed is controlled at 250r / min, the secondary beating temperature is 45℃, and secondary beating is carried out for 1.5h, to obtain a secondary beating and washing material.

[0095] The amount of the secondary beating water is 15m 3 / ton of dry magnesium carbonate powder.

[0096] The water washing aid is cetyltrimethylammonium bromide CTAB and ammonium bicarbonate; the addition amount of the cetyltrimethylammonium bromide CTAB is 1% of the total mass of the dry magnesium carbonate powder, and the addition amount of the ammonium bicarbonate is 5% of the total mass of the dry magnesium carbonate powder.

[0097] (3) Third-stage elution The secondary beating and washing material is introduced into a 3# side-washing filter press, and elution is carried out in a side-washing manner; first, the left side is used to introduce the right side, and normal-temperature first elution water is introduced to carry out elution for 30min, then the right side is used to introduce the left side, and normal-temperature second elution water is introduced to carry out elution for 30min, and the filter cake is filtered to a water content of ≤50wt%, to obtain a third-stage elution filter cake.

[0098] The amount of the first elution water is 10m 3 / ton of dry magnesium carbonate powder.

[0099] The amount of the second elution water is 10m 3 / ton of dry magnesium carbonate powder.

[0100] 4. Drying step The third-stage elution filter cake is introduced into a feeding hopper, and is fed into a drying furnace through a feeding auger, the drying temperature is controlled at 150℃, and the material is dried to a water content of ≤3.0wt%, the drying is stopped, the material is scattered, and dry magnesium carbonate powder (the bulk density is 0.56g / mL) is obtained, which is discharged into a storage bin for standby.

[0101] 5. Calcination step The dry magnesium carbonate powder is introduced into a feeding hopper, and is fed into a rotary calcination furnace through a feeding auger, the calcination temperature is controlled at 830℃, and the calcination is carried out for 45min, so as to control the activity and specific surface area of magnesium oxide, then the calcined magnesium oxide semi-finished product is obtained after crushing, which is discharged into a storage bin for standby.

[0102] 6. Post-treatment step The semi-product of calcined magnesium oxide is put into the electromagnetic powder magnetic separator, the excitation current is controlled to be 55 A, the magnetic induction intensity is 20000 GS, after the magnetic treatment, 80 mesh screen is used for screening, and then the impact mill is used for crushing to obtain the pharmaceutical grade magnesium oxide with an average particle size D50 of 8.6 μm.

[0103] The quality specification of the pharmaceutical grade magnesium oxide prepared in the example is shown in the following table:

[0104] Comparative example 1 Comparative example 1 uses the technical scheme of example 1, and the difference lies in that: 1) In the preparation step, the molar concentration of the magnesium sulfate solution is 1.5 mol / L, and the molar concentration of the sodium carbonate solution is 0.5 mol / L; 2) In the reaction-aging step, the magnesium sulfate solution and the sodium carbonate solution are not heated, and the first portion of the sodium carbonate solution and the second portion of the sodium carbonate solution are added to the magnesium sulfate solution at room temperature, and the reaction is carried out at room temperature; the molar ratio of magnesium sulfate to all sodium carbonate (the sum of the first portion and the second portion) in the magnesium sulfate solution, the first portion of the sodium carbonate solution and the second portion of the sodium carbonate solution is 1:1.

[0105] The other operations and steps are the same as those of example 1.

[0106] The quality specification of the magnesium oxide product prepared in comparative example 1 is shown in the following table:

[0107] It can be seen that the magnesium oxide content, specific surface area and activity of the magnesium oxide product prepared in comparative example 1 cannot meet the predetermined requirements, which is specifically manifested as that the magnesium oxide content and activity are reduced, and the specific surface area is increased, which directly affects the tabletting performance of the magnesium oxide.

[0108] Comparative example 2 Comparative example 2 uses the technical scheme of example 2, and the difference lies in that: in the multi-stage beating and washing step, the water washing auxiliary agent used in the first stage of beating and washing is omitted, and the second stage of beating and washing is omitted, and the third stage of leaching is directly carried out after the first stage of beating and washing is completed.

[0109] The other operations and steps are the same as those of example 1.

[0110] The quality specification of the pharmaceutical grade magnesium oxide prepared in comparative example 2 is shown in the following table:

[0111] It can be seen that after the multi-stage beating and washing in comparative example 2, the sulfate content of the prepared magnesium oxide product cannot meet the predetermined requirements.

[0112] Comparative example 3 Comparative Example 3 adopts the technical solution of Example 2, except that the calcination temperature is set to 900℃ and the calcination time is 80 min in the calcination step.

[0113] Other operations and steps are the same as those of Example 1.

[0114] The quality specifications of the pharmaceutical-grade magnesium oxide prepared in Comparative Example 3 are shown in the following table:

[0115] It can be seen that the specific surface area and activity of the magnesium oxide product prepared in Comparative Example 3 cannot meet the predetermined requirements, which is specifically manifested in that the activity of the magnesium oxide is increased and the specific surface area is decreased, directly affecting the tabletting performance of the magnesium oxide.

[0116] Comparative Example 4 The magnesium oxide products of Examples 1-3 and Comparative Examples 1-3, as well as magnesium oxide with a particle size D50 of 16.7 μm (unqualified particle size), magnesium hydroxide calcined magnesium oxide, light magnesium carbonate (bulk density 0.18 g / mL) calcined magnesium oxide, ordinary magnesium carbonate (bulk density 0.25 g / mL) calcined magnesium oxide, and magnesium carbonate (bulk density 0.45 g / mL) calcined magnesium oxide were used to perform powder direct tabletting (Chinese Pharmacopoeia 2020 Edition 0101 Tablets), and the tablet hardness was detected using a YD-1 tablet hardness tester. The specific results are shown as follows:

[0117] It can be seen that, due to the deterioration of the aforementioned related indicators, the tablet hardness of the magnesium oxide of Comparative Example 1 and Comparative Example 3 cannot meet the predetermined requirements; at the same time, the tabletting performance of magnesium oxide with unqualified particle size, magnesium hydroxide calcined magnesium oxide, and magnesium carbonate calcined magnesium oxide with a bulk density that does not meet the requirements (bulk density ≥ 0.5 g / mL) cannot meet the predetermined requirements.

[0118] Unless otherwise specified, the percentages used in the present application are mass percentages.

[0119] Finally, it should be noted that the above only describes the preferred embodiments of the present application and is not intended to limit the present application. Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent replacements to some technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for producing pharmaceutical grade magnesium oxide, characterized in that: The method comprises the following steps: a reaction-aging step, a multi-stage pulping and washing step, a drying step, a calcining step, and a post-processing step; In the reaction-aging step, polyethylene glycol is added to the magnesium sulfate solution under stirring, and after uniform mixing, the first portion of the sodium carbonate solution is added to the magnesium sulfate solution at 90-95° C. After the first portion of the sodium carbonate solution is added, the reaction is carried out by keeping the temperature constant; Continue to add the second portion of sodium carbonate solution to the magnesium sulfate solution at 90-95°C, and keep the temperature for reaction after the second portion of sodium carbonate solution is added; Then, aging is carried out at a temperature not lower than 65° C. to obtain a primary reactant; The multi-stage beating and washing step consists of the following steps: first-stage beating and washing, second-stage beating and washing, and third-stage rinsing; In the first-stage beating and washing, the primary reactant is filtered to obtain a first filter cake, which is then mixed with first-stage beating water and a washing aid, and then subjected to first-stage beating to obtain a first-stage beating and washing material; The secondary beating and washing, the primary beating and washing material is filtered to obtain a second filter cake, which is then mixed with secondary beating water and a washing aid, and subjected to secondary beating to obtain a secondary beating and washing material; The three-stage washing adopts a side-washing washing method. After the secondary pulping and washing material is washed with the first and second washing waters, it is filtered to obtain a three-stage washing filter cake.

2. The method for producing pharmaceutical grade magnesium oxide according to claim 1, wherein In the drying step, the third-stage washed filter cake is dried at 130-150° C. to a moisture content of ≤3.0 wt %, thereby obtaining magnesium carbonate dry powder; In the calcination step, the magnesium carbonate dry powder is calcined at 800-850° C. to obtain a calcined magnesium oxide semi-finished product; In the post-processing step, the calcined magnesium oxide semi-finished product is demagnetized and sieved, and then crushed to an average particle size D50 of 8-10 μm to obtain pharmaceutical grade magnesium oxide.

3. The method for producing pharmaceutical grade magnesium oxide according to claim 1, wherein In the reaction-aging step, the molar concentration of the magnesium sulfate solution is 2.0-2.5 mol / L, and the molar concentration of the sodium carbonate solution is 1.0-1.5 mol / L; The volume ratio of the first sodium carbonate solution to the second sodium carbonate solution is 1.9-2.1:1; In the magnesium sulfate solution, the first sodium carbonate solution and the second sodium carbonate solution, the molar ratio of magnesium sulfate to the total sodium carbonate is 1:1.1-1.

2.

4. The method for producing pharmaceutical grade magnesium oxide according to claim 1, wherein In the reaction-aging step, the time for adding the first portion of the sodium carbonate solution is 30-45 minutes; the insulation reaction time after the first portion of the sodium carbonate solution is added is 20-40 minutes; The time for adding the second portion of sodium carbonate solution is 30-45 minutes; the insulation reaction time after the second portion of sodium carbonate solution is added is 2-2.5 hours.

5. The method for producing pharmaceutical grade magnesium oxide according to claim 1, wherein: In the reaction-aging step, the aging time is 2-3 hours; The amount of polyethylene glycol added is 0.5-1% of the total mass of the magnesium carbonate dry powder obtained by the reaction.

6. The method for producing pharmaceutical grade magnesium oxide according to claim 1, wherein: In the first-stage beating washing, the beating speed is controlled to be 200-250 r / min, the beating temperature is 40-45° C., and the beating time is 1.5-2 h; The dosage of the first-level beating water is 14-15m 3 / ton of magnesium carbonate dry powder; The washing aids are cetyltrimethylammonium bromide and ammonium bicarbonate; the addition amount of cetyltrimethylammonium bromide is 0.5-1% of the total mass of the magnesium carbonate dry powder, and the addition amount of ammonium bicarbonate is 5-10% of the total mass of the magnesium carbonate dry powder.

7. The method for producing pharmaceutical grade magnesium oxide according to claim 1, wherein: In the secondary beating washing, the beating speed is controlled to be 200-250 r / min, the beating temperature is 40-45°C, and the beating time is 1-1.5h; The dosage of secondary beating water is 14-15m 3 / ton of magnesium carbonate dry powder; The washing aids are cetyltrimethylammonium bromide and ammonium bicarbonate; the addition amount of cetyltrimethylammonium bromide is 0.5-1% of the total mass of the magnesium carbonate dry powder, and the addition amount of ammonium bicarbonate is 2-5% of the total mass of the magnesium carbonate dry powder.

8. The method for producing pharmaceutical grade magnesium oxide according to claim 1, wherein: In the three-stage elution, the first elution water is eluted in the left-side inlet and out the right-side outlet, and the elution time is 20-30 minutes; The second rinse water is rinsed in the right side and out the left side, and the rinsing time is 20-30 minutes; The amount of the first rinse water is 9-10m 3 / ton of magnesium carbonate dry powder; The amount of the second rinse water is 9-10m 3 / ton of magnesium carbonate dry powder.

9. The method for producing pharmaceutical grade magnesium oxide according to claim 2, wherein: In the calcination step, the calcination time is 40-60 minutes; In the post-processing step, demagnetization is performed using an electromagnetic powder separator, with the excitation current controlled at 52-55A and the magnetic induction intensity at 19000-20000GS.

10. The method for producing pharmaceutical grade magnesium oxide according to claim 2, wherein: The pharmaceutical grade magnesium oxide has a magnesium oxide content of ≥96.0 wt%, an average particle size D50 of 8-10 μm, and a specific surface area of ​​15-25 m 2 / g, 30-degree citric acid activity is 30-50s, sulfate content ≤0.5wt%.

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