Research on preparation of curcumin powder by spray drying method with the support of gum Arabic and maltodextrin and improvement in its solubility

The suspension of curcumin being created tends to clump together into larger particles and settle down. One way to improve this shortcoming is to spray-dry the suspension system. The aim of this study is to optimize the powder forming process from the spray drying method. The suspension was converted to a powder with maltodextrin as a carrier. Optimization results, realized via a response surface methodology, showed that a maximal curcumin content of 4.667% could be attained under the following conditions: intake air temperature 150 °C, drying air flow of 290 m3/h and feed flow rate of 0.7 L/h. Under these conditions, the particles of obtained powder has the median size of 1.900 μm by LDS method and FESEM also showed that curcumin particles had a nearly spherical shape with a size range of 1 - 3 μm.


Introduction
Curcumin is a valuable compound found in turmeric, which has anti-inflammatory, antioxidant and cancer treatment properties (1).The problem with the use of curcumin is its low bioavailability.The pharmacokinetic study of curcumin reported by Yang K. et al. showed that the maximum concentration of curcumin in the plasma of the rat after an oral dose of 500 mg/kg was 0.06 ± 0.01 μg/ml, demonstrating bioavailability of oral use is only about 1% (2).Similarly, according to the study of Shoba G. et al., the highest concentration of curcumin in plasma was 1.35 ± 0.23 μg/ml after 1 hour of oral use at a dose of 2 g/kg in rats, while in volunteers (weight 50 -75 kg) taking a single dose of 2 g curcumin (4500 mg capsules), concentration in the plasma is very low, only about 0.006 ± 0.005 μg/ml in 1 hour (3).In the study to evaluate the bioavailability by Allam A. N. et al., at a dose of 340 mg/kg in rats, the amount of curcumin was not absorbed in the intestinal villi and the amount found in the mucins was quite large, while amount of curcumin in plasma could not be found.This also proves that curcumin has poor permeability through the gastrointestinal system (4).
Many studies on the pharmacokinetics of curcumin show that low solubility, rapid metabolism and quick elimination are the primary causes of curcumin's low bioavailability.(5) Therefore, the measures to improve the bioavailability of curcumin mainly focus on increasing solubility, decreasing metabolism or using inhibitors of curcumin's metabolism and reducing elimination, prolonging the retention time in 2 the gastrointestinal system of curcumin.(6) To achieve this goal, studies around the world have mentioned the method of improving the bioavailability of curcumin by creating systems.
After obtaining the system, in order to prolong the storage time and avoid the particles agglomerating together to form bigger particles and settling, this study has investigated the impact of parameters of the spray-drying process to create powder by using response surface methodology (RSM) in conjunction with central composite design (CCD) (7) with the objective function of curcumin content in the powder, the parameters mentioned are: temperature of the intake air, airflow for drying, and feed flow rate.

Preparation of curcumin suspension
The following mixes were homogenized using a high-pressure homogenizer (GEA Lab Homogenizer TwinPANDA 400) to create a curcumin suspension.The first mixture was made by combining 30 mL of 98% ethanol (Nguyen Quan Ltd., Vietnam) with 2 g of curcumin powder (95% purity, Apollo Ingredients Ltd., India).The second mixture included about 100 mL of distilled water and 12 g of gum Arabic (Willy Benecke GmbH, Hamburg, Germany).The two mixes were then homogenized for two cycles at 150 bar of pressure.

Preparation of curcumin powder by spray-drying method
In the first investigation, curcumin was spray-dried in turn with 3 types of carriers by using Lab Spray Dryer ASD-2000SG.The following conditions were maintained at constant levels: intake air temperature 150 °C, drying air flow 300 m 3 /h, feed flow rate 0.9 L/h and the curcumin to carrier ratio of 1:38.

Content measurement of curcumin in spray-drying powder
The absorption spectroscopy method using Helios Epsilon instrument was used to determine the curcumin content in spray-drying powder.0.05 g powder was first dissolved in 2 mL water at 60 °C, then added 6 mL ethanol 96⁰ and sonicated for 10 minutes.If the sample is too concentrated, it can be diluted to the appropriate ratio before measurement.

Response surface methodology optimization of spray-drying process
After investigating the experimental points, response surface methodology (RSM) combined with central composite design (CCD) was selected to find out the relationship between the parameters and the objective function.
Predict the influence of the parameters by analyzing the coefficients of the variables of the regression equation.The encoding variable equation could be described as follows: Where B0 represents the response coefficient at the center, Bi is the first-order response coefficient, Bii represents the second-level response coefficient, Bij is the double-interactive response coefficient, Xi represents the encoded variable of the real variables and Y is the predicted response.Three variables were included in the model (8): temperature of the intake air, airflow for drying, and feed flow rate, with curcumin content serving as the output response.
Analysis of experimental data is done through JMP Pro 13 software.R 2 is the coefficient representing the fit between the model and the experiment, the closer R 2 is to 1, the better the model is (9).

Size evaluation of the powder product
The laser diffraction spectrometry (LDS) method was used using a Horiba LA-950V2 equipment to determine the particle size distribution and the median diameter of the dispersion system.Every analysis was carried out at room temperature.

Solubility evaluation of optimal powder
The method of evaluating the solubility was carried out according to the Vietnamese Pharmacopoeia V (10).The curcumin content was determined by high performance liquid chromatography using an Agilent 1260 instrument.Solubility was evaluated by the ratio of curcumin passed 0.45 μm mesh (11) and the original amount of curcumin.

Single-factor investigations
In the initial study, conducting to spray-drying curcumin with maltodextrin, lactose and isomalt respectively.Spray-drying powder with isomalt carrier is melted right in the drying process.The results are showed in Figure 1.The content of curcumin in the powder changed markedly when using different types of carriers, the powder using maltodextrin carrier had a higher content than the powder using lactose and isomalt carrier.In this research, a high content of curcumin is essential to increase the applicability to the products in the later stages, so the maltodextrin carrier was selected to use for the other surveys.

Type of carrier
Figure 2 shows variations in curcumin content that were discovered at various intake air temperatures (130, 150, 170, 190 and 210 ℃).In terms of appearance, the color of the powder appears to darken as the temperature of the intake air rises.When drying at a temperature of 210 ⁰C, the powder has a clumping phenomenon that clings to the walls of the chamber, affecting the spray-drying efficiency.
In terms of content, when changing the temperature from 130 ⁰C to 150 ⁰C, the content of curcumin in the powder increased and decreased gradually from 170 ⁰C to 210 ⁰C, possibly due to the drying temperature is high, the formed powder and the carrier has been melt before entering the cyclone.From mentioned results above, the intake air temperature of 150 ⁰C were chosen to subsequent investigations.When the drying air flow increases, the powder color changes insignificantly.With an air flow of 240 m 3 /h, not much powder can be obtained possibly due to not enough drying air flow to take the powder into the cyclone.The change of the content is similar to the appearance, so the drying air flow of 300 m 3 /h producing the powder containing the highest curcumin content of 4.41% was selected.
Figure 4 represents variations of curcumin content with different feed flow rates.Similar to the results when changing the drying air flow, here both the appearance and the content also change almost insignificantly when the feed flow rate is changed.Therefore, the feed flow rate of 0.9 L/h with the highest curcumin content was selected as the optimal rate.In the final single-factor study, the chosen curcumin : maltodextrin ratios were 1:15, 1:20, 1:25 and 1:30.The results of this survey was illustrated in Figure 5.In terms of appearance, when reducing the amount of carrier, the color of the powder darkens gradually, because the curcumin content in the powder increases, affecting the color of the powder.The content change is quite obvious, when changing the ratio from 1:15 to 1:30, the content decreases from 4.39% to 3.18%.However, there is a big difference in the curcumin recovery rate when increasing the ratio from 1:15 to 1:20, it is possible that the amount of carrier is not enough at the ratio of 1:15 leading to the loss of active substance when spray drying.At the ratio 1:20, 1:25, 1:30, there was no significant difference in curcumin recovery, but the curcumin content in 1:20 ratio reached 4.14%, which was significantly higher than the ratio of 1:25 and 1:30.Therefore, the 1:20 cur : maltodextrin ratio was chosen.

Results of RSM optimization
The central composite design (CCD), which was used to generate parameters for further experimental runs, was based on the determined optimal set of parameters.Table 2 displays the generated parameters and the corresponding experimental results.6 shows the response surfaces used to demonstrate the interaction effects between the variables on the response surface, with the vertical axes being the curcumin content and the horizontal axes being the two investigated variables.The absent variable was preserved at its central value in each plot.It is demonstrated that the impacts of both intake air temperature and drying air flow on the curcumin content in the powder are similar, with increasing intake air temperature or drying air flow both leading to higher curcumin content in the powder.On the other hand, the interaction between intake air temperature and feed flow rate is indicated by another pattern in which an increased feed flow rate seems to lead to a decrease in curcumin content in the powder, and the optimal pair of conditions might be outside the experiment's range because the third factor (drying air flow) is kept constant at the center point.Finally, a surface plot demonstrating the interaction between the drying air flow and the feed flow rate shows that the maximum curcumin content can be achieved in the range of 280-300 m 3 /h of drying air flow.The actual and anticipated responses are represented as data points in Figure 7.The fact that the data distribution is close to the 45-degree line indicates that the experimental outcomes and predictions accord (12).Additionally, the established model and the experimental data show an excellent fit according to the calculated regression coefficient R 2 = 0.96 and the RSME value of 0.1012.

Figure 7. Interactions between investigated factors and the objective function
The influence of the individual factors on the average curcumin content in the powder is shown in Figure 8. Obviously, the curcumin content responded most quickly to changes in the feed flow rate, as shown by the slope of the curves, and the increase in speed was greater than 0.9 L/h resulted in a significant reduction in the curcumin content in the powder.On the other hand, the intake air temperature is positively correlated with the results while the drying air flow is not seem to be significantly correlated with the curcumin content in the powder.Powder has a median size of 1.900 µm, most of the particles are distributed in the region from 1-10 µm when analyzed by LDS method (Figure 9).The distribution line is bell-shaped, symmetrical and in a narrow region, showing that the system has a very good size distribution.However, the result appears in size in the area of 100 µm, which proves that the particles are clumped and clustered during the sample measurement.By FESEM method using JSM-IT800/JEOL equipment, powder particles were determined to have an almost round shape (Figure 10).The particle diameter is in the range of 1 -3 µm and the particles are relatively uniform in size, which is consistent with LDS analysis results.

Consequence of solubility evaluation
The solubility of spray-drying powder was evaluated in three buffer media with pH values of 1.2, 4.5, and 6.8.(13) Simultaneously, the initial material curcumin and the sub-optimal spray-drying powder were used as confronts to compare with the obtained product.The results are shown in Figure 11.Solubility of optimal powder in different buffer media.In general, the solubility of samples in the three study media is small (< 4%).Experiments show that the dispersion through dissolution of optimal powder is not good at all three pH conditions due to the influence of carrier.However, when using a carrier, the ability to protect curcumin from degradation is better than both confront 1 and 2.

Conclusions
After creating a suspension containing curcumin and gum Arabic, the system was spray-dried in turn with three types of carriers: maltodextrin, lactose, and isomalt.The maltodextrin carrier was selected for use in the other surveys because it had the highest content of curcumin in the powder.The preparation process was optimized using the response surface methodology with respect to the maximal content of curcumin.Three experimental parameters were examined: intake air temperature, drying air flow, and feed flow rate.The parameters after optimization process are respectively intake air temperature of 150 ℃, drying air flow of 290 m 3 /h and feed flow rate of 0.7 L/h, which corresponds to the curcumin content of 4.667%.The medium size of the powder is 1.900 µm when analyzed by LDS method.When analyzing by FESEM method, the particles are in the range of 1-3 µm in size, spherical in shape, and the particle surface is wrinkled due to the influence of heat in spray-drying process.The investigation showed that the solubility of optimal powder is not shown well, but curcumin was protected from decomposition, while ensuring stability during the release of the active element compared to confronts.In order to improve the application of the product, there should be more in-depth studies and evaluations on the antioxidant, antimicrobial, and anti-inflammatory activities of powder products.

Figure 1 .
Figure 1.Effect of different types of carriers on curcumin content of spray-drying powder.The content of curcumin in the powder changed markedly when using different types of carriers, the powder using maltodextrin carrier had a higher content than the powder using lactose and isomalt carrier.In this research, a high content of curcumin is essential to increase the applicability to the products in the later stages, so the maltodextrin carrier was selected to use for the other surveys.

Figure 2 .
Figure 2. Effect of different intake air temperature on curcumin content of spray-drying powder.Figure 3 displays the findings from four studies on the drying air flow, which were conducted at 240, 270, 300, and 330 m 3 /h.

Figure 3 .
Figure 3.Effect of different drying air flow on curcumin content of spray-drying powder.When the drying air flow increases, the powder color changes insignificantly.With an air flow of 240 m 3 /h, not much powder can be obtained possibly due to not enough drying air flow to take the powder into the cyclone.The change of the content is similar to the appearance, so the drying air flow of 300 m 3 /h producing the powder containing the highest curcumin content of 4.41% was selected.Figure4represents variations of curcumin content with different feed flow rates.Similar to the results when changing the drying air flow, here both the appearance and the content also change almost insignificantly when the feed flow rate is changed.Therefore, the feed flow rate of 0.9 L/h with the highest curcumin content was selected as the optimal rate.

Figure 4 .
Figure 4. Effect of different feed flow rateon curcumin content in the powder.In the final single-factor study, the chosen curcumin : maltodextrin ratios were 1:15, 1:20, 1:25 and 1:30.The results of this survey was illustrated in Figure5.In terms of appearance, when reducing the amount of carrier, the color of the powder darkens gradually, because the curcumin content in the powder increases, affecting the color of the powder.The content change is quite obvious, when changing the ratio from 1:15 to 1:30, the content decreases from 4.39% to 3.18%.However, there is a big difference in the curcumin recovery rate when increasing the ratio from 1:15 to 1:20, it is possible that the amount of carrier is not enough at the ratio of 1:15 leading to the loss of active substance when spray drying.At the ratio 1:20, 1:25, 1:30, there was no significant difference in curcumin recovery, but the curcumin content in 1:20 ratio reached 4.14%, which was significantly higher than the ratio of 1:25 and 1:30.Therefore, the 1:20 cur : maltodextrin ratio was chosen.

Figure 5 .
Figure 5.Effect of different curcumin : maltodextrin ratios on curcumin content and recovery efficiency of spray-drying powder.

Figure 6 .
Interaction effects of pairs of factors on the response surface.

Figure 11 .
Figure 11.Solubility of optimal powder in different buffer media.In general, the solubility of samples in the three study media is small (< 4%).Experiments show that the dispersion through dissolution of optimal powder is not good at all three pH conditions due to the influence of carrier.However, when using a carrier, the ability to protect curcumin from degradation is better than both confront 1 and 2.

Table 1 .
The bound values for the RSM optimization's examined parameters. 3

Table 2 .
Experimental parameters and responses for RSM optimization

Table 3
displays the estimation results for the standard model after it has been fitted.

Table 3 .
Values for the standard regression model's coefficients