WO2008057048A1

WO2008057048A1 - Nano & micro-sized particles of statin compounds and process for forming same

Info

Publication number: WO2008057048A1
Application number: PCT/SG2007/000377
Authority: WO
Inventors: Jianfeng Chen; Jiyao Zhang; Jimmy Sung Lai Yun; Zhigang Shen
Original assignee: Nanomaterials Technology Pte Ltd
Priority date: 2006-11-09
Filing date: 2007-11-06
Publication date: 2008-05-15

Abstract

A process for making micro-sized or nano-sized particles of one or more statin compounds, the process comprising the step of: (a) applying a shear force to (i) a statin solution comprising one or more statin compounds, and (ii) a statin-insoluble liquid in which said statin compounds are insoluble or at least partially insoluble, said applying being undertaken under conditions to form said micro-sized or nano-sized particles of said statin compounds.

Description

Nano & Micro-Sized Particles of Statin Compounds and Process for Forming Same

Technical Field The present invention generally relates to nano-sized and micro-sized particles of statin compounds and to a process for forming the same.

Background Statins are a class of drugs that can lower the level of cholesterol in the blood by reducing the production of cholesterol by the liver.

Particle size is an important factor to be considered when producing a drug formulation. Generally, it is desirable to produce formulations of small particle sizes to obtain higher surface area to volume ratio, which in turn results in improved dissolution of the drug into the biological environment and thereby minimises the required intake of the drug by the patient. One method of reducing particle size of the drug formulation is by mechanical disintegration to form the powdered drug. Exemplary mechanical disintegration processes include jet-milling, media milling or high press homogenization. The mechanical disintegration processes, however, provide limited control over the physical properties of the powdered drug, such as particle size, shape morphology, surface property and electrostatic charge.

Other methods have also been developed, including supercritical liquid-based methods, precipitation-based methods and micro-emulsion techniques. Whilst these methods may overcome the limitations of the mechanical disintegration processes outlined above, they are difficult to scale up and are expensive.

There is therefore a need to provide a process that overcomes or at least ameliorates one or more of the disadvantages described above. More particularly, there is a need to develop improved methods to control drug particle sizes in the nano-size or micro-size range for enhanced dissolution and bioavailability of the drug.

Summary

A first aspect provides a process for making micro- sized or nano-sized particles of one or more statin compounds, the process comprising the step of: (a) applying a shear force to (i) a statin solution comprising one or more statin compounds, and (ii) a statin- insoluble liquid in which said statin compounds are insoluble or at least partially insoluble, said applying being undertaken under conditions to form said micro-sized or nano-sized particles of said statin compounds.

In one embodiment, there is provided a process for making micro-sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(a) providing (i) a statin solution comprising one or more statin compounds, and (ii) a statin-insoluble liquid in which said statin compounds are insoluble or at least partially insoluble, in a chamber having a packed bed located therein; and (b) rotating said packed bed to apply a shear force to said statin solution and said statin-insoluble liquid and thereby form said micro-sized or nano-sized particles of said statin compounds. A second aspect provides a process for making micro- sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(a) providing one or more statin compounds in a solvent to form a statin solution; (b) providing a statin-insoluble liquid in which said one or more statin compounds are insoluble, or at least partially insoluble; and

(c) applying a shear force to said statin solution and said statin-insoluble liquid to thereby form said micro-sized or nano-sized particles of said statin compounds .

A third aspect provides a process for making micro- sized or nano-sized particles of one or more statin compounds, the process comprising the steps of: (a) providing one or more statin compounds in a solvent to form a statin solution;

(b) providing a statin-insoluble liquid in which said one or more statin compounds are insoluble, or at least partially insoluble; (c) providing one or more surfactants in at least one of said statin solution and said statin-insoluble liquid; and

(d) applying a shear force to said statin solution, said statin-insoluble liquid and said surfactants to thereby form said micro-sized or nano-sized particles of said statin compounds. A fourth aspect provides a process for making a suspension of micro-sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(a) providing one or more statin compounds in a solvent to form a statin solution;

(b) providing a statin-insoluble liquid in which said one or more statin compounds are insoluble, or at least partially insoluble; and

(c) applying a shear force to said statin solution and said statin-insoluble liquid to thereby form said suspension of micro-sized or nano-sized particles of said statin compounds.

A fifth aspect provides a process for making a powder comprising micro-sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(b) providing a statin-insoluble liquid in which said one or more statin compounds are insoluble, or at least partially insoluble;

(c) providing one or more surfactants in at least one of said statin solution and said statin-insoluble liquid;

(d) applying a shear force to said statin solution, said statin-insoluble liquid and said surfactants to thereby form a suspension of said micro-sized or nano-sized particles of said statin compounds;

(e) isolating said micro-sized or nano-sized particles of statin compounds from the suspension; and

(f) drying said micro-sized or nano-sized particles of statin compounds to form said powder.

A sixth aspect provides a process for making a powder comprising micro-sized or nano-sized particles of one or more statin compounds, the process comprising the steps of: (a) providing one or more statin compounds in a solvent to form a statin solution; (b) providing a statin-insoluble liquid in which said one or more statin compounds are insoluble, or at least partially insoluble;

(d) applying a shear force to said statin solution and said statin-insoluble liquid to thereby form a suspension of said micro-sized or nano-sized particles of said statin compounds;

(d) lyophilising the suspension of said micro-sized or nano-sized particles of the statin compounds to form said powder. A seventh aspect provides nano-sized particles of one or more statin compounds.

An eighth aspect provides a statin compound having an average particle size of about lOOnm to about lOμm.

A ninth aspect provides a process for making micro- sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(c) providing one or more surfactants in at least one of said statin solution and statin-insoluble liquid;

(d) applying a shear force to said statin solution, said statin-insoluble liquid and said surfactants to thereby form a suspension of said micro-sized or nano-sized particles of said statin compounds; and

(e) agitating said suspension at a temperature of about 20⁰C to about 50⁰C and for a time of about 0.2 hours to about 5 hours at an agitation speed of about 0 to about 1200 rpm.

Definitions

The following words and terms used herein shall have the meaning indicated:

The term "nano-sized" as used herein relates to an average particle size of less than about lOOOnm.

The term "micro-sized" as used herein, unless specified, relates to an average particle size of between about lμm to about lOOμm.

The term "surfactant" as used herein relates to any composition that is capable of altering surface tension between a liquid and particles of statin compound dissolved in the liquid. Unless specified otherwise, the terms "comprising" and "comprise", and grammatical variants thereof, are intended to represent "open" or "inclusive" language such that they include recited elements but also permit inclusion of additional, unrecited elements. As used herein, the term "about", typically means +/- 5% of the stated value, more typically +/- 4% of the stated value, more typically +/- 3% of the stated value, more typically, +/- 2% of the stated value, even more typically +/- 1% of the stated value, and even more typically +/- 0.5% of the stated value.

Throughout this disclosure, certain embodiments may be disclosed in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

De-tailed Disclosure of Embodiments

Exemplary, non-limiting embodiments of statin compounds and process for making the same will now be disclosed.

The statin compound is in the form of nano-sized or micro-sized particles.

The statin compound is also in the form of micro-sized or nano-sized particles having an average particle size of about lOOnm to about lOμm; about lOOnm to about 1 μm; about lOOnm to about 800nm; about lOOnm to about 600nm; about lOOnm to about 400nm; about lOOnm to about 200nm; about

200nm to about lOμm; about 400nm to about 10 μm; about

600nm to about lOμm; about 800nm to about lOμm; and about lμm to about lOμm.

The micro-sized or nano-sized particles of the statin compound are in the dispersed form. More particularly, the micro-sized or nano-sized particles are stable, and do not generally form aggregates of larger-sized particles over a period of time. The statin compound may be any statin compound. The statin compound may be selected from the group consisting of Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Atorvastatin, Rosuvastatin, Itavastatin and combinations thereof. The micro-sized or nano-sized particles of the statin compound can have a specific surface area of about 4 m²/g to about 15 m²/g; about 6 m²/g to about 15 m²/g; about 8 m²/g to about 15 m²/g; about 10 m²/g to about 15 m²/g; about 13 m²/g to about 15 m²/g; about 4 m²/g to about 13 m²/g; about 4 m²/g to about 10 m²/g; about 4 m²/g to about 8 m²/g; and about. 4 m²/g to about 6 m²/g.

The process for making one or more statin compounds, in particular micro-sized or nano-sized particles of the statin compounds, comprises the step of: (a) applying a shear force to (i) a statin solution comprising one or more statin compounds, and (ii) a statin- insoluble liquid in which said statin compounds are insoluble or at least partially insoluble, said applying being undertaken under conditions to form said micro-sized or nano-sized particles of statin compounds.

The process may comprise, before step (a) , the step of: (bl) selecting said one or more statin compounds from the group consisting of Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Atorvastatin, Rosuvastatin, Itavastatin, Cerivastatin, Pitavastatin and combinations thereof. The process may comprise, before step (a) , the step of: (b2) selecting an organic solvent to dissolve said statin compounds and thereby form said statin solution.

The selecting step (b2) may comprise the step of: (b3) selecting the organic solvent from the group consisting of: alcohols, ketones, aldehydes, and halide hydrocarbons .

The selecting step (b2) may comprise the step of: (b4) selecting the organic solvent from the group consisting of: methanol, ethanol, propanol, acetone, acetonitrile, dimethyl formamide, 1-chlorobutane, tetrahydrofuran, dimethyl amide and dimethyl sulfoxide.

The process may comprise, before step (a), the step of:

(b5) selecting the concentration of the statin compound in the statin solution from the group consisting of: about 0.5 (%w/v) to about 15 (%w/v) ; about 2 (%w/v) to about 15 (%w/v) ; about 5 (%w/v) to about 15 (%w/v) ; about

10 (%w/v) to about 15 (%w/v) ; about 0.5 (%w/v) to about 10

(%w/v); about 0.5 (%w/v) to about 5 (%w/v) ; and about 0.5 (%w/v) to about 2 (%w/v) .

The process may comprise, before step (a) , the step of:

(c) selecting water as the statin-insoluble liquid. The process may comprise, before step (a) , the step of:

(d) providing a surfactant in at least one of said statin solution and said statin-insoluble liquid.

The providing step (d) may comprise the step of:

(dl) providing the surfactant in the statin-insoluble liquid.

The providing step (d) may comprise the step of: (d2) selecting the surfactant from the group consisting of: anionic surfactants, cationic surfactants, non-ionic surfactants and polymeric surfactants.

The providing step (d) may comprise the step of:

(d3) selecting the surfactant from the group consisting of: sodium dodecyl-sulfate, sodium lauryl sulfate, sodium laurate, dioctylsodium sulphosuccinate,

TWEEN^® (polyethylene sorbitan monooleate) (i . e. , TWEEN 20^®,

TWEEN 40^®, TWEEN 60^®, TWEEN 80^®, TWEEN 85^®), SPAN^®

(sorbitan monooleate) (i . e. , SPAN 20^®, SPAN 40^®, SPAN 60^®,

SPAN 80^®, SPAN 85^®) , PLURONIC^® (Ethylene Oxide/Propylene Oxide block copolymer) (i . e. , PLURONIC L44^®, PLURONIC F68^®, PLURONIC F87^®, PLURONIC F108^®, PLURONIC F127^®) , polyoxyethylene fatty acid esters, poly (vinylpyrrolidone) , polyoxyethylene alcohol, polyethylene glycol, monodiglyceride, benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, hydroxypropyl cellulose, hydroxypropyl methylcellulose and mixtures thereof.

The providing step (dl) may comprise the step of: (d4) selecting the concentration of the surfactant in the statin-insoluble liquid from the group consisting of: about 0.05% to about 10%; about 0.05% to about 5%; about 0.05% to about 1%; about 0.05% to about 0.5%; about 0.05% to about 0.1%; about 0.1% to about 10%; about 0.5% to about 10%; about 1% to about 10%; about 5% to about 10%; and about 0.1% to 2%. The conditions in the applying step (a) may comprise the step of:

(al) providing the statin solution and the statin- insoluble liquid in a volumetric ratio selected from the group consisting of: about 1:1 to about 1:30; about 1:1 to about 1:25; about 1:1 to about 1:20; about 1:5 to about 1:15; about 1:2 to about 1:10; about 1:2 to about 1:5; about 1:5 to about 1:30; about 1:10 to about 1:30; about 1:15 to about 1:30; about 1:20 to about 1:30; about 1:25 to about 1:30; and about 1:8 to about 1:10.

The conditions in the applying step (a) may also comprise the step of:

(a2) providing the statin solution and the statin- insoluble liquid at a temperature selected from the group consisting of: about 0⁰C to about 70⁰C; about 0⁰C to about 60⁰C; about 0⁰C to about 50⁰C; about 0⁰C to about 40⁰C; about 0°C to about 30 °C; about 0⁰C to about 20⁰C; about 10⁰C to about 70°C; about 20°C to about 70°C; about 30°C to about 70⁰C; about 40⁰C to about 70⁰C; about 50⁰C to about 70°C; about 60°C to about 70°C; and about 10°C to about 40°C. The conditions in the applying step (a) may also comprise any one or more of steps (a3) to (a8) as described in the section on "Application of Shear Force" below.

Solvent for Statin Compound It should be realised that the selection of the solvent will be based on the type of statin compound used and the solubility of that statin compound in the solvent. Ideally, the statin compound should be readily soluble in the solvent to form the statin solution. The solvent can be an organic solvent. The organic solvent can be selected from the group consisting of: alcohols, ketones, aldehydes, and halide hydrocarbons. Exemplary solvents are methanol, ethanol, propanol, acetone, acetonitrile, dimethyl formamide, 1-chlorobutane, tetrahydrofuran, dimethyl amide and dimethyl sulfoxide. The concentration of statin compound in the statin solution is dependent on the type of solvent used and the solubility of the statin compound in the solvent. Typically, the concentration of the statin compound in the statin solution is selected from the group consisting of about 0.5 (%w/v) to about 15 (%w/v) ; about 2 (%w/v) to about 15 (%w/v) ; about 5 (%w/v) to about 15 (%w/v); about 10 (%w/v) to about 15 (%w/v) ; about 0.5 (%w/v) to about 10 (%w/v) ; about 0.5 (%w/v) to about 5 (%w/v) ; and about 0.5 (%w/v) to about 2 (%w/v) .

Statin-Insoluble Liquid

It should be realised that the selection of the statin-insoluble liquid will be based on the type of statin compound used and the solubility of that statin compound in the statin-insoluble liquid. Ideally, the statin compound should be insoluble or be at least partially insoluble in the statin-insoluble liquid. The statin-insoluble liquid may preferably be miscible with the statin solution containing the statin compound and the solvent.

The statin-insoluble liquid can may be an aqueous liquid. In one embodiment, the statin-insoluble liquid is water, preferably water comprising a surfactant. The surfactant may be any suitable surfactants intended for pharmaceutical use.

Suitable surfactants include anionic surfactants, cationic surfactants, non-ionic surfactants and polymeric surfactants .

Exemplary surfactants include sodium dodecyl-sulfate, sodium lauryl sulfate, sodium laurate or dioctylsodium sulphosuccinate, non-ionic surfactants such as TWEEN (polyethylene sorbitan monooleate) (i . e . , TWEEN 20^®, TWEEN 40^®, TWEEN 60^®, TWEEN 80^®, TWEEN 85^®), SPAN^® (sorbitan monooleate) (i.e. , SPAN 20^®, SPAN 40^®, SPAN 60^®, SPAN 80 , SPAN 85^®) , PLURONICS^® (ethylene oxide / propylene oxide block copolymer) (i.e. , PLURONIC L44^®, PLURONIC F68^®, PLURONIC F87^®, PLURONIC F108^®, PLURONIC F127^®) , polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters, commercially available under the trade name MYRJ^®, poly (vinylpyrrolidone) , polyoxyethylene alcohol, polyethylene glycol, monodiglycerides, benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, hydroxy-propyl cellulose, hydroxypropyl methylcellulose and mixtures thereof.

The statin-insoluble liquid may comprise an amount, by weight percentage, of a surfactant selected from the following group about 0.05% to about 10%; about 0.05% to about 5%; about 0.05% to about 1%; about 0.05% to about 0.5%; about 0.05% to about 0.1%; about 0.1% to about 10%; about 0.5% to about 10%; about 1% to about 10%; about 5% to about 10%; and about 0.1% to 2%.

Advantageously, the surfactant imparts surface charge to the particles of statin compounds, which results in electrostatic, steric or electrosteric repulsion between the particles and thereby reduces or eliminates the aggregation of the particles. Furthermore, because the statin particles do not aggregate, they remain in the dispersed form and have a narrow particle size distribution which remains substantially constant with time. Additionally, the presence of the surfactant in the mixture during the precipitation process, results in the formation of small-sized particles, particularly micro- sized or nano-sized particles. Application of Shear Force

The statin solution and the statin-insoluble liquid may be provided in a chamber comprising a packed bed. The conditions in the applying step (a) may further comprise the step of:

(a3) passing the statin solution and the statin- insoluble liquid through the packed bed to form a suspension of said micro-sized or nano-sized particles of said statin compounds. The passing step (a3) may comprise the step of:

(a4) providing the statin solution and the statin- insoluble liquid mixture in a chamber having said packed bed located therein; and

(a5) rotating said packed bed to apply the shear force to the statin-solution and the statin-insoluble liquid.

The shear force may therefore be a centrifugal force imparted on the statin solution and the statin-insoluble liquid as the packed bed rotates.

The packed bed can be of any shape. Preferably, the packed bed is substantially cylindrical in shape and/or having at least one layer of packing.

The passing step (a3) may comprise the step of: (aβ) selecting the packing from the group consisting of: wire mesh, perforated plate, corrugated plate, foam packing and combinations thereof. The arrangement of the packing in the packed bed may be structured or random. The packing can be formed from a metallic material, a non- metallic material or combinations thereof.

It will be appreciated that there can be more than one packed beds provided within the chamber.

The particles of statin compounds formed in step (a) are micro-sized or nano-sized particles or a combination thereof.

The size of the particles of statin compound can be controlled by varying the magnitude of the shear force or centrifugal force acting on the statin solution and the statin-insoluble liquid. The shear force or centrifugal force can be controlled by adjusting the speed of rotation of the packed bed. The particle size of the statin compounds decreases as the magnitude of the centrifugal force increases.

Accordingly, the rotating step (a5) may comprise the step of:

(a7) varying the magnitude of the centrifugal force acting on the statin solution and the statin-insoluble liquid to thereby control the particle size of the formed statin particles. The varying step (a7) may be effected by varying the speed of rotation of the packed bed.

The rotating step (a5) may also comprise the step of: (a8) selecting the speed of rotation of the packed bed from the group consisting of: about lOOrpm to about 5000rpm; about lOOrpm to about 3000rpm; about lOOrpm to about lOOOrpm; about lOOrpm to about 800rpm; about lOOrpm to about 600rpm; about lOOrpm to about 400rpm; about lOOrpm to about 200rpm; about 200rpm to about 5000rpm; about 400rpm to about 5000rpm; about 600rpm to about 5000rpm; about 800rpm to about 5000rpm; about lOOOrpm to about 5000rpm; about 3000rpm to about 5000rpm; and about lOOOrpm to about 3000rpm.

The centrifugal acceleration of the particles within the chamber may be about 500 m²/s to about 5000 m²/s. Maintaining Step or "Aging" Step

The process may comprise, after step (a3) , the step of: (e) maintaining the suspension at a temperature for a period of time at an agitation rate. The maintaining step (e) may comprise the step of:

(el) maintaining the suspension at a temperature selected from the group consisting of about 5⁰C to about 85°C; about 5°C to about 70⁰C; about 5°C to about 50⁰C; about 5°C to about 30 °C; about 5°C to about 10 °C; about 10°C to about 85°C; about 30°C to about 85°C; about 50⁰C to about 85°C; about 70°C to about 85°C; and about 50°C to about 60⁰C.

The maintaining step (e) may comprise the step of: (e2) maintaining the suspension at a temperature for a period of time selected from the group consisting of about 0.2 hours to about 5 hours; about 0.5 hours to about 5 hours; about 1 hour to about 5 hours; about 3 hours to about 5 hours; about 0.2 hours to about 3 hours; about 0.2 hours to about 1 hours; about 0.2 hours to about 0.5 hours; and about 1 hour to about 2 hours.

The maintaining step (e) may comprise the step of: (e3) maintaining the suspension at a temperature for a period of time at an agitation speed selected from the group consisting of about 0 rpm to about 1200 rpm; about 0 rpm to about 800 rpm; about 0 rpm to about 400 rpm; about 400 rpm to about 1200 rpm; and about 8000 rpm to about 1200 rpm.

Advantageously, it has surprisingly been found that steps (e) , (el), (e2) and (e3) above can result in smaller particle sizes of statin compounds formed as compared to when these steps have been omitted. Steps (e) , (el), (e2) and (e3) above can, for example, be carried out in a beaker that is heated at the defined temperature and having a magnetic stirrer therein to provide the agitation. Alternatively, steps (e) , (el), (e2) and (e3) above may be carried out in a rotating packed bed reactor as shown in FIG.l.

The process may comprise, after step (a3) , the step of:

(f) isolating said nano-sized particles of the statin compound from the mixture. The isolating step (f) may comprise the step of:

(fl) filtering the mixture to separate the nano-sized or micro-sized particles of the statin compound from the mixture.

The filtering step (fl) may be carried out using a Bucher funnel or a vacuum filter lined with filter paper. The isolating step (f) may comprise the step of: (f2) centrifuging the mixture to separate the nano- sized or micro-sized particles of the statin compound from the mixture. The isolating step (f) may comprise the step of:

(f3) drying said separated nano-sized particles of the statin compound. The drying step (f3) may be carried out in an oven under a vacuum, optionally at a temperature of about 50⁰C to about 70⁰C. The process may comprise, after step (a3) , the step of:

(g) lyophilising the suspension.

The lyophilising step (g) may be carried out by rapidly freezing the suspension, optionally with liquid nitrogen. After freezing, the suspension may be exposed to a temperature in the range of about 20⁰C to about 40⁰C, at a pressure of less than about 1 mbar for at least about 24 hours to obtain dried particles of the statin compounds.

Advantageously, the lyophilising step (g) , can be employed directly after passing step (a3) without having to go through maintaining step (e) or isolating step (f) , to obtain the powder of nano-sized or micro-sized particles of statin compounds.

The process may comprise, after step (a3) , the step of: (h) spray drying the suspension.

The spray-drying step (h) may be carried out in a spray tower. A drying gas, such as air or nitrogen, may pass through the spray tower to dry the suspension therein by means of a rotary atomiser. The drying gas may enter the spraying tower at a temperature of about 120⁰C to about

180⁰C and leave the spraying tower at a temperature of about 80⁰C to about 120⁰C.

Brief Description of Drawings

The accompanying drawings illustrate the disclosed embodiments and serve to explain the principles of the disclosed embodiments. It is to be understood, however, that the drawings are designed for purposes of illustration only, and not as a definition of the limits of the invention.

FIG. 1 shows a schematic diagram of a rotating packed bed reactor.

FIGS. 2a and 2b show Scanning Electron Microscope (SEM) micrographs of particles of Simvastatin compound at 500 times magnification and 200 times magnification respectively. FIGS. 3 to 16 show Scanning Electron Microscope (SEM) micrographs of particles of Simvastatin compound prepared in Examples 1 to 14 respectively.

FIGS. 17 to 27 show Scanning Electron Microscope (SEM) micrographs of particles of Simvastatin compound prepared in Examples 15 to 25 respectively.

FIGS. 28a and 28b show a Scanning Electron Microscope (SEM) micrographs of particles of Lovastatin compound at 500 times magnification and 200 times magnification respectively. FIGS. 29 to 40 show Scanning Electron Microscope (SEM) micrographs of particles of Lovastatin compound prepared in Examples 26 to 37 respectively.

FIG. 41 shows a SEM micrograph of particles of Simvastatin compound prepared in Example 38. FIG. 42 shows a SEM micrograph of particles of Simvastatin compound prepared in Example 39 (solvent: methanol).

FIG. 43 shows a SEM micrograph of particles of Simvastatin compound prepared in Example 40 (solvent: ethanol) .

FIG. 44 shows a SEM micrograph of particles of Simvastatin compound prepared in Example 41 (solvent: dimethyl formamide) .

FIG. 45 shows a SEM micrograph of particles of Simvastatin compound prepared in Example 42.

FIG. 46 shows a SEM micrograph of particles of Simvastatin compound prepared in Example 43.

Detailed Disclosure of a Preferred Embodiment

A preferred embodiment of a process for forming micro- sized or nano-sized particles of statin compounds is disclosed herein. The process comprises the steps of providing the statin compound in a solvent to form a statin solution, providing a statin-insoluble liquid in which said statin compound is insoluble or at least partially insoluble, said statin-insoluble liquid comprising a surfactant, and imparting a shear force to said statin solution and said statin-insoluble liquid to thereby form a suspension of micro-sized or nano-sized particles of the statin compound. The suspension is maintained at a temperature for a period of time and at an agitation rate, followed by filtration of the suspension to isolate the statin compound from the suspension. The isolated micro- sized or nano-sized particles of the statin compound are subsequently dried to obtain a dry powder of the statin compound .

Referring to FIG. 1, there is shown a schematic diagram of a rotating packed bed reactor _.100 which is suitable for carrying out the process for forming micro- sized or nano-sized particles of statin compounds. The reactor 100 comprises a chamber 102 having one end 114b of a shaft 114 extended horizontally into the chamber 102. The shaft 114 is driven by a motor (not shown) , which rotates the shaft 114 about its longitudinal axis 114a. The reactor 100 also comprises an outlet 106 for allowing micro-sized or nano-sized particles of statin compounds to be removed from the chamber 102.

A packed bed 120 is mounted onto the shaft 114 at end 114b in the chamber 102 as shown in FIG. 1. The packed bed 120 is substantially cylindrical in shape and comprises a structured arrangement of a plurality of layers of wire mesh having a mesh size of 5mm. The wire mesh is made from stainless steel.

A temperature jacket 108 surrounds the chamber 102 to regulate the temperature within the chamber 102. The temperature jacket 108 comprises a jacket inlet 110 for allowing heated fluid to enter, and a jacket outlet 112 for allowing the fluid to exit from the jacket.

A statin solution liquid feed distributor 104a and a statin-insoluble liquid feed distributor 104b are mounted into chamber 102 to enable introduction of the statin solution and the statin-insoluble liquid respectively at an inner surface 120a of the packed bed 120.

The statin solution liquid feed distributor 104a is linked by pipe 128a to a statin-solution liquid feed tank 130a where the statin solution containing the statin compound is stored. A pump 132a positioned along the pipe 128a pumps the statin solution from the storage tank 130a to the statin solution feed distributor 104a. The statin- insoluble liquid feed distributor 104b is also linked by pipe 128b to a statin-insoluble liquid feed tank 130b where the statin-insoluble liquid, in which the statin compound is insoluble, is stored. A pump 132b positioned along the pipe 128b pumps the statin-insoluble liquid from the storage tank 130b to the statin-insoluble liquid feed distributor 104b. A pair of flow meters 129a, 129b are positioned along the pipes 128a, 128b respectively to regulate the flow of the statin solution and the statin- insoluble liquid to the liquid feed distributors 104a, 104b. The liquid feed distributors 104a, 104b ejects the statin solution and the statin-insoluble liquid into the chamber 102 at the inner surface 120a of the packed bed 120. As the shaft 114 rotates about its longitudinal axis 114a, the packed bed 120 rotates to thereby cause the statin solution and the statin-insoluble liquid to pass through the packed bed 120 in a radial direction from the inner surface 120a toward the outer surface 120b of the packed bed. When passing through the packed bed 120, both liquids are mixed and precipitates of the statin compound are formed as a result.

In the packed bed 120, the statin solution and the statin-insoluble liquid are subjected to high shear forces in the form of centrifugal forces or gravity field created by the rotational motion of the shaft 114 and the packed bed 120 about the longitudinal axis 114a. Accordingly, the statin solution and the statin-insoluble liquid are separated into very fine droplets, threads or thin films under the high gravity field to thereby result in a high mass transfer rate between the two liquids. This results in an intense micro-mixing between the statin solution and the statin-insoluble liquid to form a uniformly- supersaturated solution in which precipitates of nano-sized statin compounds are formed.

The magnitude of the centrifugal force exerted on the mixture within the packed bed 120 is dependent on the speed of rotation of the shaft 114. The higher the speed of rotation of the shaft 114, the larger the magnitude of the centrifugal force acting on the liquids.

The surfactant imparts surface charge to the particles of statin compounds, which results in electrostatic, steric or electrosteric repulsion between the particles. The electrostatic, steric or electrosteric repulsion between the particles reduces or eliminates the aggregation of the particles during and after the precipitation process. As the statin particles formed during precipitation do not aggregate, nano-sized particles can be formed in the resultant precipitate. Furthermore, because the statin particles do not aggregate even after the precipitation process, they have a narrow particle size distribution which remains substantially constant with time.

The micro-sized or nano-sized particles of statin compounds suspended in the mixture are removed from the chamber 102 via product outlet 106. Thereafter, the suspension of micro-sized or nano-sized particles of statin compounds are maintained at a temperature of 55°C for 1.5 hours while being stirred continuously at a rate of 600 rpm. The suspension is then filtered and subsequently dried in an oven to obtain dry powder of micro-sized or nano-sized statin particles.

Alternatively, another process for forming micro-sized or nano-sized particles of statin compounds are as described above, except that no surfactant is provided in the statin-insoluble liquid and that the suspension is directly freeze-dried or lyophilised upon exiting the reactor 100 to obtain the dry powder of statin compounds. Accordingly, in this alternative process, there is no requirement for the steps of maintaining the mixture at a temperature for period of time after exiting the reactor 100 and there is also no need for any filtration and drying steps thereafter. However, the shape of the particles formed from such a process are generally thread-like in shape . Examples

Non-limiting examples of the invention will be further described in greater detail by reference to specific Examples, which should not be construed as in any way as limiting the scope of the invention.

Examples 1 to 14 - Preparation of Nano-Sized Particles of Simvastatin

Procedure 1. X₁ (% w/v) of Simvastatin was dissolved in methanol (solvent) to form a statin solution. Prior to dissolving in methanol, the particles of Simvastatin were viewed under a Scanning Electron Microscope (SEM) and the micrographs of the particles are shown in FIGS. 2a and 2b. FIG. 2a shows the SEM micrograph of the particles with a magnification of 200 times and FIG. 2b shows the SEM micrograph of the particles with a magnification of 500 times.

2. Y₁ (% w/v) of TWEEN® (surfactant) was dissolved in water to form a statin-insoluble liquid.

3. The statin solution and the statin-insoluble liquid were stored respectively in the statin solution liquid feed tank 130a and the statin-insoluble liquid feed tank 130b respectively.

4. The statin solution and the statin-insoluble liquid were pumped from the liquid feed tanks 130a, 130b to their respective liquid feed distributors 104a, 104b where the two liquids are ejected into the chamber 102 at the inner surface 120a of the packed bed 120. Flow rates of both liquids were controlled by their respective flow meters 129a, 129b. The flow rates were set to a predetermined volumetric flow-rate ratio V_RI.

5. As the packed bed rotates, the statin solution and the statin-insoluble liquid pass through the packed bed in a radial direction toward the outer surface 120b, which results in the mixing of the two liquids. A mixing temperature of Ti⁰C was maintained. The packed bed rotates at a speed of 2800 rpm.

6. The resulting suspension was collected from outlet 106 and then filtered to isolate the nano-sized simvastatin particles from the suspension.

7. The nano-sized simvastatin particles were dried in an oven at 50⁰C for 24 hours at a pressure of 0.1 mbar to obtain a dried powder of nano-sized Simvastatin particles.

8. The experimental conditions for Xi (% w/v) , Yi (% w/v) , V_RI and Ti (⁰C) for Examples 1 to 14 are described in Table 1 below.

TABLE 1

Xι (% w/v) is the percentage weight of Simvasta tin per uni t volume of methanol .

Y_x (% w/v) is the percentage weigh t of TWEEN® (surf actant) per uni t volume of wa ter.

V_H1 is the volumetric ra tio of the sta tin solution to the sta tin- insoluble liquid.

T₁ (⁰C) is the tempera ture a t which the sta tin solution and the sta tin - insoluble liquid are mixed.

9. The dried powders of nano-sized Simvastatin particles derived from the Examples 1 to 14 are viewed with a Scanning Electron Microscope (SEM) . Micrographs of the dried powders, taken with the SEM, are shown in FIGS. 3 to 16.

Generally, regardless of the choice of experimental conditions, the resulting particles of Simvastatin in these Examples (FIGS. 3 to 16) are significantly smaller as compared to the raw Simvastatin particles (FIGS. 2a and 2b). The particles of the drug as produced in Examples 1 to 14 are generally in the nano-sized range as compared to the particles of raw Simvastatin which are in the micro-sized range or larger. Effect of Surfactant Concentration Y₁ (% w/v) on Particle Size

In Example 1, no surfactant was provided in the statin-insoluble liquid, i.e., Yi = 0 % w/v. In comparing the micrograph of Example 1 (FIG. 3) with those of the remaining Examples 2 to 14 (FIGS. 4 to 15), it can be seen that the particle size of the Simvastatin compound of Example 1 is generally larger than those of Examples 2 to 14. Accordingly, the presence of the surfactant in the statin-insoluble liquid generally reduces the size of the particles of Simvastatin formed.

In Examples 2 to 5, the concentration of the surfactant increases from Yi = 0.2 % w/v in Example 2 to Yi = 1.5 % w/v in Example 5. In comparing the micrographs of these Examples (FIGS. 4 to 7), it can be seen that the particle size of the Simvastatin compound decreases when Y increases from 0.2 % w/v in Example 2 to 0.5 % w/v in Example 3, and then increases as Yi increases to 1.0 % w/v in Example 4 and 1.5 % w/v in Example 5. Accordingly, it is shown that the particle size initially decreases as the surfactant concentration increases. However, above a particular surfactant concentration (i.e., 1.0 % w/v), the particle size increases as the surfactant concentration increases. It should be noted that the particle size of the Simvastatin compound formed using a surfactant-containing statin-insoluble .liquid would still be smaller than those formed without the use of surfactants in the statin- insoluble liquid. Effect of Simvastatin Concentration X₁ (% w/v) on Particle Size

In Examples 6 to 8, the concentration of Simvastatin increases from Xi = 6 % w/v in Example 6 to Xi = 12 % w/v in Example 8. In comparing the micrographs of these Examples (FIGS. 8 to 10), there is observed a slight decrease in the particle size of the Simvastatin compound as the concentration of the Simvastatin Xi in the statin solution increases from Xi = 6 % w/v in Example 6 to Xi = 12 % w/v in Example 8.Accordingly, although not significant, the increase in concentration of the drug in the statin solution decreases the particle size of the formed particles of statin compound..

Effect of volumetric flow-rate ratio V_R1 on Particle Size

In Examples 9 to 12, the volumetric flow-rate ratio V_RI of the statin solution to the statin-insoluble liquid increases from 1:3 in Example 9 to 1:15 in Example 12. In comparing the micrographs of the nano-sized particles of Simvastatin of these Examples (FIGS. 11 to 14), it can be seen that as the volumetric flow-rate ratio increases, the shape of the particles changes from irregularly-shaped particles to uniformly rod-shaped particles. The size of the particles increases slightly as the volumetric flow- rate ratio increases.

It should be noted that above a certain volumetric flow rate ratio, i.e., V_Ri above 1:15, changes in the increases volumetric flow rate ratio would not have any significant effect on the size of the formed particles. Effect of Mixing Temperature T₁ ⁰C on Particle Size

The mixing temperature Ti⁰C in the chamber 102 changes from 5°C in Example 13 to 50⁰C in Example 14. In comparing the micrographs of these Examples (FIGS. 15 and 16) , it can be seen that the size of the particles increases significantly when the temperature increases. Accordingly, to achieve a low particle size, a low mixing temperature is desired.

Examples 15 to 25 - Preparation of Nano-Sized Simvastatin

The nano-sized Simvastatin of Examples 15 to 25 are prepared in accordance with the Example 13 described above except that Steps 6 to 9 are replaced by Steps 6¹ to 9' below. Step 6' is also known as "aging".

6". The resulting suspension was collected from outlet 106 and was maintained at a temperature of Ti' ⁰C for a period of time of Z₁ hours at an agitation speed of Ri rpm in a beaker. The agitation was achieved by means of a magnetic stirrer.

7'. The suspension was filtered to isolate the nano-sized statin particles, which are subsequently dried in an oven at 30⁰C for 24 hours at a pressure of 0.1 mbar to obtain a powder.

8'. The experimental conditions for TiM⁰C), Zi (hours) and Ri (rpm) for Examples 15 to 25 are described in Table 2 below. Table 2

Z₁ (IiOUrS) is the period of time tha t the stirring of the suspension occurs . R_± (rpm) is the speed of agi ta tion of the magnetic s tirrer in the beaker.

T₁ ¹ CC) is the tempera ture a t which the suspension collected from the reactor 100 is mixed.

9'. The dried powders of nano-sized Simvastatin particles derived from the Examples 15 to 25 are viewed with a Scanning Electron Microscope (SEM) . Micrographs of the dried powders, taken with the SEM, are shown in FIGS. 17 to 27.

Effect of Aging Temperature T₁^(⁰C) on Particle Size

In Examples 15 to 17, the aging temperature T₂ (⁰C) increases from 25°C in Example 15 to 80⁰C in Example 17.

In comparing the micrographs (FIGS. 17 to 19) of the particles in these Examples, it can be seen that the particle size remains relatively constant as the aging temperature changes from Ti'=25°C in Example 15 to Ti'=50°C in Example 16. However, as the aging temperature increases from TV=SO⁰C in Example 16 to Ti'=80°C in Example 17, the particle size increases. Accordingly, a suitable aging temperature range is between about 20⁰C to about 50⁰C. It should be noted that when the aging temperature is above 50⁰C, the particle size increases as the aging temperature increases. When the aging temperature is below 20⁰C, the aging time will be considerably longer and hence not viable.

Effect of Aging Time Zi (hours) on Particle Size

In Examples 18 to 20, the aging time Z₁ (hours) increases from 30 minutes in Example 18 to 2 hours in Example 20. In comparing the micrographs (FIGS. 20 to 22) resulting from these Examples, there is a decrease in particle size as the aging time increases from 30 minutes to 1 hour. However, there is no significant change in particle size when the aging time increases from 1 hour to 2 hours.

Effect of Speed of Agitation R₁ (rpm) during Aging on Particle Size

In Examples 21 to 25, the speed of agitation R (rpm) during aging increases from 0 rpm in Example 21 to 1,200 rpm in Example 25. FIGS. 23 to 27a show the micrographs of the particles resulting from these Examples. FIG. 27b shows a micrograph of the particles resulting from Example 25, but with twice the magnification as FIG. 27a. In comparing the micrographs, it can be seen that the particle size decreases as the speed of agitation during aging increases . Effects of Surfactant and Aging on Specific Surface Area of the Nano-Sized Stain Particles

Table 3 below compares the specific Surface Area A (m²/g) of the particles of Simvastatin derived from

Examples 1, 3, 13, 15 and 25. In all of these Examples, methanol is used as the solvent and water is used as the statin-insoluble liquid (anti-solvent) . The surfactant employed in these Examples is TWEEN®.

Table 3

In comparing the Examples in Table 3 above, the following observations are noted:

1. In Examples 15 and 25 which incorporates aging into the process, the particles of Simvastatin formed have a higher specific surface area, i.e., smaller particle size, as compared to Examples 1, 3 and 13 which does not involve aging of the mixture after the imparting step (c) .

2. In Examples 3 and 13, as the mixing temperature Ti (°C) decreases from 25°C in Example 3 to 5°C in Example 13, the specific are of the particles of the Simvastatin formed increases .

3. In Examples 15 and 25, as the aging temperature Ti' (⁰C) and agitation speed Ri (rpm) increases from 25°C and 600 rpm in Example 3 to 5°C and 1200 rpm in Example 13, the specific area of the particles of the Simvastatin formed increases, i.e., particle size decreases. Although particle size increases with aging temperature, this increase is insignificant as compared to the reduction in particle size caused by an increase in the speed of agitation of the mixture during aging. Accordingly, it is observed that the effect of increased agitation speed during aging can override the effect of increased aging temperature.

Examples 26 to 37 - Preparation of Nano-Sized Lovastatin

Procedure

1. X₂ (% w/v) of Lovastatin was dissolved in a solvent L to form a statin solution. Prior to dissolving in the solvent, the particles of Lovastatin were viewed under a Scanning Electron Microscope (SEM) and the micrographs of the particles are shown in FIGS. 28a and 28b. FIG. 28a shows the SEM micrograph of the particles with a magnification of 200 times and FIG. 28b shows the SEM micrograph of the particles with a magnification of 500 times .

2. Y₂ {% w/v) of surfactant S was dissolved in water to form a statin-insoluble liquid.

3. The statin solution and the statin-insoluble liquid were stored in the statin solution liquid feed tank 130a and the statin-insoluble liquid feed tank 130b respectively.

4. The statin solution and the statin-insoluble liquid were pumped from the liquid feed tanks 130a, 130b to their respective liquid feed distributors 104a, 104b where the two liquids are ejected into the chamber 102 at the inner surface 120a of the packed bed 120. Flow rates of both liquids were controlled by their respective flow meters 129a, 129b. The flow rates were set to a predetermined volumetric flow-rate ratio of 1:10. 5. As the packed bed rotates, the statin solution and the statin-insoluble liquidpass through the packed bed 120 in a radial direction toward the outer surface 120b, which results in the mixing of the two liquids. A mixing temperature of T₂ ⁰C was maintained. The packed bed rotates at a speed of 2800 rpm.

6. The resulting suspension was collected from outlet 106 and then filtered to isolate the nano-sized statin particles from the suspension.

7. The nano-sized statin particles are dried in an oven at 30⁰C for 24 hours at a pressure of 0.1 mbar to obtain a powder.

8. The experimental conditions for X₂ (% w/v) , surfactant used S, solvent used L and mixing temperature T₂ (⁰C) for Examples 26 to 37 are described in Table 4 below.

Table 4

X₂(% w/v) is the percentage weight of Lovastatin per unit volume of statin liquid.

Y₂(% w/v) is the percentage weight of surfactant per unit volume of water.

Vg₂ is the volumetric ratio of the statin solution to the statin- insoluble liquid.

T₂CC) is the temperature at which the statin solution and the statin- insoluble liquid is mixed. THF is tetrahydrofuran.

9. Scanning Electron Microscope (SEM) micrographs of particles of Lovastatin produced by Examples 26 to 37 are shown in FIGS. 29 to 40.

Effect of Different Types of Surfactant and Surfactant Concentration Y₁ (% w/v) on Particle Size In Example 26, no surfactant was provided in the statin-insoluble liquid, i.e., Y₂ = 0 % w/v. In comparing the micrograph of Example 26 (FIG. 29) with that of Example 27 (FIG. 30), it can be seen from the micrographs that the particle size of the Lovastatin compound is smaller when a surfactant is used. Accordingly, the presence of the surfactant in the statin-insoluble liquid reduces the size of the particles of Lovastatin formed.

In Examples 28 and 29, different types of surfactant are used. The surfactant used in Example 28 is F127 (0.5 %w/v) and the surfactant used in Example 29 is PVPk30. In comparing the micrographs (FIGS. 31 and 32), it is observed that the particle size is larger in Example 29, i.e., when the surfactant PVPk30 is used.

In Example 30, in which the surfactant F127 (0.5 %w/v) is used and the concentration of Lovastatin in the statin solution is higher as compared to Example 28, it is observed that the shape of the particles formed changes from irregularly shaped particles in Example 28 to uniformly rod-shaped particles in Example 30 (FIG. 33) . It should also be noted that the solvent used in Example 30 is THF and the solvent used in Example 28 is acetone.

In Example 31, the surfactant used is a mixture of F127 (0.25 %w/v) and PVPk30 (0.25 %w/v) . It is observed from the micrograph (FIG. 34) of the resulting Lovastatin particles that the particles are of elongated rod-shaped and thread-like shaped. In Example 32, the surfactant used is TWEEN®80 (1

%w/v) . It can be observed from the micrograph (FIG. 35) that the resulting Lovastatin particles are rod-shaped and that the particles are thicker as compared to those of Example 31.

In Example 33, the surfactant used is PEGlOOOO (5 %w/v) . It can be observed from the micrograph (FIG. 36) of the resulting Lovastatin particles that the particles are a mixture of irregularly shaped particles and rod-shaped particles. It is also observed that the particle size of the Lovastatin compound in this Example is generally smaller as compared to the rest of the Examples 26 to 32 and 34 to 37, with the exception of Example 36 which also produces particles of comparable sizes. In Example 34, the surfactant used is PEG 400 (5 %w/v) . It is observed from the micrograph (FIG. 37) of the resulting Lovastatin particles that the particles are rod- shaped and thread-like shaped, similar to the ones in Example 31. In Example 35, the surfactant used is F68 (1 %w/v) . It is observed from the micrograph (FIG. 38) of the resulting Lovastatin particles that the particles are rod- shaped, similar to the ones in Example 30.

In Example 36, the surfactant used is PVA_(3Oooo~7oooo) (3 %w/v) . It is observed from the micrograph (FIG. 39) of the resulting Lovastatin particles that the particles are irregularly-shaped, however, the size of the particles are smaller relative to the rest of the Examples 26 to 35 and 37. In Example 37, the surfactant used is PVA₍i46ooo~i86ooo) (1 %w/v) . It is observed from the micrograph (FIG. 40) of the resulting Lovastatin particles that the particles are irregularly-shaped, similar to the ones in Example 36.

Accordingly, the choice of surfactants plays a part in the resulting shape and size of the particles of Lovastatin compounds. However, generally, irregardless of the choice of surfactants, the resulting particles of the drug in these Examples (FIGS. 29 to 40) are significantly smaller as compared to raw Lovastatin particles (FIGS. 28a, 28b) and they are generally in the nano-sized range as compared to the micro-sized particles of the raw Lovastatin.

Example 38

A statin solution was formed by dissolving 12Og Simvastatin in 1000 ml of methanol (solvent) and was stored in tank 130a of FIG. 1. A statin-insoluble liquid (1OL of water) was stored in tank 130b. Both liquids were separately introduced into the chamber at the inner surface 120a of the packed bed 120 via their respective liquid feed distributors 104a, 104b. The volumetric flow-rate ratio of both liquids were 1:10. The mixing temperature was 30⁰C.

Particles of Simvastatin precipitated when the two liquids were mixed at the inner surface of the packed bed 120. The suspension, upon passing through the packed bed 120, exits through outlet 106. The packed bed 120 was rotated at a speed of 2800 rpm.

The suspension of micro-sized or nano-sized particles of Simvastatin was freeze dried to obtain a dry powder of nano-sized particles of Simvastatin having an average particle size of about 500nm as observed under SEM. A SEM micrograph of the dry powder is shown in FIG. 41. The shape of the formed particles was observed to be thread-like shaped. The specific surface area of the dry powder was observed to be 10.4m²/g.

Example 39 A statin solution was formed by dissolving 5Og Simvastatin in 500 ml of methanol (solvent) and was stored in tank 130a of FIG. 1. A statin-insoluble liquid was formed by dissolving 25g TWEEN®80 in 5000ml water and was stored in tank 130b. Both liquids were separately introduced into the chamber at the inner surface 120a of the packed bed 120 via their respective liquid feed distributors 104a, 104b. The volumetric flow-rate ratio of both liquids were 1:10. The mixing temperature was 20⁰C.

Particles of Simvastatin precipitated when the two liquids were mixed at the inner surface of the packed bed 120. The suspension, upon passing through the packed bed 120, exits through outlet 106.

The packed bed 120 was rotated at a speed of 2800 rpm. The suspension of micro-sized or nano-sized particles of Simvastatin was filtered and subsequently dried, under vacuum, in an oven at 50⁰C for 24 hours, to obtain a dry powder of nano-sized particles of Simvastatin having an average particle size of about 2000nm as observed under SEM. A SEM micrograph of the dry powder is shown in FIG. 42. The shape of the formed particles was observed to be irregularly-shaped. The specific surface area of the dry powder was observed to be 6.83m²/g.

Example 40 The nano-sized particles of Simvastatin were prepared in accordance with Example 39, except that in this Example, the mixing temperature was 5°C.

The average particles size of the produced Simvastatin particles was about 2000nm, as observed under SEM. FIG. 43 shows the SEM micrograph of the particles of Simvastatin produced in this example. The shape of the formed particles was observed to be irregularly-shaped. The specific surface area was observed to be 7.16m²/g.

Accordingly, it is observed that to achieve smaller particles sizes, a low mixing temperature is desired.

Example 41

The nano-sized particles of Simvastatin was prepared in accordance with Example 39, except that in this Example, the suspension was aged for 2h at 25°C under stirring in a tank.

The average particle size of the produced Simvastatin particles was about 1500nm, as observed by SEM. FIG. 44 shows the SEM micrograph of the particles of Simvastatin produced in this Example. The shape of the formed particles was observed to be irregularly-shaped. The specific surface area was observed to be 7.63m²/g.

Accordingly, it is observed that aging the suspension collected from outlet 106 can reduce particle size.

Example 42

The nano-sized particles of Simvastatin was prepared in accordance with Example 39, except that in this Example, the suspension was aged for 2h at 50⁰C under stirring in a tank. The average particle size of the produced Simvastatin particles was about 1500nm, as observed by SEM. FIG. 45 shows the SEM micrograph of the particles of Simvastatin produced in this Example. The shape of the formed particles was observed to be irregularly-shaped. The specific surface area was observed to be 7.81m²/g.

Example 43

The nano-sized particles of Simvastatin was prepared in accordance with Example 39, except that in this Example, the statin solution was formed by dissolving 3Og of Simvastatin in 500 ml of methanol.

The average particle size of the produced Simvastatin particles was about 700nm, as observed by SEM. FIG. 46 shows the SEM micrograph of the particles of Simvastatin produced in this Example. The shape of the formed particles was observed to be irregularly-shaped. The specific surface area was observed to be 8.86m²/g.

Applications It will be appreciated that the process for making nano-sized or micro-sized particles of Statin compounds are not limited thereto and may be extended to nano-sizing or micro-sizing other types of drugs.

It will be appreciated that the shear force that is applied to the mixture separates the mixture into very fine droplets, thread or thin film to thereby result in a high mass transfer rate between the statin-solution and the statin-insoluble liquid in the mixture. This results in an intense micro-mixing between the two liquids to form a uniformly-supersaturated solution in which precipitates of nano-sized statin compounds are formed. It will be appreciated that the particle size of the micro-size and nano-size particles of statin compounds can be controlled by varying the magnitude of the shear force applied to the mixture. Accordingly, micro-size and nano- size particles of statin compounds of desired sizes for the required applications can be achieved.

It will be appreciated that the surfactant imparts surface charge to the particles of statin compounds, which results in electrostatic, steric or electrosteric repulsion between the particles. The electrostatic, steric or electrosteric repulsion between the particles reduces or eliminates the aggregation of the particles during and after the precipitation process. As the statin particles formed during precipitation do not aggregate, nano-sized particles can be formed in the resultant precipitate. Furthermore, because the statin particles do not aggregate even after the precipitation process, they have a narrow particle size distribution which remains substantially constant with time. It will be appreciated that the capacity of the process can be scaled up to form larger quantities of micro-size or nano-size particles of statin compounds, without affecting the stability and the particle size distribution of the product. It will be apparent that various other modifications and adaptations of the invention will be apparent to the person skilled in the art after reading the foregoing disclosure without departing from the spirit and scope of the invention and it is intended that all such modifications and adaptations come within the scope of the appended claims.

Claims

1. A process for making micro-sized or nano-sized particles of one or more statin compounds, the process comprising the step of:

(a) applying a shear force to (i) a statin solution comprising one or more statin compounds, and (ii) a statin-insoluble liquid in which said statin compounds are insoluble or at least partially insoluble, said applying being undertaken under conditions to form said micro-sized or nano-sized particles of said statin compounds .

2. A process as claimed in claim 1, the process comprising, before step (a), the step of:

(bl) selecting said one or more statin compounds from the group consisting of Lovastatin, Pravastatin,

Simvastatin, Fluvastatin, Atorvastatin, Rosuvastatin,

Itavastatin, Cerivastatin, Pitavastatin and combinations thereof-.

3. A process as claimed in claim 1, the process comprising, before step (a) , the step of:

(b2) selecting an organic solvent to dissolve said statin compounds and thereby form said statin solution.

4. A process as claimed in claim 3, wherein the selecting step (b2) comprises the step of:

(b3) selecting the organic solvent from the group consisting of: alcohols, ketones, aldehydes, and halide hydrocarbons .

5. A process as claimed in claim 3, wherein the selecting step (b2) comprises the step of:

(b4) selecting the organic solvent from the group consisting of: methanol, ethanol, propanol, acetone, acetonitrile, dimethyl formamide, 1-chlorobutane, tetrahydrofuran, dimethyl amide and dimethyl sulfoxide.

6. A process as claimed in claim 1, the process comprising, before step (a), the step of:

(b5) selecting the concentration of the statin compound in the statin solution from the group consisting of: about 0.5 (%w/v) to about 15 (%w/v) ; about 2 (%w/v) to about 15 (%w/v) ; about 5 (%w/v) to about 15 (%w/v) ; about 10 (%w/v) to about 15 (%w/v) ; about 0.5 (%w/v) to about 10 (%w/v) ; about 0.5 (%w/v) to about 5 (%w/v) ; and about 0.5 (%w/v) to about 2 (%w/v) .

7. A process as claimed in claim 1, the process comprising, before step (a) , the step of:

(c)" selecting water as the statin-insoluble liquid.

8. A process as claimed in claim 1, the process comprising, before step (a) , the step of:

9. A process as claimed in claim 8, wherein the providing step (d) comprises the step of: (dl) providing the surfactant in the statin- insoluble liquid.

10. A process as claimed in claim 8, wherein the providing step (d) comprises the step of:

(d2) selecting the surfactant from the group consisting of: anionic surfactants, cationic surfactants, non-ionic surfactants and polymeric surfactants .

11. A process as claimed in claim 8, wherein the providing step (d) comprises the step of:

(d3) selecting the surfactant from the group consisting of: sodium dodecyl-sulfate, sodium lauryl sulfate, sodium laurate, dioctylsodium sulphosuccinate, TWEEN20^®, TWEEN40^®, TWEEN60^®, TWEEN80^®, TWEEN85^®, SPAN20^®, SPAN40^®, SPAN60^®, SPAN80^®, SPAN85^®, PLURONIC^®L44, PLURONIC^®F68 , PLURONIC^®F87 , PLURONIC^®F108, PLURONIC^®F127, polyoxyethylene fatty acid esters, poly (vinylpyrrolidone) , polyoxyethylene alcohol, polyethylene glycol, monodiglyceride, benzalkonium chloride, bis-2-hydroxyethyl oleyl amine, hydroxypropyl cellulose, hydroxypropyl methylcellulose and mixtures thereof.

12. A process as claimed in claim 9, wherein the providing step (dl) comprises the step of:

(d4) selecting the concentration of the surfactant in the statin-insoluble liquid from the group consisting of: about 0.05% to about 10%; about 0.05% to about 5%; about 0.05% to about 1%; about 0.05% to about

0.5%; about 0.05% to about 0.1%; about 0.1% to about 10%; about 0.5% to about 10%; about 1% to about 10%; about 5% to about 10%; and about 0.1% to 2%.

13. A process as claimed in claim 1, wherein the conditions in applying step (a) comprises the step of:

(al) providing the statin solution and the statin- insoluble liquid in a volumetric ratio selected from the group consisting of: about 1:1 to about 1:30; about 1:1 to about 1:25; about 1:1 to about 1:20; about 1:5 to about 1:15; about 1:2 to about 1:10; about 1:2 to about 1:5; about 1 : 5 to about 1:30; about 1:10 to about 1:30; about 1:15 to about 1:30; about 1:20 to about 1:30; about 1:25 to about 1:30; and about 1:8 to about 1:10.

14. A process as claimed in claim 1, wherein the conditions in applying step (a) comprises the step of:

(a2) providing the statin solution and the statin- insoluble liquid at a temperature selected from the group consisting of: about 0⁰C to about 70⁰C; about 0°C to about 60⁰C; about 0⁰C to about 50°C; about 0⁰C to about 40⁰C; about 0°C to about 30°C; about 0°C to about

20°C; about 10°C to about 70°C; about 20⁰C to about 70⁰C; about 30°C to about 70⁰C; about 40⁰C to about

70⁰C; about 50⁰C to about 70⁰C; about 60⁰C to about

70°C; and about 10°C to about 40°C.

15. A process as claimed in claim 1, wherein the conditions in applying step (a) comprises the step of:

(a3) passing the statin solution and the statin- insoluble liquid through a packed bed to form a suspension of said micro-sized or nano-sized particles of said statin compounds.

16. A process as claimed in claim 15, wherein the passing step (a3) comprises the step of:

(a4) providing the statin solution and the statin- insoluble liquid in a chamber having said packed bed located therein; and (a5) rotating said packed bed to apply the shear force to the statin solution and the statin-insoluble liquid.

17. A process as claimed in claim 15, wherein the passing step (a3) comprises the step of:

(a6) selecting the packing from the group consisting of: wire mesh, perforated plate, corrugated plate, foam packing and combinations thereof.

18. A process as claimed in claim 16, wherein the rotating step (a5) comprises the step of:

(a7) varying the speed of rotation of the packed bed to vary the magnitude of the shear force acting on the statin solution and the statin-insoluble liquid to thereby control the particle size of the formed particles.

19. A process as claimed in claim 18, wherein the varying step (a7) comprises the step of: (a8) selecting the speed of rotation of the packed bed from the group consisting of: about lOOrpm to about 5000rpm; about lOOrpm to about 3000rpm; about lOOrpm to about lOOOrpm; about lOOrpm to about 800rpm; about lOOrpm to about 600rpm; about lOOrpm to about 400rpm; about lOOrpm to about 200rpm; about 200rpm to about 5000rpm; about 400rpm to about 5000rpm; about 600rpm to about 5000rpm; about 800rpm to about 5000rpm; about lOOOrpm to about 5000rpm; about 3000rpm to about 5000rpm; and about lOOOrpm to about 3000rpm.

20. A process as claimed in claim 15, wherein the conditions in applying step (a) comprises , after step (a3) , the step of:

(e) maintaining the suspension at a temperature for a period of time at an agitation rate.

21. A process as claimed in claim 20, wherein the maintaining step (e) comprises the step of:

(el) maintaining the suspension at a temperature selected from the group consisting of about 20⁰C to about 50⁰C; about 25°C to about 50⁰C; about 30⁰C to about 50⁰C; about 35°C to about 50⁰C; about 40°C to about 50°C; about 45°C to about 50°C; about 20°C to about 45°C; about 20°C to about 40⁰C; about 20°C to about 35⁰C; about 20⁰C to about 30⁰C; and about 20⁰C to about 25°C.

22. A process as claimed in claim 20, wherein the maintaining step (e) comprises the step of:

(e2) maintaining the suspension at a temperature for a period of time selected from the group consisting of about 0.2 hours to about 5 hours; about 0.5 hours to about 5 hours; about 1 hour to about 5 hours; about 3 hours to about 5 hours; about 0.2 hours to about 3 hours; about 0.2 hours to about 1 hours; about 0.2 hours to about 0.5 hours; and about 1 hour to about 2 hours.

23. A process as claimed in claim 20, wherein the maintaining step (e) comprises the step of:

(e3) maintaining the suspension at a temperature for a period of time at an agitation speed selected from the group consisting of about 0 rpm to about 1200 rpm; about 0 rpm to about 800 rpm; about 0 rpm to about 400 rpm; about 400 rpm to about 1200 rpm; and about 8000 rpm to about 1200 rpm.

24. A process as claimed in claim 15, wherein the conditions in applying step (a) comprises, after step (a3) , the step of:

(f) isolating said nano-sized particles of the statin compounds from the suspension.

25. A process as claimed in claim 24, wherein the isolating step (f) comprises the step of:

(fl) filtering the nano-sized or micro-sized particles of the statin compounds from the suspension.

26. A process as claimed in claim 24, wherein the isolating step (f) comprises the step of:

(f2) centrifuging the mixture to separate the nano-sized or micro-sized particles of the statin compounds from the suspension.

27. A process as claimed in claim 24, wherein the isolating step (f) comprises the step of:

(f3) drying said nano-sized or micro-sized particles of the statin compounds.

28. A process as claimed in claim 1, the process comprising, after step (a3) , the step of:

(g) lyophilising the suspension.

29. A process as claimed in claim 28, wherein the lyophilising step (g) comprises the step of:

(gl) rapidly freezing the mixture with liquid nitrogen.

30. A process as claimed in claim 29, wherein the lyophilising step (g) comprises the step of:

(g2) exposing, after step (gl) , the mixture to a temperature in the range of about 20⁰C to about 40°C, at a pressure of less than about 1 mbar for at least about 24 hours to obtained dried particles of the statin compounds.

31. A process as claimed in claim 15, the process comprising, after step (a3) , the step of:

(h) spray drying the suspension.

32. Particles of statin compounds having an average particle size of about lOOnm to about lOμm; about lOOnm to about 1 μm; about lOOnm to about 800nm; about lOOnm to about 600nm; about lOOnm to about 400nm; about lOOnm to about 200nm; about 200nm to about lOμm; about 400nm to about 10 μm; about 600nm to about 10μm; about 800nm to about 10μm; and about lμm to about 10μm.

33. Particles of statin compounds as claimed in claim 32, wherein the statin compounds are selected from the group consisting of: Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Atorvastatin, Rosuvastatin, Itavastatin, Cerivastatin, Pitavastatin and combinations thereof.

34. Particles of statin compounds as claimed in claim 32, wherein the particles have a specific surface area selected from the group consisting of: about 4 m²/g to about 15 m²/g; about 6 m²/g to about 15 m²/g; about 8 m²/g to about 15 m²/g; about 10 m²/g to about 15 m²/g; about 13 m²/g to about 15 m²/g; about 4 m²/g to about 13 m²/g; about 4 m²/g to about 10 m²/g; about 4 m²/g to about 8 m²/g; and about 4 m²/g to about 6 m²/g.

35. A process for making micro-sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(c) applying a shear force to said statin solution and said statin-insoluble liquid to thereby form said micro-sized or nano-sized particles of said statin compounds.

36. A process for making micro-sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(c) providing one or more surfactants in at least one of said statin solution and statin-insoluble liquid; and

(d) applying a shear force to said statin solution, said statin-insoluble liquid and said surfactants to thereby form said micro-sized or nano- sized particles of said statin compounds.

37. A process for making a suspension of micro-sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

38. A process for making a powder comprising micro- sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(d) applying a shear force to said statin solution , said statin-insoluble liquid and said surfactants to thereby form a suspension of said micro- sized or nano-sized particles of said statin compounds;

39. A process for making a powder comprising micro- sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(d) applying a shear force to a said statin solution and said statin-insoluble liquid to thereby form a suspension of said micro-sized or nano-sized particles of said statin compounds;

(d) lyophilising said suspension of said micro- sized or nano-sized particles of the statin compounds to form said powder.

40. A process for making micro-sized or nano-sized particles of one or more statin compounds, the process comprising the steps of:

(d) applying a shear force to said statin solution, said statin-insoluble liquid and said surfactants to thereby form a suspension of said micro- sized or nano-sized particles of said statin compounds; and

(e) maintaining said suspension at a temperature of about 20°C to about 50°C, for a time of about 0.2 hours to about 5 hours at an agitation speed of about 0 rpm to about 1200 rpm.