Application of modde 7.0 software to optimize formulation of curcumin solid dispersion using spray drying method

Nội dung text: Application of modde 7.0 software to optimize formulation of curcumin solid dispersion using spray drying method

1. Journal of military pharmaco-medicine N o7-2016 APPLICATION 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 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. 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. Conclusion: The optimal formulation for preparing curcumin solid dispersion system using spray 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 we prepared solid dispersion using spray drying method with carrier as PVP K30. Curcumin that is a polyphenol extracted from Radix of Curcuma longa L . owns It found that solubility and dissolution valuable bioactivities as anti-inflammation, were enhanced significantly. Based on antioxidant, inhibition of cancer cell, this research, we continuously optimized antimicrobial [2, 3]. In according to compositions of formulation using biopharmaceutical classification, this experimental design software. In this compound belongs to IV class with less publication, we informed the result of solubility and penetration [6]. In fact, formulation optimization of CSD using curcumin is nearly insoluble in water, less Modde 7.0 software. absorption and fast elimination so its bioavaibility is too low. MATERIALS AND METHODS O O 1. Materials and instruments. Curcumin was supported by Merck Coop. H3CO OCH3 PVP K30 passed BP 2008. Other chemicals were complied reagents of pharmaceutical HO OH curcumin or analysis. To improve solubility and dissolution Modde 7.0 software was provided by rate of curcumin, as the previous publication, Umetrics Inc/MKS Instruments (USA). * Military Medical University ** Ministry of Science and Technology Corresponding author: Vu Binh Duong (vbduong2798@gmail.com) 7
2. Journal of military pharmaco-medicine N o7-2016 CSD was prepared on spray dring dissolve completely and sprayed at 110 0C, centrifugal system LPG5, China; magnetic flow rate was set at 15 mL/min, suppress thermal rotation (Stuart UC 152, UK). pressure was 0.2 MPa. Finished solid Properties of finished product was evaluated dispersion was stored in brownish glass on Dissolution Test System (Caleva 10 bottle with tightly cap. ST8/1000, UK), UV-Vis spectrometer 3. Experimental design and optimization (Biochrom Libra S70PC, UK); differential of formulation. Scanning Calorimeter (Setaram DSC 131, * Experimental design: France), Powder X-ray Diffraction System (Brucker D8 Advance, Germany), Scanning In the aim of finding the optimal CSD Electron Microscope (Nova nanoSem formulation, we designed experiments 450 FEI). using central composite face-centered model on Modde 7.0 [5]. As our previous 2. Preparation of curcumin solid publication, the main factors effected dispersion. curcumin solubility and dissolution Preparation of CSD was conducted by including ratio of curcumin/PVP K30, lutrol spray drying method [1]. Dissolve PVP F127, aerosil. In this study, these were K30, lutrol F127, aerosol in 80% EtOH, used as factors. Solubility (Y) and dissolution stirred on magnetic thermal rotater to of curcumin after 10, 20, 30 mins (Y 10 , completely solution. This solution was Y20 , Y 30 ) were used separately as the then added curcumin, kept stirring to responses in the mathematical modeling. Table 1: Variants in central composite face-centered design. Level Factors Signal Low -1 Target 0 High +1 Curcumin:PVP K30 X1 0.1 0.15 0.2 Lutrol F127 (%) X2 0.5 0.75 1 Aerosil (%) X3 3 4 5 % curcumin liberate on testing medium on Y10, Y20, Y30 Response period of 10, 20, 30 mins Y Curcumin solubility (mg/l) * 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: 2 2 2 Yi = b 0 + b 1X1 + b 2X2 + b 3X3 + b 11 (X 1) + b 22 (X 2) + b 33 (X 3) + b 12 (X 1 X2 ) + b 13 (X 1 X3) + b23 (X 2 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. 8
3. o Journal of military pharmaco-medicine N 7-2016 2 Yi = b 0 + b 1X1 + b 2X2 + b 3X3 + b 11 (X 1) + dissolution study. Curcumin that dissolved 2 2 b22 (X 2) + b 33 (X 3) + b 12 (X 1 X2 ) + b 13 (X 1 X3) in test medium was determinated by UV-Vis + b 23 (X 2 X3 ) spectrometry at 423 nm. Based on optical density of curcumin standard solution to Beside, Moddle software also predicted calculate curcumin that was solubilized in the optimal conditions to get the highest medium. solubility and dissolution of curcumin (Yi max). Finally, optimal condition was - X-ray diffraction: tested by doing experiment following the Powder X-ray diffraction patterns were prediction of software. obtained with a diffractometer (Brucker * Investigate properties of CSD: D8 Advance, Germany). The operating - Solubility: conditions were as follows: scanning angle: 5 - 50 o; scanning speed: 0.02 o/0.5s; duration: Transfer a saturate amount of curcumin 29.5 mininutes at 25 0C. or CSD (eq. to 50.0 mg curcumin) to 50 mL volume flask, make to fill with water, - Different scanning calorimetry: sonicate for 24 hours at 25 0C. This mixture Thermal analysis of curcumin, PVP K30, was stored at room temperature for 48 CSD and physical mixture of curcumin and hours more, was then filterred via 0.45 µm PVP K30 which contained same composition membrain, diluted in water (if any). of CSD were carried out using differential Optical density was measured on UV-Vis scanning calorimetry method at heating spectrometry at 423 nm, compared to rate of 5oC/min for 60 minutes and heated standard solution of curcumin to calculate from 20 - 350 oC. its solubility in both of material and CSD [4]. - Scanning electron microscope (SEM): - Dissolution test: SEM was investigated of appearance, Dissolution studies were carried out size, porosity, alignment of particles on using USP dissolution apparatus 2 and a SEM Nova Nanosem 450. paddle at a speed of 50 rpm with 900 mL 0 of H 2O as dissolution medium at 37 C. RESULTS AND DISCUSSIONS Solid dispersion powders equivalenting or 50 mg curcumin were dispersed on the 1. Experimental design and optimization. surface of the dissolution medium and the All factors were put on Modde 7.0, and time was recorded. The samples (2 mL) then, this software established design of were collected at 10, 20 and 30 mins with 17 experiments. Preparation of CSD replacement by an equal volume of medium. using dry spraying method followed this The withdrawners were then through a design. Each of experiment, solubility and 0.45 µm filter. All the readings were blanked dissolution of curcumin from CSD were with same media as it was used in the determined at 10, 20 and 30 minutes. 9
4. o Journal of military pharmaco-medicine N 7-2016 Table 2: Results of experiment design and observed response values. Exp. Normalised levels of Factors Solubility Dissolution (%) factors(matrix) (mg/l) 10 mins 20 mins 30 mins X1 X2 X3 X1 X2 X3 Y Y10 (%) Y20 (%) Y30 (%) 1 -1 -1 -1 0.1 0.5 3 5860.39 68.18 83.11 92.92 2 1 -1 -1 0.2 0.5 3 5940.33 64.95 70.4 72.45 3 -1 1 -1 0.1 1 3 5096.65 65.37 82.53 92.21 4 1 1 -1 0.2 1 3 3663.38 51.25 63.39 70.47 5 -1 -1 1 0.1 0.5 5 5733.33 49.94 64.35 70.18 6 1 -1 1 0.2 0.5 5 5472.09 47.01 58.58 57.85 7 1 1 1 0.1 0.1 5 6445.68 62.19 76.45 85.01 8 1 1 1 0.2 0.1 5 5262.24 57.65 66.42 67.46 9 -1 0 0 0.1 0.75 4 7003.85 80.81 97.25 100.65 10 1 0 0 0.2 0.75 4 6381.44 67.36 76.17 78.91 11 0 -1 0 0.15 0.5 4 6926.77 69.9 85.07 90.49 12 0 1 0 0.15 1 4 6746.9 68.65 82.46 85.59 13 0 0 -1 0.15 0.75 3 6325.77 71.58 77.69 85.16 14 0 0 1 0.15 0.75 5 6227.27 64.66 73.75 81.64 15 0 0 0 0.15 0.75 4 6468.52 81.56 89.64 91.62 16 0 0 0 0.15 0.75 4 6698.36 81.25 89.89 94.33 17 0 0 0 0.15 0.75 4 6584.15 79.52 88.05 92.04 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: 2 2 Solubility: Y = 6,853.36 - 279.25X1 - 217.41X2 + 180.16 X3 - 238.41(X 1) - 204.43(X 2) - 2 411.54(X 3) - 193.82(X 1 X2 ) - 4.82(X 1X3) + 280.79 (X2 X3). R2 = 0.920. 2 2 Dissolution for 10 mins: Y10 = 78.88 - 2.99X1 + 0.42X2 - 3.22X3 - 2.82(X 1) - 4.6(X 2) - 2 5.65(X 3) - 1.02(X 1 X2) + 0.87(X 1X3) + 3.14(X2 X3). R2 = 0.964. 2 2 Dissolution for 20 mins: Y20 = 88.49 - 5.64X1 + 0.7X2 - 3.14X3 - 2.43(X 1) - 3.38(X 2) - 2 5.38(X 3) - 0.85(X 1 X2) + 0,.7(X 1X3) + 2.46(X2 X3). R2 = 0.942. 10
5. o Journal of military pharmaco-medicine N 7-2016 2 2 Dissolution for 30 mins: Y30 = 92.61 - 7.424X1 + 1.34X2 - 4.02X3 - 2.08(X 1) - 2.9(X 2) - 2 5.36(X 3) - 0.59(X 1 X2) + 1.2(X 1X3) + 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. (a) Figure 1: 3D contour surface plot showing effect of aerosil, lutrol F127, PVP K30 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. 11
6. o Journal of military pharmaco-medicine N 7-2016 (a) (b) (c) (d) (e) (f) Figure 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. 12
7. Journal of military pharmaco-medicine N o7-2016 Dissolution 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, Y 10 = 79.77%; Y20 = 92.27%; Y 30 = 98.64%, respectively. Running experiment followed the optimal formulation to verify prediction of software. Table 3: The results of experiments verify prediction of software. Y Y10 (%) Y20 (%) Y30 (%) Predicted Actual Predicted Actual Predicted Actual Predicted Actual 1 6850.25 6999.57 79.77 79.43 92.27 93.26 98.64 100.73 2 6850.25 6879.66 79.77 80.84 92.27 94.49 98.64 99.55 3 6850.25 6845.40 79.77 79.54 92.27 92.76 98.64 99.32 4 6850.25 6999.57 79.77 80.63 92.27 93.74 98.64 100.63 5 6850.25 7025.27 79.77 80.08 92.27 93.74 98.64 101.60 6 6850.25 6905.35 79.77 80.19 92.27 93.84 98.64 101.28 6850.25 6942.47 79.77 80.12 92.27 93.64 98.64 100.52 X p > 0.05 p > 0.05 p > 0.05 p > 0.05 The results showed that the solubility 2. Property investigation of CSD. and dissolution of curcumin from CSD * Solubility: that was prepared following prediction of The solubility testing of curcumin from Modde 7.0, in period of 10, 20 and 30 CSD and original material showed that mins was undifferentiated significantly in the value in case of CSD folded 16.500 comparison to result of verified actual times in compare to material (6.942.47 experiment. The predicted - actual values mg/L vs. 0.42 mg/L). were 6,942.47 mg/L and 6,850.25 mg/L in case of solubility. These values were * X-ray diffraction: 80.12% vs. 79.77%, 93.64% vs. 92.27% X-ray diffraction patterns for orginal and 100.52% vs. 98.64% in terms of curcumin, PVP K30 and CSD were detected dissolution in period of 10, 20 and 30 mins. in fig 3. Curcumin gave numerous sharp These findings indicated that optimal narrow and intense peaks indicating its formulation preparing CSD via spray drying high crystalline. PVP gave no sharp narrow method included the ratio of curcumin: peaks and implicated it exist in amorphous. PVP K30 as 1:8.8; 0.76% lutrol F127; In physical mixture, the carrier appeared 3.85% aerosil. as an elevated baseline and interacted to 13
8. Journal of military pharmaco-medicine N o7-2016 curcumin producing characteristic diffraction and phase transition from crystalline to peaks. CSD did not show the characteristic amorphous via formation of hydrogen peaks indicating reduction in crystalline bonds between curcumin - PVP K30. Faculty of Chemistry, HUS, VNU, D8 ADVANCE-Bruker - Curcumin nguyen lieu Faculty of Chemistry, HUS, VNU, D8 ADVANCE-Bruker - PVPK30 nguyen lieu 30 00 10 00 29 00 28 00 27 00 90 0 26 00 25 00 24 00 80 0 23 00 22 00 d=5.211 (a) 21 00 (b) 70 0 20 00 19 00 18 00 60 0 17 00 16 00 15 00 50 0 14 00 Lin (Cps) Lin Lin (Cps) Lin 13 00 12 00 40 0 d=10.230 11 00 10 00 30 0 90 0 80 0 70 0 d=3.850 20 0 60 0 d=4.239 d=3.634 50 0 d=6.169 d=3.356 d=3.500 d=11.432 40 0 d=4.960 d=3.762 d=3.186 d=5.451 d=3.278 d=5.664 d=4.616 10 0 d=7.359 30 0 d=3.087 d=4.771 d=6.431 d=5.871 d=2.855 d=2.116 20 0 d=2.494 d=2.005 d=1.898 d=2.600 d=4.432 d=2.399 d=2.046 d=2.205 d=2.457 d=2.274 d=2.693 10 0 0 0 1 10 20 3 0 40 1 10 20 3 0 40 2-Theta - Scale 2-Theta - Scale File: TrieuHVQY PVPK30nguyenlieu.raw - Type: 2Th/Th locked - Start: 0.885 ° - End: 49.886 ° - Step: 0.030 ° - Step time: 0.3 s - Temp.: 25 °C (Room ) - Tim e Started: 17 s - 2-Theta: 0.885 ° - Theta: 0.500 ° - Chi: 0.00 ° - Ph File: TrieuHVQY C ur-nguyenlieu.raw - Type: 2Th/Th locked - Start: 0.885 ° - End: 49.886 ° - Step: 0.03 0 ° - Step time: 0.3 s - Temp.: 25 °C (Room) - Time Started: 11 s - 2-Theta: 0.885 ° - Theta: 0.500 ° - Chi: 0.00 ° - Phi: 0. 00-009-0816 (Q) - Curcumin - C21H20O6 - Y: 2.56 % - d x by: 1. - WL: 1.5406 - Faculty of Chemistry, HUS, VNU, D8 ADVANCE-Bruker - HHVL Cur-PVPK30 1000 Faculty of Chemistry, HUS, VNU, D8 ADVANCE-Bruker - HPTR Cur-PVPK30 10 00 900 90 0 800 (c) 80 0 (d) 700 70 0 600 60 0 500 50 0 Lin (Cps) Lin Lin (Cps) Lin 400 40 0 d=4.229 d=6.472 300 30 0 d=3.780 d=3.375 d=3.503 d=5.214 200 20 0 d=3.659 d=9.898 100 10 0 0 0 1 10 20 3 0 40 1 10 20 3 0 40 2-Theta - Scale 2-Theta - Scale File: TrieuHVQY HPTRCur-PVPK30.raw - Type: 2Th/Th locked - Start: 0.885 ° - End: 49.886 ° - Step: 0.03 0 ° - Step time: 0.3 s - Tem p.: 25 °C (Room ) - Time Started: 11 s - 2-Theta: 0.885 ° - Theta: 0.500 ° - Chi: 0.00 ° - P hi File: TrieuHVQY H HVLCur-PVPK30.raw - Type: 2Th/Th l ocked - Start: 0.885 ° - End: 49.886 ° - Step: 0.03 0 ° - Step tim e: 0.3 s - Temp.: 25 °C (Room) - Tim e Started: 12 s - 2-Theta: 0.885 ° - Theta: 0.500 ° - Chi: 0.00 ° - Phi Figure 3: X-ray diffraction patterns of PVP K30 (a), orginal curcumin (b), physical mixture of curcumin: PVP K30 (c) and CSD (4). * Differential scanning calorimetry: Figure: Experiment: PVP K30 nguyen lieu Crucible: Al 100 µl Atmosphere:Ar Figure: Experiment: Cur nguyen lieu Crucible: Al 100 µl Atmosphere: Ar 22/05/2016 Procedure: RT-300 C (Zone 2) Mass (mg): 15.23 DSC131 22/05/2016 Procedure: RT-300 C (Zone 2) Mass (mg): 20.76 DSC131 HeatFlow/mW HeatFlow/mW Exo Exo 0 0 -10 -5 -20 Peak :190.8678 °C Onset Point :169.7208 °C Enthalpy /J/g : 11.7825 (Endothermic effect) -30 -10 -40 -15 -50 -60 -20 Peak :91.2850 °C Peak :195.6205 °C Onset Point :42.3669 °C Onset Point :191.2751 °C (a) Enthalpy /J/g : 128.5615 (Endothermic effect)(b) Enthalpy /J/g : 246.2637 (Endothermic effect) -70 -25 -80 25 50 75 100 125 150 175 200 225 Furnace temperature /°C 50 75 100 125 150 175 200 225 Furnace temperature /°C Figure: Experiment: HHVL Cur - PVP K30 Crucible: Al 100 µl Atmosphere: Ar Figure: Experiment: HPTR Cur - PVP K30 Crucible: Al 100 µl Atmosphere: Ar 22/05/2016 Procedure: RT-300 C (Zone 2) Mass (mg): 13.24 DSC131 22/05/2016 Procedure: RT-300 C (Zone 2) Mass (mg): 20.13 DSC131 HeatFlow/mW HeatFlow/mW Exo Exo 0 0 -2 -5 Peak 1 :184.4112 °C -4 -10 Peak 2 :191.6883 °C Onset Point :177.7930 °C Enthalpy /J/g : 8.9469 (Endothermic effect) (3.8781 + 5.0688) -6 -15 -8 -20 Peak :87.0017 °C Onset Point :43.7985 °C Enthalpy /J/g : 223.7256 (Endothermic effect) Peak :82.1471 °C Onset Point :46.0151 °C -25 (c) -10 Enthalpy /J/g : 136.4217 (Endothermic effect) (d) 25 50 75 100 125 150 175 200 225 Furnace temperature /°C 50 75 100 125 150 175 200 225 Furnace temperature /°C Figure 4: Differential scanning calorimetry of PVP K30 (a), curcumin (b), physical mixture of curcumin: PVP K30 (c) and CSD (d). 14
9. Journal of military pharmaco-medicine N o7-2016 The possible interaction between the of curcumin indicated that curcumin was curcumin and the carrier was studied by amorphous or was presented as a solid DSC ( Fig 4). Curcumin powder showed a solution inside the PVP-K30 matrix. melting endotherm at 195.6 oC corresponding According to these results, the amorphous to it melting point at enthalpy of 138.6 j/g, property of curcumin in the formulation whereas the scan of PVP-K30 showed a with PVP-K30 was mainly responsible for broad endotherm ranging from 80 to 120°C the dissolution enhancement. due to the presence of residual moisture. * Scanning electron microscope: In physical mixture, there was a melting endotherm at 191.7 oC corresponding to SEM of CSD were measured on SEM it melting point at enthalpy of 5.1 j/g, Nova Nanosem 450. The particles of CSD less than orginal material of curcumin. that were prepared using spray drying This indicated that curcumin still existed in method, were characteristics of regular crystalline at physical mixture. Loss of spherical, smooth surface, centered hollow melting endotherm and enthalpy caused porosity. The diameter of particle was almost curcumin that dissolved in PVP K30. about 10 - 30 µm. Original curcumin The pattern of CSD showed a melting material was still existed in crystalline endotherm between 100 and 250°C, clearly ( Fig 5 ). This finding expressed due to loss of water from PVP-K30 and curcumin in CSD transferred to amorphor absenced of curcumin peak. The absence form instead crystaline as original material. (a) (b) (c) ( Figure 5: SEM of CSD (a,b) and curcumin (c). CONCLUSION 1:8.8; 0.76% lutrol F127; 3.85% aerosil. This It was applied Modde 7.0 software optimal formulation improved solubility of design and optimize formulation curcumin and its dissolution in period of preparing CSD using spray drying method. 10, 20 and 30 minutes testing archiving The results found the optimal formulation 6,942.47 mg/L, more than 80%, 90% and including the ratio of curcumin: PVP K30 as got 100%, respectively. REFERENCES 15
10. Journal of military pharmaco-medicine N o7-2016 1. Duong Quoc Toan, Vu Binh Duong . 4. Kumavat Suresh et al . Enhancement of Study on preparation of altretamin using spray solubility and dissolution rate of Curcumin by drying method. Vietnam Pharmaceutical Journal. solid dispersion technique. International 2015, No 475, pp.19-24. Research Journal of Pharmacy. 2013, 4 (5), 2. Asish K Dutta, Elizabeth Ikiki . Novel drug pp.226-232. delivery systems to improve bioavailability of 5. Sartorius Stedim Biotech Company . curcumin. Bioequivalence & Bioavailability. User guide Bio Pat Modde 7.0. 2013. 2013, 6, pp.1-9. 6. Yohei Kawabata et al . Formulation 3. Hatcher H et al . Curcumin: From ancient design for poorly water-soluble drugs based medicine to current clinical trials. Cellular on biopharmaceutics classification system: and Molecular Life Sciences. 2008, 65 (11), Basic approaches and practical applications. pp.1631-1652. International Journal of Pharmaceutics. 2011, 420, pp.1-10. 16