GB2109783A - Crystalline sodium carbonate - Google Patents
Crystalline sodium carbonate Download PDFInfo
- Publication number
- GB2109783A GB2109783A GB08233017A GB8233017A GB2109783A GB 2109783 A GB2109783 A GB 2109783A GB 08233017 A GB08233017 A GB 08233017A GB 8233017 A GB8233017 A GB 8233017A GB 2109783 A GB2109783 A GB 2109783A
- Authority
- GB
- United Kingdom
- Prior art keywords
- sodium carbonate
- sodium bicarbonate
- product
- bulk density
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01D—COMPOUNDS OF ALKALI METALS, i.e. LITHIUM, SODIUM, POTASSIUM, RUBIDIUM, CAESIUM, OR FRANCIUM
- C01D7/00—Carbonates of sodium, potassium or alkali metals in general
- C01D7/22—Purification
- C01D7/24—Crystallisation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01D—COMPOUNDS OF ALKALI METALS, i.e. LITHIUM, SODIUM, POTASSIUM, RUBIDIUM, CAESIUM, OR FRANCIUM
- C01D7/00—Carbonates of sodium, potassium or alkali metals in general
- C01D7/35—Varying the content of water of crystallisation or the specific gravity
- C01D7/37—Densifying sodium carbonate
Abstract
A method is disclosed for preparing a crystalline, substantially anhydrous uniform sodium carbonate having a bulk density of from 0.2 to 0.6 g/ml and a particle size of from 60 to 200 microns which comprises removing any extraneous particles from a solution of sodium carbonate or sodium bicarbonate, precipitating said sodium carbonate or sodium bicarbonate from the said solution by the addition of a water-miscible non- solvent therefor (eg acetone), and separating said precipitate, followed in the case where sodium bicarbonate is separated, heating the sodium bicarbonate precipitate to effect substantially complete conversion of the sodium bicarbonate into sodium carbonate, whereby the sodium carbonate produced following the heating step has the desired bulk density and particle size. Sodium carbonate produces, and sodium bicarbonate products which are produced as intermediates having the desired characteristics, are also disclosed. Preferred products will also be sterile and free-flowing and are highly suitable for combination with pharmaceutically active compounds, particularly antibiotics such as the cephalosporin antibiotic ceftazidime.
Description
SPECIFICATION
Improvements in or relating to sodium carbonate
This invention relates to improvements in or relating to a process for the preparation of sodium carbonate. More particularly it relates to an improved process for the manufacture of sodium carbonate in a form that is of value in the formulation of pharmaceuticals.
Many pharmaceuticals, including cephalosporin antibiotics are now aseptically formulated in vials in the dry state to which suitable sterile water may be added shortly prior to injection in order to produce an injectable solution. A nontoxic base is frequently included in such formulations when the antibiotics concerned are either acidic or amphoteric in order to improve the water-solubility of the active ingredient and/or to ensure that when constituted with water, the pH of the resulting liquid is physiologically acceptable. One such pharmaceutical which may be so formulated is the cephalosporin antibiotic (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2- carboxyprop-2-oxyimino)acetamido]-3-(1 - pyridi niu mmethyl)-ceph-3-em-4-carboxylate, known hereinafter as "ceftazidime". A particularly suitable non-toxic base is sodium carbonate.
Ceftazidime is described generally in UK
Specification No. 2025398 and the extremely stable pentahydrate form is described in UK
Specification No. 2063871. In the latter specification there is described the preparation of a dry blend of ceftazidime pentahydrate and anhydrous sodium carbonate, which on the addition of water gives a solution suitable for administration by injection. In the production of blends of this type on a manufacturing scale it is essential that the two constituents are intimately and uniformly mixed together and this uniform mixture is maintained until the blend is filled into vials. The vials will normally be filled with unit dosages of the active constituent and unless a uniform mixture is used the vials will not always contain identical amounts of each constituent.
In the production of uniform and intimate blends it is important that the bulk densities and particle sizes of the constituents be of the same order. The bulk density of sodium carbonate prepared by generally available chemical means is usually found to be of the order of 0.7 to 0.9 g/ml, whereas that of suitably prepared ceftazidime is of the order of 0.4 g/ml. On combining these materials, what may have been an intimate and uniform blend in the first instance may separate out and become nonuniform on, for example, standing, transferring the material from the blender, or filling the blend into vials. Vibration caused by transporting the material in bulk also may lead to separation.
Similarly, separation may occur if the particle size of the sodium carbonate is substantially different from that of ceftazidime.
Sodium carbonate is, of course, a well-known compound and a number of processes for its preparation in a variety of forms have been proposed. Thus, for example, U.S. Patent
Specification No. 1,583,663 describes a process for preparing sodium carbonate in the form of fine needle-like crystals but which as a product is soft and fluffy and has a low bulk density. This process involves a two-stage heating process, firstly at low temperature and than at high temperature.
However, sodium carbonate produced by this and other processes used in the past has not been ideal for formulating as a dry blend with some pharmaceuticals in view of the discrepancy between the particle sizes and bulk densities and the need also to provide a carrier material that is as clean and preferably sterile as possibie.
Material prepared by the method of the abovementioned U.S. patent will almost certainly contain extraneous undesirable particles.
It is also known that crystallisation is a useful means of producing relatively pure chemical compounds, and furthermore that inorganic salts may be precipitated from aqueous solution by the addition thereto of an organic water-miscible liquid in which the inorganic salt is less soluble.
However, it is not generally possible to predict exactly what the particle size or density of a crystallised product produced by these methods will be.
One method of reducing the bulk density of sodium carbonate for pharmaceutical use is comminution using for example a hammer mill or a fluid energy mill. Not only does this mechanical grinding add a further unit operation into the manufacturing process, and therefore increase cost, but also it leads to the production of material having a wide distribution of particle sizes. This material also tends to be unsuitable for blending with pharmaceuticals such as ceftazidime. It often contains a high proportion of 'fines', i.e. extremely small particles, which can separate out readily and also adversely affect the vial filling operation.
Furthermore, efficient production of sodium carbonate of low bulk density is often complicated by its tending to form aggregrates, which can lead to blockages in the plant and interruptions in the manufacturing process. A further complication is that the comminution will normally desirably be effected aseptically, which renders the procedure even more laborious.
We have now found a process for the preparation of sodium carbonate in suitable form that substantially avoids all these problems. The process we have found has considerable practicality and advantage for production on a
manufacturing scale, and the sodium carbonate prepared thereby is highly suitable for use in pharmaceutical formulations.
We therefore provide a process for preparing a
crystalline, substantially anhydrous uniform
sodium carbonate having a bulk density of from
0.2 to 0.6 g/ml and a particle size of from 60 to
200 microns which comprises removing any
extraneous particles from a solution of sodium
carbonate or sodium bicarbonate, precipitating
said sodium carbonate or sodium bicarbonate from the said solution by the addition of a watermiscible nonsolvent therefor, and separating said precipitate, followed in the case where sodium bicarbonate is separated, by heating the sodium bicarbonate precipitate to effect substantially complete conversion of the sodium bicarbonate into sodium carbonate, whereby the sodium carbonate produced has the desired bulk density and particle size.
The bulk density figures as used herein refer to the bulk density of packed material, as opposed to loose material. The packed bulk density is a measure of the volume occupied by the material when it has been shaken down to remove gaps between the particles, and may be measured by the method of British Standard 1460-1948.
The figures for particle size given herein refer to the requirement that at least 90%, and generally from 90 to 98% of the particles in a given sample will have a size within the stated limits.
In a preferred aspect of the process, the sodium carbonate product will have a bulk density of from 0.3 to 0.55 g/ml, and most preferably a bulk density of from 0.3 to 0.4 g/ml and particle size of from 60 to 150 microns. The product will most preferably be a free flowing powder.
The extraneous particles will generally be removed by a filtration step. This filtration will preferably result in the removal of particles having a size greater than 1 micron, and will preferably result in removal of particles having a size of greater than 0.2 microns. Thus, for example, filters that will, in particular, remove particles of a size of the order of 0.5 microns or greater may be used.
The sodium carbonate or sodium bicarbonate starting material will desirably be of high purity.
For example, the sodium bicarbonate will generally have a purity in excess of 95% (excluding water and sodium carbonate). The sodium carbonate will generally have a purity in excess of 95% (excluding water).. It may have any crystalline or amorphous form. Anhydrous sodium carbonate or bicarbonate or a hydrate e.g. the decahydrate of sodium carbonate may be used.
The presence of sodium carbonate contamination in the sodium bicarbonate, or of a minor amount of sodium bicarbonate impurity in the sodium carbonate is, of course, permissible.
The sodium bicarbonate or sodium carbonate will desirably be dissolved in the minimum quantity of water necessary to provide solution, thus leading to a concentrated solution. When a hydrate of sodium carbonate is employed the water of hydration will normally be taken into account when allowing for the amount of water in which to dissolve the sodium carbonate. The solution is then filtered in order to remove any extraneous particles.
In formulations for administration by injection, sterile sodium carbonate is required. Sterilisation can be carried out at any convenient stage in the production process. Thus, for example, a sterile filtration stage may be included prior to the precipitation step, all subsequent procedures involving the use of sterilised apparatus and material. Alternatively, the sodium carbonate product may be sterilised by irradiation or dry heating e.g. at from 1 60 to 3000 C. In a further alternative, the blend of sodium carbonate and pharmaceutically active material may be sterilised e.g. by irradiation ordry heating, providing of course this will not lead to any degradation.If sterilisation is to be effected by filtration the solution may be passed through a sterilising filter, i.e. one which will remove all particles of a size greater than 0.2 microns, such as bacteria and other unwanted contaminants.
Following the filtration and any optional sterilising filtration step, the sodium bicarbonate or sodium carbonate may be precipitated. This may be achieved by, for example, cooling the solution, and then adding the water-miscible nonsolvent, preferably with rapid stirring. Such a nonsolvent will itself be sterilised if a sterilising filtration step has previously been carried out, for example by passage through a sterilising filter.
Desirable non-solvents include organic liquids, such as ketones, e.g. acetone, alkanols e.g.
methanol or isopropanol or industrial methylated spirit (95% ethanol). The preferred non-solvent is acetone.
The water-miscible non-solvent will desirably be added in an amount of from 1 to 3 times the volume of the sodium bicarbonate or sodium carbonate solution. It will be realised that the relatively rapid addition of the non-solvent to the solution prevents the formation of large sodium bicarbonate or sodium carbonate crystals. When sodium bicarbonate is the starting material, this process provides a form of sodium bicarbonate which, when gently dried at, e.g., from 1 5- 350C, is itself highly suitable for being formulated with certain antibiotic compounds, for example sodium cephalothin. Sodium bicarbonate prepared in this way is generally crystalline, substantially anhydrous and uniform and has a low particle size and a bulk density compatible with may antibiotic compounds and as such, even though an intermediate, comprises a further aspect of the invention.
The sodium bicarbonate thus provided has a particle size of from 60 to 200 microns and a bulk density of from 0.3 to 0.65 g/ml, preferably a particle size of from 60 to 150 microns and a bulk density of from 0.45 to 0.55 g/ml.
The conversion of the sodium bicarbonate into the sodium carbonate will generally be effected under conditions of heat and vacuum that are effective in combination to ensure that the dissociation pressure of sodium bicarbonate is not exceeded. For example, the dissociation pressure at 700C is 120 mm Hg and at 90 C it is 414 mm
Hg. The temperature and pressure may therefore vary depending on the other and we have found a temperature of, for example, from 50 to 3000C, preferably 65 to 1 000C, at a pressure of from 2 mm to 760 mm Hg, preferably 5 to 30 mm Hg to be suitable. Typically, the heating may be effected at about 700C for from 1 6 to 20 hours at 5 mm Hg pressure.Under these conditions, total conversion to a uniform, sterile if required, substantially anhydrous, crystalline sodium carbonate has been achieved which has a bulk density of from 0.3 to 0.55 g/ml. This has been found entirely compatible with, for example, ceftazidime.
When sodium carbonate is the starting material the sodium carbonate precipitated will generally be filtered, washed and gently dried. At this stage, the decahydrate is generally obtained and this may be converted into the substantially anhydrous form by a combination of heating and vacuum. Thus, the decahydrate may be heated at from 30 to 500C, preferably under vacuum, in order to remove most of the water of crystallisation, but the remaining traces may be removed by raising the temperature. The procedure will generally take from 10 to 30 hours.
The decahydrate is conveniently heated at around 500C under vacuum for about 10 hours, followed by a short period at about 700C. Under these conditions, total conversion to a uniform, sterile if required, substantially anhydrous, generally free flowing crystalline sodium carbonate has been achieved which has a bulk density of from 0.2 to 0.6 g/ml. This has been found entirely compatible with, for example, ceftazidime.
The preferred starting material in the above process is sodium bicarbonate.
We also provide a uniform, substantially anhydrous, crystalline sodium carbonate which has a bulk density of from 0.2 to 0.6 g/ml and a particle size in the range 60-200 microns. As a further feature of the invention we provide crystalline, substantially anhydrous, uniform sodium carbonate having a bulk density of from 0.2-0.6 g/ml and a particle size of from 60200 microns, which is free from extraneous particles. As a further feature of the invention we provide free flowing, crystalline, substantially anhydrous, uniform sodium carbonate having a
bulk density of from 0.2-0.6 g/ml and a particle size of from 60-200 microns, which is free from extraneous particles.A preferred embodiment of the invention is sterile, free flowing, crystalline, substantially anhydrous, uniform sodium carbonate having a bulk density of from 0.2-0.6 g/ml and a particle size of from 60-200 microns, which is free from extraneous particles. Any such
material may be formulated with a wide range of
pharmeutical compounds. The sodium carbonate
may for example be formulated with antibiotics
such as cephalosporins or penicillins. Preferably, the sodium carbonate is formulated with
ceftazidime. Such formulations represent a further feature of the invention.
The invention will now be more particularly
described in the following non-limiting Examples.
In the Examples, all temperatures are in OC.
Example 1
The recrystallisation of sodium bicarbonate and its conversion to anhydrous sodium carbonate
Sodium bicarbonate (11.5 g) was slurried in water (100 ml) and the temperature was raised to 300 to effect dissolution. The solution was then filtered through a 0.65 micron membrane prefilter, followed by a 0.22 micron membrane sterilising filter.
The solution was cooled with stirring to 100 at which point seed crystals were added. Further cooling reduced the temperature to 30 at which point crystallisation occurred.
Acetone (100 ml) was then added to the mixture over 20 minutes to effect further crystallisation. The slurry was then filtered, washed with acetone (2x50 ml) and dried at room temperature in vacuo to yield 8.94 g (77.7% w/w) of sodium bicarbonate.
The sodium bicarbonate was then heated in vacuo at 670 to effect conversion to anhydrous sodium carbonate in a yield of 99.5%.
Loss on drying 0.5%
Assay, corrected for
loss on drying 99.5%
Acetone content less than 0.2%
Packed bulk density 0.4 g/ml
Example 2
The recrystallisation of sodium carbonate
Anhydrous sodium carbonate (150 g) was dissolved in demineralised water (850 ml) at 300.
The solution was filtered through a 0.65 micron membrane prefilterfollowed by a 0.22 micron sterilising filter. The solution was then cooled with stirring to 100 when crystallisation commenced.
At this point, acetone (1 700ml), filtered through a 0.22 micron sterilising membrane filter, was added over 1 5 minutes with cooling. The slurry was then filtered, washed with acetone (1000 ml), and dried at 350 in vacuo to produce an almost quantitative yield of anhydrous sodium carbonate.
Loss on drying 0.1% Assay, corrected for
loss on drying 99.5%
Acetone content less than 0.10m Packed bulk density 0.5 g/ml
Example 3
Recrystallisation of sodium bicarbonate
Sodium bicarbonate (44 g) was slurried in water (360 ml) and the temperature was raised to 350C to effect dissolution. The solution was then filtered through a 0.65 micron membrane prefilter followed by a 0.22 micron membrane filter and then cooled to 1 00C.
Industrial methylated spirit (500ml), which had been filtered through a 0.22 micron membrane filter, was then added to the cooled aqueous solution over 30 minutes with vigorous stirring.
The slurry was then filterd and the product washed with IMS (2x80 ml) and dried at ambient temperature (16 hours) to yield 37.95 g (86.25% w/w) of sodium bicarbonate.
Assay: 100%
Packed bulk density 0.34 g/ml
Example 4
Recrystallisation of sodium bicarbonate and conversion to sodium carbonate
Sodium bicarbonate (66 g) was slurried in water (540 ml) and the temperature was raised to 550C to effect dissolution. When dissolution was complete, stirring at 550C was maintained for a further 3 hours. The solution was then cooled to 350C and filtered through a 0.65 micron membrane prefilter followed by a 0.22 micron membrane filter. The filtrate was then further cooled to 10 C.
Industrial methylated spirit (IMS) (750 ml) which had been filtered through a 0.22 micron membrane filter was then added to the cooled aqueous solution over 30 minutes with vigorous stirring.
The slurry was then filtered and the product washed with IMS (2x120 ml) and heated in vacuo at 700C to effect conversion to anhydrous sodium carbonate, in a yield of 36.82 g.
Assay 99.1% Packed bulk density 0.23 g/ml
There are now described some pharmaceutical formulations comprising the sodium carbonate and bicarbonate of the invention.
Formulation A, for injection
Formula per blend:
Ceftazidime pentahydrate 2.037 kg
Sodium carbonate (anhydrous) 0.203 kg
The ceftazidime pentahydrate was blended with the sodium carbonate prepared according to the invention for 1 5 mins in a powder blender.
Quantities of this blend equivalent to 250 mg.
Anyhdrous ceftazidime were filled into glass vials.
In each case the vial headspace was purged with nitrogen and the vial closed using a rubber plug and a metal overseal applied by crimping.
The product may be constituted shortly before administration by dissolving in water for injections.
Formulation B, for injection
Formula per vial
Cephalothin sodium 1.056 g
Sodium bicarbonate 30 mg
Mix the sterile cephalothin sodium and sterile sodium bicarbonate prepared according to the invention in a powder blender under aseptic conditions. Fill aseptically into glass vials. Close the vials using rubber discs or plugs, held in position by aluminium overseals.
The product may be constituted by dissolving in water for injections shortly before administration.
Claims (22)
1. A process for preparing a crystalline, substantially anhydrous, uniform sodium carbonate having a bulk density of from 0.2 to 0.6 g/ml and a particle size of from 60 to 200 microns which comprises removing any extraneous particles from a solution of sodium carbonate or sodium bicarbonate, precipitating said sodium carbonate or sodium bicarbonate from the said solution by the addition of a water-miscible nonsolvent therefor, and separating said precipitate, followed, in the case where sodium bicarbonate is separated, by heating the sodium bicarbonate precipitate to effect substantially complete conversion of the sodium bicarbonate into sodium carbonate, whereby the sodium carbonate produced has the desired bulk density and particle size.
2. A process as claimed in claim 1 wherein extraneous particles having a size greater than 1 micron are removed by a filtration step.
3. A process as claimed in claim 1 or claim 2 wherein precipitation is effected using acetone.
4. A process as claimed in any one of claims 1 to 3 wherein the sodium carbonate precipitated is dried.
5. A process as claimed in any of claims 1 to 3 wherein, when sodium bicarbonate is precipitated, the sodium bicarbonate is heated under conditions of heat and vacuum which in combination are effective to ensure that the dissociation pressure of sodium bicarbonate is not exceeded.
6. A process as claimed in any of claims 1 to 5 which includes a sterilisation step.
7. A process as claimed in claim 1 substantially as hereinbefore described.
8. A process for preparing a crystalline, substantially anhydrous, uniform sodium carbonate having a bulk density of from 0.2 to 0.6 g/ml and a particle size of from 60 to 200 microns substantially as hereinbefore described with reference to the Examples.
9. Sodium carbonate whenever produced by a method as claimed in any one of claims 1 to 8.
10. A crystalline, substantially anhydrous, uniform sodium carbonate having a bulk density of from 0.2-0.6 g/ml and a particle size of from 60-200 microns.
11. A product as claimed in claim 9 or claim 10 which has a bulk density of from 0.3 to 0.4 g/ml and a particle size of from 60 to 150 microns.
12. A product as claimed in claim 10 or claim 11 which is free from extraneous particles.
13. A product as claimed in any one of claims 9 to 1 2 which is free flowing.
14. A product as claimed in any one of claims 9 to 13 which is sterile.
1 5. A product as claimed in any one of claims 9 to 14 for use in formulations with pharmaceutically active compounds.
1 6. A product as claimed in any one of claims 9 to 14 for use in formulations with antibiotics.
1 7. A product as claimed in claim 16 wherein the antibiotics are cephalosporin compounds.
18. A product as claimed in claim 1 7 wherein the cephalosporin compound is ceftazidime.
1 9. A pharmaceutical formulation comprising a pharmaceutically active compound in association with a product as claimed in any one of claims 9 to 15.
20. A crystalline, substantially anhydrous, uniform sodium bicarbonate having a bulk density of from 0.3 to 0.65 g/ml and a particle size of 60 to 200 microns.
21. A product as claimed in claim 20 for use in formulations with pharmaceutically active compounds.
22. A pharmaceutical formulation comprising sodium cephalothin in association with a product as claimed in claim 21.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08233017A GB2109783B (en) | 1981-11-20 | 1982-11-19 | Crystalline sodium carbonate |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8135048 | 1981-11-20 | ||
GB8135049 | 1981-11-20 | ||
GB08233017A GB2109783B (en) | 1981-11-20 | 1982-11-19 | Crystalline sodium carbonate |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2109783A true GB2109783A (en) | 1983-06-08 |
GB2109783B GB2109783B (en) | 1985-08-14 |
Family
ID=27261374
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08233017A Expired GB2109783B (en) | 1981-11-20 | 1982-11-19 | Crystalline sodium carbonate |
Country Status (1)
Country | Link |
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GB (1) | GB2109783B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3829093A1 (en) * | 1988-08-27 | 1990-03-01 | Hoechst Ag | Sterile, crystalline sodium carbonate and a process for the preparation thereof |
WO1999033750A1 (en) * | 1997-12-23 | 1999-07-08 | Technische Universiteit Delft | Production of water-free soda |
EP1004546A1 (en) * | 1998-11-24 | 2000-05-31 | Technische Universiteit Delft | Process for the production of sodium carbonate anhydrate |
EP1013607A1 (en) * | 1998-11-24 | 2000-06-28 | Technische Universiteit Delft | Production of water-free soda |
BE1016062A3 (en) * | 2004-06-01 | 2006-02-07 | Vaccifar Bv | ANTIBIOTIC IN THE FORM OF A WATER-SOLUBLE POWDER FOR VETERINARY AND HUMAN USE AND METHOD FOR PREPARING A SOLUTION CONTAINING ANY ANTIBIOTIC. |
-
1982
- 1982-11-19 GB GB08233017A patent/GB2109783B/en not_active Expired
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3829093A1 (en) * | 1988-08-27 | 1990-03-01 | Hoechst Ag | Sterile, crystalline sodium carbonate and a process for the preparation thereof |
DE3829093C2 (en) * | 1988-08-27 | 2000-02-10 | Hoechst Ag | A process for the production of sterile, crystalline sodium carbonate |
WO1999033750A1 (en) * | 1997-12-23 | 1999-07-08 | Technische Universiteit Delft | Production of water-free soda |
US6334989B1 (en) | 1997-12-23 | 2002-01-01 | Technische Universiteit Delft | Production of water-free soda |
EP1004546A1 (en) * | 1998-11-24 | 2000-05-31 | Technische Universiteit Delft | Process for the production of sodium carbonate anhydrate |
WO2000030976A1 (en) * | 1998-11-24 | 2000-06-02 | Technische Universiteit Delft | Process for the production of sodium carbonate anhydrate |
EP1013607A1 (en) * | 1998-11-24 | 2000-06-28 | Technische Universiteit Delft | Production of water-free soda |
US6514475B1 (en) * | 1998-11-24 | 2003-02-04 | Technische Universiteit Delft | Process for the production of sodium carbonate anhydrate |
BE1016062A3 (en) * | 2004-06-01 | 2006-02-07 | Vaccifar Bv | ANTIBIOTIC IN THE FORM OF A WATER-SOLUBLE POWDER FOR VETERINARY AND HUMAN USE AND METHOD FOR PREPARING A SOLUTION CONTAINING ANY ANTIBIOTIC. |
EP1602361A3 (en) * | 2004-06-01 | 2008-05-07 | Vaccifar BV | Antibiotic in the form of a water-soluble powder for veterinary and human use |
Also Published As
Publication number | Publication date |
---|---|
GB2109783B (en) | 1985-08-14 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PE20 | Patent expired after termination of 20 years |
Effective date: 20021118 |