AU2006313009B2 - Process to control particle size - Google Patents

Abstract

A multi-stage process to control the particle size of a pharmaceutical substance comprising the steps of: passing the pharmaceutical substance through a first stage of a particle size reduction process with a first set of particle size control parameters to obtain a feedstock of reduced median particle size and lesser distribution of median particle size for a second stage of a particle size reduction process; passing the feedstock, through a second stage of a particle size reduction process with a second set of particle size control parameters; optionally, using the product of the second stage or subsequent stages as a feedstock in further stages of a multi-stage particle size reduction process with a set of particle size control parameters for each stage; and collecting a pharmaceutical substance with a median particle size greater than 10µm and with a narrow, reproducible distribution of median particle sizes.

Description

WO 2007/053904 PCT/AU2006/001687 PROCESS TO CONTROL PARTICLE SIZE TECHNICAL FIELD A process for the production of a pharmaceutically 5 active substance with a tightly controlled, reproducible distribution of median particle size, particles of a pharmaceutically active substance with a tightly controlled, reproducible distribution of median particle size and a pharmaceutical composition containing a 10 pharmaceutically active substance with a tightly controlled, reproducible distribution of median particle size. BACKGROUND ART 15 Pharmaceutically active substances are commonly formulated into dosage forms to aid the delivery of small amounts thereof. The amount of pharmaceutically active substance that will be present in the dosage form can vary from a very small amount such as about 0.5mg up to larger 20 amounts such as about 1000mg, depending on the pharmaceutically active substance and the pharmaceutical effective amount thereof. In order to be able to accurately administer these amounts of pharmaceutically active substance, the dosage form often includes 25 pharmaceutical acceptable excipients that perform various functions depending on the dosage form and the mode of action required. These excipients have an effect on the method and rate of delivery of the pharmaceutically active substance to the patient. 30 Another aspect of pharmaceutical formulations that affects the rate of delivery or the bioavailability of the pharmaceutically active substance is the particle size. This relationship between particle size and WO 2007/053904 PCT/AU2006/001687 -2 bioavailability is well known in the pharmaceutical industry and across a range of pharmaceutical products. In 1979, studies into the effect of crystal size on the bioavailability of Benoxaprofen were conducted (Biomed 5 Mass Spectrom., 1979 Apr, 6(4), pp 173-8, Wolen RL et al; J. Pharm. Sci., 1979 Jul, 68(7), pp 850-2, Ridolfo AS et al). J. Pharm. Sci., 1980 Apr, 69(4), pp 391-4, Schoenwald RD & Stewart P disclose the effect of particle size on the ophthalmic bioavailability of dexamethasone 10 stating that "A statistically significant rank-order correlation was observed between increasing drug levels and decreasing particle size." Other examples include American Journal of Veterinary Research, 1980 Dec, 41(12), pp 2095-2101, Shastri S et al; Clinical Pharmacokinetics, 15 1998 Feb, 34(2), pp 155-62, Miller DB & Spence JD; Current Med Res Opin, 2000, 16(2), pp 134-8, Guichard JP et al; J. Microencapsul., 2001 May-June, 18(3), pp 359-71, Demirel M et al; and Pharmaceutical Dev Technol, 2004, 9(1), pp 1 13, Rasenick N & Muller BW. Also refer to US 2002035119 20 Al Rajiv, M et al; US 2003175338 Al Manoj, KP et al; WO 03/082241 A3 Kumar, PM et al; WO 03/080056 A2 Teva Pharmaceutical Industries Ltd; and US RE37516 E Grebow, PE et al that discuss the relationship between particle size and bioavailability of the pharmaceutically active 25 substance. Bioavailability can also be increased with the use of a surfactant or wetting agent. This helps to increase the solubility of the pharmaceutically active substance and thus bioavailability. However, there can be an undesired 30 interaction between the pharmaceutically active substance and the wetting agent. Therefore, it is not always beneficial to use a wetting agent to increase the WO 2007/053904 PCT/AU2006/001687 -3 solubility and/or bioavailability of a pharmaceutically active substance. Particle sizes of substances can be measured using various commonly available methods such as measurement 5 using light (eg. light-scattering methods or turbidimetric methods), sedimentation methods (eg. pipette analysis using an Andreassen pipette, sedimentation scales, photosedimentometers or sedimentation in a centrifugal force), pulse methods (eg. Coulter counter), or sorting by 10 means of gravitational or centrifugal force. There are various known methods for the control of the particle size of substances including reduction by comminution or de-agglomeration by milling and/or sieving, or particle size increase by agglomeration through 15 granulation, blending or a mixture thereof. These methods use commonly available equipment and/or methods for the reduction or increase of the particle sizes of material. However, these techniques do not allow for the production of a substance with a very narrow, reproducible and 20 consistent distribution of particle size without the need to reprocess, rework or destroy those particles outside of the required distribution. Thus, these processes can be time consuming and costly if reworking of the material under the desired size is not able to be performed. In 25 those circumstances, it is common for the fine material to be destroyed or reprocessed. Spray-drying can also be used to achieve particles in a narrow particle size distribution. However, inconsistency of the particle size of the feedstock for 30 this process can cause problems with the apparatus such as blockage of the spray jets. Multi-stage milling techniques have been used on a limited basis in the past to provide substances, such as WO 2007/053904 PCT/AU2006/001687 -4 those for use in inhalants and steroids, where the median particle size is extremely low, eg. below 5pm, with steep cut-offs on both ends of the particle size spectrum. These processes have required a step-down reduction of 5 particles from >100pm to -50pm, then to -20pm and finally to below 5pm. This last stage is not tightly controlled in that the substance with a median particle size of below 5pm of its very nature must have a narrow distribution of particle size. However, substances with median particle 10 sizes larger than -10pm but still with a narrow, reproducible and consistent distribution have not been manufactured by these techniques in the past. Other techniques that have been used to obtain uniform particles in a narrow, reproducible and consistent 15 distribution of particle sizes include layering the pharmaceutically active substance onto carrier particles having uniform particle size or spray-drying to form particles of uniform size distribution. Layering or coating requires further processing in specialised 20 equipment designed for small particles and carrier particles in the size distribution required are not always commercially available. Spray-drying techniques also require specialised equipment and it may not be possible to put the pharmaceutically active substance being handled 25 into a solution to be spray-dried. Otherwise the solvent necessary to dissolve the pharmaceutically active substance may not be available or it may not be acceptable for pharmaceutical use. This can be because the pharmaceutically active substance is not stable in 30 solution and degrades or because the solvent is not totally removed from the final product and its residual presence would be unacceptable to health authorities, thereby making the pharmaceutically active substance, and - 5 its resultant pharmaceutical product, unacceptable for registration or administration. Extrusion and spheronising are combined techniques that can give particles with a uniform size and a narrow, 5 reproducible and consistent distribution of particle size. This combined technique requires the pharmaceutically active substance to be made into a paste-like form that can be extruded. The limitation of this technique is that it is difficult to achieve the production of small particles below 10 200pm and is generally used for particles above 0.3mm (300pm). SUMMARY OF INVENTION We have surprisingly found that a narrow, reproducible and consistent distribution of median particle size for particles of a pharmaceutically active substance can be 15 achieved by using a multi-stage reduction process without the necessity to reprocess, reject or destroy large quantities of particles outside of the desired range. In a first aspect the present invention provides a multi stage process to control the particle size of a pharmaceutical 20 substance comprising the steps of: passing an initial feedstock of the pharmaceutical substance through a first stage of the multi-stage particle size reduction process, the first stage having a first set of particle size control parameters, to obtain a further 25 feedstock for at least a second stage of the multi-stage particle size reduction process; passing the further feedstock through the second stage of the multi-stage particle size reduction process, the second stage having a second set of particle size control 30 parameters, to obtain a pharmaceutical substance with a 4720974_1 (GHMatters) P24887.AU 24 September 2013 - 6 reduced median particle size and narrower distribution of median particle size than the further feedstock; collecting the pharmaceutical substance of the final stage of the multi-stage particle size reduction process with 5 a median particle size greater than 10im and with a narrow, reproducible distribution of median particle size. In an embodiment the particle size reduction process is a milling process. In an embodiment the particle size reduction process is 10 selected from the group consisting of jet milling, hammer milling, compression milling and tumble milling processes, most particularly a jet milling process. Particle size control parameters for these processes are well understood by the person skilled in the art. For example the particle size 15 reduction achieved in a jet milling process is controlled by adjusting a number of parameters, the chief ones being mill pressure and feed rate. In a hammer mill process, the particle size reduction is controlled by the feed rate, the hammer speed and the size of the opening in the grate/screen 20 at the outlet. In a compression mill process, the particle size reduction is controlled by the feed rate and amount of compression imparted to the material (e.g. the amount of force applied to compression rollers). In a second aspect the invention provides a 25 pharmaceutical substance manufactured by a process as described herein. In a third aspect the invention provides a pharmaceutical composition containing a pharmaceutical substance wherein at least 50% of the particles have a particle size deviating no 30 more than between lim and 10p1m 4720974_1 (GHMatters) P24887.AU 24 September 2013 WO 2007/053904 PCT/AU2006/001687 -7 from the median particle size, and at least one other pharmaceutically acceptable ingredient. In the claims which follow and in the preceding description of the invention, except where the context 5 requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further 10 features in various embodiments of the- invention. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge 15 in the art, in Australia or in any other country. BRIEF DESCRIPTION OF THE DRAWINGS Preferred embodiments of the invention will now be described with reference to the accompanying drawings, in 20 which: Figure 1 is graph showing the particle diameter distribution on the left hand axis, cumulative volume on the right hand axis vs particle diameter(pm) for an average of all of the separate samples set forth in Table 25 5. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The stepwise reduction of material can produce a median particle size of greater than 10pm, for example 30 between 10pm and 50pm, more preferably between 10pm and 20pm, with at least 50% of the particles having a median particle size distribution of about 1pm to 10pm. Put another way, in an embodiment at least 50% of the WO 2007/053904 PCT/AU2006/001687 -8 particles have a particle size deviating no more than between 1pm and 10pm from the median particle size. In further embodiments this may 1pm to 5pm or even 1pm to 3pm. In order to get material with a median particle size 5 of greater than 10pm with a narrow, reproducible and consistent distribution, the feedstock going into the final reduction process needs to be such that it does not have a large range of particle sizes. Therefore, the particle size of the feedstock entering into the final 10 reduction process needs to be controlled but to a lesser extent than the desired final product. In order to achieve this, the material is sequentially reduced in a series of milling processes whereby the distribution of particle sizes is gradually tightened. The reduction of 15 material with a wide distribution of particle sizes in a single process will afford a material with reduced median particle size but still with a wide distribution of particle sizes and a product whose median particle size is not uniform from one batch to the next. 20 The process of the invention involves taking the feedstock of material with a larger median particle size and a larger distribution of particle sizes than that required in the final product and reducing the median particle size and the distribution of particle sizes in a 25 step-wise manner. The stepped process takes a feedstock with a large median particle size that has a large distribution and reduces it such that the median particle size decreases and, more importantly, the distribution of particle size becomes narrower. This is then used as the 30 feedstock for the next reduction stage. This can be continued until material with the desired median particle size and distribution have been achieved.

WO 2007/053904 PCT/AU2006/001687 -9 Whilst not wishing to be contained to a specific hypothesis of how this is achieved, it is understood that the reduction process requires energy to be imparted into the material. The larger the starting material, the more 5 energy that is required to reduce it and vice-versa with regard to smaller particles. There comes a time when no more energy can be efficiently imparted into a material in a single process to achieve large reductions and the application of a large amount of energy to the smaller 10 particles reduces their size dramatically causing a large spread in the particle size distribution. Therefore, a starting feedstock that has a wide distribution of particle sizes will yield a reduced material still with a wide particle size distribution because the same amount of 15 energy has been imparted to all of the particles regardless of their size. Thus, it is believed that a multi-stage reduction process alleviates this problem by sequentially imparting smaller amounts of energy in multiple reduction processes rather than trying to impart 20 all of the energy into the material in one reduction process. The process of the invention is applicable to any pharmaceutical substance where there is a need to tightly control the particle size of the substance. The 25 pharmaceutical substance can be chosen from pharmaceutically active substances and/or from pharmaceutically acceptable excipients. The pharmaceutically active substance may be selected from anti-depressant agents such as paroxetine, fluoxetine, 30 sertraline, citalopram, escitalopram, venlafaxine, desvenlafaxine and mirtazapine, anti-epileptic agents such as carbamazepine, oxcarbazepine, gabapentin, pregabalin and tiagabine, antihypertensive agents such as ramipril, WO 2007/053904 PCT/AU2006/001687 - 10 quinapril, enalapril, perindopril, trandolapril, captopril, lisinopril, oxeprenolol, nifedipine, atenolol, verapamil, hydralazine, pindolol, metoprolol, carvedilol, bisoprolol, diltiazem, frusemide and propranolol, proton 5 pump inhibitors such as omeprazole, lansoprazole, esomeprazole, rabeprazole and pantoprazole, angiotensin type II receptor antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, anti-diabetic agents such as repaglinide and 10 the glitazones (troglitazone, ciglitazone, pioglitazone and rosiglitazone), sitagliptin, vildagliptin, saxagliptin, NVP DPP728, P32/98, FE 999011, PHX1149, anti schizophrenic agents such as aripiprazole, thioridazine, chlorpromazine, clozapine, zuclopenthixol, flupenthixol, 15 droperidol, haloperidol, risperidine, quetiapine, amisulpride and olanzapine agents for treating ADHD such as methylphenidiate and atomoxetine, and anti cholesteremia agents such as gemfibrozil, colestipol, ezetemibe, fluvastatin, simvastatin, fenofibrate, 20 atorvastatin and pravastatin, malarial treatment agents such atovaquone and proguanil or pharmaceutically acceptable salts thereof. The pharmaceutical substance can be selected from pharmaceutically acceptable excipients such as talc, 25 lactose, polyvinylpyrrolidone, cellulosic derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose. In a preferred embodiment, the invention provides a 30 process for the production of a pharmaceutical composition comprising the inclusion of a pharmaceutical substance with a median particle size of between 10pm and 50pm, with at least 50% of the particles having a median particle WO 2007/053904 PCT/AU2006/001687 - 11 size distribution of 1pm to 10pm, into a pharmaceutical dosage form. The dosage form can be selected from tablet, capsule, inhaler, injectable, suppository, solution or syrup or the like. The dosage form will optionally 5 comprise other excipients and may also be film coated for cosmetic and/or controlled rate release purposes, as are well known to those skilled in the art of pharmaceutical formulation. It has been found that material used in a suspension 10 layering spraying process is best if it has a very narrow particle size distribution, such as manufactured by the process of this invention. This is because the material with a uniform particle size gives uniform loading of the substance onto the carrier particles and gives a uniform 15 suspension that will not easily segregate or settle out. It also has the added benefit of reducing machine down time and equipment maintenance, as uniform particle size has been shown to reduce blockage of the spray jet nozzles of the spray apparatus. 20 Example 1 (Comparative) oxcarbazepine was milled to obtain a target D[v,o.s] of between 12pm to 15pm. The median particle size (D 1 y,o.s3) of the feedstock was 47.41pm with a D[,,o.

9 ] of 100.29pm. This 25 was milled in a single process and produced material with an average D[v,o.

5 3 of 15.27pm with a distribution of Dv,o.5] of 10.36pm to 25.41pm and an average D[,,o.

93 of 53.30pm with a distribution of DEv,o.9J of 44.13pm to 67.97pm.

WO 2007/053904 PCT/AU2006/001687 - 12 Table 1 - Particle Size Results Stage Sample DEv,o.s3 1pm D[v,o.93 pm 1 47.04 98.61 Feedstock 2 47.77 101.96 Mean 47.41 100.29 Sample 1 25.41 67.97 Sample 2 10.36 44.13 Micronised Sample 3 15.02 52.08 Sample 4 15.18 51.71 Sample 5 15.16 51.94 Composite 15.27 53.30 Example 2 (Comparative) Oxcarbazepine was milled to obtain a target Dv,o..5 of 5 less than 10pm. The D[v,o.

5 1 of the feedstock was 47.41pm with a D[,,o.

9 ] of 100.29pm. This was milled in a single process and produced material with an average D[v,o.s] of 5.95pm with a distribution of D[v,o.5] of 2.15pm to 6.09pm and an average D[,,o.9] of 30.47pm with a distribution of 10 D[,,o.

9 3 of 11.56pm to 31.90pm. Table 2 - Particle Size Results Stage Sample D v,o.s pm Dcv,o.

9 3 pm 1 47.04 98.61 Feedstock 2 47.77 101.96 Mean 47.41 100.29 Sample 1 2.15 11.56 Sample 2 4.91 27.25 Micronised Sample 3 3.84 19.56 Sample 4 6.09 31.90 Composite 5.95 30.47 WO 2007/053904 PCT/AU2006/001687 - 13 Example 3 (Comparative) oxcarbazepine was milled to obtain a target D[v,o.

5 3 of between 13pm to 17pm. The D[,o.5 of the feedstock was 73.33pm with a Dcy,o.

9 ] of 323.50pm. This was milled in a 5 single process and produced material with a Dcv,o.5J of 13.79pm with a distribution of D[,,o.s] of 7.50pm to 19.51pm and an average Dcv,o.

9 3 of 33.14pm with a distribution of D[rO.93 of 16.47pm to 44.34pm.

WO 2007/053904 PCT/AU2006/001687 - 14 Table 3 - Particle Size Results Stage Sample D [,o. pm D[v,o.9J pm Feedstock Feed 73.33 323.50 Sample 1 7.50 16.47 Sample 2 19.51 44.34 Micronised Sample 3 15.09 34.47 Sample 4 15.64 35.78 Composite 13.79 33.14 Example 4 Oxcarbazepine was milled in a 12" spiral jet mill to 5 produce a target Dcv,o.

5 ] of 15pm to 17pm. The D[v,o.

5 3 of the initial feedstock was 65.06pm with a range between 61.51pm and 69.35pm and with a D[v,o.9] of 177.81pm with a range between 168.78pm and 191.19pm. This was milled to produce material with an average DEv,o.5] of 33.89pm, distribution of 10 29.77pm to 37.95pm and having an average D[,,o.93 of 78.22pm, distribution of 67.66pm to 90.19pm. This was then further milled to produce the desired material with a Dcv,o.

5 3 of 16.30pm, distribution of 14.67pm to 17.29pm with a DC,,o.

9 ] of 37.22pm, distribution of 33.12pm to 39.31pm. The 15 particle size control parameters were set for the first pass, and then re-set when the product of that pass was used as the feedstock for a second pass, as set forth in Table 4. 20 Table 4 - Air Jet Milling Parameters Pass Pass 1 2 Mill pressure 5 14 (psi) Venturi 15 15 pressure (psi) Feed rate 10 11 (kg/hr) WO 2007/053904 PCT/AU2006/001687 - 15 The resultant material was collected in 5 drums. Each drum was sampled at the top, middle and bottom and the Dcv,o.sJ pm ( or median particle size) and the DEv,O.

9 3 determined for each sample as set forth in Table 5 for each 5 stage of the process. These samples all show a tight particle size distribution following the second pass. Particle size measurements were made using a Malvern Mastersizer S laser diffraction instrument operated according to standard operating procedure. The data is 10 presented graphically in Fig 1.

WO 2007/053904 PCT/AU2006/001687 - 16 Table 5 - Particle Size Results Stage Sample D [,o.53 D [,o.

9 3 Top 65.54 187.36 Top 66.55 180.14 Top 64.82 174.50 Top 63.90 173.62 Top 63.65 174.94 Middle 66.51 179.80 Middle 69.08 187.62 Middle 65.86 180.63 Feedstock Middle 63.67 178.16 Middle 63.12 170.57 Bottom 65.81 175.42 Bottom 69.35 191.19 Bottom 63.88 174.57 Bottom 61.51 168.78 Bottom 62.66 169.87 Mean 65.06 177.81 Stage Sample D[v,o.5] D[v,o.9J Micronised Top 34.91 77.21 First Pass Top 35.28 81.28 Top 33.12 74.85 Top 32.80 76.10 Top 34.94 85.01 Middle 35.86 77.29 Middle 35.44 81.80 Middle 34.86 82.63 Middle 29.77 67.97 Middle 32.80 76.31 Bottom 30.65 67.66 - 17 Bottom 37.95 90.19 Bottom 34.09 79.61 Bottom 32.94 77.39 Bottom 32.93 77.93 Mean 33.89 78.22 Stage Sample Dv,0. 5 ] D[v,o.

9 ] Top 14.67 33.12 Top 16.39 38.50 Top 16.77 39.31 Top 16.19 36.58 Top 15.24 35.04 Middle 16.02 35.92 Middle 17.29 38.96 Micronised Middle 16.11 37.92 Second Pass Middle 16.88 37.48 Middle 15.18 34.03 Bottom 16.96 38.94 Bottom 16.90 38.85 Bottom 16.87 38.73 Bottom 16.47 37.14 Bottom 16.49 37.73 ,Mean 16.30 37.22 It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

- 17a In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims (22)

1. A multi-stage process to control the particle size of a pharmaceutical substance comprising the steps of: passing an initial feedstock of the pharmaceutical substance through a first stage of the multi-stage particle size reduction process, the first stage having a first set of particle size control parameters, to obtain a further feedstock for at least a second stage of the multi-stage particle size reduction process; passing the further feedstock through the second stage of the multi-stage particle size reduction process, the second stage having a second set of particle size control parameters, to obtain a pharmaceutical substance with a reduced median particle size and narrower distribution of median particle size than the further feedstock; collecting the pharmaceutical substance of the final stage of the multi-stage particle size reduction process with a median particle size greater than 10pm and with a narrow, reproducible distribution of median particle size.

2. The process of claim 1 wherein the median particle size is between 10pm and 50p1m.

3. The process of claim 1 or 2 wherein at least 50% of the particles have a particle size deviating no more than between 1pm and 10pm from the median particle size. 47210941 (GHMatters) P24887.AU 24 September 2013 - 19

4. The process of claim 3 wherein at least 50% of the particles have a particle size deviating no more than between 1pm and 5pm from the median particle size.

5. The process of claim 4 wherein at least 50% of the particles have a particle size deviating no more than between lpm and 3pm from the median particle size.

6. The process of any one of claims 1-5 wherein the particle size reduction process is a milling process.

7. The process of claim 6 wherein the particle size reduction process is selected from the group consisting of jet milling, hammer milling, compression milling and tumble milling processes.

8. The process of any one of claims 1-7 wherein the pharmaceutical substance is a pharmaceutically active ingredient.

9. The process of claim 8 wherein the pharmaceutically active ingredient is selected from the group consisting of anti-depressant agents such as paroxetine, fluoxetine, sertraline, citalopram, escitalopram, venlafaxine, desvenlafaxine and mirtazapine, anti-epileptic agents such as carbamazepine, oxcarbazepine, gabapentin, pregabalin and tiagabine, antihypertensive agents such as ramipril, quinapril, enalapril, perindopril, trandolapril, captopril, lisinopril, oxeprenolol, nifedipine, atenolol, verapamil, hydralazine, pindolol, metoprolol, carvedilol, bisoprolol, diltiazem, frusemide and propranolol, proton pump inhibitors such as omeprazole, lansoprazole, esomeprazole, rabeprazole and pantoprazole, 47210941 (GHMatters) P24887.AU 24 September 2013 - 20 angiotensin type II receptor antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, anti-diabetic agents such as repaglinide, glitazones such as troglitazone, ciglitazone, pioglitazone and rosiglitazone, sitagliptin, vildagliptin, saxagliptin, NVP DPP728, P32/98, FE 999011, PHX1149, anti-schizophrenic agents such as aripiprazole, thioridazine, chlorpromazine, clozapine, zuclopenthixol, flupenthixol, droperidol, haloperidol, risperidine, quetiapine, amisulpride and olanzapine agents for treating ADHD such as methylphenidiate and atomoxetine, and anti cholesteremia agents such as gemfibrozil, colestipol, ezetemibe, fluvastatin, simvastatin, fenofibrate, atorvastatin and pravastatin, malarial treatment agents such atovaquone and proguanil, or pharmaceutically acceptable salts thereof.

10. The process of claim 9 wherein the pharmaceutically active ingredient is oxcarbazepine or a pharmaceutically acceptable salt thereof.

11. The process of any one of claims 1-7 wherein the pharmaceutical substance is a pharmaceutically acceptable excipient.

12. The process of claim 11 wherein the pharmaceutically acceptable excipient is selected from the group consisting of talc, lactose, polyvinylpyrrolidone and cellulosic derivatives.

13. The process of claim 12 wherein the pharmaceutically acceptable excipient is selected from the group consisting of lactose, polyvinylpyrrolidone, 47210941 (GHMatters) P24887.AU 24 September 2013 - 21 hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose.

14. The process of any one of claims 1-13 which is a 2 stage process, a 3 stage process, or a 4 stage process.

15. The process of any one of claims 1-14 wherein the multi-stage particle size reduction process comprises one or more subsequent stages each comprising the step of: passing the feedstock of the previous stage of the multi-stage particle size reduction process through a subsequent stage, the subsequent stage having a set of particle size control parameters, to obtain a pharmaceutical substance with a reduced median particle size and narrower distribution of median particle size than the feedstock.

16. The process of any one of claims 1-15 wherein measurements to determine the median particle size and distribution of median particle size are made using a Malvern Mastersizer S laser diffraction instrument.

17. A pharmaceutical substance manufactured by a process as claimed in any one of claims 1-16.

18. A pharmaceutical substance with a median particle size greater than 10pm and with a narrow, reproducible distribution of median particle size, wherein at least 50% of the particles have a particle 47210941 (GHMatters) P24887.AU 24 September 2013 - 22 size deviating no more than between 1pm and 10pm from the median particle size.

19. The pharmaceutical substance of claim 18 wherein at least 50% of the particles have a particle size deviating no more than between 1pm and 5pm from the median particle size.

20. The pharmaceutical substance of claim 18 wherein at least 50% of the particles have a particle size deviating no more than between lpm and 3pm from the median particle size.

21. A pharmaceutical composition containing a pharmaceutical substance manufactured by a process as claimed in any one of claims 1-16, or a pharmaceutical substance as claimed in any one of claims 18-20, and at least one other pharmaceutically acceptable ingredient.

22. A multi-stage process, a pharmaceutical substance manufactured by the multi-stage process, or a pharmaceutical composition containing a pharmaceutical substance manufactured by the multi stage process, or a pharmaceutical substance as defined in claim 18, substantially as herein before described with reference to Example 4. 47210941 (GHMatters) P24887.AU 24 September 2013