Objectives: To optimize formulation of curcumin solid dispersion (CSD). Methods: Prepare curcumin solid dispersion using spray drying method and apply Modde 7.0 software to design the experiments and optimize the formulations.
Trang 1APPLICATION OF MODDE 7.0 SOFTWARE TO OPTIMIZE
FORMULATION OF CURCUMIN SOLID DISPERSION
USING SPRAY DRYING METHOD
Vu Binh Duong*; Nguyen Hai Dang Trieu*; Pham Van Hien*
Trinh Thanh Hung**; Nguyen Trong Diep*; Pham Thi Thanh Huong*
SUMMARY
curcumin solid dispersion using spray drying method and apply Modde 7.0 software to design the experiments and optimize the formulations Results: The optimal formulation to prepare curcumin solid dispersion system using spray drying method including: ratio of curcumin: PVP K30 (1:8.8, w/w) composed 0.76% of lutrol F127 and 3.85% aerosil With this optimal formulation, the solubility of curcumin was 6942.47g/L and the dissolution reached 100% in period of 30 minutes
drying method was established that is potential to enhance bioavaibility of this active component
* Key words: Curcumin solid dispersion; Spray drying method; Optimization; Experimental design
INTRODUCTION
Curcumin that is a polyphenol extracted
from Radix of Curcuma longa L owns
valuable bioactivities as anti-inflammation,
antioxidant, inhibition of cancer cell,
antimicrobial… [2, 3] In according to
biopharmaceutical classification, this
compound belongs to IV class with less
solubility and penetration [6] In fact,
curcumin is nearly insoluble in water, less
absorption and fast elimination so its
bioavaibility is too low
OCH3
OH
H3CO
HO
curcumin
To improve solubility and dissolution
rate of curcumin, as the previous publication,
we prepared solid dispersion using spray drying method with carrier as PVP K30
It found that solubility and dissolution were enhanced significantly Based on this research, we continuously optimized compositions of formulation using experimental design software In this publication, we informed the result of formulation optimization of CSD using Modde 7.0 software
MATERIALS AND METHODS
1 Materials and instruments
Curcumin was supported by Merck Coop PVP K30 passed BP 2008 Other chemicals were complied reagents of pharmaceutical
or analysis
Modde 7.0 software was provided by Umetrics Inc/MKS Instruments (USA)
* Military Medical University
** Ministry of Science and Technology
Corresponding author: Vu Binh Duong (vbduong2798@gmail.com)
Trang 2CSD was prepared on spray dring
centrifugal system LPG5, China; magnetic
thermal rotation (Stuart UC 152, UK)
Properties of finished product was evaluated
on Dissolution Test System (Caleva 10
ST8/1000, UK), UV-Vis spectrometer
(Biochrom Libra S70PC, UK); differential
Scanning Calorimeter (Setaram DSC 131,
France), Powder X-ray Diffraction System
(Brucker D8 Advance, Germany), Scanning
Electron Microscope (Nova nanoSem
450 FEI)
2 Preparation of curcumin solid
dispersion
Preparation of CSD was conducted by
spray drying method [1] Dissolve PVP
K30, lutrol F127, aerosol in 80% EtOH,
stirred on magnetic thermal rotater to
completely solution This solution was
then added curcumin, kept stirring to
dissolve completely and sprayed at 1100C, flow rate was set at 15 mL/min, suppress pressure was 0.2 MPa Finished solid dispersion was stored in brownish glass bottle with tightly cap
3 Experimental design and optimization
of formulation
* Experimental design:
In the aim of finding the optimal CSD formulation, we designed experiments using central composite face-centered model on Modde 7.0 [5] As our previous publication, the main factors effected curcumin solubility and dissolution including ratio of curcumin/PVP K30, lutrol F127, aerosil In this study, these were used as factors Solubility (Y) and dissolution
of curcumin after 10, 20, 30 mins (Y10,
Y20, Y30) were used separately as the responses in the mathematical modeling
% curcumin liberate on testing medium on
period of 10, 20, 30 mins
* Optimization of experiment:
After having the result of designing experiment, using Modde 7.0 software to investigate the effect of factors (independent variables) to responses by publishment of quadric equation scheming factors - responses correlation as the following:
Yi = b0 + b1X1 + b2X2 + b3X3 + b11(X1)2 + b22(X2)2 + b33(X3)2 + b12(X1 X2 ) + b13(X1 X3) +
b23 (X2 X3 )
Beside, Moddle software also predicted the optimal conditions to get the highest solubility and dissolution of curcumin (Yi max) Finally, optimal condition was tested by doing experiment following the prediction of software
Trang 3Yi = b0 + b1X1 + b2X2 + b3X3 + b11(X1)2 +
b22(X2)2 + b33(X3)2 + b12(X1 X2 ) + b13(X1 X3)
+ b23 (X2 X3 )
Beside, Moddle software also predicted
the optimal conditions to get the highest
solubility and dissolution of curcumin
(Yi max) Finally, optimal condition was
tested by doing experiment following the
prediction of software
* Investigate properties of CSD:
- Solubility:
Transfer a saturate amount of curcumin
or CSD (eq to 50.0 mg curcumin) to 50 mL
volume flask, make to fill with water,
sonicate for 24 hours at 250C This mixture
was stored at room temperature for 48
hours more, was then filterred via 0.45 µm
membrain, diluted in water (if any)
Optical density was measured on UV-Vis
spectrometry at 423 nm, compared to
standard solution of curcumin to calculate
its solubility in both of material and CSD [4]
- Dissolution test:
Dissolution studies were carried out
using USP dissolution apparatus 2 and a
paddle at a speed of 50 rpm with 900 mL
of H2O as dissolution medium at 370C
Solid dispersion powders equivalenting or
50 mg curcumin were dispersed on the
surface of the dissolution medium and the
time was recorded The samples (2 mL)
were collected at 10, 20 and 30 mins with
replacement by an equal volume of medium
The withdrawners were then through a
0.45 µm filter All the readings were blanked
with same media as it was used in the
dissolution study Curcumin that dissolved
in test medium was determinated by UV-Vis spectrometry at 423 nm Based on optical density of curcumin standard solution to calculate curcumin that was solubilized in medium
- X-ray diffraction:
Powder X-ray diffraction patterns were obtained with a diffractometer (Brucker D8 Advance, Germany) The operating conditions were as follows: scanning angle:
5 - 50o; scanning speed: 0.02o/0.5s; duration: 29.5 mininutes at 250C
- Different scanning calorimetry:
Thermal analysis of curcumin, PVP K30, CSD and physical mixture of curcumin and PVP K30 which contained same composition
of CSD were carried out using differential scanning calorimetry method at heating rate of 5oC/min for 60 minutes and heated from 20 - 350oC
- Scanning electron microscope (SEM): SEM was investigated of appearance, size, porosity, alignment of particles on SEM Nova Nanosem 450
RESULTS AND DISCUSSIONS
1 Experimental design and optimization
All factors were put on Modde 7.0, and then, this software established design of
17 experiments Preparation of CSD using dry spraying method followed this design Each of experiment, solubility and dissolution of curcumin from CSD were determined at 10, 20 and 30 minutes
Trang 4Table 2: Results of experiment design and observed response values
Exp Normalised levels of
factors(matrix)
(mg/l)
Dissolution (%)
The analyzer of obtained data was carried out using ANOVA The parameter was evaluated using F - test and a polynomial equations were generated for responses Mathematically, relationship that was generated using multiple line arregression analysis for the study variables were expressed in term of coded factors as the following:
Solubility: Y = 6,853.36 - 279.25X1 - 217.41X2 + 180.16 X3 - 238.41(X1)2 - 204.43(X2)2 - 411.54(X3)2 - 193.82(X1 X2 ) - 4.82(X1X3) + 280.79 (X2 X3)
R2 = 0.920
Dissolution for 10 mins: Y10 = 78.88 - 2.99X1 + 0.42X2 - 3.22X3 - 2.82(X1)2 - 4.6(X2)2 - 5.65(X3)2 - 1.02(X1 X2) + 0.87(X1X3) + 3.14(X2 X3)
R2 = 0.964
Dissolution for 20 mins: Y20 = 88.49 - 5.64X1 + 0.7X2 - 3.14X3 - 2.43(X1)2 - 3.38(X2)2 - 5.38(X3)2 - 0.85(X1 X2) + 0,.7(X1X3) + 2.46(X2 X3)
R2 = 0.942
Trang 5Dissolution for 30 mins: Y30 = 92.61 - 7.424X1 + 1.34X2 - 4.02X3 - 2.08(X1)2 - 2.9(X2)2 - 5.36(X3)2 - 0.59(X1 X2) + 1.2(X1X3) + 2.13(X2 X3)
R2 = 0.961
Above equations noted that it had a close correlation between PVP, lutreol F127 and aerosil to corresponding solubility and dissolution rate of curcumin from CSD with all correlation coefficients that were not less than 0.9 It means that, these factors effected solubility and dissolution rate of curcumin from CSD Fig 1 (a,b) showed 3D contour surface plot showing effect of factors to responses
to solubility of curcumin from CSD
The results in fig 1 indicated that the more PVP K30 and PVP K30 increased, the more curcumin solubility of CSD increased The effect levels of PVP K30 and lutrol F127 were the same Meanwhile, increasing 3 - 4% of aerosil improved solubility of curcumin but keeping increasing of this excipient to 5% possessed tendency decreasing of active ingredient solubility in test medium This was explained by lipophilic property of aerosil
(a)
Trang 6Figure 2: The 3D contour surface and prediction plot showing effect of factors
(independent variables) to dissolution of curcumin for duration test of
10 mins (a,b), 20 mins (c,d) and 30 mins (e,f)
The results in fig 2 showed that, increasing of PVP K30 improved dissolution of
curcumin in all withdrawn points for 10, 20 or 30 mins Raise of lutrol F127 possessed
decreasing potency of curcumin dissolution in period of 20 and 30 mins testing
(a)
(b)
(c)
(d)
(e)
(f)
Trang 7Dissolution of curcumin archived the highest at 4% aerosil and decreased while raising
of this expicient
Modde 7.0 also predicted the optimal formulation to prepare CSD including ratio of curcumin: PVP K30 as 1:8.8 (w/w) compose 0.76% lutrol F127 and 3.85% aerosil The theory solubility and dissolution of curcumin were Y = 6,850.25 mg/L, Y10 = 79.77%;
Y20 = 92.27%; Y30 = 98.64%, respectively
Running experiment followed the optimal formulation to verify prediction of software
Table 3: The results of experiments verify prediction of software
The results showed that the solubility
and dissolution of curcumin from CSD
that was prepared following prediction of
Modde 7.0, in period of 10, 20 and 30
mins was undifferentiated significantly in
comparison to result of verified actual
experiment The predicted - actual values
were 6,942.47 mg/L and 6,850.25 mg/L in
case of solubility These values were
80.12% vs 79.77%, 93.64% vs 92.27%
and 100.52% vs 98.64% in terms of
dissolution in period of 10, 20 and 30 mins
These findings indicated that optimal
formulation preparing CSD via spray drying
method included the ratio of curcumin:
PVP K30 as 1:8.8; 0.76% lutrol F127;
3.85% aerosil
2 Property investigation of CSD
* Solubility:
The solubility testing of curcumin from CSD and original material showed that the value in case of CSD folded 16.500 times in compare to material (6.942.47 mg/L vs 0.42 mg/L)
* X-ray diffraction:
X-ray diffraction patterns for orginal curcumin, PVP K30 and CSD were detected
in fig 3 Curcumin gave numerous sharp narrow and intense peaks indicating its high crystalline PVP gave no sharp narrow peaks and implicated it exist in amorphous
In physical mixture, the carrier appeared
as an elevated baseline and interacted to
Trang 8curcumin producing characteristic diffraction
peaks CSD did not show the characteristic
peaks indicating reduction in crystalline
and phase transition from crystalline to amorphous via formation of hydrogen bonds between curcumin - PVP K30
physical mixture of curcumin: PVP K30 (c) and CSD (4)
* Differential scanning calorimetry:
physical mixture of curcumin: PVP K30 (c) and CSD (d)
Furnace temperature /°C
HeatFlow/mW
- 25
- 20
- 15
- 10
-5
0
Peak :91.2850 °C
Onset Point :42.3669 °C
Enthalpy /J/g : 246.2637 (Endothermic effect)
Peak :190.8678 °C Onset Poi nt :169.7208 °C Enthal py /J/g : 11.7825 (Endothermi c effect)
Fi gure:
Experiment: PVP K30 nguyen l ieu
Procedure: RT -300 C (Zone 2)
DSC131
Exo
Furnace temperature /°C
HeatFlow/mW
-80 -70 -60 -50 -40 -30 -20 -10 0
Peak :195.6205 °C Onset Point :191.2751 °C Enthalpy /J/g : 128.5615 (Endothermi c effect)
Fi gure:
Experiment: Cur nguyen li eu Procedure: RT -300 C (Zone 2) DSC131
Exo
Furnace temperat ure /°C
H eatFlow/mW
-25
-20
-15
-10
-5
0
Peak :87.0017 °C
Onset Point :43.7985 °C
Enthal py /J/g : 223.7256 (Endothermi c effect)
Peak 1 :184.4112 °C Onset Point :177.7930 °C Enthal py /J/g : 8.9469 (Endothermi c effect) (3.8781 + 5.0688)
Fi gure:
Experiment: HHVL Cur - PVP K30
Procedure: RT -300 C (Zone 2)
DSC131
Exo
Furnace temperature /°C
HeatFlow/mW
-10 -8 -6 -4 -2 0
Peak :82.1471 °C Onset Poi nt :46.0151 °C Enthalpy /J/g : 136.4217 (Endothermi c effect)
Figure:
Experiment: HPT R Cur - PVP K30 Procedure: RT-300 C (Zone 2) DSC131
Exo
Fa cu lty o f C he m istry , H US , V NU , D 8 A D VA NC E -Br uk er - P VP K 3 0 ng uye n lieu
F ile : T r ie uH V Q Y P V PK 3 0n g u yen li eu ra w - T yp e : 2 T h/ T h lo cked - S t art: 0 8 8 5 ° - E nd : 4 9 8 8 6 ° - S t e p: 0 0 30 ° - S te p t i m e : 0 3 s - T e mp : 2 5 ° C (R o om ) - T im e S t ar t ed : 17 s - 2- T h e t a: 0 8 8 5 ° - T h eta : 0 5 00 ° - C hi : 0 00 ° - Ph
0
10 0
20 0
30 0
40 0
50 0
60 0
70 0
80 0
90 0
10 0 0
2-T heta - Sc ale
Fa cu lty o f C hemistry, H US , V NU, D 8 AD VA NC E -Bruker - Cu rcum in nguye n lieu
00 -0 09 -0 81 6 ( Q) - Cu rcu m in - C2 1H2 0 O6 - Y : 2 56 % - d x b y: 1 - W L: 1 5 4 06 -
F ile : Tr ie uHV Q Y C ur- ng uye n lie u ra w - Type : 2Th / Th loc ke d - Sta rt : 0.8 85 ° - En d : 4 9 8 86 ° - S te p : 0 03 0 ° - S te p t im e: 0.3 s - Te m p : 2 5 °C ( Roo m ) - Tim e Sta rte d: 1 1 s - 2 -Th eta : 0.8 85 ° - The ta: 0 5 0 0 ° - Ch i: 0.0 0 ° - P h i: 0.
0
10 0
40 0
70 0
10 00
13 00
16 00
19 00
22 00
25 00
28 00
2- Theta - Sc ale
Fa cu lty o f C he m i stry , H U S , V N U , D 8 A D V A NC E -B r uk er - H P T R C u r-P V P K3 0
File : T r ie uH V Q Y H PT R C ur -P VP K 30 ra w - T yp e : 2 Th /Th lo ck ed - S tar t: 0 88 5 ° - E n d: 49 88 6 ° - S t e p: 0 0 3 0 ° - S t ep ti m e : 0 3 s - T em p : 25 °C (R o om ) - Ti m e S t a rt ed : 11 s - 2- T he t a: 0 88 5 ° - Th et a : 0 5 00 ° - C hi : 0 00 ° - P hi
0
10 0
20 0
30 0
40 0
50 0
60 0
70 0
80 0
90 0
10 00
2-Theta - S c ale
F a cu lty o f C he m istry , H U S , V N U , D 8 A D V A N C E -B r uk er - HH V L C ur -PV P K 3 0
F ile : T r ie uH V Q Y H HVL C u r-P V PK 3 0.ra w - Ty p e: 2T h /Th l oc ke d - Sta rt: 0.8 85 ° - En d : 4 9 8 8 6 ° - S tep : 0 03 0 ° - Ste p tim e: 0 3 s - T e m p : 2 5 ° C ( R oo m ) - Tim e S tarte d: 1 2 s - 2 -Th eta : 0.8 85 ° - The ta: 0 50 0 ° - Ch i: 0.0 0 ° - P h i
0
10 0
20 0
30 0
40 0
50 0
60 0
70 0
80 0
90 0
10 00
2-T heta - S c ale
Trang 9(
The possible interaction between the
curcumin and the carrier was studied by
DSC (Fig 4) Curcumin powder showed a
melting endotherm at 195.6oC corresponding
to it melting point at enthalpy of 138.6 j/g,
whereas the scan of PVP-K30 showed a
broad endotherm ranging from 80 to 120°C
due to the presence of residual moisture
In physical mixture, there was a melting
endotherm at 191.7oC corresponding to
it melting point at enthalpy of 5.1 j/g,
less than orginal material of curcumin
This indicated that curcumin still existed in
crystalline at physical mixture Loss of
melting endotherm and enthalpy caused
almost curcumin that dissolved in PVP K30
The pattern of CSD showed a melting
endotherm between 100 and 250°C,
due to loss of water from PVP-K30 and
absenced of curcumin peak The absence
of curcumin indicated that curcumin was amorphous or was presented as a solid solution inside the PVP-K30 matrix According to these results, the amorphous property of curcumin in the formulation with PVP-K30 was mainly responsible for the dissolution enhancement
* Scanning electron microscope:
SEM of CSD were measured on SEM Nova Nanosem 450 The particles of CSD that were prepared using spray drying method, were characteristics of regular spherical, smooth surface, centered hollow porosity The diameter of particle was about 10 - 30 µm Original curcumin material was still existed in crystalline
clearly (Fig 5) This finding expressed
curcumin in CSD transferred to amorphor form instead crystaline as original material
Figure 5: SEM of CSD (a,b) and curcumin (c)
CONCLUSION
It was applied Modde 7.0 software
design and optimize formulation
preparing CSD using spray drying method
The results found the optimal formulation
including the ratio of curcumin: PVP K30 as
1:8.8; 0.76% lutrol F127; 3.85% aerosil This optimal formulation improved solubility of curcumin and its dissolution in period of
10, 20 and 30 minutes testing archiving 6,942.47 mg/L, more than 80%, 90% and got 100%, respectively
REFERENCES
Trang 101 Duong Quoc Toan, Vu Binh Duong
Study on preparation of altretamin using spray
drying method Vietnam Pharmaceutical Journal
2015, No 475, pp.19-24
delivery systems to improve bioavailability of
curcumin Bioequivalence & Bioavailability
2013, 6, pp.1-9
medicine to current clinical trials Cellular
and Molecular Life Sciences 2008, 65 (11),
pp.1631-1652
solubility and dissolution rate of Curcumin by solid dispersion technique International
Research Journal of Pharmacy 2013, 4 (5),
pp.226-232
User guide Bio Pat Modde 7.0 2013
design for poorly water-soluble drugs based
on biopharmaceutics classification system: Basic approaches and practical applications International Journal of Pharmaceutics 2011,
420, pp.1-10