Spray-Drying Technology

Abstract

This chapter provides an in-depth review of spray-drying technology and its application to the formulation of poorly water-soluble drugs. In the early part of the chapter, the fundamentals of the process are discussed, including process theory, process components, equipment options, equipment by scale, various feeds, and typical solvent systems. In the latter part of the chapter, the application of spray drying to the formulation of poorly water-soluble drugs is discussed. Particular emphasis is given to spray drying for amorphous solid dispersion systems. The path toward developing an amorphous spray-dried dispersion and conversion to a final dosage form is covered in detail. Additionally, several academic and industrial examples are presented, illustrating the benefits of the process as a formulation technology and its commercial viability. Finally, the application of spray drying to inhalation as well as emerging applications, i.e., spray congealing and micro-encapsulation, are reviewed. This chapter provides comprehensive coverage of the spray-drying process and its uses as a formulation technology toward the enhancement of drug delivery with poorly water-soluble compounds.

Appendices

Method Capsule 1Preparation and Characterization of Spray-Dried Microparticles

Based on the method reported by De Jaeghere et al. (2000)

Objective

• Produce and characterize amorphous spray-dried microparticles of CGP 70726 with Eudragit L100-55 for enhanced oral absorption

Equipment and Materials

• CGP 70726

• Eudragit L100-55 (methacrylic acid copolymer)

• Methanol

• Büchi Mini Spray Dryer, Model 190

• Malvern Mastersizer® 2000

• PW 1729 X-ray generator

Method

• Feed preparation: In 300 g of methanol, dissolve CGP 70726 (1% w/w) and Eudragit L100-55 (4% w/w) with stirring.

• Spray-drying parameters:

  • Nozzle type: pneumatic two-fluid

  • Nozzle diameter: 0.5 mm

  • Collection system: cyclone

  • Drying gas: nitrogen

  • Feed: methanolic solution, 5% (w/w) solids

  • Feed rate: 4 mL/min

  • Inlet temperature: 50°C

  • Outlet temperature: 37–42°C

  • Aspirator setting: 15

• Morphology assessment: PXRD

• Particle-size analysis: laser light diffraction

• In vivo performance  : single dose, oral administration in beagle dogs (n  =  4)

Results

• The average production yield of the spray-dried micro-particles for two runs was 67%

• The spray-dried microparticles were determined to be amorphous by PXRD

• The mean particle diameters of two spray-dried microparticle batches were 10.0  ±  1.5 μm and 9.2  ±  1.3 μm as determined by laser light diffraction.

• The amorphous spray-dried microparticles substantially enhanced the oral absorption of CGP 70726 over the crystalline drug (plasma levels not quantifiable).

• The amorphous spray-dried microparticles produced exposures that were greater than twofold that of nanoparticles produced by an emulsion–diffusion method in the fed state.

Method Capsule 2Polymer Selection for an ASDD System by Supersaturated In Vitro Dissolution Screening

Based on the method reported by Curatolo et al. (2009).

Objective

• Employ a supersaturated in vitro dissolution test (micro-centrifuge method) to rank order the performance of polymers as carriers for compound 5 in ASDD systems

Equipment and Reagents

• Compound 5 (API), pure crystalline and amorphous

• Polymers: HPMCAS-MF, CAP, CAT, HPMC, HPMCP, PVP

• Phosphate buffered saline, pH 6.5

• Mobile phase: 60/40 1.7% ammonioum ascorbate/acetonitrile

• Controlled temperature box at 37°C

• Micro-centrifuge tube (polypropylene, Sorenson Bioscience Inc.)

• Vortex mixer (Fisher Vortex Genie 2)

• Micro-centrifuge, Marathon, Model Micro A

• Pipette (Gilson Pipetman P-100)

• HPLC (Hewlett Packard 1090 HPLC, Phenomenex Ultracarb ODS 20 analytical column, absorbance measured at 215 nm with a diode array spectrophotometer)

Method

• Amorphous solid dispersion formulations of compound 5 (10% w/w) and the various polymer carriers were produced by spray drying from organic solution.

• In a controlled temperature box at 37°C, 4.0 mg of each ASDD powder was weighed into an empty micro-centrifuge tube. Then, 2.0 mL of phosphate buffered saline (pH 6.5) was added to the tube (theoretical maximum drug concentration 200 μg/mL).

• The tube was then closed, timer started, and the tube was mixed continuously for 60 s with a vortex mixer on the highest speed.

• The tube was transferred to the centrifuge and allowed to stand for 6 min; then centrifuged at 13,000× g for 60 s.

• A 25 μL sample was removed from the supernatant using a pipette at 10 min after the timer was started.

• The solids in the centrifuge tube were then re-suspended by vortex mixing for 30 s.

• The centrifuge tube was returned to the centrifuge and allowed to stand ­undisturbed until the next sample time point.

• At each time point (5, 10, 20, 40, 90 min) the tube was centrifuged, supernatant sampled, and solids re-suspended as described.

Results

• All ASDD formulations showed significant initial supersaturation relative to the pure crystalline and amorphous compound 5. The rank order of C _max was as follows: HPMCAS-MF  >  CAP  >  CAT  >  HPMC  >  HPMCP  >  PVP  >  pure API (crystalline and amorphous).

• Subsequent precipitation of supersaturated compound 5 was seen for all ASDD formulations. The rank order of extent of supersaturation for the f­ormulations was as follows: HPMCAS-MF  >  CAP  >  CAT  >  HPMC  >  HPMCP  >  PVP.

• From this study, HPMCAS-MF was identified as the optimum polymer carrier in an ASDD system with compound 5 with respect to in vitro dissolution performance.

Method Capsule 3Spray Drying of AMG-517 with HPMCAS-MF

Based on the method reported by Kennedy et al. (2008).

Objective

• To prepare amorphous solid dispersions of AMG-517 in HPMCAS-MF at 15% and 50% drug loading.

• Equipment and Reagents

• AMG-517, micronized free base (API)

• HPMCAS-MF (AQOAT AS-MF, Shin-Etsu Chemical Company)

• Ethyl acetate (99.5% minimum)

• Büchi Mini Spray Dryer, Model B290

• Malvern Mastersizer 2000 equipped with a Hydro 2000 μP wet dispersion cell

• Phillips automated X-ray powder diffractometer, X’Pert PRO

• Modulated DSC, Q1000 by TA Instruments

• 40°C/75% RH stability chamber

• Method

• Feed preparation: HPMCAS-MF was dissolved in ethyl acetate at a concentration of 2% (w/w). AMG-517 was then dissolved in the polymer solution to a concentration of 0.353% or 2% (w/w) to produce drug:polymer ratios of 15:85 and 50:50.

• Spray-drying parameters:

  • System: Open cycle

  • Nozzle type: 48 KHz ultrasonic atomizing nozzle, 2 W power supply

  • Atomizing air: focusing nitrogen at 30 SLPM

  • Collection system: cyclone

  • Drying gas: nitrogen

  • Drying gas flow rate: 300 SLPM

  • Feed: ethyl acetate solution, 2.353% and 4% (w/w) solids

  • Feed rate: 0.75 mL/min

  • Inlet temperature: 75°C

  • Aspirator setting: Bypassed

• Morphology assessment: PXRD

• Determination of T _g’s: Modulated DSC

• Particle-size analysis: laser light diffraction

• Stability assessment  : accelerated storage at 40°C/75% RH

• In vivo performance  : single dose, oral administration in cynomolgus monkeys (n  =  6)

Results

• Powder yields for the 15% and 50% drug load AMG-517:HPMCAS-MF ­formulations were 80.5% and 50% respectively.

• Median particle size (volume based diamber d₅₀) was 34.75 and 40.7 μm for the 15% and 50% drug load ASDDs, respectively.

• At both drug loadings, the ASDD formulations were determined by PXRD to be amorphous and found by MDSC to be single-phase systems with T _g’s of 106 and 98°C for the low and high drug load formulations, respectively.

• The ASDD systems were found to remain PXRD amorphous after six months storage at 40°C/75% RH.

• The 15% drug load ASDD formulation in a capsule (with 5% SDS) yielded 163% greater exposure in monkeys as compared to micronized crystalline AMG-517 in aqueous suspension.

Method Capsule 4Fluidized Spray Drying of VX-950 (Telaprevir) with HPMCAS

Based on the method reported by Bittorf et al. (2010)

Objective

• Employ fluidized spray drying (FSD) to produce an ASDD product composed of VX-950 and HPMCAS suitable for direct compression, i.e., greater average particle size and bulk density versus traditional spray drying.

Equipment and Materials

• VX-950 (telaprevir)

• HPMCAS (Aqoat, Shin-Etsu)

• Dichloromethane

• 8,000 L stirred tank reactor

• Niro PSD-4 spray dryer (Drying capacity 1,250 kg/h) configured in FSD mode (closed cycle)

• Pressure nozzle (Spraying Systems MFP (Maximum Free Passage) SK Series SPRAYDRY® Nozzles Series variety, orifice 52 with core 27)

Method

• Feed preparation: Charge VX-950 (85% w/w) and HPMCAS (15% w/w) to the stirred tank reactor. Then add sufficient dichloromethane to achieve a solids content of 20% (w/w). Stir until a clear solution is obtained while keeping the reactor at 20°C.

• Fluidized Spray-drying parameters:

  • Drying gas: nitrogen, co-current

  • Feed: dichloromethane solution, 20% (w/w) solids

  • Feed rate: 151 kg/h

  • Feed pressure: 22 bar

  • Inlet temperature: 75  ±  3°C

  • Outlet temperature: 35  ±  5°C

  • $\Delta {\text{P}}_{\text{cyclone}}:10-{\text{ 12 mm H}}_{2}\text{O}$

  • Fines return position: middle

  • Fluid Bed 1 temperature set point: 40°C

  • Fluid Bed 2 temperature set point: 35°C

  • Fluid Bed 3 temperature set point: 30°C

Results

• Product properties:

  • Bulk density: 0.32 g/mL

  • Tap density: 0.41 g/mL

  • d10: 16.47 μm

  • d50: 60.03 μm

  • d90: 151.05 μm

  • Span 2.24

  • Distribution: unimodal

• Product obtained was suitable for direct tablet compression.

Method Capsule 5Spray Congealing of Vitamin E

Objective

• Employ spray congealing to produce amorphous Vitamin E

Equipment and Materials

• Vitamin E

• Büchi Mini Spray Dryer, Model B290 equipped with spray congealing features

Method

• Feed preparation: Charge Vitamin E in a thermo regulated vessel and heat up to 60°C (keep temperature above at least 10°C).

• Spray congealing:

  • Drying gas: nitrogen, co-current

  • Feed: Vitamin E melted

  • System: Open cycle

  • Nozzle type: two-fluid nozzle

  • Collection system: cyclone

  • Drying gas: nitrogen

  • Drying gas flow rate: fan at 100%

  • Inlet temperature: −5°C

• Morphology assessment: SEM

• Particle-size analysis: laser light diffraction

Results

• Powder yields 80%.

• Median particle size (volume based diamber d₅₀) was 40 μm.

• Smooth spherical particles

Method Capsule 6Micro-encapsulation of Itraconazole

Objective

• Micro-encapsulation of itraconazole by spray drying

• Equipment and Materials

• Milled itraconazole (Dv90  <  10μ)

• Gelatin

• Sucrose

• Deionized water

• Niro Mobile Minor

Method

• Feed preparation: a solution of Gelatin was prepared in hot water (60°C) at a concentration of 2% w/w. Sucrose was added (Sucrose:Gelatin 4:1). After sucrose dissolution itraconazole (10% of total solids) was added.

• Spray drying:

  • Drying gas: nitrogen, co-current

  • Feed: Suspension of itraconazole

  • System: Closed cycle

  • Nozzle type: two-fluid nozzle

  • Collection system: cyclone

  • Drying gas: nitrogen

  • Drying gas flow rate: 80 kg/h

  • Atomization gas flow rate: 2.6 kg/H

  • Feed flow rate: 1.3 kg/h

  • Inlet temperature: 150°C

  • Outlet temperature: 80°C

• Morphology assessment: SEM

• Particle-size analysis: laser light diffraction

Results

• Powder yield: 85%.

• Median particle size (volume based diamber d₅₀) was 25 μm.

• Particle morphology: corrugated spheres