|Publication number||USRE33086 E|
|Application number||US 07/071,991|
|Publication date||Oct 10, 1989|
|Filing date||Jul 10, 1987|
|Priority date||Dec 21, 1982|
|Also published as||CA1209040A, CA1209040A1, DE3390423C2, DE3390423T0, DE3390423T1, EP0162043A1, EP0162043B1, US4614648, WO1984002468A1|
|Publication number||07071991, 071991, US RE33086 E, US RE33086E, US-E-RE33086, USRE33086 E, USRE33086E|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (19), Non-Patent Citations (4), Referenced by (6), Classifications (23), Legal Events (5)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present invention relates to an improved process for manufacturing effervescent mixtures and tablets containing in particular active principles for pharmaceutical use.
In this domain, positive progress has been made by the techniques described in French Pat. Nos. 71 12175 and 71 35069.
These techniques employ three stages of operation:
(1) Careful humidification of the sodium bicarbonate by a very small quantity of demineralized water, then addition of citric acid and possibly of glycocoll (binding agent), all this in a mixer of the kneader type, which starts off the reaction of the bicarbonate on the citric acid;
(2) pre-drying of the mixture in fluid bed obtained by blowing hot air, which interrupts the reaction;
(3) final drying, likewise in fluid bed, obtained by blowing hot air.
The two Patents mentioned above described with precision the details of the modus operandi for each of the three phases: duration, temperature of the air, humidity content, speed of the air jet, etc., and the man skilled in the art may usefully refer to them.
Although very interesting, this technique presents the drawback of necessitating the transfer of the filler, after step (1), from the mixer to the drier. Consequently, the effervescent reaction triggered off in the mixer cannot be mastered with total precision as its interruption, which occurs in step (2) in the drier, depends on the time for emptying and transferring the filler towards the drier, which time varies from one batch to the following.
This variation in time has a considerable repercussion on the quality of the grain at the end of granulation.
No solution to this problem of industrial working has been found since the invention of the technique, about twelve years ago, despite the obvious interest in solving it and the attempts which have been made to that end.
It has now been discovered, according to the invention, that all of the reactions and operations described hereinabove can be carried out in one and the same multi-function apparatus.
Taking into account the very high precision required in these operations in order to satisfy the very strict quality requirements laid down by the pharmaceutical industry (particularly concerning the homogeneity of the finished granule, and the interruption at a very precise degree of advance of the reaction initiated by the addition of solvent), this was not considered possible.
However, Applicant has achieved this result and, moreover, has also improved the quality of the granules.
The invention will be more readily understood on reading the following description with reference to the accompanying drawings, in which:
FIG. 1 shows the apparatus, and in particular the granulator-drier, used for the tests referred to hereinbelow according to one variant embodiment of the invention.
The references in FIG. 1 have the following meanings:
A: hygrometric treatment of the air
B: dry incoming air
C: powder in suspension
D: humid outgoing air
1, 3 and 7: filters
2 and 8: turbines
4: heating element
5: heat regulating system
6: solvent spray
The operation of such an apparatus is obvious and is, moreover, generally known.
FIG. 2 schematically shows the arrangement of apparatus according to another variant of the invention in a production tower.
In FIG. 2, the references have the following meanings:
1. production tower
2. storage hoppers
3. automatic supply
4. mixing-granulation-drying apparatus
5. heat exchange hopper
6. band mixer
According to a first variant of the invention (FIG. 1), a granulator-drier operating entirely in fluid bed is used.
Granulator-driers of the type which will be described hereinafter have been known for a long time.
However, it was not thought possible that the turbulence created in such apparatus by the blowing of air could suffice to suitably "imbricate" the particles of the starting reactive materials, which is essential in the technical sector in question, and it was thought, on the contrary, that only a "mechanical" stirring, i.e. of the type obtained by the blades in the mixers used in the prior known technique, could give a valid result. This is why no attempt has ever been made to use the granulator-driers, which are nonetheless well known.
It has now been unexpectedly discovered that these apparatus enable the particles of the starting material used in the technique in question to be correctly imbricated.
It is therefore possible to carry out the three operational steps mentioned above in one and the same apparatus, with the following very important advantages both as regards the quality of the products and industrial profitability:
no emptying or transfer of the reaction mixture, therefore providing the possibility of interrupting the effervescent reaction in extremely precise manner; this in turn leads to the disappearance of the differences which might be noted from one batch to another in the prior known technique;
saving of time
the conventional mixers had to be placed under aspiration in order to avoid a rise in pressure due to the formation of CO2. In addition, they had to be regularly unclogged. These two factors caused considerable losses of powder, which are not found in the new process according to the invention (about 1%);
possibility of calculating parameters of and automating the granulator-driers used, which was very difficult, if not impossible, in the prior known technique.
The principle of wet granulation used makes it possible to obtain, from powders of defined calibre, an elaborate product whose granulometric characteristics are adapted for subsequent compression.
The process of granulation also enables mixtures of powders of homogeneous chemical composition to be obtained by using fluidization.
Granulation consists in a fixation by chemical bond of the particles of sodium bicarbonate and of citric acid. These chemical bonds are obtained by an addition of a defined quantity of demineralized water which provokes a partial effervescent reaction with the formation of mono-, di- or trisodium citrate. These molecules of sodium citrate are considered as bridges bonding the particles of sodium bicarbonate and the particles of citric acid and give the mixture the physical properties of compressibility.
The effervescent reaction triggered off by an outside addition of 1 to 6% by weight of aqueous solvent (water or wetting solution) will continue by itself as it is generative of water, and it will be interrupted by drying by means of hot dry air (60°-70° C.).
The .[.proces.]. .Iadd.process .Iaddend.of granulation-drying is applicable in particular to the production of an excipient type effervescent mixture on which the active principles and lubricants are added in a subsequent operation; by way of example, we shall cite the parameters defined for buffered effervescent aspirin, for which a wet-process granulation is effected on 3 compounds: sodium bicarbonate, citric acid and possibly glycocoll (binding agent).
It is also applicable to the production of an effervescent mixture containing one or more active principles. By way of example, we shall cite the parameters defined for a formula containing paracetamol.
According to a second variant, the invention enables a process of production employing a vacuum to be carried out in particularly .[.effective manner.]. .Iadd.efficient.Iaddend.. This technique makes it possible:
to eliminate the seperate wetting and drying phase
to shorten production time, thus improving productivity
to save energy without forgetting the lesser risk of chemical destabilization by a treatment from solvents.
A further original feature of the invention resides in the fact that the apparatus have been grouped together in a vertical production tower.
According to this second variant (FIG. 2), the process for producing effervescent granules intended for compression is characterized by the creation of a tower 1 in which the following operations are carried out:
1. The weighing of raw materials from storage hoppers 2,
2. the automatic supply (3) of all or part of these raw materials in the mixer-granulator-drier 4,
3. the mixing, granulation and drying of the effervescent granule in vacuo,
4. the cooling in a heat exchange hopper 5 by fluidization more compact than a drier employing fluidized air bed,
5. calibration by oscillating granulator and final mixing in a band mixer 6 for example of the Gondard type on scales for calculating the yield,
6. emptying (7) of this mixer into containers of the Flo-Bin type.
Operations 1 to 6 occur vertically downwardly, transfers taking place by gravity and being dustfree. The interest resides in the fact that the 3 operations of point 3 (mixing, granulation, drying) can be automated from the standpoint of monitoring of the process.
Similarly, operations 1 to 5 in their chronological sequence may be automated. Such automatization renders the process economical from the standpoint of manpower (about 1 t/hr. for 2 persons) by elimination of the interruptions between the operations.
The apparatus serving for mixing-granulation-drying is composed of a perfectly sealed tank, provided with a system of mechanical stirring for mixing the incorporated powders and equipped with lump-breaking cutters which divide the agglomerates formed by the solvent during wetting. This tank must also comprise:
a double wall allowing passage of a heat-exchanging fluid
a trap for admission and emptying of the raw materials
a vacuum-creating apparatus which enables a minimum pressure of 70 millibars to be obtained.
All the mechanical or physical elements intervening in the successive operations of granulation-drying are monitored by thermometric probe, by measurement of amperage and vacuum.
By way of example, an apparatus of the adapted DVT Lodige type is suitable. A further originality of the invention resides in the use of a heat exchange hopper for cooling the granules.
The following Examples illustrate the invention without, however, limiting the scope thereof. For the general modus operandi, reference will be made to the above-mentioned French Patents. Examples 1 to 4 relate to the first variant, and I and II to the second variant of the invention.
reactive principle: aspirin
for 255.22 kg of powder.
Incorporate successively the sodium bicarbonate, the citric acid and the glycocoll; switch on the turbine of the granulator at an output allowing fluidization of the powders.
Air temperature: 64° C.
The solvent is always sprayed on the powders in suspension in air, which makes it possible to increase the exchange surface between the base particles and the acid particles; at this stage of operation, the output and spray time must be monitored.
The rate of flow of air is to be monitored so as to avoid too great a turbulence of the powders in the cavity of the apparatus, which would render the particles fragile.
Temperature of incoming air: 64° C.
Granulation on granulator-drier of an effervescent mixture containing a plurality of active principles.
______________________________________Formula of granulation______________________________________Paracetamol 28 kgMonosodium carbonate 100 kgMonopotassium carbonate 3.740 kgSorbitol 25.500 kgAnhydrous citric acid 73.000 kgAscorbic acid 17.000 kgTOTAL 247.24 kg______________________________________
Operation is carried out as in Example 1.
Air temperature: 64° C.
Nature of the solvent: solvent of manoxol in water
Operation is carried out as in Example 1.
Temperature of air: 64° C.
Operation is carried out as in Example 1.
For the following two Examples, operation is carried out as in Examples 1 and 2, from the formulations hereinbelow:
______________________________________Disodium sulfate 20.200 kgSodium bromide 7.100 kgDisodium phosphate 13.800 kgMonosodium carbonate 101.000 kgAnhydrous citric acid 89.000 kg______________________________________
Nature of the solvent: aqueous solution by doxylamine succinate
______________________________________Monosodium carbonate 108.000 kgAnhydrous citric acid 14.500 kgBetaine citrate 142.000 kg______________________________________
Nature of the solvent: demineralized water.
The tests were carried out on a mixture of the 58 kg of powders.
The different raw materials mentioned above are successively incorporated in the mixer 4 without taking into account any physical incompatibilities existing therebetween. The premix is effected in 3 minutes. During this period of time, the temperature of the powder is raised by introducing a heat-exchange liquid in the double jacket of the mixer.
Operation 2: Incorporation of the solvent in the mixer
The solvent is a mixture of water/sodium dioctylsulfosuccinate.
Wetting by spraying, or aspiration of the solvent under .[.partical.]. .Iadd.partial .Iaddend.vacuum.
Concentration of the solvent: 0.64% with respect to the weight of the powder.
Granulation is effected under atmospheric pressure for 5 minutes.
This is obtained by reducing the atmospheric pressure to 70 millibars; at that pressure, the boiling point of the solvent is attained. Drying continues by raising the temperature.
This operation lasts about 37 minutes, stoppage of drying being triggered off by monitoring the residual humidity of the powder.
The advantages of this technique are as follows:
obtaining of a granule of better quality, in particular one which is more homogeneous,
use of sufficiently low thermal zones, for the thermolabile active products not to be destabilized,
complete automation possible,
the addition of heat necessary for evaporation of the solvent is very little.
Example II--Example of mixing by direct compression
PEG (polyethylene glycol)
(1) The calcium carbasalate will be stored in one of hoppers 2. It will then be pre-weighed at 3 and incorporated in the mixer-granulator-drier 4.
In this variant of the invention, the automation of the tower makes it possible to eliminate the functions of mixing and granulation and to conserve only the drying function of apparatus 4.
(2) After drying, the calcium carbasalate is sent into cooler 5 in order to return the product to its initial temperature.
(3) Calibration is effected, either by simple passage over a grid, or by crushing, the choice being made as a function of the nature of the products delivered.
(4) Emptying into a band mixer 6 in which the product is exactly weighed.
The four operations mentioned above are then repeated for the lysine carbamate and the citric acid.
After reception of these three constituents in the mixer, the auxiliary constituents: aroma, PEG and ammonium saccharinate, are added into the band mixer.
The running of the mixer and its working principle guarantee the required quality of the active principle of this formula from the standpoint of homogeneity.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US2463962 *||May 17, 1947||Mar 8, 1949||Fearn Lab Inc||Product for producing effervescing carbonated beverages|
|US2497057 *||Apr 12, 1947||Feb 7, 1950||Toilet bowl -gleanee|
|US2877159 *||Apr 26, 1957||Mar 10, 1959||Ciba Pharm Prod Inc||Method for preparing tablet granulations|
|US2985562 *||Mar 27, 1958||May 23, 1961||Warner Lambert Pharmaceutical||Effervescent compositions|
|US2999293 *||Sep 12, 1957||Sep 12, 1961||Warner Lambert Pharmaceutical||Process of granulating effervescent materials|
|US3401216 *||Jan 9, 1964||Sep 10, 1968||Bristol Myers Co||Methods for preparing pharmaceutical compositions|
|US3480185 *||Jun 20, 1966||Nov 25, 1969||Johnson & Johnson||Charged effervescing agent and medicament dispensing metering valve-actuated aerosol container producing a dose of medicament and carbonation in water|
|US3773922 *||Apr 6, 1972||Nov 20, 1973||Fr Dev Rech Sofrader||Method for the manufacture of effervescent tablets|
|US3903255 *||Oct 11, 1974||Sep 2, 1975||Rohm & Haas||Effervescent potassium chloride tablet|
|US3946996 *||Apr 17, 1973||Mar 30, 1976||Barmag Barmer Maschinenfabrik Aktiengesellschaft||Mixing and granulating apparatus|
|US4093710 *||Jul 7, 1976||Jun 6, 1978||Sandoz, Inc.||Rapid dissolving effervescent granules|
|US4153678 *||Jul 17, 1978||May 8, 1979||American Cyanamid Company||Levamisole effervescent tablets|
|US4267164 *||Jan 31, 1980||May 12, 1981||Block Drug Company Inc.||Effervescent stannous fluoride tablet|
|US4614648 *||Dec 20, 1983||Sep 30, 1986||Jean Bru||Process for manufacturing effervescent granules and tablets|
|AT372299B *||Title not available|
|DE1060093B *||Apr 25, 1958||Jun 25, 1959||Ciba Geigy||Neue Methode zur Herstellung eines Tablettengranulates|
|EP0011489A1 *||Nov 15, 1979||May 28, 1980||Beecham Group Plc||An analgesic effervescent powder and process for its preparation|
|EP0076340A1 *||Oct 6, 1981||Apr 13, 1983||Gerhard Dr. Gergely||Process for manufacturing effervescent granules which may be transformed, when required, into effervescent tablets|
|FR2092893A1 *||Title not available|
|1||Bartsch, "Die Pharmazeutische Industrie", vol. 41, pp. 696-698 (1979).|
|2||*||Bartsch, Die Pharmazeutische Industrie , vol. 41, pp. 696 698 (1979).|
|3||Lieberman et al., "Pharmaceutical Dosage Forms: Tablets", vol. 3, pp. 34-37 (1982).|
|4||*||Lieberman et al., Pharmaceutical Dosage Forms: Tablets , vol. 3, pp. 34 37 (1982).|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US5298261 *||Dec 24, 1992||Mar 29, 1994||Oregon Freeze Dry, Inc.||Rapidly distintegrating tablet|
|US5348745 *||May 5, 1992||Sep 20, 1994||Miles Inc.||Aqueous granulation solution and a method of tablet granulation|
|US5503846 *||Mar 17, 1993||Apr 2, 1996||Cima Labs, Inc.||Base coated acid particles and effervescent formulation incorporating same|
|US6620433||Jul 3, 2002||Sep 16, 2003||Laboratorios Belmac, S.A.||Dispersible and soluble galenic paracetamol formulation, method for its preparation and its applications|
|US8721167 *||Feb 6, 2006||May 13, 2014||Shinagawa Machinery Works Co., Ltd.||Kneading and granulating machine|
|US20090135666 *||Feb 6, 2006||May 28, 2009||Satoru Watano||Kneading and granulating machine|
|U.S. Classification||424/44, 514/961, 252/183.12, 252/183.13, 34/63, 514/629, 252/363.5, 34/92, 516/19, 514/474, 514/163, 514/960, 34/65|
|International Classification||A61K9/46, A61J3/06, A61K9/00, B01J2/16|
|Cooperative Classification||Y10S514/96, Y10S514/961, B01J2/16, A61K9/0007|
|European Classification||B01J2/16, A61K9/00L6|
|Feb 26, 1990||FPAY||Fee payment|
Year of fee payment: 4
|Apr 6, 1992||AS||Assignment|
Owner name: BRU, NICOLE, LEGAL HEIR OF THE ESTATE OF HENRI JEA
Free format text: LETTERS OF TESTAMENTARY;ASSIGNOR:BRU, HENRI J.L. DECEASED BY PHILIPPE LECUYER NOTARY;REEL/FRAME:006073/0188
Effective date: 19920207
|Feb 25, 1994||FPAY||Fee payment|
Year of fee payment: 8
|Jul 29, 1994||AS||Assignment|
Owner name: RECHERCHE ET PROPRIETE INDUSTRIELLE, FRANCE
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BRU, NICOLE;REEL/FRAME:007080/0397
Effective date: 19940630
|Mar 27, 1998||FPAY||Fee payment|
Year of fee payment: 12