US2540253A - Granulation process - Google Patents
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- US2540253A US2540253A US75288A US7528849A US2540253A US 2540253 A US2540253 A US 2540253A US 75288 A US75288 A US 75288A US 7528849 A US7528849 A US 7528849A US 2540253 A US2540253 A US 2540253A
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Definitions
- This invention relates to a method of granulation suitable for the preparation of tablets.
- the initial step in the preparation of tablets involves the conversion of the ingredients from a finely powdered to a granulated form.
- a conventional method of. granulation referred to as the moist granulating process, consists of the addition to the powder mixture of'moistening liquids, such as alcohol, water or acetone with a binder dissolved therein, causing the line particles to adhere and to remain adherent after dryin Bind r o u iorn WhiQll. ar pli m sed n ude sucrose. syru s. ela n. sp i mucilage of acacia, mucilage-of tragacanth, etc.
- the use of this method is, objectionable in many cases because of the initial destructive effect of the solvent or the subsequent instability of the substances to; be compressed.
- The. process is likewise unsuitable for mixtures, which are incompatiblein the presence of moisture.
- An alternative method of granulation is that of preoonipression or slugging, Themixed ingredicuts, in finely powdered form, are compressed into rather large discs or slugs which are. then broken and passed through a sieve of the proper size. Unsatisfactory resultsare obtained if the ingredientseither possess poo;- compression qualities, or are of a hygroscopic nature.
- An object of this invention is to provide a new and improved process for the granulation of substances which are either hydroscopic or can be slugged only with difficulty.
- Another object of this invention is to provide a new and improved granulation process for the preparation of tablets of improved stability.
- a still further object of this invention is to provide a new and improved granulation process for the preparation of catalysts in tablet form suitable for industrial purposes.
- the granulation of finely,v divided material may be effected by the use of amixture consisting of an anhydrous halo,- genated non-polar solvent, together with a binder thatis solublev in this solvent and also soluble in water.
- Themixture to be tableted is mixed with a solution of thewater soluble binding agent dissolved in the non-polar solvent, the amount of binder used ranging. from 1-6%. of the, composite weight of the mixture. sufficientnon-spolar solvent. is used to dissolve the binder therein and to convert the mixture to a damp non-fluid mass.
- the moistened mass is forced through asieve, dried and sieved again.
- the size of the mesh used depends upon the size of the tablet to be. made.
- Carbowax-GOOO is an excellent lubricant for the subsequent compression of the granules into.
- a lubricant such as stearic acid, or preferably a salt of this acid, such as magnesium stearate, is well distributed finely divided form over the granulation prior to compression. The use of a lubricant insures uniform feeding into the dies preventing' (a) malformations of the tablets caused by granules adhering to the dies and punches after the compression operation, and lb) sticking of the punches.
- the method of this invention has been advantageously applied to the preparation of various medicinal tabletsv including tablets of thiamine hydrochloride (Vitamin 131), tablets of Urecholine, tablets of l-isoamidone, tablets of aspirin, phenacetin and caffeine, etc.
- these tablets could not be conveniently prepared by the conventional moist granulating process.
- Granulated, tableted and extruded catalysts including the catalyst commonly used in the synthesis of methyl alcohol, said catalyst containing 50 mole percent each of chromic oxide and zinc oxide, have also been prepared by this improved process.
- process of this invention can be used for the preparation of tablets generally, and is not in any way restricted or confined to tablets used for medicinal or therapeutic purposes solely.
- Example 1 Tablets of thiamine hydrochloride containing the following ingredients were prepared as fol- The thiamine hydrochloride and lactose were triturated in a mortar and then sifted through a #40 sieve. The Carbowax-6000 was dissolved in the ethylene dichloride and this solution was added to the thiamine-lactose mixture with trituration. After thorough incorporation, the damp mass was pressed through a sieve and the resulting granules were dried at 40 C. for 0.5 hour. The granules were then pressed through a #16 sieve.
- the corn starch and magnesium stearate were triturated in a mortor and sifted through a #60 sieve onto the granulation. After thorough mixing, the granulation was compressed into 0.200 g. tablets.
- the granules were compressed into tablets of a Stokes F single punch tablet machine, punches of various sizes being used to prepare tablets of different weights.
- Example 2 Tablets of Urecholine containing the following ingredients were prepared as follows:
- the Urecholine and lactrose were thoroughly triturated in a mortar and then moistened with the ethylene dichloride solution of Carbowax 6000. The mass was pressed through a #10 sieve and dried for 0.5 hour at 40 C. The dried granules were then pressed through a #16 sieve. The corn starch and magnesium stearate were triturated together and sifted through a #60 sieve onto the granulation. After thorough mixing, the granulation was compressed into tablets of 0.075 g.
- Example 4 Tablets of aspirin, phenacetin and caffeine containing the following ingredients were prepared as follows:
- the phenacetin and caffeine were thoroughly mixed and granulated in the same manner with a solution of 2 g. of Carbowax-GOOO in 30 cc. of carbon tetrachloride. After drying the two lots of granules for 1 hour at 40 0., they were pressed separately through a #14 sieve. The corn starch, talc and magnesium stearate were triurated together in a mortar and divided in half. One half was sifted through a #60 sieve onto the aspirin granulation, and the second half onto the phenacetincaifeine granulation. The two separate granulated masses were then thoroughly mixed and compressed into 0.400 g. tablets.
- The. ascorbicv acid, citric acid, anhydrous dextrose and/1.0 g. of the corn starch were triturated thoroughly ina. mortar.
- the CarbowaX-6000 was dissolved in the ethylene dichloride, and this sol'utionwas addedto themixed powders with trituration. After thorough incorporation, the damp mass was pressed through a sieve, and the resulting granules were dried at C. for 0.5. hour. These granules were then broken down to proper size by first repressing through a #lcsieve andlthen through a #14 sieve. 5.0 g.
- cornstarch was sifted onto the dried'granules (#60" sieve) and the lubricated granule mixture was tumbledifor. 0.5 hour to effect mixing. The granules were then compressed into tablets weighing 1.00'g. each.
- the penicillin calcium was weighed out under low humidity conditions (less than 20% relative humidity) to protect the penicillin remaining in the container. The following operations were carried out at a relative humidity of 31% and at a temperature of 26 C.
- the penicillin calcium and sodium citrate were triturated in a mortar.
- the Carbowax-GOOO was dissolved in the ethylene dichloride and this solution was added to: the mixed powders with trituration. After thorough mixing, the damp mass was pressed through a #10 sieve, and the resulting granules were dried at 40 C. for 0.5 hour. These granules were then broken down to proper size by first repressing them through a #10 sieve and then through a #14 sieve.
- the corn starch was sifted onto the dried granules with a sieve and a lubricant granule mixture was tumbled for 0.5 hour to effect thorough mixing. The granules were then compressed into tablets weighing 0.500 g. each.
- the sodium bicarbonate was' granulated with asolution oi4;5 g. of Carbowax-6000 in sufficient ethylene dichloride to make-4.5 cc. of solution. Tliis 'solution was added to the sodium bicarbonate ina mortar and after thoroughly incorporating the solution, the damp mass was granulated in a manneridentical to that described in the preceding paragraph.
- the acid granules and the sodiumbicarbonate granules were combined and thoroughly" mixed by tumbling for 0.5- hour.
- Themixed' granules were compressed without additional lubrication into tablets of 060g.
- Catalyst tablets containing the following ingredients were prepared as follows:
- the process of preparing granules of therapeutic materials comprising the steps of mixing an active therapeutic agent, together with a solid water-soluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the moist nonfluid mass thus obtained into discrete granules and removing said non-polar solvent from said granules.
- the process of preparing granules of therapeutic materials comprising the steps of mixing an active therapeutic agent, together with a solid Water-soluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500 and being present in the amount of about 1-6% of the composite weight of the mixture, and the amount of said non-polar solvent being sufiicient to convert said mixture to a damp non-fluid mass, forming said moist nonfluid mass thus obtained into discrete granules by extrusion through apertures of fixed size and removing said non-polar solvent from said granules.
- the process of preparing therapeutic tablets comprising the steps of mixing an active therapeutic agent, together with a solid watersoluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500 and being present in the amount of about 1-6% of the composite weight of the mixture, and the amount of said non-polar solvent being suflicient to convert said mixture to a damp non-fluid mass, forming said moist nonfluid mass thus obtained into discrete granules by extrusion through apertures of fixed size,
- the process of preparing thiamine hydrochloride tablets comprising the steps of mixing thiamine hydrochloride, together with a solid water-soluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the moist non-fluid mass thus obtained into discrete granules, removing said non-polar solvent from said granules, lubricating said granules and compressing said granules to form tablets.
- the process of preparing stable water-soluble ascorbic acid tablets comprising the steps of mixing ascorbic acid together with a solid watersoluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500, fOrming the damp non-fluid mass thus obtained into discrete granules, removing said non-polar solvent from said granules, lubricating said granules and compressing said granules to form tablets.
- the process of preparing stable effervescent tablets comprising the steps of mixing separately, the acid and basic constituents of said mixture, together with a solid water-soluble polyethylene glycol dissolved in an anhydrous chlorinated nonpolar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the damp non-fluid masses separately obtained into discrete granules, removing said non-polar solvent from said separate masses, mixing said dried acid and basic granules, and compressing said mixture of granules into tablets.
Description
Patented Feb. 6, 1951 GEANULATION Pnoonss Walter C. Gakenheimer, Westfield, N J1, assignorto Merck & (30., Inc., Railway, N. 1., a corpora-.
tion of New Jersey No Drawing. Application February 8, 1949, Serial No. 75,283,
Sfllaims. 1
This invention relates to a method of granulation suitable for the preparation of tablets.
The initial step in the preparation of tablets involves the conversion of the ingredients from a finely powdered to a granulated form. A conventional method of. granulation, referred to as the moist granulating process, consists of the addition to the powder mixture of'moistening liquids, such as alcohol, water or acetone with a binder dissolved therein, causing the line particles to adhere and to remain adherent after dryin Bind r o u iorn WhiQll. ar pli m sed n ude sucrose. syru s. ela n. sp i mucilage of acacia, mucilage-of tragacanth, etc. The use of this method is, objectionable in many cases because of the initial destructive effect of the solvent or the subsequent instability of the substances to; be compressed. The. process is likewise unsuitable for mixtures, which are incompatiblein the presence of moisture.
An alternative method of granulation is that of preoonipression or slugging, Themixed ingredicuts, in finely powdered form, are compressed into rather large discs or slugs which are. then broken and passed through a sieve of the proper size. Unsatisfactory resultsare obtained if the ingredientseither possess poo;- compression qualities, or are of a hygroscopic nature.
An object of this invention is to provide a new and improved process for the granulation of substances which are either hydroscopic or can be slugged only with difficulty.
Another object of this invention is to provide a new and improved granulation process for the preparation of tablets of improved stability. A
further object of thisinvention is to provide a granulation process for the production of medicinal tablets that will retain their therapeutic potencies for relatively long periods of time.
A still further object of this invention is to provide a new and improved granulation process for the preparation of catalysts in tablet form suitable for industrial purposes.
Other objects and advantages will be readily apparent from the following disclosure.
It has been discovered that the granulation of finely,v divided material may be effected by the use of amixture consisting of an anhydrous halo,- genated non-polar solvent, together with a binder thatis solublev in this solvent and also soluble in water. Themixture to be tableted is mixed with a solution of thewater soluble binding agent dissolved in the non-polar solvent, the amount of binder used ranging. from 1-6%. of the, composite weight of the mixture. sufficientnon-spolar solvent. is used to dissolve the binder therein and to convert the mixture to a damp non-fluid mass. The moistened mass is forced through asieve, dried and sieved again. The size of the mesh used depends upon the size of the tablet to be. made.
soluble in both water and organic liquids, and
which have an average molecular weight of about 6000 to 7500. These substances resemble natural waxes in appearance and texture but are soluble in a much wider range of solvents. In addition, Carbowax-GOOO is an excellent lubricant for the subsequent compression of the granules into.
tablets.
Inert substances such as sucrose, lactose, starch, etc, are commonly added when the mixtures to be tableted are insufficient to give a tablet of practical size; otherwise their use is unnecessary. A lubricant such as stearic acid, or preferably a salt of this acid, such as magnesium stearate, is well distributed finely divided form over the granulation prior to compression. The use of a lubricant insures uniform feeding into the dies preventing' (a) malformations of the tablets caused by granules adhering to the dies and punches after the compression operation, and lb) sticking of the punches.
A unique feature. in this. process, of particular and singular importance in. the production of granulated, tableted and. extruded catalysts to be used in the. chemical and. petroleum industries, is the fact that the. final products contain a very low. percentagenf organic material, as compared to the products made with conventional binders such assucrose, gelatin, acacia, tragacanth, etc. Likewise, another feature is the maintenance of anhydrous. conditions throughout the process.
The method of this invention has been advantageously applied to the preparation of various medicinal tabletsv including tablets of thiamine hydrochloride (Vitamin 131), tablets of Urecholine, tablets of l-isoamidone, tablets of aspirin, phenacetin and caffeine, etc. Heretofore, these tablets could not be conveniently prepared by the conventional moist granulating process.
In addition, by using this special. granulating process, it has been possible to prepare tablets of therapeutic compositions such as ascorbic acid tablets, penicillin tablets, etc. which are completely soluble in water, thereby facilitating the oral administration of these substances to adults and infants as aqueous solutions or in combination with soluble nutrients.
Likewise, the difilculties associated with. the production of stable effervescent granules and tablets have been obviated by the use of my method. The resulting products are completely and rapidly soluble possessing none of the hygroscopic properties usually associated with these types of products.
Granulated, tableted and extruded catalysts, including the catalyst commonly used in the synthesis of methyl alcohol, said catalyst containing 50 mole percent each of chromic oxide and zinc oxide, have also been prepared by this improved process.
It should be noted that the process of this invention can be used for the preparation of tablets generally, and is not in any way restricted or confined to tablets used for medicinal or therapeutic purposes solely.
The following examples illustrate the methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.
Example 1 Tablets of thiamine hydrochloride containing the following ingredients were prepared as fol- The thiamine hydrochloride and lactose were triturated in a mortar and then sifted through a #40 sieve. The Carbowax-6000 was dissolved in the ethylene dichloride and this solution was added to the thiamine-lactose mixture with trituration. After thorough incorporation, the damp mass was pressed through a sieve and the resulting granules were dried at 40 C. for 0.5 hour. The granules were then pressed through a #16 sieve.
The corn starch and magnesium stearate were triturated in a mortor and sifted through a #60 sieve onto the granulation. After thorough mixing, the granulation was compressed into 0.200 g. tablets.
In this and in the subsequent examples, the granules were compressed into tablets of a Stokes F single punch tablet machine, punches of various sizes being used to prepare tablets of different weights.
Example 2 Tablets of Urecholine containing the following ingredients were prepared as follows:
The Urecholine and lactrose were thoroughly triturated in a mortar and then moistened with the ethylene dichloride solution of Carbowax 6000. The mass was pressed through a #10 sieve and dried for 0.5 hour at 40 C. The dried granules were then pressed through a #16 sieve. The corn starch and magnesium stearate were triturated together and sifted through a #60 sieve onto the granulation. After thorough mixing, the granulation was compressed into tablets of 0.075 g.
Ebample 3 Tablets of l-isoamidone containing the following ingredients were prepared as follows:
Per Per 1000 Tablet Tablets 1-Isoamidone hydrochloride monohydrate g- 0.0050 5. 0 Lactoseg 0. 1400 140. 0 Sucrose .g 0. 0300 30.0 OarbowaX-BOOO- g 0. 0040 4. 0 Ethylene dichloride. cc (35) Corn starch g- 0. 0200 20. 0 Magnesium stearate g 0. 0010 1.0
Example 4 Tablets of aspirin, phenacetin and caffeine containing the following ingredients were prepared as follows:
Per Per 1000 Tablet Tablets Aspirin -g 0. 1050 195 Phenacetrm- .g 0. 1300 Oaflcine g. 0. 0330 33 Carbowax-6000 g 0. 0040 4 Carbon tctrachlor cc (60) Gem starch g 0. 0130 13 Talc 0. 0230 23 Magnesium stearate g 0. 0020 2 All ingredients were dried at 50 C. for 24 hours. The aspirin was granulated by mixing with it a solution of 2 g. of Carbowax-BOOO in 30 cc. of carbon tetrachloride and pressing the moist mass through a #10 sieve. The phenacetin and caffeine were thoroughly mixed and granulated in the same manner with a solution of 2 g. of Carbowax-GOOO in 30 cc. of carbon tetrachloride. After drying the two lots of granules for 1 hour at 40 0., they were pressed separately through a #14 sieve. The corn starch, talc and magnesium stearate were triurated together in a mortar and divided in half. One half was sifted through a #60 sieve onto the aspirin granulation, and the second half onto the phenacetincaifeine granulation. The two separate granulated masses were then thoroughly mixed and compressed into 0.400 g. tablets.
1 Example 5' Tablets of Ascorbic Acid containing the following ingredients were prepared as follows: I
The. ascorbicv acid, citric acid, anhydrous dextrose and/1.0 g. of the corn starch were triturated thoroughly ina. mortar. The CarbowaX-6000 was dissolved in the ethylene dichloride, and this sol'utionwas addedto themixed powders with trituration. After thorough incorporation, the damp mass was pressed through a sieve, and the resulting granules were dried at C. for 0.5. hour. These granules were then broken down to proper size by first repressing through a #lcsieve andlthen through a #14 sieve. 5.0 g. of cornstarch was sifted onto the dried'granules (#60" sieve) and the lubricated granule mixture was tumbledifor. 0.5 hour to effect mixing. The granules were then compressed into tablets weighing 1.00'g. each.
These tablets, stored in. screw-capped glass jars at room temperature for 12 months, showed no loss in ascorbicacidcontent;
Example. 6.
Tablets of penicillin containing. the following ingredients were prepared as follows:
The penicillin calcium was weighed out under low humidity conditions (less than 20% relative humidity) to protect the penicillin remaining in the container. The following operations were carried out at a relative humidity of 31% and at a temperature of 26 C. The penicillin calcium and sodium citrate were triturated in a mortar. The Carbowax-GOOO was dissolved in the ethylene dichloride and this solution was added to: the mixed powders with trituration. After thorough mixing, the damp mass was pressed through a #10 sieve, and the resulting granules were dried at 40 C. for 0.5 hour. These granules were then broken down to proper size by first repressing them through a #10 sieve and then through a #14 sieve. The corn starch was sifted onto the dried granules with a sieve and a lubricant granule mixture was tumbled for 0.5 hour to effect thorough mixing. The granules were then compressed into tablets weighing 0.500 g. each.
These tablets, stored in screw-capped glass jars at room temperature for 12 months, retained full therapeutic penicillin potency. '15
Example. 7
Effervescent tablets containing. the: following ingredients were prepared aslfollows:
Pee Per Tablet; Tablets Citric acid, dried-at 55 0. M48 hrs; ..g 0.1084 l 19. 0 Tartaric acid, dried at 55 C. for 48 hrs g 0. 1595 28. 0- Sodium bicarbonate, dried at 55 O. for 48 hrs g; 0.8019. 53. 0 Carbowax-6000 g o 0. 0302 5. 3 Ethylene dichloride cc (53) The following operations were carried out at a relative humidity of 28% and at a temperature of 25? C. The citric acid andtartaric aciclWere triturated with a' mortar and pestle to a fine powder. 03' g. Carbowaxe6000 was dissolved in sufiicient'ethylene dichloride. to make 8cc. of a solution, which was added to the dampacids: with trituration; After. thorough mixing; the damp masswas pressed through a #10 sieve: and the resulting granules were dried at 40 C; for 05 hour; These granules were then blOkGHIdOWII to proper size by first repressing them through a #10" sieve and then through a #14 sieve.
The sodium bicarbonate was' granulated with asolution oi4;5 g. of Carbowax-6000 in sufficient ethylene dichloride to make-4.5 cc. of solution. Tliis 'solution was added to the sodium bicarbonate ina mortar and after thoroughly incorporating the solution, the damp mass was granulated in a manneridentical to that described in the preceding paragraph.
The acid granules and the sodiumbicarbonate granules were combined and thoroughly" mixed by tumbling for 0.5- hour. Themixed' granules were compressed without additional lubrication into tablets of 060g.
These tablets were stored in screw-cappedjars at room temperature for 12 "months. At'the end of this period of time, there has been no change in physical appearance or decrease in effervescence on addition to water; nor had there been any release of carbon dioxide in the glass jar;
Example. 8
Catalyst tablets containing the following ingredients were prepared as follows:
Per Per 330 Tablet Tablets" Chromium-Dioxide; g 0. 3027 100. 0 Zinc Oxide g 0. 2460 81.4 Carbowax-.6000. l" .g 0.0060 1.8 Ethylene dichloride. l cc (30) T c g 0.0553 18.3
The following operations were carried out at 18% relative humidity and 23 C; temperature. The chromium trioxide and zinc oxide were triturated with a mortar and a pestle to a fine powder. 1.8 g. of Carbowax-6000 was dissolved in 30 cc. of ethylene dichloride, and this solution was added to the oxides with trituration. After thorough mixing, the damp mass was pressed through a #10 sieve and the resulting granules were dried at 23 C. for 4 hours. These granules were then broken down to proper size by repressing them through a #16 sieve. 18.3 g. of talc was thoroughlymixed with these granules by tumbling, and the mixture was compressed into tablets weighing 0.6100 geach.
Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the scope of the appended claims, they are to be considered as part of this invention.
I claim:
1. The process of preparing granules of therapeutic materials comprising the steps of mixing an active therapeutic agent, together with a solid water-soluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the moist nonfluid mass thus obtained into discrete granules and removing said non-polar solvent from said granules.
2. The process of preparing granules of therapeutic materials comprising the steps of mixing an active therapeutic agent, together with a -51" solid water-soluble polyethylene glycol dissolved in carbon tetrachloride, said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the non-fluid moist mass thus obtained into discrete granules and removing said carbon tetrachloride from said granules.
3. The process of preparing granules of therapeutic materials comprising the steps of mixing an active therapeutic agent, together with a solid water-soluble polyethylene glycol dissolved in ethylene dichloride, said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the damp non-fluid mass thus obtained into discrete granules and removing said ethylene dichloride from said granules.
4. The process of preparing granules of therapeutic materials comprising the steps of mixing an active therapeutic agent, together with a solid Water-soluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500 and being present in the amount of about 1-6% of the composite weight of the mixture, and the amount of said non-polar solvent being sufiicient to convert said mixture to a damp non-fluid mass, forming said moist nonfluid mass thus obtained into discrete granules by extrusion through apertures of fixed size and removing said non-polar solvent from said granules.
5. The process of preparing therapeutic tablets comprising the steps of mixing an active therapeutic agent, together with a solid watersoluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500 and being present in the amount of about 1-6% of the composite weight of the mixture, and the amount of said non-polar solvent being suflicient to convert said mixture to a damp non-fluid mass, forming said moist nonfluid mass thus obtained into discrete granules by extrusion through apertures of fixed size,
removing said non-polar solvent from said granules and compressing said granules to form tablets.
6. The process of preparing thiamine hydrochloride tablets comprising the steps of mixing thiamine hydrochloride, together with a solid water-soluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the moist non-fluid mass thus obtained into discrete granules, removing said non-polar solvent from said granules, lubricating said granules and compressing said granules to form tablets.
7. The process of preparing stable water-soluble ascorbic acid tablets comprising the steps of mixing ascorbic acid together with a solid watersoluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500, fOrming the damp non-fluid mass thus obtained into discrete granules, removing said non-polar solvent from said granules, lubricating said granules and compressing said granules to form tablets.
8. The process of preparing an eifervescent granule mixture which comprises mixing separately, the acid and basic constituents of said mixture, together with a solid water-soluble polyethylene glycol dissolved in an anhydrous chlorinated non-polar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the damp non-fluid masses separately obtained into discrete granules by extrusion through apertures of fixed size, removing said non-polar solvent from said separate masses and mixing said dried acid and basic granules.
9. The process of preparing stable effervescent tablets comprising the steps of mixing separately, the acid and basic constituents of said mixture, together with a solid water-soluble polyethylene glycol dissolved in an anhydrous chlorinated nonpolar solvent, said polyethylene glycol having a molecular weight of about 6000 to 7500, forming the damp non-fluid masses separately obtained into discrete granules, removing said non-polar solvent from said separate masses, mixing said dried acid and basic granules, and compressing said mixture of granules into tablets.
WALTER C. GAKENHEIMER.
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PA'I'ENTS Number Name Date 2,149,005 Bockmuhl Feb. 29, 1939 2,195,596 Nitardy Apr. 2, 1940 OTHER REFERENCES McClelland, Chemical and Engineering News, vol. 23, Feb. 10, 1945, pages 247-50251.
Claims (1)
1. THE PROCESS OF PREPARING GRANULES OF THERAPEUTIC MATERIAL COMPRISING THE STEPS OF MIXING AND ACTIVE THERAPEUTIC AGENT, TOGETHER WITH A SOLID WATER-SOLUBLE POLYETHYLENE GLYCOL DISSOLVED IN AN ANHYDROUS CHLORINATED NON-POLAR SOLVENT SAID POLYETHYLENE GLYCOL HAVING A MOLECULAR WEIGHT OF ABOUT 6000 TO 7500, FORMING THE MOIST NONFLUID MASS THUS OBTAINED INTO DISCRETE GRANULES AND REMOVING SAID NON-POLAR SOLVENT FROM SAID GRANULES.
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US75288A US2540253A (en) | 1949-02-08 | 1949-02-08 | Granulation process |
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US75288A US2540253A (en) | 1949-02-08 | 1949-02-08 | Granulation process |
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US2540253A true US2540253A (en) | 1951-02-06 |
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US75288A Expired - Lifetime US2540253A (en) | 1949-02-08 | 1949-02-08 | Granulation process |
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Cited By (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2698822A (en) * | 1951-04-28 | 1955-01-04 | Fougera & Co Inc E | Cardiac glycoside buccal composition |
US2742396A (en) * | 1952-08-13 | 1956-04-17 | Purdue Research Foundation | Ointment base |
US2895881A (en) * | 1957-04-04 | 1959-07-21 | Wynn Pharmacal Corp | Quinidine gluconate sustained medication tablet |
US2928770A (en) * | 1958-11-28 | 1960-03-15 | Frank M Bardani | Sustained action pill |
US2977235A (en) * | 1958-03-27 | 1961-03-28 | Merck & Co Inc | Water-soluble tablet for the curing of meat |
US2984543A (en) * | 1957-03-19 | 1961-05-16 | Pierre F Smith | Stabilization of effervescent carbonate powders |
US2991226A (en) * | 1958-02-03 | 1961-07-04 | Frosst & Co Charles E | Long-acting wax-like talc pillage of penicillin |
US3042621A (en) * | 1957-11-01 | 1962-07-03 | Colgate Palmolive Co | Detergent composition |
US3042622A (en) * | 1957-11-01 | 1962-07-03 | Colgate Palmolive Co | Abrasive cleaning composition |
US3067105A (en) * | 1959-09-22 | 1962-12-04 | Nopco Chem Co | Vitamin compositions and processes for producing same |
US3082091A (en) * | 1956-07-03 | 1963-03-19 | Pierre F Smith | Effervescing composition in particle form |
US3096248A (en) * | 1959-04-06 | 1963-07-02 | Rexall Drug & Chemical Company | Method of making an encapsulated tablet |
US3105792A (en) * | 1960-11-29 | 1963-10-01 | Warner Lambert Pharmaceutical | Stable effervescent compositions and method of preparing same |
US3136692A (en) * | 1961-06-30 | 1964-06-09 | Strong Cobb Arner Inc | Effervescent composition containing polyvinylpyrrolidone |
US3295992A (en) * | 1963-08-28 | 1967-01-03 | Richardson Merrell Inc | Reducing the stickiness of hot candy |
US3331696A (en) * | 1962-01-20 | 1967-07-18 | Boehringer & Soehne Gmbh | Dragee coating composition |
US3347682A (en) * | 1966-06-23 | 1967-10-17 | Lancet Lab Inc | Colorant tablet |
US3511914A (en) * | 1967-01-31 | 1970-05-12 | Schering Corp | Throat lozenge vehicle |
US3789119A (en) * | 1971-06-01 | 1974-01-29 | Parke Davis & Co | Stabilized molded sublingual nitroglycerin tablets |
US3862311A (en) * | 1971-04-12 | 1975-01-21 | Ciba Geigy Corp | Novel method of enhancing progestational endometrial proliferation with progesterone |
US3873727A (en) * | 1971-06-01 | 1975-03-25 | Parke Davis & Co | Stabilization of molded sublingual nitroglycerin tablets |
US4101650A (en) * | 1977-04-06 | 1978-07-18 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Pepstatin floating minicapsules |
US4321263A (en) * | 1980-09-30 | 1982-03-23 | Rowell Laboratories, Inc. | Psyllium compositions |
US4343789A (en) * | 1979-07-05 | 1982-08-10 | Yamanouchi Pharmaceutical Co., Ltd. | Sustained release pharmaceutical composition of solid medical material |
US4347235A (en) * | 1981-09-03 | 1982-08-31 | Miles Laboratories, Inc. | Water-soluble tablet |
US4478819A (en) * | 1982-04-26 | 1984-10-23 | Roussel Rclaf | Novel oral preparations |
US4557926A (en) * | 1983-09-06 | 1985-12-10 | Monsanto Company | Method and tablet for sanitizing toilets |
US4624849A (en) * | 1984-11-02 | 1986-11-25 | The Procter & Gamble Company | Antimicrobial lozenges |
US4650669A (en) * | 1985-07-30 | 1987-03-17 | Miles Laboratories, Inc. | Method to make effervescent calcium tablets and calcium tablets produced thereby |
US4702919A (en) * | 1984-10-09 | 1987-10-27 | Takeda Chemical Industries, Ltd. | Granules of thiamine salt and the production thereof |
EP0243521A1 (en) * | 1986-04-30 | 1987-11-04 | Werner Prof. Dr. Thorn | Preparation for oral administration |
USRE32811E (en) * | 1983-06-02 | 1988-12-27 | S. C. Johnson & Son, Inc. | Easily dispersible dietary fiber product and method for producing the same |
US5286748A (en) * | 1981-01-05 | 1994-02-15 | Eby Iii George A | General method of shortening the duration of common colds by application of medicaments to tissues of oral cavity |
US5340591A (en) * | 1992-01-24 | 1994-08-23 | Fujisawa Pharmaceutical Co., Ltd. | Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2149005A (en) * | 1935-11-09 | 1939-02-28 | Winthrop Chem Co Inc | Shaped medicinal preparation |
US2195596A (en) * | 1936-11-07 | 1940-04-02 | Squibb & Sons Inc | Protected-vitamin-containing tablet |
-
1949
- 1949-02-08 US US75288A patent/US2540253A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2149005A (en) * | 1935-11-09 | 1939-02-28 | Winthrop Chem Co Inc | Shaped medicinal preparation |
US2195596A (en) * | 1936-11-07 | 1940-04-02 | Squibb & Sons Inc | Protected-vitamin-containing tablet |
Cited By (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2698822A (en) * | 1951-04-28 | 1955-01-04 | Fougera & Co Inc E | Cardiac glycoside buccal composition |
US2742396A (en) * | 1952-08-13 | 1956-04-17 | Purdue Research Foundation | Ointment base |
US3082091A (en) * | 1956-07-03 | 1963-03-19 | Pierre F Smith | Effervescing composition in particle form |
US2984543A (en) * | 1957-03-19 | 1961-05-16 | Pierre F Smith | Stabilization of effervescent carbonate powders |
US2895881A (en) * | 1957-04-04 | 1959-07-21 | Wynn Pharmacal Corp | Quinidine gluconate sustained medication tablet |
US3042622A (en) * | 1957-11-01 | 1962-07-03 | Colgate Palmolive Co | Abrasive cleaning composition |
US3042621A (en) * | 1957-11-01 | 1962-07-03 | Colgate Palmolive Co | Detergent composition |
US2991226A (en) * | 1958-02-03 | 1961-07-04 | Frosst & Co Charles E | Long-acting wax-like talc pillage of penicillin |
US2977235A (en) * | 1958-03-27 | 1961-03-28 | Merck & Co Inc | Water-soluble tablet for the curing of meat |
US2928770A (en) * | 1958-11-28 | 1960-03-15 | Frank M Bardani | Sustained action pill |
US3096248A (en) * | 1959-04-06 | 1963-07-02 | Rexall Drug & Chemical Company | Method of making an encapsulated tablet |
US3067105A (en) * | 1959-09-22 | 1962-12-04 | Nopco Chem Co | Vitamin compositions and processes for producing same |
US3105792A (en) * | 1960-11-29 | 1963-10-01 | Warner Lambert Pharmaceutical | Stable effervescent compositions and method of preparing same |
US3136692A (en) * | 1961-06-30 | 1964-06-09 | Strong Cobb Arner Inc | Effervescent composition containing polyvinylpyrrolidone |
US3331696A (en) * | 1962-01-20 | 1967-07-18 | Boehringer & Soehne Gmbh | Dragee coating composition |
US3295992A (en) * | 1963-08-28 | 1967-01-03 | Richardson Merrell Inc | Reducing the stickiness of hot candy |
US3347682A (en) * | 1966-06-23 | 1967-10-17 | Lancet Lab Inc | Colorant tablet |
US3511914A (en) * | 1967-01-31 | 1970-05-12 | Schering Corp | Throat lozenge vehicle |
US3862311A (en) * | 1971-04-12 | 1975-01-21 | Ciba Geigy Corp | Novel method of enhancing progestational endometrial proliferation with progesterone |
US3789119A (en) * | 1971-06-01 | 1974-01-29 | Parke Davis & Co | Stabilized molded sublingual nitroglycerin tablets |
US3873727A (en) * | 1971-06-01 | 1975-03-25 | Parke Davis & Co | Stabilization of molded sublingual nitroglycerin tablets |
US4101650A (en) * | 1977-04-06 | 1978-07-18 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Pepstatin floating minicapsules |
US4343789A (en) * | 1979-07-05 | 1982-08-10 | Yamanouchi Pharmaceutical Co., Ltd. | Sustained release pharmaceutical composition of solid medical material |
US4404183A (en) * | 1979-07-05 | 1983-09-13 | Yamanouchi Pharmaceutical Co., Ltd. | Sustained release pharmaceutical composition of solid medical material |
US4321263A (en) * | 1980-09-30 | 1982-03-23 | Rowell Laboratories, Inc. | Psyllium compositions |
WO1983003353A1 (en) * | 1980-09-30 | 1983-10-13 | Rowell Lab Inc | Psyllium compositions |
US5286748A (en) * | 1981-01-05 | 1994-02-15 | Eby Iii George A | General method of shortening the duration of common colds by application of medicaments to tissues of oral cavity |
US4347235A (en) * | 1981-09-03 | 1982-08-31 | Miles Laboratories, Inc. | Water-soluble tablet |
US4478819A (en) * | 1982-04-26 | 1984-10-23 | Roussel Rclaf | Novel oral preparations |
USRE32811E (en) * | 1983-06-02 | 1988-12-27 | S. C. Johnson & Son, Inc. | Easily dispersible dietary fiber product and method for producing the same |
US4557926A (en) * | 1983-09-06 | 1985-12-10 | Monsanto Company | Method and tablet for sanitizing toilets |
US4702919A (en) * | 1984-10-09 | 1987-10-27 | Takeda Chemical Industries, Ltd. | Granules of thiamine salt and the production thereof |
US4624849A (en) * | 1984-11-02 | 1986-11-25 | The Procter & Gamble Company | Antimicrobial lozenges |
US4650669A (en) * | 1985-07-30 | 1987-03-17 | Miles Laboratories, Inc. | Method to make effervescent calcium tablets and calcium tablets produced thereby |
EP0243521A1 (en) * | 1986-04-30 | 1987-11-04 | Werner Prof. Dr. Thorn | Preparation for oral administration |
US5340591A (en) * | 1992-01-24 | 1994-08-23 | Fujisawa Pharmaceutical Co., Ltd. | Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine |
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