WO2007072072A2

WO2007072072A2 - Crystallisation apparatus and process with supercritical fluid

Info

Publication number: WO2007072072A2
Application number: PCT/GB2006/050428
Authority: WO
Inventors: David Hipkiss
Original assignee: Accentus Plc
Priority date: 2005-12-20
Filing date: 2006-12-05
Publication date: 2007-06-28
Also published as: GB0810663D0; GB0525852D0; GB2446352A; GB2446352B; WO2007072072A3

Abstract

Crystallisation is brought about in a process utilising supercritical fluid either as solvent or antisolvent, wherein a solution that is being changed into a supersaturated condition is subjected to intense ultrasound to initiate nucleation. The solution may have the supercritical fluid as solvent, being changed to being supersaturated by a first-stage expansion. Or a solution may be contacted with the supercritical fluid as an antisolvent, so it becomes supersaturated.

Description

Crystallisation Apparatus and Process with supercritical fluid

This invention relates to an apparatus for forming crystals of a variety of different materials, and to the process associated with this apparatus.

Over the last 20 years various processes have been developed for bringing about crystallisation or precipitation using gases at supercritical conditions.

This is particularly applicable using carbon dioxide, as its critical temperature is sufficiently low that elevated temperatures are not required, so that thermally labile compounds can be treated. One process, which may be referred to as Rapid Expansion of Super Critical

Solutions (RESS) involves dissolving the solid material in the supercritical solvent, and then depressurising to near atmospheric pressure so that the solute precipitates out. Such a process is for example described in US 4 970 093. Another process, described in WO 03/004142, which may be referred to as Supercritical Assisted Atomisation (SAA) , involves dissolving the material in a solvent, and then dissolving carbon dioxide in this solution in a packed bed operating under elevated pressure, so as to form a solution that contains both the solid and carbon dioxide. This solution is then passed through a thin wall aperture so as to be atomised and to decrease the pressure to near atmospheric, forming a spray of small droplets that rapidly evaporate. Supercritical gases can also act as antisolvents, and in a process which may be referred to as Supercritical Anti-Solvent precipitation (SAS) the material is dissolved in a suitable solvent which is then contacted with a supercritical antisolvent. The use of supercritical gases has also been described in US 2004/0202681, to form a particles consisting of combinations of pharmaceutical materials. The materials are dissolved in a solvent and then mixed with supercritical carbon dioxide under pressure, so that the solvent dissolves in the carbon dioxide and the materials precipitate as a powder.

The critical properties (critical temperature, T_c, and critical pressure P_c) of some typically used fluids are shown in the table:

Table

In the case of a supercritical fluid, that is to say a fluid that is above both its critical temperature and its critical pressure, there can be no liquid phase. The fluid has a density comparable to that of a liquid (e.g. about 0.47 g/cm³ for carbon dioxide), and has many of the properties of a liquid, such as acting as a solvent, and yet it behaves as a gas in that it occupies all the available volume. A problem that can arise with processes such as RESS as described above, in which the supercritical fluid is allowed to expand to around atmospheric pressure, is that the changes occur so rapidly that the material in solution is left in an amorphous form.

According to the present invention there is provided a method of bringing about crystallisation in a process utilising supercritical fluid either as solvent or antisolvent, wherein a solution that is being changed into a supersaturated condition is subjected to intense ultrasound to initiate nucleation.

For example, a material may be dissolved in a supercritical fluid; the pressure or temperature is decreased (so that the resulting solution becomes supersaturated) and at this stage the solution is subjected to ultrasound; the solution is then depressurised to about atmospheric pressure so that the material precipitates out, forming crystals on the nuclei generated by the ultrasound. Preferably the solution is allowed to stand in the supersaturated state after being subjected to ultrasound, to allow crystals nuclei to grow, prior to being depressurised.

In another example a material is dissolved in a liquid solvent, and the solution is injected into supercritical fluid (which then acts as an antisolvent) ; ultrasound is introduced into the solution to initiate nucleation as the concentration of the material rises due to the effect of the antisolvent.

The invention also provides an apparatus for performing such a method.

The invention will now be further and more particularly described by way of example only, and with reference to the accompanying drawings, in which:

Figure 1 shows a flow diagram of a plant for performing a crystallisation process; and

Figure 2 shows a flow diagram of an alternative plant for performing a crystallisation process.

Referring to figure 1 there is shown a plant 10 for performing a modification of the RESS process. As is known, this process can be used if the material is soluble in the supercritical fluid, or alternatively the material may first be dissolved in a co-solvent and then added to the supercritical fluid; the co-solvent must be miscible in the supercritical fluid. Carbon dioxide from a storage vessel 12 is supplied through a pump 14 to a dissolution vessel 16 which is maintained at a temperature and pressure such that the carbon dioxide is in the supercritical state. The material or materials to be precipitated are introduced into the vessel 16 through an inlet duct 18 (either in solid form, or as a solution in a co-solvent) so as to form a saturated solution in the supercritical carbon dioxide.

This solution is passed through an outlet duct 20 which leads to a holding tank 22 which is held at a slightly lower pressure than the dissolution vessel 16. The duct 20 incorporates a pressure reduction valve 24 followed by an irradiation duct 26 within which the solution is subjected to intense ultrasound. This duct 26 consists of a stainless-steel pipe 27 to the outside of which are attached several ultrasonic transducers 28 via coupling blocks, for example the transducers 28 being arranged in circumferential rings of five transducers, and there being for example three such circumferential rings (only four such transducers 28 are shown) , such that the ultrasonic intensity at the inner surface of the pipe 26 is less than 4 W/cm², for example about 2 W/cm²; the power deposition within the pipe 27 is preferably in the range 20 to 100 W/litre. The transducers 28 are electrically connected to a signal generator 30 set at say 20 kHz. The holding tank 22 is preferably of such a size that the solution remains in it for several minutes, preferably at least 30 minutes, to allow time for any crystal nuclei initiated by the ultrasound to grow. The solution from the holding tank 22 is then passed through a flow control valve 32 to a spray nozzle 34 in a vessel 36 held substantially at atmospheric pressure.

As mentioned above, within the vessel 16 a saturated solution is formed. As this passes through the pressure reduction valve 24 into the holding tank 22, the solution becomes supersaturated. The high intensity ultrasound may cause cavitation, and in any event it initiates the formation of crystal nuclei. While it remains in the holding tank 22 these crystal nuclei gradually grow, and consequently the spray nozzle 34 is ejecting droplets which already contain crystal nuclei. Hence the material is formed in a substantially crystalline form as a powder in the spraying vessel 36.

It will be appreciated that this plant 10 is shown by way of example only, and that the invention can be applied in a wide range of different contexts. The plant 10 can be modified in many ways while remaining within the scope of the invention.

Referring now to figure 2 there is shown a plant 40 for performing a modified version of the SAS process, those components which are identical to those shown in figure 1 being referred to by the same reference numerals. Carbon dioxide from a storage vessel 12 is supplied through a pump 14 to a dissolution vessel 42 which is maintained at a temperature and pressure such that the carbon dioxide is in the supercritical state. The dissolution vessel 42 has a top tubular section 44 which is of narrower diameter, and which has several ultrasonic transducers 28 attached to its outside via coupling blocks, for example the transducers 28 being arranged in circumferential rings of three transducers, and there being for example four such circumferential rings (only four such transducers 28 are shown) , such that the ultrasonic intensity at the inner surface of the pipe 26 is less than 4 W/cm², for example about 1.7 W/cm²; the power deposition within the pipe 27 is preferably in the range 20 to 100 W/litre. The transducers 28 are electrically connected to a signal generator 30.

The material or materials to be precipitated are introduced into the vessel 42 from a storage vessel 46, which contains the materials in solution in a suitable solvent, via a pump 48 and a duct 50 to a spray nozzle 52 at the top end of the top section 44. The droplets formed by the spray nozzle 52 are subjected to ultrasound from the transducers 28 and at the same time the surrounding carbon dioxide acts as an antisolvent, extracting the solvent, so that the droplets becomes supersaturated and at the same time the ultrasound triggers nucleation. Consequently a precipitate containing crystals of the materials forms in the container 42, and this can be recovered through the outlet duct 54. The remaining mixture of the solvent and supercritical carbon dioxide is fed through an outlet duct 55 into a separation vessel 56 at lower pressure, in which liquid (solvent) and gaseous (carbon dioxide) phases separate, and may be re-used.

In one modification to the plant 40 the spray nozzle 52 is at the downstream end of the tubular section 44, so the ultrasound is applied immediately before the solution is sprayed into the antisolvent. In another modification the vessel 42 is of the same diameter as the tubular irradiation section 44. In both the plant 10 and the plant 40 the frequency of the ultrasonic irradiation may be in the range 10 kHz to 200 kHz, more preferably between 15 kHz and 50 kHz, and typically about 20 kHz, although it may be varied during the course of the irradiation, for example the frequency varying sinusoidally between 19 kHz and 21 kHz.

When processing complex compounds such as proteins, which can be denatured if subjected to excessive temperatures or excessive ultrasonic intensity, it will be appreciated that the ultrasonic intensity required would be less; in such a situation it may be sufficient to provide an ultrasonic intensity high enough to cause streaming, rather than cavitation.

Claims

1. A method of bringing about crystallisation in a process utilising supercritical fluid either as solvent or antisolvent, wherein a solution that is being changed into a supersaturated condition is subjected to intense ultrasound to initiate nucleation.

2. A method as claimed in claim 1 wherein a material is dissolved in a supercritical fluid; the pressure or temperature is decreased so that the resulting solution becomes supersaturated, and at this stage the solution is subjected to ultrasound; the solution is then depressurised to about atmospheric pressure so that the material precipitates out, forming crystals of the material on the nuclei generated by the ultrasound.

3. A method as claimed in claim 2 wherein the solution is allowed to stand in the supersaturated state after being subjected to ultrasound, to allow crystals nuclei to grow, prior to being depressurised.

4. A method as claimed in claim 1 wherein a material is dissolved in a liquid solvent, and the solution is injected into supercritical fluid which acts as an antisolvent; ultrasound is introduced into the solution to initiate nucleation as the concentration of the material rises due to the effect of the antisolvent.

5. An apparatus for performing a method as claimed in any one of the preceding claims.