002/2011

Spray drying of polylactic acid (PLA) with the Nano Spray Dryer B-90

Application Note 002/2011 Version A, Copyright © 2011 BÜCHI Labortechnik AG 2/7

1 Introduction

Applications of PLAApplications of PLAApplications of PLAApplications of PLA

PLA (polylactic acid) is a colourless, glossy and stiff thermoplastic polymer that has received great atten-tion from the biomedical field and the packaging area over the last few years, as a biocompatible, non tissue reactive and biodegradable material [1, 2]. PLA belongs to the family of aliphatic polyesters (Figure 1) and is derived for example from corn starch, tapioca or sugarcanes. PLA is used especially for medical applications, such as for sutures, stents, dialysis media, drug delivery devices, tissue repairing and engineering as well as equipment [2, 3].

Types of PLATypes of PLATypes of PLATypes of PLA

Mechanical and degradation properties of PLA de-pend mainly on molecular weight, crystallinity and the insertion of possible copolymers [4]. Due to the chiral nature of lactic acid, several distinct forms of polylactic acid exist: poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA) and the hybrid form poly(L-lactide-co-D,L-lactide) (PLDLLA) [4, 5].

For this Application Note the Resomer type R 202 H formulation was used, a biodegradable polymer made on the basis of DL-lactic acid and a registered trade-mark of Evonik Röhm GmbH (former Boehringer Ingelheim). It is a white, amorphous, nearly odourless powder with neutral taste and has a molecular weight of 10-18 kDa (inherent viscosity of 0.16 to 0.24 dL/g measured at 0.1% in CHCl3, 25°C) [6].

PLA was selected because of its favourable glass transition temperature, which is at around 44-48°C [6]. The glass transition temperature is an important pa-rameter of the polymer, defined as the temperature at which an amorphous material transits from a hard and relatively brittle state into a molten or rubber state. Spray dried particles are typically amorphous due to the fast evaporation times and due to the lack of abil-ity to form crystalline structures [7].

The solventThe solventThe solventThe solventssss

Before creating particles by spray drying, the PLA has to be dissolved. Dichloromethane (DCM) was selected as dissolvent due to its high solvation capacity for PLA [8], its low boiling point of 40°C and because it is con-sidered to be the least toxic of the halogenated sol-vents [9]. Additionally, ethanol (EtOH) which is miscible with water and many organic solvents was used as a versatile solvent. A mixture of DCM and ethanol in a

ratio of 70:30 (v/v) was previously determined as the best solvent mixture for spray drying PLA [10].

Use of spray dryingUse of spray dryingUse of spray dryingUse of spray drying

In pharmaceutical applications spray drying is often used for drying amorphous drugs [11, 12], to generate mucoadhesive microspheres or to design novel con-trolled drug release systems [13]. The investigation on the formation of PLA micro-spheres by spray drying is justified by interesting re-sults presented in relevant literature [14-17]. A variety of PLA R 202 H solutions were spray dried, leading to spherical microspheres resulting in a very specific surface area [14-17].

Nano Spray Dryer BNano Spray Dryer BNano Spray Dryer BNano Spray Dryer B----90909090

The Nano Spray Dryer B-90 utilizes three main tech-nologies: • A piezoelectric

nozzle for spray generation

• A laminar flow of drying gas for gentle dryingAn electrostatic particle collector for submicron- and nano particle collection pro-viding high yields

Its main advantages are: • a high separation efficiency of up to 99%,a simple

particle collection, andintegrated outlet gases filter helping to protect users and the environment.

Droplets are generated by a piezoelectric driven ac-tuator, vibrating a thin, perforated, stainless steel membrane in a small spray cap (see Figure 2). The membrane (spray mesh) features an array of precise, micron sized holes (4.0, 5.5 or 7.0 µm). The actuator moves at an ultrasonic frequency, caus-ing the membrane to vibrate, thereby ejecting millions of precisely sized droplets every second with a very narrow droplet size distribution [18].

GoalsGoalsGoalsGoals

The goal of this Application Note is to test the feasibil-ity of the Nano Spray Dryer B-90 to spray dry PLA solutions in DCM and ethanol.

The spray cap size was varied during the experiments in order to see its influence on particle size and mor-phology. The highest sprayable concentration and optimal inlet temperature were evaluated in order to receive high yields.

Figure 1: Structure of PLA

Figure 2: Principle of droplet genera-

tion by piezoelectric driven mem-

brane vibration

Application Note 002/2011 Version A, Copyright © 2011 BÜCHI Labortechnik AG 3/7

2 Methods

EquipmentEquipmentEquipmentEquipment

• Nano Spray Dryer B-90 with Dehumidifier B-296 and aspirator in open mode (BUCHI Labortechnik AG)

• Analytical balance (accuracy +/- 0.1 mg, New Classic MF, Mettler Toledo)

• Scanning electron microscope (Tabletop TM-1000, Hitachi)

• Moisture Analyzer B-302 (BUCHI Labortechnik AG)

• Magnetic stirrer (MR Mini, BUCHI Labortechnik AG)

• 50 ml glass beaker (Duran) • Magnetic stir bars (made of PTFE, Semadeni)

Chemicals and MaterialsChemicals and MaterialsChemicals and MaterialsChemicals and Materials

• Resomer R 202 H (poly D,L-lactide, mat no. 60640658, lot no. 1044907, Boehringer Ingelheim Pharma Gmbh & Co. KG)

• Dichloromethane (mat. no., 34856, lot no. 665P6MMV, Sigma Aldrich)

• Ethanol 99% (Brenntag AG)

Sample preparationSample preparationSample preparationSample preparation

Samples with a concentration of 1.0 % (w/w) were prepared as starting solutions. 1.0 g of PLA was weighted and mixed with 100 g of a 30:70 v% etha-nol/dichloromethane solvent mixture. For some ex-periments the PLA solution was further diluted. The solution was stirred for about 10 minutes until a clear solution was received. For every experiment 50 g of solution were transferred into a 50 ml glass beaker including a magnetic stir bar. The solution was stirred continuously during the spray drying run. The beaker was sealed with Parafilm foil to prevent the dichloro-methane from evaporating during the drying process.

ExperimentExperimentExperimentExperimentalalalal procedure procedure procedure procedure

The selected process parameters have an important influence on the success of the spray drying process. The parameters were kept as stable as possible dur-ing the experiments in order to obtain reproducible results. Each combination was tested in triplicate. The here presented results are the mean values of these three runs.

1. Compressed air was used as drying gas.

2. The drying gas flow rate was of 140 L/min result-ing an the inside pressure of 60 mbar. The laminar drying gas flow and piezoelectric atomization lead to a gentle evaporation.

3. The inlet temperature was varied between 20, 25, 30, 35 and 40°C. Depending on the selected spray cap size the outlet temperature and the spray head temperature varied accordingly.

4. The feed rate of the Nano Spray Dryer B-90 de-pends on the size of the spray membrane applied. For the experiments a spray rate of 60% was used. The viscosity of the solution is a further fac-tor that influences the sample throughput.

5. After reaching the set inlet temperature, a solution with 30:70 ethanol to dichloromethane ratio was sprayed in order to stabilize the outlet tempera-ture. Then the sample was sprayed. In every run 50g of the sample were sprayed.

6. The dried particles were collected in an electro-static particle collector. Before collecting the par-ticles manually with a rubber spatula, the collector cylinder was left to cool down to room tempera-ture. The resulting powder was weighted and filled into a vial.

7. The relative yield (%) was calculated by dividing the weight of the collected powder by the amount of sample sprayed, then multiplied by 100.

8. The morphology and particle size of the spray dried PLA powder was studied through a scan-ning electron microscope (SEM). The moisture content was determined by an infrared Moisture Analyzer B-302.

3 Results and discussion

The influence of sample concentration (Table 1, in blue), inlet temperature (Table 1, in yellow) and spray cap mesh size (Table 1, in green) on particle size and morphology, yield and residual solvent content was tested during the experiments.

Influence of total solution coInfluence of total solution coInfluence of total solution coInfluence of total solution connnncentration on centration on centration on centration on particle sizeparticle sizeparticle sizeparticle size

Two different concentrations (0.2% and 1% of the total solids amount) were tested with a 7.0 µm spray cap. The experiments were performed at 17°C to 20°C inlet temperature using the Dehumidifier B-296 to dehumidify and cool down the inlet drying gas.

The influence on particle size and distribution detected was minimal. Compared to the higher concentrations, the lower concentrated samples showed a clearly different morphology (shrivelled and transparent spheres). The results are displayed in Figure 2.

Application Note 002/2011 Version A, Copyright © 2011 BÜCHI Labortechnik AG 4/7

Table 1: Spray drying parameters and results (constant parameters: 70:30 DCM to EtOH, 50g of solution, air as drying gas, 140 L/min drying gas flow, 60% spray feed rate, 60 mbar inside pressure, 47 Hz aspirator speed, n.a. means not measured)

Figure 2: SEM pictures of the experiments with different total solution concentrations (0.2% on the left and 1% on the right), 7.0 µm

Influence of the temperatureInfluence of the temperatureInfluence of the temperatureInfluence of the temperature on the part on the part on the part on the parti-i-i-i-cle size and residual solvent contentcle size and residual solvent contentcle size and residual solvent contentcle size and residual solvent content

The influence of the inlet temperature on formed parti-cles. was tested at 25°C, 30°C, 35°C and 40°C A spray cap size of 7.0 µm and a concentration of 1% of solids were used for the experiment.

A marginal reduction of residual solvent content from 0.15% (at 20°C, 25°C and 30°C) up to 0.10% (at 30° and 35°C) was observed.

An influence of inlet temperature on particle size and distribution could not be detected. However, a clear linear correlation between the inlet and the outlet tem-perature was detected (Figure 3). With an increasing inlet temperature the relative yield also increased.

T out = 0.44 T in + 14.4

10

15

20

25

30

35

40

10 20 30 40 50

Inlet temperature [°C]

Ou

tle

t te

mp

era

ture

[°C

]

Figure 3: Correlation between inlet and outlet drying gas tempera-

ture in the Nano Spray Dryer B-90 spraying DCM solutions.

Experiment NrExperiment NrExperiment NrExperiment Nr 1111 2222 3333 4444 5555 6666 7777 8888

Spray head sizeSpray head sizeSpray head sizeSpray head size (µm)(µm)(µm)(µm) 7.0 7.0 7.0 7.0 7.0 7.0 5.55.55.55.5 4.0 Solid Solid Solid Solid concentratconcentratconcentratconcentratiiiionononon (w%)(w%)(w%)(w%) 0000.2.2.2.2 1.01.01.01.0 1.0 1.0 1.0 1.0 1.0 1.0

T inlet (°C)T inlet (°C)T inlet (°C)T inlet (°C) 17 20 25252525 30303030 35353535 40404040 35 35

AAAAspirator speedspirator speedspirator speedspirator speed (Hz) (Hz) (Hz) (Hz) 47 47 47 47 47 47 47 47

T outlet (°C)T outlet (°C)T outlet (°C)T outlet (°C) 21 24 26 28 30 32 30 30

T spray head (°C)T spray head (°C)T spray head (°C)T spray head (°C) 28 31 33 42 46 50 42 44

Spray drying timeSpray drying timeSpray drying timeSpray drying time (min) (min) (min) (min) 22 25 30 28 28 28 95 155

YYYYield (ield (ield (ield (mmmmg)g)g)g) n.a. 227 285 310 418 410 444 370

Yield (%)Yield (%)Yield (%)Yield (%) n.a. 45 57 62 83 82 88 74

Particle size (µm)Particle size (µm)Particle size (µm)Particle size (µm) 1 to 10 0.8 to 9 0.8 to 13 0.7 to 13 0.8 to 12 0.8 to 15 0.7 to 7 0.4 to 4

Particle morpholParticle morpholParticle morpholParticle morpholoooogygygygy spherical,

transparent spherical spherical spherical spherical spherical spherical spherical

RRRResidual esidual esidual esidual ssssolvent olvent olvent olvent

ccccoooonnnntenttenttenttent (w%) (w%) (w%) (w%) 0.15 0.14 0.14 0.14 0.10 0.10 0.10 0.10

Application Note 002/2011 Version A, Copyright © 2011 BÜCHI Labortechnik AG 5/7

25°C 30°C

35°C 40°C

Table 1: SEM pictures of experiments with different inlet temperatures

Influence of the spray cap size on Influence of the spray cap size on Influence of the spray cap size on Influence of the spray cap size on the the the the particle size and morphoparticle size and morphoparticle size and morphoparticle size and morphollllogyogyogyogy

The influence of different spray drying membranes (7.0, 5.5 and 4.0 µm) on the particle size and morphology was evaluated during the experiments.

Figure 5 (top) shows homogeneous spherical particles of sizes ranging from 1 to 10 µm. With the use of the 5.5 µm spray cap (middle) most of the particles were of a size ranging between 0.7 to 7 µm. The mean size of particles sprayed with the 4.0 µm spray cap (bottom) lies between 0.4 and 4 µm. The conducted study demonstrates that: • All the particles observed were spherical. • A bigger membrane size leads to a bigger parti-

cle and wider size distribution. • The yield was quite high, typically between 50%

and 88% for 50 mg of sample sprayed.

0

20

40

60

80

100

120

140

4 µm 5.5 µm 7 µm

Spray cap size

Fe

ed

ra

te [

g/h

]

Figure 4: Feed rate of DCM samples in correlation to spray cap size

Application Note 002/2011 Version A, Copyright © 2011 BÜCHI Labortechnik AG 6/7

Figure 5: SEM pictures of PLA particles prepared with different spray

cap sizes 4.0 µm (top), 5.5 µm (middle) and 7.0 µm (bottom).

ConclusionsConclusionsConclusionsConclusions

Microspheres of different mixing ratios of PLA can be easily prepared by spray drying. The results of this study suggest that: 1. the selection of the spray cap size affects the parti-

cle size and its distribution; 2. the total solution concentration can control the

amount of PLA in the final particles; 3. the control of processing variables, especially inlet

temperature and feed rate, allows for the production of micro particles of low moisture content with high yields of up to 88%.

ReferencesReferencesReferencesReferences

[1] Garlotta D. et al. (2002): A Literature review of Poly (Lactic Acid), Journal of Polymers and the Environ-ment, Vol. 9, Nr. 2.

[2] Kulkarni R. K. et al. (1966): Polylactic acid for surgi-cal implants, Technical rept., Army medical biome-chanical research Lab, Washington DC, AD0636716 http://oai.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=AD0636716.

[3] Trimaille T. et al. (2006): Poly(hexyl-substituted lac-tides): Novel injectable hydrophobic drug delivery system, Wiley InterScience, DOI: 10.1002/jbm.a.30888.

[4] Resomer Brochure (March 2011, V 1.0): Evonik Röhm GmbH, Darmstadt, Germany, http://resomer.evonik.com/product/resomer/en/downloads/brochures/pages/default.aspx.

[5] Arpagaus C. and Schafroth N. (2007): Spray Dried Biodegradable Polymers as target material for Con-trolled Drug Delivery, best@buchi no. 46, BÜCHI Labortechnik AG, Flawil, Switzerland, http://www.buchi.com/best-buchi.491.0.html.

[6] Supplier of Resomer R 202 H: Sigma-Aldrich (2011), http://www.sigmaaldrich.com/materials-science/polymer-science/resomer.html

[7] Schöttle I. A. (2006): Spray Drying of PLA and PLGA microparticles for controlled release of pulmonary dosage forms, Dissertation, University Mainz.

[8] Youan B.C. (2007): Microencapsulation of Superox-ide Dismutase into Biodegradable Microparticles by Spray-Drying. Drug Delivery, Vol. 11, p. 209-214.

[9] Blanco M.D. (2005): 5-Fluorouracil-loaded micro-spheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: Characteri-zation and drug release. Journal of Microencapsulation, Vol. 22, No. 6, p. 671-682.

Application Note 002/2011 Version A, Copyright © 2011 BÜCHI Labortechnik AG 7/7

[10] Schafroth N., Arpagaus C., Jadhav U. Y., Makne S., Douroumis D. (2010), Nano and Microparticle Engi-neering of Water Insoluble Drugs Using a Novel Spray-Drying Process. Colloids and Surfaces B: Biointerfaces, doi:10.1016/j.colsurfb.2011.09.038

[11] Corrigan O. I. et al. (1983): Physicochemical proper-ties of Spray Dried drugs: phenobarbitone and hy-droflumethiazide, Drug Development and Industrial Pharmacy, Vol. 9, p. 1.

[12] Corrigan O. I. et al. (1984): Amorphous spray dried hydroflumethiazide-polyvinylpyrrolidone systems: physiochemical properties, Journal of Pharmacy and Pharmacology, Vol. 36, p. 217.

[13] Palmieri G. F. et al. (2001): Spray Drying as a Method for Microparticulate Controlled Release Sys-tems Preparation: Advantages and Limits. I. Water-Soluble Drugs, Drug Development and Industrial Pharmacy, Vol. 27 (3), p. 195-196.

[14] Zebunnissa R. et al. (2010): Investigation of interac-tion of biodegradable micro- and nanoparticulate drug delivery systems with platelets, Journal of Pharmacy and Pharmacology, Vol. 63, p. 26-32.

[15] Farahidah M. et al. (2008): Engineering Biodegrad-able Polyester Particles With Specific Drug Target-ing and Drug Release Properties, Wiley Inter-Science, DOI: 10.1002/jps.21082.

[16] In-Sook K. et al. (2005): Physicochemical charac-terization of poly(L-lactic acid) and poly(D,L-lactide-co-glycolide) nanoparticles with polyethylenimine as gene delivery carrier, International Journal of Phar-maceutics, Vol. 298, p. 255-262.

[17] Elke W. et al. (1999): Microencapsulation of DNA using poly(DL-lactide-co-glycolide): stability issues and release characteristics, Journal of Controlled Release, Vol. 61, Nr 3, p. 361-374.

[18] Nano Spray Dryer B-90 (2009): Operation Manual, BÜCHI Labortechnik AG, Flawil, Switzerland.