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Preparation and dissolution characteristic evaluation of carvedilol-Kollicoat IR solid dispersions with HPMC and MC as combined carriers
Journal Pre-proof Preparation and dissolution characteristic evaluation of carvedilol-Kollicoat IR solid dispersions with HPMC and MC as combined carriers Ziyue Xi, Wei Zhang, Zisen Gao, Luyao Xie, Lu Chen, Mingshu Cui, Yanru Xi, Lu Xu PII:
S0032-5910(19)30924-6
DOI:
https://doi.org/10.1016/j.powtec.2019.10.095
Reference:
PTEC 14862
To appear in:
Powder Technology
Received Date: 19 April 2019 Revised Date:
7 September 2019
Accepted Date: 25 October 2019
Please cite this article as: Z. Xi, W. Zhang, Z. Gao, L. Xie, L. Chen, M. Cui, Y. Xi, L. Xu, Preparation and dissolution characteristic evaluation of carvedilol-Kollicoat IR solid dispersions with HPMC and MC as combined carriers, Powder Technology (2019), doi: https://doi.org/10.1016/j.powtec.2019.10.095. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
1
Preparation and Dissolution Characteristic Evaluation of
2
Carvedilol-Kollicoat IR Solid Dispersions with HPMC and MC
3
as Combined Carriers
4
Ziyue Xia, Wei Zhanga, Zisen Gaob, Luyao Xiea, Lu Chena, Mingshu Cuia, Yanru Xia, Lu Xua*
5
a. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016,
6
China;
7
b. Key Laboratory of Structure-Based Drug Design Discovery of Ministry of Education, Shenyang
8
Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China;
9
* Correspondence: [email protected]; Tel.: 024-43520583
10
Abstract
11
In this study, the abilities of hydroxypropyl methylcellulose (HPMC) and methylcellulose (MC)
12
as nonionic surfactants to improve the dissolution rate of carvedilol solid dispersions (CAR SDs) with
13
Kollicoat IR as a carrier were clearly demonstrated. CAR SDs were prepared using the solvent
14
evaporation method, and their physicochemical properties were characterized by scanning electron
15
microscopy (SEM) and X-ray diffraction (XRD). The results suggested that CAR in SDs existed in an
16
amorphous form. In vitro dissolution experiments and molecular docking (MD) simulations were
17
conducted to confirm the storage stability of CAR SDs. In order to study the mechanism of
18
solubilization ability, molar solubilization ratio (MSR) and micelle-water partition coefficient (Kmic)
19
were calculated. The results showed that the MSR and logKmic values of MC/Kollicoat IR 1:3 were
20
around 30-fold higher than the single surfactants. Above all, HPMC and MC have great potentials to
21
improve the dissolution characteristics of CAR-Kollicoat IR SDs.
22
Keywords: Carvedilol, Kollicoat IR, Solid dispersion, Surfactant, Solubilization mechanism
23
1. Introduction
24
Carvedilol
(Figure
1a)
(CAR,
{1-[carbazolyl-(4)-oxy]-3-[2-methoxyphenoxyethylamino]
25
propanol-(2)}) is a non-selective ɑ, β1, and β2 adrenergic receptor antagonist with antioxidant
26
properties. Therefore, CAR has been used in clinical practice for the treatment of cardiovascular
27
diseases (hypertension, congestive heart failure, or myocardial infarction) [1]. As a biopharmaceutical 1
28
classification system (BCS) class II drug, CAR has high membrane permeability, slow dissolution rate
29
because of low water solubility, and is administered as a large oral dose [2]. Its low solubility may
30
hinder the absorption of the drug in the small intestine and colon. Thus, it is necessary to improve the
31
dissolution rate of CAR. At present, methods applied to improve the dissolution rate of insoluble drugs
32
include solid dispersions (SDs) [3-4], liquisolid compacts [5-6], and self-emulsion systems [7-8].
33
Among these methods, solid dispersion is one of the most effective methods.
34
In the past five decades, solid dispersion techniques have been continuously developed and have
35
become one of the most effective approaches to improve the dissolution rate and bioavailability of
36
poorly water-soluble drugs [3]. Traditional single polymers such as hydroxypropyl methyl cellulose
37
(HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), and polyvinylpyrrolidone (PVP), and
38
novel materials including Kollidon K-30, Kollidon CL, and Soluplus® have been widely used as
39
carriers in solid dispersion to improve the dissolution and to prevent crystallization of drugs. With the
40
development of SDs, binary polymer systems were also used as carriers in the preparation of SDs [9] to
41
improve stability significantly compared to single carriers. Moreover, binary carriers with the addition
42
of surfactants based on the single polymer have been shown to enhance bioavailability by solubilizing
43
and supersaturating drugs in the gastrointestinal88i fluids. In recent studies, CAR SDs were prepared
44
using many types of polymers as carriers including single polymers like HPMC [10], HPMCAS [11],
45
and Soluplus® [3], or binary polymers such as Eudragit /Tween 80 and PVP/Tween 80 [2]. Despite the
46
existence of some relevant studies, research into the surfactants HPMC and MC as combined carriers
47
added to CAR SDs to improve dissolution of poorly water-soluble drugs and the relative mechanism of
48
solubilization is still rare.
49
Herein, CAR SDs were prepared using the solvent evaporation method with different ratios of the
50
surfactants and Kollicoat IR (Figure 1d). HPMC (Figure 1b) and methyl cellulose (MC, Figure 1c)
51
were chosen as nonionic surfactants. X-Ray Diffractometry (XRD) and Scanning Electron Microscopy
52
(SEM) were used to characterize the solid-state of CAR. In vitro release performance was applied to
53
evaluate the dissolution ability and storage stability of CAR SDs. Furthermore, to study the mechanism,
54
several kinetic models were fitted to confirm the effect of the surfactant incorporated with SDs. With
55
the molecular docking and kinetic models studies of solid dispersion, the solubility mechanism of CAR
56
SDs could be better understood, which provides insights into the theory of drug release. Additionally,
57
the critical micelle concentration (CMC), molar solubilization ratio (MSR), and micellar-water 2
58
partition coefficient Kmic were calculated for the surfactants. Overall, the results, highlighted here,
59
provided new insights into surfactants addition for future design of efficient poorly water-soluble drug
60
delivery systems. As far as is known by the authors of this study, this is the first time that CAR solid
61
dispersions were prepared with Kollicoat IR and the nonionic surfactants HPMC and MC as
62
combined carriers.
63
2. . Materials and methods
64
2.1. Materials
65
Carvedilol with purity of more than 99% was purchased from Jiuding Chemical Reagent
66
Corporation, Shanghai, China; Kollicoat IR was obtained from BASF, Germany; hydroxypropyl
67
methylcellulose (HPMC) E5 was obtained from Sunhere Pharmaceutical Excipients Chemical Reagent
68
Corporation, Anhui, China; and methylcellulose 55 HD100 (MC) was supplied by Head Chemical
69
Reagent Corporation, Shangdong, China. Other chemical agents were obtained from Yu Wang
70
Chemical Reagent Corporation, Shangdong, China. All other chemicals and solvents were of reagent
71
grade and were used without further purification.
72
2.2. Preparation of carvedilol-loaded solid dispersions
73
Solid dispersions were prepared using the solvent evaporation method [12]. Polymers and CAR
74
with different ratios were completely dissolved in ethanol, and the weight ratios between the drug and
75
excipient were designed as shown at Table 1. The above solution was mixed and organic solvent was
76
removed by rotary evaporation. The resulting substance was dried in vacuum oven for 48 h at 80℃,
77
ground carefully, and sieved (60 mesh) to obtain CAR SDs.
78
2.3. Physicochemical characterization
79
2.3.1. Scanning electron microscopy (SEM)
80
The surface topographies of the pure CAR and the CAR-loaded SDs were observed using a
81
scanning electron microscope (S-3400N, Hitachi). The powders were fixed to a brass specimen holder
82
using double-sided adhesive tape and were made electrically conductive by coating with gold (6
83
nm/min) in a vacuum (6 Pa), using a Hitachi Ion Sputter (E-1030) for 300 s at 15 mA. 3
84
2.3.2. X-ray diffraction analysis (XRD)
85
X-ray diffraction (XRD) patterns (Rigaku Smart Lab, Japan) were recorded using a powder X-ray
86
diffractometer. Diffraction patterns were obtained using a step width of 0.02˚ with a detector resolution
87
in 2θ between 5-40˚ and a scan speed of 2 s per step at 25 ℃ [13].
88
2.4. Dissolution properties
89
2.4.1. In vitro dissolution studies
90
In vitro dissolution studies of pure carvedilol, physical mixture (PM), and solid dispersions (SDs)
91
were carried out using the United States Pharmacopeia (USP) Apparatus II paddle method (100 rpm,
92
37℃, and 900 mL dissolution medium) with a ZRS-8G dissolution tester (Shanghai, China) [14].
93
Roughly 10 mg of sample powder was placed in the dissolution medium and 5 mL of artificial
94
intestinal fluid (pH 6.8 phosphate buffer solution) and artificial gastric fluid (pH 1.2 hydrochloric acid
95
solution) was withdrawn 10, 20, 30, 40, 50, 60, 90, 120 and 180 min prior to filtration using a 0.45 µm
96
filter. The concentration of samples was analyzed using an ultraviolet spectrophotometer (756 PC
97
UV-2200, Shanghai, China) at 240 nm. All measurements were repeated three times.
98
In order to further study the kinetic release of CAR, DDSolver software [15] was used to fit the
99
following kinetic models: Zero-order, First-order, Korsmeyer–Peppas, Makoid, Peppas–Sahlin, and
100
Weibull.
101
2.4.2. Storage stability experiment
102
Freshly prepared solid dispersions including IR3, HIR2, and MIR2, and the solid dispersions were
103
kept for two months at 25℃ and 60% relative humidity (RH), and were analyzed for in vitro dissolution
104
to evaluate the storage stability of the CAR SDs. Besides, the moisture analysis was conducted to
105
confirm the storage stability of SDs with the different RH ranging from 10% to 90% respectively. The
106
methodology used in for the in vitro dissolution experiments was the same as is detailed in Section
107
2.4.1. All tests were repeated three times.
108
2.5. Molecular docking of CAR/Kollicoat IR-SD
109
AutoDock 4.0 software was employed to assess the molecular interactions of CAR/Kollicoat
4
110
IR-SD by molecular docking. The molecular docking results of the Kollicoat IR and CAR molecules
111
were analyzed by Discovery Studio Visualizer 4.5 and the Discovery Studio Visualizer 4.5 was also
112
used for molecular interaction analysis (http://accelrys.com/products/discovery-studio/) [16]. The
113
molecular structures of pure CAR and the polymer Kollicoat IR are shown in Figures 1a and 1d,
114
created using the SYBYL 6.9.1 software package (Tripos Inc. St. Louis, MO, USA). The optimal
115
parameters were as follows: the maximum number of interactions was 10,000, and the frequency of
116
energy variety was 0.005 kcal/ (mol × Å).
117
The preferred parameters of the AutoDock 4.0 software were as follows: the maximum number of
118
energy assessments was raised to 25,000,000, the interactions of the Solis & Wets local search were
119
3000, the number of individuals in a population was 300, and the number of generations was 100.
120
Results differing by < 2Å in positional root mean square deviation were clustered together [17]. In
121
every group, the lowest binding energy configure ration with the highest frequency percentage was
122
chosen as the symbol of the group. All other parameters were set at the default values.
123
2.6.
124
2.6.1. Determination of critical micelle concentration (CMC)
Effect of HPMC, MC on CAR SDs
125
Different concentrations of surfactant solution were prepared, and the maximum bubble pressure
126
method (Figure 2) was used to determine the critical micelle concentration (CMC) values for the single
127
polymer and binary polymers systems [18]. When surface adsorption reaches saturation, corresponding
128
to the concentration where the surface is no longer saturated, the curve reaches a turning point, and the
129
concentration at this point is the critical micelle concentration [19]. The measured surface tension
130
values were accurate to within ±0.1 mN·m-1. The CMC values were determined by plotting γ as a
131
function of the logarithm values (log C) of the surfactant solution concentrations over a wide
132
concentration range [20], as shown in Figure 8.
133
2.6.2. Evaluation of solubilization ability
134
The differences in the molar solubilization ratios (MSR) and the partition coefficients (Kmic) of
135
HPMC, MC, HIR5, and MIR4 between the micelle and water suggested the solubilization capacity of
136
the surfactants. A large number of experiments on the solubilization of CAR with single surfactants 5
137
HPMC, and MC and with two kinds of different surfactants in mixed systems with varying ratios were
138
performed [20]. The excess amounts of CAR were added into HPMC, MC, HIR5, and MIR4 solutions
139
of different concentrations. The solubilization ability was determined by adding 3 mL phosphate buffer
140
(pH 6.8) into the above solutions and placing the resulting mixture into 10-mL tubes. Then, tubes were
141
equilibrated at 37 °C for 48 h in a thermostatic tank at about 110 rpm. Samples were then centrifuged at
142
9000 g for 20 min to discard the excess crystalline particles. Finally, the solutions were analyzed by
143
using 756 PC UV-2200 spectrophotometers (Shanghai, China) at a wavelength of 240 nm.
144
2.7. Statistical analysis
145
All data were analyzed using Graphpad Prism 7 (GraphPad Software, San Diego, CA) using
146
two-tailed Student’s test. All experiments were performed in triplicate unless otherwise mentioned.
147
Error bars used in this work are SD. p < 0.05 is statistically significant.
148
3. Results and discussion
149
3.1. Scanning electron microscopy (SEM)
150
SEM images of pure CAR, Kollicoat IR, CAR/Kollicoat IR 1:5-SD, CAR/HPMC/Kollicoat IR
151
1:1.67:3.33-SD, and CAR/MC/Kollicoat IR 1:1.25:3.75-SD are shown in Figure 3. Pure CAR was
152
observed as flake-shaped, indicating a crystalline form (Figure 3a). Kollicoat IR was in a spherical
153
granular form (Figure 3b). However, when CAR was loaded into SDs, the crystalline form of CAR
154
disappeared (Figure 3c, Figure 3d and Figure 3e), which indicated that CAR present in the SDs
155
prepared by the solvent evaporation method was in an amorphous state. Thus, CAR was adsorbed on
156
the excipients successfully by making CAR-SDs [2].
157
3.2. X-ray diffraction analysis (XRD)
158
XRD was also used to analyze the crystallization of CAR in solid dispersions. On the one hand,
159
the diffractograms showed amorphous halos and no crystalline peaks for CAR-loaded SDs (Figure 4),
160
indicating the complete amorphous state of the SDs, which was in agreement with the SEM images.
161
The diffractogram of PM of single carriers also showed no diffraction peak apart from the Kollicoat IR
162
peaks at about 20˚(2θ), demonstrating that the corresponding surfactants were also transformed to an
163
amorphous state. Crystalline CAR (Figure 3a) and PMs, on the other hand, showed the expected 6
164
characteristic crystalline diffraction peaks at 2θ of 6˚,11˚,13˚,17˚,18˚,24˚,26˚ and 29˚, suggesting that
165
untreated CAR exists in a crystalline state [21].
166
3.3. Dissolution properties
167
3.3.1. In vitro dissolution
168
An in vitro release study was performed to determine the most appropriate vehicle in the
169
construction of the CAR SDs [8]. Dissolution profiles of prepared solid dispersions in artificial gastric
170
fluid (pH 1.2 hydrochloric acid solution) and artificial intestinal fluid (pH 6.8 PBS) are presented in
171
Figure 5. It was noted that the CAR SD with the Kollicoat IR at a ratio of 1:5 improved the solution of
172
CAR compared to the other ratios in pH 6.8 PBS. However, dissolution rate at 3h has been improving
173
approximately one-fold by addition HPMC or MC as surfactants. Furthermore, both HIR5 and MIR4
174
also improved CAR dissolution rate. The cumulative percentage of MIR3 reached over 80% within 10
175
min, and MIR3 also improved dissolution rate. Compared to the traditional carriers of solid dispersion
176
such as HPMC, HPMCP, PVP and so on[10], the binary polymer system could improve the dissolution
177
more effectively, which can be attributed to the combined action of MC and HPMC as micelles and
178
Kollicoat IR, respectively. Furthermore, less CAR release in hydrochloric acid solution (pH 1.2) means
179
significantly reduced gastric stimulation, which is helpful in promoting compliance of patients.
180
As is shown in Table 2, the release profiles of CAR, IR3, HIR2, and MIR2 are fitted to
181
Makoid-Banakar, First-order equations, which were better than the other kinetic models fitted.
182
3.3.2. Storage Stability
183
In vitro dissolution tests and moisture analysis of CAR SDs were determined again after two
184
months and the results are shown in Figure 6 and Table 3. As shown in Table 3, the cumulative drug
185
release of CAR SDs including IR3, HIR2, and MIR2 that had been stored for two months decreased
186
slightly (approximately 3.05%, 1.09%, and 0.91%, respectively) compared to the freshly prepared SDs,
187
and the optimized group was MIR2. The results shown in Figure 6 indicated that during the storage
188
process SDs were extremely stable and the carrier Kollicoat IR probably maintained the stability due to
189
the characteristic hydrogen bonding between CAR and Kollicoat IR [22]. According to the results of
190
other groups compared to IR3, the other groups may exhibit the same mechanism as Kollicoat IR but
7
191
the MIR2 group has stronger molecular interactions.
192
3.4. CAR–Kollicoat IR interactions in molecular docking simulation
193
Kollicoat IR as a carrier of SD effectively improved dispersibility of the drug by molecular
194
interactions. The interaction between the carrier and the drug obviously reduced reaggregation and
195
agglomeration of the drug, thereby increasing drug dissolution rate and improving bioavailability. In
196
Figure 7, the interactions of CAR with Kollicoat IR are shown at the molecular level, with both the
197
polymer and the drug in skeleton and electron cloud views. In general, the polymer going through a
198
hydrophobic interaction with the drug induce the free energy; according to thermodynamics, negative
199
free energy (△G<0) indicates a relatively stable system, while the opposite (△G>0) is an unstable
200
system during the drug dispersion in the polymer. The bonding energy value of the drug and polymer
201
was −4.33 kcal/mol, proving that CAR had an interaction with Kollicoat IR through the formation of
202
hydrophobic bonds instead of the single molecules becoming aggregated.
203
3.5. Effect of HPMC, MC on CAR SDs
204
3.5.1. Critical micelle concentration
205
The minimum surface tension and the CMC are highly important parameters for the
206
characterization of surfactants [23]. Surfactants have saturation solubility in a special solution and no
207
longer dissolve after reaching the saturation. However, designing a surfactant according to the principle
208
of CMC can greatly increase the solubility. Thus, the maximum bubble pressure method was used to
209
determine the CMCs of HPMC, MC, HIR5, and MIR4. The surface tension of aqueous surfactant
210
solutions initially decreases sharply with the increase in the solution concentration, but changes slowly
211
or shows no change after reaching a certain concentration (CMC). Therefore, the inflection points of
212
the curves of surface tension against the logarithm of the surfactant concentration were taken as CMC
213
values. Figure 8 shows that MC had the highest surface tension, followed by MIR4, HPMC, and finally
214
HIR5. CMC values can be calculated according to Eq. (1), as shown in Table 4.
215
∆
∆ೢ
=
ఊ
ఊೢ
,
(1)
216
where ∆ℎ is the liquid column height difference of surfactants, ∆ℎ௪ is the liquid column height
217
difference of water, γ is the surface tension of surfactants, and ߛ௪ is the surface tension of water. All 8
218
the values are measured at same temperature (25°C).
219
3.5.2. Solubilization calculation
220
A useful method to evaluate the effectiveness of surfactants at solubilizing a given substance is to
221
calculate the molar solubilization ratios (MSR) and the partition coefficients (Kmic). MSR is defined as
222
the number of moles of the organic compound solubilized per mole of the micellized surfactant[20].
223
The MSR can be calculated using Eq. (2), ௌ ିௌಾ
224
MSR =
225
In this formula, Ct represents the molar concentration of the surfactant solution at concentrations
226
greater than the CMC, Scmc is the molar solubility of CAR when the surfactant concentration is equal to
227
the CMC, and St is the total apparent molar solubility of CAR in the surfactant solution corresponding
228
to Ct.
ିெ
,
(2)
229
According to the phase separation model of micellar solubilization, the micelle-water partition
230
coefficient (Kmic) is used to describe the effectiveness of solubilization. A partition coefficient, Kmic,
231
exists between the micellar phase and the aqueous phase [23]. Its relationship to the MSR is described
232
as follows:
233
ܭ =
234
where Xmic is the molar concentration of the micellar phase, and Xw is the methane molar
235
ೢ
,
(3)
concentration of the aqueous phase. ெௌோ
236
ܺ =
237
ܺ௪ = ܵெ × ܸ௪ ,
238
In this equation, Vw is the mole volume of water equal to 0.01805 L·mol-1 at 25°C.
239
Rearranging Eqs. (3)-(5), Kmic can be expressed as:
240
ܭ =
241
According to Eq. (2) and the CMC values of the surfactant, a liner fitting method was used to
242
calculate the MSR of HPMC, MC, HIR5, and MIR4. The value of Kmic is dependent on several factors
243
including the chemistry of the surfactant, the solubilization, and the temperature of the system. The log
244
Kmic can be calculated using Eq. (6), as is shown in Table 4.
ଵାெௌோ
,
ெௌோ
(ଵାெௌோ)ௌಾ ೈ
(4) (5)
,
(6)
9
245
During the linear fitting process of MSR, the correlation coefficient R2 was greater than 0.95,
246
indicating that the results were highly reliable and truly reflect the solubilization ability of the different
247
surfactants. In a nonionic surfactant solution, the solubilization ability orders of MSR and Kmic were
248
MIR4 > HIR5, which has the inversely proportional relationship with solubilization ability, indicating
249
the greater solubilization ability of HIR5. These results were consistent with the dissolution results
250
detailed above.
251
3.5.3. Solubilization mechanisms
252
HPMC and MC as nonionic surfactants are both less irritating than anionic and cationic
253
surfactants. In addition, they are highly stable due to their nonionic states in solution, and they cannot
254
be degraded even in the presence of strong electrolyte inorganic salts or pH changes. Surfactants can be
255
used as crystalline inhibitors to increase the supersaturation of active pharmaceutical ingredients in
256
vivo when the concentration of solution is above the CMC. There are two steps needed to generate
257
supersaturated solutions after drug crystallization, including nucleation and crystal growth. The
258
activation energy for nucleation mainly comes from interfacial tension between the medium and the
259
small particles. The high curvature between the medium and the small particles must be overcome for
260
nucleation to occur[24]. In other words, the activation energy is not overcome until a certain degree of
261
supersaturation is reached, so no new nuclei are formed for a certain period of time. The state in which
262
no nuclei are formed is called metastable. On the one hand, HPMC and MC maybe expand this region.
263
The uniform nucleation rate of pellets (J) is given by Eq. (7), య ଵగ௩ య ఊೞ
264
J = A݁ ݔቂ−
265
where v is the molecular volume of the crystalline solute, A is the exponential pre-kinetic factor, T
266
is the absolute temperature, S is the degree of supersaturation, and γns is the interface energy between
267
the solvent and the nucleus [4].
ଷ(்)య (୪୬ ௌ)మ
ቃ,
(7)
268
Therefore, non-surface-active compounds that increase solubility could explicitly reduce the
269
nucleation rate by influencing the degree of supersaturation. At the same time, the interfacial tension
270
will decrease in the presence of surfactants. On the other hand, the condition of surfactants dispersed in
271
SDs are shown in Scheme 1. Surfactants have hydrophobic group ends and hydrophilic group ends,
272
when the surfactant is put into the water, hydrophobic group will be positioned toward the air and the
10
273
hydrophilic group is positioned downward. Once the surfactant solution reaches saturation, a micelle is
274
formed. On the outside of the micelle is a hydrophilic group, and on the inside is a hydrophobic group.
275
Due to the hydrophobicity of CAR SD, they will be encapsulated into the micelle, thus increasing the
276
solubility of CAR SD in the solution [25].
277
4. Conclusions
278
CAR SDs were reformulated with Kollicoat IR, Kollicoat IR/HPMC, and Kollicoat IR/MC
279
carriers using the solvent evaporation method. The obtained results suggest that HPMC and MC as
280
both uncommon nonionic surfactants and auxiliary excipients maintain good stability and solubilization
281
ability. Moreover, a molecular docking simulation showed that intermolecular interaction occurred and
282
suggested a relatively stable system. This is the first study in which Kollicoat IR was used as carrier to
283
prepare CAR SDs. In vitro cumulative drug release of CAR was significantly improved by about 30%,
284
and the addition of HPMC and MC further greatly enhanced the dissolution rate. In brief, CAR solid
285
dispersions with HPMC and MC added to Kollicoat IR as binary polymer systems have great potential
286
for pharmaceutically effective oral drug formulation. This study may provide a new view for designing
287
different formulations to improve dissolution ability in the future.
288
Acknowledgement
289 290
Authors acknowledge Head Chemical Reagent Corporation (Shandong, China) for gift sample of methylcellulose.
291
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292
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polymer for supercritical fluid assisted preparation of carvedilol solid dispersions. International Journal
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Environmental Quality, 45(2016), 1405-1412.
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novel composition of ticagrelor by solid dispersion technique for increasing solubility and intestinal
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permeability. International Journal of Pharmaceutics, 555(2019), 11-18.
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Biopharmaceutics, 2015,8(94), 106-115.
359
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solubilization by organic surfactant aggregates. Chemical Papers, 72(2018), 1467-1475.
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solubility of poorly water-soluble drugs. Journal of Drug Delivery Science and Technology,
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364
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365
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366
non-ionic surfactant. Colloids and Surfaces A, 533(2017), 41-47.
14
Table 1 Formulation compositions of CAR SDs and some relevant physical mixture (PM) with different weigh ratios. The weight ratio between drug and binary polymers (Kollicoat IR /HPMC and Kollicoat IR /MC) was 1:5. Single polymer Batch no.
Binary polymers ratios
Drug Kollicoat IR
Kollicoat IR /HPMC
Kollicoat IR /MC
IR 1
1
1
IR 2
1
3
IR 3
1
5
HIR 1
1
1/1
HIR 2
1
2/1
HIR 3
1
3/1
HIR 4
1
5/1
HIR5 (PM)
-
2/1
MIR1
1
1/1
MIR2
1
3/1
MIR3
1
5/1
MIR4 (PM)
-
3/1
Table 2 The kinetic release rate of and R2 coefficients of CAR and prepared solid dispersions obtained from release data fitting analyses based on kinetic equations. Kinetic Equations
CAR
IR3
HIR2
MIR2
Zero-order
= 16.568 + 0.262
= 52.049 + 0.068
= 56.547 + 0.164
= 71.589 + 0.243
= +
R2=0.9240
R2=0.2992
R2=0.4767
R2=0.4439
First-order
= 59.423 × [1 − . ]
= 62.797 × [1 − . ]
= × [1 − ]
R2=0.9345
R2=0.9456
R2=0.9897
R2=0.9937
Korsmeyer-Peppas
= 4.546 × .#$
= 34.976 × . %
= 32.940 × . %
= 38.691 × .%
= × "
R2=0.9940
R2=0.6388
R2=0.7682
R2=0.7339
= 17.051 .& # × .#
= 16.751 .#% × .#
= 15.643 .!%# × .!
= 2.755 .
Makoid-Banakar
!
× .%
= 76.192 × [1 − .
]
= 102.048 × [1 − .! ]
= " ×
R2=0.9964
R2=0.9903
R2=0.9444
R2=0.9469
Peppas-Sahlin
= 4.623 .! − 0.012
= 13.993 .! − 0.725
= 15.310 .! − 0.727
= 19.679 − 0.913
= .! + %
R2=0.9881
R2=0.9562
R2=0.9360
R2=0.9352
= 100{1 − [(
Weibull = 100{1 − ((
* )⁄, .
}
0.123 )⁄&%.&&$]
} = 100{1 − ((
R2=0.9948
0.456 )⁄%.
R2=0.6814
$ .
} = 100{1 − ((
0.760 )⁄&. %.
} = 100{1 − ((
R2=0.8360
5.541 )⁄%#. &.
R2=0.9936
Table 3 The evaluation of storage stability of different formulations (mean ± SD, n=3). Groups
Before 2 months
After 2 months
Difference value
Stability
IR3
54.55±3.60%
57.60±0.05%
-3.05±0.05%
Good
HIR2
66.22±1.09%
65.55±0.43%
-1.09±0.67%
Good
MIR2
87.76±0.71%
86.85±1.77%
-0.91±0.71%
Excellent
}
Table 4 CMC, MSR and log Kmic values for different surfactants. Samples
HPMC
MC
HIR5
MIR4
CMC (mg/mL)
0.1
0.4
0.08
0.2
MSR
0.0004
0.0007
0.0016
0.0024
log Kmic
2.42
2.59
2.95
3.18
Figure 1. Chemical structures of the (a) pure CAR and the monomer units of (b) HPMC, (c) MC and (d) Kollicoat IR
Figure 2. The equipment of maximum bubble pressure method to determine CMC.
Figure 3. SEM images of (a) pure CAR, (b)Kollicoat IR, (c) IR3, (d) HIR2, (e) MIR2. Scale bar is shown in the graph.
Figure 4. X-ray powder diffraction of (a) pure CAR, (b) Kollicoat IR, (c) PM of IR3, (d) IR3, (e) HIR5, (f) PM of HIR2, (g) HIR2, (h) MIR4, (i) PM of MIR2 (l) MIR2.
Figure 5. Dissolution profiles of CAR solid dispersions in pH 6.8 PBS with (a) different ratios of Kollicoat IR and CAR , (b) addition of surfactants. (c) dissolution profiles of CAR solid dispersions in pH 1.2 hydrochloric acid solution. (mean ± SD, n=3). *p<0.05, **p<0.01 and ***p<0.001 compared to the CAR group.
Figure 6. In vitro dissolution and moisture analysis of CAR SDs with different carriers that have stored for two months (mean ± SD, n=3). (a) IR3; (b) HIR2; (c) MIR2; (d) Weight gain of different solid dispersions (mean ± SD, n=3).
Figure 7. Docking conformation of carvedilol complexed with Kollicoat IR. CAR and polymer are both shown in 3D structure representation. Two different views of integral conformations relevant with polymer, called CAR-Kollicoat IR SD, were displayed with the molecule and polymer shown.
Figure 8. Plots of surface tension (γ) as a function of the logarithm values of the total surfactant concentration (log C) of the single and different mixed CAR SDs systems with different concentration in the solution.
Scheme 1. Possible solubilization mechanism of surfactants.
1. The solubilization mechanism of surfactants added to SDs were clearly illustrated. 2. Kollicoat IR was the first time used as carrier to prepare CAR SDs. 3. The molecular modeling explained the reason why improved solubility in vitro.
S0032-5910(19)30924-6
DOI:
https://doi.org/10.1016/j.powtec.2019.10.095
Reference:
PTEC 14862
To appear in:
Powder Technology
Received Date: 19 April 2019 Revised Date:
7 September 2019
Accepted Date: 25 October 2019
Please cite this article as: Z. Xi, W. Zhang, Z. Gao, L. Xie, L. Chen, M. Cui, Y. Xi, L. Xu, Preparation and dissolution characteristic evaluation of carvedilol-Kollicoat IR solid dispersions with HPMC and MC as combined carriers, Powder Technology (2019), doi: https://doi.org/10.1016/j.powtec.2019.10.095. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
1
Preparation and Dissolution Characteristic Evaluation of
2
Carvedilol-Kollicoat IR Solid Dispersions with HPMC and MC
3
as Combined Carriers
4
Ziyue Xia, Wei Zhanga, Zisen Gaob, Luyao Xiea, Lu Chena, Mingshu Cuia, Yanru Xia, Lu Xua*
5
a. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016,
6
China;
7
b. Key Laboratory of Structure-Based Drug Design Discovery of Ministry of Education, Shenyang
8
Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China;
9
* Correspondence: [email protected]; Tel.: 024-43520583
10
Abstract
11
In this study, the abilities of hydroxypropyl methylcellulose (HPMC) and methylcellulose (MC)
12
as nonionic surfactants to improve the dissolution rate of carvedilol solid dispersions (CAR SDs) with
13
Kollicoat IR as a carrier were clearly demonstrated. CAR SDs were prepared using the solvent
14
evaporation method, and their physicochemical properties were characterized by scanning electron
15
microscopy (SEM) and X-ray diffraction (XRD). The results suggested that CAR in SDs existed in an
16
amorphous form. In vitro dissolution experiments and molecular docking (MD) simulations were
17
conducted to confirm the storage stability of CAR SDs. In order to study the mechanism of
18
solubilization ability, molar solubilization ratio (MSR) and micelle-water partition coefficient (Kmic)
19
were calculated. The results showed that the MSR and logKmic values of MC/Kollicoat IR 1:3 were
20
around 30-fold higher than the single surfactants. Above all, HPMC and MC have great potentials to
21
improve the dissolution characteristics of CAR-Kollicoat IR SDs.
22
Keywords: Carvedilol, Kollicoat IR, Solid dispersion, Surfactant, Solubilization mechanism
23
1. Introduction
24
Carvedilol
(Figure
1a)
(CAR,
{1-[carbazolyl-(4)-oxy]-3-[2-methoxyphenoxyethylamino]
25
propanol-(2)}) is a non-selective ɑ, β1, and β2 adrenergic receptor antagonist with antioxidant
26
properties. Therefore, CAR has been used in clinical practice for the treatment of cardiovascular
27
diseases (hypertension, congestive heart failure, or myocardial infarction) [1]. As a biopharmaceutical 1
28
classification system (BCS) class II drug, CAR has high membrane permeability, slow dissolution rate
29
because of low water solubility, and is administered as a large oral dose [2]. Its low solubility may
30
hinder the absorption of the drug in the small intestine and colon. Thus, it is necessary to improve the
31
dissolution rate of CAR. At present, methods applied to improve the dissolution rate of insoluble drugs
32
include solid dispersions (SDs) [3-4], liquisolid compacts [5-6], and self-emulsion systems [7-8].
33
Among these methods, solid dispersion is one of the most effective methods.
34
In the past five decades, solid dispersion techniques have been continuously developed and have
35
become one of the most effective approaches to improve the dissolution rate and bioavailability of
36
poorly water-soluble drugs [3]. Traditional single polymers such as hydroxypropyl methyl cellulose
37
(HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), and polyvinylpyrrolidone (PVP), and
38
novel materials including Kollidon K-30, Kollidon CL, and Soluplus® have been widely used as
39
carriers in solid dispersion to improve the dissolution and to prevent crystallization of drugs. With the
40
development of SDs, binary polymer systems were also used as carriers in the preparation of SDs [9] to
41
improve stability significantly compared to single carriers. Moreover, binary carriers with the addition
42
of surfactants based on the single polymer have been shown to enhance bioavailability by solubilizing
43
and supersaturating drugs in the gastrointestinal88i fluids. In recent studies, CAR SDs were prepared
44
using many types of polymers as carriers including single polymers like HPMC [10], HPMCAS [11],
45
and Soluplus® [3], or binary polymers such as Eudragit /Tween 80 and PVP/Tween 80 [2]. Despite the
46
existence of some relevant studies, research into the surfactants HPMC and MC as combined carriers
47
added to CAR SDs to improve dissolution of poorly water-soluble drugs and the relative mechanism of
48
solubilization is still rare.
49
Herein, CAR SDs were prepared using the solvent evaporation method with different ratios of the
50
surfactants and Kollicoat IR (Figure 1d). HPMC (Figure 1b) and methyl cellulose (MC, Figure 1c)
51
were chosen as nonionic surfactants. X-Ray Diffractometry (XRD) and Scanning Electron Microscopy
52
(SEM) were used to characterize the solid-state of CAR. In vitro release performance was applied to
53
evaluate the dissolution ability and storage stability of CAR SDs. Furthermore, to study the mechanism,
54
several kinetic models were fitted to confirm the effect of the surfactant incorporated with SDs. With
55
the molecular docking and kinetic models studies of solid dispersion, the solubility mechanism of CAR
56
SDs could be better understood, which provides insights into the theory of drug release. Additionally,
57
the critical micelle concentration (CMC), molar solubilization ratio (MSR), and micellar-water 2
58
partition coefficient Kmic were calculated for the surfactants. Overall, the results, highlighted here,
59
provided new insights into surfactants addition for future design of efficient poorly water-soluble drug
60
delivery systems. As far as is known by the authors of this study, this is the first time that CAR solid
61
dispersions were prepared with Kollicoat IR and the nonionic surfactants HPMC and MC as
62
combined carriers.
63
2. . Materials and methods
64
2.1. Materials
65
Carvedilol with purity of more than 99% was purchased from Jiuding Chemical Reagent
66
Corporation, Shanghai, China; Kollicoat IR was obtained from BASF, Germany; hydroxypropyl
67
methylcellulose (HPMC) E5 was obtained from Sunhere Pharmaceutical Excipients Chemical Reagent
68
Corporation, Anhui, China; and methylcellulose 55 HD100 (MC) was supplied by Head Chemical
69
Reagent Corporation, Shangdong, China. Other chemical agents were obtained from Yu Wang
70
Chemical Reagent Corporation, Shangdong, China. All other chemicals and solvents were of reagent
71
grade and were used without further purification.
72
2.2. Preparation of carvedilol-loaded solid dispersions
73
Solid dispersions were prepared using the solvent evaporation method [12]. Polymers and CAR
74
with different ratios were completely dissolved in ethanol, and the weight ratios between the drug and
75
excipient were designed as shown at Table 1. The above solution was mixed and organic solvent was
76
removed by rotary evaporation. The resulting substance was dried in vacuum oven for 48 h at 80℃,
77
ground carefully, and sieved (60 mesh) to obtain CAR SDs.
78
2.3. Physicochemical characterization
79
2.3.1. Scanning electron microscopy (SEM)
80
The surface topographies of the pure CAR and the CAR-loaded SDs were observed using a
81
scanning electron microscope (S-3400N, Hitachi). The powders were fixed to a brass specimen holder
82
using double-sided adhesive tape and were made electrically conductive by coating with gold (6
83
nm/min) in a vacuum (6 Pa), using a Hitachi Ion Sputter (E-1030) for 300 s at 15 mA. 3
84
2.3.2. X-ray diffraction analysis (XRD)
85
X-ray diffraction (XRD) patterns (Rigaku Smart Lab, Japan) were recorded using a powder X-ray
86
diffractometer. Diffraction patterns were obtained using a step width of 0.02˚ with a detector resolution
87
in 2θ between 5-40˚ and a scan speed of 2 s per step at 25 ℃ [13].
88
2.4. Dissolution properties
89
2.4.1. In vitro dissolution studies
90
In vitro dissolution studies of pure carvedilol, physical mixture (PM), and solid dispersions (SDs)
91
were carried out using the United States Pharmacopeia (USP) Apparatus II paddle method (100 rpm,
92
37℃, and 900 mL dissolution medium) with a ZRS-8G dissolution tester (Shanghai, China) [14].
93
Roughly 10 mg of sample powder was placed in the dissolution medium and 5 mL of artificial
94
intestinal fluid (pH 6.8 phosphate buffer solution) and artificial gastric fluid (pH 1.2 hydrochloric acid
95
solution) was withdrawn 10, 20, 30, 40, 50, 60, 90, 120 and 180 min prior to filtration using a 0.45 µm
96
filter. The concentration of samples was analyzed using an ultraviolet spectrophotometer (756 PC
97
UV-2200, Shanghai, China) at 240 nm. All measurements were repeated three times.
98
In order to further study the kinetic release of CAR, DDSolver software [15] was used to fit the
99
following kinetic models: Zero-order, First-order, Korsmeyer–Peppas, Makoid, Peppas–Sahlin, and
100
Weibull.
101
2.4.2. Storage stability experiment
102
Freshly prepared solid dispersions including IR3, HIR2, and MIR2, and the solid dispersions were
103
kept for two months at 25℃ and 60% relative humidity (RH), and were analyzed for in vitro dissolution
104
to evaluate the storage stability of the CAR SDs. Besides, the moisture analysis was conducted to
105
confirm the storage stability of SDs with the different RH ranging from 10% to 90% respectively. The
106
methodology used in for the in vitro dissolution experiments was the same as is detailed in Section
107
2.4.1. All tests were repeated three times.
108
2.5. Molecular docking of CAR/Kollicoat IR-SD
109
AutoDock 4.0 software was employed to assess the molecular interactions of CAR/Kollicoat
4
110
IR-SD by molecular docking. The molecular docking results of the Kollicoat IR and CAR molecules
111
were analyzed by Discovery Studio Visualizer 4.5 and the Discovery Studio Visualizer 4.5 was also
112
used for molecular interaction analysis (http://accelrys.com/products/discovery-studio/) [16]. The
113
molecular structures of pure CAR and the polymer Kollicoat IR are shown in Figures 1a and 1d,
114
created using the SYBYL 6.9.1 software package (Tripos Inc. St. Louis, MO, USA). The optimal
115
parameters were as follows: the maximum number of interactions was 10,000, and the frequency of
116
energy variety was 0.005 kcal/ (mol × Å).
117
The preferred parameters of the AutoDock 4.0 software were as follows: the maximum number of
118
energy assessments was raised to 25,000,000, the interactions of the Solis & Wets local search were
119
3000, the number of individuals in a population was 300, and the number of generations was 100.
120
Results differing by < 2Å in positional root mean square deviation were clustered together [17]. In
121
every group, the lowest binding energy configure ration with the highest frequency percentage was
122
chosen as the symbol of the group. All other parameters were set at the default values.
123
2.6.
124
2.6.1. Determination of critical micelle concentration (CMC)
Effect of HPMC, MC on CAR SDs
125
Different concentrations of surfactant solution were prepared, and the maximum bubble pressure
126
method (Figure 2) was used to determine the critical micelle concentration (CMC) values for the single
127
polymer and binary polymers systems [18]. When surface adsorption reaches saturation, corresponding
128
to the concentration where the surface is no longer saturated, the curve reaches a turning point, and the
129
concentration at this point is the critical micelle concentration [19]. The measured surface tension
130
values were accurate to within ±0.1 mN·m-1. The CMC values were determined by plotting γ as a
131
function of the logarithm values (log C) of the surfactant solution concentrations over a wide
132
concentration range [20], as shown in Figure 8.
133
2.6.2. Evaluation of solubilization ability
134
The differences in the molar solubilization ratios (MSR) and the partition coefficients (Kmic) of
135
HPMC, MC, HIR5, and MIR4 between the micelle and water suggested the solubilization capacity of
136
the surfactants. A large number of experiments on the solubilization of CAR with single surfactants 5
137
HPMC, and MC and with two kinds of different surfactants in mixed systems with varying ratios were
138
performed [20]. The excess amounts of CAR were added into HPMC, MC, HIR5, and MIR4 solutions
139
of different concentrations. The solubilization ability was determined by adding 3 mL phosphate buffer
140
(pH 6.8) into the above solutions and placing the resulting mixture into 10-mL tubes. Then, tubes were
141
equilibrated at 37 °C for 48 h in a thermostatic tank at about 110 rpm. Samples were then centrifuged at
142
9000 g for 20 min to discard the excess crystalline particles. Finally, the solutions were analyzed by
143
using 756 PC UV-2200 spectrophotometers (Shanghai, China) at a wavelength of 240 nm.
144
2.7. Statistical analysis
145
All data were analyzed using Graphpad Prism 7 (GraphPad Software, San Diego, CA) using
146
two-tailed Student’s test. All experiments were performed in triplicate unless otherwise mentioned.
147
Error bars used in this work are SD. p < 0.05 is statistically significant.
148
3. Results and discussion
149
3.1. Scanning electron microscopy (SEM)
150
SEM images of pure CAR, Kollicoat IR, CAR/Kollicoat IR 1:5-SD, CAR/HPMC/Kollicoat IR
151
1:1.67:3.33-SD, and CAR/MC/Kollicoat IR 1:1.25:3.75-SD are shown in Figure 3. Pure CAR was
152
observed as flake-shaped, indicating a crystalline form (Figure 3a). Kollicoat IR was in a spherical
153
granular form (Figure 3b). However, when CAR was loaded into SDs, the crystalline form of CAR
154
disappeared (Figure 3c, Figure 3d and Figure 3e), which indicated that CAR present in the SDs
155
prepared by the solvent evaporation method was in an amorphous state. Thus, CAR was adsorbed on
156
the excipients successfully by making CAR-SDs [2].
157
3.2. X-ray diffraction analysis (XRD)
158
XRD was also used to analyze the crystallization of CAR in solid dispersions. On the one hand,
159
the diffractograms showed amorphous halos and no crystalline peaks for CAR-loaded SDs (Figure 4),
160
indicating the complete amorphous state of the SDs, which was in agreement with the SEM images.
161
The diffractogram of PM of single carriers also showed no diffraction peak apart from the Kollicoat IR
162
peaks at about 20˚(2θ), demonstrating that the corresponding surfactants were also transformed to an
163
amorphous state. Crystalline CAR (Figure 3a) and PMs, on the other hand, showed the expected 6
164
characteristic crystalline diffraction peaks at 2θ of 6˚,11˚,13˚,17˚,18˚,24˚,26˚ and 29˚, suggesting that
165
untreated CAR exists in a crystalline state [21].
166
3.3. Dissolution properties
167
3.3.1. In vitro dissolution
168
An in vitro release study was performed to determine the most appropriate vehicle in the
169
construction of the CAR SDs [8]. Dissolution profiles of prepared solid dispersions in artificial gastric
170
fluid (pH 1.2 hydrochloric acid solution) and artificial intestinal fluid (pH 6.8 PBS) are presented in
171
Figure 5. It was noted that the CAR SD with the Kollicoat IR at a ratio of 1:5 improved the solution of
172
CAR compared to the other ratios in pH 6.8 PBS. However, dissolution rate at 3h has been improving
173
approximately one-fold by addition HPMC or MC as surfactants. Furthermore, both HIR5 and MIR4
174
also improved CAR dissolution rate. The cumulative percentage of MIR3 reached over 80% within 10
175
min, and MIR3 also improved dissolution rate. Compared to the traditional carriers of solid dispersion
176
such as HPMC, HPMCP, PVP and so on[10], the binary polymer system could improve the dissolution
177
more effectively, which can be attributed to the combined action of MC and HPMC as micelles and
178
Kollicoat IR, respectively. Furthermore, less CAR release in hydrochloric acid solution (pH 1.2) means
179
significantly reduced gastric stimulation, which is helpful in promoting compliance of patients.
180
As is shown in Table 2, the release profiles of CAR, IR3, HIR2, and MIR2 are fitted to
181
Makoid-Banakar, First-order equations, which were better than the other kinetic models fitted.
182
3.3.2. Storage Stability
183
In vitro dissolution tests and moisture analysis of CAR SDs were determined again after two
184
months and the results are shown in Figure 6 and Table 3. As shown in Table 3, the cumulative drug
185
release of CAR SDs including IR3, HIR2, and MIR2 that had been stored for two months decreased
186
slightly (approximately 3.05%, 1.09%, and 0.91%, respectively) compared to the freshly prepared SDs,
187
and the optimized group was MIR2. The results shown in Figure 6 indicated that during the storage
188
process SDs were extremely stable and the carrier Kollicoat IR probably maintained the stability due to
189
the characteristic hydrogen bonding between CAR and Kollicoat IR [22]. According to the results of
190
other groups compared to IR3, the other groups may exhibit the same mechanism as Kollicoat IR but
7
191
the MIR2 group has stronger molecular interactions.
192
3.4. CAR–Kollicoat IR interactions in molecular docking simulation
193
Kollicoat IR as a carrier of SD effectively improved dispersibility of the drug by molecular
194
interactions. The interaction between the carrier and the drug obviously reduced reaggregation and
195
agglomeration of the drug, thereby increasing drug dissolution rate and improving bioavailability. In
196
Figure 7, the interactions of CAR with Kollicoat IR are shown at the molecular level, with both the
197
polymer and the drug in skeleton and electron cloud views. In general, the polymer going through a
198
hydrophobic interaction with the drug induce the free energy; according to thermodynamics, negative
199
free energy (△G<0) indicates a relatively stable system, while the opposite (△G>0) is an unstable
200
system during the drug dispersion in the polymer. The bonding energy value of the drug and polymer
201
was −4.33 kcal/mol, proving that CAR had an interaction with Kollicoat IR through the formation of
202
hydrophobic bonds instead of the single molecules becoming aggregated.
203
3.5. Effect of HPMC, MC on CAR SDs
204
3.5.1. Critical micelle concentration
205
The minimum surface tension and the CMC are highly important parameters for the
206
characterization of surfactants [23]. Surfactants have saturation solubility in a special solution and no
207
longer dissolve after reaching the saturation. However, designing a surfactant according to the principle
208
of CMC can greatly increase the solubility. Thus, the maximum bubble pressure method was used to
209
determine the CMCs of HPMC, MC, HIR5, and MIR4. The surface tension of aqueous surfactant
210
solutions initially decreases sharply with the increase in the solution concentration, but changes slowly
211
or shows no change after reaching a certain concentration (CMC). Therefore, the inflection points of
212
the curves of surface tension against the logarithm of the surfactant concentration were taken as CMC
213
values. Figure 8 shows that MC had the highest surface tension, followed by MIR4, HPMC, and finally
214
HIR5. CMC values can be calculated according to Eq. (1), as shown in Table 4.
215
∆
∆ೢ
=
ఊ
ఊೢ
,
(1)
216
where ∆ℎ is the liquid column height difference of surfactants, ∆ℎ௪ is the liquid column height
217
difference of water, γ is the surface tension of surfactants, and ߛ௪ is the surface tension of water. All 8
218
the values are measured at same temperature (25°C).
219
3.5.2. Solubilization calculation
220
A useful method to evaluate the effectiveness of surfactants at solubilizing a given substance is to
221
calculate the molar solubilization ratios (MSR) and the partition coefficients (Kmic). MSR is defined as
222
the number of moles of the organic compound solubilized per mole of the micellized surfactant[20].
223
The MSR can be calculated using Eq. (2), ௌ ିௌಾ
224
MSR =
225
In this formula, Ct represents the molar concentration of the surfactant solution at concentrations
226
greater than the CMC, Scmc is the molar solubility of CAR when the surfactant concentration is equal to
227
the CMC, and St is the total apparent molar solubility of CAR in the surfactant solution corresponding
228
to Ct.
ିெ
,
(2)
229
According to the phase separation model of micellar solubilization, the micelle-water partition
230
coefficient (Kmic) is used to describe the effectiveness of solubilization. A partition coefficient, Kmic,
231
exists between the micellar phase and the aqueous phase [23]. Its relationship to the MSR is described
232
as follows:
233
ܭ =
234
where Xmic is the molar concentration of the micellar phase, and Xw is the methane molar
235
ೢ
,
(3)
concentration of the aqueous phase. ெௌோ
236
ܺ =
237
ܺ௪ = ܵெ × ܸ௪ ,
238
In this equation, Vw is the mole volume of water equal to 0.01805 L·mol-1 at 25°C.
239
Rearranging Eqs. (3)-(5), Kmic can be expressed as:
240
ܭ =
241
According to Eq. (2) and the CMC values of the surfactant, a liner fitting method was used to
242
calculate the MSR of HPMC, MC, HIR5, and MIR4. The value of Kmic is dependent on several factors
243
including the chemistry of the surfactant, the solubilization, and the temperature of the system. The log
244
Kmic can be calculated using Eq. (6), as is shown in Table 4.
ଵାெௌோ
,
ெௌோ
(ଵାெௌோ)ௌಾ ೈ
(4) (5)
,
(6)
9
245
During the linear fitting process of MSR, the correlation coefficient R2 was greater than 0.95,
246
indicating that the results were highly reliable and truly reflect the solubilization ability of the different
247
surfactants. In a nonionic surfactant solution, the solubilization ability orders of MSR and Kmic were
248
MIR4 > HIR5, which has the inversely proportional relationship with solubilization ability, indicating
249
the greater solubilization ability of HIR5. These results were consistent with the dissolution results
250
detailed above.
251
3.5.3. Solubilization mechanisms
252
HPMC and MC as nonionic surfactants are both less irritating than anionic and cationic
253
surfactants. In addition, they are highly stable due to their nonionic states in solution, and they cannot
254
be degraded even in the presence of strong electrolyte inorganic salts or pH changes. Surfactants can be
255
used as crystalline inhibitors to increase the supersaturation of active pharmaceutical ingredients in
256
vivo when the concentration of solution is above the CMC. There are two steps needed to generate
257
supersaturated solutions after drug crystallization, including nucleation and crystal growth. The
258
activation energy for nucleation mainly comes from interfacial tension between the medium and the
259
small particles. The high curvature between the medium and the small particles must be overcome for
260
nucleation to occur[24]. In other words, the activation energy is not overcome until a certain degree of
261
supersaturation is reached, so no new nuclei are formed for a certain period of time. The state in which
262
no nuclei are formed is called metastable. On the one hand, HPMC and MC maybe expand this region.
263
The uniform nucleation rate of pellets (J) is given by Eq. (7), య ଵగ௩ య ఊೞ
264
J = A݁ ݔቂ−
265
where v is the molecular volume of the crystalline solute, A is the exponential pre-kinetic factor, T
266
is the absolute temperature, S is the degree of supersaturation, and γns is the interface energy between
267
the solvent and the nucleus [4].
ଷ(்)య (୪୬ ௌ)మ
ቃ,
(7)
268
Therefore, non-surface-active compounds that increase solubility could explicitly reduce the
269
nucleation rate by influencing the degree of supersaturation. At the same time, the interfacial tension
270
will decrease in the presence of surfactants. On the other hand, the condition of surfactants dispersed in
271
SDs are shown in Scheme 1. Surfactants have hydrophobic group ends and hydrophilic group ends,
272
when the surfactant is put into the water, hydrophobic group will be positioned toward the air and the
10
273
hydrophilic group is positioned downward. Once the surfactant solution reaches saturation, a micelle is
274
formed. On the outside of the micelle is a hydrophilic group, and on the inside is a hydrophobic group.
275
Due to the hydrophobicity of CAR SD, they will be encapsulated into the micelle, thus increasing the
276
solubility of CAR SD in the solution [25].
277
4. Conclusions
278
CAR SDs were reformulated with Kollicoat IR, Kollicoat IR/HPMC, and Kollicoat IR/MC
279
carriers using the solvent evaporation method. The obtained results suggest that HPMC and MC as
280
both uncommon nonionic surfactants and auxiliary excipients maintain good stability and solubilization
281
ability. Moreover, a molecular docking simulation showed that intermolecular interaction occurred and
282
suggested a relatively stable system. This is the first study in which Kollicoat IR was used as carrier to
283
prepare CAR SDs. In vitro cumulative drug release of CAR was significantly improved by about 30%,
284
and the addition of HPMC and MC further greatly enhanced the dissolution rate. In brief, CAR solid
285
dispersions with HPMC and MC added to Kollicoat IR as binary polymer systems have great potential
286
for pharmaceutically effective oral drug formulation. This study may provide a new view for designing
287
different formulations to improve dissolution ability in the future.
288
Acknowledgement
289 290
Authors acknowledge Head Chemical Reagent Corporation (Shandong, China) for gift sample of methylcellulose.
291
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292
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14
Table 1 Formulation compositions of CAR SDs and some relevant physical mixture (PM) with different weigh ratios. The weight ratio between drug and binary polymers (Kollicoat IR /HPMC and Kollicoat IR /MC) was 1:5. Single polymer Batch no.
Binary polymers ratios
Drug Kollicoat IR
Kollicoat IR /HPMC
Kollicoat IR /MC
IR 1
1
1
IR 2
1
3
IR 3
1
5
HIR 1
1
1/1
HIR 2
1
2/1
HIR 3
1
3/1
HIR 4
1
5/1
HIR5 (PM)
-
2/1
MIR1
1
1/1
MIR2
1
3/1
MIR3
1
5/1
MIR4 (PM)
-
3/1
Table 2 The kinetic release rate of and R2 coefficients of CAR and prepared solid dispersions obtained from release data fitting analyses based on kinetic equations. Kinetic Equations
CAR
IR3
HIR2
MIR2
Zero-order
= 16.568 + 0.262
= 52.049 + 0.068
= 56.547 + 0.164
= 71.589 + 0.243
= +
R2=0.9240
R2=0.2992
R2=0.4767
R2=0.4439
First-order
= 59.423 × [1 − . ]
= 62.797 × [1 − . ]
= × [1 − ]
R2=0.9345
R2=0.9456
R2=0.9897
R2=0.9937
Korsmeyer-Peppas
= 4.546 × .#$
= 34.976 × . %
= 32.940 × . %
= 38.691 × .%
= × "
R2=0.9940
R2=0.6388
R2=0.7682
R2=0.7339
= 17.051 .& # × .#
= 16.751 .#% × .#
= 15.643 .!%# × .!
= 2.755 .
Makoid-Banakar
!
× .%
= 76.192 × [1 − .
]
= 102.048 × [1 − .! ]
= " ×
R2=0.9964
R2=0.9903
R2=0.9444
R2=0.9469
Peppas-Sahlin
= 4.623 .! − 0.012
= 13.993 .! − 0.725
= 15.310 .! − 0.727
= 19.679 − 0.913
= .! + %
R2=0.9881
R2=0.9562
R2=0.9360
R2=0.9352
= 100{1 − [(
Weibull = 100{1 − ((
* )⁄, .
}
0.123 )⁄&%.&&$]
} = 100{1 − ((
R2=0.9948
0.456 )⁄%.
R2=0.6814
$ .
} = 100{1 − ((
0.760 )⁄&. %.
} = 100{1 − ((
R2=0.8360
5.541 )⁄%#. &.
R2=0.9936
Table 3 The evaluation of storage stability of different formulations (mean ± SD, n=3). Groups
Before 2 months
After 2 months
Difference value
Stability
IR3
54.55±3.60%
57.60±0.05%
-3.05±0.05%
Good
HIR2
66.22±1.09%
65.55±0.43%
-1.09±0.67%
Good
MIR2
87.76±0.71%
86.85±1.77%
-0.91±0.71%
Excellent
}
Table 4 CMC, MSR and log Kmic values for different surfactants. Samples
HPMC
MC
HIR5
MIR4
CMC (mg/mL)
0.1
0.4
0.08
0.2
MSR
0.0004
0.0007
0.0016
0.0024
log Kmic
2.42
2.59
2.95
3.18
Figure 1. Chemical structures of the (a) pure CAR and the monomer units of (b) HPMC, (c) MC and (d) Kollicoat IR
Figure 2. The equipment of maximum bubble pressure method to determine CMC.
Figure 3. SEM images of (a) pure CAR, (b)Kollicoat IR, (c) IR3, (d) HIR2, (e) MIR2. Scale bar is shown in the graph.
Figure 4. X-ray powder diffraction of (a) pure CAR, (b) Kollicoat IR, (c) PM of IR3, (d) IR3, (e) HIR5, (f) PM of HIR2, (g) HIR2, (h) MIR4, (i) PM of MIR2 (l) MIR2.
Figure 5. Dissolution profiles of CAR solid dispersions in pH 6.8 PBS with (a) different ratios of Kollicoat IR and CAR , (b) addition of surfactants. (c) dissolution profiles of CAR solid dispersions in pH 1.2 hydrochloric acid solution. (mean ± SD, n=3). *p<0.05, **p<0.01 and ***p<0.001 compared to the CAR group.
Figure 6. In vitro dissolution and moisture analysis of CAR SDs with different carriers that have stored for two months (mean ± SD, n=3). (a) IR3; (b) HIR2; (c) MIR2; (d) Weight gain of different solid dispersions (mean ± SD, n=3).
Figure 7. Docking conformation of carvedilol complexed with Kollicoat IR. CAR and polymer are both shown in 3D structure representation. Two different views of integral conformations relevant with polymer, called CAR-Kollicoat IR SD, were displayed with the molecule and polymer shown.
Figure 8. Plots of surface tension (γ) as a function of the logarithm values of the total surfactant concentration (log C) of the single and different mixed CAR SDs systems with different concentration in the solution.
Scheme 1. Possible solubilization mechanism of surfactants.
1. The solubilization mechanism of surfactants added to SDs were clearly illustrated. 2. Kollicoat IR was the first time used as carrier to prepare CAR SDs. 3. The molecular modeling explained the reason why improved solubility in vitro.