Process for the production of particles

Abstract

A process for the production of particles comprises the steps of formation of a solution of a desired substance in a suitable solvent; ii) generation of an aerosol from the solution of said substance; iii) collection of the aerosol droplets in a vessel containing a non-solvent of said substance; and iv) the application of ultrasound to the droplets dispersed in the non-solvent to effect crystallisation of said substance. The particles produced find application in for example pharmaceutical and agrochemical formulations, especially in inhalation formulations.

Claims

1-44. (canceled)

45. A process for the production of particles comprising the steps of i) formation of a solution of a desired substance in a suitable solvent; ii) generation of an aerosol from the solution of said substance; iii) collection of the aerosol droplets in a vessel containing a non-solvent of said substance; and iv) application of ultrasound to the droplets dispersed in the non-solvent to effect crystallisation of said substance.

46. A process as claimed in claim 45 wherein solvent evaporates from the aerosol droplets between generation of the aerosol and collection of the aerosol droplets in the non-solvent.

47. A process as claimed in claim 46 wherein the extent of solvent evaporation is such that upon collection of the droplets in the non-solvent at least 80% by mass of each droplet is molecules of the desired substance.

48. A process as claimed in any preceding claim wherein the concentration of the pharmaceutically acceptable substance in the solution formed in step i) of the process is from 50 mg/ml to 200 mg/ml.

49. A process as claimed in claim 48 wherein the solution is a saturated solution of the desired substance.

50. A process as claimed in any preceding claim wherein the method of aerosol generation is a high air pressure atomizer or an electrohydrodynamic spray atomiser.

51. A process as claimed in any preceding claim wherein the droplets produced by the aerosol generator have an initial diameter between 1 m and 50 m.

52. A process as claimed in any one of claims 45 to 50 for the production of nanometer size particles wherein the droplets produced by the aerosol generator have an initial diameter between 10 nm and 1 m.

53. A process as claimed in any preceding claim wherein the non-solvent in which the aerosol droplets are collected contains an emulsifier.

54. A process as claimed in any preceding claim wherein the desired substance is a pharmaceutically acceptable substance or an agrochemically active substance.

55. A process as claimed in claim 54 wherein the desired substance is a drug.

56. A process as claimed in claim 55 wherein the drug is suitable for use in an inhalation formulation.

57. A process as claimed in claim 56 wherein the drug is salbutamol.

58. Crystalline particles, especially particles suitable for use in a pharmaceutical or agrochemical formulation, characterised in that the particles are substantially spherical.

59. Crystalline particles as claimed in claim 58 wherein the particles are drug particles.

60. Crystalline particles as claimed in claim 58 or 59 wherein the particles have nanometre scale surface corrugations.

61. Crystalline particles preparable by a process as claimed in any one of claims 45 to 57.

62. An apparatus comprising i) an aerosol generator, ii) a collection vessel for collecting aerosol droplets, and iii) a means of applying ultrasound to the collected aerosol droplets.

63. A pharmaceutical or agrochemical composition comprising particles as claimed in any one of claims 14 to 17 or made by a process as claimed in one of claims 45 to 57.

64. Use of crystalline particles as claimed in any one of claims 58 to 61 or made by a process as claimed in any one of claims 45 to 57 for the manufacture of a medicament.

Description

[0048] By way of example, certain embodiments of the invention will now be described with reference to the accompanying drawings, in which:

[0049] FIG. 1 is a schematic representation of an electrohydrodynamic spraying system

[0050] FIG. 2 is a schematic representation of a high pressure atomisation system

[0051] FIG. 3 shows the particle size distribution of paracetamol particles before and after electrohydrodynamic spraying and sonocrystallisation

[0052] FIG. 4 shows paracetamol particles before being subjected to the process of the invention

[0053] FIG. 5 shows paracetamol particles after being subjected to the process of the invention

[0054] FIG. 6 shows scanning electron micrographs of paracetamol particles produced by the air pressure atomisation embodiment of the invention with increasing drug concentration (A-B 1% w/w, C-D 5% w/w and E-F 10% w/w respectively).

[0055] FIG. 7 shows a scanning electron micrograph of BDP particles produced from a 2% w/w BDP-ethanol solution by the high pressure atomisation embodiment of the invention.

[0056] FIG. 8 shows a scanning electron micrograph of particles of crystalline budesonide produced from an 8% w/w budesonide solution in dichloromethane by the high pressure atomisation embodiment of the invention.

[0057] In the embodiment of the invention shown in FIG. 1, an electrohydrodynamic spraying system is used to generate the aerosol. The electrohydrodynamic spraying dispersion system comprises a single stainless steel capillary (2) or an array of stainless steel capillaries positioned vertically above a collection vessel (3) containing a non-solvent of the substance e.g. drug and a solution of the substance is forced through each capillary via a syringe pump (1) at a constant volume flow rate. Each capillary is connected to a variable high voltage supply (4). A camera (7) and monitor (8) are arranged as shown.

[0058] In order to produce the requisite monodispersed aerosol, it is necessary to generate a Taylor cone-jet by careful selection of the volume flow rate and the bias applied to the capillary needle. The size of the monodispersed droplets can be adjusted by varying the solute concentration and inner diameter of the capillary. The separation distance between the point where the droplets are ejected from the capillary and the surface of the non-solvent can also be adjusted to adjust the viscosity of the droplets. Table 4 gives suitable ranges of the variable parameters.

[0059] The highly charged aerosolised droplets are subsequently collected in the non-solvent. The non-solvent is grounded by an earthed metal electrode (5) which ensures stability of the Taylor cone and subsequent discharging of the droplets. A low concentration of an emulsifier is added to aid the dispersion of the charged droplets. The crystallisation of the supersaturated droplets is effected by the application of ultrasound via an ultrasonic emitter (6) located at the bottom of the reactor in ultrasonic bath (9).

TABLE-US-00004 TABLE 4 Parameter Range Flow rate 3 l/min to 300 l/min Applied High Voltage 3.8 kV to 15 kV Inner Diameter of Capillaries 200 m to 2 mm Drug Concentration 0.1% to Maximum solubility Capillary-Solution Separation Distance 2 to 10 cm Emulsifier <0.1%

[0060] In a further embodiment of the invention illustrated in FIG. 2, a high pressure atomisation system is used to generate an aerosol. A solution of the substance e.g. drug in an appropriate solvent is sprayed through an orifice (10) with an appropriate supporting air flow rate provided by high pressure supply 12. The flow rate of the solvent is controlled by a syringe pump (1). As in the electrohydrodynamic spraying method, the aerosol droplets are collected in a continuous phase non-solvent of the substance (3). A typical separation distance between the point the aerosol droplets are ejected and the surface of the non-solvent is around 15 cm. The whole system is generally hermetically sealed with a side arm (11) attached to the flask providing a flow path of the air through the system. Nucleation of the droplets collected in the crystallisation vessel is induced via ultrasonic energy.

EXAMPLE 1

Preparation of Crystalline Paracetamol Particles

[0061] Method

[0062] The electrohydrodynamic spraying embodiment of the invention described above was used to produce paracetamol particles. A 7.5%w/w solution of paracetamol in ethanol was used to fill a syringe that was connected via tubing to capillary needles. The syringe was driven under controlled flow rates by a suitable syringe driver (Harvard PHD2000). The high voltage supply was increased until the spray from the capillary was in the form of a stable cone jet. The aerosol droplets were collected in a continuous phase in a crystallisation vessel. The continuous phase was cyclohexane with the addition of a low concentration of emulsifier. The emulsifier was added to stabilise the quasi-emulsion of the dispersed phase. Nucleation of the aerosol droplets was induced by ultrasonic energy supplied to the crystallisation vessel. The crystallised particles were collected by filtration and washed with a non-solvent via a 0.22 m filter and subsequently dried at 40 C. The experimental conditions used for generating the paracetamol particles are summarised in Table 5.

TABLE-US-00005 TABLE 5 Parameter Experimental Conditions Flow rate 70 l/min Applied High Voltage 9.5 kV Inner Diameter of Capillaries 2001 m-1.6 mm Drug Concentration 7.5% w/w Capillary-Solution Separation Distance 5 cm Emulsifier 0.01% Span 80 Non-Solvent Cyclohexane

[0063] Results

[0064] FIG. 3a shows the cumulative size distribution for the original paracetamol particles used to make up the 7.5%w/w solution. The original paracetamol particles are clearly polydispersed. FIG. 3b shows the cumulative size distribution for the particles produced by electrohydrodynamic spraying and sonocrystallisation. The particles produced by electrohydrodynamic spraying and sonocrystallisation have a narrow size distribution between 1 m and 5 m. The crystallinity of the particles produced by electrohydrodynamic spraying and sonocrystallisation was verified by differential scanning calorimetry and X-ray powder diffraction. FIG. 4 shows a scanning electron micrograph of the original paracetamol particles and FIG. 5 those produced by electrohydrodynamic spraying and sonocrystallisation. The particles produced by the process of the invention are substantially spherical, and this contrast with the original particles can be clearly seen.

EXAMPLE 2

Preparation of Crystalline Paracetamol Particles and Beclomethasone Dipropionate (BDP) Particles

[0065] A high pressure atomisation system, as described above, was used to produce paracetamol particles and beclomethasone dipropionate (BDP) particles.

[0066] A solution of paracetamol in ethanol was sprayed through a 0.7 mm diameter orifice with a supporting air flow rate of 600 l/h. The flow rate of the solvent was controlled by a syringe pump and was set at 16 ml/h. The aerosol droplets were collected in cyclohexane via a conical shaped crystallisation vessel. The distance between the atomiser orifice and the collection vessel was pre-set at well-defined separation distances. A typical separation distance was around 15 cm. The whole system was hermetically sealed. A side arm attached to the flask provided a flow path of the air through the system. Nucleation of the droplets collected in the crystallisation vessel was induced via ultrasonic energy. The crystalline particles were collected by filtration and washed with a non-solvent via a 0.22 m and subsequently dried. FIG. 6 shows scanning electron micrographs of paracetamol particles produced by the air pressure atomisation system with increasing drug concentration (1% w/w, 5% w/w and 10% w/w respectively).

[0067] The use of the high pressure atomisation system was also utilised for the production of Beclomethasone dipropionate particles. FIG. 7 shows a scanning electron micrograph of the particles produced from a 2% w/w BDP-ethanol solution. The experimental conditions of the high pressure atomisation system were the same as for paracetamol.

EXAMPLE 3

Statistical Analysis Comparison of Micronized Particles with Particles Produced by the Process of the Invention

[0068] For statistical analysis, the cumulative percentage is plotted on a probability scale (ordinate) versus logarithm of the particle size (abscissa). In most cases, the cumulative frequency distributions tend to follow a log-normal distribution. Differences in particle size distributions were characterised by parameters derived from comparing certain percentiles values from each distribution. The computed distribution parameters were median separation energy, skewness, and kurtosis.

[0069] The central tendency of each distribution is characterised by its median separation energy, the energy required to detach 50% of the adhered particles. The Yule coefficient of skewness measures the degree of deviation of a distribution from symmetry. The non-dimensional quantity can take any value between 1 and 1. Where skewness is zero, an even distribution of data around one standard deviation of the median is suggested. For a strongly non-zero measurement, an asymmetric, skewed distribution is suggested. Distributions with a positive skewness are skewed towards the high particle size tail, whereas distributions with negative skewness are skewed towards the lower particle size tail. Kurtosis denotes the shape of the distribution about the centre. The coefficient of kurtosis has a value between 0.99 an 1.11 for a normal type distribution (mesokurtic), while more negative values indicate an increase in the flatness of the frequency distribution (platykurtic), and more positive values show an increased peakness for the particle size distribution (leptokurtic). The various expressions used to calculate the statistical parameters are provided below.

[00001]$\mathrm{Skewness}$$\mathrm{Sk}=\frac{\left(e_{84.1.Math.\%}-2.Math.e_{50.Math.\%}+e_{15.9.Math.\%}\right)}{\left(e_{84.1.Math.\%}-e_{15.9.Math.\%}\right)}$$\mathrm{Kurtosis}$$\mathrm{ku}=\sqrt{\frac{e_{15.9.Math.\%}/e_{84.1.Math.\%}}{e_{75.Math.\%}/e_{25.Math.\%}}}$

TABLE-US-00006 TABLE 6 Analysis of micronised paracetamol and controlled atomisation and sonocrystallization of paracetamol High Pressure Micronised EHD Sprayed Atomisation Median 2.74 2.31 3.05 Diameter/m Skewness 0.381 0.250 Kurtosis 0.260 0.425

TABLE-US-00007 TABLE 7 Analysis of micronised and controlled atomisation and crystallization of beclomethasone dipropionate High pressure Micronised atomisation Median 3.33 1.20 Diameter/m Skewness 0.326 0.266 Kurtosis 0.321 0.401

[0070] The results clearly show that the particles produced by the process of the present invention have a lower skewness (i.e. a more symmetrical distribution) and a higher kurtosis (i.e. a less dispersed distribution) than particles produced by prior art processes. These parameters lead to improved utility in pharmaceutical compositions.

EXAMPLE 4

Preparation of Crystalline Budesonide Particles

[0071] A high pressure atomisation system, as described previously, was used to produce budesonide particles within a well-defined particle size range. FIG. 8 shows a scanning electron micrograph of the particles produced upon spraying 8% w/w budesonide solution in dichloromethane through a 0.7 mm diameter orifice with a supporting air flow rate of 600 l/h. The flow rate of the solvent was set at 40 ml/hour. The aerosol droplets were collected in hexane at a separation distance of 20 cm.