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Title:
METHOD AND APPARATUS FOR THE CRYSTALLIZATION OF ONE OR MORE COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2004/081264
Kind Code:
A1
Abstract:
The method of the invention for the crystallization of one or more compounds from a solution or melt containing the same is carried out by exposing said solution or melt for the effect of an electric field. The method is mainly characterized by the steps of using a metal electrode as one electrode and said solution or melt to be crystallized as the other electrode. An insulation layer is used between the electrodes, the solution is connected to a conductor, and the electrodes are connected to a power source as a result of which the solution or melt to be crystallized is polarized and crystallized in controlled conditions. The invention is also concerned with an apparatus, which is characterized by a vessel containing a solution or melt to be crystallized, a metal electrode, another electrode consisting of said solution or melt to be crystallized, and an insulation layer between the electrodes. The solution is connected to a condutor and the electrodes are connected to a power source.

Application Number:
PCT/FI2004/000134
Publication Date:
September 23, 2004
Filing Date:
March 10, 2004
Export Citation:
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Assignee:
REIJONEN MIKA TAPIO (FI)
International Classes:
B01D9/00; C30B7/00; C30B7/12; C30B9/00; C30B9/14; (IPC1-7): C30B7/12; B01D9/00
Foreign References:
FR2837400A12003-09-26
US5378337A1995-01-03
US5525198A1996-06-11
Other References:
DATABASE WPI Section Ch Week 200229, Derwent World Patents Index; Class B04, Page D13, AN 2002-240420, XP002286786
Attorney, Agent or Firm:
INNOPAT LTD. (Espoo, FI)
Söderman, Päivi (P.O. Box 556, Espoo, FI)
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Claims:
CLAIMS
1. Method of crystallization of one or more compounds from a solution (6) or melt containing the same by exposing said solution or melt for the effect of an electric field, characterized bythestepsof using a metal electrode as one electrode and said solution (6) or melt to be crystallized as the other electrode, using an insulation layer (2) between the electrodes, connecting the solution (6) to a conductor (4), connecting said electrodes to a power source as a result of which the solution (6) or melt to be crystallized is polarized and crystallized in controlled conditions.
2. Method of claim 1, characterized in that the electrodes are connected to a power source by means of said conductor (4), whereby the electrode connected to the positive pole of the power source works as an anode and the electrode connected to the negative pole of the power source works as cathode.
3. Method of claim 2, characterized in that the metal electrode is the anode and said solution (6) or melt to be crystallized is the cathode.
4. Method of daim 1, characterized in that the compound (s) to be crystallized is/are pharmaceutical (s), additive (s) to be used in pharmaceuticals, racemic mixtures, diastereomers, tautomers, salts, esters or other derivatives or mixtures thereof, pigments, amino acids, peptides, proteins, hydrocarbons, amines, alkanes, alkenes, alkynes, carboxylic acids, organometals, polymers or biopolymers or mixtures thereof.
5. Method of claim 1, characterized in that the insulating layer (2) is a polymer, such as polyethylene, polyester, polypropylene, polystyrene, polyolefine, polyvinyl chloride, polyamide, polyurethane, polycarbonate, polyvinylidinefluoride, plexi glass, polysulfon, polyfenylsulfide, polytetrafluorethylene, Teflon4, other fluorinated compounds, akryl, polyethenetereftalate, copolymer or mixtures thereof, glass, resin, enamel, rubber, quartz, a ceramic compound or some oxide or mixtures thereof.
6. Method of claim 1, characterized in that the solvents for the substances to be crystallized are organic, inorganic solvents or mixtures thereof.
7. Method of claim 1, characterized in that the solution to be crystallized is supersaturated.
8. Method of claim 1, characterized in that the metal electrode and the conductor are of aluminum, tantalum, titanium, copper, chromium, gold, silver, nickel, tin, platinum, stainless steel, magnesium, zinc, palladium, a transition metal, such as zirconium, molybdenum, niobium, or mixtures thereof or of graphite.
9. Method of claim 1, c h a r a c t e r i z e d in that the crystallization is controlled by varying the voltage of the power source.
10. Method of claim 1, characterized in that the crystallization is controlled by mean of the distance between insulation layer (2) and the conductor (4).
11. Apparatus for the crystallization of one or more pharmaceuticals or additives or mixtures of those from a solution (6) or melt containing the same by exposing said solution or melt for the effect of an electric field, c h a r a c t e r i z e d by a vessel (7) containing said solution (6) or melt to be crystallized, a metal electrode, another electrode consisting of said solution (6) or melt to be crystallized, an insulation layer (2) between the electrodes, the solution (6) being connected to a conductor (4), said electrodes being connected to a power source.
12. Apparatus of claim 11, characterized in that the electrodes are connected to a power source by means of said conductor (4), whereby the electrode connected to the positive pole of the power source works as an anode and the electrode connected to the negative pole of the power source works as cathode.
13. Apparatus of claim 11, characterized in that the metal electrode is the anode and said solution (6) or melt to be crystallized is the cathode.
14. Apparatus of claim 11, characterized in that it comprises several parallel electrodes arranged turned to a roll or stack.
15. Apparatus of claim 11, characterized in that it comprises several parallel electrodes besides each other.
16. Apparatus of claim 11, characterized in that the compound (s) to be crystallized is/are pharmaceutical (s), additive (s) to be used in pharmaceuticals, racemic mixtures, diastereomers, tautomers, salts, esters or other derivatives or mixtures thereof, pigments, amino acids, peptides, proteins, hydrocarbons, amines, alkanes, alkenes, alkynes, carboxylic acids, organometals, polymers or biopolymers or mixtures thereof.
17. Apparatus of claim 11, c h a r a c t e r i z e d in that the insulating layer (2) is a polymer, such as polyethylene, polyester, polypropylene, polystyrene, polyolefine, polyvinyl chloride, polyamide, polyurethane, polycarbonate, polyvinylidinefluoride, plexi glass, polysulfon, polyfenylsulfide, polytetrafluorethylene, Teflon@, other fluorinated compounds, akryl, polyethenetereftalate, copolymer or mixtures thereof, glass, resin, enamel, rubber, quartz, a ceramic compound or some oxide or mixtures thereof.
18. Apparatus of claim 11, characterized in that the solvents for the substances to be crystallized are organic, inorganic solvents or mixtures thereof.
19. Apparatus of claim 11, characterized in that the solution to be crystallized is supersaturated.
20. Apparatus of claim 11, characterized in that the metal electrode and the conductor are of aluminum, tantalum, titanium, copper, chromium, gold, silver, nickel, tin, platinum, stainless steel, steel, magnesium, zinc, palladium, a transition metal, such as zirconium, molybdenum, niobium, or mixtures thereof or of graphite.
Description:
METHOD AND APPARATUS FOR THE CRYSTALLIZATION OF ONE OR MORE COMPOUNDS TECHNICAL FIELD The invention is concerned with a method for the crystallization of one or more compounds, such as pharmaceuticals, or of additives of these, or mixtures of these, especially a method wherein an electric field is used for the control of the crystallization.

BACKGROUND ART In the chemical industry, crystallization is used for many purposes. It is especially important to control the crystallization of pharmaceutica) s, pigments, explosives, foodstuffs and fertilizers are prepared. It is also important to control the crystallization of additives of those. E. g. polymorphs of hydrocarbons are often used as fillers in different pharmaceutiials. Furthermore, pharmaceuticals, or pharmaceuticals together with additives or with other pharmaceuticals, can form mixed crystals with different properties.

Compounds with more than one crystal form are called polymorphous substances.

Polymorphism is very common in pharmaceuticals. Polymorphs generally have different physical properties, which influence on the formulation properties of the compound, on the solubility and on the biological activity. Due to the differences of the polymorphs of the same compound, new polymorphs of pharmaceuticals are treated as new pharmaceuticals in legislation.

A substance, which is very conductive, is called a conductor. These are for example metals and some forms of other substances. E. g. the graphite form of carbon is a conductor. A substance, which is not conductive, is called an insulator, including for example plastics, glasses and rubbers. In US Patent 6,563, 694, it is presented that the low conductivity of an electrolytic solution makes it an insulator.

Charging of a capacitor generally takes place very quickly because of an orientation of the electric charges. The chemical oxidation/reduction reaction in an accumulator is, in turn, generally very slow. In electrolysis, opposite ions are going to opposite electrodes.

Many pharmaceutical consist of two different enantiomers, in other words of mirror isomers, one of which has the ability to bind itself to a target molecule. 80 % of the pharmaceutical in the market contain such optical isomers, generally in form of a mixture. Generally, one of the enantiomers is ineffective, effects only a little or has undesired effects. An example of this is the thalidomide medicine, which was used at 1950s for example for preventing sickness during pregnancy. On 1961 it was removed from the market as a medicine causing fetal defects. Later, it was confirmed that the reason to the defects was the S (-) form of thatidomide, the other one, the R (+) enantiomer being still able to hinder sickness. In stereo or space isomerism, also the optical cis-trans and conformation isomers are included. The more atoms the molecule has the more different structures are possible due to a different three-dimensional structure. Optical isomers are common in nature, but in the laboratory, selective production of a given isomer is very difficult still today. Organic compounds often have chiral carbon atoms, the bonds can rotate and furthermore many organic molecules are big, and thus different three-dimensional forms of the molecules exist. There are also many internal attraction and repulsion forces inside the molecule and between the molecules. These forces are important in the synthesis of the pharmaceutical in order to get the effect of the pharmaceutical, for example by binding them to the target receptor of the organism.

The activity of the compound can depend on small differences such as in the case with optical isomers. Lactic acid is present in the nature in the form of two stereo isomers.

One of the isomers can been found in muscles, the other one in sour milk. The structures of these isomers differ from each other only in that the mutual space position of the atoms are different in them. The molecules are mirror images to each other. A mixture of enantiomers containing equally much of both enantiomers is called a racemic mixture. From an external view, such a mixture seems to be optically inactive. Synthetically prepared mixtures are generally inactive. The asymmetric centers are built in them during the synthesis. The substances in nature, on the contrary, are often optically active, which appears for example in the function of enzymes. It might be possible to economically produce only one optical isomer in the future, for example one of the isomers of thalidomide might in the future be a safe medicine against sickness if the isomers can be separated from each other in an industrial scale.

There is a good example of cis-trans isomerism in the human body: For the eye sight, the fast photochemical conversion of cis-1 1-retinal to trans-11-retinal and the slower returning in dark of trans-11-retinal back to cis-11-retinal is important. A third stereo isomeric form, the conformation isomers of a compound is caused by coiled simple bonds resulting in different forms of the molecule. Conformation polymorphism and configuration polymorphism are different kinds of polymorphism. When a molecule has a different conformation in different polymorphic forms, it is question about conformation polymorphism. When the polymorphism is caused by geometric isomerism (cis-trans isomers or tautomers) it is question about configuration polymorphism.

Many pharmaceuticals can form solvates with the solvent during crystallization. When the solvent is water, they are called hydrates. If the crystal does not contain crystal water, it is called an anhydrate. This phenomena is called pseudopolymorphy.

The effects of electric fields on molecules have been shown in connection with the production of polymorphs. The molecules of a substance to be crystallized by means of an electric field that can be regulated can be brought in such an advantageous position from which the desired crystal form can be achieved. A so called polarization takes place in the molecule. In other words the ends of the molecule become electrically charged. In the book, Y. Y. Yan and R. S. Neve, The effect of electric fields on polymorphism crystallisation, Heat Transfer Science and Technology 2000, p. 745-750 edited by Bu-Xuan Wang, China, there is shown the effect of an electric field on the production of polymorphs. A traditional solution is presented, in which the compound to be crystallized is put between electrodes and an electric field is connected.

The effect of polarization has been shown in connection with the production of polymorphs by David W. Oxtoby, Crystals in a flash, Nature Vol 420 2002,277-278, who writes about polarization of molecules caused by an electric field made by laser.

The molecular energy is hereby reduced as a result of the forming of a small dipole moment. This effect favors the orientation of the molecules in a given way. This phenomenon took place only with linearly polarized laser light but not with circularly proceeding laser light. The US Patent 6,426, 406 is concerned with a method for using laser light to control the crystal form.

An electric field decreases spontaneous crystallization. G. Arunmozhi, E. De M.

Comes, J. L. Ribeiro, Ferroelectric properties of TGS crystals grown under an intense DC electric field, Physica B 325 (2003), 26-34, shows how the spontaneous crystallization is decreased as an influence of an electric field.

Different polymorphs have been achieved from different solvents by changing the dipole moment. (P. Selvarengan, P. I<olandaivel : Studies of solvent effects on conformers of glycine molecule, Journal of Molecular Structure (Theochem) 617 (2002), 99-106).

Nowadays a crystallization process is most commonly controlled by preparing an optimal supersaturated solvent composition by selecting the crystallization temperature/gradient, by selecting a suitable additive or additives and by using a crystal seed to start the crystallization.

The composition of the electrolyte is apparently very important for the properties of the aluminum electrolyte capacitor and is therefore an object for intensive research. The electrolyte solution can consist of inorganic or organic compounds such as sugars (Tsai M-L, et al High-performance electrolyte in the presence of n-dextrose and its derivatives for aluminum electrolytic capacitors. Journal of Power Sources 112 (2002) 643-648). In an electrolyte capacitor, one of the electrodes is less conductive than a metal electrode (http ://www.faradnet.com/deeley/chapt_02.htm#polarization filed 8.10. 2003), and for example water solutions of many pharmaceutical are not too conductive and not insulators. In a medical biophysics copy written by Kyosti Heimonen, it is told that it is the 3-D structure of the molecules and the direction of the dipole moment that decide the exact grouping of the molecules (http : l/cc. oulu. fi/-fysiowww/pdf/lbf/luento2. pdf page 5 filed 8.10. 2003), which partly forms the theoretical background of the invention.

In the article A. D. Buckingham, P. Fisher. Linear electro-optic effect in optically active liquids. Chemical Physics Letters 297 1998 239-246, there is presented two methods, only with one of which the enantiomers can be separated. This can be done with a method, wherein the liquid is not put in a prisma, but is one of the components. On page 244, it is explained that in the same electric field, the enantiomers have different sum frequencies of the electricity production induced by the electric field (ESFG). <BR> <BR> <P>Oailly active molecules react identicall with non-optical molec ales but differently with other optically active molecules. Thus, the different enantiomers of a racemic mixture in a melt state or in solution can be crystallized apart from each other when the liquid is evaporated. This separation is based on the fact that the different chiral molecules are stereo specific also with themselves. A spontaneous separation of enantiomers is not very common. Optical isomerism can take place on crystal and/or molecule level.

On 1846, Louis Pasteur worked with a sodium ammonium salt of tartaric acid. Pasteur crystallized these salts and noticed that there were small inclined surfaces in the salts of the acid, which seemed to be turned in only one direction. The salts of racemic acid also contained such hemihedral surfaces, but they were directed either in a given direction or, in some crystals, in an opposite direction. Pasteur soon found out some ways to separate the right and left rotated forms from each other. In one test he let the optically active base form a salt for example with racemic acid and a mixture of right and left rotated salts of salts of racemic acid were achieved. These had a different solubility and they could be separated by crystallization.

Rotation can take place in crystals or molecules. If a compound containing an asymmetric carbon atom is synthesized in a laboratory only by means of optically inactive reagents, their racemic form is always achieved. In methods performed by enzymes present in living organisms there are usually achieved, even if not always, the optically active form. Apparently the enzymes themselves are optically active and therefor cause asymmetric synthesis. Also in laboratories, asymmetric synthesis can be performed using optically active reagents for example as catalysts or for forming salts. If compounds containing two asymmetric carbon atoms are used, so called diastereoisomers can be achieved. These differ from each other for example with respect to their solubility and they can be separated from each other. By releasing the optical isomers from their salts, also the isomers can be separated from each other. If an optically active compound is heated in a temperature of about 20QC or more, racemization takes place which means that the optically active form becomes an inactive racemic mixture. This is caused by the fact that the valences or the electron orbits of the carbon atoms are deviated from their original positions by the influence of the heat movement so that a stochastic distribution of I ft and right turned forms is achieved, in other words, a racemic mixture. (Tarje Enkvist : Johdatusta organiseen kemiaan, Kustannusosakeyhtio Otava, Helsinki, 1966).

For example in ibuprofen, which is used as a pharmaceutical, there is a chiral carbon.

In the article Tan, Soo Choon, Patel, Bravesh K. , Jackson, Stephen H. D. , Cameron G., Hutt, Andrew J. Ibuprofen stereochemistry: double-the-trouble ? Enantiomer (1999), 4 (3-4), 195-203 enantiomers of ibuprofen are presented.

In the most common crystallization methods, supersaturated solutions are made by using suitable solvents of the substance to be crystallized, which possibly also is seeded with a desired seed to start the crystallization process. The surface charges are important in the precipitation of the proteins and the packing of those. The supersaturated state can be maintained by reducing the temperature, by removing the solvent from the liquid of crystallization and by adding a compound that speeds up the crystallization or by adding chemically reactive substances. The purpose of a given solvent composition is to bring the molecule to be crystallized in the desired position by means of electro-chemical power to achieve the right result. For example the glycine molecule has a different dipole moment with different forms in different solvents (P.

Selvarengan, P. Kolandaivel : Studies of solvent effects on conformers of glycine molecular, Journal of Molecular Structure (Theochem) 617 (2002), 99-106).

In modern prior art, the compound to be crystallized is brought between electrodes. A possible electrolysis is prevented by placing air statues on both sides of the compounds to be crystallized as in the publication M. Taleb, C. Didierjean, C. Jelsch, J. P. Mangeot, B. Capelle ja A. Aubry, Crystallization of proteins under an external electric field, Journal of Crystal Growth 200 (1999) 575-582 sekä IVl. Taleb, C.

Didierjean, J. P. Mangeot ja A. Aubry, Equilibrium kinetics of lysozyme crystallization under an external electric field, Journal of Grystal Growth 232 (2001), 250-255, or by placing the compound to be crystallized in oil in order to slow down the movement of anions and cations, as in US Patent 5,525, 198. Typically such as in the patents US 4, 529, 488, US 5, 522, 198, JP2001240499, RU2083501 and JP2001322900, two electrodes are put in a solution to be crystallized. In US Patent 6,004,445, the solution to be crystallized act as an electrolyte between metal electrodes.

H. Cano, N. Gapas, J. P. Canselier presents an investigation with ibuprofen and geometrical restrictions of the molecules in crystallization in Experimental study on the ibuprofen crystal growth morphology in solution. Journal of Crystal Growth 224 (2001) 335-341.

In the EP patent application 1114886 A1, a compound is crystallized in the solution by means of an electric field. The compound to be crystallized is put between two electrodes on a solid substance. The crystallization is controlled by charges on the surface on the solid substance. In EP 0821987 B1, the crystallization is controlled by means of surface charges of a solid substance, which is in contact with the substance to be crystallized.

Electric energy is first converted to light energy, which then is converted to chemical energy. Furthermore, destruction of the compound caused by light might take place in this method and polarization of a bigger area can be difficult to achieve. For this method called"Method for using laser light to control crystal form"a patent has been granted on 2002, US 6,426, 406. A method called"Controlled nucleation of protein crystals"of the same inventor got a patent on 2003, US 6, 596,077 and there is also the international publication WO 03/012177. Alfaglycine-polymorphism has been achieved in crystal form from a water solution and gammaglycine polymorphism from an organic solvent on November 2002. In the magazine Nature, there was written about a new method wherein in electric energy was converted to light energy which converted to chemical energy of the molecule because of the dipole moment induced. If the light was circularly polarized, alfaglycine was formed as normally, but when the light was linearly polarized, surprisingly, gammaglycine was achieved.

Spontaneous crystallization can sometimes be reduced for example with low temperature, such as with cold-drying. Then the heat movement is decreased and the crystallization starts but there is no way to influence on the position of the molecule in the crystallization.

Also the following publications and books are presented as prior art: DE4028805, EP 1114886, US 4,529, 488, US 5, 378, 337 and US5, 525, 198 and Yan, Y. Y. ; Neve, R. S., "The effect of electric fields on polymorphism crystallization. "Heat Transfer Science and Technology 2000, Higher Education Press, Beijing, 2000. p. 745-750.

In W09531405, there is presented the forming of an electric field but no production of polymorphism.

The actual prior art used in optical isomery appears from the following publications. In US Patent 6,541, 631, preparation of an optically active derivative is presented, in US Patent 6,521, 445 an optically active ester is presented, in US Patent 6,437, 167, a chromatographic method to separate enantiomers is presented, a stereo selective method is presented in WO 02057475 to be used in a enzymatic process and in US Patent 6, 485, 650 the use of a liquid membrane is presented for the separation of the enantiomers.

Xianhua Zhang, Jin Ouyang, W. R. G. Baeyens, Suodi Zhai, Yiping Yang, Guangming Huang. Enantiomeric separation of b-blockers by HPLC using R-1-naphthylglycine and 3,5-dinitrobenzoic acid as chiral stationary phase. Journal of Pharmaceutical and Biomedical Analysis 31 (2003) 1047-1057 presents that polarization of a moving phase has a big influence in the presented liquid chromatography method for the separation of enantiomers.

M. Brent Busby, Omar Maldonado, Guyla Vigh present Eledrophoretic enantiomer separations at high pH using the new, single-isomer octakis (2, 3-dimethyl-6-0-sulTo)-g- cyclodextine as a chiral resolving agent. In the Journal of Chromatography A, 990 (2003) 63-73, there is presented an electrophoretic method for the separation of enantiomers.

Rong Wang, Zheng-Ping Jia, Xiao-Li Hu, Li-Ting Xu, Ycng-Min Li, Li-Ren Chen.

Determination of serum thyroxine enantiomers in patients by liquid chromatography with a chiral mobile phase. Journal of chromatography B, 785 (2003) 353-359: There is presented a clinical medium for the separation of the enantiomers of tyroxine from human serum with an exchange method of a chiral ligand.

THE OBJECT OF THE INVENTION The object of the invention is to screen and obtain desired polymorphs and a method to produce desired polymorphs and also to separate stereoisomers from each other.

SUMMARY OF THE INVENTION The method of the invention for the crystallization of one or more compounds from a solution or melt containing the same is carried out by exposing said solution or melt for the effect of an electric field. The method is manly characterized by the steps of using a metal electrode as one electrode and said solution or melt to be crystallized as the other electrode. An insulation layer is used between the electrodes, the solution is connected to a conductor, and the electrodes are connected to a power source as a result of which the solution or melt to be crystallized is polarized and crystallized in controlled conditions.

The invention is also concerned with an apparatus, which is characterized by a vessel containing a solution or melt to be crystallized, a metal electrode, another electrode consisting of said solution or melt to be crystallized, and an insulation layer between the electrodes. The solution is connected to a conductor and the electrodes are connected to a power source.

The preferable embodiments of the invention have the characteristics of the subclaims.

Different connections are possible in the invention. Thus, the electrodes are connected to a power source by means of said conductor, whereby the electrode connected to the positive pole of the power source works as an anode and the electrode connected to the negative pole of the power source works as cathode. Usually, the metal electrode is the anode, and the solution to be crystallized is used as cathode and the insulation is e. g. aluminum oxide or Teflon@. In some embodiments the metal electrode can be the cathode and the solution to be crystallized the anode, which is possible e. g. when the insulation is e. g. Teflon@.

Usually, the condition in electrolyte condensers is that the electrolyte works as the negative pole, in other words electrons are"pushed"therein, because there are no free electrons to take from. When the conductor is considered as an electrode, and in this text this meaning is included in the word"conductor", and the poles are the opposite, electrons ca be drawn therefrom and the polarization takes place in the opposite direction. In an aluminum oxide insulation layer a self-correcting electrolysis takes place, if the connection is in the right direction.

The invention makes use of the fact that when neutral atoms and molecules are placed in an electric field they tend to polarize meaning that the centre of charge of their constituent electrons having a given total charge is displaced by a certain distance with respect to the centre of charge of their constituent atomic nuclei and a dipole moment is thus formed in the molecules. The dipole moment of a compound is a function of the total charge of its constituent molecules and the distance by which it is displaced. In the invention, the dipole moment turns those molecules that act as one of the electrodes by influencing on the electrons of the molecules by means of a electrolyte capacitor like system by polarizing the compound. During this polarization, the molecules are clumped together so that the crystallization starts.

The use of an insulation layer provides an essential advantage compared for example to methods using electrolysis. In many methods, the compound to be crystallized is placed into the insulation layer, but in the method of the invention, it works as one of the electrodes, as a solution or a melt, and combined with a conductor. In addition to the properties of the insulation I yer, another difference to prior art is that the compound to be crystallized itself works as one of the electrodes in a polarized state.

The desired reaction, i. e. the crystallization, or at least the start or end of this, takes place during this polarization. In the invention, there is used direct polarization, wherein electric energy is transferred to chemical energy in contrary to e. g. the laser method.

The polarization itself is a well known phenomenon and theoretically clarified but as a technical solution for the crystallization of compounds by means of an electrolyte capacitor like system it is new.

The simples way in the invention to control the polarization of the molecules is to have an electrolyte solution in a glass vessel, where in the compound to be crystallized has been solved to form a supersaturated solution and by having a power supply with which the voltage is regulated between the electrodes. The crystallization can be controlled by e. g. regulating the voltage to be suitable and by means of the temperature, the pressure and by evaporation.

The method of the invention has an extensive use as every compound can be polarized. Especially proteins are difficult to crystallize in prior art methods, because they are often ampholytes of big size and the crystallization of those is problematic in that 30-70% of the solvent usually remains in the products in prior art methods, as appears e. g. in US Patent US 5,525, 198. Proteins are also denaturated very easily in crystallization methods of prior art. New pharmaceuticals are very often difficult to crystallize and remain sticky, also problems that are solved with the method of the invention.

Many advantages are achieved with that the compound itself works as one of the electrodes. In known systems, wherein an electric field is used in the crystallization, the compound to be crystallized is a medium between two electrodes and only small amounts can be used at a time and factors influencing the crystallization can not be measured as easily as in the invention because the systems of prior art are complex with respect to the measuring apparatus. In the invention for example the temperature, conductivity, the pH, the removal of the solvent etc. can easily be measured directly from the electrode. As also the nucleation, i. e. the forming of the seed crystal, takes place in a controlled way in the electrode consisting of the compound itself, the crystallization can be controlled all the way through which is important because different compounds require different conditions for the best result.

As the compound to be crystallized works as an electrode and is not in a narrow space between the electrodes, different factors can directly be measured by regulating such properties as the temperature, the pressure, the agitation, and the state, the capacity of the method can be increased by increasing the voltage or by means of other compounds, whereby the conductor can be at a longer distance from the insulation layer. The molecules can be in a homogenous or non-homogenous electric field.

In the pharmaceutical industry, it is often important to perform the process in sterile conditions and this can be easily done with the method of the invention without for example moving and wearing parts. Nowadays the solvents used in the preparation of pharmaceuticals and the impurities in the synthesis cause a safety risk for the pharmaceutical as many of them remain in the crystal or stay there as a part of the crystal. It is possible to get rid of the solvent rest and the impurities by means of the invention. The economy of the process improves as in the crystallization process, there is always achieved the right crystal form. In the screening of pharmaceuticals and other kind of biologically active compounds, there is today used molecule modeling and synthetic for the presentation of an optimal molecule. By means of the invention, a model protein and an active test substance can be crystallized to a mixed crystal and the mutual compatibility can be figured out, which facilitates the investigation. Also the different polymorphic forms required by registering authorities can be investigated.

Furthermore, the process of the invention can be continuous or be performed as a batch process.

Melt substances are crystallized both in the organic and the inorganic chemical industry and with the invention it is possible to control the crystallization of these. Also mixed crystals of pharmaceutical and proteins are important.

Instead of using an electrolyte solution in an electrolyte capacitor like system, the invention uses a solution or melt of a pharmaceutical or of pharmaceuticals or other compounds, which can be crystallized as one of the electrodes by means of a polarization effect, either during the whole crystallization or only during a part of it for example during the time for forming of a nucleus crystal or during the nucleation or during the growth of the crystal.

If the information is formed during the nucleation of the crystallization, it is enough that only the nucleation phase of the compound to be crystallized takes place in an electric field and when the crystallization has started, the solution can be removed into another vessel. The method of the invention can easily be regulated by means of the voltage.

The method can be influenced by the selection of solvent or solvents, pH, pharmaceutical, pharmaceuticals and additives but usually the invention advantageously does not require strong physical or chemical loads as e. g. water can be used as solvent.

In a simple embodiment form of the invention, the scalability and capacity of the method is apparently good and easy to automate, possibly directly to be a part of the rest off the process. The method can probably be carried out both as a batch and a continuous process. There are on the other hand no moving parts in the method of the invention and the insulation layer can be made strong. The crystallization can with the method of the invention be performed in high GMP (good manufacturing practice) purity requirements and sterile conditions. This is not restricted to the use of aluminum or aluminum oxide insulation layers, which are used by the electronic industry, but can be made of desired metals and polymers.

In the following the invention is described by means of some figures and examples by referring to some preferable embodiments. The intention is not to restrict the invention to the details in these descriptions. E. g. the connection of the electrodes to the power source can be different than in the figures.

FIGURES Figure 1 is a schematic view of the principle of the invention Figure 2A is an embodiment of the invention seen from above Figure 2B is another embodiment of the invention seen from above Figures 3A presents the prior art crystallization of caffeine between an insulation layer and the anode without being connected to a voltage source Figures 3B presents the crystallization of caffeine according to the invention between an insulation layer and the anode when connected to a voltage source Figure 4A presents a powder X-ray diffraction analysis image of the crystallization of glycine-amino acid with a method of the invention, wherein the solution was connected to the negative pole of the cathode and the anode was connected to the positive pole Figure 4B presents a powder X-ray diffraction analysis image of the crystallization of glycine-amino acid with a method of the invention, wherein the solution was connected to the positive pole of the cathode and the anode was connected to the negative pole Figure 5 presents the crystallization of a water solution containing taurine-amino acid Figure 6A presents the parts of mixed crystals calculated according to their intensity prepared with the method of figure 5 Figure 6B presents the parts of mixed crystals calculated according to their intensity and breadth prepared with the method of figure 5 Figure 7A presents ibuprofen crystals achieved with a method according to prior art Figure 7B presents ibuprofen crystals achieved with a method according to the invention DETAILED DESCRIPTION Figure 1 presents a general view of the invention. The invention makes use of a system, wherein one or more metal electrodes 1 are connected with a conductor 9 to the positive pole of a power source 5. The system also comprises a solution 6 in a vessel 7, the solution containing the substance to be crystallized and working as the other electrode. The solution is connected with a conductor 4 to the negative pole of the power source 5. There is an insulating layer 2 between the solution 6 and the metal electrode 1.

The substance (s) to be crystallized islare pharmaceuticals, additives to be used in pharmaceuticals, racemic mixtures, diastereomers, tautomers, salts, esters or other derivatives or mixtures thereof, pigments, amino acids, peptides, proteins, hydrocarbons, amines, alkanes, alkenes, alkynes, carboxylic acids, organometals, polymers or biopolymers or mixtures thereof.

The solvents for the substances to be crystallized are organic, inorganic solvents or mixtures thereof.

The insulating layer is for instance a polymer, such as polyethylene, polyester, polypropylene, polystyrene, polyolefine, polyvinyl chloride, polyamide, polyurethane, <BR> <BR> <BR> polycarbonate, polyvinylidinefluoride, plexi glass, polysulfon, polyfenylsulfide, <BR> <BR> <BR> <BR> <BR> polyetrafluorethylene, Teflon#, other fluorinated compounds, akryl, polyethenetereftalate, copolymer or mixtures thereof, glass, resin, enamel, rubber, quartz, a ceramic compound or some oxide or mixtures thereof.

The metal electrode and the conductors can for instance be of aluminum, tantal, titanium, copper, chromium, gold, silver, nickel, tin, platinum, stainless steel, steel, magnesium, zinc, palladium, a transition metal, such as zirconium, molybdenum, niobium, or mixtures thereof or of graphite.

The solution of the substance to be crystallized is made as a supersaturated solution in its solvent or a melt. The supersaturated state is influenced on by changing conditions such as cooling, changing the temperature in different parts of the solution, and/or by evaporating the solvent (s), in the vessel 7, which can be closed and which is lined with e. g. a polymer.

The properties, such as the conductivity, of the solution or the melt can be amended by e. g. changing the pH or the solution, the temperature or with other substances. In the method of the invention, the solution is exposed to an electric field by introducing a voltage into the system by means of the power source 5. The voltage and its direction can be varied within 0-100kV. The electric field formed is preferably a homogeneous one 3a, even if it partly might be non-homogenic 3b.

As a result of the electric field introduced, the solution 6 is polarized. When a voltage is applied, an electric field is produced in the liquid, affecting the orientation of the molecules. The degree of polarization can be influenced by means of the voltage. The effect is slighter at lower voltages, and increases as the voltage (and the resulting field) increases. The degree of polarization effected can also be influenced by the distance between the insulating layer and the conductor in the solution.

The parts in the vessel 7 can be fastened e. g. by means of silicon or styrox so that they can not move as a consequence of e. g. pressure, agitating or through flowing. A through flow can be performed in the vessel by means of an inlet or outlet tube. The crystals can even be dried in the same apparatus, pressurized and then agitated. The crystals can e. g. be removed through an outlet valve or, if the anode, insulation or conductor are lengthways, then e. g. with a moving base.

For example by using stainless steel as the metal and Teflon# as a thin insulation and by using a thicker layer of TeflonD as a lining for the crystallization vessel, an apparatus can be constructed, which fulfills even more strict clean requirements and stands a broad temperature and pressure range. The conductor can be brought trough the lead-in rubber. The apparatus can be built so tight that the pressure can be raised or decreased. The electronic has to be built so that it can not come in contact with the metal cover. A good insulation can be achieved with a PVC plastic and the metal cover has to be earthed of safety reasons. The apparatus should be foreseen with a fuse.

Figure 2A is an embodiment of the invention seen from above. This apparatus of the invention comprises several parallel electrodes arranged turned to a roll.

Figure 2B is another embodiment of the invention seen from above. This apparatus comprises several parallel electrodes besides each other.

Figures 3A presents the prior art crystallization of caffeine between an insulation layer below the conductor and the anode without being connected to a voltage source and figure 3B presents the crystallization of caffeine according to the invention between an insulation layer below the conductor and the anode when connected to a voltage source.

In the example of figures 3A-3B, the metal electrode 1 being the anode was a film of aluminum taken from an aluminum electrolyte capacitor (Panasonic 80V, 10000 : F, +85°C). In order to prepare the insulation layer 2, it was coated with a polyester film pocket (Laminating Pouches@, fellows USA). The temperature of the lamination apparatus was set to the value of 10, and the system was brought three times through the lamination rolls. (Pouch laminator, Rahmqvist, model MYLAM-12, Korea). 100 ml of a saturated water solution of caffeine prepared in room temperature to be the solution 6 to be crystallized was placed in two similar plastic vessels 7 (13, 5 x 4,9 cm). one of them was connected to a voltage source 5 (9V DC) through an aluminum conductor 4 (4, 9 cm x 13, 5 cm) The aluminum, anode 1 coated with a polyester film 2 was beneath and on the caffeine water solution, there was an aluminum conductor 4 of the same Panasonic capacitor as above. Both systems were then placed in a heat closet (Heraeus UT 6760, Germany) of 50°C for 16 hours. Thereafter, microscope pictures (Leica DM LB, Germany) were taken from the crystals formed between the conductor and the anode.

It was noted that, with the method of the invention, when the vessel was connected to a voltage source, the crystals grew more in the direction of the electrical field, which can be seen in figure 3B, and not against the electrical field, as in figure 3A, when the vessel 7 was not connected to a voltage source.

The crystal orientation and crystal size affect the macroscopic properties of the compound.

Figure 4A presents a X-ray powder diffraction (XRPD) analysis image of the crystallization of glycine-amino acid with a method of the invention, wherein the solution was connected to the negative pole of the cathode and the anode was connected to the positive pole. Thus, the electrodes were connected in the right way, i. e. the solution 6 was connected to the negative pole of the cathode and the anode was connected to the positive pole in a voltage of 9V DC. Two samples were taken from the glycine water solution and they were allowed to crystallize for 5 days in two 30 ml Petri vessels of 30 ml. One of them had an electrolyte capacitor (Marcon, 000: F, 35V) in the middle, washed with distilled water and dried in room temperature with the outer shells removed Figure 4B presents a powder X-ray diffraction analysis image of the crystallization of glycine-amino acid with a method of the invention, wherein the solution was connected to the positive pole of the cathode and the anode was connected to the negative pole.

Figure 5 presents the crystallization of a water solution containing taurine-amino acid according to the invention in form of a X-ray powder diffraction analysis presentation.

The crystal structure can be determined by means of the diffractograms. The position of the peaks tells about of a unit and the height of the peak, e.e. the intensity about the position of the atoms. New peaks can be seen in figures 4A, 4B and 5A and thus the crystal structure is changed when using the method of the invention, which has an effect on many properties of the compound.

Figure 6A presents the parts of mixed crystals calculated according to intensity from the crystallization of figure 5. Figure 6B presents the parts of mixed crystals calculated according to intensity and breadth from the crystallization of figure 5.

The percentage of the new product has been calculated by means of the new peaks and the intensity of them. The part of the mixed crystal has increases with the method of the invention.

In figures 7A-7B, an excess of racemic ibuprofen was allowed to solve for 1 hour in distilled water in room temperature. The achieved supersaturated solution was heated up to 70°C, and there was still much unsolved ibuprofen. Hot clear solution was poured with two petri vessels. One of the Petri vessels had an electrolyte capacitor (Marcon, 10 000: F, 35V) in the middle washed with distilled water, dried in room temperature and the outer shells removed and in a voltage of 8V DC. Both Petri vessels were in room temperature all the time. During the first 30 minutes, no crystallization could be seen in any of the Petri vessels. The Petri vessels were left in 12 hours, whereafter ibuprofen crystals were formed in both vessels. The liquid, still remaining in the Petri vessels was impregnated in a paper in the same way and the crystals were studied with light microscopy.

Figure 7A presents a light microscopy image of ibuprofen crystals achieved with a method according to prior art and figure 7B presents the ibuprofen crystals achieved with a method according to the invention.

FURTHER EXAMPLE In a further example of an embodiment of the invention, two similar aluminum plates (with a thickness of 0,5 cm, one of which was coated with E-CTFE fluoropolymer of a thickness of 250 : m, i. e. ALU 2 (http ://www. aic. fi/tuotteet. html, filed 1. 3. 2Q04)) were put in a plastic vessel with a lining of polytetrafluorethene. Power source : CPS 0550 7313 SW TECH CENTER DRIVE, PORTLAND, OR 9223 : 1000V direct voltage and the distance of 1, 8 cm was filled with tap water. Conductors between the aluminum plate and the coated aluminum plate, which were bored in the aluminum plates wit the banana connection. A polarization was achieved by means of both connection ways; in either direction.

For one skilled in the art it is clear that the invention is not limited to the details of the presented examples, as to the selected metal electrode and insulation, and that the invention can be performed in other forms without being outside the scope of the claims.