United States Patent (19) 11 Patent Number: 4,614,648

Bru (45) Date of Patent: Sep. 30, 1986

54 PROCESS FOR MANUFACTURING (56) References Cited
EFFERVESCENT GRANULES AND TABLETS
U.S. PATENT DOCUMENTS
76) Inventor: Jean Bru, 24 Rue Raphael, Paris 2,463,962 3/1949 Gorcica et al. ............ 252/188.31 X
75016, France 2,497,057 2/1950 Papeet al. ....... ... 252/188.31 X
2,985,562 5/1961 Millard et al. ........................ 424/44
2,999,293 9/1961 Taff et al. ........ . 424/44X
21 Appl. No.: 643,980 3,401,216 9/1968 Coletta .............................. 424/44X
3,480,185 11/1969 Steinberg et al. ... 252/350X
22 PCT Filed: Dec. 20, 1983 3,773,922 11/1973 Gergely ............... ... 252/188.31 X
3,903,255 9/1975 Gusman et al. ....................... 424/44
(86). PCT No.: PCT/FR83/00253 4,267,164 5/1981 Yeh et al. .............................. 424/44
S371 Date: Aug. 20, 1984 FOREIGN PATENT DOCUMENTS
S 102(e) Date: Aug. 20, 1984 0.011489 5/1980 European Pat. Off. .............. 424/44
0.076340 4/1983 European Pat. Off. .
2092893 1/1972 France .
87 PCT Pub. No.: WO84/02468
PCT Pub. Date: Jul. 5, 1984 Primary Examiner-Richard D. Lovering
Attorney, Agent, or Firm-Ostrolenk, Faber, Gerb &
Soffen
30 Foreign Application Priority Data
57) ABSTRACT
Dec. 21, 1982 FR) France ........... 82. 21476
Nov. 30, 1983 IFR) France ................................ 83 19143 The invention relates to a process for manufacturing
effervescent tablets consisting in the steps of careful
51) Int. Cl. .......................... A61L 9/04; B01F 3/12; humidifying of the acid-base mixture, pre-drying and
CO6D 5/10 final drying and granulating.
52 U.S. C. ................................. 424/44; 252/188.31; It has been found that these operations can be per
252/350; 252/.363.5; 514/163; 514/474; formed in a single apparatus, either integrally in fluid
514/629; 514/960; 514/961 bed, or with vacuum-drying.
58) Field of Search ................... 252/157, 188.31, 350,
252/.363.5; 424/44; 514/960,961 9 Claims, 2 Drawing Figures
U.S. Patent Sep. 30, 1986 Sheet 1 of 2 4,614,648

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U.S. Patent Sep. 30, 1986 sheet 2 of 2 4,614,648

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B: dry incoming air
PROCESS FOR MANUFACTURING C: powder in suspension
EFFERVESCENT GRANULES AND TABLETS D: humid outgoing air
1, 3 and 7: filters
The present invention relates to an improved process 2 and 8: turbines
for manufacturing effervescent mixtures and tablets 4: heating element
containing in particular active principles for pharma 5: heat regulating system
ceutical use. 6: solvent spray
In this domain, positive progress has been made by The operation of such an apparatus is obvious and is,
the techniques described in French Pat. Nos. 71 12175 O moreover, generally known.
and 71 35069.
These techniques employ three stages of operation: FIG. 2 schematically shows the arrangement of appa
(1) Careful humidification of the sodium bicarbonate by ratus according to another variant of the invention in a
production tower.
a very small quantity of demineralized water, then In FIG. 2, the references have the following mean
addition of citric acid and possibly of glycocoll (bind 15 ings:
ing agent), all this in a mixer of the kneader type, production tower
which starts off the reaction of the bicarbonate on the storage hoppers
citric acid; automatic supply
(2) pre-drying of the mixture in fluid bed obtained by mixing-granulation-drying apparatus
blowing hot air, which interrupts the reaction; heat exchange hopper
(3) final drying, likewise in fluid bed, obtained by blow band mixer
ing hot air. emptying -q
The two Patents mentioned above describe with pre
cision the details of the modus operandi for each of the DESCRIPTION
three phases: duration, temperature of the air, humidity 25
content, speed of the air jet, etc., and the man skilled in According to a first variant of the invention (FIG. 1),
the art may usefully refer to them. a granulator-drier operating entirely in fluid bed is used.
Although very interesting, this technique presents the Granulator-driers of the type which will be described
drawback of necessitating the transfer of the filler, after hereinafter have been known for a long time.
step (1), from the mixer to the drier. Consequently, the 30 However, it was not thought possible that the turbu
effervescent reaction triggered off in the mixer cannot lence created in such apparatus by the blowing of air
be mastered with total precision as its interruption, could suffice to suitably "imbricate” the particles of the
which occurs in step (2) in the drier, depends on the starting reactive materials, which is essential in the
time for emptying and transferring the filler towards the technical sector in question, and it was thought, on the
drier, which time varies from one batch to the follow 35 contrary, that only a "mechanical' stirring, i.e. of the
ing. type obtained by the blades in the mixers used in the
This variation in time has a considerable repercussion prior known technique, could give a valid result. This is
on the quality of the grain at the end of granulation. why no attempt has ever been made to use the granula
No solution to this problem of industrial working has tor-driers, which are nonetheless well known.
been found since the invention of the technique, about 40 It has now been unexpectedly discovered that these
twelve years ago, despite the obvious interest in solving apparatus enable the particles of the starting material
it and the attempts which have been made to that end. used in the technique in question to be correctly imbri
It has now been discovered, according to the inven cated.
tion, that all of the reactions and operations described It is therefore possible to carry out the three opera
hereinabove can be carried out in one and the same 45 tional steps mentioned above in one and the same appa
multi-function apparatus. ratus, with the following very important advantages
Taking into account the very high precision required both as regards the quality of the products and indus
in these operations in order to satisfy the very strict trial profitability:
quality requirements laid down by the pharmaceutical no emptying or transfer of the reaction mixture, there
industry (particularly concerning the honogeneity of 50 fore providing the possibility of interrupting the ef
the finished granule, and the interruption at a very pre fervescent reaction in extremely precise manner; this
cise degree of advance of the reaction initiated by the in turn leads to the disappearance of the differences
addition of solvent), this was not considered possible. which might be noted from one batch to another in
However, Applicant has achieved this result and, the prior known technique;
moreover, has also improved the quality of the gran 55 saving of time
ules. the conventional mixers had to be placed under aspira
BRIEF DESCRIPTION OF THE DRAWINGS tion in order to avoid a rise in pressure due to the
formation of CO2. In addition, they had to be regu
The invention will be more readily understood on larly unclogged. These two factors caused consider
reading the following description with reference to the 60 able losses of powder, which are not found in the new
accompanying drawings, in which: process according to the invention (about 1%);
FIG. 1 shows the apparatus, and in particular the possibility of calculating parameters of and automating
granulator-drier, used for the tests referred to hereinbe the granulator-driers used, which was very difficult,
low according to one variant embodiment of the inven if not impossible, in the prior known technique.
tion. 65 The principle of wet granulation used makes it possi
The references in FIG. 1 have the following mean ble to obtain, from powders of defined calibre, an elabo
ings: rate product whose granulometric characteristics are
A: hygrometric treatment of the air adapted for subsequent compression.
 4,614,648
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This process of granulation also enables mixtures of Similarly, operations 1 to 5 in their chronological
powders of homogeneous chemical composition to be sequence may be automated. Such automatization ren
obtained by using fluidization. ders the process economical from the standpoint of
Granulation consists in a fixation by chemical bond of manpower (about 1 t/hr. for 2 persons) by elimination
the particles of sodium bicarbonate and of citric acid. 5 of the interruptions between the operations.
These chemical bonds are obtained by an addition of a The apparatus serving for mixing-granulation-drying
defined quantity of demineralized water which pro is composed of a perfectly sealed tank, provided with a
vokes a partial effervescent reaction with the formation System of mechanical stirring for mixing the incorpo
of mono-, di- or trisodium citrate. These molecules of rated powders and equipped with lump-breaking cut
Sodium citrate are considered as bridges bonding the ters which divide the agglomerates formed by the sol
particles of sodium bicarbonate and the particles of vent during wetting. This tank must also comprise:
citric acid and give the mixture the physical properties a double wall allowing passage of a heat-exchanging
of compressibility. fluid
The effervescent reaction triggered off by an outside a trap for admission and emptying of the raw materials
15 a vacuum-creating apparatus which enables a minimum
addition of 1 to 6% by weight of aqueous solvent (water
or wetting solution) will continue by itself as it is gene pressure of 70 millibars to be obtained.
rative of water, and it will be interrupted by drying by All the mechanical or physical elements intervening
means of hot dry air (60-70° C.). in the successive operations of granulation-drying are
The proces of granulation-drying is applicable in monitored by thermometric probe, by measurement of
particular to the production of an excipient type effer amperage and vacuum.
vescent mixture on which the active principles and By way of example, an apparatus of the adapted DVT
lubricants are added in a subsequent operation; by way Lödige type is suitable. A further originality of the
of example, we shall cite the parameters defined for invention resides in the use of a heat exchange hopper
buffered effervescent aspirin, for which a wet-process for cooling the granules.
25 The following Examples illustrate the invention with
granulation is effected on 3 compounds: sodium bicar
bonate, citric acid and possibly glycocol (binding out, however, limiting the scope thereof. For the gen
agent). eral modus operandi, reference will be made to the
It is also applicable to the production of an efferves above-mentioned French Patents. Examples 1 to 4 re
cent mixture containing one or more active principles. late to the first variant, and I and II to the second vari
30 ant of the invention.
By way of example, we shall cite the parameters defined
for a formula containing paracetamol. EXAMPLE 1
According to a second variant, the invention enables reactive principle: aspirin
a process of production employing a vacuum to be effervescent mixture:
carried out in particularly effective manner. This tech 35 sodium bicarbonate
nique makes it possible: citric acid
to eliminate the separate wetting and drying phase glycocol (optional)
to shorten production time, thus improving productiv for 255.22 kg of powder.
ity
to save energy 40 Operation 1: Premix
without forgetting the lesser risk of chemical destabili Incorporate successively the sodium bicarbonate, the
Zation by a treatment from solvents. citric acid and the glycocoll; switch on the turbine of
A further original feature of the invention resides in the granulator at an output allowing fluidization of the
the fact that the apparatus have been grouped together powders.
in a vertical production tower. 45 Air temperature: 64 C.
According to this second variant (FIG. 2), the pro
cess for producing effervescent granules intended for Operation 2: Spraying
compression is characterized by the creation of a tower Solvent=demineralized water
1 in which the following operations are carried out: The solvent is always sprayed on the powders in
1. The weighing of raw materials from storage 50 suspension in air, which makes it possible to increase the
hoppers 2, exchange surface between the base particles and the
2. the automatic supply (3) of all or part of these raw acid particles; at this stage of operation, the output and
materials in the mixer-granulator-drier 4, spray time must be monitored.
3. the mixing, granulation and drying of the efferves
cent granule in vacuo, 55 Operation 3: Drying
4. the cooling in a heat exchange hopper 5 by fluidiza The rate of flow of air is to be monitored so as to
tion more compact than a drier employing fluidized air avoid too great a turbulence of the powders in the cav
bed, ity of the apparatus, which would render the particles
5. calibration by oscillating granulator and final mix fragile.
ing in a band mixer 6 for example of the Gondard type 60 Temperature of incoming air: 64 C.
on Scales for calculating the yield,
6. emptying (7) of this mixer into containers of the EXAMPLE 2
Flo-Bin type. Granulation on granulator-drier of an effervescent
Operations 1 to 6 occur vertically downwardly, mixture containing a plurality of active principles.
transfers taking place by gravity and being dustfree. 65
The interest resides in the fact that the 3 operations of
point 3 (mixing, granulation, drying) can be automated Formula of granulation
from the standpoint of monitoring of the process. Paracetamol 28 kg
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-continued Wetting by spraying, or aspiration of the solvent
Formula of granulation under partical vacuum.
Monosodium carbonate 100 kg
Concentration of the solvent: 0.64% with respect to
Monopotassium carbonate 3.740 kg 5
the weight of the powder.
Sorbito 25,500 kg Operation 3: Granulation
Anhydrous citric acid 73,000 kg
Ascorbic acid 17.000 kg Granulation is effected under atmospheric pressure
TOTAL 247.24 kg for 5 minutes.
10 Operation 4: Drying
Operation 1: Premix This is obtained by reducing the atmospheric pres
Operation is carried out as in Example 1. sure to 70 millibars; at that pressure, the boiling point of
Air temperature: 64 C. the solvent is attained. Drying continues by raising the
temperature.
Operation 2: Spraying 15 This operation lasts about 37 minutes, stoppage of
Nature of the solvent: solvent of manoxol in water drying being triggered off by monitoring the residual
Operation is carried out as in Example 1. humidity of the powder.
The advantages of this technique are as follows:
Operation 3: Drying obtaining of a granule of better quality, in particular one
Temperature of air: 64 C. 20 which is more homogeneous,
Operation is carried out as in Example 1. use of sufficiently low thermal zones, for the thermola
For the following two Examples, operation is carried bile active products not to be destabilized,
out as in Examples 1 and 2, from the formulations here complete automation possible,
inbelow: the addition of heat necessary for evaporation of the
25 solvent is very little.
EXAMPLE 3 Example II-Example of mixing by direct compression
Formulation:
Disodium sulfate 20,200 kg Calcium carbasalate
Sodium bromide 7.100 kg 30 Lysine carbamate
Disodium phosphate 13.800 kg
Monosodium carbonate 101.000 kg Citric acid
Anhydrous citric acid 89.000 kg Arona
PEG (polyethylene glycol)
Nature of the solvent: aqueous solution by doxylamine Ammonium saccharinate:
- 35
Succinate Description of manufacture
EXAMPLE 4 (1) The calcium carbasalate will be stored in one of
hoppers 2. It will then be pre-weighed at 3 and incorpo
Monosodium carbonate 108.000 kg 40
rated in the mixer-granulator-drier 4.
Anhydrous citric acid 14.500 kg In this variant of the invention, the automation of the
Betaine citrate 142.000 kg tower makes it possible to eliminate the functions of
mixing and granulation and to conserve only the drying
Nature of the solvent: demineralized water.
function of apparatus 4.
(2) After drying, the calcium carbasalate is sent into
Example I-Example of granulation 45 cooler 5 in order to return the product to its initial
temperature.
Formulation (3) Calibration is effected, either by simple passage
paracetamol over a grid, or by crushing, the choice being made as a
vitamin C function of the nature of the products delivered.
sodium bicarbonate 50 (4) Emptying into a band mixer 6 in which the prod
citric acid uct is exactly weighed.
potassium bicarbonate The four operations mentioned above are then re
sorbitol. peated for the lysine carbamate and the citric acid.
The tests were carried out on a mixture of the 58 kg After reception of these three constituents in the
of powders. 55 mixer, the auxiliary constituents: aroma, PEG and am
Operation 1: Premix monium saccharinate, are added into the band mixer.
The running of the mixer and its working principle
The different raw materials mentioned above are guarantee the required quality of the active principle of
successively incorporated in the mixer 4 without taking this formula from the standpoint of homogeneity.
into account any physical incompatibilities existing 60 What is claimed is:
therebetween. The premix is effected in 3 minutes. Dur 1. A process for the manufacture of effervescent tab
ing this period of time, the temperature of the powder is lets in which the powdered raw materials therefor are
raised by introducing a heat-exchange liquid in the dou mixed and the mixture is carefully humidified by a sol
ble jacket of the mixer. vent followed by granulation and drying, wherein the
Operation 2: Incorporation of the solvent in the mixer 65 steps of mixing said raw materials, humidifying the
mixture with the solvent and drying are conducted
The solvent is a mixture of water/sodium dioctylsul inside the same apparatus, wherein the drying step is
fosuccinate. performed in vacuo.
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2. The process of claim 1, wherein the components of and drying is obtained in this apparatus by creating a
the mixture are: VaCl).
effervescent mixture: 6. The process of claim 5, wherein the granules are
sodium bicarbonate then cooled by passing in a heat exchange hopper.
citric acid 7. The process of claim 5, wherein the mixing means
and the solvent is demineralized water.
comprises a system of mechanical stirring with lump
breaking cutters, the means for introducing the solvent
3. The process of claim 2, wherein the effervescent comprises a system of aspiration of the solvent by cre
mixture contains glycocoll. ation of a vacuum or a spraying system supplied by a
4. The process of claim 1, wherein the mixture com O pump, and the means for regulating the temperature
prises: comprises a double jacket where a heat-exchange fluid
paracetamol circulates.
monosodium carbonate 8. The process of claim 7, wherein the raw materials
monopotassium carbonate in powder form are as follows:
15 paracetamol
sorbitol vitamin C
anhydrous citric acid sodium bicarbonate
ascorbic acid citric acid
and the solvent is a solution of manoxol in water. potassium bicarbonate
5. The process of claim 1, wherein said apparatus 20 sorbitol.
comprises in particular: 9. A process as claimed in claim 5 wherein the raw
mixing means materials in powdered form are as follows:
calcium carbasalate
means for introducing the solvent lysine carbamate
means for regulating the temperature 25 citric acid.
means for creating a vacuum,

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