Supporting information
Factors affecting crystallization kinetics of fenofibrate (FNT) and its implication on the
generation of nanocrystalline solid dispersions via spray drying
Poonam Singh Thakur1, Sneha Sheokand1 and Arvind K Bansal1*
1Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S Nagar, Mohali, Punjab, India;
S1. Selection of solvent ratio
Solvent hold-up study for feed solution of FNT-MAN system was carried out by taking different proportions of acetone:water mixture viz. 80:20, 75:25, 70:30, 65:35, 60:40 and 55:45. The proportions of FNT:MAN were 50:50 and 90:10, with a total of 2% w/w solid content in the feed solution. The study was carried out for 72 h and the prepared solutions were observed for appearance of turbidity and precipitation (Table S1).
Table S1. Hold-up study for the selection of suitable proportion of acetone:water solvent system.
Holding Time Acetone :water (Volume: 50 ml)
80:20 75:25 70:30 65:35 60:40 55:45
0 h Precipitate Precipitate clear clear Clear clear
2h Precipitate Precipitate clear clear Clear turbid
4 h Precipitate Precipitate turbid clear Clear Precipitate 24h Precipitate Precipitate Precipitate clear Clear Precipitate 48 h Precipitate Precipitate Precipitate clear Clear Precipitate 72 h Precipitate Precipitate Precipitate clear Clear Precipitate
S2. Temperature dependent precipitation kinetics of FNT
A solution of FNT in acetone was prepared in three different concentrations of 1mg/ml, 10 mg/ ml and 100 mg/ml, in glass vials (10 ml). An accurate volume of 10 μl (using Eppendorf micropipette) of each solution was mixed with 20 μl of water, on glass slides that were already kept on the stage of the optical microscope and observed for the morphology of generated FNT crystals.
S3. Predissolved excipients driven precipitation kinetics of FNT
Table S2. Compositions of feed solutions containing different combinations of ingredients.
FNT 600 - - -
FNT-MAN 600 1400 - -
FNT-SLS 600 - - 72
FNT-DOSS 600 - 72 -
FNT-SLS-DOSS 600 36 36
S3.1 Accurate volumes of 4 ml of the prepared solutions were taken in separate glass vials. The open vials were then placed in a shaker water bath (Julabo Labortechnik GmbH, Germany) maintained at 60 rpm and 60±0.5 °C. Samples were withdrawn from each vial at appropriate time intervals of 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 30.0, 35.0, 40.0, 45.0, 50.0, 55.0 and 60.0 min. The samples were filtered through 0.1 μm
nylon syringe filter and analyzed for drug content using HPLC method. tind was calculated for all the
samples.
S3.2 Impact of solubilized excipients on supersaturation and morphology of FNT
FNT MAN SLS DOSS 40x 100X 100x 500x
Figure S1. Micrographs of crystals in samples (a) FNT; (b) MAN; [(c)] SLS; [(e), (f)] FNT-DOSS
S4. Preparation of solid dispersion
The crystalline solid dispersion of FNT and MAN were prepared using a laboratory scale spray dryer (LU228 Model, Labultima Ltd., Mumbai, India) mm in two different proportions of 10:1(FNT:MAN) and 10:10 (FNT:MAN) in two different proportions of 10:1 and 10:10, coded as FNT10MAN1 and FNT10MAN10, respectively. MAN present in solid dispersion was labelled as ‘native’ MAN. The
process parameters were: inlet temperature 60 °C, atomization air pressure 1.2 kg/cm2, vacuum 100 mm
ml/min using a 2-way nozzle with an orifice size of 0.7 mm. The spray-dried powder was stored in a desiccator at ambient conditions over phosphorus pentoxide, until further use.
S5. Sessile drop contact angle and wetting kinetics
The wetting process with water was quantified for the work of adhesion (Wa), work of immersion (Wi) and work of spreading (Ws) using Eqs. (1), (2) and (3) derived from Young’s equation.
Contact angle measurements (t = 7 s) and surface tension of different probe liquids were used to determine the Wa, Wi, and Ws for the FNT powder (Table 3). Thermodynamic driving force for each
process is indicated by the work value, where a negative value denotes the spontaneity of the process 40.
S6. Miscibility study with FNT and DOSS using hot stage microscopy
Studies were performed in Leica DMLP polarized microscope (Leica Microsystems Wetzlar GmbH, Germany), equipped with Linkam LTS 350 hot stage. In one protocol, FNT and DOSS were kept side by side. They were heated to 200 ºCat heating rate of 20 ºC/min in between 2 slides, (cycle 1). After melting of FNT they observed for dissolution of DOSS in melted FNT. In another protocol, DOSS was melted and FNT was added to it and observed for their behaviour. It was observed that in the first case (when FNT get melted), DOSS started dissolving even before its melting at their boundary (Fig a). In the second case, FNT started dissolving when added to the melted DOSS. This showed that FNT and DOSS forms a miscible system with each other.
FN T m el ted FNT FNT melting initiation DOSS
DOSS initiates dissolving FNT and DOSS un-melted
DOSS FNT FNT DOSS FN T m el ted D O SS m el ted FNT disappearing in DOSS melt Homogeneous mix formation for both FNT added in melted DOSS at 200⁰ C FNT DOSS FNT DOSS D O SS m el ted
Figure S2. Micrographs representing the miscibility of FNT and DOSS during heating cycle S7. Solid state characterization of generated solid dispersion
The generated solid dispersions FNT10MAN1 and FNT1MAN1 along with MAN were characterized for
their polymorphic form using DSC (Figure S3). It was found that β-form (Tm – 167.71 °C) of MAN
presents in all the samples. Moreover, polymorph I (Tm - 81.5 °C) of FNT presents in two solid
dispersions. -6 -4 -2 0 Heat Flow (W/g) -50 0 50 100 150 200 Temperature (°C)
Exo Up Universal V4.5A TA Instruments
β-MAN
FNT1MAN1
FNT10MAN1
Figure S3. Thermal behavior of β-MAN, FNT1MAN1 and FNT10 MAN1 upon heating cycle1 and cycle 3 using differential scanning calorimetry and hot stage microscopy
S8. Hot Stage Microscopy for non-isothermal crystallization kinetics
The onset temperatures for the crystallization of FNT were ~27 °C and 22 °C in FNT10MAN1 and FNT10MAN10 samples, respectively. However, the end set temperatures of complete crystallization were similar in both samples (~40 °C). Early onset but similar end set of crystallization in FNT10MAN10 sample implied that MAN, at a concentration similar to FNT, acted as a nucleant as well as a physical barrier to crystal growth to FNT.
Figure 10. A representative heating cycle (cycle 3) of FNT10MAN1 sample showing the onset of crystallization of FNT at the
boundary of solid MAN particles at 27°C and completion of crystallization at 40 °C (a temperature window of 13 °C for
crystallization). L en s= 4 0 X , T = 2 8 C L en s = 4 0 X , T = 2 7 C L en s= 4 0 X , T = 2 9 .2 C L en s= 1 0 0 X , T = 3 0 .6 C L en s= 2 0 0 X , T = 3 1 .9 C L en s= 2 0 0 X , T = 3 8 .0 C L en s= 2 0 0 X , T = 4 0 .7 C Crystallization completion L en s= 2 0 0 X , T = 3 3 C L en s= 2 0 0 X , T = 3 4 C L en s= 2 0 0 X , T = 3 5 C L en s= 2 0 0 X , T = 3 6 C L en s= 2 0 0 X , T = 3 7 .0 C Initiation of Nucleation Faster growth of crystals -Magnified same area MAN FNT a b c d e f g h i j k l
Figure S4. A representative heating cycle (cycle 3) of FNT10MAN1 sample showing the onset of crystallization of FNT at the boundary of solid MAN particles at 27 °C and completion of crystallization at 40 °C (a temperature window of 13 °C for crystallization). Where the image a showing representative image where FNT is in melted state and MAN in the form of tiny particles dispersed in melt. Circle showing (b-d) point of initiation of crystallization. Arrow pointing toward initiation of crystallization (image a-d) and further crystal growth (e-l) .
Figure 11. A representative heating cycle (cycle 3) of FNT10MAN10 sample showing the onset of crystallization of FNT at the boundary
of solid MAN particles at 22°C and completion of crystallization at 39°C (a temperature window of 17 °C for crystallization).
L en s = 2 0 0 X , T = 1 8 C L en s = 2 0 0 X , T = 2 6 .3 C
Growing very slowly in the direction of arrow L en s = 2 0 0 X , T = 2 8 C L en s = 2 0 0 X , T = 3 5 .6 C L en s = 2 0 0 X , T = 3 4 .2 C L en s = 2 0 0 X , T = 3 2 C L en s = 2 0 0 X , T = 3 0 C L en s = 2 0 0 X , T = 3 6 C L en s = 2 0 0 X , T = 3 7 .3 C L en s = 2 0 0 X , T = 3 8 .2 C L en s = 2 0 0 X , T = 3 8 .5 C Completion of crystallization L en s = 2 0 0 X , T = 2 2 C Melted FNT in vicinity of MAN MAN FNT MAN a b c d e f g h i j k l
Figure S5. A representative heating cycle (cycle 3) of FNT10MAN10 sample showing the onset of crystallization of FNT at the boundary of solid MAN particles at 22 °C and completion of crystallization at 39°C (a temperature window of 17 °C for crystallization). Where the image (a) showing representative image where FNT is in melted state and MAN in the form of particles surrounding the melt of FNT. the Circle showing (b and c) point of initiation of crystallization. the arrow pointing toward initiation of crystallization (image a-d) and further crystal growth (e-l).
