WO2003094892A1

WO2003094892A1 - Conversion of amorphous material to a corresponding crystalline material by spray drying and utilization of the crystalline spray dried material in drug formulations

Info

Publication number: WO2003094892A1
Application number: PCT/FI2003/000353
Authority: WO
Inventors: Tapio Lankinen; Päivi HARJUNEN; Kristiina JÄRVINEN; Petteri Paronen; Vesa-Pekka Lehto
Original assignee: Focus Inhalation Oy
Priority date: 2002-05-07
Filing date: 2003-05-06
Publication date: 2003-11-20
Also published as: AU2003227783A1; FI20020857A0; FI20020857A

Abstract

The invention concerns a method for performing a conversion of an amorphous material to a corresponding essentially crystalline material. At least partly amorphous material is spray dried using a feed solution which is a suspending medium in which said material is practically insoluble. The invention further concerns an inhalation formulation containing a pharmaceutically active agent, a carrier and optionally conventional excipients used in inhalation formulations. At least one of the components have been spray dried using a feed solution which is a suspending medium in which said component is practically insoluble, for converting the amorphous component into an essentially crystalline form. The amorphous component is e.g. lactose or salbutamol, and the suspending medium may be ethanol.

Description

Conversion of amorphous material to a corresponding crystalline material by spray drying and utilization of the crystalline spray dried material in drug formulations.

The Background of the Invention

The present invention is directed to a method for performing a simple conversion of an amorphous material to a corresponding crystalline material by spray drying using an appropriate feed solution. The appropriate feed solution is any solution where the amorphous material is practically insoluble. The produced crystalline spray dried material can be used as an active compound or an excipient in drug formulations; e.g. in inhalation powders.

The Technical Field of the Invention

Crystallization from the solutions can be considered to be the result of three processes, (i) supersaturation of the solution, i.e. the ratio of actual concentration of a drug to the solubility at the specific temperature, (ii) formation of crystal nuclei and (iii) crystal growth round the nuclei (Florence and Attwood: Physicochemical Principles of Pharmacy, 2^nd Ed. p. 24, Macmillan Press, Hong Kong 1989). Supersaturation can be achieved by cooling, by evaporation, by the addition of a precipitant or by a chemical reaction. The crystallization conditions strongly affect chemical and physical properties of the resulting crystallized material.

Common crystallization processes include melt quenching, freeze- and spray drying and drying of solvated crystals (Yu, Adv. Drug. Del. Rev. 48: 27-42, 2001). Spray drying is a commonly used method in order to modify the crystal properties, such as particle size, crystal habit, crystallinity content, polymorphism and crystal moisture. Spray drying converts a liquid into a powder in a one-step process, producing fine, and dustless or agglomerated pow- ders, usually approximately spherical with a narrow size range and generally hollow (Di Martino et al., Int. J. Pharm. 213: 209-221, 2001). Spray drying has been shown to produce predominantly amorphous material due to rapid solification (Chidavaenzi et al., Int. 3. Pharm. 159: 67-74, 1997; Chidavaenzi et al., Int. 1 Pharm. 216: 43-49, 2001; Newell et al., Int. J. Pharm. 217: 45- 56, 2001, Stubberud and Forbes, Int. J. Pharm. 163: 145-156, 1998; Ueno et al., J. Pharm. Pharmacol. 50: 1213-1219, 1998). The greatest advantage of amorphous solids is that they typically have higher solubility and higher dissolution rate than corresponding crystals (Hancock and Parks, Pharm. Res. 17: 397-404, 2000; Yu, Adv. Drug. Del. Rev. 48: 27-42, 2001). However, the utilization of amorphous solids in drug is often restricted due to the fact that amorphous solids are less stable physically and chemically than corresponding crystals. Thus, highly crystalline materials are often needed for commercial applications.

When the temperature of the environment is higher than the glass transition temperature of an amorphous material, the amorphous material converts spontaneously to a corresponding crystalline material (Buckton, Adv. Drug. Deliv. Rev. 26: 17-27, 1997; Stubberud and Forbes, Int. 1 Pharm. 163: 145-156, 1998). This can be explained by the fact that when the glass transition temperature of the amorphous material is lower than the temperature of the environment the molecules have sufficient flexibility to realign and form the crystals. The moisture sorbed by the amorphous material induces typically conversion of the amorphous material to a corresponding crystalline material since absorption of a vapor (which may be water or organic) lowers the glass transition temperature.

Crystallization of carbohydrates and derivatives, such as lactose and mannitol and sorbitol, which are common pharmaceutical excipients, present special challenges (Yu, Adv. Drug. Del. Rev. 48: 27-42, 2001). For example, lactose, 4-(β-D-galactosido-)-D-glucose, can be obtained in either two basic isomeric forms, α and β -lactose, or as an amorphous form. In solution lactose takes on two anomeric forms, α and β, but crystallizes normally as an α-lactose monohydrate from water (Yu, Adv. Drug. Del. Rev. 48: 27-42, 2001).

As discussed above, spray drying is a useful method in order to modify the crystal properties of the solid materials. However, spray drying has been shown to produce predominantly amorphous material due to rapid solifica- tion (Chidavaenzi et al., Int. J. Pharm. 159: 67-74, 1997; Chidavaenzi et al., Int. J. Pharm. 216: 43-49, 2001; Newell et al., Int. J. Pharm. 217: 45-56, 2001, Stubberud and Forbes, Int. J. Pharm. 163: 145-156, 1998; Ueno et al., 1 Pharm. Pharmacol. 50: 1213-1219, 1998). In the present invention the problem has been solved using an appropriate feed solution as described below.

The Summary of the Invention The present invention describes a method for performing a simple and rapid conversion of an amorphous material to a corresponding crystalline material by spray drying using an appropriate feed solution. The amorphous material that is aimed to convert to the corresponding crystalline material may have been produced by any method, including melt quenching, freeze-and spray drying, milling, wet granulation and drying of solvated crystals. The conversion of an amorphous material to the corresponding crystalline material occurs when the sample is spray dried using feed solution where the amorphous material is practically insoluble. The crystalline material produced by the abovementioned method can be used as an active drug or as an excipi- ent in any drug formulations.

Using lactose and salbutamol sulphate, that are utilized commonly as a carrier and a micronized drug powder in inhalation, respectively, as examples, this invention considers the general utility of spray drying for producing highly crystalline materials for drug formulations. Brief Description of the Drawings

Figure la: Microcalorimetric heat flow signals for the lactose samples before (solid line, amorphicity 100%) and after (dashed line, amorphicity 12%) spray drying from ethanol. The exothermic peaks (upwards) are indicative of the recrystallization of the amorphous portion of lactose.

Figure lb: Microcalorimetric heat flow signals for the lactose samples before (solid line, amorphicity 77%) and after (dashed line, amorphicity 9%) spray drying from ethanol. The exothermic peaks (upwards) are indicative of the recrystallization of the amorphous portion of lactose. Figure lc: Microcalorimetric heat flow signals for the lactose samples before (solid line, amorphicity 45%) and after (dashed line, amorphicity 6%) spray drying from ethanol. The exothermic peaks (upwards) are indicative of the recrystallization of the amorphous portion of lactose. Figure Id: Microcalorimetric heat flow signals for the lactose samples before (solid line, amorphicity 15%) and after (dashed line, amorphicity 0%) spray drying from ethanol. The exothermic peak (upwards) are indicative of the recrystallization of the amorphous portion of lactose. Figure le: Microcalorimetric heat flow signals for the salbutamol sulphate samples before (solid line, amorphicity 11%) and after (dashed line, amor- phicity 0%) spray drying from ethanol. The exothermic peaks (upwards) are indicative of the recrystallization of the amorphous portion of lactose.

Figure 2a: XRPD patterns for the lactose samples before (solid line, amorphicity 100%) and after (dashed line, amorphicity 12%) spray drying from ethanol.

Figure 2b: XRPD patterns for the lactose samples before (solid line, amorphicity 77%) and after (dashed line, amorphicity 9%) spray drying from ethanol. Figure 2c: XRPD patterns for the lactose samples before (solid line, amor- phicity 45%) and after (dashed line, amorphicity 6%) spray drying from ethanol. Figure 2d: XRPD patterns for the lactose samples before (solid line, amorphicity 15% and after (dashed line, amorphicity 0%) spray drying from ethanol.

Figure 2e: XRPD patterns for the salbutamol sulphate samples before (solid line, amorphicity 11%) and after (dashed line, amorphicity 0%) spray drying from ethanol.

Figure 3a: SEM micrographs for the lactose samples before (A, amorphicity 100%) and after (B, amorphicity 12%) spray drying from ethanol. Figure 3b: SEM micrographs for the lactose samples before (A, amorphicity 77%) and after (B, amorphicity 9%) spray drying from ethanol. Figure 3c: SEM micrographs for the lactose samples before (A, amorphicity 45%) and after (B, amorphicity 6%) spray drying from ethanol. Figure 3d: SEM micrographs for the lactose samples before (A, amorphicity 15%) and after (B, amorphicity 0%) spray drying from ethanol.

Figure 3e: SEM micrographs for the salbutamol sulphate samples before (A, amorphicity 11%) and after (B, amorphicity 0%) spray drying from ethanol.

The Detailed Description of the Invention Definitions

An amorphous solid can be defined with reference to a crystalline solid: similar to crystalline solid, an amorphous solid may have short range molecular order but unlike a crystalline solid, an amorphous solid has no long-range order of molecular packing or well-defined molecular conformation if the constituent molecules are conformationally flexible (Yu, Adv. Drug. Del. Rev. 48: 27-42, 2001).

The General Description of the Invention

During studies related to spray drying of solid materials in order to modify the crystal properties of the materials, the present inventors surprisingly discovered that conversion of an amorphous material occurred during the spray drying when the amorphous material was insoluble in feed solution. Based on this finding the method of the present invention was developed and its efficacy was evaluated. It was found that partly or totally amorphous lactose was possible to convert to corresponding totally or highly crystalline lactose by spray drying using ethanol as a feed solution. 100 % amorphous lactose was prepared by spray drying α-lactose monohydrate from water. The partly amorphous lactose samples were produced by spray drying using wa- teπethanol mixture as a feed solution (Harjunen et al., Eur. J. Pharm. Sci. 13(Suppl. 2): S18-19, 2001).

The present invention was developed based on these original findings and is directed to a simple and rapid but efficient method for conversion of amorphous material to corresponding crystalline material. The greatest advantage of this method is the fact that conversion of an amorphous material to a crystalline material occurs during spray drying while other physical properties, such as particle size and shape, do not notably change during crystallization.

The most preferred embodiment of the present invention relates to ability of the present method to modify materials intended for use in inhalation powders.

EXAMPLE 1

In this example, the effect of spray drying using ethanol as a feed solution on physical properties of 100 % amorphous lactose was studied.

Amorphicity of the sample was determined by isothermal heat-conduction microcalorimeter (IMC) TAM 2277 (Thermometric Ab, Sweden). The miniature humidity chamber technique (Angberg et al., Int. J. Pharm. 81:153-167, 1992; Angberg et al., Int. 1 Pharm. 83:11-23, 1992) was employed to detect the thermal response for the recrystallization of amorphous lactose. The ex- tent of heat evolution was directly related to the degree of amorphicity. During the measurement, the sample was recrystallized due to the moisture adsorbed from the saturated salt solution (ca. 54% RH), which was included in the hermetically sealed sample ampoule as a dessicant, together with the sample. Morphology of particles was evaluated with a scanning electron microscope (SEM) (XL 30 ESEM TMP, FEI Company, the Czech Republic). Characterization of crystal forms was performed by means of X-ray powder diffraction (XRPD) (Philips PW1050, the Netherlands). Particle size distribution was determined using Malvern Mastersizer S (Malvern Instruments Ltd., Mal- vern, UK).

More specifically, 100 % amorphous lactose was produced by spray drying of 15 % (w/w) aqueous lactose solution with a Buchi Mini-Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland), α-lactose monohydrate (Pharmatose^®325 M, DMV, Holland) was dissolved in water at room temperature (20°C) before spray drying. The spray drying variables were as follows: outlet temperature 105°C, inlet temperature 160°C, atomizer air flow rate 700 normliter/h, feed rate 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 12. The diameter of the nozzle was 0.7 mm.

The conversion of 100 % amorphous lactose to 88% crystalline lactose was performed by spray drying a 15 % (w/w) lactose suspension containing 15 g 100 % amorphous lactose and 85 g ethanol (Primalco, Finland). 100 % amorphous lactose was produced as described above. Spray drying was per- formed with a Buchi Mini-Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland). 100 % amorphous lactose was mixed in ethanol for 5 minutes at room temperature (20°C) before spray drying. The spray drying variables were as follows: outlet temperature 82°C, inlet temperature 105°C, atomizer air flow rate 700 normliter/h, feed rate 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm. The results are shown in Tables 1 and 2 and Figures la, 2a and 3a (IMC, XRPD, SEM). According to the tables and the figures, conversion of 100 % amorphous lactose into 88 % crystalline lactose occurred during spray drying using ethanol as a feed solution while particle size and shape were not nota- bly affected.

Table 1: The ratio of ethanol to water in feed material and the consequent nature of the spray dried lactose.

Ratio of ethanol Amorphicity Distribution of particle size to water % (w/w) (μm)

D 10% D 50% D 90%

0:100 100 3 9 39

20:80 77 4 14 58

30:70 45 6 39 77

40:60 15 20 56 121

Table 2: The nature of a highly crystalline spray dried lactose produced by spray drying lactose samples shown in Table 1 again using ethanol as a feed solution.

Initial amorphicity Amorphicity of Distribution of particle size of the sample the spray dried (μm)

% (w/w) sample D 10% D 50% D % (w/w) 90%

100 12 3 14 43

77 9 3 8 53

45 6 3 15 66

15 0 4 34 75

Figure 3a shows lactose samples before (A, amorphicity 100%) and after (B, amorphicity 12%) spray drying from ethanol. EXAMPLE 2

In this example, the effect of spray drying using ethanol as a feed solution on physical properties of 77 % amorphous lactose was studied.

Amorphicity of the sample was determined by isothermal heat-conduction microcalorimeter (IMC) TAM 2277 (Thermometric Ab, Sweden). The miniature humidity chamber technique (Angberg et al., Int. 1 Pharm. 81:153-167, 1992; Angberg et al., Int. J. Pharm. 83:11-23, 1992) was employed to detect the thermal response for the recrystallization of amorphous lactose. The extent of heat evolution was directly related to the degree of amorphicity. During the measurement, the sample was recrystallized due to the moisture adsorbed from the saturated salt solution (ca. 54% RH), which was included in the hermetically sealed sample ampoule as a dessicant, together with the sample. Morphology of particles was evaluated with a scanning electron microscope (SEM) (XL 30 ESEM TMP, FEI Company, the Czech Republic). Characterization of crystal forms was performed by means of X-ray powder diffraction (XRPD) (Philips PW1050, the Netherlands). Particle size distribution was determined using Malvern Mastersizer S (Malvern Instruments Ltd., Mal- vern, UK).

More specifically, 77 % amorphous lactose was produced by spray drying of 15 % (w/w) lactose suspension with a Buchi Mini-Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland). The ratio of ethanol (Primalco, Finland) to water in the feed solution was 20:80. α-lactose monohydrate (Pharmatose^®325 M, DMV, Holland) was mixed in ethanol:water (20:80) solution for 5 minutes at room temperature (20°C) before spray drying. The spray drying variables were as follows: outlet temperature 77-78°C, inlet temperature 106°C, atomizer air flow rate 700 normliter/h, feed rate 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm. The conversion of 77 % amorphous lactose to 91 % crystalline lactose was performed by spray drying a 15 % (w/w) lactose suspension containing 15 g 77 % amorphous lactose and 85 g ethanol. 77 % amorphous lactose was produced as described above. Spray drying was performed with a Buchi Mini- Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland). 77 % amorphous lactose was mixed in ethanol for 5 minutes at room temperature (20°C) before spray drying. The spray drying variables were as follows: outlet temperature 83°C, inlet temperature 106°C, atomizer air flow rate 700 normliter/h, feed rate 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm.

The results are shown in Tables 1 and 2 and Figures lb, 2b and 3b (IMC, XRPD, SEM). According to the tables and the figures, conversion of 77 % amorphous lactose into 91 % crystalline lactose occurred during spray drying using ethanol as a feed solution while particle size and shape were not notably affected.

Figure 3b shows lactose samples before (A, amorphicity 77%) and after (B, amorphicity 9%) spray drying from ethanol.

EXAMPLE 3

In this example, the effect of spray drying using ethanol as a feed solution on physical properties of 45 % amorphous lactose was studied.

Amorphicity of the sample was determined by isothermal heat-conduction microcalorimeter (IMC) TAM 2277 (Thermometric Ab, Sweden). The miniature humidity chamber technique (Angberg et al., Int. J. Pharm. 81:153-167, 1992; Angberg et al., Int. J. Pharm. 83:11-23, 1992) was employed to detect the thermal response for the recrystallization of amorphous lactose. The ex- tent of heat evolution was directly related to the degree of amorphicity. During the measurement, the sample was recrystallized due to the moisture ad- sorbed from the saturated salt solution (ca. 54% RH), which was included in the hermetically sealed sample ampoule as a dessicant, together with the sample. Morphology of particles was evaluated with a scanning electron microscope (SEM) (XL 30 ESEM TMP, FEI Company, the Czech Republic). Char- acterization of crystal forms was performed by means of X-ray powder diffraction (XRPD) (Philips PW1050, the Netherlands). Particle size distribution was determined using Malvern Mastersizer S (Malvern Instruments Ltd., Malvern, UK).

More specifically, 45 % amorphous lactose was produced by spray drying of 15 % (w/w) lactose suspension with a Buchi Mini-Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland). The ratio of ethanol (Primalco, Finland) to water in the feed solution was 30:70. α-lactose monohydrate (Pharmatose^®325 M, DMV, Holland) was mixed in ethanohwater (30:70) so- lution for 5 minutes at room temperature (20°C) before spray drying. The spray drying variables were as follows: outlet temperature 78°C, inlet tem- peraturel06°C, atomizer air flow rate 700 normliter/h, feed rate 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm.

The conversion of 45 % amorphous lactose to 94% crystalline lactose was performed by spray drying a 15 % (w/w) lactose suspension containing 15 g 45 % amorphous lactose and 85 g ethanol. 45 % amorphous lactose was produced as described above. Spray drying was performed with a Buchi Mini- Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland). 45 % amorphous lactose was mixed in ethanol for 5 minutes at room temperature (20°C) before spray drying. The spray drying variables were as follows: outlet temperature 83°C, inlet temperature 106°C, atomizer air flow rate 700 normliter/h, feed rate 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm. The results are shown in Tables 1 and 2 and Figures lc, 2c and 3c (IMC, XRPD, SEM). According to the tables and the figures, conversion of 45 % amorphous lactose into 94 % crystalline lactose occurred during spray drying using ethanol as a feed solution while particle size and shape were not nota- bly affected.

Figure 3c shows lactose samples before (A, amorphicity 45%) and after (B, amorphicity 6%) spray drying from ethanol.

EXAMPLE 4

In this example, the effect of spray drying using ethanol as a feed solution on physical properties of 15 % amorphous lactose was studied.

Amorphicity of the sample was determined by isothermal heat-conduction microcalorimeter (IMC) TAM 2277 (Thermometric Ab, Sweden). The miniature humidity chamber technique (Angberg et al., Int. 1 Pharm. 81:153-167, 1992; Angberg et al., Int. J. Pharm. 83:11-23, 1992) was employed to detect the thermal response for the recrystallization of amorphous lactose. The extent of heat evolution was directly related to the degree of amorphicity. Dur- ing the measurement, the sample was recrystallized due to the moisture adsorbed from the saturated salt solution (ca. 54% RH), which was included in the hermetically sealed sample ampoule as a dessicant, together with the sample. Morphology of particles was evaluated with a scanning electron microscope (SEM) (XL 30 ESEM TMP, FEI Company, the Czech Republic). Char- acterization of crystal forms was performed by means of X-ray powder diffraction (XRPD) (Philips PW1050, the Netherlands). Particle size distribution was determined using Malvern Mastersizer S (Malvern Instruments Ltd., Malvern, UK).

More specifically, 15 % amorphous lactose was produced by spray drying of 15 % (w/w) lactose suspension with a Buchi Mini-Spray Drier 190 (Buchi La- boratorium-Technic AG, Switzerland). The ratio of ethanol (Primalco, Finland) to water in the feed solution was 40:60. -lactose monohydrate (Pharma- tose^®325 M, DMV, Holland) was mixed in ethanol.water (40:60) for 5 minutes at room temperature (20°C) before spray drying. The spray drying vari- ables were as follows: outlet temperature 77°C, inlet temperature 105°C, atomizer air flow rate 700 normliter/h, pump speed 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm.

The conversion of 15 % amorphous lactose to 100 % crystalline lactose was performed by spray drying a 15 % (w/w) lactose suspension containing 15 g 15 % amorphous lactose and 85 g ethanol. 15 % amorphous lactose was produced as described above. Spray drying was performed with a Buchi Mini- Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland). 15 % amor- phous lactose was mixed in ethanol for 5 minutes at room temperature (20°) before spray drying. The spray drying variables were as follows: outlet temperature 82°C, inlet temperature 105°C, atomizer air flow rate 700 normliter/h, feed rate 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm

The results are shown in Tables 1 and 2 and Figures Id, 2d and 3d (IMC, XRPD, SEM). According to the tables and the figures, conversion of 15 % amorphous lactose into 100 % crystalline lactose occurred during spray drying using ethanol as a feed solution while particle size and shape were not notably affected.

Figure 3d shows lactose samples before (A, amorphicity 15%) and after (B, amorphicity 0%) spray drying from ethanol. EXAMPLE 5

In this example, the effect of spray drying using ethanol as a feed solution on crystallinity of 11 % amorphous salbutamol sulphate (Focus Inhalation Oy) was studied.

Amorphicity of the sample was determined by isothermal heat-conduction microcalorimeter (IMC) TAM 2277 (Thermometric Ab, Sweden). The miniature humidity chamber technique (Angberg et al., Int. 1 Pharm. 81:153-167, 1992; Angberg et al., Int. J. Pharm. 83:11-23, 1992) was employed to detect the thermal response for the recrystallization of amorphous lactose. The extent of heat evolution was directly related to the degree of amorphicity. During the measurement, the sample was recrystallized due to the moisture adsorbed from the saturated salt solution (ca. 54% RH), which was included in the hermetically sealed sample ampoule as a dessicant, together with the sample. Morphology of particles was evaluated with a scanning electron microscope (SEM) (XL 30 ESEM TMP, FEI Company, the Czech Republic). Characterization of crystal forms was performed by means of X-ray powder diffraction (XRPD) (Philips PW1050, the Netherlands). Particle size distribution was determined using Malvern Mastersizer 2000 (Malvern Instruments Ltd., Malvern, UK).

The conversion of 11 % amorphous salbutamol sulphate to 100 % crystalline salbutamol sulphate was performed by spray drying a 9 % (w/w) salbutamol sulphate suspension containing 5.5 g 11 % amorphous salbutamol sulphate and 55 g ethanol (Primalco, Finland). Spray drying was performed with a Buchi Mini-Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland). 11 % amorphous salbutamol sulphate was mixed in ethanol for 15 minutes at room temperature (20°) before spray drying. The spray drying variables were as follows: outlet temperature 78°C, inlet temperature 104°C, atomizer air flow rate 800 normliter/h, feed rate 6 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm. The results are shown in Table 3 and Figures le, 2e and 3e (IMC, XRPD, SEM). According to the figures, conversion on an 11 % amorphous salbutamol sulphate to 100 % crystalline salbutamol sulphate occurred during spray drying using ethanol as a feed solution.

Table 3: Amorphicity and distribution of particle size (μm) of salbutamol sulphate before (micronized) and after spray drying from ethanol.

Distribution of particle size

Salbutamol sulAmorphicity (μm) phate % (w/w) D 10% D 50% D 90%

Micronized 11 0.1 0.3 2.9

Spay dried 0 0.1 1.1 3.3

Figure 3e shows salbutamol sulphate samples before (A, amorphicity 11%) and after (B, amorphicity 0%) spray drying from ethanol.

EXAMPLE 6 In this example, effects of crystalline spray dried lactose used as a carrier in inhalation powder on pulmonary deposition of budesonide was studied.

More specifically, α-Lactose monohydrate (Pharmatose^®325 M, DMV, Holland), micronised budesonide (batch 5067/M1) and dry powder inhaler, Tai- fun^®, were supplied by Focus, Ltd., Finland. Absolute ethanol was obtained from Primalco, Finland. Hexane (HPLC grade) and methanol were purchased from Rathburn, Scotland. Acetonitrile (HPLC grade) was purchased from Merck, Germany. All other used materials were of analytical grade.

The 100 % crystalline lactose was prepared by spray drying from the suspension containing 30 g an untreated commercial -lactose monohydrate and 70 g ethanol. Spray drying was performed with a Buchi Mini-Spray Drier 190 (Buchi Laboratorium-Technic AG, Switzerland). A commercial α-lactose monohydrate was mixed in ethanol for 5 minutes at room temperature (20°) before spray drying. The spray drying variables were as follows: outlet tem- perature 78°C, inlet temperature 105°C, atomizer air flow rate 700 normliter/h, feed rate 7 ml/min, air flow rate (dial setting) 15, heating rate (dial setting) 7. The diameter of the nozzle was 0.7 mm.

An untreated commercial α-lactose monohydrate was used as a control carrier.

Budesonide:carrier ratio was 1: 15.1 (w/w) in formulations. The formulations were prepared with the suspending method (Lankinen, Patent WO 99/34778.). Briefly, micronized budesonide was dispersed 5 minutes in hex- ane by ultrasonic and suspension was mixed at 300-400 rpm. After that hex- ane and crystalline spray dried lactose were added while mixing was continued 10 minutes without ultrasonic. Suspension was filtered by Bϋchner (GF 52 Ref. No. 428248, Schleicher & Schuell) and budesonide formulation was dried in the evaporator. Finally formulation was sieved manually (0 1.0 mm) and was packed into tightly closed plastic bottles and stored 5-7 days in a desiccator (33% RH at room temperature). After that, budesonide formulation was weighed accurately into the two Taifun® inhalers and they were stored one day in a testcloset 25°C / 60% RH (WK 11-180/40, Weiss Tecnik Gmbh) prior to the studies. Formulations were placed in the stability cham- ber at 40°C/75% RH in polystyrene tubes for one month for stability evaluation.

Budesonide was analysed by HPLC. The HPLC system consisted of a Spectra System^® detector, a Spectra Series^® pump, a Spectra Series^® autosampler, a Spectra Series^® solvent degasser (Thermo Separation Products, USA) and a 150 x 4.0 mm I.D. column packed with 5 μm Inertsil C-8 (GL Sciences inc.). The homogeneity of each formulation was examined both after the preparation and after storage of formulation one month at 40°C/75% RH.

Uniformity of emitted budesonide dose (theoretical value 100 μg) was inves- tigated in the testcloset (25 °C / 60 % RH). The first 25 doses were portioned via Taifun^® singly into the dosage unit sampling apparatus (Ph. Eur. 3^rd ed., 1997). The first 5 doses were omitted when results were calculated (i.e. doses from 6 to 25 were included). The test was performed at flow rate of 30 I min^"1 and flow time was 8 s. Emitted budesonide doses were studied in duplicate (i.e. two inhalers were studied). The emitted budesonide doses were studied also after storage of formulation one month in polystyrene tube at 40°C/75% RH.

The pulmonary deposition of budesonide was evaluated using the "Andersen" Sampler (Ph. Eur.) with vacuum pump and 3-way valve and operated at a flow rate of 28.3 I min^"1. The Andersen sampler consists of a throat, presepa- rator, eight stages and a final filter. The test was carried out using the same two inhalers, which were used when uniformity of emitted budesonide doses were studied. 20 doses were released from Taifun^® to cascade impactor at intervals of one minute. Deposition of budesonide from both inhalers was determined twice, i.e. deposition of doses from 26 to 45 and from 46 to 65 was studied. The collection stages of the impactor, the preseparator and throat were washed with methanoksodium dihydrogen phosphate buffer (0.017M, pH 3.2) mixture (50:50 V/V). Budesonide concentration in samples was analysed by HPLC. In vitro deposition of budesonide was studied also after storage of formulation one month in polystyrene tube at 40°C/75% RH.

A variety of parameters were employed to characterize the deposition profiles of budesonide as explained below. The recovered mass (RM) was the sum of budesonide from each of the cascade impactor stages (plates + frame 0-7 and filter), metal throat including the DPI adapter and from the preseparator. The fine particle mass (FPM) was the sum of the amount of budesonide recovered from stages 2 to 7 and the filter. Respiratory fraction (RF%) was calculated as the ratio of FPM to RM. The Mass Media Aerodynamic diameter (MMAD) was calculated with the cumulative drug percent- ages at each stage from filter to the stage 0. MMAD value was read as the particle size at the cumulative percentage value of 50%.

Table 4 shows that the homogeneity of both formulations was good.

Table 4 shows that when either an untreated α-lactose monohydrate or crystalline spray dried lactose was used as a carrier, the emitted budesonide doses were close to the theoretical dose (100 μg) both initially and after storage of formulation one month at 40°C / 75% RH.

The MMAD values of budesonide particles indicate that the respiratory properties of budesonide were comparable from the both tested formulations initially and after storage (Table 4).

Table 4 shows that when compared to a control carrier (i.e. an untreated α-lactose monohydrate), crystalline spray dried lactose increased RF% value initially. Table 4 shows that inhalation powder that contained crystalline spray dried lactose as a carrier was more stable than the control formulation. This is indicated by the fact that in the case of crystalline spray dried lactose, the RF% value was not markedly changed during storage while in the case of a control formulation, the RF% values were higher after storage than initially. Consequently, the present results demonstrate that crystalline spray dried lactose is better carrier for inhalation powder than the commercial unmodified α-lactose monohydrate.

Table 4: Influence of spray drying of lactose from ethanol on budesonide content of formulation, mean emitted dose and its relative standard devation (RDS%), mass media aerodynamic diameter (MMAD) and respirable fraction of the emitted dose (RF%) initially and after 1 month storage (40 °C / 75% RH). Taifun^® was used as the DPI.

Carrier Time label Budesonide Emitted content doses MMAD RF

(μg) Mean dose (μm) (%)

RSD

(μg)

(%)

An untreated Inital 60 98 2.5 25 α-lactose value monohydrate

An untreated 1 month 60 93 2.3 40 α-lactose storage monohydrate

Crystalline spray Inital 59 86 10 3.0 38 dried lactose value

Crystalline spray 1 month 58 86 2.9 41 dried lactose storage

Claims

1. A method for performing a conversion of an amorphous material to a corresponding essentially crystalline material characterized in that the at least partly amorphous material is spray dried using a feed solution which is a suspending medium in which said material is practically insoluble.

2. A method according to claim 1, characterized in that the amorphous material and the suspending medium are mixed together and then spray dried.

3. A method according to claim 2, characterized in that the amorphous material and the suspending medium are mixed for up to 5 minutes at 20°C.

4. A method according to any of claims 1 to 3, characterized in that the a least partly amorphous material is an active agent, carrier, excipient or equivalent.

5. A method according to claim 4, characterized in that said material is used in an inhalation formulation.

6. A method according to any of claims 1 to 5, characterized in that the at least partly amorphous material is lactose.

7. A method according to any of claims 1 or 5, characterized in that the at least partly amorphous material is salbutamol.

8. Inhalation formulation containing a pharmaceutically active agent, a carrier and optionally conventional excipients used in inhalation formulations, characterized in that at least one of the components have been spray dried using a feed solution which is a suspending medium in which said compo- nent is practically insoluble for converting the amorphous component into an essentially crystalline form thereof.

9. Inhalation formulation according to claim 8, characterized in that said component is a carrier for an inhalation powder.

10. Inhalation formulation according to claim 9, characterized in that said carrier is lactose.

11. Inhalation formulation according to any of claims 8 to 10, characterized in that said component is an pharmaceutically active agent.

12. Inhalation formulation according to claim 11, characterized in that said active agent is salbutamol.