`
`European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 283–288
`
`www.elsevier.com/locate/ejpb
`
`Research paper
`
`Dissolution enhancement of fenofibrate by micronization, cogrinding
`and spray-drying: Comparison with commercial preparations
`
`Markus Vogt a,b, Klaus Kunath b, Jennifer B. Dressman a,*
`
`a Department of Pharmaceutical Technology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
`b Global Pharmaceutical Development, Merck KGaA, Darmstadt, Germany
`
`Received 3 May 2006; accepted in revised form 15 May 2007
`Available online 21 May 2007
`
`Abstract
`
`Several techniques were compared for improving the dissolution of fenofibrate, a poorly soluble drug. Particle size reduction was real-
`ized by jet milling (micronization; cogrinding with lactose, polyvinylpyrrolidone or sodium lauryl sulphate) and by media milling using a
`bead mill (nanosizing) with subsequent spray-drying. Solid state characterization by X-ray diffraction and Differential Scanning Calo-
`rimetry verified the maintenance of the crystalline state of the drug after dry milling and its conversion to the amorphous state during
`spray-drying. Micronization of fenofibrate enhanced its dissolution rate in biorelevant media (8.2% in 30 min) compared to crude mate-
`rial (1.3% in 30 min). Coground mixtures of the drug increased the dissolution rate further (up to 20% in 30 min). Supersaturated solu-
`tions were generated by nanosizing combined with spray-drying, this process converted fenofibrate to the amorphous state. Fenofibrate
`drug products commercially available on the German and French markets dissolved similarly to crude or micronized fenofibrate, but
`significantly slower than the coground or spray-dried fenofibrate mixtures. The results suggest that cogrinding and spray-drying are pow-
`erful techniques for the preparation of rapidly dissolving formulations of fenofibrate, and could potentially lead to improvements in the
`bioavailability of oral fenofibrate products.
`Ó 2007 Elsevier B.V. All rights reserved.
`
`Keywords: Biorelevant media; Cogrinding; Dissolution rate enhancement; Fenofibrate; Jet milling; Micronization; Particle size reduction; Spray-drying
`
`1. Introduction
`
`Poorly water-soluble drugs often require high doses in
`order to reach therapeutic plasma concentrations after oral
`administration. Improvement in the extent and rate of dis-
`solution is highly desirable for such compounds, as this can
`lead to an increased and more reproducible oral bioavail-
`ability and subsequently to clinically relevant dose reduc-
`tion and more reliable therapy.
`Nowadays, pharmaceutical technology provides many
`approaches to enhance the dissolution rate of poorly solu-
`ble drugs. Physical modifications often aim to increase the
`surface area, solubility and/or wettability of the powder
`
`* Corresponding author. Department of Pharmaceutical Technology,
`Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. Tel.:
`+49 69 798 29680; fax: +49 69 798 29694.
`E-mail address: dressman@em.uni-frankfurt.de (J.B. Dressman).
`
`0939-6411/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
`doi:10.1016/j.ejpb.2007.05.010
`
`particles and are therefore focused on particle size reduc-
`tion or generation of amorphous states [1,2]. The increase
`in bioavailability after micronization of drugs, e.g., by jet
`or ball milling has been well documented (e.g., danazol
`[3], progesterone [4], digoxin [5]). Cogrinding processes
`are comparatively seldom described in the literature and
`have often employed large quantities of water-soluble poly-
`mers as dispersion carriers [6,7]. Reduction of particle size
`to the nanometer scale can be achieved by precipitation or
`by milling. The latter requires special techniques such as
`bead milling [8,9] or high pressure homogenization [10].
`In order to obtain a dry form, further pharmaceutical oper-
`ations are required (e.g., lyophilisation or spray-drying).
`Spray-drying is known to produce amorphous material
`due to rapid solvent evaporation [11].
`Fenofibrate has been used for many years to lower cho-
`lesterol levels and its pharmacokinetic profile is well under-
`stood [12,13]. Originally launched in 1975, it is currently on
`
`Page 1
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`LUPIN EX. 1018
`Lupin v. iCeutica
`US Patent No. 9,017,721
`
`
`
`284
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`M. Vogt et al. / European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 283–288
`
`the market in more than 85 countries [14]. The compound
`is practically insoluble in water [15,16] and has high lipo-
`philicity (log P = 5.24) [12]. Thus the dissolution rate of
`fenofibrate is expected to limit its absorption from the gas-
`trointestinal tract. Attempts to increase the oral bioavail-
`ability of the drug have therefore chiefly centered on
`particle size reduction. Increasing the rate and extent of
`dissolution of fenofibrate by micronization has been shown
`to lead directly to an increased oral bioavailability, which
`in turn enables dosage reduction [12]. Recently, ‘‘suprabio-
`available’’ tablets have been developed combining the clas-
`sic micronization process with a specific microcoating
`technology, through which micronized drug particles are
`coated onto hydrophilic polyvinylpyrrolidone (PVP) cores
`[14].
`The current paper compares the production of fenofi-
`brate preparations by several physical techniques including
`micronization; cogrinding with lactose, polyvinylpyrroli-
`done (PVP) and sodium lauryl sulphate (SLS); and nano-
`sizing in a bead mill combined with spray-drying. These
`preparations were evaluated with respect to their X-ray
`diffraction (XRD), Differential Scanning Calorimetry
`(DSC) and dissolution behaviour. In vitro dissolution
`studies of the formulations were performed in biorelevant
`media and included comparison with two commercial
`fenofibrate products from the German market (Lipan-
`thylÒ, LipidilÒ) and one product from the French market
`(SecalipÒ).
`
`2. Materials and methods
`
`2.1. Chemicals
`
`Fenofibrate was purchased from Sigma (Steinheim, Ger-
`many). Its chemical structure is given in Fig. 1. SLS, lactose
`monohydrate and Polyvidone 25 (PVP) were from Merck
`KGaA (Darmstadt, Germany). Sodium taurocholate was
`obtained from Prodotti Chimici E Alimentari S.P.A.
`(Basaluzzo,
`Italy). Egg-phosphatidylcholine, Lipoid E
`PC, was purchased from Lipoid GmbH (Ludwigshafen,
`Germany). All other chemicals used were of HPLC grade
`or analytical grade. Commercial products of fenofibrate
`were LipanthylÒ (lot 77744/NK, expiry 01/2009), LipidilÒ
`(lot 74493, expiry 01/2006) and SecalipÒ (lot 74185, expiry
`02/2008).
`
`2.2. Solubility determination
`
`The solubility of fenofibrate was determined in water
`and the biorelevant media FaSSIF (Fasted State Simulated
`
`O
`
`Me
`
`O
`
`Me
`
`Me
`
`O
`
`Me
`
`Cl
`
`O
`
`Fig. 1. Chemical structure of fenofibrate (MW = 360.8).
`
`Intestinal Fluid) and FeSSIF (Fed State Simulated Intesti-
`nal Fluid) [17] using a standardized shake flask method at
`37 °C with shake times of 48 h. The sample was then fil-
`tered through a 0.22 lm membrane filter and the filtrate
`was assayed per HPLC.
`
`2.3. Preparation of physical mixtures and commercial
`products
`
`Physical mixtures were prepared by physically blending
`fenofibrate (10%) with excipient(s), and then manually fill-
`ing the blend into Coni-Snap Supro A hard gelatine cap-
`sules (Conisnap, Belgium). The commercial products of
`fenofibrate were all hard gelatine capsules. They were
`quantitatively emptied, then appropriate amounts of the
`powder accurately weighed and manually filled into Coni-
`Snap Supro A hard gelatine capsules.
`
`2.4. Preparation of micronized drugs and coground mixtures
`
`Micronized fenofibrate and coground mixtures were
`prepared by milling the drug by itself or as a physical mix-
`ture with various excipients in an Alpine 50 AS jet mill
`(Hosokawa Alpine AG, Germany) operating at 5 bar air
`pressure and a feed rate of 0.5–1.0 g/min. The milled pow-
`der was then manually filled into Coni-Snap Supro A hard
`gelatine capsules, after blending with lactose (if necessary)
`to obtain a concentration of the active substance of 10%.
`Homogeneity of the mixtures was confirmed by quantita-
`tive HPLC determination of the drug content after accu-
`rate weighing of an aliquot of powder (n = 3), dissolving
`and diluting with mobile phase.
`
`2.5. Preparation of spray-dried powder
`
`A nanoparticulate dispersion of fenofibrate was pre-
`pared by a media milling process using a Dyno Mill (Willy
`A. Bachofen AG Maschinenfabrik, Switzerland) operating
`in the circulation mode. A 300 ml cylindrical steel vessel
`with inside coating was filled with 0.1 mm grinding spheres
`to fill approximately 85% of the volume. A 600 ml suspen-
`sion containing 30 g fenofibrate, 30 g lactose and 3 g SLS in
`water was pre-treated in an Ultra-Turrax at 20,500 min 1
`before processing in the mill for 90 min – it had been pre-
`viously demonstrated that nanoparticles are produced
`quantitatively after that period of milling. A Bu¨ chi Mini
`Spray Dryer B-191 (Bu¨ chi Labortechnik AG, Switzerland)
`was connected directly to the mill, enabling continuous
`transfer of the suspension from the milling chamber outlet
`to the spray nozzle. The mill was kept operating during the
`spray-drying process in order to maintain homogeneity of
`the suspension. Just before starting the spray dryer, the
`nanoparticulate suspension was diluted with 300 ml water.
`The spray dryer was fitted with a 0.7 mm pneumatic nozzle
`and operated at 6 bar air pressure, 11 ml/min pump speed,
`600 l/h air flow rate, 80% aspirator level and 150 °C inlet
`temperature.
`
`Page 2
`
`
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`M. Vogt et al. / European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 283–288
`
`285
`
`2.6. Particle size measurement
`
`2.11. Statistical evaluation and presentation
`
`Particle size was determined by laser light diffraction.
`The equipment consisted of a Malvern Mastersizer 2000
`(Malvern Instruments, Germany)
`including a Scirocco
`2000 module for dry measurement purposes operating at
`3.0 bar air pressure for dispersion – it had been established
`that a sufficient dispersion of particles but no milling
`occurs at this level of air pressure – with evaluation of data
`by Malvern software version 4.0 using the Fraunhofer
`approximation as the evaluation algorithm [18].
`
`2.7. HPLC analysis
`
`The system consisted of a Merck Hitachi pump
`L-6200 A, a Merck Column Thermostat T-6300 operating
`at 36 °C, a Merck Hitachi Interface D-6000 A, a Merck
`Hitachi UV–Vis Detector L-4250 and a Merck Hitachi
`Autosampler AS-4000 A. Data acquisition and evaluation
`was performed with Merck Hitachi D-7000 Chromatogra-
`phy Data Station Software version 4.0. Using a LiChro-
`spher 60 RP select B 125-3 (5 lm) column and a mobile
`phase consisting of 40% of pure water and 60% of acetoni-
`trile at a flow rate of 1.35 ml/min, fenofibrate was eluted at
`approximately 3 min. The detection wavelength was set at
`288 nm.
`
`2.8. X-ray diffraction studies
`
`Powder X-ray diffraction was used to assess the degree
`of crystallinity of micronized, coground and spray-dried
`fenofibrate at ambient temperature using a Bruker AXS
`diffractometer (Bruker AXS GmbH, Germany) with a
`PSD-50 M detector and EVA Application Software version
`6. Measurements were performed with a Cu Ka radiation
`source at 40 kV voltage, 30 mA current and a scanning
`speed of 2°/min.
`
`2.9. Differential scanning calorimetry
`
`DSC curves were obtained by a Differential Scanning
`Calorimeter (DSC 821e, Mettler-Toledo, Switzerland) at a
`heating rate of 5 K/min from 25 to 250 °C under nitrogen.
`
`2.10. Dissolution testing
`
`Release from the capsules was determined in a cali-
`brated USP XXVIII apparatus 2 (paddle method)
`in
`900 ml medium using a PharmaTest dissolution tester
`(Type PTWS, PharmaTest, Germany) operating at 75
`rpm and 37 °C. Helix sinkers (11/31, 8/23, Sotex GmbH,
`Germany) were used to prevent floating of the capsules.
`Samples were taken according to USP guidelines by with-
`drawal of 3 ml at each sampling time. Each sample was
`immediately filtered through a 0.2 lm PTFE filter and
`appropriately diluted with HPLC mobile phase prior to
`analysis.
`
`Results from solubility determinations (n = 3) and dis-
`solution studies (n = 3) are presented as mean values with
`standard deviations. Particle
`size distribution data,
`d(0.10), d(0.50) and d(0.90), are reported based on volume.
`
`3. Results and discussion
`
`3.1. Solubility studies
`
`Table 1 summarizes the experimentally determined sol-
`ubility of fenofibrate in pure water, FaSSIF and FeSSIF
`as well as in the corresponding buffers free of bile compo-
`nents (blank media). With an aqueous solubility of 0.3 lg/ml
`(at 37 °C), fenofibrate is clearly poorly soluble. FaSSIF
`and FeSSIF sharply increase the solubility of fenofibrate.
`With a reported log P of 5.24 [12], it is to be expected that
`fenofibrate would be solubilised well by micellar struc-
`tures [19,20]. Even so, at a dose of 60 mg, fenofibrate still
`exhibits high dose:solubility ratios: 4.4 L in FaSSIF and
`1.7 L in FeSSIF. The solubility of fenofibrate is therefore
`expected to limit its absorption from the gastrointestinal
`tract.
`
`3.2. Dissolution studies after dry milling processes
`
`In Fig. 2 the dissolution of three coground mixtures of
`fenofibrate is compared with a physical mixture of lactose
`and micronized fenofibrate and also with unprocessed
`fenofibrate. Dissolution from unprocessed fenofibrate
`approximated zero order kinetics with a very slow dissolu-
`tion rate (<10% in 3 h). The enhancement of the dissolu-
`tion rate from crude to micronized fenofibrate is in
`accordance with its pronounced particle size reduction
`(Table 2).
`Physically mixing lactose with micronized fenofibrate
`resulted in a further improvement in the dissolution rate,
`but fenofibrate still took over 3 h to approach the satura-
`tion limit. By contrast, the mixture coground with lactose
`reached the saturation limit within 30 min. The superiority
`of the coground mixture over the physical mixture cannot
`be explained simply by particle size changes: the particle
`size distribution was slightly coarser after cogrinding. It
`is likely that the presence of the hydrophilic lactose on
`the fenofibrate surface enabled more effective wetting of
`the coground powder mixture. The mixture coground with
`lactose and SLS optimized the dissolution rate of fenofi-
`brate further, reaching the saturation limit within 15 min.
`It is hypothesized that the wettability of the small lipophilic
`
`Table 1
`Solubility study of fenofibrate in various media at 37 °C in lg/ml
`(mean ± SD)
`
`Water
`
`Blank FaSSIF
`
`FaSSIF
`
`Blank FeSSIF
`
`FeSSIF
`
`0.3 ± 0.0
`
`0.2 ± 0.0
`
`13.7 ± 0.5
`
`0.2 ± 0.0
`
`35.6 ± 1.0
`
`Page 3
`
`
`
`286
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`
`fenofibrate particles was further improved by the presence
`of the surfactant.
`Cogrinding of fenofibrate with PVP was slightly less suc-
`cessful in increasing the dissolution rate than the coground
`
`Table 2
`Particle size distribution of fenofibrate in various formulations and
`commercial products
`
`d(0.10) (lm)
`
`d(0.50) (lm)
`
`d(0.90) (lm)
`
`a
`
`dissolved
`
`25%
`
`20%
`
`15%
`
`10%
`
`5%
`
`0%
`
`0
`
`b
`
`dissolved
`
`25%
`
`20%
`
`15%
`
`10%
`
`5%
`
`0%
`
`0
`
`c
`
`dissolved
`
`70%
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`0
`
`30
`
`60
`
`90
`Time [min]
`
`120
`
`150
`
`180
`
`30
`
`60
`
`90
`Time [min]
`
`120
`
`150
`
`180
`
`30
`
`60
`
`90
`Time [min]
`
`120
`
`150
`
`180
`
`Fenofibrate, crude
`Fenofibrate, micronized
`Fenofibrate/lactose
`Fenofibrate/PVP
`Fenofibrate/SLS/lactose
`Fenofibrate, co-spray-dried
`LipanthylÒ powder
`LipidilÒ powder
`SecalipÒ powder
`
`1.7
`0.9
`0.9
`0.6
`0.8
`0.8
`
`2.9
`1.9
`2.9
`
`7.7
`2.2
`3.8
`2.6
`1.9
`1.6
`
`42.7
`19.9
`38.8
`
`40.9
`4.2
`8.0
`5.2
`3.7
`3.5
`
`231.3
`242.9
`206.2
`
`mixture with lactose. Polymers, including PVP, are known
`to be able to surround fine drug crystals, hindering their
`recrystallization from solution [21,22] by reducing the sur-
`face area for crystallization on the drug particles – but this
`can also hinder dissolution by forming a barrier to pene-
`trating water molecules [23–25].
`Dissolution rate enhancement of drugs by cogrinding
`with surfactants is often caused by generation of amor-
`phous drug [26,27]. Indeed, the mechanical stress associ-
`ated with milling may cause partial amorphous states,
`since the particle surface may be destabilized by the energy
`input, generating an amorphous layer on the crystalline
`core [28]. In the jet milling experiments, however, fenofi-
`brate was found to maintain its crystallinity. Identical X-
`ray patterns and a very sharp melting endotherm in the
`DSC thermogram (onset approximately 80 °C) for unpro-
`cessed and jet milled fenofibrate verified the crystalline
`structure of the drug (Fig. 3). Thus, cogrinding provides
`a technology for enhancing dissolution without changing
`the crystalline form of the drug. This may be advantageous
`in terms of the physical stability of the drug, maintaining
`the release properties of the drug product with time.
`For highly lipophilic compounds like fenofibrate, it has
`been hypothesized that the uptake across the gut mem-
`brane is very efficient, resulting in sink conditions in the
`gut lumen, where the drug is dissolving. In such cases, an
`enhancement in dissolution rate would be expected to be
`reflected in a higher absorption rate and hence bioavailabil-
`ity, even when no supersaturation occurs.
`
`b
`Fig. 2. Dissolution profiles of 60 mg fenofibrate in FaSSIF (n = 3, ±SD).
`(a) Comparison of commercial preparations: (m) indicates micronized
`active in physical mixture with lactose. (s) indicates unprocessed drug
`substance in physical mixture with lactose. (n) indicates LipidilÒ powder;
`(+) indicates LipanthylÒ powder; (·) indicates SecalipÒ powder. (b)
`Coground mixtures: (s) indicates unprocessed drug substance in physical
`mixture with lactose; (·) indicates micronized active in physical mixture
`with lactose; (n) indicates a binary coground mixture with lactose; (m)
`indicates a binary coground mixture with PVP (1:1), physically blended
`with lactose; (+) indicates a tertiary coground mixture with SLS/lactose
`(1:44). (c) Spray-dried formulation with lactose and SLS. Dotted lines
`indicate the fenofibrate solubility limit in the medium.
`
`Page 4
`
`
`
`M. Vogt et al. / European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 283–288
`
`287
`
`Lipidil
`
` 1
`
` 10
`Particle size (µm)
`
` 100
`
` 600
`
` 4.5
` 4
` 3.5
` 3
` 2.5
` 2
` 1.5
` 1
` 0.5
`0
` 0.1
`
`Volume (%)
`
`60
`
`Fig. 4. Particle size distribution (frequency curves) of the commercial
`fenofibrate powders LipidilÒ, LipanthylÒ and SecalipÒ.
`
`generation of the supersaturated solution could be attrib-
`uted to the almost complete conversion of crystalline to
`amorphous fenofibrate. Fig. 3 demonstrates that only very
`small crystalline spikes, which correspond to the crystalline
`form of the unprocessed drug substance, occurred on the
`amorphous halo in the X-ray diffraction pattern. The
`excipients were also converted to the amorphous state,
`whereby the content of SLS may have been too small to
`reliably detect reduced amounts of the crystalline form.
`Correspondingly, DSC investigation confirmed a very
`minor melting endotherm for fenofibrate (onset approxi-
`mately 80 °C) in the nanosized/spray-dried formulation.
`
`3.4. Dissolution studies of commercial fenofibrate
`formulations
`
`Particle size and dissolution from the commercial fenof-
`ibrate products LipanthylÒ and LipidilÒ (German market)
`and SecalipÒ (French market) were compared to the fenof-
`ibrate formulations prepared by micronization, cogrinding
`and nanosizing/spray-drying. Fig. 4 illustrates the particle
`size distribution of the commercial fenofibrate powders.
`LipanthylÒ and SecalipÒ exhibited identical
`frequency
`curves. LipidilÒ showed higher quantities of smaller parti-
`cles, but, generally, the overall particle size distributions of
`the powders do not allow a firm conclusion to be drawn
`about the relative particle size of the active drug. Fig. 2
`reveals that the dissolution profiles of LipidilÒ powder
`and micronized fenofibrate on the one hand, and those of
`LipanthylÒ powder, SecalipÒ powder and unprocessed
`fenofibrate on the other hand, are identical, implying that
`LipidilÒ contains the drug in a micronized form while Seca-
`lipÒ and LipanthylÒ appear to contain coarse fenofibrate.
`The coground and spray-dried products prepared in our
`laboratories showed a much higher dissolution rate.
`
`10
`
`20
`
`30
`40
`2-Theta -Scale
`
`milled
`
`crude
`50
`
`spray-dried
`
`10
`
`20
`
`40
`30
`2-Theta -Scale
`
`50
`
`60
`
`milled
`crude
`
`Integral -416,09 mJ
`normalis. -85,65 Jg^-1
`Onset 80,55 °C
`Peak 81,62 °C
`
`Integral 178,81 mJ
`normalis. -86,62 Jg^-1
`Onset
`80,31 °C
`Peak 80,85 °C
`
`80
`
`200
`
`°C
`
`spray-dried
`
`Integral -5,97 mJ
`normalis. -1,43 Jg^-1
`Onset
`79,69 °C
`Peak 80,48 °C
`
`Integral -317,81 mJ
`normalis. -76,12 Jg^-1
`Onset
`174,08 °C
`Peak 177,35 °C
`
`12000
`
`10000
`
`8000
`
`6000
`
`4000
`
`2000
`
`a
`
`Lin (Counts)
`
`b
`
`2000
`
`1000
`
`Lin (Counts)
`
`c
`
`mW
`
`0
`
`-5
`
`-10
`
`-15
`
`-20
`
`
`
`mW
`
`d
`
`0
`
`-1
`
`-2
`
`-3
`
`-4
`
`-5
`
`80
`
`180
`
`°C
`
`Fig. 3. X-ray analysis (a and b) and DSC (c and d) of untreated and milled
`fenofibrate as well as the spray-dried drug.
`
`3.3. Dissolution studies after nanosizing/spray-drying
`
`4. Summary and conclusion
`
`Fig. 2 also shows the dissolution profile in FeSSIF of
`fenofibrate prepared by nanosizing and spray-drying. The
`formulation, which contained lactose and SLS, reached a
`supersaturation, with peak concentrations at 10 min. This
`initial supersaturation proved to be unstable: recrystalliza-
`tion and precipitation occurred rapidly and the concentra-
`tion returned to the saturation limit within about 3 h. The
`
`Commercial products of fenofibrate (LipanthylÒ and
`SecalipÒ) show poor dissolution rates, similar to that of
`unprocessed fenofibrate powder. LipidilÒ powder showed
`enhanced dissolution, similar to that of micronized fenof-
`ibrate. Nonetheless, the dissolution performance of all
`three commercial products was significantly lower com-
`pared to coground mixtures. Fenofibrate was maintained
`
`Page 5
`
`
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`
`in crystalline state after cogrinding, which may be advan-
`tageous in the context of maintaining the release charac-
`teristics of
`the product over time. Spray-drying of a
`nanoparticulate fenofibrate suspension prepared by media
`milling generated amorphous fenofibrate, which showed
`an unstable supersaturation in biorelevant media.
`In conclusion, cogrinding and nanosizing/spray-drying
`are powerful techniques for the preparation of rapidly dis-
`solving formulations of fenofibrate. Both processes could
`potentially lead to better bioavailability of fenofibrate drug
`products.
`
`References
`
`[1] B.C. Hancock, G. Zografi, Characteristics and significance of the
`amorphous state in pharmaceutical systems, J. Pharm. Sci. 86 (1997)
`1–12.
`[2] M.J. Grau, O. Kayser, R.H. Mu¨ ller, Nanosuspensions of poorly
`soluble drugs – reproducibility of small scale production, Int. J.
`Pharm. 196 (2000) 155–157.
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