Title of Invention	PRODUCTION OF CRYSTALLINE MATERIALS BY USING HIGH INTENSITY ULTRASOUND
Abstract	1. A method for production of crystalline material, the method comprising forming a saturated solution of the 5 material, gradually changing the temperature of the solution so it becomes supersaturaued, and subjecting the solution to irradiation by high-intensity ultrasound, wherein the method involves: a) finding the temperature which provides the least 10 degree of supersaturation at which crystals form from the solution on brief application of ultrasound, and then b) subjecting the solution while it is supersaturated, at this temperature, to ultrasound for a brief interval such that crystals are formed, and then 15 c) allowing the crystals in the solution to grow without irradiation by continuing to change the temperature of the solution.

Title of Invention

PRODUCTION OF CRYSTALLINE MATERIALS BY USING HIGH INTENSITY ULTRASOUND

Abstract

1. A method for production of crystalline material, the method comprising forming a saturated solution of the 5 material, gradually changing the temperature of the solution so it becomes supersaturaued, and subjecting the solution to irradiation by high-intensity ultrasound, wherein the method involves: a) finding the temperature which provides the least 10 degree of supersaturation at which crystals form from the solution on brief application of ultrasound, and then b) subjecting the solution while it is supersaturated, at this temperature, to ultrasound for a brief interval such that crystals are formed, and then 15 c) allowing the crystals in the solution to grow without irradiation by continuing to change the temperature of the solution.

Full Text	PRODUCTION OF CRYSTALLINE MATERIALS BY USING HIGH INTENSITY ULTRASOUND. This invention relates to a method for crystallisation of ingredients that may be suitable for 5 use in pharmaceuticals. The use of high intensity ultrasound to trigger nucleation in a supersaturated solution, so that crystallisation occurs, is known, and an apparatus for 10 this purpose is for example described in GB 2 276 567 A. The benefits of triggering nucleation in this fashion are of particular relevance when very pure crystalline products are to be formed, as the purity of the solution and the cleanliness of the vessel surfaces means that 15 crystallisation nuclei are not otherwise present. Certain compounds would be desirable for use in pharmaceuticals, but have been found particularly difficult to crystallise; this relates in particular to disaccharides such as D-glucose or D-xylose. Similar 2 0 problems arise with other organic compounds such as aspartic acid, and the compound a-L-aspartyl-L-phenylalanine methyl ester (aspartame). It has often been found necessary to add crystal modifiers to a saturated solution of such compounds to ancourage the formation of 25 crystals, as a saturated solution may have to be cooled considerably below the saturation temperature before crystallisation occurs; with some organic materials this■ under-cooling may be as much as 100 K. That is to say, a supersaturated solution may remain in a metastable state 30 for a prölonged period, which may be many months. The use of an immersed ultrasonic probe or horn to subject a saturated solution to ultrasound is commonly used, but it has been found that some cavitation occurs at the surface of the horn, this causing erosion of the horn and 35 consequential generation of very small raetal particles (say about 0.1 run in diameter); consequently this process would not be acceptable for generating crystalline material for use as a pharmaceutical ingrediënt. Accordingly the present invention provides a method 5 for production of crystalline material, the method comprising forming a saturated solution of the material, changing the temperature of the solution so it becomes supersaturated, and subjecting the solution to irradiation by high intensity ultrasound, the ultrasound 10 being applied only while the solution is supersaturated, and being applied only until crystals are formed, and then allowing the crystals in the solution to grow without irradiation. 15 Preferably the ultrasound is applied for a time no more than 10 seconds, for example 2 seconds or 3 seconds. The ultrasound most preferably is applied for a brief interval of say less than 5 seconds, and then the solution inspected to see if any crystals have been 20 formed; if no crystals have been formed than the ultrasound may again be applied for a brief interval, and the solution again inspected. This may be repeated until crystals appear, after which ultrasound is no longer applied. Further gradual cooling of the solution, 25 subsequent to the application of ultrasound, will lead to growth of the crystals formed during the ultrasonic insonation. Hence this method enables large crystals to be grown. 30 The ultrasound may be applied to the supersaturated solution in a vessel using a multiplicity of ultrasonic transducers attached to a wall of the vessel in an array extending both circumferentially and longitudinally, each transducer being connected to a signal generator so that 2 35 the transducer radiates no more than 3 W/cm , the transducers being sufficiently close together and the number of transducers being sufficiently high that the power dissipation within the vessel is between 25 and 150 W/litre. The values of power given here are these of the electrical power delivered to the transducers, as this is 5 relatively easy to deterraine. Such an irradiation vessel is described in WO 00/35579. Surprisingly it has been found that with such a vessel there is no cavitation at the surface of the wall, so that there is no erosion of the wall and consequently no formation of small particles 10 of metal. The crystalline inaterial made by this method can, be very pure, as additives are not required and the crystallisation procedure does not introducé contaminants, so that it would be suitable both for food use and for pharmaceutical use, 15 It is desirable to ensure no focusing of the ultrasound occurs, and this may be achieved by energising groups of adjacent transducers in succession. Where the vessel is cylindrical it is particularly preferable to 20 avoid energising diametrically opposite transducers at the same time. The non-focusing can also be achieved by energising adjacent transducers, or adjacent groups of transducers, at different frequencies; and in particular to vary the frequency at which each transducer. or group 25 of transducers is en-argized over a limited range, for example between 19.5 kHz and 20.5 kHz. The invention will now be further and more particularly described, by way of example only, and with 30 reference to the accompanying drawing which shows a cross-sectional view of a batch crystallisation irradiator. Referring to the drawing, a batch crystallisation 35 irradiator 10 includes a stainless-steel vessel 12 of internal diameter 0.31 m and of wall thickness 2 mm. To the outside of the wall are attached sixty transducer modules 14 closely packed in a square array. Each transducer module 14 comprlses a 50 W piezoelectric transducer 16 which resonates at 20 kHz, attached to a 5 conically flared titanium coupling block 18 by which it is connected to the wall, the wider end of each block being of diameter 53 mm. The transducer modules define five circumferfential rings each of twelve modules 14, the centres of the coupling blocks 18 being on a square pitch 10 of 82 mm. The irradiator 10 also incorporates three signal generators 20 (only one is shown) each of which drives the transducers 16 in a pair of adjacent longitudinal rows and another such pair of rows one third of the circumference apart from the first pair. 15 In use of the irradiator 10 the vessel 12 is filled ■^ with a solution and the temperature of the vessel is gradually lowered (assuming the solubility decreases as the temperature decreases) using a cooling jacket 22, and 20 the contents of the vessel 12 are stirred. Consequently the solution will become saturated and then supersaturated. When the temperature is about 10 K below that at which saturation occurs, the transducers are energized briefly, each generator 20 being energized for 25 0.8 second successively. Each transducer irradiates 50 W over a circle of diameter 63 mm, that is an intensity of 2 1.6 W/cm . The ultrasonic energy is dissipated over the cylindrical volume of the vessel 12, which is about 31 litres, so if all the transducers 16 were energised 30 simultaneously the power density would be about 100 W/litre. To avoid focusing, only one signal generator 20 is energized at any one time, so the energy deposition is about 33 W/litre. After 0.8 second, a different generator 20 is energized, and so on. After 2.4 seconds 35 each transducer has been energized, and application of ultrasound is terminated. The contents of the vessel 12 are then inspected, to see if any crystals have formed. If there are no crystals this activation procedure is repeated. Once crystals are observed, application of ultrasound is terminated, and the temperature of the 5 vessel 12 is gradually lowered. In a modification the signal generators 20 may generate signals at a frequency that varies between 19.5 and 20.5 kHz, the signals f;:om different signal 10 generators 20 varying independently of each other. With this irradiator 10 the power intensity is such that cavitation does not occur at the surface of the wall, so erosion of the vessel 12 does not occur. 15 Nevertheless the power density is sufficiënt to ensure nucleation in a saturated solution. An experiment to investigate the effect of ultrasound on crystallisation has been performed, as 20 follows. An aqueous solution of D-xylose containing 25 g D-xylose per 10 ml water was prepared, which would be saturated at 50°C. This was than cooled at a rata of 0.2 K/min to 20°C, and .the resulting solid products were separated and isolated. As a control, in ene case the 25 transducers 14 were not energized; in this case crystals did not appear until the temperature had dropped to 35°C. If the transducers 14 were energized for a period of 2 minutes, starting at 46°C, then crystals appeared at 43°C. If the transducers 14 were energized continuously, 30 starting at 50"C, then the resulting crystals were very small, and Information on sizes was not obtained. Table 1 gives the temperature T at which solid first appeared and also shows the effect on crystal size distribution by indicating the crystal size (in pm) for different 35 cumulative percentiles (by mass): 5 Since the solutions were saturated at 50°C, ideally crystallisation should commence as soon as the temperature drops below 50°C. The short application of ultrasound markedly reduces the metastable zone width to only about 7 K (as compared to about 14 K in the absence 10 of ultrasound). It also gives a significant increase in the crystal sizes that are formed. Continuous application of ultrasound reduces the metastable zone width even more, to about 4 K." 15 It will be appreciated that the conditions that applied in this particular experiment do not exactly correspond to the method of the present invention, but that the results indicate that it would be appropriate to cool the solution to about 4 3°C before subjecting it to 20 brief irradiation. In performing the present invention, the temperature to which the solution is to be cooled before the brief application of ultrasound will differ for different 25 solutions, depending on the material, the solvent and the concentration, and must therefore be found by experiment. It may be ascertained by experiments similar to those described above. The solution is first subjected to continuous ultrasound as it is cooled, and the 30 temperature at which crystals form (T, which in the example above was 46°C) is observed. Further tests are then carried out, cooling the solution to different temperatures within a few degrees above or below T to find the highest temperature at which crystals form on application of a brief pulse of ultrasound. Typically this is within 5 K of the temperature T observed with 5 continuous ultrasound. Aspartame is the a-dipeptide ester L-aspartyl-L-phenylalanine methyl ester and is an important synthetic low-calorie sweetening agent. It is about 200 times 10 sweeter than sugar and does not leave a bitter aftertaste, and so is used in a wide range of products. It is, however, difficult to crystallise without use of crystal modifiers, particularly from aqueous solution. Surprisingly, it has been found possible to produce 15 satisfactory crystals of aspartame directly from an aqueous solution using the present method. A saturated solution of aspartame in warm pure water is prepared, and introduced into the vessel 12. The temperature of the solution is gradually cooled to about 10 K below the 20 temperature at which it would be saturated, and is subjected to ultrasonic irradiation as described above for a short time, for example 2.4 s. The solution is then inspected, and if crystals have formed as a result of the ultrasonic irradiation, then the temperature of 25 the vessel is gradually cooled over a period of a few hours down to room temperature. This process has been found to produce aspartame crystals between 100 and 250 \|iiti in size, which are easy 30 to separate from the remaining liquid for example by filtration. By avoiding the need for additives the purity of the product is ensured. The inspection to check if any crystals have formed 35 as a result of the ultrasonic irradiation may be an inspection by eye, while shining a light into the solution, as the small crystals sparkle. It will be appreciated that the method is applicable using different apparatus, and may be applied on a 5 continuous rather than a batch basis. For example a saturated solutior. may be cs.used to flow along a duet in which its temperature gradually decreases, the duet incorporating a flow-through ultrasonic irradiation module at a position at which the solution has reached 10 the appropriate temperature, so that the solution is briefly irradiated as it flows thrcugh the module. In this case the transducers of the ultrasonic irradiation module might be activated continuously or in a pulsed mode. 15 The method is applicable to many different chemical compounds. For example it may be used for proteins and amino acids, and for antibiotics. By way of example, the following measurements have been made with the three 20 amino acids L-leucine, L-phenylalanine, and L-histadine. Saturated solutions in water were prepared at 75°C, the concentrations being 3.3, 6.2 and 11.3 g/100 g water respectively (after 24 hours in contact with solid 25 material). Four samples were taken of each solution, and were then cooled at a steady rate of 0.2°C/min. In half the cases the samples were subjected to a 10 s burst of ultrasound every 5 minutes until crystals were observed. No ultrasound was applied to the others. The temperature, 30 T, at which crystals first appeared is shown in Table 2, Tu being the cases with ultrasound, and Tx these without ultrasound. It will be appreciated that in each case the application of ultrasound reduces the metastable zone width, so the crystals appear at a higher temperature. 5 The effect is most dramatic in the case of leucine, where the metastable zone is decreased from about 22.5 K to about 9.8 K. In addition, the ultrasound has an effect on the crystal size distribution, so that the crystals are larger. For example Table 3 shows measurements of 10 the resulting crystal size distributions, as measured with a Malvern Mastersizer 2000, for histadine and phenylalanine, showing the partiele sizes (in \|J,m) for different cumulative percentiles (by mass). TABLE 3 I 10% j 50% j 90% Histadine no ultrasound 15.8 59.9 166.3 Histadine ultrasound 20.6 89.6 370.8 Phenylalanine no ultrasound 133.9 352.4 655.9 Phenylalanine ultrasound 159.9 420.9 776.1 15 As another application, a saturated solution may be insonated so as to generate crystals, and then be added to a larger volume of solution so that the crystals act as seed crystals for the entire volume. For example 2 0 there might be 4000 litres of a saturated solution in a crystallisation tank, which is gradually cooled or to which anti-solvent is added. When it is sufficiently supersaturated, a small quantity (eg 40 1) is transferred into an irradiation chamber (eg sucked up through a pipe) 25 at the same temperature as the tank; there it is subjected to ultrasound so that crystals are formed; it is then transferred back into the tank. If no crystals are formed, this operation may be repeated. \/\]g^ Claimg 1. A method for production of crystalline material, the method comprising forming a saturated solution of the 5 material, gradually changing the temperature of the solution so it becomes supersaturaued, and subjecting the solution to irradiation by high-intensity ultrasound, wherein the method involves: a) finding the temperature which provides the least 10 degree of supersaturation at which crystals form from the solution on brief application of ultrasound, and then b) subjecting the solution while it is supersaturated, at this temperature, to ultrasound for a brief interval such that crystals are formed, and then 15 c) allowing the crystals in the solution to grow without irradiation by continuing to change the temperature of the solution. 2. A method as claimed in claim 1 wherein the solution 20 is subjected to ultrasound for less than lOs. 3. A method as claimed in any one of the preceding claims wherein the ultrasound is provided to the supersaturated solution in a vessel using a multiplicity 2 5 of ultrasonic transducers attached to a wall of the vessel in an array extending both circumferentially and longitudinally, each transducer being connected to a signal generator so that the transducer radiates no more 2 than 3 W/cm , the transducers bexng sufficiently close 3 0 together and the number of transducers being sufficiently high that the power dissipation within the vessel is between 25 and 150 W/litre. 4. A method as claimed in any one of the preceding 3 5 claims wherein ultrasound is applied in such a way that no focusing of the ultrasound occurs. 5. A method as claimed in claim 4 wherein focusing is prevented by energising groups of adjacent transducers in succession. 5 6. A method as claimed in claim 4 or claim 5 wherein focusing is prevented by energising adjacent transducers, or adjacent groups of transducers, at different freguencies. 10 7. A method as claimed in any one of the preceding claims wherein the crystalline material is aspartame. 8. A method as claimed in any one of the preceding 15 claims wherein the crystalline material is an amino acid. 9. A method for production of crystalline material, substantially as hereinabove described and illustrated with reference to the accompanying drawings. Dated this 29 day of November 2004 DePENNING & DePENNING AGENT FOR THE APPLICANTS

Full Text

PRODUCTION OF CRYSTALLINE MATERIALS BY USING HIGH INTENSITY ULTRASOUND.
This invention relates to a method for crystallisation of ingredients that may be suitable for 5 use in pharmaceuticals.
The use of high intensity ultrasound to trigger nucleation in a supersaturated solution, so that crystallisation occurs, is known, and an apparatus for
10 this purpose is for example described in GB 2 276 567 A. The benefits of triggering nucleation in this fashion are of particular relevance when very pure crystalline products are to be formed, as the purity of the solution and the cleanliness of the vessel surfaces means that
15 crystallisation nuclei are not otherwise present. Certain compounds would be desirable for use in pharmaceuticals, but have been found particularly difficult to crystallise; this relates in particular to disaccharides such as D-glucose or D-xylose. Similar
2 0 problems arise with other organic compounds such as
aspartic acid, and the compound a-L-aspartyl-L-phenylalanine methyl ester (aspartame). It has often been found necessary to add crystal modifiers to a saturated solution of such compounds to ancourage the formation of
25 crystals, as a saturated solution may have to be cooled considerably below the saturation temperature before crystallisation occurs; with some organic materials this■ under-cooling may be as much as 100 K. That is to say, a supersaturated solution may remain in a metastable state
30 for a prölonged period, which may be many months. The use of an immersed ultrasonic probe or horn to subject a saturated solution to ultrasound is commonly used, but it has been found that some cavitation occurs at the surface of the horn, this causing erosion of the horn and
35 consequential generation of very small raetal particles
(say about 0.1 run in diameter); consequently this process

would not be acceptable for generating crystalline material for use as a pharmaceutical ingrediënt.
Accordingly the present invention provides a method 5 for production of crystalline material, the method
comprising forming a saturated solution of the material, changing the temperature of the solution so it becomes supersaturated, and subjecting the solution to irradiation by high intensity ultrasound, the ultrasound 10 being applied only while the solution is supersaturated, and being applied only until crystals are formed, and then allowing the crystals in the solution to grow without irradiation.
15 Preferably the ultrasound is applied for a time no more than 10 seconds, for example 2 seconds or 3 seconds.
The ultrasound most preferably is applied for a brief interval of say less than 5 seconds, and then the solution inspected to see if any crystals have been
20 formed; if no crystals have been formed than the
ultrasound may again be applied for a brief interval, and the solution again inspected. This may be repeated until crystals appear, after which ultrasound is no longer applied. Further gradual cooling of the solution,
25 subsequent to the application of ultrasound, will lead to growth of the crystals formed during the ultrasonic insonation. Hence this method enables large crystals to be grown.
30 The ultrasound may be applied to the supersaturated solution in a vessel using a multiplicity of ultrasonic transducers attached to a wall of the vessel in an array extending both circumferentially and longitudinally, each
transducer being connected to a signal generator so that
2
35 the transducer radiates no more than 3 W/cm , the
transducers being sufficiently close together and the

number of transducers being sufficiently high that the power dissipation within the vessel is between 25 and 150 W/litre. The values of power given here are these of the electrical power delivered to the transducers, as this is 5 relatively easy to deterraine. Such an irradiation vessel is described in WO 00/35579. Surprisingly it has been found that with such a vessel there is no cavitation at the surface of the wall, so that there is no erosion of the wall and consequently no formation of small particles
10 of metal. The crystalline inaterial made by this method can, be very pure, as additives are not required and the crystallisation procedure does not introducé contaminants, so that it would be suitable both for food use and for pharmaceutical use,
15
It is desirable to ensure no focusing of the ultrasound occurs, and this may be achieved by energising groups of adjacent transducers in succession. Where the vessel is cylindrical it is particularly preferable to
20 avoid energising diametrically opposite transducers at the same time. The non-focusing can also be achieved by energising adjacent transducers, or adjacent groups of transducers, at different frequencies; and in particular to vary the frequency at which each transducer. or group
25 of transducers is en-argized over a limited range, for example between 19.5 kHz and 20.5 kHz.
The invention will now be further and more particularly described, by way of example only, and with 30 reference to the accompanying drawing which shows a cross-sectional view of a batch crystallisation irradiator.
Referring to the drawing, a batch crystallisation 35 irradiator 10 includes a stainless-steel vessel 12 of
internal diameter 0.31 m and of wall thickness 2 mm. To

the outside of the wall are attached sixty transducer modules 14 closely packed in a square array. Each transducer module 14 comprlses a 50 W piezoelectric transducer 16 which resonates at 20 kHz, attached to a 5 conically flared titanium coupling block 18 by which it is connected to the wall, the wider end of each block being of diameter 53 mm. The transducer modules define five circumferfential rings each of twelve modules 14, the centres of the coupling blocks 18 being on a square pitch
10 of 82 mm. The irradiator 10 also incorporates three signal generators 20 (only one is shown) each of which drives the transducers 16 in a pair of adjacent longitudinal rows and another such pair of rows one third of the circumference apart from the first pair.
15
In use of the irradiator 10 the vessel 12 is filled ■^ with a solution and the temperature of the vessel is gradually lowered (assuming the solubility decreases as the temperature decreases) using a cooling jacket 22, and
20 the contents of the vessel 12 are stirred. Consequently the solution will become saturated and then supersaturated. When the temperature is about 10 K below that at which saturation occurs, the transducers are energized briefly, each generator 20 being energized for
25 0.8 second successively. Each transducer irradiates 50 W
over a circle of diameter 63 mm, that is an intensity of
2
1.6 W/cm . The ultrasonic energy is dissipated over the
cylindrical volume of the vessel 12, which is about 31 litres, so if all the transducers 16 were energised
30 simultaneously the power density would be about 100
W/litre. To avoid focusing, only one signal generator 20 is energized at any one time, so the energy deposition is about 33 W/litre. After 0.8 second, a different generator 20 is energized, and so on. After 2.4 seconds
35 each transducer has been energized, and application of ultrasound is terminated. The contents of the vessel 12

are then inspected, to see if any crystals have formed. If there are no crystals this activation procedure is repeated. Once crystals are observed, application of ultrasound is terminated, and the temperature of the 5 vessel 12 is gradually lowered.
In a modification the signal generators 20 may generate signals at a frequency that varies between 19.5 and 20.5 kHz, the signals f;:om different signal 10 generators 20 varying independently of each other.
With this irradiator 10 the power intensity is such that cavitation does not occur at the surface of the wall, so erosion of the vessel 12 does not occur. 15 Nevertheless the power density is sufficiënt to ensure nucleation in a saturated solution.
An experiment to investigate the effect of ultrasound on crystallisation has been performed, as
20 follows. An aqueous solution of D-xylose containing 25 g D-xylose per 10 ml water was prepared, which would be saturated at 50°C. This was than cooled at a rata of 0.2 K/min to 20°C, and .the resulting solid products were separated and isolated. As a control, in ene case the
25 transducers 14 were not energized; in this case crystals did not appear until the temperature had dropped to 35°C. If the transducers 14 were energized for a period of 2 minutes, starting at 46°C, then crystals appeared at 43°C. If the transducers 14 were energized continuously,
30 starting at 50"C, then the resulting crystals were very small, and Information on sizes was not obtained. Table 1 gives the temperature T at which solid first appeared and also shows the effect on crystal size distribution by indicating the crystal size (in pm) for different
35 cumulative percentiles (by mass):

5 Since the solutions were saturated at 50°C, ideally crystallisation should commence as soon as the temperature drops below 50°C. The short application of ultrasound markedly reduces the metastable zone width to only about 7 K (as compared to about 14 K in the absence 10 of ultrasound). It also gives a significant increase in the crystal sizes that are formed. Continuous application of ultrasound reduces the metastable zone width even more, to about 4 K."
15 It will be appreciated that the conditions that applied in this particular experiment do not exactly correspond to the method of the present invention, but that the results indicate that it would be appropriate to cool the solution to about 4 3°C before subjecting it to
20 brief irradiation.
In performing the present invention, the temperature to which the solution is to be cooled before the brief application of ultrasound will differ for different
25 solutions, depending on the material, the solvent and the concentration, and must therefore be found by experiment. It may be ascertained by experiments similar to those described above. The solution is first subjected to continuous ultrasound as it is cooled, and the
30 temperature at which crystals form (T, which in the
example above was 46°C) is observed. Further tests are then carried out, cooling the solution to different

temperatures within a few degrees above or below T to find the highest temperature at which crystals form on application of a brief pulse of ultrasound. Typically this is within 5 K of the temperature T observed with 5 continuous ultrasound.
Aspartame is the a-dipeptide ester L-aspartyl-L-phenylalanine methyl ester and is an important synthetic low-calorie sweetening agent. It is about 200 times
10 sweeter than sugar and does not leave a bitter
aftertaste, and so is used in a wide range of products. It is, however, difficult to crystallise without use of crystal modifiers, particularly from aqueous solution. Surprisingly, it has been found possible to produce
15 satisfactory crystals of aspartame directly from an
aqueous solution using the present method. A saturated solution of aspartame in warm pure water is prepared, and introduced into the vessel 12. The temperature of the solution is gradually cooled to about 10 K below the
20 temperature at which it would be saturated, and is
subjected to ultrasonic irradiation as described above for a short time, for example 2.4 s. The solution is then inspected, and if crystals have formed as a result of the ultrasonic irradiation, then the temperature of
25 the vessel is gradually cooled over a period of a few hours down to room temperature.
This process has been found to produce aspartame crystals between 100 and 250 |iiti in size, which are easy 30 to separate from the remaining liquid for example by filtration. By avoiding the need for additives the purity of the product is ensured.
The inspection to check if any crystals have formed 35 as a result of the ultrasonic irradiation may be an inspection by eye, while shining a light into the

solution, as the small crystals sparkle.
It will be appreciated that the method is applicable using different apparatus, and may be applied on a 5 continuous rather than a batch basis. For example a
saturated solutior. may be cs.used to flow along a duet in which its temperature gradually decreases, the duet incorporating a flow-through ultrasonic irradiation module at a position at which the solution has reached
10 the appropriate temperature, so that the solution is briefly irradiated as it flows thrcugh the module. In this case the transducers of the ultrasonic irradiation module might be activated continuously or in a pulsed mode.
15
The method is applicable to many different chemical compounds. For example it may be used for proteins and amino acids, and for antibiotics. By way of example, the following measurements have been made with the three
20 amino acids L-leucine, L-phenylalanine, and L-histadine.
Saturated solutions in water were prepared at 75°C, the concentrations being 3.3, 6.2 and 11.3 g/100 g water respectively (after 24 hours in contact with solid
25 material). Four samples were taken of each solution, and were then cooled at a steady rate of 0.2°C/min. In half the cases the samples were subjected to a 10 s burst of ultrasound every 5 minutes until crystals were observed. No ultrasound was applied to the others. The temperature,
30 T, at which crystals first appeared is shown in Table 2, Tu being the cases with ultrasound, and Tx these without ultrasound.

It will be appreciated that in each case the application of ultrasound reduces the metastable zone width, so the crystals appear at a higher temperature. 5 The effect is most dramatic in the case of leucine, where the metastable zone is decreased from about 22.5 K to about 9.8 K. In addition, the ultrasound has an effect on the crystal size distribution, so that the crystals are larger. For example Table 3 shows measurements of 10 the resulting crystal size distributions, as measured with a Malvern Mastersizer 2000, for histadine and
phenylalanine, showing the partiele sizes (in |J,m) for different cumulative percentiles (by mass).
TABLE 3 I 10% j 50% j 90%
Histadine no ultrasound 15.8 59.9 166.3
Histadine ultrasound 20.6 89.6 370.8
Phenylalanine no ultrasound 133.9 352.4 655.9 Phenylalanine ultrasound 159.9 420.9 776.1
15
As another application, a saturated solution may be insonated so as to generate crystals, and then be added to a larger volume of solution so that the crystals act as seed crystals for the entire volume. For example
2 0 there might be 4000 litres of a saturated solution in a crystallisation tank, which is gradually cooled or to which anti-solvent is added. When it is sufficiently supersaturated, a small quantity (eg 40 1) is transferred into an irradiation chamber (eg sucked up through a pipe)
25 at the same temperature as the tank; there it is
subjected to ultrasound so that crystals are formed; it is then transferred back into the tank. If no crystals are formed, this operation may be repeated.

\/\]g^ Claimg
1. A method for production of crystalline material, the
method comprising forming a saturated solution of the
5 material, gradually changing the temperature of the
solution so it becomes supersaturaued, and subjecting the solution to irradiation by high-intensity ultrasound, wherein the method involves:
a) finding the temperature which provides the least
10 degree of supersaturation at which crystals form from the solution on brief application of ultrasound, and then
b) subjecting the solution while it is supersaturated, at
this temperature, to ultrasound for a brief interval such
that crystals are formed, and then
15 c) allowing the crystals in the solution to grow without irradiation by continuing to change the temperature of the solution.
2. A method as claimed in claim 1 wherein the solution
20 is subjected to ultrasound for less than lOs.
3. A method as claimed in any one of the preceding
claims wherein the ultrasound is provided to the
supersaturated solution in a vessel using a multiplicity
2 5 of ultrasonic transducers attached to a wall of the
vessel in an array extending both circumferentially and longitudinally, each transducer being connected to a signal generator so that the transducer radiates no more
2
than 3 W/cm , the transducers bexng sufficiently close
3 0 together and the number of transducers being sufficiently
high that the power dissipation within the vessel is between 25 and 150 W/litre.
4. A method as claimed in any one of the preceding
3 5 claims wherein ultrasound is applied in such a way that no focusing of the ultrasound occurs.

5. A method as claimed in claim 4 wherein focusing is
prevented by energising groups of adjacent transducers in
succession.
5
6. A method as claimed in claim 4 or claim 5 wherein
focusing is prevented by energising adjacent transducers,
or adjacent groups of transducers, at different
freguencies. 10
7. A method as claimed in any one of the preceding claims wherein the crystalline material is aspartame.
8. A method as claimed in any one of the preceding
15 claims wherein the crystalline material is an amino acid.

9. A method for production of crystalline material, substantially as
hereinabove described and illustrated with reference to the accompanying drawings.
Dated this 29 day of November 2004
DePENNING & DePENNING
AGENT FOR THE APPLICANTS

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Patent Number

252728

Indian Patent Application Number

2693/CHENP/2004

PG Journal Number

22/2012

Publication Date

01-Jun-2012

Grant Date

29-May-2012

Date of Filing

29-Nov-2004

Name of Patentee

PROSONIX LIMITED

Applicant Address

ONE LONDON WALL LONDON EC2Y 5AB

Inventors:

#	Inventor's Name	Inventor's Address
1	MCCUASLAND,LINDA,JANE	OF 20 SHEPHERD GARDENS,ABINGDON,OXFORDSHIRE OX14 5PR

PCT International Classification Number

B01D9/00

PCT International Application Number

PCT/GB03//01905

PCT International Filing date

2003-03-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0212626.6	2004-05-31	U.K.