Clay as a matrix former for spray drying of drug nanosuspensions

International Journal of Pharmaceutics 465 (2014) 83–89

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Clay as a matrix former for spray drying of drug nanosuspensions Yuancai Dong a, *, Wai Kiong Ng a , Jun Hu a , Shoucang Shen a , Reginald B.H. Tan a,b, ** a b

Institute of Chemical and Engineering Sciences, 1 Pesek Road, Jurong Island, 627833, Singapore Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, 119260, Singapore

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 December 2013 Received in revised form 17 January 2014 Accepted 15 February 2014 Available online 19 February 2014

Utilization of sugars (e.g. lactose, sucrose) as matrix formers for spray drying of drug nanosuspensions is associated with two drawbacks: (1) sugars are incapable of preventing agglomeration of drug nanoparticles (NPs) in the suspension state; and (2) the spray-dried sugars are usually amorphous and hygroscopic. This work aimed to apply a clay, montmorillonite (MMT) as an alternative matrix former for spray drying of drug nanosuspensions with fenofibrate (feno) as a model compound. Drug nanosuspensions were synthesized by liquid antisolvent precipitation with different amount of MMT followed by spray drying. It is found that MMT is able to reduce the agglomeration of drug nanoparticles in the suspension state, as observed from the gradual alleviation of the clogging with the increased clay during the spray drying. The spray-dried feno NPs/MMT powders exhibited a much lower moisture sorption than spray-dried feno NPs/lactose powders as evidenced by the dynamic vapor sorption (DVS) analysis. The dissolution within 5 min for the spray-dried feno NPs/MMT powders at drug:MMT weight ratio of 1:3 was 81.4  1.8% and the total dissolution within 60 min was 93.4  0.9%. Our results demonstrate that MMT is a useful matrix former for preservation of the high dissolution rate of nanosized drug particles after drying. ã 2014 Elsevier B.V. All rights reserved.

Keywords: Clay Montmorillonite Spray-drying Drug nanosuspensions Dissolution

1. Introduction Nanosizing, leading to the creation of an extremely enhanced surface area and increased saturation solubility, is an effective approach to expedite the dissolution rate of the poorly watersoluble drugs and result in an improved bioavailability (Rabinow, 2004; Kesisoglou et al., 2007; Shegokar and Müller, 2010; Möschwitzer, 2013). Size diminution to the submicron range can be realized by either “top-down” approach from the large coarse drug particles (milling and high pressure homogenization) or “bottom-up” means from the drug solution (e.g. liquid antisolvent precipitation, supercritical fluid technology, etc.) (Sinha et al., 2013). Whichever the approach used, suspensions of the nanoparticles (NPs), i.e. nanosuspensions, are generally the initial product form achieved, as the water and/ or solvent have to be used in most of the nanosizing processes. Drug nanoparticles in the suspension state, however, are not stable, as they tend to grow and agglomerate, especially the nanosuspensions of poorly water-soluble drugs (Liu et al., 2007; Verma et al., 2011). Therefore, in terms of the stability as well as

* Corresponding author. Tel.: +65 67963864; fax: +65 63166183. ** Corresponding author. Tel.:+65 67963841; fax: +65 63166183. E-mail addresses: [email protected] (Y. Dong), [email protected] (R. B.H. Tan). http://dx.doi.org/10.1016/j.ijpharm.2014.02.025 0378-5173/ã 2014 Elsevier B.V. All rights reserved.

the convenience for the patient, drug nanosuspensions are required to be processed into the dried powders, which can be achieved by spray drying, freeze drying, pelletization or granulation (Chaubal and Popescu, 2008; Van Eerdenbrugh et al., 2008a; Cerdeira et al., 2013). Agglomeration of the individual nanoparticles, however, would occur upon drying leading to a reduced effective surface area and slower dissolution rate. To preserve the high dissolution rate of the nanosized drug particles, some water-soluble sugar-based matrix formers are frequently used in the drying process to prevent agglomeration, e.g. lactose, sucrose, etc. After drying, the individual nanoparticles are embedded inside or layered onto the sugar particles. Upon redispersion, sugars are immediately dissolved releasing the individual nanoparticles to the medium and resulting in a high dissolution rate. However, two inherent drawbacks are associated with the sugar matrix formers: first, sugars are incapable of preventing agglomeration of drug nanoparticles in the suspension state (Chaubal and Popescu, 2008), as the dissolved sugar molecules cannot form a permanent solid barrier against particle–particle interaction (Fig. 1(a)). Previously, our group has synthesized drug nanosuspensions using liquid antisolvent precipitation followed by spray drying to achieve the redispersible powders (Hu et al., 2011). It was observed that clogging in the pumping tubing frequently occurred during the spray-drying process due to the formation of the large agglomerated lumps. Once clogging arose,

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Fig. 1. Schematic description of suspension and dried state of NPs with (a) lactose and (b) MMT as a matrix former.

pumping of the drug nanosuspensions to the spray drier failed to proceed. Second, sugars, after the spray drying process, are generally amorphous and hygroscopic. More strict conditions for storage or further processing (tableting or capsule-filling) are thus required. Therefore, an alternative matrix former is demanded to circumvent the problems encountered using the sugars. In literature, some insoluble alternative matrix formers, e.g. microcrystalline cellulose, SiO2, etc., have been reported to exhibit excellent performance for preservation of high dissolution rate of drug nanoparticles after drying (Van Eerdenbrugh et al., 2008b,c,d, 2009). Clays, owing to the high specific surface area and ion exchange/ adsorption capability, favorable rheological characteristics (swelling, dispersion as well as thixotropic and colloidal properties), nontoxicity and chemical inertness, have been broadly used in the oral and dermal pharmaceutical formulations. As active ingredients, clays have generally been used as gastrointestinal protectors, osmotic oral laxatives, antidiarrhoea agents, antiseptics dermatological protectors, etc.; as excipients, clays have been frequently used as lubricants, disintegrants, drug carriers, emulsifying/ thickening/anticaking agents, etc. (Isabel Carretero 2002; Aguzzi et al., 2007; Del Hoyo, 2007; López-Galindo et al., 2007; Isabel Carretero and Pozo, 2009, 2010). Among a wide spectrum of clays, montmorillonite (MMT) is more extensively investigated due to its comparatively higher surface area, higher ion exchange and adsorption capability, and excellent rheological behavior. MMT belongs to the smectite group and is formed by stacking of a number of aluminosilicate layers with 2:1 structure, i.e. one layer is composed of an alumina octahedral sheet sandwiched by two silica tetrahedral sheets. As an active, MMT is used to treat diarrheal and painful symptoms associated with oesophageal-gastric and intestinal diseases (e.g. SMECTA1). As excipients, MMT is capable of controlling the drug release by intercalation of the drug molecules in the interlayers (Park et al., 2008; Joshi et al., 2009) or by forming composites with polymers (Dong and Feng, 2005; Campbell et al., 2009). Moreover, the dissolution rate of the poorly water-soluble drugs could be accelerated by adsorption of the drug molecules onto the MMT surface (McGinity and Harris, 1980).

This work is aimed at seeking an alternative matrix former for spray drying of drug nanosuspensions. The ideal matrix former needs to fulfill the below requirements: (1) it is able to prevent the agglomeration of the drug nanoparticles in the suspension state; (2) it is able to preserve the high dissolution rate of drug nanoparticles after drying; and (3) inclusion of the matrix former has no negative effect on the rheological properties of the nanosuspensions; thus, the spray drying can be operated smoothly without clogging. For this purpose, MMT clay is proposed as an alternative matrix former for spray drying of drug nanosuspensions. The stabilization mechanism of MMT on the nanoparticles is depicted in Fig.1(b). In the suspension state, the freshly synthesized nanoparticles are instantaneously adsorbed onto the large surfaces of the plate-shaped MMT; therefore, the particle–particle interactions and the subsequent agglomeration are alleviated. After spray drying, the nanoparticles are immobilized and layered onto the MMT surface. Upon redispersion, the individual nanoparticles are desorbed and released to the medium followed by a rapid dissolution. In this work, fenofibrate (feno) was used as a model hydrophobic compound. Drug nanosuspensions in the presence of MMT were synthesized by liquid antisolvent precipitation technique, which was processed into the dried powders by an immediate spray drying. Morphology of the nanoparticles and the dried powders were visualized by field emission scanning electronic microscopy (FESEM). Physical state of the samples was analyzed by X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Moisture sorption behaviors of the spray-dried products were determined by dynamic vapor sorption (DVS). Finally, dissolution was performed to evaluate the success of MMT as a matrix former for drug nanoparticles. 2. Materials and methods 2.1. Materials Fenofibrate, polyvinylpyrrolidone 10 (PVP10) and sodium dodecyl sulfate (SDS) were purchased from Sigma–Aldrich. MMT (CLOISITE1Ca++) was a gift from Southern Clays Products Inc. HPLC grade ethanol was supplied by Fisher Scientific. D.I water was used throughout the work. 2.2. Synthesis and spray drying fenofibrate nanosuspensions Fenofibrate nanosuspensions were synthesized by liquid antisolvent precipitation technique. Briefly, 20 mg/ml fenofibrate, 2 mg/ ml PVP10 and different amount of MMT were dissolved/suspended in ethanol, 3 ml of which was injected to 9 ml water leading to the formation of fenofibrate nanosuspensions. Spray drying (Büchi B290) was immediately performed under the below process parameters: the inlet temperature was set as 140  C; the flow rate of nitrogen was 40 mm; the aspiration and pumping rate was 100% and 20%, respectively. The spray-dried feno NPs/MMT powders with different amount of MMT were denoted as different drug:MMT weight ratios correspondingly, i.e. 1:1, 1:2, 1:3 and 1:4. They were stored in a capped bottle at the ambient conditions for 3 days before physical characterization and dissolution measurement. 2.3. Solubility of fenofibrate in the antisolvent precipitation system Since the antisolvent precipitation of fenofibrate nanoparticles and the followed spray drying was completed within 3 min, the solubility of fenofibrate in the antisolvent precipitation system was determined in this time range. Briefly, 1 ml 20 mg/ml fenofibrate ethanol solution with 2 mg/ml PVP10 and different amount of MMT was mixed with 3 ml water under stirring. After 3 min, the obtained suspension was filtered through 220 nm syringe filter. The filtrate

Y. Dong et al. / International Journal of Pharmaceutics 465 (2014) 83–89 Table 1 Solubility of fenofibrate in the antisolvent precipitation system with different amount of MMT.

was analyzed by HPLC analysis (Agilent 1100 with Agilent Eclipse XDB-C18 column, 5 mm, 4.6  150 mm). The mobile phase was a mixture of 70% acetonitrile and 30% water, which was delivered at 1.5 ml/min. The drug was detected at 280 nm. The concentration achieved was considered to be the solubility of fenofibrate in the antisolvent precipitation system within 3 min. 2.4. Morphology Morphology of the raw fenofibrate, MMT, freshly synthesized drug nanoparticles and spray-dried products were observed by FESEM (JEOL JSM-6700F). Suspensions or powders were deposited onto the double-sided carbon tape and sputtered for 90 s before visualization.

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Drug:MMT weight ratio

Solubility (mg/ml)

No MMT 1:1 1:2 1:3 1:4

4.56  0.19 19.63  0.26 13.93  4.33 14.67  1.99 6.58  1.47

3.2. Morphology

Moisture sorption behaviour of the spray-dried drug nanoparticles with MMT or lactose as the matrix former was conducted using Dynamic Vapour Sorption analyzer (GVS Advantage, Surface Measurement Systems (SMS) Ltd., London, UK). The required %RH (relative humidity) was controlled by mixing dry nitrogen and nitrogen saturated with water vapour in the corresponding proportions using mass flow controller. Approximately 20 mg of sample was weighed and conducted under 0–90%RH in steps of 10% RH for each experiment. The system was considered to be in equilibrium if the rate change of mass was less than 0.002%/min. All experiments were conducted at 25  C.

Fenofibrate nanosuspensions were synthesized by liquid antisolvent precipitation technique in the presence of the stabilizer PVP10 and the matrix former MMT. Spray drying was performed instantaneously to obtain the dried products. It was observed that, the clogging during the spray drying process was gradually reduced with the increase of MMT amount. There was hardly clogging detected at 1:3 and 1:4 drug:MMT weight ratios. This demonstrates that MMT is able to prevent the agglomeration of the drug nanoparticles in the suspension state, which is most likely via the adsorption of the submicron particles onto its huge surface. In addition, MMT suspension possesses excellent flowability. Thus, spray drying of fenofibrate nanosuspensions by inclusion of MMT is able to be operated smoothly without clogging. Fig. 2 displays the morphology of raw fenofibrate, MMT, freshly synthesized fenofibrate nanoparticles and the typical spray-dried feno NPs/MMT powders. As seen in Fig. 2(a), raw fenofibrate exhibited a block-like shape with the size ranging from several to tens of microns. Fig. 2(b) displayed the plate-shaped MMT particles with the size of less than 10 mm. The size of the freshly precipitated fenofibrate particles prepared with drug:MMT weight ratio of 1:3 was less than one micron with rhombohedral or close-to-rhombohedral shape confirming the formation of nanoparticles (Fig. 2(c)). The spraydried feno NPs/MMT powders prepared with drug:MMT weight ratio of 1:3 were close-to-spherical lumps with the size of several to more than 10 mm (Fig. 2(d)). Under high magnifications, it can be observed that the spray-dried particles were constituted by a number of the plate-shaped MMT particles (Fig. 2(e)). All the other fenofibrate nanoparticles and spray-dried feno NPs/MMT powders prepared with different drug:MMT ratios showed similar morphology without observable difference (pictures not shown).

2.8. Dissolution

3.3. DSC

2.5. DSC Thermograms of the raw fenofibrate, MMT and the spray-dried products were investigated using Diamond DSC Calorimeter (PerkinElmer). The sample was heated to 140  C at 10  C/min in N2 atmosphere. 2.6. XRD Diffractograms of the raw fenofibrate, MMT and the spraydried products were analyzed by D8-ADVANCE (BRUKER) X-ray diffractometer from 2–40 (2u) at a step of 0.017 using Cu Ka radiation. 2.7. DVS

Dissolution profiles of the raw fenofibrate and the spray-dried products were measured according to the USP XXV type II (paddle) method (VK 7010, VARIAN). The dissolution medium was 900 ml water containing 0.025 M SDS. An equivalent 20 mg fenofibrate powders were used for dissolution. The paddle speed and the bath temperature were 100 rpm and 37  C, respectively. 0.5 ml of the medium was sampled at specific intervals and filtered (pore size: 220 nm) for HPLC analysis as described above. 3. Results and discussion 3.1. Solubility Table 1 lists the solubility of fenofibrate (within 3 min) in the mixture of 1 ml ethanol (containing 2 mg PVP10) and 3 ml water in the presence of different amount of MMT. As can be seen, the solubility of fenofibrate ranged from 4.56 to 19.63 mg/ml. Since the final drug concentration was 5 mg/ml in the antisolvent precipitation system, it can thus be concluded that nearly 100% of the soluble fenofibrate was precipitated out into solid particles during the antisolvent precipitation process.

Thermograms of raw fenofibrate, MMT and the spray-dried feno NPs/MMT powders between 20–130  C are presented in Fig. 3. As can be seen, MMT did not show noticeable physical transitions in the investigated range. Raw fenofibrate exhibited a melting peak at 83.4  C and the enthalpy was determined to 90.9 J/g. For the spraydried feno NPs/MMT products, the melting peak was shifted to 78.6–79.9  C and the enthalpy was decreased to 51.90, 55.80, 56.13 and 52.19 J/g for the products with the drug:MMT weight ratio of 1:1, 1:2, 1:3 and 1:4, respectively. This demonstrates that the formed fenofibrate nanoparticles had an increased extent of amorphization. The reason is that, perfect fenofibrate crystals are hardly achieved under the rapid precipitation and instant drying process. 3.4. XRD Fig. 4 displays the XRD diffractograms of raw fenofibrate, MMT and the spray-dried feno NPs/MMT powders. Raw fenofibrate exhibited characteristic crystalline peaks at 2u of 11.8,12.6,14.3 16.1, 16.8 and 22.1. The characteristic peak of (0 0 1) plane for MMT was observed at 5.8 . For the spray-dried products, the distinct

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Fig. 2. Morphology of (a) raw fenofibrate (b) MMT (c) freshly synthesized fenofibrate nanoparticles at drug:MMT weight ratio of 1:3 (d) spray-dried feno NPs/MMT powders at drug:MMT weight ratio of 1:3 and (e) high magnification of (d).

fenofibrate XRD peaks were still maintained with decreased intensity demonstrating the presence of nanoparticles in the crystalline state. In addition, there still existed the characteristic peak of MMT at the same 2u position demonstrating that MMT is not exfoliated or intercalated by drug molecules in the antisolvent precipitation-spray drying process.

[(Fig._3)TD$IG]

3.5. Moisture sorption profiles by DVS One of the drawbacks using the sugar (e.g. lactose, sucrose) as the matrix former as mentioned previously is that, the spray-dried sugars are usually amorphous and tend to absorb moisture. Flowability, redispersion and dissolution of the dried drug NPs/ sugar powders would thus be negatively affected. In our study, it was observed that, after one day, the spray-dried feno NPs/lactose powders have experienced stickiness and loss of flowability at the ambient conditions due to the absorption of moisture. Under the

Fig. 3. Thermograms of raw fenofibrate (feno), MMT and the spray-dried feno NPs/ MMT powders.

Y. Dong et al. / International Journal of Pharmaceutics 465 (2014) 83–89

[(Fig._6)TD$IG]

[(Fig._4)TD$IG]

Fig. 6. Dissolution behaviours of raw fenofibrate (feno) and spray-dried feno NPs/ MMT powders at different feno:MMT weight ratios.

Fig. 4. XRD diffractograms of raw fenofibrate (feno), MMT and the spray-dried feno NPs/MMT powders.

same conditions, however, the spray-dried feno NPs/MMT powders have not seen the significant change in flowability even after six months compared to the freshly prepared products. To measure the moisture sorption profiles of the spray-dried feno NPs with MMT or lactose as the matrix former, DVS was carried out using step adsorption (10–90%RH). It can be observed from Fig. 5 that, the spray-dried feno NPs/lactose powders exhibited an increasingly higher moisture sorption uptake from 10 to 50%RH in comparison with the spray-dried feno NPs/MMT powders. At 50%RH, feno NPs/ lactose powders exhibited 63.5% higher moisture uptake than feno NPs/MMT powders (10.27% vs 6.28%). In addition, recrystallization of the amorphous lactose occurred at 50%RH, which is resulted from the increased molecular mobility (i.e. a lower glass transition temperature Tg) due to the absorption of a larger amount of moisture. Moisture uptake of the spray-dried feno NPs/lactose powders was decreased afterwards due to the formation of the crystalline lactose (Paterson et al., 2005; Foster et al., 2006). 3.6. Dissolution To evaluate the success of MMT as a matrix former, dissolution was performed on the spray-dried feno NPs/MMT powders. In our preliminary studies, the solubility of fenofibrate in the dissolution medium (0.025 M SDS aqueous solution at 37  C) was 287.3  1.4 mg/ml; while the solubility was determined to be 281.0  0.7 and 285.8  30.3 mg/ml, respectively by inclusion of 0.088 (for 20 mg drug dissolution dosage with feno NPs/MMT 1:3 product) and 0.644 mg/ml (for 145 mg drug dissolution dosage with feno NPs/MMT 1:3 product) MMT into the above medium. Therefore, dissolution in this study was performed in sink

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conditions and the presence of MMT did not induce striking change of fenofibrate solubility in the dissolution medium. Fig. 6 displays the dissolution behaviours of the raw fenofibrate and spray-dried feno NPs/MMT powders with different drug:MMT weight ratios. As can be seen, for raw fenofibrate, there was only 2.8  0.1% of drug dissolved within 5 min and the total dissolution within 60 min was 22.7  0.8%. In comparison, all the spray-dried feno NPs/MMT products exhibited a highly initial burst dissolution (0–5 min) followed by a slower dissolution rate (5–20 min). After 20 min, the dissolution has reached a plateau, and there was no significant difference for the accumulative dissolution within 20 and 60 min. In addition, with the increase of drug:MMT weight ratio from 1:1 to 1:2 and 1:3, the dissolution within 5 min was increased from 54.0  0.5% to 68.9  0.6% and 81.4  1.8%; the total dissolution within 60 min was increased from 69.8  0.4% to 88.1  1.0% and 93.4  0.9%, respectively. The accelerated dissolution of feno NPs/ MMT powders could be ascribed to both the diminished size (i.e. enlarged surface area and increased saturation solubility) and the increased extent of amorphization of drug particles (Dong et al., 2010). The results clearly demonstrate that MMT is an effective matrix former for preservation of the high dissolution rate of the drug nanoparticles after drying. Moreover, increasing MMT amount provides more surfaces for the adsorption of the synthesized nanoparticles; the possible agglomeration in the suspension and in the drying process is thus more alleviated leading to the increased dissolution. However, further increasing drug:MMT to 1:4 did not result in the corresponding more dissolution: its dissolution was faster than that of drug:MMT weight ratio of 1:1 but slower than those of 1:2 and 1:3. This is probably because that with higher amount of MMT, drug nanoparticles are deeply entrapped inside

[(Fig._5)TD$IG]

[(Fig._7)TD$IG]

Fig. 5. Vapor sorption profiles of the spray-dried feno NPs/MMT and feno NPs/ lactose powders.

Fig. 7. Dissolution behaviours of the spray-dried feno NPs/MMT powders (drug: MMT weight ratio 1:3) with/without PVP10.

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Fig. 8. Dissolution behaviours of the spray-dried feno NPs/MMT powders (drug: MMT weight ratio 1:3) by predispersion of MMT in water and ethanol.

the dried products and redispersion of higher amount of MMT may take a longer time. PVP10 was used in this work as the stabilizer for the formation of drug nanoparticles by liquid antisolvent precipitation; and MMT was the matrix former for the formed nanoparticles. Type and concentration of the stabilizers have great influence on the size, shape and physicochemical properties of the synthesized particles (Matteucci et al., 2006; Verma et al., 2011). Indeed, clays including MMT have been long used as the solid stabilizers for emulsions (Yan and Masliyah, 1995; Sullivan and Kilpatrick, 2002). To investigate if MMT could be solely used as both the stabilizer and matrix former, a control sample was prepared by omitting PVP10 in the ethanol solution and the dissolution behaviour is illustrated in Fig. 7. As can be seen, without PVP10, the spray-dried feno NPs/MMT powders exhibited a much slower dissolution rate: the dissolved drug was reduced from 81.4  1.8% to 45.8  1.3 within 5 min and the total dissolution within 60 min was decreased from 93.4  0.9 to 85.3  4.1%. The result indicates that in comparison with MMT, PVP10 is not a good matrix former but plays essential role in the synthesis of the drug nanoparticles by the liquid antisolvent precipitation. The afore-described results are based on the products synthesized by pre-dispersion of MMT in the ethanol–drug solution. The feno NPs/MMT powders by predispersion of MMT in water were also prepared and the dissolution behaviour is shown in Fig. 8. It can be seen that, there was no significant difference for the particles synthesized by pre-dispersion of MMT in the ethanol or water. This is presumably due to the fact that MMT has excellent dispersion behaviour both in water and ethanol. Therefore, MMT is able to be instantly and homogeneously dispersed in the mixture of ethanol

[(Fig._9)TD$IG]

Fig. 9. Dissolution behaviours of the spray-dried feno NPs/MMT powders (drug: MMT weight ratio 1:3) at dose of 20 and 145 mg.

and water upon mixing. Adsorption of the formed nanoparticles onto the MMT surface is thus not influenced by pre-dispersion of MMT in the water or ethanol. The aforementioned dissolution profiles were achieved based on an equivalent dose of 20 mg fenofibrate instead of 145 mg prescribed by the pharmacopeia, as a smaller dose is often applied in the literature for research purpose (Hu et al., 2011; Niu et al., 2013). To evaluate the performance of the spray-dried feno NPs/MMT products, we also examined the dissolution profile using a dose of equivalent 145 mg drug. From Fig. 9, the spray-dried feno NPs/MMT powders with a dose of 145 mg drug exhibited a highly initial burst dissolution (80.3  0.4%) within 5 min, which has no significant difference in comparison with that of 20 mg fenofibrate. Within 60 min, the dissolution based on 145 mg fenofibrate (90.2  1.5%) is only slightly smaller than that with 20 mg drug (93.4  0.9%). The similar dissolution behaviours of the spray-dried feno NPs/MMT at different dose could be ascribed to the hydrophilicity and the excellent dispersibility of MMT in the medium. 4. Conclusions MMT clay was adopted as a matrix former in the fenofibrate nanosuspensions for spray drying. It was observed that MMT is able to prevent the agglomeration of the nanoparticles in the suspension state as observed from the continuing reduction of clogging with the increase of MMT amount during the spray drying process. Dissolution of the spray-dried feno NPs/MMT products was found to be biphasic with a highly initial burst dissolution followed by a slower dissolution. The feno NPs/MMT powders with drug:MMT weight ratio of 1:3 exhibited 81.4  1.8% dissolution within 5 min and the total dissolution within 60 min was 93.4  0.9%. Similar dissolution behaviours were observed for the spray-dried feno NPs/ MMT product with a dose of 20 and 145 mg drug. MMT is demonstrated to be an effective matrix former for spray drying of drug nanosuspensions and preservation of the nanoparticlesassociated high dissolution rate. Acknowledgement This work was supported by project grant ICES/07-122B01 from A*STAR (Agency for Science, Technology and Research) of Singapore. References Aguzzi, C., Cerezo, P., Viseras, C., Caramella, C., 2007. Use of clays as drug delivery systems: possibilities and limitations. Applied Clay Science 36, 22–36. Campbell, K., Qi, S., Craig, D.Q.M., Mcnally, T., 2009. Paracetamol-loaded poly (e-caprolactone) layered silicate nanocomposites prepared using hot-melt extrusion. Journal of Pharmaceutical Sciences 98, 4831–4843. Cerdeira, A.M., Mazzotti, M., Gander, B., 2013. Formulation and drying of miconazole and itraconazole nanosuspensions. International Journal of Pharmaceutics 443, 209–220. Chaubal, M.V., Popescu, C., 2008. Conversion of nanosuspensions into dry powders by spray drying: a case study. Pharmaceutical Research 25, 2302–2308. Del Hoyo, C., 2007. Layered double hydroxides and human health: an overview. Applied Clay Science 36, 103–121. Dong, Y., Feng, S.S., 2005. Poly(D,L-lactide-co-glycolide)/montmorillonite nanoparticles for oral delivery of anticancer drugs. Biomaterials 26, 6068–6076. Dong, Y., Ng, W.K., Hu, J., Shen, S., Tan, R.B.H., 2010. A continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs. International Journal of Pharmaceutics 386, 256–261. Foster, K.D., Bronlund, J.E., Paterson, A.H.J., 2006. Glass transition related cohesion of amorphous sugar powders. Journal of Food Engineering 77, 997–1006. Hu, J., Ng, W.K., Dong, Y., Shen, S., Tan, R.B.H., 2011. Continuous and scalable process for water-redispersible nanoformulation of poorly aqueous soluble APIs by antisolvent precipitation and spray-drying. International Journal of Pharmaceutics 404, 198–204. Isabel Carretero, M., 2002. Clay minerals and their beneficial effects upon human health. Applied Clay Science 21, 155–163.

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