GB2600464A

GB2600464A - Process of preparing active pharmaceutical ingredient salts

Info

Publication number: GB2600464A
Application number: GB2017267.2A
Authority: GB
Inventors: Kiritkumar Bhatt Saumil; Douroumis Dennis; Sadeque Hossain Md
Original assignee: Cubic Pharmaceuticals Ltd; University of Greenwich
Current assignee: Cubic Pharmaceuticals Ltd; University of Greenwich
Priority date: 2020-10-30
Filing date: 2020-10-30
Publication date: 2022-05-04
Also published as: GB202017267D0

Abstract

A process of preparing an active pharmaceutical ingredient salt, the process comprising the steps of: (i) forming a mixture comprising an active pharmaceutical ingredient, a salt forming substance and one or more solvents; (ii) contacting the mixture with a supercritical fluid to form a salt of the active pharmaceutical ingredient and the salt forming substance; and (iii) obtaining the active pharmaceutical ingredient salt. The preferred pharmaceutical ingredient is ketoconazole and the preferred salt is an oxalate. Preferably, the solvents are all organic solvents. The preferred supercritical fluids are supercritical carbon dioxide or supercritical nitrogen. Preferably, the pKa difference between the active pharmaceutical ingredient and the salt forming substance is 1 or more. More preferably, the active pharmaceutical ingredient is basic, the salt forming substance is an acid and the pKa difference between the basic active pharmaceutical ingredient and the acid is 1 or more. The present invention also relates to the active pharmaceutical ingredient salt obtained/obtainable from the above process. The present invention further relates to pharmaceutical compositions comprising said active pharmaceutical ingredient salt and to the use of such an active pharmaceutical ingredient salt in the treatment and prevention of medical disorders and diseases.

Description

Process of Preparing Active Pharmaceutical Ingredient Salts

Field of the Invention

The present invention relates to a process of preparing a salt of an active pharmaceutical ingredient and a salt forming substance and to the active pharmaceutical ingredient salt obtained/obtainable therefrom. The present invention further relates to pharmaceutical compositions comprising said active pharmaceutical ingredient salt and to the use of such an active pharmaceutical ingredient salt in the treatment and prevention of medical disorders and diseases.

Background of the Invention

Salts of an active pharmaceutical ingredient can diversify the number of crystal forms that exist for an active pharmaceutical ingredient and they may provide improvements in physicochemical properties.

There is a need to provide processes for the preparation of active pharmaceutical ingredient salts that can be easily scaled up and used both for batch or continuous processing at an industrial scale and/or provides a useful alternative to known process.

There is also a need to provide active pharmaceutical ingredient salts with improved physicochemical properties and/or those that provide a useful alternative to known active pharmaceutical ingredient salts.

Summary of the Invention

A first aspect of the invention provides a process of preparing an active pharmaceutical ingredient salt, the process comprising the steps of: (i) forming a mixture comprising an active pharmaceutical ingredient, a salt forming substance and one or more solvents; (ii) contacting the mixture with a supercritical fluid to form a salt of the active pharmaceutical ingredient and the salt forming substance; and (iii) obtaining the active pharmaceutical ingredient salt.

A second aspect of the invention provides an active pharmaceutical ingredient salt obtained/obtainable from the first aspect of the invention.

A third aspect of the invention provides a composition comprising an active pharmaceutical ingredient salt of the second aspect of the invention and a pharmaceutically acceptable excipient.

A fourth aspect of the invention provides the active pharmaceutical ingredient salt of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, for use in medicine, and/or for use in the treatment or prevention of a disease, disorder or condition.

Brief Description of the Drawings

Figure 1 shows a Differential Scanning Calorimetry (DSC) analysis comparing starting material and the active pharmaceutical ingredient salt from example 1. From top to bottom the samples are: (1) oxalic acid, (2) ketoconazole and (3) ketoconazole oxalate salt.

Figure 2 shows an XRPD diffractogram comparing starting materials and the active pharmaceutical ingredient salt from example 1. From top to bottom the samples are: (1) ketoconazole oxalate salt, (2) oxalic acid and (3) ketoconazole.

Figure 3 shows a quantitative XRPD conducted using Rietveld refinement overlaying the ketoconazole salt from example 1 with the previously reported data in the Cambridge Structural Database for a ketoconazole oxalate salt.

Detailed Description of the Invention

or Supercritical fluid processing is a processing technology that may be easily scaled up and used both for batch or continuous processing at an industrial scale.

Processing of pharmaceutical solids using supercritical fluid is described in Pando et al. RSC Advances 2016, 6, PP 71134-71150.

Differences between solid forms of an active pharmaceutical ingredient can have profound effects on the properties the compound. A process using supercritical fluid for preparing active pharmaceutical ingredient salts may provide active pharmaceutical ingredient salts of high purity and may further enhance their dissolution rates and bioavailability by reducing their particle size. -3 -

The term 'active pharmaceutical ingredient salt' is used to refer to a sail formed /c) between an active pharmaceutical ingredient and a salt forming substance, e.g. to an ionisable active pharmaceutical ingredient that has been combined with a counter-ion to form a neutral complex.

In certain embodiments, a reaction to form a salt compound, may take place when the pKa difference between an active pharmaceutical ingredient and a salt forming substance is 1 or more.

As used herein an 'active pharmaceutical ingredient' is a substance intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body.

or In the pharmaceutical industry, a salt formation approach is commonly used for an ionizable drug to increase solubility and dissolution rate. Salts are formed via proton transfer from an acid to a base. A stable ionic bond may be formed when the difference of pKa between an acid and a base (pKa) is (or more, typically greater than 2 and preferably greater than 3. The counter-ion containing salt changes the pH at the dissolving surface of a salt particle in the diffusion layer, resulting in a higher dissolution rate of the salts compared with that of the corresponding free forms. According to the Henderson-Hasselbalch equations, the change of pH highly influences the aqueous solubility of an ionizable drug. In theory, the solubility of a weak basic drug increases exponentially with decreasing pH at the pH range between its pKa and pH max (pH of maximum solubility in the pH-solubility profile). -4 -

In certain embodiments, when the active pharmaceutical ingredient is acidic, e.g. a weak acidic drug (e.g. ibuprofen or phenytoin), the salt forming substance may be a base and the pKa difference between the acidic active pharmaceutical ingredient and the base may be 1 or more, typically greater than 2, preferably greater than 3 or preferably more than 7 or above. These bases may be selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium glycinate, sodium lysinate, sodium glycinate monohydrate, Nmethylglucosamine, potassium glycinate and tribasic sodium and potassium phosphates.

In certain embodiments, when the active pharmaceutical ingredient is basic, e.g. a weak basic drug (e.g. propranolol, cetirizine, or diphenhydramine), the salt forming substance may be an acid and the pKa difference between the basic active pharmaceutical ingredient and the acid may be 1 or more, typically greater than 2 or preferably greater than 3 or preferably more than 7 or above. When a dicarboxylic acid (e.g. oxalic acid) or a benzoic sulfimide (e.g. saccharin) is used as a salt forming agent with a weakly basic active pharmaceutical ingredient (e.g. ketoconazole or lamotrigine), the pKa of the salt forming agent is typically less than 7.

In certain embodiments, the active pharmaceutical ingredient is selected from the group consisting of acetylsalicylic acid, albendazole, 4 -aminosalicylic acid, acetaminophen, aripiprazole, aspirin, carbamazepine, carvedilol, desipramine, diclofenac, diflunisal, ethenzamide, ethambutol, ethionamide, erlotinib, gentisic acid, haloperidol, isoniazid, indoprofen, indomethacin, lamotrigine, lamivudine, lidocaine, or linogliride, ketoprofen, ketoconazole, miconazole, meloxicam, olanzapine, phenobarbital, pyrazinamide, rifampicin, sulfamethazine, theophylline, tinidazole and zidovudine. Preferably, the active pharmaceutical ingredient is selected from the group consisting of carbamazepine, indomethacin and ketoconazole, more preferably the active pharmaceutical ingredient is ketoconazole.

In certain embodiments, the salt forming substance is a pharmaceutically acceptable substance. Preferably, the salt forming substance is another active pharmaceutical ingredient or a non-active pharmaceutically acceptable substance. Preferably, the salt forming substance is a non-active pharmaceutically acceptable substance include acetic acid, adipic acid, benzoic acid, besylic acid, benzathine, carbonic acid, cinnamic acid, citric acid, choline, D,L -lactic acid, diethylamine, edisylic acid, fumaric acid, glucuronic -5 -acid, gluconic acid, glutaric acid, hesperetin, hippuric acid, 1 -arginine,1 -lysine, maleic acid, malic acid, malonic acid, mefenamic acid, methane sulfonic acid, naphthalene sulfonic acid, nicotinamide, oleic acid, oxalic acid, pamoic acid, phenobarbital, procaine, piperazine, succinic acid, stearic acid, sulfuric acid, tartaric acid, trifluoroacetic acid, tosylic acid, tromethamine. More preferably, the salt forming substance is oxalic acid.

In certain embodiments, the salt forming substance is an acid or a base. Preferably, the salt forming substance is an acid, more preferably a mono-acid or a di-acid.

In certain embodiments, the stoichiometric ratio of the active pharmaceutical ingredient to the salt forming substance is from 10:1 to 1:10 (e.g. from 5:1 to 1:5, from 2:1 to 1:2, or about 1:1)(API: salt forming substance).

The active pharmaceutic ingredient salt may be a mono-, di-, tri-or multi-salt.

Preferably the salt is a mono-or di-salt.

In certain embodiments, the individual constituents of the active pharmaceutical ingredient salt (i.e. the active pharmaceutical ingredient and the salt forming substance) are solid at 20°C at atmospheric pressure.

In certain embodiments, the active pharmaceutical ingredient is ketoconazole and the salt forming substance is oxalic acid.

or In certain embodiments, the one or more solvents are aqueous and/or organic solvents. Preferably, at least one of the one or more solvents is an organic solvent. More preferably, the one or more solvents are all organic solvents. Suitable organic solvents include tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropyl alcohol and n-butanol.

Preferably, the one or more solvents are selected from polar organic solvents such as ethanol, methanol and acetone.

In certain embodiments, in step (i) the active pharmaceutical ingredient and the salt forming substance are dissolved in the one or more solvents to form a solution.

Preferably, in step (i) the active pharmaceutical ingredient and the salt forming substance are dissolved in the one or more organic solvents to form a solution. -6 -

In certain embodiments, none of the one or more solvents in step (i) is a supercritical fluid.

In certain embodiments, the one or more solvents are miscible with the supercritical fluid. Preferably, the one or more solvents are all organic solvents and are miscible with the supercritical fluid.

Various supercritical fluid processes exist for contacting a mixture, such as the mixture /0 in step (ii), with a supercritical fluid. Examples of such supercritical fluid processes include, but are not limited to supercritical anti-solvent ('SAS') crystallisation, atomisation and anti-solvent ('AAS') crystallisation, supercritical fluid enhanced atomization ('SEA') and gas anti-solvent ('GAS') crystallisation. Supercritical fluid processes and equipment are described in Pando et al. RSC Advances 2016, 6, pp 71134-71150 or in Padrela et al. European Journal of Pharmaceutical Sciences, 2006, 28, pp 6-17.

As used herein, the term 'supercritical fluid' refers to a fluid at or above its critical pressure (R) and critical temperature (Te) simultaneously. Thus, a fluid above its critical pressure and at its critical temperature is in a supercritical state. A fluid at its critical pressure and above its critical temperature is also supercritical.

In certain embodiments, the supercritical fluid is selected from the group consisting of carbon dioxide (CO2), nitrogen (N2), water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, acetone, nitrous oxide and mixtures thereof. Preferably, the supercritical fluid is supercritical CO2 or N,, more preferably N2. Carbon dioxide has a Te of 304.1 K and a Pe of 7.38 MPa.

In certain embodiments, in the process of step (ii) the mixture is contacted with a supercritical fluid in supercritical anti-solvent ("SAS") crystallisation process or an atomisation and anti-solvent ("AAS") crystallisation process.

Typically, a SAS process is based on the relatively low solvent power of supercritical fluids for solutes (such as active pharmaceutical ingredients and salt forming substances) and its good miscibility with organic solvents. Typically, the active pharmaceutical ingredient and the salt forming substance are dissolved in one or more -7 -organic solvents and contacted with the supercritical fluid which may induce precipitation to form the active pharmaceutical ingredient salt. For example, a supercritical fluid may be introduced into a precipitation vessel (e.g. using a high-pressure pump) such that the precipitation vessel is pressurised (e.g. at a pressure greater than ambient pressure); and the solution (comprising the active pharmaceutical ingredient and the salt forming substance) may also be introduced into the precipitation vessel (e.g. sprayed into via an inlet nozzle). Preferably, the supercritical fluid and the solution may be introduced in either order or simultaneously. Preferably, the supercritical fluid and the solution may both be introduced into the precipitation jo vessel via a coaxial nozzle and may be mixed (e.g. in a mixing chamber within the coaxial nozzle) prior to introduction into the precipitation vessel. Preferably, the active pharmaceutical ingredient salt may be obtained from the precipitation vessel (e.g. by filtration).

In certain embodiments, e.g. typically in a SAS process, in step (i) of the process the active pharmaceutical ingredient and the salt forming substance are dissolved in one or more organic solvents to form a solution and in step (ii) the solution and the supercritical fluid are introduced into a pressurised precipitation vessel (e.g. at pressure greater than 0.1 MPa, or preferably at a pressure between 2-20 MPa or preferably between 5-15 MPa). Preferably, the supercritical fluid and the solution are mixed (preferably they are mixed at a pressure greater than 0.1 MPa, or preferably at a pressure between 2-20 MPa or preferably between 5-15 MPa) prior to introduction into the precipitation vessel. Preferably, the supercritical fluid and the solution are both introduced into the precipitation vessel via a coaxial nozzle and are mixed (e.g. by or introduction into a mixing chamber within the coaxial nozzle)(preferably they are mixed at a pressure greater than 0.1 MPa, or preferably at a pressure between 2-20 MPa or preferably between 5-15 MPa) prior to introduction into the precipitation vessel. Preferably, the one or more solvents are miscible with the supercritical fluid. Preferably, the active pharmaceutical ingredient salt is obtained from the precipitation vessel (e.g. by filtration).

Typically, an AAS process is similar to an SAS process except that in a SAS process the precipitation vessel is typically pressurised whereas for an AAS process the precipitation vessel is typically at ambient pressure. Typically, the active pharmaceutical ingredient and the salt forming substance are dissolved in one or more organic solvents and contacted with the supercritical fluid which may induce -8 -precipitation to form the active pharmaceutical ingredient salt. Typically in an AAS process the solution (comprising the active pharmaceutical ingredient and the salt forming substance) and the supercritical fluid are mixed in a pressurised mixing chamber (e.g. at a pressure greater than ambient pressure) prior to introduction into a precipitation vessel at ambient pressure and the consequential depressurisation may enhance atomization of the solution. Preferably, in an AAS process a solution (comprising the active pharmaceutical ingredient and the salt forming substance) and the supercritical fluid are both introduced to the precipitation vessel through a coaxial nozzle and are mixed (e.g. in a mixing chamber within the coaxial nozzle) prior to depressurisation on introduction to the precipitation vessel. Preferably, the active pharmaceutical ingredient salt may be obtained from the precipitation vessel (e.g. by filtration).

In certain embodiments, e.g. typically in a AAS process, in step (i) of the process the active pharmaceutical ingredient and the salt forming substance are dissolved in one or more organic solvents to form a solution and in step (ii) the solution and the supercritical fluid are introduced into a precipitation vessel at ambient pressure (e.g. at about 0.1 MPa). Preferably, the supercritical fluid and the solution are mixed (preferably they are mixed at a pressure greater than 0.1 MPa, or preferably at a pressure between 2-20 MPa or preferably between 5-15 MPa) prior to introduction into the precipitation vessel. Preferably, the supercritical fluid and the solution are both introduced into the precipitation vessel via a coaxial nozzle and may be mixed (e.g. by introduction into a mixing chamber within the coaxial nozzle)(preferably they are mixed at a pressure greater than 0.1 MPa, or preferably at a pressure between 2-20 or MPa or preferably between 5-15 MPa) prior to introduction into the precipitation vessel. Preferably, the one or more solvents are miscible with the supercritical fluid. Preferably, the active pharmaceutical ingredient salt is obtained from the precipitation vessel (e.g. by filtration).

In certain embodiments, in the process of step (ii), the mass flow ratio of the mixture from step (i) to the supercritical fluid is from 0.01 (g /g) to 0.5 (g/g)(mixture: supercritical fluid). Preferably, the mass flow ratio of the mixture from step (i) to the supercritical fluid is from 0.01 (g/g) to 0.2 (g/g). -9 -

In certain embodiments, the process of step (ii) is performed at a pressure of 0.1-20 MPa. Preferably, the process of step (ii) is performed at a pressure of 2-20 MPa or preferably of 5-15 MPa.

In certain embodiments, the process of step (ii) is performed at a temperature of 0-80°C. Preferably, process of step (ii) is performed at a temperature of 20-50°C.

In certain embodiments, the process of step (ii) is performed for a period of up to 1 hour. Preferably, the process of step (ii) is performed for a period of up to 30 minutes, jo or up to 20 minutes or tip to 15 minutes.

In certain embodiments, the active pharmaceutical ingredient salt is obtained as crystalline solid.

In certain embodiments, the active pharmaceutical ingredient salt is obtained from the mixture by filtration. Preferably, the active pharmaceutical ingredient salt is obtained from the mixture by filtration under vacuum.

In certain embodiments, the active pharmaceutical ingredient salt is obtained from the mixture substantially solvent free. Preferably, the active pharmaceutical ingredient salt obtained from the mixture comprises less than 2% w/w, less 1% vv/w, less than 0.i% w/w, less than 0.01% w/w, or no solvent.

In certain embodiments, the process of step (ii) is a continuous process.

In certain embodiments, an active pharmaceutical ingredient salt is produced at a scale of 0.5-3 kg/hr or more, typically 5 kg/hr or more, preferably 7 kg/h or more. For example, in some embodiments the process may be carried out over 1 hour or more, (e.g. 3 hours or more, 5 hours or more, or 7 hours or more) with 0.5-3 kilos or more, typically 5 kilos or more, preferably 7 kilos or more of active pharmaceutical ingredient salt being produced per hour of processing time.

In certain embodiments, the active pharmaceutical ingredient salt obtained comprises particles having a mean diameter of less than 20 pm, or less than 10 gm, or less than 5 35 gm, or less than 1 um or less than 0.1 pm. In a preferred embodiment, the active pharmaceutical ingredient salt comprises particles with a mean diameter of between -10 - 0.05 um to km um, or preferably 0.1 pm to 20 gm, or preferably 0.1 um to in pm. The mean particle diameter may be measured using conventional techniques for example by photon correlation spectroscopy or scanning electron microscopy. Preferably, the measurement technique is photon correlation spectroscopy. As used herein, the particle mean diameter refers to a volume mean diameter.

In certain embodiments, the active pharmaceutical ingredient salt obtained has a chemical purity of at least 95 wt%, more preferably at least 98 wt%, more preferably at least 99 wt%, more preferably at least 99.5 wt%, even more preferably at least 99.8 /0 wt%, and most preferably at least 99.9 wt%, preferably as measured by HPLC or XRPD.

In certain embodiments, the active pharmaceutical ingredient salt obtained has a degree of crystallinity of 90% or more, 95% or more, or 99 % or more. As used herein the degree of crystallinity is the weight percentage of the active pharmaceutical ingredient salt which is in one or more crystalline forms, expressed as a percentage of the total weight of the active pharmaceutical ingredient salt.

A second aspect of the invention provides an active pharmaceutical ingredient salt obtained/obtainable by a process according to the first aspect of the invention.

For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred or optional embodiment of any aspect of the present invention should also be considered as a preferred or optional embodiment of any other aspect of the present invention.

Examples

Example 1: ketoconazole oxalate salt 5 Preparation method 1: Ketoconazole (crz) and oxalic acid (OA) (1:1.1) were accurately weighed and dissolved in a mixture of solvents (1:1 v/v methanol:acetone) and placed in the gas chamber and supercritical CO2 (scCO2) was supplied continuously at specific flow and pressure (pressure mobarho MPa)(equipment Thar Process Inc., USA). The temperature of the gas chamber was maintained at 40°C for the entire process. The process was run for 15 and 30 minutes in two different instances. After the process, resulting solid crystal was collected and oven dried for further analysis.

Preparation method 2: For an atomization enhancement process, a clear solution containing KTZ and oxalic acid was pumped through a coaxial nozzle where the solution mixed with the scCO2 in the mixing chamber before depressurization into the precipitation vessel. The precipitating solid was collected for further analysis.

Analysis: The prepared solid materials were investigated by the DSC. Figure 1 shows the thermal events which occurred in all the samples analysed. It can be found that KTZ has a sharp or melting point at 150.47 °C whereas oxalic acid displayed a melting point at 192°C. The solid resulting from KTZ:oxalic acid (1:1.1) anti solvent process (preparation method 1) and atomization enhancement scCO2 process (preparation method 2) showed a unique endothermic peak at approximately 194.77° C. There is no other endothermic event noticed in both materials, which indicates the formation of new material compared to parent materials. Comparing with the previously reported KTZ:0A salt data from Martin et al. (Cryst. Growth Des. 2013, 13, 10, pp 4295-4304, Ketoconazole Salt and Co-crystals with Enhanced Aqueous Solubility'), KTZ:0A (1:1.1) matches with the melting point of KTZ oxalate salt formed by solution crystallization methods, confirming the formation of KTZ oxalate salt.

-12 -All the samples including bulk KTZ, oxalic acid and KTZ:oxalic acid salt solid were further analysed by using XRPD to identify the crystal data obtained from each solid. This newly obtained data was compared with the previously reported data from the Cambridge Structural Database by using TOPAS software. The percentage of the match between newly obtained crystal data with previously reported data is identified by Rietveld refinement of TOPAS V4.2 (Bruker). Though good fitting depends on visual fitting of the crystalline peak, it is generally agreed that if the weighted profile R factor (Rwp) is within or around 3 times of the expected R factor (Rexp), the match or refinement is satisfactory (Toby, B. H., R factors in Rietveld analysis: How good is io good enough?, Powder Diffraction, 2006, 21(01), pp 67-70). The main intense peaks for KTZ appear at 7.28°, 9.5°, 10.69°, 11.96°, 16.13°, 17.5°, 20.01° and 27.65° 20. The oxalic acid, showed diffraction peaks at 16.09°, 19.03°, 20.11°, 26.24°, and 31.57° 20.

/5 Characteristic diffraction peak observed for bulk materials and salt analysed by XRPD: Sample Peaks 29 scale KTZ 7.28°, 9.5°, 10.69°, 11.96°, 16.13°, 17.5°, 20.01°, 27.65° Oxalic acid 16.09°, 19.03°, 20.11°, 26.24°, 31-57° KTZ oxalate salt 8.75°, 10.81°, 11.95°, 13.27°, 17.72°, 18.5°, 19.89°, 20.42°, 28.14° As observed, a distinct crystalline profile was obtained for the KTZ oxalic acid supercritical fluid processed solid materials at 8.75°, 10.81°, 11.95°, 13.27°, 17.72°, 18.5°, 19.89°, 20.42°, and 28.14° 20 which does not match with the bulk KTZ and oxalic acid crystal data that confirms the formation of a new solid crystal. Furthermore KTZ: oxalic acid crystal diffraction data was compared with the previously reported data, by Martin et al. (Cryst. Growth Des. 2013, 13, 10, pp 4295-4304, Ketoconazole Salt and Co-crystals with Enhanced Aqueous Solubility') in the Cambridge Structural Database. The similarity between these two data is confirmed by the Rietveld refinement using *=3 or TOPAS software where Rwp is within two times of Rexp (Figure 3). The similarity between these newly obtained crystal data with the previously reported data confirms the formation KTZ: oxalic acid salt with a purity close to 1w%.

R-Values Rexp: 4.68 Rwp: 8.56 Rp: 6.59 GOF: 1.83 -13 -Rex') : 5.36 Rwp: 9.82 Rif: 7.81 DIV: 0.76 Figure 3 shows a Rietveld refinement of the XRPD data for the KTZ oxalate.

It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

-14 -Claims 1. A process of preparing an active pharmaceutical ingredient salt, the process comprising the steps of: (i) forming a mixture comprising an active pharmaceutical ingredient, a salt forming substance and one or more solvents; (ii) contacting the mixture with a supercritical fluid to form a salt of the active pharmaceutical ingredient and the salt forming substance; and (iii) obtaining the active pharmaceutical ingredient salt. 2. 3. 4. 5. or 6. 7. 8. 9.
A process according to claim 1, wherein the pKa difference between the active pharmaceutical ingredient and the salt forming substance is 1 or more.
A process according to claim 1 or 2, wherein the active pharmaceutical ingredient is basic, the salt forming substance is an acid and the pKa difference between the basic active pharmaceutical ingredient and the acid is 1 or more.
A process according to any preceding claim, wherein the one or more solvents are all organic solvents.
A process according to any preceding claim, wherein in step (i) the active pharmaceutical ingredient and the salt forming substance are dissolved in the one or more solvents to form a solution.
A process according to any preceding claim, wherein the one or more solvents are miscible with the supercritical fluid.
A process according to any preceding claim, wherein the supercritical fluid is supercritical CO-or N2.
A process according to any preceding claim, wherein in step (i) of the process the active pharmaceutical ingredient and the salt forming substance are dissolved in one or more organic solvents to form a solution and in step (ii) the solution and the supercritical fluid are introduced into a pressurised precipitation vessel at a pressure between 5-15 MPa.
A process according to any one of claims 1-7, wherein in step (i) of the process the active pharmaceutical ingredient and the salt forming substance are -15 -dissolved in one or more organic solvents to form a solution and in step (ii) the solution and the supercritical fluid are introduced into a precipitation vessel at ambient pressure.
10. A process according to claim 9, wherein the supercritical fluid and the solution are mixed at a pressure between 5-15 MPa prior to introduction into the precipitation vessel.
A process according to any preceding claim, wherein the active pharmaceutical /c) ingredient salt is obtained from the mixture by filtration.
12. A process according to any preceding claim, wherein the active pharmaceutical ingredient salt is obtained as a crystalline solid.
13. A process according to any preceding claim, wherein the active pharmaceutical ingredient salt obtained comprises particles having a mean diameter of less than 5 Prn*
14. A process according to any preceding claim, wherein the active pharmaceutical ingredient salt obtained has a chemical purity of at least 99.5 wt% as measured by HPLC or XRPD.
15. An active pharmaceutical ingredient salt obtained/obtainable by a process as defined in any preceding claim. or16. A composition comprising an active pharmaceutical ingredient salt according to claim 15 and a pharmaceutically acceptable excipient.