Fast and Environmentally Friendly Microfluidic Technique for the

Dec 11, 2017 - In this paper, we report on the development of a novel technique for the fabrication of polymer microspheres where the polymer is disso...
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Fast and Environmentally Friendly Microfluidic Technique for the Fabrication of Polymer Microspheres Yanlin Zhang, Robert W. Cattrall, and Spas D. Kolev* School of Chemistry, The University of Melbourne, Victoria 3010, Australia S Supporting Information *

ABSTRACT: This paper reports on a novel microfluidic technique for the fabrication of microspheres of synthetic polymers including poly(vinyl chloride) (PVC), poly(vinylidene fluoride-co-hexafluoropropylene) (PVDFHFP), poly(lactic acid) (PLA), and polystyrene (PS). The polymers are dissolved in tetrahydrofuran (THF) and the method is based on the diminished solubility of THF in a 20% (w/v) NaCl solution which allows the formation of droplets of the polymer solution. These polymer solution droplets are generated in a microfluidic system and their desolvation is accomplished within seconds by allowing the droplets to rise by buoyancy through a NaCl solution with a concentration lower than 15%. The size and morphology of the resultant polymer microspheres have been investigated by optical and scanning electron microscopy. Apart from the elimination of the use of highly toxic solvents as in conventional methods for manufacturing of polymer microspheres, the newly developed technique has the advantages of providing faster desolvation of the polymer solution droplets and a higher yield of microspheres compared to emulsification-based techniques.

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INTRODUCTION Microspheres, also known as microbeads, have found wide applications in different areas such as drug delivery,1−6 biotechnology,7,8 catalysis,9 coatings,10 chemical sensing,11 and bead injection analysis (BIA).12−14 Microspheres of a synthetic polymer can be prepared either by polymerization of its monomers15 or from a solution of the polymer using various physical fabrication techniques.16 Compared to the polymerization approaches which are only applicable to some polymers, the physical fabrication techniques using polymer solutions can be applied to any polymer as long as a suitable solvent is available to dissolve the polymer. Such approaches have attracted wide interest because they utilize fewer chemicals and involve a simple 2-stage operational procedure. The first stage results in the generation of microdroplets of the polymer solution which is followed by the second desolvation stage in which solid microspheres are obtained. A number of protocols have been reported for the fabrication of microspheres by using different droplet generation approaches, such as stirring,17 static mixing,18 extrusion,19,20 and dripping.21,22 Droplet desolvation is usually performed using solvent evaporation23,24 or solvent extraction/evaporation.25 All these techniques are based on emulsification in which the polymer is first dissolved in an organic solvent such as dichloromethane,18,19 chloroform,20,26 acetonitrile,27 or toluene,28 and the solution is then dispersed in the form of microdroplets in a continuous phase, usually an aqueous surfactant solution. These approaches exhibit a number of disadvantages, i.e., (i) a key limitation of these techniques is the difficulty in controlling the size of the microspheres, and this normally gives rise to polydispersity,22,28,29 which causes unsatisfactory © XXXX American Chemical Society

performance in applications (e.g., nonuniform rate of release of the loaded in the microspheres therapeutics);30 (ii) the desolvation of the polymer droplets is generally a slow process, typically taking hours for the removal of the solvent unless reduced pressure is applied;31,32 (iii) recovery of the solvents is not economical and they are normally released into the atmosphere during the microdroplet desolvation process, which is of considerable environmental and health concern; (iv) complete removal of the solvent from the microspheres is difficult to achieve, thus making them undesirable for medical applications (e.g., drug delivery33); and (v) the most commonly used stirring emulsification approach often yields only 50% to 80% of microspheres due to aggregation and agglomeration and therefore a significant fraction of the raw materials including the polymer and the additives is wasted.26,34,35 A spray-drying approach eliminates some of the above-mentioned problems. However, the high temperature needed for the evaporation of the organic solvent may cause degradation of some thermosensitive components such as proteins and peptides.36 Microfluidic techniques have provided novel approaches for the fabrication of microspheres.29,31,32,37−44 These techniques have several advantages including the use of simple and robust devices and the fabrication of microspheres with a low degree of polydispersity. However, most of the reported microfluidic approaches still involve an emulsification step and therefore suffer from most of the disadvantages of the batch-wise emulsification techniques. In addition, the microfluidic devices Received: October 13, 2017 Revised: November 28, 2017

A

DOI: 10.1021/acs.langmuir.7b03574 Langmuir XXXX, XXX, XXX−XXX

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Langmuir reported in the literature usually have very low productivity unless a multichannel system is used.45 One microfluidic system involved the use of ethyl acetate as the solvent for polylactide microspheres preparation with poly(ethylene glycol)-b-polylactide as the surfactant in which desolvation was accomplished quickly via solvent diffusion due to the high solubility of ethyl acetate in water.46 However, the productivity of this system was very low. In this paper, we report on the development of a novel technique for the fabrication of polymer microspheres where the polymer is dissolved in tetrahydrofuran (THF), which is a relatively nontoxic and water-soluble organic solvent,47 and the droplet generation and subsequent desolvation are performed using aqueous NaCl solutions in the absence of any surfactants. This technique employs a simple and robust microfluidic device coupled to two syringe pumps and a desolvation column for the fabrication of the microspheres. Poly(vinyl chloride) (PVC), poly(vinylidene fluoride-co-hexafluoropropylene) (PVDFHFP), poly(lactic acid) (PLA), and polystyrene (PS) were used as model polymers in this study.

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Figure 1. Schematic diagram of the microsphere fabrication device (P1 and P2: syringe pumps, V1 and V2: three-way solenoid valves, 1: desolvation glass column, 2: rubber stopper, 3: T-junction segmenter, a, b, and c: delivery PTFE tubing for the polymer solution, the 20% NaCl solution and the segmented solutions, respectively). desolvation of the microspheres their density exceeded that of the aqueous solution and resulted in the microspheres descending to the bottom of the desolvation column. After separation from the saline solution by filtration with subsequent air-drying overnight for the removal of the moisture on the microspheres’ surface, the diameter of the microspheres was determined as the average of 200 microspheres measured with the software of an Olympus CH-2 optical microscope (Selby Anax, Australia). The polydispersity index (PDI) of the microspheres was calculated as the relative standard deviation of their diameters. The morphology of the microspheres was investigated with a scanning electron microscope (SEM) (Nova Nanolab 200, FEI, USA). In the latter case this was done after carbon coating with a sputter coater (K950X EMITECH, UK). All the fabrication experiments, with the exception of those used to study the temperature effect, were carried out at 24 ± 1 °C.

EXPERIMENTAL SECTION

Solutions. Individual solutions of the model polymers PVC (Mw 43 kDa, 62 kDa, 80 kDa, and 233 kDa), PVDF-HFP (Mw 400 kDa), PLA (Mw 260 kDa), and PS (Mw 192 kDa), all purchased from SigmaAldrich, were prepared by dissolving them in THF (Sigma-Aldrich). Optimization of the parameters of the microfluidic system was carried out using THF solutions of PVC (Mw 43 kDa) which contained 0.005% (w/v) methyl red (May and Baker) to allow better visibility of the microspheres in the fabrication process. The complete dissolution of PVC and PVDF-HFP in THF required 4 h of stirring at room temperature and 24 h of stirring at 40 °C, respectively. It should be noted that all concentrations of polymers in THF and NaCl in aqueous solutions in the subsequent discussions are expressed in w/v percentage. Determination of the Solubility of THF in NaCl Solutions. The solubility of THF in aqueous NaCl solutions and the rate of desolvation of the polymer solution droplets are important polymer microsphere fabrication parameters. Therefore, the solubility of THF in aqueous NaCl solutions of various concentrations was determined by mixing 5 mL of the NaCl solution with 5 mL of THF containing 200 mg L−1 of methyl red in a 10 mL capped graduated polypropylene test tube for 20 s and measuring the final volumes of the two phases after their separation. The percentage of THF dissolved in the aqueous phase was calculated as the decrease in the volume of the THF phase after vortex mixing and phase separation divided by the initial volume of the aqueous phase (5 mL). Microsphere Fabrication Device and Operational Procedure. The microsphere fabrication device is shown schematically in Figure 1. Two syringe pumps (NE-1000, New Era Pump Systems Inc., USA), one of which (P1) was equipped with a 5 mL gastight glass syringe and the other (P2) with a 25 mL disposable plastic syringe, were used for the delivery of the polymer solution and the 20% NaCl aqueous solution, respectively, through polytetrafluoroethylene (PTFE) tubing with 0.5 mm inner diameter (i.d.) to the device’s T-junction segmenter with bore diameter of 0.5 mm. At the segmenter, the polymer stream was segmented by the 20% NaCl aqueous stream to form polymer solution droplets which were subsequently delivered through tubing c to the vertically positioned desolvation glass column (4 cm i.d. and 40 cm height) of the device containing 5% NaCl aqueous solution. The volume of the 5% NaCl solution (150 to 250 mL) was determined by the desired microsphere size. The polymer solution droplets initially rose upward as a result of their density being lower than that of the 5% NaCl solution in the desolvation column. This process was accompanied by desolvation which resulted in the formation of solid polymer microspheres with increasing density. After complete

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RESULTS AND DISCUSSION Polymer Solution Droplet Formation in the Microfluidic System and Desolvation. THF is miscible with deionized water, but its solubility in water diminishes rapidly at increasing concentrations of NaCl (Figure 2). When the

Figure 2. Solubility of THF in aqueous NaCl solution. Error bars are not shown because the standard deviations for all experimental points were under 0.1.

concentration of NaCl in the aqueous phase was 5% or higher, a clear interface was observed between the organic and the aqueous phases after phase separation, although THF was partially dissolved in the aqueous phase. In a 20% NaCl solution, the solubility of THF was found to be close to 4% (Figure 2), and under such conditions, the polymers did not precipitate in contact with the aqueous phase during the droplet formation in the segmenter, and transportation along the delivery tubing c in the microfluidic system (Figure 1). At B

DOI: 10.1021/acs.langmuir.7b03574 Langmuir XXXX, XXX, XXX−XXX

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Langmuir lower than 20% NaCl concentration, polymer−THF droplets were found to desolvate quickly and solvent-free polymer was precipitated in the flowthrough sections of the microfluidic fabrication device mentioned above and this often caused their blockage. Therefore, it was decided to use a 20% NaCl solution as the aqueous stream for the formation of polymer solution droplets which were subsequently desolvated in the solution of lower NaCl concentration (5%) located in the desolvation column (Figure 1). A NaCl concentration in the aqueous segments of over 20% did not make a noticeable difference regarding the characteristics of the microspheres. The influence of the following design and operational parameters of the fabrication device affecting the characteristics of the polymer microspheres was studied: the hydrophilicity of the segmenter and delivery tubing c; the composition of the polymer solution and aqueous saline solution in the desolvation column; the flow rates of the organic and aqueous streams propelled through delivery tubing a and b, respectively. A study of the effect of these parameters on the size and surface morphology of microspheres made of PVC (Mw 43 kDa) is described in the subsequent sections. Hydrophilicity of the Segmenter and Tubing c. It was established that the inner walls of the segmenter and tubing c (Figure 1) had to be hydrophilic to allow the formation of monodisperse droplets of the polymer solution and to prevent adherence of the polymer solution to the internal tubing walls. Because of the hydrophobic nature of the fluoropolymers used for manufacturing the segmenter and tubing c, the polymer solution formed a thin layer on the internal walls of the microfluidic flowthrough sections of the fabrication device which did not allow the formation of monodisperse droplets of the polymer solution. Therefore, it was necessary to make these internal surfaces hydrophilic. There are different techniques to achieve such a surface property conversion including plasma treatment48 and hydrophilic coating.49 In the present research, the internal surfaces were pretreated with a KMnO4 solution (1% KMnO4 in 0.1 M H2SO4) to oxidize any organic substances adsorbed on these surfaces and to coat them with a thin layer of MnO2. As a result of this treatment, the polymer solution did not adhere on the surface any more, implying that the surfaces had become less hydrophobic and the formation and delivery of the desired monodisperse droplets of the polymer solution were achieved. Effect of the Polymer Solution Concentration. The effect of the polymer solution concentration on the average size, shape, and morphology of the resulting polymeric microspheres was studied. As shown in Figure 3, the size of the microspheres increased with increasing PVC concentration in THF. The average diameters and PDI values of the microspheres fabricated with 1%, 2%, 3%, 4%, and 5% PVC solutions were 82.3 μm and 4.0%, 100.5 μm and 5.3%, 156.3 μm and 3.6%, 167.4 μm and 6.1%, and 174.3 μm and 3.9%, respectively. The corresponding histograms are shown in Figure 4. The increase in the average microsphere diameter with increasing PVC concentration in the polymer solution could be explained by the fact that the size of the droplets generated in the microfluidic section of the fabrication device was practically independent of the polymer concentration. This resulted in droplets obtained from more concentrated PVC solutions containing larger amounts of PVC and therefore producing larger microspheres. These results indicated that altering the polymer concentration allowed straightforward manipulation of

Figure 3. Effect of the PVC solution concentration on the average diameter of the PVC microspheres. Experimental conditions: polymer solution flow rate, 2 μL s−1; 20% NaCl aqueous solution flow rate, 14 μL s−1; tubing c i.d. and length, 0.5 mm and 10 cm; NaCl concentration for desolvation, 5%. Error bars are ± standard deviation (SD).

Figure 4. Histograms of the PVC microspheres for different PVC solution concentrations (● 1%, ○ 2%, ▲ 3%, ⧫ 4%, and ■ 5%). Experimental conditions as in Figure 3.

the average diameter of the microspheres depending on the intended application. The use of PVC solutions with polymer concentrations higher than 5% resulted in coalescence of the polymer solution droplets inside and outside tubing c (Figure 1) due to the higher viscosity of the polymer solution. In addition, the polymer microspheres produced under such conditions had irregular shapes. Figure 5a−e illustrates how the shape of the PVC microspheres was affected by the polymer solution concentration. Surface morphology inspection using SEM revealed that smooth microsphere surfaces were obtained (e.g., Figure 5f and Figure S1, Supporting Information). Influence of the Flow Rates. The flow rates of the polymer solution and the 20% NaCl solution delivered by syringe pumps P1 and P2 (Figure 1), respectively, had a significant effect on the average diameter and dispersity of the microspheres. The effect of the ratio of the flow rate of the 20% NaCl solution to the flow rate of the polymer solution, which was kept at 1, 2, or 3 μL s−1, was examined in the range from 3:1 to 7:1, and it was observed that a ratio lower than 6:1 resulted in coalescence of the polymer solution droplets in tubing c due to the proximity of adjacent droplets. At a flow rate ratio of 7:1 no droplet coalescence was observed and this ratio was applied in the subsequent experiments where the polymer C

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Figure 5. Optical images illustrating the effect of the PVC solution concentration ((a) 1%, (b) 2%, (c) 3%, (d) 4%, (e) 5%) on the size of the corresponding polymer microspheres. An SEM image (f) of a PVC microsphere obtained with a 2% PVC solution. Experimental conditions as in Figure 3. The microspheres in the optical images were colored using methyl red. All scale bars are equal to 200 μm except for (f) which is 50 μm.

Figure 7. Optical images of microspheres obtained with different NaCl concentrations of the desolvation solution ((a) 2%, (b) 3%, (c) 4%, (d) 5%, (e) 10%). Remaining experimental conditions as in Figure 6 except for the PVC solution flow rate of 3 μL s−1. All scale bars are equal to 200 μm.

surfaces (Figure S2, Supporting Information). By increasing the NaCl concentration, the microspheres became more spherical. Therefore, it was concluded that a minimum NaCl concentration of 5% was needed to obtain acceptable sphericity. The height of the NaCl solution column was another important parameter affecting the desolvation of the polymer solution droplets. Without sufficient height, complete desolvation of the droplets could not be accomplished before they reached the solution surface where incompletely desolvated droplets formed polymer flakes and/or agglomerates. Experiments showed that in the case of 5% NaCl in the desolvation solution, a solution column height of 18 cm (226 mL for a column of 4 cm i.d.) was necessary for complete desolvation of the PVC solution droplets containing initially from 1% to 5% PVC. The desolvation time under these conditions was approximately 20 s. For smaller-size microspheres a lower solution column height was adequate. For instance, for the fabrication of 33 μm microspheres with tubing c of 0.25 mm i.d. and a 2% PVC solution, a total desolvation column height of 10 cm was sufficient and the desolvation time in this case was about 2 s because the droplets were completely desolvated within the first 1 cm of their rise toward the surface of the desolvation solution. It is worth mentioning that when a higher NaCl concentration was used for desolvation, the column height needed to be increased accordingly due to the higher buoyancy exerted by the saline water with a higher density and the higher rate of rising of the droplets in the desolvation column. For instance, an increase in the column height of approximately 5 cm was needed for complete desolvation of the polymer solution droplets when the NaCl concentration was increased to 10%. Effect of the Tubing c Diameter on the Microsphere Average Diameter and Dispersity. The effect of the tubing c diameter (Figure 1) on the average diameter of the microspheres and their dispersity was studied by using tubing with 0.35, 0.50, and 0.80 mm internal diameter. As shown in Figure 8, the microsphere diameter increased with increasing the tubing internal diameter. The corresponding average microsphere diameters for the three tubing internal diameters studied were 79.6, 156.3, and 262 μm, respectively, indicating that the tubing diameter is another parameter that could be used to manipulate the microsphere size. Effect of Polymer Molar Mass on Surface Morphology. The effect of the PVC molar mass on the morphology of the microspheres was examined by using PVC with different molar masses. The optical microscopic images (Figure 9) and

solution flow rate was varied. Figure 6 illustrates the significance of the polymer solution flow rate on the average

Figure 6. Effect of the polymer solution flow rate (● 1 μL s−1, ◯ 2 μL s−1, ▲ 3 μL s−1, ⧫ 4 μL s−1, and ■ 5 μL s−1) on the size and distribution of the PVC microspheres. Experimental conditions: tubing c i.d. and length, 0.5 mm and 10 cm; flow rate ratio, 7:1; PVC concentration, 3%.

diameter and the dispersity of PVC microspheres at a 7:1 flow rate ratio. Compared to 2 or 3 μL s−1, a flow rate of 1 μL s−1 of the polymer solution resulted in the formation of relatively large microspheres. This could be caused by the lower frequency of segmentation of the polymer solution stream by the 20% NaCl solution stream due to its low shear force at a low flow rate of 1 μL s−1. With a polymer solution flow rate of 1, 2, or 3 μL s−1 the microspheres were relatively monodisperse (Figure 6), while at higher flow rates, microsphere polydispersity increased significantly. This effect was mainly caused by droplet coalescence at the outlet of tube c. The average diameters and PDI values of the microspheres fabricated at polymer solution flow rates of 1, 2, 3, 4, and 5 μL s−1 were 164.8 μm and 3.0%, 156.7 μm and 3.6%, 156.3 μm and 3.6%, 152.6 μm and 8.5%, and 141.5 μm and 26.5%, respectively. Desolvation Parameters. The effect of the NaCl concentration in the desolvation solution on the formation of microspheres was studied using a 3% PVC solution. For NaCl concentrations of the desolvation solution lower than 5%, the microspheres often had irregular shapes (Figure 7) and uneven D

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preconcentration of analytes in chemical analysis is expected to be of considerable interest. PLA is of interest for the fabrication of microspheres for drug delivery,22,26,52 while PS microspheres have important biological applications such as blood flow measurement.7 Optical images of the microspheres obtained using different concentrations of these polymers are shown in Figure 10. It was found that, similarly to PVC, the average diameter of the microspheres increased with increasing the polymer concentration in the corresponding THF solutions (Figure S5, Supporting Information). The optical images (Figure 10, (1), (2), and (3)) indicate poor sphericity of PVDF-HFP, PLA, and PS microspheres when their concentration in THF was high (2% or 3%). Therefore, in this case it would be more appropriate to use the term microparticle rather than microsphere. The poor sphericity was also confirmed by SEM imaging (Figure 10, (4)) which also revealed that the surfaces of the microparticles were not smooth. On the basis of the results obtained with PVC with higher molecular mass (Figure 9) it was concluded that the nonspherical shape and uneven surface of the PVDFHFP, PLA, and PS microparticles was most likely caused by the large molecular mass of these polymers (400 kDa, 260 kDa, and 192 kDa for PVDF-HFP, PLA, and PS, respectively) and the high viscosity of their solutions. Suitability of Solvents Other than THF. Acetone and cyclohexanone are suitable solvents for PS and PVC, respectively, while PLA is highly soluble in dichloromethane and chloroform. Therefore, the suitability of these solvents for the microfluidic fabrication of microspheres of these polymers was tested. It was found that the solubility of acetone in NaCl solution was too high for stable droplet formation and desolvation. For instance, acetone is miscible with 10% NaCl solution, its solubility is about 37% in 20% NaCl solution and about 22% in 30% NaCl solution. In the last case, NaCl precipitated as acetone dissolved in the aqueous solution. As a consequence, its PS solution could not form stable droplets in these aqueous solutions. In comparison, cyclohexanone was barely soluble in NaCl solutions or water and its polymer solution droplets could not be desolvated before they reached the surface of the desolvation column where they formed an organic layer. Dichloromethane and chloroform droplets were too dense and sank to the bottom of the desolvation column where they aggregated. Therefore, it was concluded that all three solvents were not suitable for the newly developed microfluidic fabrication technique. Comparison with Other Microfluidic Techniques. The productivity of the newly developed microfluidic fabrication technique, based on the droplet generation process only, was found to be significantly higher than that of other single channel microfluidic techniques for the fabrication of microspheres with similar particle sizes29,38 (Table 1).

Figure 8. Microspheres obtained with tubing c having an i.d. of (a) 0.35 mm, (b) 0.50 mm, and (c) 0.80 mm. Remaining experimental conditions as in Figure 7. All scale bars are equal to 200 μm.

the SEM images (Figure S3, Supporting Information) show that the microspheres fabricated from PVC with a molar mass of 43 kDa had a spherical shape and a smooth surface. The sphericity of the microspheres markedly decreased as PVC with higher molar mass was used and a larger proportion of the microparticles of PVC with a 233 kDa molar mass had irregular shapes (Figure S3, Supporting Information). These results are likely to be caused by the higher viscosity of the polymer solutions of PVC with higher molar mass resulting in the slower polymer deposition in the solidification process and the subsequent formation of irregularly shaped particles. Effect of Desolvation Temperature. Desolvation was carried out at different temperatures and the resultant PVC microspheres are shown in Figure S4 (Supporting Information). At lower temperature (e.g., 15 °C) a high degree of polydispersity (PDI = 14%) was observed due to the relatively high viscosity of the solutions which enhanced the coalescence between droplets. By increasing the desolvation solution temperature, the polydispersity became less pronounced due to the lower solution viscosity which facilitated the faster upward movement of the droplets on one hand thus diminishing droplet coalescence and enhanced droplet desolvation on the other. However, the increase of the temperature from 24 to 33 °C did not make a significant difference in the average diameter and morphology of the microspheres. It is also worth mentioning that high temperature may lead to lower entrapment efficiency of active components by the microspheres.50 Therefore, it was concluded that room temperature was most suitable for droplet desolvation, particularly in the case when an active component (e.g., small molecule therapeutics or liquid phase extractants) was to be loaded in the microspheres in the fabrication process. Fabrication of PVDF-HFP, PLA, and PS Microspheres. It was of interest to explore the possibility of applying the approach outlined above for the fabrication of PVC microspheres to the fabrication of microspheres of PVDF-HFP, PLA, and PS. These polymers were selected for different reasons. PVDF-HFP based polymer inclusion membranes (PIMs) offer superior permeability and stability compared to PIMs made of traditionally used polymers for this purpose such as PVC and cellulose triacetate.51 Therefore, the application of polymer inclusion PVDF-HFP-based microspheres for separation and

Figure 9. Optical microscopic images of PVC microspheres using PVC with different molar masses ((a) Mw 43 kDa, (b) Mw 62 kDa, (c) Mw 80 kDa, (d) Mw 233 kDa). Remaining experimental conditions as in Figure 7. All scale bars are equal to 200 μm. E

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Figure 10. Images of microspheres of PVDF-HFP (a), PLA (b), and PS (c) not containing methyl red. Optical images for polymer concentrations: 1% (1), 2% (2), 3% (3). SEM images (4) for polymer concentrations of 3%. Remaining experimental conditions as in Figure 7. All scale bars in (1), (2), and (3) are equal to 200 μm.

Table 1. Productivity Comparison of Different Single Channel Microfluidic Methods polymer

solvent

microsphere size

PLGA PLA PLGA PCLd PLGA PLGA Present method, PVC, PVDF-HFP, PLA, PS

c

11−41 18−150 34.2 210−330 145 1−30 50−200

b

DCM DCM DCM Chloroform DCM DCM THF

productivitya (mg h−1) 80 64 30 150 0.2 324 (3 μL s−1 flow rate)

desolvation time

ref.

3 min (under reduced pressure) 30 min (in vacuum oven) 2.5 h 3h 5h 48 h