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Enhanced dissolution of naproxen from pure-drug, crystalline nanoparticles: A case study formulated into spray-dried granules and compressed tablets
Accepted Manuscript Enhanced dissolution of naproxen from pure-drug, crystalline nanoparticles: A case study formulated into spray-dried granules and compressed tablets Veronika Braig, Christoph Konnerth, Wolfgang Peukert, Geoffrey Lee PII: DOI: Reference:
S0378-5173(18)30734-8 https://doi.org/10.1016/j.ijpharm.2018.09.069 IJP 17817
To appear in:
International Journal of Pharmaceutics
Received Date: Revised Date: Accepted Date:
20 August 2018 27 September 2018 28 September 2018
Please cite this article as: V. Braig, C. Konnerth, W. Peukert, G. Lee, Enhanced dissolution of naproxen from puredrug, crystalline nanoparticles: A case study formulated into spray-dried granules and compressed tablets, International Journal of Pharmaceutics (2018), doi: https://doi.org/10.1016/j.ijpharm.2018.09.069
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Enhanced dissolution of naproxen from pure-drug, crystalline nanoparticles: A case study formulated into spray-dried granules and compressed tablets
VERONIKA BRAIG1, CHRISTOPH KONNERTH2, WOLFGANG PEUKERT2 & GEOFFREY LEE1,* 1
Division of Pharmaceutics, Friedrich-Alexander-University, Erlangen,
Germany 2
Institute of Particle Technology, Friedrich-Alexander-University,
Erlangen, Germany Revised version Submitted to: International Journal of Pharmaceutics
*Corresponding author. Tel.: +49 9131/85 295 52 Email address: [email protected] (G. Lee).
1
ABSTRACT
2
This is a case study of the use of rapidly-dissolving naproxen crystalline
3
nanoparticles to prepare compressed tablets. The dissolution rates of
4
different formulations were determined: the crystalline pure-drug
5
nanodispersion, a pure-drug microsuspension, a granule prepared by
6
spray drying the nanodispersion with mannitol, and a tablet prepared by
7
compressing the granule with a bulking agent and a disintegrant. The
8
goal was to determine the influence of each of the process steps on the
9
rapid dissolution of the nanodispersion. A procedure was developed to
10
allow sampling during the first 120 seconds of dissolution. Dissolution of
11
the nanodispersion was completed after 60 seconds under both sink and
12
non-sink conditions. Spray drying with mannitol delayed dissolution
13
slightly under both sink and non-sink conditions. Under sink conditions a
14
microsuspension (volume median size 11 µm) showed similar rapid
15
dissolution to the nanodispersion. We propose this to be a result of rapid
16
shrinkage of the microparticles on dissolution under sink conditions. This
17
nullifies any effects of specific surface on dissolution rate. Under non-
18
sink conditions the microparticles retain their lower specific surface for a
19
longer time during dissolution and dissolve therefore more slowly. When
20
compressed into tablets, the dissolution rates of nanoparticles or
21
microparticles were determined primarily by the tablet disintegration time;
1 22
the influence of sink or non-sink conditions was only observable after
23
disintegration.
24 25
Keywords: low-soluble drug; dissolution; spray-drying; nanosuspension;
26
tablet.
27 28
2 29
1. Introduction
30 31
Crystalline nanoparticles made of a pure, poorly water-soluble drug
32
are known to be able to produce high rates of dissolution (Merisko-
33
Liversidge & Liversidge, 2008). Some examples taken from the literature
34
illustrate this: griseofulvin nanoparticles of diameter 122 nm were
35
reported to dissolve rapidly, i.e. more than 80 % in less than 2 minutes
36
(Murdande et al., 2015); fenofibrate nanoparticles of diameter below 300
37
nm dissolved in less than 2 minutes (Anhalt et al., 2012); naproxen
38
nanoparticles of 150 nm diameter reached equilibrium dissolution 'within
39
a few minutes' (Junke et al., 2015); and Tsinman et al. (2012, 2013)
40
reported 'almost immediate' dissolution to saturation of naproxen
41
nanoparticles of diameter 153 nm. This rapid dissolution is explained by
42
referring to the Noyes-Whitney equation (Noyes & Whitney, 1897) which
43
predicts a high dissolution rate from the large specific surface, Sv [m2/kg],
44
of the nanoparticles (Matteucci et al., 2007). A higher than equilibrium
45
saturation solubility of nanoparticles is of little importance for the
46
dissolution rate. Van Eerdenbrugh et al. (2010) demonstrated that
47
measured values of saturation solubility of nanoparticles of Z-average
48
diameter 150 nm were only slightly higher than at equilibrium, which
49
agreed with calculations using the Ostwald-Freundlich equation.
50
3 51
Pure-drug, crystalline nanoparticles can be incorporated into a
52
solid dosage form for oral administration such as, for example, the
53
compressed tablet. A nanoparticle dispersion ('nanodispersion') is first
54
converted into a solid via some sort of drying process, for example spray
55
drying (Kumar et al., 2015), vacuum drying (Heng et al., 2010) or freeze
56
drying (Chaubal & Popescu, 2008; Jassim & Hussein, 2014). This solid is
57
then tabletted by direct compression using microcrystalline cellulose as a
58
favoured bulking agent (Jassim & Hussein, 2014; Winarti et al., 2017;
59
Tanuwijaya & Karsono, 2013; Tanuwijaya et al., 2014). Note that the
60
same procedure has also been used to tablet polymeric nanoparticles
61
suitable for loading with a drug (Engel et al., 2014; Murakami et al.,
62
2000; Elzoghby et al., 2015). The danger for pure-drug, crystalline
63
nanoparticle is that their incorporation on tabletting into the solid dosage
64
form may lead to loss of the rapid dissolution behaviour of the original
65
nanodispersion, as observed by Heng et al. (2010) and Jassim &
66
Hussein (2014). Intuitively, this could be caused either by the initial
67
drying process used to convert the nanodispersion into a solid suitable
68
for direct tabletting or by the subsequent formulation and compression
69
steps used to make the tablets (Tanuwijaya & Karsono, 2013).
70 71
In this paper we present a case study of the use of naproxen
72
crystalline nanoparticles to prepare compressed tablets. We approach
73
this issue in a systematic way. The drug was selected as being a
4 74
representative molecule having low solubility in water, i.e. 0.0159 mg/mL
75
at 25 °C (Yalkowski & He, 2003), and falling into BCS class II (Löbmann
76
et al., 2011). Its dissolution is expected therefore to be rate limiting for
77
oral bioavailability. The dissolution rates of the following three
78
formulations as steps along the way to prepare a tablet were determined:
79
i) the pure drug, crystalline nanodispersion; ii) a granule prepared by
80
spray drying the nanodispersion with mannitol as a crystalline bulking
81
agent; iii) a tablet prepared by compressing the granule with a bulking
82
agent and a disintegrant. By adopting a systematic approach it was
83
possible to determine the influence of each of the process steps on the
84
initial rapid dissolution of the nanodispersion. A particular goal was to
85
establish a straightforward procedure for measuring rapid dissolution
86
which allowed sampling during the first 120 seconds of dissolution.
87
Junke et al. (2015) noted that dissolution of a nanodispersion can be so
88
fast that the processes of sample collection, phase separation and
89
analysis cannot readily be achieved. The use of dialysis sacs introduces
90
a delay in detecting drug release until the dissolved drug molecules have
91
diffused through the sac and into the dialysis medium (Kumar et al.,
92
2015). Our method of rapid sampling also avoids complex spectroscopic
93
techniques (Anhalt et al., 2012; Tsinmann et al., 2013) that require
94
specialized instrumentation and use indirect evaluation.
95
5 96
2. Materials and methods
97 98
2.1 Materials
99 100
Microparticulate naproxen powder (raw material) was obtained
101
from Fluorochem (Hadfield, UK) via Bayer AG (Leverkusen, Germany).
102
Hydroxypropyl cellulose in SSL-grade was kindly provided by Nisso
103
Chemical Europe GmbH (Düsseldorf, Germany). Dioctyl sulfosuccinate
104
sodium salt was purchased from Alfa Aesar GmbH & Co. KG (Karlsruhe,
105
Germany) and D-Mannitol from Sigma-Aldrich (Darmstadt, Germany).
106
The following excipients were used for tabletting: the bulking agent
107
Mannogem® EZ from SPI Pharma (Wilmington, DE, USA) was donated
108
by Lehmann & Voss & Co. (Hamburg, Germany); the bulking agent
109
Vivapur® Type 301 was provided by JRS Pharma GmbH & Co.
110
(Holzmühle, Germany); the distintegrant Kollidon CL-SF was obtained
111
from BASF SE (Ludwigshafen, Germany). Talc, magnesium stearate and
112
Aerosil® 200 were purchased from Caesar & Lorentz GmbH (Hilden,
113
Germany).
114 115
For preparing the buffers the following salts and reagents were
116
used: potassium dihydrogen phosphate, disodium phosphate dihydrate,
117
citric acid monohydrate, sodium chloride, sodium hydroxide 1N and
6 118
hydrochloric acid 1N, all from Carl Roth GmbH + Co. KG (Karlsruhe,
119
Germany). Acetonitrile was received from Fisher Chemical (Schwerte,
120
Germany). Demineralised water used in this study was produced by a
121
PURELAB® Ultra water system (ELGA LabWater, Veolia Water Solutions
122
& Technologies, Sanite-Maurice, France).
123 124
2.2 Methods
125 126 127
2.2.1 Saturated solubility at different pH An excess of solid naproxen raw material was dispersed in the
128
particular buffer of interest and agitated in closed vials for at least 48 h at
129
37 ± 1 °C in a shaking water bath. Each vial was then removed from the
130
water bath and its entire contents immediately filtered through an Anotop
131
25 Plus filter with a pore diameter of 0.1 µm (Whatman, VWR
132
International GmbH, Darmstadt, Germany) to remove the undissolved
133
drug. The filtrate was immediately diluted with buffer before determining
134
the naproxen content using HPLC analysis (see below). The delay time
135
between removing a vial from the water bath and dilution of the filtrate
136
was estimated to be 10 seconds.
137 138 139 140
2.2.2 Production of nanodispersions and microsuspensions 5.0 % w/w naproxen raw material was dispersed with overnight stirring in a stabilizer solution that comprised 0.75 % w/w hydroxypropyl
7 141
cellulose and 0.0025 % w/w dioctyl sulfosuccinate Na in McIlvaine 0.132
142
M phosphate/citrate buffer pH 2.8. The buffer solution had been pre-
143
saturated with naproxen by stirring overnight at room temperature with
144
an excess of solid drug. The resulting microsuspension was either used
145
directly in the experiments or nanomilled to produce the nanodispersion.
146
This was done using a vertically aligned, laboratory-scale, stirred media
147
batch mill (PE75, Netzsch-Feinmahltechnik GmbH, Selb, Germany)
148
equipped with a zirconia-lined double-walled grinding chamber (capacity
149
= 0.6 L) connected to an external thermostat FPW80-SL (Julabo GmbH,
150
Seelbach, Germany) for temperature control (Konnerth et al., 2017). The
151
process temperature was set to 20.0 ± 1.0 °C using a thermostat. A total
152
of 1.8 kg of wear-resistant, yttrium-stabilized, zirconium oxide milling
153
beads (YTZ®; density, ρGM, = 6050 kg/m3 and diameter, dGM, = 0.4 -
154
0.5 mm, Tosho Inc., Tokyo, Japan) and 100 g of the naproxen
155
microsuspension were filled into the grinding chamber. The agitator
156
speed of the Al2O3 three-disc-stirrer was set to 2000 rpm corresponding
157
to a stirrer tip speed of 6.7 m/s. Milling was performed for 180 minutes
158
after which time the nanodispersion was removed from the mill and
159
stored at 4 - 8 °C until used in a dissolution experiment or processed
160
further.
161 162
2.2.3 Spray drying
8 163
The nanodispersion was spray dried using a Büchi Mini spray-dryer
164
B-290 (Büchi Labortechnik AG, Flawil, Switzerland) equipped with an
165
external peristaltic pump MS-4/12-100 (Ismatec®, Cole Parmer GmbH,
166
Wertheim, Germany) and a high-efficiency-cyclone (Maury et al., 2005).
167
Prior to spray drying, the nanodispersion was diluted 1:1 with a 20.0 %
168
w/w mannitol solution in 0.132 M McIllvaine phosphate/ citrate buffer pH
169
2.8. The resulting liquid feed had therefore the following composition: 2.5
170
% w/w naproxen, 10.0 % w/w mannitol, 0.375 % w/w hydroxypropyl
171
cellulose and 0.00125 % w/w dioctyl sulfosuccinate Na which gave a
172
total solids' content of approximately 12.9 % w/w (value rounded up).
173
The liquid feed was atomized by a two-fluid-nozzle (Büchi) with a nozzle
174
diameter of 0.7 mm. The liquid feed flow rate was set to 3 mL/min and
175
the atomizing air to 2 bar pressure. Ambient air was used as a drying gas
176
at an aspirator rate of 80 % corresponding to an air flow of 525 L/min.
177
The inlet temperature of the drying air was set to a constant 150 °C and
178
the exhaust air temperature monitored continually. The spray dryer was
179
first equilibrated to a steady outlet temperature on water before changing
180
to the liquid feed. The powder yield was removed from the glass
181
collecting vessel at the base of the cyclone.
182 183 184 185
2.2.4 Tabletting All excipients were first sieved through mesh size 300 µm before being blended with either the spray dried nanodispersion or the naproxen
9 186
microparticles of the raw material. The excipients for the nanoparticle
187
tablets (Table 1) were blended for 15 min in a TURBULA® mixer T2C
188
(Willy A. Bachofen AG - Maschinenfabrik, Muttenz, Switzerland) before
189
adding the spray dried naproxen in mannitol and blending for an
190
additional 5 min. A higher amount of Mannogem® EZ was used for the
191
tablets with microparticles (Table 1) to account for the lack of mannitol
192
that had been used in the spray dried nanodispersion. In this case the
193
excipients were pre-blended before adding the naproxen microparticle
194
raw material and blending for a total of 20 min. Each powder was filled
195
manually into the die of a Korsch laboratory single-press punch EK0
196
(Korsch AG, Berlin, Germany) and compressed by hand. The process
197
conditions were: 13 mm diameter flat, round die; fill weight = 550 mg.
198 199 200
2.2.5 Analytical Techniques The particle size distribution of the nanodispersion was determined
201
by dynamic light scattering (DLS; Zetasizer nano ZS, Malvern
202
Instruments, Malvern, UK) and of the microsuspension by laser
203
diffraction (LD: Mastersizer 2000 with Hydro 2000 S dispersion unit,
204
Malvern Instruments, Malvern, UK). Each sample was properly diluted
205
before measurement with the 0.132 M McIlvaine buffer pH 2.8 that had
206
been pre-saturated with naproxen. Both the DLS and LD results are
207
presented in the Discussion as mean for x10,3; x50,3; and x90,3 ,
208
corresponding to the volumetric size distributions.
10 209 210
Drug dissolution rate was determined using the USP II paddle
211
apparatus VK7000 (Vankel Technology Group Inc. Cary, NC, USA) at 37
212
± 0.5 °C and a paddle rotating speed of 100 rpm. The pH of of the
213
release medium was selected to give one of the following drug solubility
214
conditions, where c(t) is the dissolved naproxen concentration, c0 is the
215
maximum achievable concentration should the naproxen sample of
216
weight, m0, completely dissolve at a particular pH, and cs is naproxen's
217
saturated solubility at the same pH: i) sink conditions, i.e. c(t) ≤ 0.1 x cs ,
218
generated with 0.095 mol/L phosphate buffer at pH 6.8 and where c0 = cs
219
x 0.02; ii) non-sink conditions, i.e. c(t) > 0.1 x cs , generated with 0.132 M
220
phosphate buffer at pH 4.2 below saturation solubility where c0 = cs x
221
0.81; iii) non-sink conditions generated with HCl/NaCl at pH 2.2 above
222
saturation solubility where c0 = cs x 1.81. Under sink conditions (i) the
223
maximum dissolved concentration of naproxen is therefore at most 10 %
224
of its saturation solubility. Under non-sink conditions (ii or iii), the
225
maximum dissolved concentration is above 10 % saturation and can be
226
either less than 100 % saturation (ii), or more than 100 % saturation (iii).
227
The naproxen dissolution rate was determined from the nanodispersion,
228
from the microsuspension, from the spray dried nanodispersion, and
229
from the tabletted, dried nanodispersion or tabletted microparticle raw
230
material. In each case, sufficient test substance (dispersion, suspension,
11 231
spray-dried powder or tablet) was used that contained a weight m0 = 40
232
mg of naproxen. This amount of test substance was placed in the
233
dissolution medium, and then samples of 2 mL volume were removed
234
after short time intervals of 10 s, 30 s, 60 s, 90 s and 120 s, followed by
235
samples drawn at later times up to 120 min. After removal, each test
236
sample was rapidly pushed through a 0.02 µm pore diameter filter
237
(Whatman® Anotop® 10 syringe filter, VWR International, Darmstadt,
238
Germany) and immediately diluted with the release medium. This rapid
239
sampling procedure required the simultaneous deployment of two - three
240
persons. The time between sample removal and creation of the filtrate on
241
the underside of the membrane filter was estimated to be 5 - 10 seconds.
242
The content of naproxen was then determined using high-performance
243
liquid chromatography (HPLC).
244 245
The quantitative analysis of naproxen by HPLC was performed
246
using a 1260 Infinity II LC system (Agilent Technologies Inc., Santa
247
Clara, CA, USA) connected to a 1260 Infinity II Variable Wavelength
248
Detector. A Eurosphere II 100-5 C 18 Vertex Plus Column (150 x 4.6
249
mm) was used with an integrated pre-column (Knauer Wissenschaftliche
250
Geräte GmbH, Berlin, Germany). The mobile phase was composed of
251
phosphate/citrate buffer 2.8 (McIlvaine) and acetonitrile (50:50) by
252
volume at a flow rate of 1 mL/min. The column oven was set to 25 °C
253
and detection was performed at
= 273 nm. Under these conditions the
12 254
naproxen had a retention time of 6.2 min. The resulting chromatograms
255
were evaluated with the OpenLAB CDS – Agilent GC Drivers software.
256
The dissolution profiles were represented as % dissolved, i.e. m(t)/m0 x
257
100, versus time, t.
258 259
3. Results and discussion
260 261
3.1 Dissolution behaviour from nanodispersions under sink or non-sink
262
conditions
263
The saturation solubilities determined for the naproxen raw
264
material are given in Table 2 at pHs 6.8, 4.2 and 2.2. Note that the pKa of
265
naproxen is 4.20 (Wassvik et al., 2006). The values of cs given in Table 2
266
were used to define the solubility conditions for the subsequent
267
dissolution studies, i.e. sink conditions at c0 = cs x 0.02, non-sink
268
conditions below saturation solubility at c0 = cs x 0.81, and non-sink
269
conditions above saturation solubility at c0 = cs x 1.81 (c0 is the maximum
270
achievable concentration at complete dissolution).
271 272
Figure 1A show the plots of % dissolved amount of naproxen,
273
m(t)/m0 x 100, from the nanodispersions versus time, t. The plots
274
illustrate the fast dissolution under all three solubility conditions, although
275
the final dissolved concentrations, c, differ. There is some published
13 276
previous work on the dissolution of naproxen nanodispersions stabilized
277
with hydroxypropyl cellulose and sodium lauryl sulphate and of 150 nm
278
median diameter. Tsinman et al. (2013) reported their 'almost immediate'
279
dissolution, although the kinetics of dissolution were not disclosed.
280
These authors used a spectroscopic technique to quantify the naproxen
281
based on differences in second derivative UV spectrum between
282
dissolved and solid drug (Tsinman et al., 2012). Junke et al. (2015) used
283
a pH-metric technique and reported 'rapid dissolution' that reached
284
equilibrium within a few minutes. The first time point of these
285
measurements was 2 minutes and a value for m(t)/m0 x 100 of
286
approximately 80 % was reached after 15 minutes. The kinetic results
287
presented in Figure 1A demonstrate, however, that dissolution of the
288
nanodispersion is completed during the first 60 seconds of the
289
experiment under the conditions we used. They also discriminate
290
between the three different solubility conditions. Under sink conditions,
291
i.e. c(t) ≤ 0.1 x cs and c0 = cs x 0.02, the result is as expected in that the
292
complete amount of naproxen had dissolved after 1 minute, i.e. m(t)/m0 x
293
100 reached the value of 100 %. The change to non-sink conditions, i.e.
294
c(t) > 0.1 x cs , but still below saturation solubility, i.e. c0 = cs x 0.81,
295
slowed down dissolution, although this was still completed after 5
296
minutes (Figure 1A). The slower approach to maximum dissolution after
297
c(90%) with c0 = cs x 0.81, might be a result of enhanced aggregation of
298
the very small residual nanoparticles left at this time. According to the
14 299
Noyes-Whitney equation, the dissolution rate, dm(t)/dt, will decline
300
linearly as the value of [cs - c(t)] decreases during dissolution under non-
301
sink conditions. But dissolution should progress to completeness
302
provided that c0 does not exceed cs (this ignores possible
303
supersaturation) as has been demonstrated using equations derived for
304
decrease in particle size with time (Liu et al., 2013). Yet not all of the
305
naproxen, m0, had dissolved at the end of the experiment: m(t)/m0 x 100
306
reached a maximum of only approximately 90 % after 30 minutes and did
307
not increase further after 120 minutes (not shown in Figure 1A). The
308
measured pH of the buffer remained unchanged during dissolution, so
309
this is not the cause of the failure to each m(t)/m0 x 100 of 100 %. The
310
result obtained under non-sink conditions, i.e. c(t) > 0.1 x cs , but now
311
above saturation solubility, i.e. c0 = cs x 1.81, is given in the kinetic plot in
312
Figure 1A. It shows the same rapid dissolution as seen under the other
313
two solubility conditions with dissolution having been completed after 1
314
minute. Yet the maximum value of m(t)/m0 reached lies well below that
315
under sink conditions, but is equal to the saturation solubility of naproxen
316
at this pH of 2.2 of cs = 0.025 mg/mL (Table 2). The dissolution of the
317
naproxen nanoparticles under the non-sink condition of c0 = cs x 1.81
318
progresses therefore up to saturation solubility after 1 minute and then
319
stops. This is in accord with Noyes-Whitney. No supersaturation is
320
observed. We see therefore that neither of the two non-sink conditions
15 321
examined hindered the very rapid dissolution of the nanodispersion
322
within the first minute.
323 324
The samples removed during the dissolution process were passed
325
through a 20 nm pore diameter membrane filter to remove non-dissolved
326
drug nanoparticles. We expect no, or at worst, only a negligible fraction
327
of the nanoparticles with diameter below this size which could have
328
passed through the filter. The average diameter of the nanoparticles as
329
measured using photon correlation spectroscopy was x50,3 of 166 nm with
330
a range given by x10,3 of 92 nm and x90,3 of 309 nm. Matteucci et al.
331
(2007) examined the dissolution of itraconazole nanodispersions of size
332
200 - 600 nm and found no difference in dissolution profiles between
333
filtering through 20 nm or 200 nm pore diameter filters. The implication
334
was that the filtering technique with 20 nm pore diameter let no
335
undissolved nanoparticle through into the filtrate.
336 337
3.2 Dissolution behaviour from spray dried nanodispersion with mannitol
338 339
The dry powder yield of the spray dried naproxen/mannitol was 60
340
% and contained a weight ratio of mannitol/naproxen of (4:1). Naproxen
341
has a high melting point (152-154 °C) compared with other BCS class 2
342
drugs. Figure 1B shows how the dissolution profiles of the spray dried
343
powder are broadly similar to those of the nanodispersion under all three
16 344
solubility conditions, just somewhat lower. Under the non-sink conditions,
345
c0 = cs x 0.81 or c0 = cs x 1.81, the values for m(t)/m0 x 100 are still
346
increasing after 5 minutes' dissolution time. After, at the latest, 30
347
minutes the spray-dried solid under the non-sink conditions has reached
348
the same m(t)/m0 x 100 as the rapidly-dissolving nanodispersion under
349
sink conditions (not shown in Figure 1B for clarity). The inclusion of the
350
nanoparticles within the spray dried mannitol leads therefore to a small
351
hindrance in their dissolution, detectable during the first 60 seconds.
352
Previous studies of spray dried drug nanoparticles with mannitol have
353
consistently reported more rapid dissolution than obtained with the
354
nanoparticles alone. For example, the more rapid dissolution of
355
griseofulvin nanoparticles of Z-average diameter 210 nm after spray
356
drying with mannitol (1:2 parts by weight) was attributed to improvement
357
in wetting of the nanoparticles by the crystalline mannitol (Shah et al.,
358
2016). We note that the presence of mannitol (2 % w/w) has also been
359
shown to increase the dissolution rate of powdered naproxen in water
360
and attributed to mannitol's effect in decreasing solution viscosity (Paus
361
et al., 2015). These effects are not, however, observed in the current
362
study because the dissolution rate of the naproxen nanodispersion in the
363
first 60 seconds is very high (Figure 1A), indeed 'almost immediate' (cf.
364
Tsinman et al., 2012, 2013). There are also no signs of the 2 - 4 minute
365
delay in dissolution of spray dried itraconazole in mannitol reported by
366
Chaubal & Popescu (2008) and attributed to slow hydration and
17 367
disintegration of drug aggregates. Spray dried pure mannitol is fully
368
crystalline under the process conditions used here (Elversson & Millqvist-
369
Fureby, 2005). The spray dried nanoparticles with mannitol (1:4) were
370
crystalline according to wide-angle X-ray diffraction (diffractogram not
371
shown). During droplet drying of a mannitol solution a process of phase-
372
separation takes place (Schiffter & Lee, 2007) and the crystallization of
373
the mannitol will engulf the naproxen nanoparticles in the final spray-
374
dried solid. This is a rapid process during spray drying that occurs within
375
milliseconds for droplets of the size generated in the Büchi two-fluid
376
nozzle (Masters, 1991). A rapid crystallisation of mannitol is expected to
377
produce a uniform distribution of the nanoparticles within the solid
378
(Thommes et al., 2011; Pomazi et al., 2011). The small hindrance in
379
dissolution observed in Figure 1B is a result of this engulfment where the
380
mannitol particles must first disintegrate or dissolve to release the
381
naproxen nanoparticles and allow them to dissolve.
382 383
The spray dried nanodispersion with mannitol measured at non-
384
sink conditions but still below saturation solubility, i.e. c0 = cs x 0.81, did
385
not reach complete dissolution (Figure 1B), as seen already with the
386
nanodispersion. At the end of the experiment (t = 120 min, not shown in
387
Figure 1B) the value for m(t)/m0 x 100 was 92 %. The measured pH of
18 388
the buffer remained unchanged during dissolution, so this is not the
389
cause of the failure to each m(t)/m0 of 100 %.
390 391
3.3 Comparison of dissolution behaviour of nanodispersion with
392
microsuspension
393 394
The microsuspension, not having been milled, had much larger
395
particle size than the nanodispersion. The laser diffraction analysis result
396
is a x50,3 of 11.7 µm with a range given by x10,3 of 4.1 µm and x90,3 of 29.3
397
µm. Although the larger size and hence smaller specific surface area of
398
the microparticles should reduce their dissolution rate, this is not the
399
case when measured under sink conditions, i.e. c0 = cs x 0.02. Figure 2
400
shows almost identical dissolution profiles from the microsuspension and
401
nanodispersion during the first 60 seconds and the subsequent 5
402
minutes to complete dissolution, i.e. m(t)/m0 x 100 ≥ 97 %. At first sight
403
this is a surprising result because Noyes-Whitney predicts a lower
404
dissolution rate with the smaller specific surface of the microparticles.
405
We assume complete wetting of the particle surface in the dispersions
406
which contain 0.75 % w/w hydroxypropyl cellulose and 0.0025 % w/w
407
dioctyl sulfosuccinate Na. This dissolution result is not an artefact of the
408
rapid sampling and filtration method used here, because a distinction in
409
dissolution rate is observed between microsuspension and
410
nanodispersion under the non-sink condition above saturation solubility,
19 411
i.e. c0 = cs x 1.81 also shown in Figure 2. The dissolution rate from the
412
microsuspension is lower and the value of m(t)/m0 x 100 reached after 5
413
minutes is smaller.
414 415
The effects of specific surface on dissolution behaviour depend on
416
whether sink conditions exist. At the very high dissolution rate under sink
417
conditions, the microparticles shrink rapidly and have largely
418
disappeared after 60 seconds (m(t)/m0 x 100 has reached ≥ 85 % in
419
Figure 2). Their initial large size and small specific surface is therefore
420
rapidly lost during dissolution and cannot affect dissolution rate viewed
421
over 5 minutes or longer. In contrast, under non-sink conditions above
422
saturation solubility, i.e. c0 = cs x 1.81, the dissolved concentration, c(t),
423
rapidly approaches saturation, cs, after only a small shrinkage of the
424
micro-particles. The value of [c(t) - cs] in the Noyes-Whitney equation
425
rapidly declines with time towards zero which will reduce dissolution rate
426
linearly. The large size and small specific surface of the microparticles is
427
retained therefore for longer times during dissolution under non-sink
428
conditions and hence gives a measurably lower rate of dissolution. The
429
overall result is that the comparative behaviour of microsuspension and
430
nanodispersion is different under sink and non-sink conditions. Under
431
sink conditions the micro-particles and nanoparticles exhibit the same
20 432
very rapid dissolution; under non-sink conditions above saturation
433
solubility, the microparticles show slower dissolution.
434 435
These findings are supported by previous disclosures in the
436
literature. Particularly, Murdande et al. (2015) reported only weak effects
437
of the size of nanoparticles and microparticles in the range 122 nm to
438
11.3 µm on their dissolution rate from dispersions under sink conditions.
439
Larger differences could, however, be observed under non-sink
440
conditions. The results in Figure 2 make this distinction more clearly
441
because non-sink conditions above saturation solubility were used, i.e. c0
442
= cs x 1.81, rather than non-sink conditions below saturation used by
443
Murande et al. (2015), i.e. in their case c0 = cs x 0.55. These authors
444
concluded that sink conditions were unsuitable to discriminate between
445
the dissolution behaviour of such disperse systems. This is supported by
446
Anhalt et al. (2012) who reported that larger sized nanoparticles reduced
447
the dissolution rates of fenofibrate under non-sink conditions.
448 449
3.4 Dissolution behaviour from tabletted, spray dried nanodispersion or
450
microparticulate raw material
451 452 453
The tablets made from the microparticulate raw material had greater hardness than those prepared from the spray-dried
21 454
nanodispersion containing mannitol (Table 3). The effects of mannitol on
455
tablet hardness are known to depend on the other formulation
456
components and their pre-treatment and can lead to either more (Omar
457
et al., 2017) or less (Molokhia et al., 1982) hardness. The major
458
difference is, however, the much shorter disintegration time of the tablets
459
made from the microparticles (Table 3). This is a result of the higher
460
content of the rapidly-dissolving bulking agent Mannogem EZ, some 61
461
% versus 21 %. The rapid dispersion of the Mannogem EZ (spray dried
462
mannitol) enhances distintegration to a much greater extent than the
463
regular mannitol used to co-spray dry the nanodispersion, at the same
464
level of Kollidon CL-SF.
465 466
The microparticle tablet under sink conditions, i.e. c0 = cs x 0.02,
467
shows rapid dissolution within the initial 2 minutes and produces an
468
m(t)/m0 of ≥ 0.97 after 5 minutes (Figure 3). The tablet disintegrates fully
469
within 2 minutes (Table 3) and the microparticles, once released from the
470
tablet, dissolve very rapidly in sink conditions, as already seen for the
471
microsuspension in Figure 2. Recall that under sink conditions the
472
microsuspension dissolves as rapidly as the nanodispersion (cf. Figure
473
2). The nanoparticle tablets show distinctly slower dissolution than the
474
micoparticulate tablets and requires 15 minutes for complete dissolution,
475
i.e. for m(t)/m0 x 100 to reach ≥ 97 %. This is therefore a much slower rate
22 476
than the almost immediate dissolution of the nanodispersion under sink
477
conditions (cf. Figure 1). The tablet disintegration time is, however, 9.5
478
minutes (Table 3) which retards release of the nanoparticles from the
479
tablet formulation surrounding them. Once released, dissolution of the
480
nanoparticles under sink conditions is extremely rapid; but before this is
481
reached dissolution is hindered by the prolonged disintegration of the
482
tablet. Heng et al. (2010) determined that the distintegration time of
483
tablets containing cefuroxime nanoparticles only marginally influenced
484
dissolution. This was likely because a vacuum-dried nanodispersion was
485
used for tabletting in which the nanoparticles were highly aggregated, if
486
not fused by solid bridges formed by crystallization of previously-
487
dissolved mannitol. Our use of spray dried nanoparticles embedded in
488
mannitol avoids this problem (cf. Figure 2).
489 490
Under non-sink conditions above saturation solubility, i.e. c0 = cs x
491
1.81, the position is reversed. The microparticles show slow dissolution
492
with m(t)/m0 still well below 100 % after 60 min and also below the
493
saturation solubility (Figure 3). Despite the very short disintegration time
494
(Table 3) and rapid release of the microparticles from the tablet
495
formulation, their subsequent dissolution under non-sink conditions is
496
slow, as already shown by the microsuspension (Figure 2). In contrast to
497
this behaviour, the nanoparticles again suffer from the prolonged
498
disintegration time of the tablet (Table 2). Once released from the tablet
23 499
formulation, however, the nanoparticles dissolve rapidly under non-sink
500
conditions (cf. Figure 1). The result is that the measured dissolution from
501
the nanoparticle tablet is delayed but then reaches the level of saturation
502
solubility after 15 minutes (Figure 3). The slowly-distintegrating tablet
503
delays release of the nanoparticles to the dissolution medium under both
504
sink and non-sink conditions. The result under non-sink conditions is that
505
overall dissolution of the nanoparticles from the slowly-disintegrating
506
tablet is more rapid than that of the microparticles from the fast-
507
distintegrating-tablet.
508 509
4. Conclusions
510 511
We draw the following conclusion from this work:
512 513
i) By using a rapid sampling procedure it was possible to determine
514
the rate of dissolution of the naproxen nanodispersion during the first
515
minutes of dissolution. The dissolution was completed after the first 60
516
seconds of the experiment under both sink conditions and non-sink
517
conditions.
518 519
ii) The naproxen nanodispersion could be spray dried with mannitol
520
at a weight ration of mannitol/naproxen of (4:1) with a dry powder yield of
24 521
60 %. The dissolution rate was only slightly lower during the initial 60
522
seconds compared with the nanodispersion under both sink and non-sink
523
conditions. For such rapidly-dissolving nanoparticles the use of a highly
524
water-soluble carrier thus hinders slightly dissolution. Such carriers
525
which are assumed to enhance wetting of nanodispersions, will not
526
always produce enhanced dissolution.
527 528
iii) Under sink-conditions both the nanodispersion (size 166 nm) and a
529
microsuspension (size 11 µm) show very rapid dissolution kinetics when
530
using sampling times of below 10 - 20 sec. We suggest this is a result of
531
the rapid shrinkage of the microparticles on dissolution under sink
532
conditions which nullifies any effects of specific surface on dissolution
533
rate. Under non-sink conditions the microparticles dissolve more slowly
534
because they retain their lower specific surface for a longer time during
535
dissolution. A way to distinguish differences in dissolution rate between
536
nanoparticles and microsuspension may therefore be the use of even
537
short sampling times.
538 539
iv) differences in the dissolution rate of nanoparticles or microparticles
540
from compressed tablets are determined by both the tablet disintegration
541
time and whether sink or non-sink conditions exist in the dissolution
542
medium.
543
25 544
Acknowledgements
545 546
We gratefully acknowledge the financial support of the Deutsche
547
Forschungsgemeinschaft (DFG, grant PE 427/24-1) and the Cluster of
548
Excellence - Engineering of Advanced Materials (EAM) for funding this
549
project. We also acknowledge Dr. W. Hoheisel, Dr. M. Ostendorf und Dr.
550
J. Uhlmann from Bayer AG for the many useful discussions.
551
26 552
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mini-depot tablets by direct compression. J. Cont. Rel. 67: 29-36.
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Noyes, A., Whitney, W., 1897. The rate of solution of solid substances in
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Omar, S., AbdAlla, F., Abdelgawad, N., 2017. Effects of mannitol on
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Paus, R., Prudic, A., Ji, Y., 2015. Influence of excipients on solubility and
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649 650
Pomazi, A., Ambrus, R., Sipos, P., Szabo-Revesz, P., 2011. Analysis of
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microcomposites. J. Pharm. Biomed. Anal. 56(2): 183-190.
653 654
Schiffter, H., Lee, G., 2007. Single-droplet evaporation kinetics and
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catalase. J. Pharm. Sci. 96(9): 2284-2295.
658 659 660
Shah, D., Patel, M., Murdande, S., Dave, R., 2016. Influence of spray
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drying and dispersing agent on surface and dissolution properties of
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grisepfulvin micro and nanocrystals. Drug Devel. Ind. Pharm. 42(11):
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1842-1850.
664 665
Tanuwijaya, J., Karsono, 2013. The effects of crospovidone and
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669 670
Tanuwijaya, J., Karsono, Harahap, H., 2014. Characterization of
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672
Chem. Tech. Res. 6(2): 955-961.
673 674
Thommes, M., Ely, D., Carvajal, M., Pinal, R., 2011. Improvement of the
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677 678
Tsinman, K., Tsinman, O., Riebesehl, B., Juhnke, M., 2012. Comparison
679
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680
dissolution from untreated and micronized powder. Proceedings
681
(Abstracts) of Annual Meeting of American Association of
682
Pharmaceutical Scientists (AAPS).
683
32 684
Tsinman, K., Tsinman, O., Riebesehl, B., Grandeury, A., Juhnke, M.,
685
2013. In situ method for monitoring free drug concentration released
686
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687
American Association of Pharmaceutical Scientists (AAPS).
688 689
Wassvik, C., Holmen, A., Bergström, C., Zamora, I., Artursson, P., 2006.
690
Contribution of solid-state properties to the aqueous solubility of drugs.
691
Eur. J. Pharm. Sci. 29(3-4): 294-305.
692 693
Winarti, L., Ameliana, L., Nurahmanto, D., 2017. Formula optimization of
694
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695
Indonesian J. Pharm. 28 (1): 53-64.
696 697
Yalkowsky, S., He, Y., 2003. Handbook of Aqueous Solubility Data. CRC
698
Press LLC, Boca Raton, FL, USA, p. 962.
699 700 701
.
33 702
Legends to Figures
703 704
Figure 1. Dissolution profiles of naproxen under various solubility
705
conditions. m(t) = amount dissolved at time, t; m0 = amount of naproxen
706
added to dissolution medium; c0 = maximum achievable concentration
707
should the naproxen amount, m0, be completely dissolved; cs =
708
naproxen's saturation solubility. c0 = cs x 0.02 = sink conditions; c0 = cs x
709
0.81 = non-sink conditions but below saturation solubility; c0 = cs x 1.81 =
710
non-sink conditions above saturation solubility. A) Effect of different
711
solubility conditions on dissolution of naproxen nanodispersion. B)
712
Comparison of dissolution profiles of naproxen nanodispersion and spray
713
dried naproxen/mannitol (1:4).
714 715
Figure 2. Comparison of dissolution profiles of naproxen nanodispersion
716
and naproxen microsuspension of raw material (see Materials) under
717
various solubility conditions. m(t) = amount dissolved at time, t; m0 =
718
amount of naproxen added to dissolution medium; c0 = maximum
719
achievable concentration should the naproxen amount, m0, be
720
completely dissolved; cs = naproxen's saturation solubility. c0 = cs x 0.02
721
= sink conditions; c0 = cs x 0.81 = non-sink conditions but below
722
saturation solubility; c0 = cs x 1.81 = non-sink conditions above saturation
723
solubility.
34 724 725
Figure 3. Dissolution profiles of naproxen from compressed tablets
726
containing either spray-dried nanodispersion or microparticulate raw
727
material. m(t) = amount dissolved at time, t; m0 = amount of naproxen
728
added to dissolution medium; c0 = maximum achievable concentration
729
should the naproxen amount, m0, be completely dissolved; cs =
730
naproxen's saturation solubility. c0 = cs x 0.02 = sink conditions; c0 = cs x
731
1.81 = non-sink conditions above saturation solubility. Note different time
732
scale from that used in Figures 1 and 2.
733 734
35 735 736
Table 1: Powder compositions used to prepare tablets from spray dried
737
nanodispersions or microsuspensions. The spray dried
738
nanodispersion of naproxen in mannitol (49 %) contained
739
sufficient naproxen to produce 7 % w/w of the drug in the final
740
tablet formulation.
741
Substance
Nanodispersion Microsuspension [% w/w]
[% w/w]
49
-
-
7
Mannogem® EZ
21
61
Vivapur® Type 301
24
26
Kollidon® CL-SF
3
3
talc-magnesium-
3
3
spray-dried nanodispersion of naproxen in mannitol naproxen raw material
stearate-Aerosil (ratio 6:3:1 w/w) 742 743
36 744
Table 2: Values for saturation solubility, cs, of naproxen in dependence
745
of pH at 37 °C. Results are given as mean average ± standard
746
deviation for n = 3.
747
pH
Saturation solubility cs [mg/mL]
748 749
6.8
2.78 ± 0.032
4.2
0.057 ± 0.000
2.2
0.025 ± 0.002
37 750
Table 3: Characteristics of tablets prepared from spray dried
751
nanodispersions or microsuspensions of naproxem. The spray
752
dried nanodispersion of naproxen contained mannitol. In all cases
753
n = 5 tablets.
754
Property
Tablets made from
Tablets made
spray-dried
from naproxen
nanodispersion
microparticle raw material
height [mm]
3.7 ± 0.05
3.9 ± 0.02
diameter [mm]
13.1 ± 0.03
13.1 ± 0
hardness [N]
43.6 ± 8.5
57.4 ± 4.7
10 ± 0
1.0 ± 0.2
9.5 ± 3.5
2.0 ± 0
distintegration time at pH 6.8 [min] disintegration time at pH 2.2 [min] 755 756
38
757
758 759 760
39
761 762
40
763 764
41
765
S0378-5173(18)30734-8 https://doi.org/10.1016/j.ijpharm.2018.09.069 IJP 17817
To appear in:
International Journal of Pharmaceutics
Received Date: Revised Date: Accepted Date:
20 August 2018 27 September 2018 28 September 2018
Please cite this article as: V. Braig, C. Konnerth, W. Peukert, G. Lee, Enhanced dissolution of naproxen from puredrug, crystalline nanoparticles: A case study formulated into spray-dried granules and compressed tablets, International Journal of Pharmaceutics (2018), doi: https://doi.org/10.1016/j.ijpharm.2018.09.069
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Enhanced dissolution of naproxen from pure-drug, crystalline nanoparticles: A case study formulated into spray-dried granules and compressed tablets
VERONIKA BRAIG1, CHRISTOPH KONNERTH2, WOLFGANG PEUKERT2 & GEOFFREY LEE1,* 1
Division of Pharmaceutics, Friedrich-Alexander-University, Erlangen,
Germany 2
Institute of Particle Technology, Friedrich-Alexander-University,
Erlangen, Germany Revised version Submitted to: International Journal of Pharmaceutics
*Corresponding author. Tel.: +49 9131/85 295 52 Email address: [email protected] (G. Lee).
1
ABSTRACT
2
This is a case study of the use of rapidly-dissolving naproxen crystalline
3
nanoparticles to prepare compressed tablets. The dissolution rates of
4
different formulations were determined: the crystalline pure-drug
5
nanodispersion, a pure-drug microsuspension, a granule prepared by
6
spray drying the nanodispersion with mannitol, and a tablet prepared by
7
compressing the granule with a bulking agent and a disintegrant. The
8
goal was to determine the influence of each of the process steps on the
9
rapid dissolution of the nanodispersion. A procedure was developed to
10
allow sampling during the first 120 seconds of dissolution. Dissolution of
11
the nanodispersion was completed after 60 seconds under both sink and
12
non-sink conditions. Spray drying with mannitol delayed dissolution
13
slightly under both sink and non-sink conditions. Under sink conditions a
14
microsuspension (volume median size 11 µm) showed similar rapid
15
dissolution to the nanodispersion. We propose this to be a result of rapid
16
shrinkage of the microparticles on dissolution under sink conditions. This
17
nullifies any effects of specific surface on dissolution rate. Under non-
18
sink conditions the microparticles retain their lower specific surface for a
19
longer time during dissolution and dissolve therefore more slowly. When
20
compressed into tablets, the dissolution rates of nanoparticles or
21
microparticles were determined primarily by the tablet disintegration time;
1 22
the influence of sink or non-sink conditions was only observable after
23
disintegration.
24 25
Keywords: low-soluble drug; dissolution; spray-drying; nanosuspension;
26
tablet.
27 28
2 29
1. Introduction
30 31
Crystalline nanoparticles made of a pure, poorly water-soluble drug
32
are known to be able to produce high rates of dissolution (Merisko-
33
Liversidge & Liversidge, 2008). Some examples taken from the literature
34
illustrate this: griseofulvin nanoparticles of diameter 122 nm were
35
reported to dissolve rapidly, i.e. more than 80 % in less than 2 minutes
36
(Murdande et al., 2015); fenofibrate nanoparticles of diameter below 300
37
nm dissolved in less than 2 minutes (Anhalt et al., 2012); naproxen
38
nanoparticles of 150 nm diameter reached equilibrium dissolution 'within
39
a few minutes' (Junke et al., 2015); and Tsinman et al. (2012, 2013)
40
reported 'almost immediate' dissolution to saturation of naproxen
41
nanoparticles of diameter 153 nm. This rapid dissolution is explained by
42
referring to the Noyes-Whitney equation (Noyes & Whitney, 1897) which
43
predicts a high dissolution rate from the large specific surface, Sv [m2/kg],
44
of the nanoparticles (Matteucci et al., 2007). A higher than equilibrium
45
saturation solubility of nanoparticles is of little importance for the
46
dissolution rate. Van Eerdenbrugh et al. (2010) demonstrated that
47
measured values of saturation solubility of nanoparticles of Z-average
48
diameter 150 nm were only slightly higher than at equilibrium, which
49
agreed with calculations using the Ostwald-Freundlich equation.
50
3 51
Pure-drug, crystalline nanoparticles can be incorporated into a
52
solid dosage form for oral administration such as, for example, the
53
compressed tablet. A nanoparticle dispersion ('nanodispersion') is first
54
converted into a solid via some sort of drying process, for example spray
55
drying (Kumar et al., 2015), vacuum drying (Heng et al., 2010) or freeze
56
drying (Chaubal & Popescu, 2008; Jassim & Hussein, 2014). This solid is
57
then tabletted by direct compression using microcrystalline cellulose as a
58
favoured bulking agent (Jassim & Hussein, 2014; Winarti et al., 2017;
59
Tanuwijaya & Karsono, 2013; Tanuwijaya et al., 2014). Note that the
60
same procedure has also been used to tablet polymeric nanoparticles
61
suitable for loading with a drug (Engel et al., 2014; Murakami et al.,
62
2000; Elzoghby et al., 2015). The danger for pure-drug, crystalline
63
nanoparticle is that their incorporation on tabletting into the solid dosage
64
form may lead to loss of the rapid dissolution behaviour of the original
65
nanodispersion, as observed by Heng et al. (2010) and Jassim &
66
Hussein (2014). Intuitively, this could be caused either by the initial
67
drying process used to convert the nanodispersion into a solid suitable
68
for direct tabletting or by the subsequent formulation and compression
69
steps used to make the tablets (Tanuwijaya & Karsono, 2013).
70 71
In this paper we present a case study of the use of naproxen
72
crystalline nanoparticles to prepare compressed tablets. We approach
73
this issue in a systematic way. The drug was selected as being a
4 74
representative molecule having low solubility in water, i.e. 0.0159 mg/mL
75
at 25 °C (Yalkowski & He, 2003), and falling into BCS class II (Löbmann
76
et al., 2011). Its dissolution is expected therefore to be rate limiting for
77
oral bioavailability. The dissolution rates of the following three
78
formulations as steps along the way to prepare a tablet were determined:
79
i) the pure drug, crystalline nanodispersion; ii) a granule prepared by
80
spray drying the nanodispersion with mannitol as a crystalline bulking
81
agent; iii) a tablet prepared by compressing the granule with a bulking
82
agent and a disintegrant. By adopting a systematic approach it was
83
possible to determine the influence of each of the process steps on the
84
initial rapid dissolution of the nanodispersion. A particular goal was to
85
establish a straightforward procedure for measuring rapid dissolution
86
which allowed sampling during the first 120 seconds of dissolution.
87
Junke et al. (2015) noted that dissolution of a nanodispersion can be so
88
fast that the processes of sample collection, phase separation and
89
analysis cannot readily be achieved. The use of dialysis sacs introduces
90
a delay in detecting drug release until the dissolved drug molecules have
91
diffused through the sac and into the dialysis medium (Kumar et al.,
92
2015). Our method of rapid sampling also avoids complex spectroscopic
93
techniques (Anhalt et al., 2012; Tsinmann et al., 2013) that require
94
specialized instrumentation and use indirect evaluation.
95
5 96
2. Materials and methods
97 98
2.1 Materials
99 100
Microparticulate naproxen powder (raw material) was obtained
101
from Fluorochem (Hadfield, UK) via Bayer AG (Leverkusen, Germany).
102
Hydroxypropyl cellulose in SSL-grade was kindly provided by Nisso
103
Chemical Europe GmbH (Düsseldorf, Germany). Dioctyl sulfosuccinate
104
sodium salt was purchased from Alfa Aesar GmbH & Co. KG (Karlsruhe,
105
Germany) and D-Mannitol from Sigma-Aldrich (Darmstadt, Germany).
106
The following excipients were used for tabletting: the bulking agent
107
Mannogem® EZ from SPI Pharma (Wilmington, DE, USA) was donated
108
by Lehmann & Voss & Co. (Hamburg, Germany); the bulking agent
109
Vivapur® Type 301 was provided by JRS Pharma GmbH & Co.
110
(Holzmühle, Germany); the distintegrant Kollidon CL-SF was obtained
111
from BASF SE (Ludwigshafen, Germany). Talc, magnesium stearate and
112
Aerosil® 200 were purchased from Caesar & Lorentz GmbH (Hilden,
113
Germany).
114 115
For preparing the buffers the following salts and reagents were
116
used: potassium dihydrogen phosphate, disodium phosphate dihydrate,
117
citric acid monohydrate, sodium chloride, sodium hydroxide 1N and
6 118
hydrochloric acid 1N, all from Carl Roth GmbH + Co. KG (Karlsruhe,
119
Germany). Acetonitrile was received from Fisher Chemical (Schwerte,
120
Germany). Demineralised water used in this study was produced by a
121
PURELAB® Ultra water system (ELGA LabWater, Veolia Water Solutions
122
& Technologies, Sanite-Maurice, France).
123 124
2.2 Methods
125 126 127
2.2.1 Saturated solubility at different pH An excess of solid naproxen raw material was dispersed in the
128
particular buffer of interest and agitated in closed vials for at least 48 h at
129
37 ± 1 °C in a shaking water bath. Each vial was then removed from the
130
water bath and its entire contents immediately filtered through an Anotop
131
25 Plus filter with a pore diameter of 0.1 µm (Whatman, VWR
132
International GmbH, Darmstadt, Germany) to remove the undissolved
133
drug. The filtrate was immediately diluted with buffer before determining
134
the naproxen content using HPLC analysis (see below). The delay time
135
between removing a vial from the water bath and dilution of the filtrate
136
was estimated to be 10 seconds.
137 138 139 140
2.2.2 Production of nanodispersions and microsuspensions 5.0 % w/w naproxen raw material was dispersed with overnight stirring in a stabilizer solution that comprised 0.75 % w/w hydroxypropyl
7 141
cellulose and 0.0025 % w/w dioctyl sulfosuccinate Na in McIlvaine 0.132
142
M phosphate/citrate buffer pH 2.8. The buffer solution had been pre-
143
saturated with naproxen by stirring overnight at room temperature with
144
an excess of solid drug. The resulting microsuspension was either used
145
directly in the experiments or nanomilled to produce the nanodispersion.
146
This was done using a vertically aligned, laboratory-scale, stirred media
147
batch mill (PE75, Netzsch-Feinmahltechnik GmbH, Selb, Germany)
148
equipped with a zirconia-lined double-walled grinding chamber (capacity
149
= 0.6 L) connected to an external thermostat FPW80-SL (Julabo GmbH,
150
Seelbach, Germany) for temperature control (Konnerth et al., 2017). The
151
process temperature was set to 20.0 ± 1.0 °C using a thermostat. A total
152
of 1.8 kg of wear-resistant, yttrium-stabilized, zirconium oxide milling
153
beads (YTZ®; density, ρGM, = 6050 kg/m3 and diameter, dGM, = 0.4 -
154
0.5 mm, Tosho Inc., Tokyo, Japan) and 100 g of the naproxen
155
microsuspension were filled into the grinding chamber. The agitator
156
speed of the Al2O3 three-disc-stirrer was set to 2000 rpm corresponding
157
to a stirrer tip speed of 6.7 m/s. Milling was performed for 180 minutes
158
after which time the nanodispersion was removed from the mill and
159
stored at 4 - 8 °C until used in a dissolution experiment or processed
160
further.
161 162
2.2.3 Spray drying
8 163
The nanodispersion was spray dried using a Büchi Mini spray-dryer
164
B-290 (Büchi Labortechnik AG, Flawil, Switzerland) equipped with an
165
external peristaltic pump MS-4/12-100 (Ismatec®, Cole Parmer GmbH,
166
Wertheim, Germany) and a high-efficiency-cyclone (Maury et al., 2005).
167
Prior to spray drying, the nanodispersion was diluted 1:1 with a 20.0 %
168
w/w mannitol solution in 0.132 M McIllvaine phosphate/ citrate buffer pH
169
2.8. The resulting liquid feed had therefore the following composition: 2.5
170
% w/w naproxen, 10.0 % w/w mannitol, 0.375 % w/w hydroxypropyl
171
cellulose and 0.00125 % w/w dioctyl sulfosuccinate Na which gave a
172
total solids' content of approximately 12.9 % w/w (value rounded up).
173
The liquid feed was atomized by a two-fluid-nozzle (Büchi) with a nozzle
174
diameter of 0.7 mm. The liquid feed flow rate was set to 3 mL/min and
175
the atomizing air to 2 bar pressure. Ambient air was used as a drying gas
176
at an aspirator rate of 80 % corresponding to an air flow of 525 L/min.
177
The inlet temperature of the drying air was set to a constant 150 °C and
178
the exhaust air temperature monitored continually. The spray dryer was
179
first equilibrated to a steady outlet temperature on water before changing
180
to the liquid feed. The powder yield was removed from the glass
181
collecting vessel at the base of the cyclone.
182 183 184 185
2.2.4 Tabletting All excipients were first sieved through mesh size 300 µm before being blended with either the spray dried nanodispersion or the naproxen
9 186
microparticles of the raw material. The excipients for the nanoparticle
187
tablets (Table 1) were blended for 15 min in a TURBULA® mixer T2C
188
(Willy A. Bachofen AG - Maschinenfabrik, Muttenz, Switzerland) before
189
adding the spray dried naproxen in mannitol and blending for an
190
additional 5 min. A higher amount of Mannogem® EZ was used for the
191
tablets with microparticles (Table 1) to account for the lack of mannitol
192
that had been used in the spray dried nanodispersion. In this case the
193
excipients were pre-blended before adding the naproxen microparticle
194
raw material and blending for a total of 20 min. Each powder was filled
195
manually into the die of a Korsch laboratory single-press punch EK0
196
(Korsch AG, Berlin, Germany) and compressed by hand. The process
197
conditions were: 13 mm diameter flat, round die; fill weight = 550 mg.
198 199 200
2.2.5 Analytical Techniques The particle size distribution of the nanodispersion was determined
201
by dynamic light scattering (DLS; Zetasizer nano ZS, Malvern
202
Instruments, Malvern, UK) and of the microsuspension by laser
203
diffraction (LD: Mastersizer 2000 with Hydro 2000 S dispersion unit,
204
Malvern Instruments, Malvern, UK). Each sample was properly diluted
205
before measurement with the 0.132 M McIlvaine buffer pH 2.8 that had
206
been pre-saturated with naproxen. Both the DLS and LD results are
207
presented in the Discussion as mean for x10,3; x50,3; and x90,3 ,
208
corresponding to the volumetric size distributions.
10 209 210
Drug dissolution rate was determined using the USP II paddle
211
apparatus VK7000 (Vankel Technology Group Inc. Cary, NC, USA) at 37
212
± 0.5 °C and a paddle rotating speed of 100 rpm. The pH of of the
213
release medium was selected to give one of the following drug solubility
214
conditions, where c(t) is the dissolved naproxen concentration, c0 is the
215
maximum achievable concentration should the naproxen sample of
216
weight, m0, completely dissolve at a particular pH, and cs is naproxen's
217
saturated solubility at the same pH: i) sink conditions, i.e. c(t) ≤ 0.1 x cs ,
218
generated with 0.095 mol/L phosphate buffer at pH 6.8 and where c0 = cs
219
x 0.02; ii) non-sink conditions, i.e. c(t) > 0.1 x cs , generated with 0.132 M
220
phosphate buffer at pH 4.2 below saturation solubility where c0 = cs x
221
0.81; iii) non-sink conditions generated with HCl/NaCl at pH 2.2 above
222
saturation solubility where c0 = cs x 1.81. Under sink conditions (i) the
223
maximum dissolved concentration of naproxen is therefore at most 10 %
224
of its saturation solubility. Under non-sink conditions (ii or iii), the
225
maximum dissolved concentration is above 10 % saturation and can be
226
either less than 100 % saturation (ii), or more than 100 % saturation (iii).
227
The naproxen dissolution rate was determined from the nanodispersion,
228
from the microsuspension, from the spray dried nanodispersion, and
229
from the tabletted, dried nanodispersion or tabletted microparticle raw
230
material. In each case, sufficient test substance (dispersion, suspension,
11 231
spray-dried powder or tablet) was used that contained a weight m0 = 40
232
mg of naproxen. This amount of test substance was placed in the
233
dissolution medium, and then samples of 2 mL volume were removed
234
after short time intervals of 10 s, 30 s, 60 s, 90 s and 120 s, followed by
235
samples drawn at later times up to 120 min. After removal, each test
236
sample was rapidly pushed through a 0.02 µm pore diameter filter
237
(Whatman® Anotop® 10 syringe filter, VWR International, Darmstadt,
238
Germany) and immediately diluted with the release medium. This rapid
239
sampling procedure required the simultaneous deployment of two - three
240
persons. The time between sample removal and creation of the filtrate on
241
the underside of the membrane filter was estimated to be 5 - 10 seconds.
242
The content of naproxen was then determined using high-performance
243
liquid chromatography (HPLC).
244 245
The quantitative analysis of naproxen by HPLC was performed
246
using a 1260 Infinity II LC system (Agilent Technologies Inc., Santa
247
Clara, CA, USA) connected to a 1260 Infinity II Variable Wavelength
248
Detector. A Eurosphere II 100-5 C 18 Vertex Plus Column (150 x 4.6
249
mm) was used with an integrated pre-column (Knauer Wissenschaftliche
250
Geräte GmbH, Berlin, Germany). The mobile phase was composed of
251
phosphate/citrate buffer 2.8 (McIlvaine) and acetonitrile (50:50) by
252
volume at a flow rate of 1 mL/min. The column oven was set to 25 °C
253
and detection was performed at
= 273 nm. Under these conditions the
12 254
naproxen had a retention time of 6.2 min. The resulting chromatograms
255
were evaluated with the OpenLAB CDS – Agilent GC Drivers software.
256
The dissolution profiles were represented as % dissolved, i.e. m(t)/m0 x
257
100, versus time, t.
258 259
3. Results and discussion
260 261
3.1 Dissolution behaviour from nanodispersions under sink or non-sink
262
conditions
263
The saturation solubilities determined for the naproxen raw
264
material are given in Table 2 at pHs 6.8, 4.2 and 2.2. Note that the pKa of
265
naproxen is 4.20 (Wassvik et al., 2006). The values of cs given in Table 2
266
were used to define the solubility conditions for the subsequent
267
dissolution studies, i.e. sink conditions at c0 = cs x 0.02, non-sink
268
conditions below saturation solubility at c0 = cs x 0.81, and non-sink
269
conditions above saturation solubility at c0 = cs x 1.81 (c0 is the maximum
270
achievable concentration at complete dissolution).
271 272
Figure 1A show the plots of % dissolved amount of naproxen,
273
m(t)/m0 x 100, from the nanodispersions versus time, t. The plots
274
illustrate the fast dissolution under all three solubility conditions, although
275
the final dissolved concentrations, c, differ. There is some published
13 276
previous work on the dissolution of naproxen nanodispersions stabilized
277
with hydroxypropyl cellulose and sodium lauryl sulphate and of 150 nm
278
median diameter. Tsinman et al. (2013) reported their 'almost immediate'
279
dissolution, although the kinetics of dissolution were not disclosed.
280
These authors used a spectroscopic technique to quantify the naproxen
281
based on differences in second derivative UV spectrum between
282
dissolved and solid drug (Tsinman et al., 2012). Junke et al. (2015) used
283
a pH-metric technique and reported 'rapid dissolution' that reached
284
equilibrium within a few minutes. The first time point of these
285
measurements was 2 minutes and a value for m(t)/m0 x 100 of
286
approximately 80 % was reached after 15 minutes. The kinetic results
287
presented in Figure 1A demonstrate, however, that dissolution of the
288
nanodispersion is completed during the first 60 seconds of the
289
experiment under the conditions we used. They also discriminate
290
between the three different solubility conditions. Under sink conditions,
291
i.e. c(t) ≤ 0.1 x cs and c0 = cs x 0.02, the result is as expected in that the
292
complete amount of naproxen had dissolved after 1 minute, i.e. m(t)/m0 x
293
100 reached the value of 100 %. The change to non-sink conditions, i.e.
294
c(t) > 0.1 x cs , but still below saturation solubility, i.e. c0 = cs x 0.81,
295
slowed down dissolution, although this was still completed after 5
296
minutes (Figure 1A). The slower approach to maximum dissolution after
297
c(90%) with c0 = cs x 0.81, might be a result of enhanced aggregation of
298
the very small residual nanoparticles left at this time. According to the
14 299
Noyes-Whitney equation, the dissolution rate, dm(t)/dt, will decline
300
linearly as the value of [cs - c(t)] decreases during dissolution under non-
301
sink conditions. But dissolution should progress to completeness
302
provided that c0 does not exceed cs (this ignores possible
303
supersaturation) as has been demonstrated using equations derived for
304
decrease in particle size with time (Liu et al., 2013). Yet not all of the
305
naproxen, m0, had dissolved at the end of the experiment: m(t)/m0 x 100
306
reached a maximum of only approximately 90 % after 30 minutes and did
307
not increase further after 120 minutes (not shown in Figure 1A). The
308
measured pH of the buffer remained unchanged during dissolution, so
309
this is not the cause of the failure to each m(t)/m0 x 100 of 100 %. The
310
result obtained under non-sink conditions, i.e. c(t) > 0.1 x cs , but now
311
above saturation solubility, i.e. c0 = cs x 1.81, is given in the kinetic plot in
312
Figure 1A. It shows the same rapid dissolution as seen under the other
313
two solubility conditions with dissolution having been completed after 1
314
minute. Yet the maximum value of m(t)/m0 reached lies well below that
315
under sink conditions, but is equal to the saturation solubility of naproxen
316
at this pH of 2.2 of cs = 0.025 mg/mL (Table 2). The dissolution of the
317
naproxen nanoparticles under the non-sink condition of c0 = cs x 1.81
318
progresses therefore up to saturation solubility after 1 minute and then
319
stops. This is in accord with Noyes-Whitney. No supersaturation is
320
observed. We see therefore that neither of the two non-sink conditions
15 321
examined hindered the very rapid dissolution of the nanodispersion
322
within the first minute.
323 324
The samples removed during the dissolution process were passed
325
through a 20 nm pore diameter membrane filter to remove non-dissolved
326
drug nanoparticles. We expect no, or at worst, only a negligible fraction
327
of the nanoparticles with diameter below this size which could have
328
passed through the filter. The average diameter of the nanoparticles as
329
measured using photon correlation spectroscopy was x50,3 of 166 nm with
330
a range given by x10,3 of 92 nm and x90,3 of 309 nm. Matteucci et al.
331
(2007) examined the dissolution of itraconazole nanodispersions of size
332
200 - 600 nm and found no difference in dissolution profiles between
333
filtering through 20 nm or 200 nm pore diameter filters. The implication
334
was that the filtering technique with 20 nm pore diameter let no
335
undissolved nanoparticle through into the filtrate.
336 337
3.2 Dissolution behaviour from spray dried nanodispersion with mannitol
338 339
The dry powder yield of the spray dried naproxen/mannitol was 60
340
% and contained a weight ratio of mannitol/naproxen of (4:1). Naproxen
341
has a high melting point (152-154 °C) compared with other BCS class 2
342
drugs. Figure 1B shows how the dissolution profiles of the spray dried
343
powder are broadly similar to those of the nanodispersion under all three
16 344
solubility conditions, just somewhat lower. Under the non-sink conditions,
345
c0 = cs x 0.81 or c0 = cs x 1.81, the values for m(t)/m0 x 100 are still
346
increasing after 5 minutes' dissolution time. After, at the latest, 30
347
minutes the spray-dried solid under the non-sink conditions has reached
348
the same m(t)/m0 x 100 as the rapidly-dissolving nanodispersion under
349
sink conditions (not shown in Figure 1B for clarity). The inclusion of the
350
nanoparticles within the spray dried mannitol leads therefore to a small
351
hindrance in their dissolution, detectable during the first 60 seconds.
352
Previous studies of spray dried drug nanoparticles with mannitol have
353
consistently reported more rapid dissolution than obtained with the
354
nanoparticles alone. For example, the more rapid dissolution of
355
griseofulvin nanoparticles of Z-average diameter 210 nm after spray
356
drying with mannitol (1:2 parts by weight) was attributed to improvement
357
in wetting of the nanoparticles by the crystalline mannitol (Shah et al.,
358
2016). We note that the presence of mannitol (2 % w/w) has also been
359
shown to increase the dissolution rate of powdered naproxen in water
360
and attributed to mannitol's effect in decreasing solution viscosity (Paus
361
et al., 2015). These effects are not, however, observed in the current
362
study because the dissolution rate of the naproxen nanodispersion in the
363
first 60 seconds is very high (Figure 1A), indeed 'almost immediate' (cf.
364
Tsinman et al., 2012, 2013). There are also no signs of the 2 - 4 minute
365
delay in dissolution of spray dried itraconazole in mannitol reported by
366
Chaubal & Popescu (2008) and attributed to slow hydration and
17 367
disintegration of drug aggregates. Spray dried pure mannitol is fully
368
crystalline under the process conditions used here (Elversson & Millqvist-
369
Fureby, 2005). The spray dried nanoparticles with mannitol (1:4) were
370
crystalline according to wide-angle X-ray diffraction (diffractogram not
371
shown). During droplet drying of a mannitol solution a process of phase-
372
separation takes place (Schiffter & Lee, 2007) and the crystallization of
373
the mannitol will engulf the naproxen nanoparticles in the final spray-
374
dried solid. This is a rapid process during spray drying that occurs within
375
milliseconds for droplets of the size generated in the Büchi two-fluid
376
nozzle (Masters, 1991). A rapid crystallisation of mannitol is expected to
377
produce a uniform distribution of the nanoparticles within the solid
378
(Thommes et al., 2011; Pomazi et al., 2011). The small hindrance in
379
dissolution observed in Figure 1B is a result of this engulfment where the
380
mannitol particles must first disintegrate or dissolve to release the
381
naproxen nanoparticles and allow them to dissolve.
382 383
The spray dried nanodispersion with mannitol measured at non-
384
sink conditions but still below saturation solubility, i.e. c0 = cs x 0.81, did
385
not reach complete dissolution (Figure 1B), as seen already with the
386
nanodispersion. At the end of the experiment (t = 120 min, not shown in
387
Figure 1B) the value for m(t)/m0 x 100 was 92 %. The measured pH of
18 388
the buffer remained unchanged during dissolution, so this is not the
389
cause of the failure to each m(t)/m0 of 100 %.
390 391
3.3 Comparison of dissolution behaviour of nanodispersion with
392
microsuspension
393 394
The microsuspension, not having been milled, had much larger
395
particle size than the nanodispersion. The laser diffraction analysis result
396
is a x50,3 of 11.7 µm with a range given by x10,3 of 4.1 µm and x90,3 of 29.3
397
µm. Although the larger size and hence smaller specific surface area of
398
the microparticles should reduce their dissolution rate, this is not the
399
case when measured under sink conditions, i.e. c0 = cs x 0.02. Figure 2
400
shows almost identical dissolution profiles from the microsuspension and
401
nanodispersion during the first 60 seconds and the subsequent 5
402
minutes to complete dissolution, i.e. m(t)/m0 x 100 ≥ 97 %. At first sight
403
this is a surprising result because Noyes-Whitney predicts a lower
404
dissolution rate with the smaller specific surface of the microparticles.
405
We assume complete wetting of the particle surface in the dispersions
406
which contain 0.75 % w/w hydroxypropyl cellulose and 0.0025 % w/w
407
dioctyl sulfosuccinate Na. This dissolution result is not an artefact of the
408
rapid sampling and filtration method used here, because a distinction in
409
dissolution rate is observed between microsuspension and
410
nanodispersion under the non-sink condition above saturation solubility,
19 411
i.e. c0 = cs x 1.81 also shown in Figure 2. The dissolution rate from the
412
microsuspension is lower and the value of m(t)/m0 x 100 reached after 5
413
minutes is smaller.
414 415
The effects of specific surface on dissolution behaviour depend on
416
whether sink conditions exist. At the very high dissolution rate under sink
417
conditions, the microparticles shrink rapidly and have largely
418
disappeared after 60 seconds (m(t)/m0 x 100 has reached ≥ 85 % in
419
Figure 2). Their initial large size and small specific surface is therefore
420
rapidly lost during dissolution and cannot affect dissolution rate viewed
421
over 5 minutes or longer. In contrast, under non-sink conditions above
422
saturation solubility, i.e. c0 = cs x 1.81, the dissolved concentration, c(t),
423
rapidly approaches saturation, cs, after only a small shrinkage of the
424
micro-particles. The value of [c(t) - cs] in the Noyes-Whitney equation
425
rapidly declines with time towards zero which will reduce dissolution rate
426
linearly. The large size and small specific surface of the microparticles is
427
retained therefore for longer times during dissolution under non-sink
428
conditions and hence gives a measurably lower rate of dissolution. The
429
overall result is that the comparative behaviour of microsuspension and
430
nanodispersion is different under sink and non-sink conditions. Under
431
sink conditions the micro-particles and nanoparticles exhibit the same
20 432
very rapid dissolution; under non-sink conditions above saturation
433
solubility, the microparticles show slower dissolution.
434 435
These findings are supported by previous disclosures in the
436
literature. Particularly, Murdande et al. (2015) reported only weak effects
437
of the size of nanoparticles and microparticles in the range 122 nm to
438
11.3 µm on their dissolution rate from dispersions under sink conditions.
439
Larger differences could, however, be observed under non-sink
440
conditions. The results in Figure 2 make this distinction more clearly
441
because non-sink conditions above saturation solubility were used, i.e. c0
442
= cs x 1.81, rather than non-sink conditions below saturation used by
443
Murande et al. (2015), i.e. in their case c0 = cs x 0.55. These authors
444
concluded that sink conditions were unsuitable to discriminate between
445
the dissolution behaviour of such disperse systems. This is supported by
446
Anhalt et al. (2012) who reported that larger sized nanoparticles reduced
447
the dissolution rates of fenofibrate under non-sink conditions.
448 449
3.4 Dissolution behaviour from tabletted, spray dried nanodispersion or
450
microparticulate raw material
451 452 453
The tablets made from the microparticulate raw material had greater hardness than those prepared from the spray-dried
21 454
nanodispersion containing mannitol (Table 3). The effects of mannitol on
455
tablet hardness are known to depend on the other formulation
456
components and their pre-treatment and can lead to either more (Omar
457
et al., 2017) or less (Molokhia et al., 1982) hardness. The major
458
difference is, however, the much shorter disintegration time of the tablets
459
made from the microparticles (Table 3). This is a result of the higher
460
content of the rapidly-dissolving bulking agent Mannogem EZ, some 61
461
% versus 21 %. The rapid dispersion of the Mannogem EZ (spray dried
462
mannitol) enhances distintegration to a much greater extent than the
463
regular mannitol used to co-spray dry the nanodispersion, at the same
464
level of Kollidon CL-SF.
465 466
The microparticle tablet under sink conditions, i.e. c0 = cs x 0.02,
467
shows rapid dissolution within the initial 2 minutes and produces an
468
m(t)/m0 of ≥ 0.97 after 5 minutes (Figure 3). The tablet disintegrates fully
469
within 2 minutes (Table 3) and the microparticles, once released from the
470
tablet, dissolve very rapidly in sink conditions, as already seen for the
471
microsuspension in Figure 2. Recall that under sink conditions the
472
microsuspension dissolves as rapidly as the nanodispersion (cf. Figure
473
2). The nanoparticle tablets show distinctly slower dissolution than the
474
micoparticulate tablets and requires 15 minutes for complete dissolution,
475
i.e. for m(t)/m0 x 100 to reach ≥ 97 %. This is therefore a much slower rate
22 476
than the almost immediate dissolution of the nanodispersion under sink
477
conditions (cf. Figure 1). The tablet disintegration time is, however, 9.5
478
minutes (Table 3) which retards release of the nanoparticles from the
479
tablet formulation surrounding them. Once released, dissolution of the
480
nanoparticles under sink conditions is extremely rapid; but before this is
481
reached dissolution is hindered by the prolonged disintegration of the
482
tablet. Heng et al. (2010) determined that the distintegration time of
483
tablets containing cefuroxime nanoparticles only marginally influenced
484
dissolution. This was likely because a vacuum-dried nanodispersion was
485
used for tabletting in which the nanoparticles were highly aggregated, if
486
not fused by solid bridges formed by crystallization of previously-
487
dissolved mannitol. Our use of spray dried nanoparticles embedded in
488
mannitol avoids this problem (cf. Figure 2).
489 490
Under non-sink conditions above saturation solubility, i.e. c0 = cs x
491
1.81, the position is reversed. The microparticles show slow dissolution
492
with m(t)/m0 still well below 100 % after 60 min and also below the
493
saturation solubility (Figure 3). Despite the very short disintegration time
494
(Table 3) and rapid release of the microparticles from the tablet
495
formulation, their subsequent dissolution under non-sink conditions is
496
slow, as already shown by the microsuspension (Figure 2). In contrast to
497
this behaviour, the nanoparticles again suffer from the prolonged
498
disintegration time of the tablet (Table 2). Once released from the tablet
23 499
formulation, however, the nanoparticles dissolve rapidly under non-sink
500
conditions (cf. Figure 1). The result is that the measured dissolution from
501
the nanoparticle tablet is delayed but then reaches the level of saturation
502
solubility after 15 minutes (Figure 3). The slowly-distintegrating tablet
503
delays release of the nanoparticles to the dissolution medium under both
504
sink and non-sink conditions. The result under non-sink conditions is that
505
overall dissolution of the nanoparticles from the slowly-disintegrating
506
tablet is more rapid than that of the microparticles from the fast-
507
distintegrating-tablet.
508 509
4. Conclusions
510 511
We draw the following conclusion from this work:
512 513
i) By using a rapid sampling procedure it was possible to determine
514
the rate of dissolution of the naproxen nanodispersion during the first
515
minutes of dissolution. The dissolution was completed after the first 60
516
seconds of the experiment under both sink conditions and non-sink
517
conditions.
518 519
ii) The naproxen nanodispersion could be spray dried with mannitol
520
at a weight ration of mannitol/naproxen of (4:1) with a dry powder yield of
24 521
60 %. The dissolution rate was only slightly lower during the initial 60
522
seconds compared with the nanodispersion under both sink and non-sink
523
conditions. For such rapidly-dissolving nanoparticles the use of a highly
524
water-soluble carrier thus hinders slightly dissolution. Such carriers
525
which are assumed to enhance wetting of nanodispersions, will not
526
always produce enhanced dissolution.
527 528
iii) Under sink-conditions both the nanodispersion (size 166 nm) and a
529
microsuspension (size 11 µm) show very rapid dissolution kinetics when
530
using sampling times of below 10 - 20 sec. We suggest this is a result of
531
the rapid shrinkage of the microparticles on dissolution under sink
532
conditions which nullifies any effects of specific surface on dissolution
533
rate. Under non-sink conditions the microparticles dissolve more slowly
534
because they retain their lower specific surface for a longer time during
535
dissolution. A way to distinguish differences in dissolution rate between
536
nanoparticles and microsuspension may therefore be the use of even
537
short sampling times.
538 539
iv) differences in the dissolution rate of nanoparticles or microparticles
540
from compressed tablets are determined by both the tablet disintegration
541
time and whether sink or non-sink conditions exist in the dissolution
542
medium.
543
25 544
Acknowledgements
545 546
We gratefully acknowledge the financial support of the Deutsche
547
Forschungsgemeinschaft (DFG, grant PE 427/24-1) and the Cluster of
548
Excellence - Engineering of Advanced Materials (EAM) for funding this
549
project. We also acknowledge Dr. W. Hoheisel, Dr. M. Ostendorf und Dr.
550
J. Uhlmann from Bayer AG for the many useful discussions.
551
26 552
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682
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698
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699 700 701
.
33 702
Legends to Figures
703 704
Figure 1. Dissolution profiles of naproxen under various solubility
705
conditions. m(t) = amount dissolved at time, t; m0 = amount of naproxen
706
added to dissolution medium; c0 = maximum achievable concentration
707
should the naproxen amount, m0, be completely dissolved; cs =
708
naproxen's saturation solubility. c0 = cs x 0.02 = sink conditions; c0 = cs x
709
0.81 = non-sink conditions but below saturation solubility; c0 = cs x 1.81 =
710
non-sink conditions above saturation solubility. A) Effect of different
711
solubility conditions on dissolution of naproxen nanodispersion. B)
712
Comparison of dissolution profiles of naproxen nanodispersion and spray
713
dried naproxen/mannitol (1:4).
714 715
Figure 2. Comparison of dissolution profiles of naproxen nanodispersion
716
and naproxen microsuspension of raw material (see Materials) under
717
various solubility conditions. m(t) = amount dissolved at time, t; m0 =
718
amount of naproxen added to dissolution medium; c0 = maximum
719
achievable concentration should the naproxen amount, m0, be
720
completely dissolved; cs = naproxen's saturation solubility. c0 = cs x 0.02
721
= sink conditions; c0 = cs x 0.81 = non-sink conditions but below
722
saturation solubility; c0 = cs x 1.81 = non-sink conditions above saturation
723
solubility.
34 724 725
Figure 3. Dissolution profiles of naproxen from compressed tablets
726
containing either spray-dried nanodispersion or microparticulate raw
727
material. m(t) = amount dissolved at time, t; m0 = amount of naproxen
728
added to dissolution medium; c0 = maximum achievable concentration
729
should the naproxen amount, m0, be completely dissolved; cs =
730
naproxen's saturation solubility. c0 = cs x 0.02 = sink conditions; c0 = cs x
731
1.81 = non-sink conditions above saturation solubility. Note different time
732
scale from that used in Figures 1 and 2.
733 734
35 735 736
Table 1: Powder compositions used to prepare tablets from spray dried
737
nanodispersions or microsuspensions. The spray dried
738
nanodispersion of naproxen in mannitol (49 %) contained
739
sufficient naproxen to produce 7 % w/w of the drug in the final
740
tablet formulation.
741
Substance
Nanodispersion Microsuspension [% w/w]
[% w/w]
49
-
-
7
Mannogem® EZ
21
61
Vivapur® Type 301
24
26
Kollidon® CL-SF
3
3
talc-magnesium-
3
3
spray-dried nanodispersion of naproxen in mannitol naproxen raw material
stearate-Aerosil (ratio 6:3:1 w/w) 742 743
36 744
Table 2: Values for saturation solubility, cs, of naproxen in dependence
745
of pH at 37 °C. Results are given as mean average ± standard
746
deviation for n = 3.
747
pH
Saturation solubility cs [mg/mL]
748 749
6.8
2.78 ± 0.032
4.2
0.057 ± 0.000
2.2
0.025 ± 0.002
37 750
Table 3: Characteristics of tablets prepared from spray dried
751
nanodispersions or microsuspensions of naproxem. The spray
752
dried nanodispersion of naproxen contained mannitol. In all cases
753
n = 5 tablets.
754
Property
Tablets made from
Tablets made
spray-dried
from naproxen
nanodispersion
microparticle raw material
height [mm]
3.7 ± 0.05
3.9 ± 0.02
diameter [mm]
13.1 ± 0.03
13.1 ± 0
hardness [N]
43.6 ± 8.5
57.4 ± 4.7
10 ± 0
1.0 ± 0.2
9.5 ± 3.5
2.0 ± 0
distintegration time at pH 6.8 [min] disintegration time at pH 2.2 [min] 755 756
38
757
758 759 760
39
761 762
40
763 764
41
765