IE19990720A1 - Controlling uniformity of crystalline precipitates - Google Patents
Controlling uniformity of crystalline precipitatesInfo
- Publication number
- IE19990720A1 IE19990720A1 IE1999/0720A IE990720A IE19990720A1 IE 19990720 A1 IE19990720 A1 IE 19990720A1 IE 1999/0720 A IE1999/0720 A IE 1999/0720A IE 990720 A IE990720 A IE 990720A IE 19990720 A1 IE19990720 A1 IE 19990720A1
- Authority
- IE
- Ireland
- Prior art keywords
- solvent
- product
- precipitate
- vortex mixer
- precursor therefor
- Prior art date
Links
- 239000002244 precipitate Substances 0.000 title claims description 29
- 239000000047 product Substances 0.000 claims description 34
- 239000012296 anti-solvent Substances 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 27
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 18
- 239000002245 particle Substances 0.000 claims description 14
- 238000001556 precipitation Methods 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000010924 continuous production Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000839 emulsion Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229940119837 Isopropyl Alcohol Drugs 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 229960004592 isopropanol Drugs 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 238000005020 pharmaceutical industry Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0059—General arrangements of crystallisation plant, e.g. flow sheets
-
- B01F3/08—
-
- B01F5/0057—
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/2405—Stationary reactors without moving elements inside provoking a turbulent flow of the reactants, such as in cyclones, or having a high Reynolds-number
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00051—Controlling the temperature
- B01J2219/00074—Controlling the temperature by indirect heating or cooling employing heat exchange fluids
- B01J2219/00105—Controlling the temperature by indirect heating or cooling employing heat exchange fluids part or all of the reactants being heated or cooled outside the reactor while recycling
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00051—Controlling the temperature
- B01J2219/00159—Controlling the temperature controlling multiple zones along the direction of flow, e.g. pre-heating and after-cooling
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00162—Controlling or regulating processes controlling the pressure
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J8/00—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes
- B01J8/005—Separating solid material from the gas/liquid stream
- B01J8/006—Separating solid material from the gas/liquid stream by filtration
Abstract
Abstract *IQnL1(H.11ng L41i:unnnL;3'
Description
invention relates to A method and apparatus for
the wanufn Lure of produc%a in aha form of Controlled
uniform size precipitates.
In the manufacture of a number of chemical products,
particularly in the pharmaceutical industry, using a
precipitation process, it is desired to achieve a high
standard of uniformity of particle size in the
precipitates and also to control the particle size,
generally with the object of achieving a precipitate in
the form of uniform small size crystallites. This can be
difficult to achieve as crystal growth can occur rapidly
and this leads to non-uniformities because of variations
in the time periods for which different parts of the
precipitate may be exposed to solvent containing
unprecipitated solute.
The invention provides, in one of its aspects, a
method for the manufacture of a product in the form of a
controlled uniform particle size precipitate, which
method comprises supplying to a first tangential input of
a fluidic vortex mixer a solvent containing the product
or a precursor therefor in solution, supplying to a
second tangential input of the fluidic vortex mixer an
anti-solvent, whereby rapid mixing of the solvent and
anti-solvent takes place in the vortex mixer and a
precipitate of the product or precursor therefor is
produced in the solvent/anti-solvent mix emerging from an
axial outlet of the vortex mixer, and feeding said
emerging mix from the axial outlet directly into a
precipitate entrapment device.
By anti-solvent we mean a fluid which promotes
precipitation from the solvent of the_product 9;"/A __
precursor in solution in the solvent. Anti-solvent may
thus have any one of a number of forms depending upon the
particular product/precursor, the nature of the solvent
and the precipitation process. For example,
precipitation from a hot solution can be promoted by
cooling, so that the anti—solvent can be a cold fluid.
It may comprise the same liquid as the hot solvent or may
be a different liquid and, preferably, to provide for
continuous re-cycling, is more volatile than the solvent.
Or the anti-solvent may comprise a cold gas or a fluid
which promotes the precipitation via a chemical reaction
or by its effect upon the solubility of the product or
precursor in the solvent.
By precipitate entrapment device, we mean any device
which will have the effect of so trapping the precipitate
as to prevent, or reduce the possibility for, further
growth of precipitate particles. For a product which
precipitates as crystallites, the entrapment device
conveniently comprises a filter medium.
The invention also provides apparatus for the
manufacture of a product in the form of a controlled
uniform particle size precipitate, which apparatus
comprises a fluidic vortex mixer with a first tangential
input connected to a source of solvent containing the
product or a precursor therefor, and a second tangential
input connected to a source of anti-solvent, the fluidic
vortex mixer having an axial outlet connected directly
into a precipitate entrapment device.
In one arrangement according to the invention the
entrapment device is a filter bed which has the effect of
rapidly removing precipitate forming in the axial outlet
of the vortex mixer from the solvent/anti-solvent mix
containing a precipitated product or precursor therefor,
IE 990720
and thus preventing or reducing the possibility of
further growth of the precipitate.
In such an apparatus there is preferably provided a
conduit for conveying the filtrate to a component, such
as an evaporator, for concentrating and re—heating the
solvent containing unprecipitated product or precursor
therefor and separating anti—solvent. Evaporated anti-
solvent may be collected and recovered for re-use by
condensation and cooling as necessary. Heated solvent
containing unprecipitated product or precursor therefor
is combined with a product make-up stream for return to
the first tangential input of the fluidic vortex mixer in
a continuous process.
In certain manufacturing processes, the first stage
of precipitation yields an oily phase which is, for
example, a metastable form of the final crystalline
product. For such processes, the entrapment device
conveniently comprises a stirred tank, the oily
precipitate emerging from the axial outlet of the fluidic
vortex mixer as an emulsion containing small uniform oil
particles. These are held in the tank and prevented from
coalescing by the stirring for long enough for the oil
particles to transform into solid crystallites, after
which separation may be effected by, for example,
filtration or centrifugation.
Recovered solvent/anti-solvent mix from this
separation may be collected and recovered for re-use as
described above.
Specific methods and constructions of apparatus
embodying the invention will now be described by way of
example and with reference to the drawings filed
herewith, in which:
IE 990720
Figure 1 is a block schematic diagram of an
apparatus, and
Figure 2 is a block schematic diagram of another
apparatus.
Figure 1 illustrates a crystallisation facility made
up of four key components: a fluidic vortex mixer 11, a
filter bed 12, a reduced pressure distillation column 13
and a condenser and cooler vessel 14.
Anti-solvent from a supply (not shown) is introduced
via pipeline 15 into the cooling region of the condenser
and cooler vessel 14. A connection 16 provides for anti-
solvent recovered from reduced pressure evaporator 13 to
be supplied to the condenser and cooler vessel 14. A
pipeline 1? is connected to a first tangential input of
the fluidic vortex mixer 11 and is supplied with hot
solvent containing product or a precursor therefor in
solution from the combination of a product makeup supply
at 19 and concentrate from the reduced pressure
evaporator 13. Cold anti-solvent from the vessel 14 is
fed at 17 into a second tangential input of the fluidic
vortex mixer 11. An intimate mix of the hot solution and
cold anti-solvent is formed very rapidly in the fluidic
vortex mixer 11 and emerges at 20 to be received directly
onto the filter bed 12, illustrated as a moving medium,
which separates precipitated product (or product
precursor) rapidly from the mix. Filtrate passing
through the filter bed 12 is carried by pipeline 21 to
the reduced pressure evaporator 13, in which filtrate
containing unprecipitated product (or precursor) is
concentrated, re-heated and returned together with
product makeup 19 to the first tangential input of the
fluidic vortex mixer 11.
IE 990720
In this example, the anti-solvent is the same liquid
as the solvent (a typical example being isopropylalcohol)
but, being cold, promotes precipitation by cooling the
solution. It will be appreciated that the anti-solvent
may comprise any suitable fluid that will effect the
required precipitation on contact with the solution. If
the anti-solvent is more volatile than the solvent, this
will lead to more efficient operation of the reduced
Indeed,
liquefied carbon dioxide) gas is used as
pressure evaporator l3. if a cold gas or
liquefied (e.g.
anti-solvent, then the function of the reduced pressure
evaporator 13 will simply be to re-heat the filtrate and
drive off entrained or dissolved gas. It may be
convenient simply to vent such gas driven off in the
reduced pressure evaporator 13, but if it is to be re-
used, then it will need to be cooled (but not necessarily
condensed).
Figure 2 illustrates a form of apparatus for use in
a process in which precipitate first forms as an oily
phase which eventually solidifies into crystalline
product. Here again, fluidic vortex mixer 23 serves to
form.rapidly an intimate mix of hot solution supplied at
26 to a first tangential input and cold anti—solvent
supplied at 25 to a second tangential input. The oily
phase precipitate emerges from axial outlet 27 as an
emulsion of dispersed oil particles. Formation of a fine
emulsion comprising small uniform sized oil particles is
encouraged by designing the fluidic vortex mixer 23 to
have a large pressured differential across it typically >
bar.
Axial outlet 27 leads directly into the precipitate
entrapment device which, in this example, comprises tank
28 provided with a stirrer 29 operated with sufficient
IE 990720
vigour to maintain the emulsion in its finely dispersed
state for long enough for the metastable oil particles to
solidify as fine crystalline product.
In a process of this type, the anti-solvent is
usually different from, but miscible with, the solvent.
Typically a non—polar anti-solvent is used where the
solvent is polar. For example, if isopropylalcohol is
used as a polar solvent, non—polar methylene chloride may
be used as a anti-solvent. Methylene chloride is
miscible in isopropylalcohol but diminishes the
properties of isopropylalcohol to dissolve solute and
thus promotes precipitation. In another example, heptane
may be used as non—polar anti-solvent.
Once solidified precipitate has formed, this can the
separated by filtration or centrifugation and the
filtrate recovered for re-use in a manner similar to that
It will be
appreciated that the principal of operation illustrated
described with reference to Figure 1.
by Figure 2 can be adapted for continuous operation by
extending the stirred tank 28 into a continuous conduit
or plug flow vessel in which agitation is maintained, the
length of the conduit or vessel being such that the fine
emulsion is maintained for long enough for the
solidification to occur.
IE 990720
Claims (11)
1. A method for the manufacture of a product in the form of a controlled uniform particle size precipitate, which method comprises supplying to a first tangential input of a fluidic vortex mixer a solvent containing the product or a precursor therefor in solution, supplying to a second tangential input of the fluidic vortex mixer an anti-solvent, whereby rapid mixing of the solvent and anti-solvent takes place in the vortex mixer and a precipitate of the product or precursor therefor is produced in the solvent/anti-solvent mix emerging from an axial outlet of the vortex mixer, and feeding said emerging mix from the axial outlet directly into a precipitate entrapment device.
2. Apparatus for the manufacture of a product in the form of a controlled uniform particle size precipitate, which apparatus comprises a fluidic vortex mixer with a first tangential input connected to a source of solvent containing the product or a precursor therefor, and a second tangential input connected to a source of anti- solvent, the fluidic vortex mixer having an axial outlet connected directly into a precipitate entrapment device.
3. Apparatus as claimed in claim 2, wherein the entrapment device is a filter bed which has the effect of rapidly removing precipitate forming in the axial outlet of the vortex mixer.
4. Apparatus as claimed in claim 2 or claim 3, wherein there is provided a conduit for conveying filtrate to a component for concentrating and re-heating the solvent containing unprecipitated product or precursor therefor and separating anti-solvent. IE 990720
5. Apparatus as claimed in claim 4, wherein means is provided for evaporated anti-solvent to be collected and recovered for re-use by condensation and cooling
6. Apparatus as claimed in claim 4 or claim 5, wherein the said component for concentrating and re-heating the solvent containing unprecipitated product or precursor therefor comprises a reduced pressure evaporator.
7. Apparatus as claimed in claim 6, wherein a conduit is provided for combining heated solvent containing unprecipitated product or precursor therefor from the said evaporator with a product make-up stream for return to the first tangential input of the fluidic vortex mixer in a continuous process.
8. Apparatus as claimed in claim 2 for use in manufacturing processes in which the first stage of precipitation yields an oily phase, wherein the entrapment device comprises a stirred receptacle.
9. Apparatus has claimed in claim 8, wherein the said receptacle comprises a conduit or vessel of sufficient length in relation to the flow for the oily phase to solidify before leaving the receptacle. form of a controlled uniform particle size precipitate
A method for the manufacture of a product in the substantially as hereinbefore described.
11. Apparatus for the manufacture of a product in the form of a controlled uniform particle size precipitate substantially as hereinbefore described with reference to, and illustrated in,
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBUNITEDKINGDOM04/09/19989819225.5 | |||
| GB9819225A GB2341120B (en) | 1998-09-04 | 1998-09-04 | Controlling uniformity of crystalline precipitates |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IE19990720A1 true IE19990720A1 (en) | 2000-05-03 |
| IE990720A1 IE990720A1 (en) | 2000-05-03 |
| IE83889B1 IE83889B1 (en) | 2005-05-04 |
Family
ID=
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