RESEARCH ARTICLE – Pharmaceutical Nanotechnology
Preparation and Solidification of Redispersible Nanosuspensions XIN ZHANG,1 JIAN GUAN,1 RUI NI,1 LUK CHIU LI,2 SHIRUI MAO1 1 2
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China Abbott Laboratories, Abbott Park, Illinois 60064
Received 8 April 2014; revised 24 April 2014; accepted 25 April 2014 Published online 19 May 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24015 ABSTRACT: To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2166–2176, 2014 acceptable redispersibility. Keywords: high-pressure homogenization method; nanosuspensions; spray drying; Peclet number; redispersibility; nanotechnology; drying; stabilization; dissolution
INTRODUCTION An increasing number of poorly water-soluble drug candidates have been generated in recent years as the outcome of more productive drug discovery efforts by the pharmaceutical industry.1,2 However, it has been a challenge in solving the poor bioavailability of these drugs for preclinical investigations using conventional solubility enhancement methods.3 Nanolization, the process of forming a nanosuspension of a solid drug has evolved as a promising strategy in formulating a poorly water-soluble drug for preclinical research and clinical development. The superior in vivo performance via oral delivery of a drug in the form of nanoparticles is generally attributed to bioavailability enhancement and elimination of food effects, which have been shown to be the results of fast dissolution because of the vast surface area and increased solubility associated with nanoparticles.4–7 The preparation of nanosuspensions can be achieved by a top-down method, a bottomup method, or a combination of both.3 Because of the more streamlined process-flow pattern and the solvent-free feature, top-down methods have been developed for the production of a few commercially successful nanoparticle-based products. A top-down method commonly involves the use of either highpressure homogenization or media milling. The particle size reduction by high-pressure homogenization is mainly achieved by the cavitation force generated when particles are passing through a gap at an extremely high velocity. The key limitation of this method is that the solid content/drug concentration of the suspension being homogenized cannot to be very high to
Correspondence to: Shirui Mao (Telephone: +86-24-23986358; Fax: +86-2423986358; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 103, 2166–2176 (2014)
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ensure effective particle size reduction. Therefore, it is imperative to remove excessive water from the nanosuspension during manufacturing or convert the nanosuspension into a dry powder form that can be further processed into a solid finished product. Many methods have been developed to directly incorporate a nanosuspension into the manufacturing of a solid dosage form. Coating of a drug nanosuspension onto a substrate material (core tablets or granules/pellets) by either pan film coating or fluidized bed coating exhibits many advantages, such as enhanced drug release, improved stability, and bioavailability, and has been successfully utilized for commercial production.8,9 However, the coating method is not suitable for a high-dosed drug because of the large quantity of nanosuspension required. In this case, it becomes more feasible to convert a fluid nanosuspension into a dry powder form via drying, which can be subsequently used in the manufacturing of the solid dosage form. Freeze-drying and spray drying are the two processes that have been evaluated for converting a nanosuspension into a powder form.10–12 When considering the relatively high-energy consumption and long-processing time of the freeze-drying process and the lack of desirable processing characteristics (i.e., flowability) of a freeze-dried product, spray drying has been the method of choice in transforming a nanosuspension into a powder in particular for solid dosage form manufacturing.13,14 Prior to spray drying, a high concentration of protectants is usually added to the nanosuspension at a protectant to drug ratio ranging from 0.7 to 3.15,16 Protectants are water-soluble sugars such as mannitol, lactose, and trehalose, which are added to prevent nanoparticles from aggregating during the drying process.17 The addition of protectants will greatly reduce the drug content of the spray-dried powder and this is particularly undesirable for formulations with a high drug loading; hence, it is advantageous to prepare dry powder of a nanosuspension
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without further addition of drying protectants. It has been reported that appropriate stabilizer could play a critical role in preventing nanoparticle aggregation during a drying process.18 Yue et al.19 studied the influence of drug properties and type of stabilizers on the preparation and solidification of nanosuspensions, and the results showed that polymeric stabilizers present a better potential to stabilize nanosuspensions during drying process compared with that of surfactant stabilizers. Also, drying protectant-free powders of nanosuspensions with high dispersibility can be obtained at a high voltage using the electrospray-drying method.20 Therefore, it is the aim of this study to investigate the feasibility of preparing redispersible spray-dried nanosuspensions through screening of stabilizers and optimizing spray-drying process parameters. Nanosuspensions of lovastatin, a BCS class II drug, were prepared using high-pressure homogenization. The nanosuspensions were subsequently spray dried with no protectant added. The effects of spray-drying process parameters, type and concentration of stabilizers, and drug concentration on the redispersibility of the dried nanosuspension powders were investigated. The results were further analyzed and explained with proposed mechanisms.
MATERIALS AND METHODS Materials Lovastatin was purchased from Hubei Prosperity Galaxy Chemical Company, Ltd. (Wuhan, China). Poloxamer 188 (F68) and Poloxamer 407 (F127) were generously provided by BASF (Shanghai, China). Povidone K12 (PVP K12), Povidone K17 (PVP K17), and Povidone K29/30 (PVP K30) were kindly donated by ISP. Sodium dodecyl sulfate (SDS) (Amresco, solon, OH), hydroxypropyl methylcellulose 2910 (HPMC 2910) (ShinEtsu Chemical Company, Ltd., Tokyo, Japan), and polyvinyl alcohol 205 (PVA 205) (Kuraray Company Ltd., Tokyo, Japan) were commercially purchased. Preparation of Nanosuspension and Particle Size Characterization Coarse drug powder (0.5%, w/w) was dispersed in distilled water containing specified amount of stabilizers under moderate stirring. Lovastatin nanosuspensions were prepared by highpressure homogenization as reported previously.14 The coarse dispersion was first passed through a high-pressure homogenizer AH100D (ATS Engineering Inc., Shanghai, China) at three different pressures (200, 500, and 800 bar) with two cycles per each pressure. The resultant suspension was subsequently passed through the homogenizer at a final pressure of 1300 bars for 20 cycles. Particle size and polydispersity index (PI) analysis of the nanosuspensions were conducted by photon correlation spectroscopy with a Nano ZS90 (Malvern Instruments, Worcestershire, UK). Samples of nanosuspensions were diluted to an appropriate concentration and were measured at 25◦ C and at a scattering angle of 90◦ . Spray Drying of Nanosuspensions and Determination of Redispersibility Spray drying of the lovastatin nanosuspensions was carried out by using a laboratory-scale spray dryer SD-1000 (Tokyo Rikakikai Company, Ltd., Tokyo, Japan). Nanosuspensions were atomized through the two-fluid nozzle at different presDOI 10.1002/jps.24015
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sures and dried at different inlet air temperatures. Other processing parameters were fixed: drying air flow was 0.6 m3 /min and feed rate was 2.8 mL/min. Spray-dried powders were redispersed in distilled water and shaked gently for 10 s to yield a suspension with the same concentration as the nanosuspension prior to spray drying and particle size measurement was conducted with the resultant suspension. Redispersibility index (RDI) was used to evaluate the redispersibility of the spray-dried powders and is calculated as: RDI =
D D0
× 100%,
where D represents the mean particle size of the redispersed suspension formed by the spray-dried powder and D0 is the particle size of the nanosuspension prior to spray drying. When the RDI value is close to 100%, the spray-dried powder is said to be completely redispersed, forming nanoparticles with the same size as those in the nanosuspension.18 X-ray Powder Diffraction X-ray powder diffraction (XRPD) patterns were obtained at a wide X-ray scattering angle range (22 = 5◦ –45◦ ) with a PW3040/60 X-ray diffractometer (PANalytical B.V., Almelo, The Netherlands). The Cu-K" radiation at 40 kV and 40 mA was applied. Differential Scanning Calorimetry A spray-dried nanosuspension sample was characterized using a differential scanning calorimeter TGA/DSC-1 (MettlerToledo Ltd., Schwerzenbach, Switzerland) and the result was compared with that of the coarse drug powder. Prior to measurement, samples were accurately weighed into an aluminum pan and then sealed with a punched cover. Samples were heated from 30◦ C to 180◦ C at a rate of 5◦ C/min in a nitrogen atmosphere. Scanning Electron Microscopy The morphology of the samples was examined using a SUPRA 35 Field-Emission Scanning Electron Microscope (Zeiss, Jena, Germany) with an accelerating voltage of 17 kV. Prior to analysis, the mounted samples were coated with gold and dried under vacuum. Short-Term Physical Stability The physical stability of lovastatin nanosuspensions was evaluated at 25◦ C; particle size was determined at predetermined time points over 1 week time period. In Vitro Dissolution In vitro dissolution experiments were carried out at 37◦ C with a paddle speed of 50 rpm. A sample of 60 mg of lovastatin was dispersed in 900 mL of phosphate buffer (pH 7.4) containing 0.1% SDS. Six milliliter samples were collected at predetermined time intervals and filtered through a 0.15-:m millipore filter (cellulose acetate). The concentration of dissolved lovastatin in samples was determined by an UV Spectrophotometer UV-2000 (Unico Instrument Company, Ltd., Shanghai, China) at 238 nm. Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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Figure 1. Influence of stabilizers (F68 and K30) concentrations (expressed as the percentage mass over the drug mass.) on particle size of nanosuspensions.
Statistical Analysis The results are expressed as mean ± SD calculated from at least three measurements. The significance of difference between two values was performed by the Student’s t-test at a probability level of 0.05.
RESULTS AND DISCUSSION Influence of Stabilizers on the Particle Size of Nanosuspensions Influence of Stabilizer Concentration The effect of stabilizer concentration on the extent of particle size reduction in lovastatin nanosuspensions was investigated with samples prepared with a nonionic surfactant (F68) and a polymeric stabilizer (PVP K30). The stabilizer concentration in the nanosuspension is expressed as the percentage mass over the drug mass (Fig. 1). Irrespective of the stabilizer type, the particle size of lovastatin decreased with increasing stabilzer concentration from 5% to 20% and there is a slight increase in particle size beyond 20%. During the preparation of nanosuspensions, the selection of the type and concentration of stabilizers is usually critical and experimental.6 The concentration of a stabilizer should be adequate to provide complete surface coverage of the nanoparticles formed so that stabilization can be achieved with respect to aggregation.4,21 As shown in Figure 1, the particle size of lovastatin nanosuspensions reached a minimum at 20% stabilizer concentration but the particle size started to increase beyond this stabilizer level. In the case of polymeric stabilizers, the increase in bulk viscosity of the suspension at a higher stabilizer concentration would probably make particle size reduction less efficient.22 Therefore, a stabilizer concentration of 20% was used in preparing lovastatin nonosuspensions in this study. Influence of Stabilizer Type The results shown in Figure 1 also indicate that the polymeric stabilizer (PVP K30) seems to be more effective in particle Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
size reduction than the nonionic surfactant (F68), hence more polymers were included for further invesitigation. Lovastatin nanosuspensions were prepared with five different polymeric stabilizers (HPMC 2910, PVP K30, PVP K17, PVP K12, and PVA), two noninic surfactants (F68 and F127), and one ionic surfactant (SDS), all at a level of 20% of the drug concentration. The mean particle size (Z-ave) and PI value of the nanosuspensions were determined and presented in Figure 2. All the nanosuspensions evaluated showed particle size below 500 nm but the smallest particle size was achieved in the nanosuspension formulated with PVP K17. To evaluate whether a greater extent of particle size reduction can be achieved by a combination of two different types of stabilizer, a lovastatin nanosuspension was prepared with PVP K17 (20%) and SDS (5%). However, no statistically significant difference (p > 0.05) was shown in particle size of the nanosuspension containing PVP K17 and that being formulated with the two stabilizers combined. As shown in Figure 2, the type of stabilizers evaluated in this study had remarkable influence on the particle size of lovastatin nanosuspensions form via high-pressure homogenization. It is interesting to note that the particle size of the nanosuspension formulated with PVP K17 was significantly smaller (p < 0.05) than those formulated with PVP K30 and PVP K12, respectively. It seems to be difficult to explain this result solely based on the viscosity effect associated with molecular weight; hence, the molecular structure difference can be another contributory factor. Although the viscosity of PVP K12 is the lowest, the shortest chain length of the molecules may not provide effective steric stabilization in comparison with PVP K30 and K17. Because of its medium molecular weight, the balance between the negative viscosity effect and positive structural effect may result in the superior stabilization effect of PVP K17 as shown in this study. A binary stabilizer system consisting of PVP K17 and SDS was also evaluated. It has been reported that SDS molecules could bind to the positive nitrogen of PVP and extend the PVP chains when SDS concentration was at its critical micelle concentration range.23,24 However, no statistical difference in particle size was observed between the DOI 10.1002/jps.24015
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Figure 2. Particle size and PI value of lovastatin nanosuspension stabilized by different stabilizers.
Figure 3. Particle size of lovastatin nanosuspension stabilized by different stabilizers at room temperature over 1 week.
nanosuspension formulated with PVP K17 and that with the binary stabilizer system. This result indicates that with the possible extension of the molecular chain of PVP K17 because of interaction with SDS, the binary stabilizer system did not improve the extent of particle size reduction of lovastatin. Short-Term Stability The short-term stability of the nanosuspensions in terms of particle size was examined during storage at room temperature for 1 week. The results shown in Figure 3 indicate that lovastatin nanosuspensions stabilized by different stabilizers were physically stable at room temperature for 1 week as there was no apparent increase in particle size. This short-term stability of nanosuspensions allows a reasonable time interval before further processing (spray drying) of the nanosuspensions after homogenization. As the lovastatin nanosuspension stabilized with PVP K17 yielded the smallest particle size, this formulation was selected for the investigation of the impact of process parameters on the redispersibility of the spray-dried powder of the nanosuspension. DOI 10.1002/jps.24015
Influence of Spray-Drying Process Parameters Influence of Inlet Air Temperature Inlet air temperature is a key process parameter of a spraydrying operation; although other process parameters are kept constant, it directly controls the drying rate of the atomized droplets and the microstructure of the final product.25 Inlet air temperatures in the range of 80◦ C–150◦ C have been reported for the spray drying of nanosuspensions.13,15,16,26 In this study, inlet air temperatures varying from 70◦ C to 130◦ C were used, whereas the other process parameters were kept constant: air flow rate at 0.6 m3 /min, atomizing pressure at 200 kpa, and feed rate at 2.8 mL/min. Figure 4 shows the RDI value of spraydried nanosuspensions as a function of the inlet air temperature. It is clear that RDI values exhibited an upward trend with higher inlet air temperatures, indicating that a fast drying rate achieved at a high inlet air temperature resulted in a spray-dried powder with poor redispersibility. When a statistical ranking of RDI values was performed, the inlet air temperatures can be divided into four different groups: 70◦ C, 80–90◦ C, 100–110◦ C, and 120–130◦ C. There is no significant difference Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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Figure 4. Redispersibility index value of spray-dried lovastatin nanosuspension powder stabilized by PVP K17 at different inlet temperatures.
within the group, but statistically significant difference was seen between groups (p < 0.05) as presented in Figure 4. These results clearly demonstrated that the inlet air temperature affected the extent of aggregation of nanoparticles during spray drying, which correlated with the degree of redispersibility of the resultant spray-dried powder. To evaluate the extent of water removal at different inlet air temperatures, the moisture content of the spray-dried powders were determined. The moisture contents for all spray-dried powders were found ranging from 1.3% to 1.9% and there was no indication that lower moisture content was achieved at a higher inlet air temperature. In consideration of the lowest RDI value and the acceptable moisture content of the spraydried powder prepared at an inlet air temperature of 70◦ C, this temperature was selected for the preparation of lovastatin nanosuspensions for further investigation in this study. The SEM photomicrographs of the spray-dried powders prepared at different inlet air temperatures are shown in Figure 5. All the dried particles were spherical in shape and composed of a large number of nanoparticles; however, it is clear that the extent of nanoparticle aggregation varied with inlet air temperature. At inlet temperature 130◦ C and 110◦ C (Figs. 5a and 5b), the extent of the aggregation of nanoparticles appears to be greater as the boundary between nanoparticles became less definite with discernible evidence of nanoparticle coalescence. In comparison, the extent of aggregation/coalescence of nanoparticles was less in microparticles formed at lower inlet air temperatures (90◦ C and 70◦ C) as more definite boundaries were seen between nanoparticles (Figs. 5c and 5d). Therefore, it is reasonable to conclude that the decreased RDI value (greater redispersibilty) of spray-dried powders prepared at a lower inlet air temperature was the result of a lower degree of aggregation/coalescence of nanoparticles during spray drying. Influence of Atomizing Pressure The impact of atomization pressure was also investigated with respect to the redispersibility of spray-dried nanosuspensions. A higher atomization pressure provides greater energy for atZhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
omization and results in smaller droplet size.25 Although the inlet air temperatures were fixed at 70◦ C and 110◦ C, respectively, atomizing pressures in the range of 160 to 240 kpa were used to prepare nanosuspensions with their RDI values measured and analyzed. As shown in Figure 6, the influence of atomizing pressure on the RDI value of spray-dried nanosuspensions was dependent on the inlet air temperature used. At an inlet air temperature of 70◦ C, the RDI value decreased with the increase of atomizing pressures and the lowest RDI value was achieved at the highest atomizing pressure of 240 kpa. In comparison, at an inlet temperature of 110◦ C, the influence of atomizing pressure on the RDI value was not significant in the range of 160–220 kpa; significant RDI decrease was only observed at an atomizing pressure of 240 kpa (p < 0.05). With the above results on the combined effect of inlet air temperature and atomizing pressure on the RDI values of a spray-dried nanosuspension, we can conclude that the spray drying of drying protectant-free nanosuspensions should be carried out at a low inlet air temperature and a high atomizing pressure to ensure good redispersibility of the final product. Significant impact of the spray-drying process parameters on the redispersibility of dried nanosuspensions was shown by results of this study. The further analysis and explanation of these results can be attempted by the concept of the Peclet number (Pe) that is derived to describe the interplay of evaporation rate of the liquid medium and the diffusion rate of nanoparticles in a droplet formed by atomization during a spray-drying process. It can be expressed by the following equation:
Pe =
R2 Jd D
(1)
where, Jd is the drying time for a droplet, R is the diameter of the droplet, and D is the diffusion coefficient of nanoparticles in a droplet. R2 /D represents the time for nanoparticles to diffuse from the edge to the center of droplets.27 In general, when the Peclet number is high, as in the case of short drying time (fast drying rate), nanoparticles will have less time to diffuse to the center and may concentrate on the surface of the droplet,28,29 resulting in greater chance for nanoparticle aggregation/coalescence. In addition, the capillary pressure generated during water evaporation is the key driving force to draw nanoparticles close to each other and facilitate aggregation/coalescence of nanoparticles.30 When the Peclet number is low, nanoparticles have more time to diffuse from the surface to the core of the droplets, giving rise to more homogeneous distribution of nanoparticles throughout the spray-dried powder with reduced degree of aggregation/coalescence29,31,32 and improved redispersibility. Figure 7 schematically describes the spray-drying process of nanosuspension droplets. This can provide a plausible explanation for the improved redispersibility of spray-dried nanosuspensions prepared at a low inlet air temperature. During a spray-drying process, an increase of atomizing pressure produces droplets with reduced radius, which will result in a smaller Peclet number. This means a shorter diffusion time for the nanoparticles to reach the core of the droplet, leading to a more uniform distribution of nanoparticles within the spray-dried microparticles with less aggregation/coalescence. Furthermore, decreased droplets with a smaller size will form smaller microparticles,33,34 which contain less nanoparticles; DOI 10.1002/jps.24015
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Figure 5. SEM images of spray-dried powders stabilized by PVP K17 at different inlet temperatures: (a) 130◦ C, (b) 110◦ C, (c) 90◦ C, and (d) 70◦ C.
Figure 6. Redispersibility value of spray-dried lovastatin nanosuspensions stabilized by PVP K17 at different atomizing pressures.
therefore, the probability of particle aggregation decreased leading to an improved redispersibility of the dried powders and lower RDI values for the dried nanosuspensions prepared at highest atomizing pressure employed in this study at both 70◦ C and 110◦ C can be obtained. Influence of Stabilizers When the influence of stabilizers on the redispersibility of a spray-dried nanosuspension was evaluated, lovastatin nanosuspensions were formulated with different stabilizers and spray dried at an inlet temperature of 70◦ C and an atDOI 10.1002/jps.24015
omizing pressure of 240 kpa. Results are depicted in Figure 8; significant difference in RDI values was found between nanosuspensions stabilized with surfactants and those containing polymeric stabilizers. For nanosuspensions stabilized by polymers, such as PVA, HPMC 2910, PVP K17, and PVP K30, the spray-dried powders exhibited highly redispersible characteristics. It is noteworthy that the spray-dried powder stabilized by PVA exhibited the best redispersibility (lowest RDI value) in spite of the relatively larger particle size of the nanosuspension (472 nm). No significant difference in RDI values was found for nanosuspensions stabilized with PVP K30, PVP K17, and HPMC 2910, respectively, whereas the nanosuspension stabilized with PVP K12 yielded spray-dried powder with a significantly poorer resdispersibility (a higher RDI value). Spray-dried powders of nanosuspensions stabilized with surfactants were generally less redispersible in comparison with those formulated with polymeric stabilizers. An ionic surfactant (SDS) seems to be more effective than the two nonionic surfactants (F68 and F127) in suppressing aggregation/coalescence of nanoparticles during spray drying as shown by the higher redispersibility of the spray-dried powder. A nanosuspension formulated with a binary stabilizer system (20% PVP K17 and 5% SDS) was prepared and spray dried; a significantly improved redispersibility was observed when comparing to the powders obtained from nanosuspensions prepared with a single stabilizer system (p < 0.05). Figure 9 shows the SEM photomicrographs of microparticles in spray-dried powders prepared from nanosuspensions formulated with different stabilizers. In the microparticles from the nanosuspension stabilized by the binary stabilizer system, the distribution of nanoparticles was seen with more defined boundaries between them. On the contrary, microparticles obtained from nanosuspensions stabilized with F68, SDS, and Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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Figure 7. Schematic description of the drying process of nanosuspension droplets with different Peclet number.
Figure 8. Redispersibility index value of spray-dried lovastatin nanosuspension powders stabilized by different stabilizers (20% of the drug) at inlet temperature of 70◦ C and atomizing pressure of 240 kpa.
PVP K12 were shown to be composed of nanoparticles with a greater extent of aggregation/coalescence. The difference in the aggregation/coalescence state of the nanoparticles as seen in the microparticles may explain the difference in redispersibility characteristics of the powder. Because of the superior redispersibilty of the spray-dried powder from the nanosuspension Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
formulated with the binary stabilizer system (PVP K17-SDS), it was used for additional characterization and investigation. It was noted that spray-dried nanosuspensions prepared with different types of stabilizers exhibited different redispersion characteristics, which are probably attributed to different stabilization mechanisms provided to reduce the aggregation/coalescence of nanoparticles during spray drying. The potential influence of different stabilizers is also illustrated in Figure 7. Polymeric stabilizers form multiple layers around nanoparticles giving rise to a steric barrier for aggregation/coalescence and the strength of the multiple layer is apparently a function of the polymer chain length. The RDI value of spray-dried nanosuspension stabilized by PVP K12 is higher than those stabilized by PVP K17 and K30 can probably be explained by the formation of a weaker physical barrier with its much shorter molecular chains. It is also noted that the RDI values of spray-dried nanosuspensions stabilized with surfactants are significantly higher than those formulated with polymers, likely because of the less effective stabilization associated with a weaker protective layer formed by a surfactant. On the basis of the RDI values presented in Figure 8, it is clear that the electrostatic stabilization provided by an ionic surfactant is more effective than the steric stabilization by a nonionic surfactant. Although a binary stabilizer system (PVP K17 and SDS) did not result in greater extent of particle size reduction of the nanosuspension (Fig. 2), enhanced redispersibility was shown by spray-dried nanosuspension prepared with the binary stabilizer system. This study demonstrated that stabilizing effect of electrostatic repulsion provided by surfactants and steric protection provided by short-chain polymeric materials are not strong enough to prevent particles from aggregation DOI 10.1002/jps.24015
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Figure 9. SEM images of spray-dried nanosuspension stabilized with (a) PVP K17–SDS; (b) SDS; (c) PVP K12; (d) F68.
after spray-drying process. However, by the combination of long-chain polymeric material and surfactants, particle size increased only by 11% (RDI value from 100% to 110%), indicating improved stability and redispersibility. Similar results were reported by He et al.35 Compared with traditional surfactants, denaturation of proteins, such as soybean protein isolate, whey protein isolate, $-lactoglobulin, which combined electrostatic and steric stabilization mechanism, showed excellent stabilization performance during nanosization and drying process,9,35 and redispersibility results showed that both particle size and size distribution of redispersed nanosuspensions were similar with that of the original nanosuspensions.9 Influence of Drug Concentration From the processing efficiency point of view, nanosuspensions with a higher drug concentration are more desirable for spray drying because less water is needed to be removed. In this study, by keeping the concentration of stabilizer at 20% of the drug content, the influence of drug loading of the nanosuspension on the redispersibility of spray-dried powder was further investigated. As showed in Figure 10, spray-dried powders prepared from nanosuspensions with a drug concentration ranging from 0.5% to 3% did not show significant difference in redispersibility. Characterization of Spray-Dried Powders Crystal Form High-energy input during particle size reduction may induce crystalline form change.36 The solid-state properties of the drug in spray-dried powders were evaluated by XRPD and diffraction scanning calorimetry (DSC) analysis, respectively. Figure 11a presents the XRPD pattern of the spray-dried powder of lovastatin nanosuspension; the sharp peaks indicate the crystalline DOI 10.1002/jps.24015
Figure 10. Influence of lovastatin concentration on the RDI value of spray-dried powders stabilized by K17–SDS at inlet temperature of 70◦ C and atomizing pressure of 240 kpa.
form of the drug. By comparing with the characteristic peaks in the pattern of a lovastatin powder, it is clear that lovastatin maintained its original crystalline structure after homogenization and spray drying. This indicated that the crystalline form of lovastatin was not altered during high-pressure homogenization and spray drying. As shown in Figure 11b, the DSC results revealed that the endothermic peak of the spray-dried powders was similar to that of the original drug. The results of this study demonstrated Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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Figure 11. Characterization of spray-dried lovastatin nanosuspensions stabilized by PVP K17–SDS and coarse lovastatin (a) X-ray diffraction patterns; (b) DSC thermograms.
that both high-pressure homogenization and spray drying did not change the crystalline structure of lovastatin. As shown by the results of the DSC and XRPD analysis, the crystalline nature of lovastatin was not changed in the spraydried nanosuspensions, but the melting onset peak (162.3◦ C) was slightly left shifted as compared with that of the original drug powder (169.2◦ C). This temperature shift can be the result of the nanosize of the particles as predicted by the Gibbs– Thomson equation on the reduction in the melting point of small crystals.37 Similar observations were also reported by others.14,38 As shown by the XRPD patterns, the relatively reduced intensity and broadening of the peaks seen in the pattern of the nanoparticles can also be the results of nanolization via high-pressure homogenization.39 In Vitro Dissolution Study On the basis of the solubility of lovastatin in different SDS solutions, one sink condition (0.3% SDS) and two nonsink conditions (0.15% SDS and 0.1% SDS) were selected for this study to determine the dissolution profile of a coarse drug powder, a nanosuspension, and a spray-dried drug powder prepared from the nanosuspension. As shown in Figure 12, no apparent difference in dissolution behavior was found for lovastatin nanosuspensions in the three different dissolution media and complete drug dissolution was observed in 10 min. On the contrary, when a lovastatin coarse powder was tested, drug dissolution rate and extent decreased greatly under the nonsink condition. Therefore, the selection of a nonsink condition for dissolution test can provide a greater differential power in particular when a nanosuspension is evaluated; hence, a phosphate buffer containing 0.1% SDS was selected as the dissolution medium for this study. Figure 13 shows that the dissolution profile of a spray-dried powder of a nanosuspension of lovastatin is not statistically different (f2 > 50) from that determined for a freshly prepared nanosuspension with the same formulation. This result confirms that spray drying of a well-formulated nanosuspension under optimized processing conditions can result in a powder retaining the superior in vitro dissolution characteristics of the nanosuspension. Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
Figure 12. In vitro dissolution profiles of lovastatin coarse powder and lovastatin nanosuspension stabilized by PVP K17–SDS in different dissolution media.
As depicted by Figure 12, lovastatin nanosuspension and lovastatin coarse powder displayed significantly different dissolution profiles in 0.1% SDS dissolution medium. The fast dissolution profile of lovastatin nanosuspension is mainly because of the remarkably increased surface area. Similar dissolution performance in 0.1% SDS dissolution medium was also shown for the nanosuspension before and after spray drying. This further confirms that the spray-drying process did not adversely affect the fast dissolution characteristics of a nanosuspension.
CONCLUSIONS In this study, dry powders of lovastatin nanosuspensions were prepared by high-pressure homogenization followed by spray drying without the use of protectant. It was found that inlet air temperature, atomizing pressure, and the type of stabilizers used in the nanosuspension formulation had significant DOI 10.1002/jps.24015
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Figure 13. In vitro dissolution profiles of lovastatin coarse powder, spray-dried nanosuspension powder, and original nanosuspension stabilized by PVP K17–SDS in 0.1% SDS dissolution medium.
influence on the redispersibility of the spray-dried powders. SEM photomicrographs of the spray-dried powders showed that the spherical microparticles were composed of nanoparticles with different degrees of aggregation/coalescence. Among the spray-drying process parameters investigated, the inlet air temperature had the most significant impact on the extent of aggregation/coalescence of the nanoparticles, whereas the effect of atomizing pressure was more pronounced at a low inlet air temperature. These two variables were found to be the determining factors on the redispersibility of the spray-dried powder; a less degree of nanoparticle aggregation/coalescence resulted in an improved dispersibility. The dispersibility of spray-dried powder was shown to be further improved by using a binary stabilizer system that is capable of providing a dual stabilization mechanism: electrostatic and steric stabilization.
ACKNOWLEDGMENTS This project is financially supported by Liaoning Institutions excellent talents support plan (No. LR2013047).
REFERENCES 1. Lipinski C. 2002. Poor aqueous solubility-an industry wide problem in drug discovery. Am Pharm Rev 5:82–85. 2. Merisko-Liversidge E, Liversidge GG. 2011. Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water soluble compounds using wet media milling technology. Adv Drug Deliv Rev 63(6):427–440. 3. Keck CM, Muller RH. 2006. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm 62(1):3–16. 4. Van Eerdenbrugh B, Van den Mooter G, Augustijns P. 2008. Topdown production of drug nanocrystals: Nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm 364(1):64–75. 5. Patravale VB, Date AA, Kulkarni RM. 2004. Nanosuspensions: A promising drug delivery strategy. J Pharm Pharmacol 56(7):827– 840. DOI 10.1002/jps.24015
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6. Zhang X, Li LC, Mao S. 2014. Nanosuspensions of poorly water soluble drugs prepared by top-down technologies. Curr Pharm Des 20(3):388–407. 7. Che X, Zheng X, Sun C, Di C, Jiang T, Wang S. 2012. Drug nanocrystals: A state of the art formulation strategy for preparing the poorly water-soluble drugs. AJPS 7(2):85–95. 8. Luo Y, Xu L, Tao X, Xu M, Feng J, Tang X. 2013. Preparation, characterization, stability and in vitro-in vivo evaluation of pellet-layered Simvastatin nanosuspensions. Drug Dev Ind Pharm 39(7):936–946. 9. He W, Lu Y, Qi J, Chen L, Yin L, Wu W. 2013. Formulating food protein-stabilized indomethacin nanosuspensions into pellets by fluidbed coating technology: Physical characterization, redispersibility, and dissolution. Int J Nanomed 8:3119–3128. 10. Moschwitzer JP, Muller RH. 2013. Factors influencing the release kinetics of drug nanocrystal-loaded pellet formulations. Drug Dev Ind Pharm 39(5):762–769. 11. Kayaert P, Anne M, Van den Mooter G. 2011. Bead layering as a process to stabilize nanosuspensions: Influence of drug hydrophobicity on nanocrystal reagglomeration following in-vitro release from sugar beads. J Pharm Pharmacol 63(11):1446–1453. 12. Chung NO, Lee MK, Lee J. 2012. Mechanism of freeze-drying drug nanosuspensions. Int J Pharm 437(1–2):42–50. 13. Chaubal MV, Popescu C. 2008. Conversion of nanosuspensions into dry powders by spray drying: A case study. Pharm Res 25(10):2302– 2308. 14. Sun W, Mao S, Shi Y, Li LC, Fang L. 2011. Nanonization of itraconazole by high pressure homogenization: Stabilizer optimization and effect of particle size on oral absorption. J Pharm Sci 100(8):3365–3373. 15. Nekkanti V, Pillai R, Venkateshwarlu V, Harisudhan T. 2009. Development and characterization of solid oral dosage form incorporating candesartan nanoparticles. Pharm Dev Technol 14(3):290–298. 16. Mou D, Chen H, Wan J, Xu H, Yang X. 2011. Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with pH-dependent solubility. Int J Pharm 413(1–2):237– 244. 17. Abdelwahed W, Degobert G, Stainmesse S, Fessi H. 2006. Freezedrying of nanoparticles: Formulation, process and storage considerations. Adv Drug Deliv Rev 58(15):1688–1713. 18. Yue PF, Wan J, Wang Y, Li Y, Ma YQ, Yang M, Hu PY, Yuan HL, Wang CH. 2013. d-Alpha-tocopherol acid polyethylene glycol 1000 succinate, an effective stabilizer during solidification transformation of baicalin nanosuspensions. Int J Pharm 443(1–2):279–287. 19. Yue PF, Li Y, Wan J, Yang M, Zhu WF, Wang CH. 2013. Study on formability of solid nanosuspensions during nanodispersion and solidification: I. Novel role of stabilizer/drug property. Int J Pharm 454(1):269–277. 20. Ho H, Lee J. 2012. Redispersible drug nanoparticles prepared without dispersant by electro-spray drying. Drug Dev Ind Pharm 38(6):744– 751. 21. Jacobs C, Muller RH. 2002. Production and characterization of a budesonide nanosuspension for pulmonary administration. Pharm Res 19(2):189–194. 22. Ghosh I, Bose S, Vippagunta R, Harmon F. 2011. Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth. Int J Pharm 409(1– 2):260–268. 23. Dan A, Ghosh S, Moulik SP. 2008. The solution behavior of poly(vinylpyrrolidone): Its clouding in salt solution, solvation by water and isopropanol, and interaction with sodium dodecyl sulfate. J Phys Chem B 112(12):3617–3624. 24. Cattoz B, de Vos WM, Cosgrove T, Crossman M, Prescott SW. 2012. Manipulating interfacial polymer structures through mixed surfactant adsorption and complexation. Langmuir 28(15):6282–6290. 25. Cal K, Sollohub K. 2010. Spray drying technique. I: Hardware and process parameters. J Pharm Sci 99(2):575–586. 26. Pilcer G, Vanderbist F, Amighi K. 2009. Preparation and characterization of spray-dried tobramycin powders containing nanoparticles for pulmonary delivery. Int J Pharm 365(1–2):162–169. Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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27. Stroock AD, Dertinger SK, Ajdari A, Mezic I, Stone HA, Whitesides GM. 2002. Chaotic mixer for microchannels. Science 295(5555):647– 651. 28. Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA. 2002. Trojan particles: Large porous carriers of nanoparticles for drug delivery. Proc Natl Acad Sci USA 99(19):12001–12005. 29. Sen D, Spalla O, Tache O, Haltebourg P, Thill A. 2007. Slow drying of a spray of nanoparticles dispersion. In situ SAXS investigation. Langmuir 23(8):4296–4302. 30. Maskara A, Smith DM. 1997. Agglomeration during the drying of fine silica powders, part II: The role of particle solubility. J Am Ceram Soc 80(7):1715–1722. 31. Vehring R. 2008. Pharmaceutical particle engineering via spray drying. Pharm Res 25(5):999–1022. 32. Paudel A, Worku ZA, Meeus J, Guns S, Van den Mooter G. 2013. Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: Formulation and process considerations. Int J Pharm 453:253–284.
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33. Masters K. 1979. Applications of spray drying. In Spray drying handbook. 3rd ed. New York: Halsted Press, pp 481–516. 34. Lindeløv J, Wahlberg M. 2009. Spray drying for processing of nanomaterials. J Phys 170(1):7. 35. He W, Lu Y, Qi JP, Chen LY, Hu FQ, Wu W. 2013. Food proteins as novel nanosuspension stabilizers for poorly water-soluble drugs. Int J Pharm 441(1–2):269–278. 36. Teeranachaideekul V, Junyaprasert VB, Souto EB, Muller RH. 2008. Development of ascorbyl palmitate nanocrystals applying the nanosuspension technology. Int J Pharm 354(1–2):227–234. 37. Jackson CL, McKenna GB. 1990. The melting behavior of organic materials confined in porous solids. J Chem Phys 93:9002–9011. 38. Dolenc A, Kristl J, Baumgartner S, Planinsek O. 2009. Advantages of celecoxib nanosuspension formulation and transformation into tablets. Int J Pharm 376(1–2):204–212. 39. Deng Z, Xu S, Li S. 2008. Understanding a relaxation behavior in a nanoparticle suspension for drug delivery applications. Int J Pharm 351(1–2):236–243.
DOI 10.1002/jps.24015
Preparation and Solidification of Redispersible Nanosuspensions XIN ZHANG,1 JIAN GUAN,1 RUI NI,1 LUK CHIU LI,2 SHIRUI MAO1 1 2
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China Abbott Laboratories, Abbott Park, Illinois 60064
Received 8 April 2014; revised 24 April 2014; accepted 25 April 2014 Published online 19 May 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24015 ABSTRACT: To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2166–2176, 2014 acceptable redispersibility. Keywords: high-pressure homogenization method; nanosuspensions; spray drying; Peclet number; redispersibility; nanotechnology; drying; stabilization; dissolution
INTRODUCTION An increasing number of poorly water-soluble drug candidates have been generated in recent years as the outcome of more productive drug discovery efforts by the pharmaceutical industry.1,2 However, it has been a challenge in solving the poor bioavailability of these drugs for preclinical investigations using conventional solubility enhancement methods.3 Nanolization, the process of forming a nanosuspension of a solid drug has evolved as a promising strategy in formulating a poorly water-soluble drug for preclinical research and clinical development. The superior in vivo performance via oral delivery of a drug in the form of nanoparticles is generally attributed to bioavailability enhancement and elimination of food effects, which have been shown to be the results of fast dissolution because of the vast surface area and increased solubility associated with nanoparticles.4–7 The preparation of nanosuspensions can be achieved by a top-down method, a bottomup method, or a combination of both.3 Because of the more streamlined process-flow pattern and the solvent-free feature, top-down methods have been developed for the production of a few commercially successful nanoparticle-based products. A top-down method commonly involves the use of either highpressure homogenization or media milling. The particle size reduction by high-pressure homogenization is mainly achieved by the cavitation force generated when particles are passing through a gap at an extremely high velocity. The key limitation of this method is that the solid content/drug concentration of the suspension being homogenized cannot to be very high to
Correspondence to: Shirui Mao (Telephone: +86-24-23986358; Fax: +86-2423986358; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 103, 2166–2176 (2014)
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ensure effective particle size reduction. Therefore, it is imperative to remove excessive water from the nanosuspension during manufacturing or convert the nanosuspension into a dry powder form that can be further processed into a solid finished product. Many methods have been developed to directly incorporate a nanosuspension into the manufacturing of a solid dosage form. Coating of a drug nanosuspension onto a substrate material (core tablets or granules/pellets) by either pan film coating or fluidized bed coating exhibits many advantages, such as enhanced drug release, improved stability, and bioavailability, and has been successfully utilized for commercial production.8,9 However, the coating method is not suitable for a high-dosed drug because of the large quantity of nanosuspension required. In this case, it becomes more feasible to convert a fluid nanosuspension into a dry powder form via drying, which can be subsequently used in the manufacturing of the solid dosage form. Freeze-drying and spray drying are the two processes that have been evaluated for converting a nanosuspension into a powder form.10–12 When considering the relatively high-energy consumption and long-processing time of the freeze-drying process and the lack of desirable processing characteristics (i.e., flowability) of a freeze-dried product, spray drying has been the method of choice in transforming a nanosuspension into a powder in particular for solid dosage form manufacturing.13,14 Prior to spray drying, a high concentration of protectants is usually added to the nanosuspension at a protectant to drug ratio ranging from 0.7 to 3.15,16 Protectants are water-soluble sugars such as mannitol, lactose, and trehalose, which are added to prevent nanoparticles from aggregating during the drying process.17 The addition of protectants will greatly reduce the drug content of the spray-dried powder and this is particularly undesirable for formulations with a high drug loading; hence, it is advantageous to prepare dry powder of a nanosuspension
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without further addition of drying protectants. It has been reported that appropriate stabilizer could play a critical role in preventing nanoparticle aggregation during a drying process.18 Yue et al.19 studied the influence of drug properties and type of stabilizers on the preparation and solidification of nanosuspensions, and the results showed that polymeric stabilizers present a better potential to stabilize nanosuspensions during drying process compared with that of surfactant stabilizers. Also, drying protectant-free powders of nanosuspensions with high dispersibility can be obtained at a high voltage using the electrospray-drying method.20 Therefore, it is the aim of this study to investigate the feasibility of preparing redispersible spray-dried nanosuspensions through screening of stabilizers and optimizing spray-drying process parameters. Nanosuspensions of lovastatin, a BCS class II drug, were prepared using high-pressure homogenization. The nanosuspensions were subsequently spray dried with no protectant added. The effects of spray-drying process parameters, type and concentration of stabilizers, and drug concentration on the redispersibility of the dried nanosuspension powders were investigated. The results were further analyzed and explained with proposed mechanisms.
MATERIALS AND METHODS Materials Lovastatin was purchased from Hubei Prosperity Galaxy Chemical Company, Ltd. (Wuhan, China). Poloxamer 188 (F68) and Poloxamer 407 (F127) were generously provided by BASF (Shanghai, China). Povidone K12 (PVP K12), Povidone K17 (PVP K17), and Povidone K29/30 (PVP K30) were kindly donated by ISP. Sodium dodecyl sulfate (SDS) (Amresco, solon, OH), hydroxypropyl methylcellulose 2910 (HPMC 2910) (ShinEtsu Chemical Company, Ltd., Tokyo, Japan), and polyvinyl alcohol 205 (PVA 205) (Kuraray Company Ltd., Tokyo, Japan) were commercially purchased. Preparation of Nanosuspension and Particle Size Characterization Coarse drug powder (0.5%, w/w) was dispersed in distilled water containing specified amount of stabilizers under moderate stirring. Lovastatin nanosuspensions were prepared by highpressure homogenization as reported previously.14 The coarse dispersion was first passed through a high-pressure homogenizer AH100D (ATS Engineering Inc., Shanghai, China) at three different pressures (200, 500, and 800 bar) with two cycles per each pressure. The resultant suspension was subsequently passed through the homogenizer at a final pressure of 1300 bars for 20 cycles. Particle size and polydispersity index (PI) analysis of the nanosuspensions were conducted by photon correlation spectroscopy with a Nano ZS90 (Malvern Instruments, Worcestershire, UK). Samples of nanosuspensions were diluted to an appropriate concentration and were measured at 25◦ C and at a scattering angle of 90◦ . Spray Drying of Nanosuspensions and Determination of Redispersibility Spray drying of the lovastatin nanosuspensions was carried out by using a laboratory-scale spray dryer SD-1000 (Tokyo Rikakikai Company, Ltd., Tokyo, Japan). Nanosuspensions were atomized through the two-fluid nozzle at different presDOI 10.1002/jps.24015
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sures and dried at different inlet air temperatures. Other processing parameters were fixed: drying air flow was 0.6 m3 /min and feed rate was 2.8 mL/min. Spray-dried powders were redispersed in distilled water and shaked gently for 10 s to yield a suspension with the same concentration as the nanosuspension prior to spray drying and particle size measurement was conducted with the resultant suspension. Redispersibility index (RDI) was used to evaluate the redispersibility of the spray-dried powders and is calculated as: RDI =
D D0
× 100%,
where D represents the mean particle size of the redispersed suspension formed by the spray-dried powder and D0 is the particle size of the nanosuspension prior to spray drying. When the RDI value is close to 100%, the spray-dried powder is said to be completely redispersed, forming nanoparticles with the same size as those in the nanosuspension.18 X-ray Powder Diffraction X-ray powder diffraction (XRPD) patterns were obtained at a wide X-ray scattering angle range (22 = 5◦ –45◦ ) with a PW3040/60 X-ray diffractometer (PANalytical B.V., Almelo, The Netherlands). The Cu-K" radiation at 40 kV and 40 mA was applied. Differential Scanning Calorimetry A spray-dried nanosuspension sample was characterized using a differential scanning calorimeter TGA/DSC-1 (MettlerToledo Ltd., Schwerzenbach, Switzerland) and the result was compared with that of the coarse drug powder. Prior to measurement, samples were accurately weighed into an aluminum pan and then sealed with a punched cover. Samples were heated from 30◦ C to 180◦ C at a rate of 5◦ C/min in a nitrogen atmosphere. Scanning Electron Microscopy The morphology of the samples was examined using a SUPRA 35 Field-Emission Scanning Electron Microscope (Zeiss, Jena, Germany) with an accelerating voltage of 17 kV. Prior to analysis, the mounted samples were coated with gold and dried under vacuum. Short-Term Physical Stability The physical stability of lovastatin nanosuspensions was evaluated at 25◦ C; particle size was determined at predetermined time points over 1 week time period. In Vitro Dissolution In vitro dissolution experiments were carried out at 37◦ C with a paddle speed of 50 rpm. A sample of 60 mg of lovastatin was dispersed in 900 mL of phosphate buffer (pH 7.4) containing 0.1% SDS. Six milliliter samples were collected at predetermined time intervals and filtered through a 0.15-:m millipore filter (cellulose acetate). The concentration of dissolved lovastatin in samples was determined by an UV Spectrophotometer UV-2000 (Unico Instrument Company, Ltd., Shanghai, China) at 238 nm. Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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Figure 1. Influence of stabilizers (F68 and K30) concentrations (expressed as the percentage mass over the drug mass.) on particle size of nanosuspensions.
Statistical Analysis The results are expressed as mean ± SD calculated from at least three measurements. The significance of difference between two values was performed by the Student’s t-test at a probability level of 0.05.
RESULTS AND DISCUSSION Influence of Stabilizers on the Particle Size of Nanosuspensions Influence of Stabilizer Concentration The effect of stabilizer concentration on the extent of particle size reduction in lovastatin nanosuspensions was investigated with samples prepared with a nonionic surfactant (F68) and a polymeric stabilizer (PVP K30). The stabilizer concentration in the nanosuspension is expressed as the percentage mass over the drug mass (Fig. 1). Irrespective of the stabilizer type, the particle size of lovastatin decreased with increasing stabilzer concentration from 5% to 20% and there is a slight increase in particle size beyond 20%. During the preparation of nanosuspensions, the selection of the type and concentration of stabilizers is usually critical and experimental.6 The concentration of a stabilizer should be adequate to provide complete surface coverage of the nanoparticles formed so that stabilization can be achieved with respect to aggregation.4,21 As shown in Figure 1, the particle size of lovastatin nanosuspensions reached a minimum at 20% stabilizer concentration but the particle size started to increase beyond this stabilizer level. In the case of polymeric stabilizers, the increase in bulk viscosity of the suspension at a higher stabilizer concentration would probably make particle size reduction less efficient.22 Therefore, a stabilizer concentration of 20% was used in preparing lovastatin nonosuspensions in this study. Influence of Stabilizer Type The results shown in Figure 1 also indicate that the polymeric stabilizer (PVP K30) seems to be more effective in particle Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
size reduction than the nonionic surfactant (F68), hence more polymers were included for further invesitigation. Lovastatin nanosuspensions were prepared with five different polymeric stabilizers (HPMC 2910, PVP K30, PVP K17, PVP K12, and PVA), two noninic surfactants (F68 and F127), and one ionic surfactant (SDS), all at a level of 20% of the drug concentration. The mean particle size (Z-ave) and PI value of the nanosuspensions were determined and presented in Figure 2. All the nanosuspensions evaluated showed particle size below 500 nm but the smallest particle size was achieved in the nanosuspension formulated with PVP K17. To evaluate whether a greater extent of particle size reduction can be achieved by a combination of two different types of stabilizer, a lovastatin nanosuspension was prepared with PVP K17 (20%) and SDS (5%). However, no statistically significant difference (p > 0.05) was shown in particle size of the nanosuspension containing PVP K17 and that being formulated with the two stabilizers combined. As shown in Figure 2, the type of stabilizers evaluated in this study had remarkable influence on the particle size of lovastatin nanosuspensions form via high-pressure homogenization. It is interesting to note that the particle size of the nanosuspension formulated with PVP K17 was significantly smaller (p < 0.05) than those formulated with PVP K30 and PVP K12, respectively. It seems to be difficult to explain this result solely based on the viscosity effect associated with molecular weight; hence, the molecular structure difference can be another contributory factor. Although the viscosity of PVP K12 is the lowest, the shortest chain length of the molecules may not provide effective steric stabilization in comparison with PVP K30 and K17. Because of its medium molecular weight, the balance between the negative viscosity effect and positive structural effect may result in the superior stabilization effect of PVP K17 as shown in this study. A binary stabilizer system consisting of PVP K17 and SDS was also evaluated. It has been reported that SDS molecules could bind to the positive nitrogen of PVP and extend the PVP chains when SDS concentration was at its critical micelle concentration range.23,24 However, no statistical difference in particle size was observed between the DOI 10.1002/jps.24015
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Figure 2. Particle size and PI value of lovastatin nanosuspension stabilized by different stabilizers.
Figure 3. Particle size of lovastatin nanosuspension stabilized by different stabilizers at room temperature over 1 week.
nanosuspension formulated with PVP K17 and that with the binary stabilizer system. This result indicates that with the possible extension of the molecular chain of PVP K17 because of interaction with SDS, the binary stabilizer system did not improve the extent of particle size reduction of lovastatin. Short-Term Stability The short-term stability of the nanosuspensions in terms of particle size was examined during storage at room temperature for 1 week. The results shown in Figure 3 indicate that lovastatin nanosuspensions stabilized by different stabilizers were physically stable at room temperature for 1 week as there was no apparent increase in particle size. This short-term stability of nanosuspensions allows a reasonable time interval before further processing (spray drying) of the nanosuspensions after homogenization. As the lovastatin nanosuspension stabilized with PVP K17 yielded the smallest particle size, this formulation was selected for the investigation of the impact of process parameters on the redispersibility of the spray-dried powder of the nanosuspension. DOI 10.1002/jps.24015
Influence of Spray-Drying Process Parameters Influence of Inlet Air Temperature Inlet air temperature is a key process parameter of a spraydrying operation; although other process parameters are kept constant, it directly controls the drying rate of the atomized droplets and the microstructure of the final product.25 Inlet air temperatures in the range of 80◦ C–150◦ C have been reported for the spray drying of nanosuspensions.13,15,16,26 In this study, inlet air temperatures varying from 70◦ C to 130◦ C were used, whereas the other process parameters were kept constant: air flow rate at 0.6 m3 /min, atomizing pressure at 200 kpa, and feed rate at 2.8 mL/min. Figure 4 shows the RDI value of spraydried nanosuspensions as a function of the inlet air temperature. It is clear that RDI values exhibited an upward trend with higher inlet air temperatures, indicating that a fast drying rate achieved at a high inlet air temperature resulted in a spray-dried powder with poor redispersibility. When a statistical ranking of RDI values was performed, the inlet air temperatures can be divided into four different groups: 70◦ C, 80–90◦ C, 100–110◦ C, and 120–130◦ C. There is no significant difference Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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Figure 4. Redispersibility index value of spray-dried lovastatin nanosuspension powder stabilized by PVP K17 at different inlet temperatures.
within the group, but statistically significant difference was seen between groups (p < 0.05) as presented in Figure 4. These results clearly demonstrated that the inlet air temperature affected the extent of aggregation of nanoparticles during spray drying, which correlated with the degree of redispersibility of the resultant spray-dried powder. To evaluate the extent of water removal at different inlet air temperatures, the moisture content of the spray-dried powders were determined. The moisture contents for all spray-dried powders were found ranging from 1.3% to 1.9% and there was no indication that lower moisture content was achieved at a higher inlet air temperature. In consideration of the lowest RDI value and the acceptable moisture content of the spraydried powder prepared at an inlet air temperature of 70◦ C, this temperature was selected for the preparation of lovastatin nanosuspensions for further investigation in this study. The SEM photomicrographs of the spray-dried powders prepared at different inlet air temperatures are shown in Figure 5. All the dried particles were spherical in shape and composed of a large number of nanoparticles; however, it is clear that the extent of nanoparticle aggregation varied with inlet air temperature. At inlet temperature 130◦ C and 110◦ C (Figs. 5a and 5b), the extent of the aggregation of nanoparticles appears to be greater as the boundary between nanoparticles became less definite with discernible evidence of nanoparticle coalescence. In comparison, the extent of aggregation/coalescence of nanoparticles was less in microparticles formed at lower inlet air temperatures (90◦ C and 70◦ C) as more definite boundaries were seen between nanoparticles (Figs. 5c and 5d). Therefore, it is reasonable to conclude that the decreased RDI value (greater redispersibilty) of spray-dried powders prepared at a lower inlet air temperature was the result of a lower degree of aggregation/coalescence of nanoparticles during spray drying. Influence of Atomizing Pressure The impact of atomization pressure was also investigated with respect to the redispersibility of spray-dried nanosuspensions. A higher atomization pressure provides greater energy for atZhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
omization and results in smaller droplet size.25 Although the inlet air temperatures were fixed at 70◦ C and 110◦ C, respectively, atomizing pressures in the range of 160 to 240 kpa were used to prepare nanosuspensions with their RDI values measured and analyzed. As shown in Figure 6, the influence of atomizing pressure on the RDI value of spray-dried nanosuspensions was dependent on the inlet air temperature used. At an inlet air temperature of 70◦ C, the RDI value decreased with the increase of atomizing pressures and the lowest RDI value was achieved at the highest atomizing pressure of 240 kpa. In comparison, at an inlet temperature of 110◦ C, the influence of atomizing pressure on the RDI value was not significant in the range of 160–220 kpa; significant RDI decrease was only observed at an atomizing pressure of 240 kpa (p < 0.05). With the above results on the combined effect of inlet air temperature and atomizing pressure on the RDI values of a spray-dried nanosuspension, we can conclude that the spray drying of drying protectant-free nanosuspensions should be carried out at a low inlet air temperature and a high atomizing pressure to ensure good redispersibility of the final product. Significant impact of the spray-drying process parameters on the redispersibility of dried nanosuspensions was shown by results of this study. The further analysis and explanation of these results can be attempted by the concept of the Peclet number (Pe) that is derived to describe the interplay of evaporation rate of the liquid medium and the diffusion rate of nanoparticles in a droplet formed by atomization during a spray-drying process. It can be expressed by the following equation:
Pe =
R2 Jd D
(1)
where, Jd is the drying time for a droplet, R is the diameter of the droplet, and D is the diffusion coefficient of nanoparticles in a droplet. R2 /D represents the time for nanoparticles to diffuse from the edge to the center of droplets.27 In general, when the Peclet number is high, as in the case of short drying time (fast drying rate), nanoparticles will have less time to diffuse to the center and may concentrate on the surface of the droplet,28,29 resulting in greater chance for nanoparticle aggregation/coalescence. In addition, the capillary pressure generated during water evaporation is the key driving force to draw nanoparticles close to each other and facilitate aggregation/coalescence of nanoparticles.30 When the Peclet number is low, nanoparticles have more time to diffuse from the surface to the core of the droplets, giving rise to more homogeneous distribution of nanoparticles throughout the spray-dried powder with reduced degree of aggregation/coalescence29,31,32 and improved redispersibility. Figure 7 schematically describes the spray-drying process of nanosuspension droplets. This can provide a plausible explanation for the improved redispersibility of spray-dried nanosuspensions prepared at a low inlet air temperature. During a spray-drying process, an increase of atomizing pressure produces droplets with reduced radius, which will result in a smaller Peclet number. This means a shorter diffusion time for the nanoparticles to reach the core of the droplet, leading to a more uniform distribution of nanoparticles within the spray-dried microparticles with less aggregation/coalescence. Furthermore, decreased droplets with a smaller size will form smaller microparticles,33,34 which contain less nanoparticles; DOI 10.1002/jps.24015
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Figure 5. SEM images of spray-dried powders stabilized by PVP K17 at different inlet temperatures: (a) 130◦ C, (b) 110◦ C, (c) 90◦ C, and (d) 70◦ C.
Figure 6. Redispersibility value of spray-dried lovastatin nanosuspensions stabilized by PVP K17 at different atomizing pressures.
therefore, the probability of particle aggregation decreased leading to an improved redispersibility of the dried powders and lower RDI values for the dried nanosuspensions prepared at highest atomizing pressure employed in this study at both 70◦ C and 110◦ C can be obtained. Influence of Stabilizers When the influence of stabilizers on the redispersibility of a spray-dried nanosuspension was evaluated, lovastatin nanosuspensions were formulated with different stabilizers and spray dried at an inlet temperature of 70◦ C and an atDOI 10.1002/jps.24015
omizing pressure of 240 kpa. Results are depicted in Figure 8; significant difference in RDI values was found between nanosuspensions stabilized with surfactants and those containing polymeric stabilizers. For nanosuspensions stabilized by polymers, such as PVA, HPMC 2910, PVP K17, and PVP K30, the spray-dried powders exhibited highly redispersible characteristics. It is noteworthy that the spray-dried powder stabilized by PVA exhibited the best redispersibility (lowest RDI value) in spite of the relatively larger particle size of the nanosuspension (472 nm). No significant difference in RDI values was found for nanosuspensions stabilized with PVP K30, PVP K17, and HPMC 2910, respectively, whereas the nanosuspension stabilized with PVP K12 yielded spray-dried powder with a significantly poorer resdispersibility (a higher RDI value). Spray-dried powders of nanosuspensions stabilized with surfactants were generally less redispersible in comparison with those formulated with polymeric stabilizers. An ionic surfactant (SDS) seems to be more effective than the two nonionic surfactants (F68 and F127) in suppressing aggregation/coalescence of nanoparticles during spray drying as shown by the higher redispersibility of the spray-dried powder. A nanosuspension formulated with a binary stabilizer system (20% PVP K17 and 5% SDS) was prepared and spray dried; a significantly improved redispersibility was observed when comparing to the powders obtained from nanosuspensions prepared with a single stabilizer system (p < 0.05). Figure 9 shows the SEM photomicrographs of microparticles in spray-dried powders prepared from nanosuspensions formulated with different stabilizers. In the microparticles from the nanosuspension stabilized by the binary stabilizer system, the distribution of nanoparticles was seen with more defined boundaries between them. On the contrary, microparticles obtained from nanosuspensions stabilized with F68, SDS, and Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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Figure 7. Schematic description of the drying process of nanosuspension droplets with different Peclet number.
Figure 8. Redispersibility index value of spray-dried lovastatin nanosuspension powders stabilized by different stabilizers (20% of the drug) at inlet temperature of 70◦ C and atomizing pressure of 240 kpa.
PVP K12 were shown to be composed of nanoparticles with a greater extent of aggregation/coalescence. The difference in the aggregation/coalescence state of the nanoparticles as seen in the microparticles may explain the difference in redispersibility characteristics of the powder. Because of the superior redispersibilty of the spray-dried powder from the nanosuspension Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
formulated with the binary stabilizer system (PVP K17-SDS), it was used for additional characterization and investigation. It was noted that spray-dried nanosuspensions prepared with different types of stabilizers exhibited different redispersion characteristics, which are probably attributed to different stabilization mechanisms provided to reduce the aggregation/coalescence of nanoparticles during spray drying. The potential influence of different stabilizers is also illustrated in Figure 7. Polymeric stabilizers form multiple layers around nanoparticles giving rise to a steric barrier for aggregation/coalescence and the strength of the multiple layer is apparently a function of the polymer chain length. The RDI value of spray-dried nanosuspension stabilized by PVP K12 is higher than those stabilized by PVP K17 and K30 can probably be explained by the formation of a weaker physical barrier with its much shorter molecular chains. It is also noted that the RDI values of spray-dried nanosuspensions stabilized with surfactants are significantly higher than those formulated with polymers, likely because of the less effective stabilization associated with a weaker protective layer formed by a surfactant. On the basis of the RDI values presented in Figure 8, it is clear that the electrostatic stabilization provided by an ionic surfactant is more effective than the steric stabilization by a nonionic surfactant. Although a binary stabilizer system (PVP K17 and SDS) did not result in greater extent of particle size reduction of the nanosuspension (Fig. 2), enhanced redispersibility was shown by spray-dried nanosuspension prepared with the binary stabilizer system. This study demonstrated that stabilizing effect of electrostatic repulsion provided by surfactants and steric protection provided by short-chain polymeric materials are not strong enough to prevent particles from aggregation DOI 10.1002/jps.24015
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Figure 9. SEM images of spray-dried nanosuspension stabilized with (a) PVP K17–SDS; (b) SDS; (c) PVP K12; (d) F68.
after spray-drying process. However, by the combination of long-chain polymeric material and surfactants, particle size increased only by 11% (RDI value from 100% to 110%), indicating improved stability and redispersibility. Similar results were reported by He et al.35 Compared with traditional surfactants, denaturation of proteins, such as soybean protein isolate, whey protein isolate, $-lactoglobulin, which combined electrostatic and steric stabilization mechanism, showed excellent stabilization performance during nanosization and drying process,9,35 and redispersibility results showed that both particle size and size distribution of redispersed nanosuspensions were similar with that of the original nanosuspensions.9 Influence of Drug Concentration From the processing efficiency point of view, nanosuspensions with a higher drug concentration are more desirable for spray drying because less water is needed to be removed. In this study, by keeping the concentration of stabilizer at 20% of the drug content, the influence of drug loading of the nanosuspension on the redispersibility of spray-dried powder was further investigated. As showed in Figure 10, spray-dried powders prepared from nanosuspensions with a drug concentration ranging from 0.5% to 3% did not show significant difference in redispersibility. Characterization of Spray-Dried Powders Crystal Form High-energy input during particle size reduction may induce crystalline form change.36 The solid-state properties of the drug in spray-dried powders were evaluated by XRPD and diffraction scanning calorimetry (DSC) analysis, respectively. Figure 11a presents the XRPD pattern of the spray-dried powder of lovastatin nanosuspension; the sharp peaks indicate the crystalline DOI 10.1002/jps.24015
Figure 10. Influence of lovastatin concentration on the RDI value of spray-dried powders stabilized by K17–SDS at inlet temperature of 70◦ C and atomizing pressure of 240 kpa.
form of the drug. By comparing with the characteristic peaks in the pattern of a lovastatin powder, it is clear that lovastatin maintained its original crystalline structure after homogenization and spray drying. This indicated that the crystalline form of lovastatin was not altered during high-pressure homogenization and spray drying. As shown in Figure 11b, the DSC results revealed that the endothermic peak of the spray-dried powders was similar to that of the original drug. The results of this study demonstrated Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
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Figure 11. Characterization of spray-dried lovastatin nanosuspensions stabilized by PVP K17–SDS and coarse lovastatin (a) X-ray diffraction patterns; (b) DSC thermograms.
that both high-pressure homogenization and spray drying did not change the crystalline structure of lovastatin. As shown by the results of the DSC and XRPD analysis, the crystalline nature of lovastatin was not changed in the spraydried nanosuspensions, but the melting onset peak (162.3◦ C) was slightly left shifted as compared with that of the original drug powder (169.2◦ C). This temperature shift can be the result of the nanosize of the particles as predicted by the Gibbs– Thomson equation on the reduction in the melting point of small crystals.37 Similar observations were also reported by others.14,38 As shown by the XRPD patterns, the relatively reduced intensity and broadening of the peaks seen in the pattern of the nanoparticles can also be the results of nanolization via high-pressure homogenization.39 In Vitro Dissolution Study On the basis of the solubility of lovastatin in different SDS solutions, one sink condition (0.3% SDS) and two nonsink conditions (0.15% SDS and 0.1% SDS) were selected for this study to determine the dissolution profile of a coarse drug powder, a nanosuspension, and a spray-dried drug powder prepared from the nanosuspension. As shown in Figure 12, no apparent difference in dissolution behavior was found for lovastatin nanosuspensions in the three different dissolution media and complete drug dissolution was observed in 10 min. On the contrary, when a lovastatin coarse powder was tested, drug dissolution rate and extent decreased greatly under the nonsink condition. Therefore, the selection of a nonsink condition for dissolution test can provide a greater differential power in particular when a nanosuspension is evaluated; hence, a phosphate buffer containing 0.1% SDS was selected as the dissolution medium for this study. Figure 13 shows that the dissolution profile of a spray-dried powder of a nanosuspension of lovastatin is not statistically different (f2 > 50) from that determined for a freshly prepared nanosuspension with the same formulation. This result confirms that spray drying of a well-formulated nanosuspension under optimized processing conditions can result in a powder retaining the superior in vitro dissolution characteristics of the nanosuspension. Zhang et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:2166–2176, 2014
Figure 12. In vitro dissolution profiles of lovastatin coarse powder and lovastatin nanosuspension stabilized by PVP K17–SDS in different dissolution media.
As depicted by Figure 12, lovastatin nanosuspension and lovastatin coarse powder displayed significantly different dissolution profiles in 0.1% SDS dissolution medium. The fast dissolution profile of lovastatin nanosuspension is mainly because of the remarkably increased surface area. Similar dissolution performance in 0.1% SDS dissolution medium was also shown for the nanosuspension before and after spray drying. This further confirms that the spray-drying process did not adversely affect the fast dissolution characteristics of a nanosuspension.
CONCLUSIONS In this study, dry powders of lovastatin nanosuspensions were prepared by high-pressure homogenization followed by spray drying without the use of protectant. It was found that inlet air temperature, atomizing pressure, and the type of stabilizers used in the nanosuspension formulation had significant DOI 10.1002/jps.24015
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Figure 13. In vitro dissolution profiles of lovastatin coarse powder, spray-dried nanosuspension powder, and original nanosuspension stabilized by PVP K17–SDS in 0.1% SDS dissolution medium.
influence on the redispersibility of the spray-dried powders. SEM photomicrographs of the spray-dried powders showed that the spherical microparticles were composed of nanoparticles with different degrees of aggregation/coalescence. Among the spray-drying process parameters investigated, the inlet air temperature had the most significant impact on the extent of aggregation/coalescence of the nanoparticles, whereas the effect of atomizing pressure was more pronounced at a low inlet air temperature. These two variables were found to be the determining factors on the redispersibility of the spray-dried powder; a less degree of nanoparticle aggregation/coalescence resulted in an improved dispersibility. The dispersibility of spray-dried powder was shown to be further improved by using a binary stabilizer system that is capable of providing a dual stabilization mechanism: electrostatic and steric stabilization.
ACKNOWLEDGMENTS This project is financially supported by Liaoning Institutions excellent talents support plan (No. LR2013047).
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DOI 10.1002/jps.24015
