3rd International Conference on Material, Mechanical and Manufacturing Engineering (IC3ME 2015)

Preparation and in Vitro Dissolution of Curcumin Tablets

Yuanping Wang a, Chuqin Yu* b, Zhixiang Ganc , Zhongbo Xied
Guangdong Pharmaceutical University, Guangzhou, 510006, China
a
[email protected], [email protected](corresponding author) , [email protected],
d
[email protected]

Keywords: Curcumin; dissolution; tablets; preparation process; response surface methodology

Abstract. Objectives: To prepare curcumin tablets, and evaluate their in vitro dissolution. Methods:
Curcumin was dissolved in acetone, wet-granulation and tableting. The amount of Poloxamer 188
and Gremophor RH40 were chosen as factors, and the in vitro dissolution at 120 min was used as
evaluation index. The best prescription was screened by response surface method of two factors and
three levels. UV-visible spectrophotometry was used as detection methods. Results: In this study, the
standard curve was in good linearity with the range of 2.5~5.0μg·mL-1, r = 0.9996. The average
recovery was 98.08%, RSD = 0.61%. The obtained prescription: Curcumin: Poloxamer 188:
Gremophor RH40 = 1: 2.52: 0.40, the in vitro dissolution at 45 min and 120 min were 64.85% and
95.12% respectively. Dissolution of the best prescription of curcumin obtained twice higher than the
raw curcumin and physical mixtures, and higher than commercial products. Conclusions:The
preparation method of curcumin tablets is simple and reliable, which significantly improves the
dissolution of curcumin.

Introduction
Curcumin which was medicinal and edible products was mainly from the root of Curcuma aromatica
Salisb, turmeric roots, Curcuma Rhizome, Acorus calamus L roots, etc. In medicine it has antioxidant,
anti-inflammatory, anti-proliferative, anti-cancer, anti-bacterial infection, liver damage and other
effects protection [1]. In recent years, it has been found to have immunomodulatory effect and a
significant effect on the prevention of Alzheimer's disease[2]. Due to its low toxicity (LD50 in mice
was greater than 2g. kg-1 [3]), the US FDA had evaluated its extensive safety. However, curcumin has
some shortcomings such as poorly dissolution in water, sensitive to light, heat and iron ion, easily
hydrolyzed in neutral and alkaline environment, content declining sharply under outdoor lighting [4],
decreasing after autoclaving, low oral bioavailability [5] etc. Various preparation methods were
reported in literature which mainly used polyvinylpyrrolidone (PVP K30), polyethylene glycol (PEG)
as carriers to prepare curcumin solid dispersion in order to improve its dissolution [6-8], but the
preparation process was complicated and high cost, which was not suitable for large-scale production.
In this study, the response surface methodology (RSM) was used to obtain the best preparation of
curcumin tablets, thus to increase its dissolution and bioavailability as well as to simplify the
production process and facilitate the large-scale production and lower production costs.

Reagent and Instrument

Curcumin substance(Cur, Hebei days Asahi natural pigment Ltd.); Curcumin reference (Guangzhou
Qiyun Sheng Technology Co., Ltd., content: HPLC≥98%); Poloxamer 188 (P188, BASF);
Gremophor RH40 (Gremophor RH40, BASF); Crosslinked povidone (PVPP, the United States
Specialty Products company); Silica powder (SiO2, Guangzhou Jie Fu trading Co., Ltd.);
Low-substituted hydroxypropyl cellulose (L-HPC, Guangzhou Jie Fu trading Co., Ltd.); Lactose
(Beijing Feng Jingqiu commercial limited liability company); Microcrystalline cellulose (MCC,
Anhui mountains and rivers of medicinal materials Co., Ltd.); Magnesium stearate (MS, Guangzhou
Jie Fu trading Co., Ltd.); Curcumin capsules (US Priscilla Pleasant company); Sodium chloride
(NaCl, Tianjin Zhiyuan chemical Reagent Co.); Sodium dodecyl sulfate (SDS, Tianjin Zhiyuan
Chemicals Limited); Acetone (Tianjin Damao Chemical Reagent Factory).

© 2015. The authors - Published by Atlantis Press 516

ZRS-8G Intelligent Dissolution Tester (Tianjin Tianda Tianfa Technology Co., Ltd.); ZKT-18F
vacuum degassing device (Tianjin Tianda Tianfa Technology Co., Ltd.); GZX-9246 MBE Digital
Blast Oven (Shanghai Bo Xun Industrial Co., Ltd. medical Equipment Factory); UV-1800 UV-
visible spectrophotometer (Shimadzu Corporation, Kyoto, Japan); BS 224S electronic balance
(Beijing Sartorius instrument systems, Inc.); YP3001N electronic balance (Shanghai precision
Scientific instruments Ltd.); ZP-5B rotary tablet machine (Shanghai Tianfeng pharmaceutical
Machinery Co.); RCT magnetic stirrer (Germany IKA company); KQ-100 ultrasonic cleaner
(Kunshan Ultrasonic instrument Co., Ltd.); TDL-60B desktop centrifuge (Shanghai Anting scientific
Instrument Factory); MA35 electronic moisture Analyzer (Guangzhou Great Technology instrument
Co., Ltd.).

Methods and Results

Study on the Dissolution Method
Preparation of the Solution
Preparation of the Dissolution Medium
Take 11.7ml hydrochloric acid into 50ml volumetric flask, dilute with water to the mark, to obtain
hydrochloric acid. Take about 2g NaCl and SDS respectively, with precise metage, adding the above
hydrochloric acid 16.4ml, and diluted into 1000ml with water, degassing, then obtain the dissolution
medium.
Preparation of the Standard Solution
About 10mg of Cur standard, with precise metage, was placed in a 500ml brown volumetric flask,
adding 20ml of 95% ethanol, ultrasonic 5min, then cooled, with dissolution medium to the scale,
finally obtained standard solution.
Tested Sample Solution Preparation
Take 20 curcumin tablets, grinded into fine. About 200mg of fine powder, was placed in a 500ml
brown volumetric flask, adding proper amount of 95% ethanol, ultrasonic 5min, then cooled ,with
dissolution medium to the scale.
UV Absorbance Wavelength Selection
Measured standard solution 5ml and placed it into 20ml brown volumetric flask , with dissolution
medium to the scale, filtered, and took successive filtrate, Geometric (V/V) ethanol dissolution
medium was used as blank control in the wavelength range of 300-500nm scanning. Cur in 429nm
had maximum absorbance, so wavelength of 429nm was selected for Cur maximum absorbance.
Membrane Adsorption Test
According to the method of dissolution determination,one piece of curcumin tablets was taken into
the dissolution cup, and the samples were taken for 9 copies, each 10ml. Three of them were placed in
the 10ml centrifuge tube, with the rotating speed of 5000r·min-1,centrifuged for 15min. The
dissolution medium was used as the blank control,and theabsorbance of the supernatant was
measured at the wavelength of 429nm. The remaining six copies all passed over 0.8μm micropore
filter membrane, three of which were abandoned 2ml of the initial filtrate, while the other three were
abandoned 3ml of the initial filtrate. Take the successive filtrate and the dissolution medium as blank
control respectively and determine the absorbance at the wavelength of 429nm. Results showed that
the average value of 2ml membrane adsorption capacity was 1.96%, and 3ml was 0.03%, which were
less than 2%.
Standard Curve
The standard solution was diluted with the dissolution medium to a series concentrations of solutions
of 2.5, 3.0, 3.5, 4.0, 4.5 and 5.0μg·ml-1. Filter and take the successive filtrate with geometric ethanol
dissolution medium as blank control, determinate the absorbance at the wavelength of 429nm . The
concentration C used as y axis on the ceiling light value for X axis for linear regression, the regression
equation was as follows C=0.0072A+0.00005, the related coefficient r = 0.9996. The results showed
that the linear relationship was good in the range of 2.5 to 5μg·ml-1.

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 Precision Test
According to the determination method of dissolution, take one piece of curcumin tablet into a
dissolution cup, sample 60ml at 45min, filter, take the successive filtrate, the dissolution medium as
blank control, determine the absorbance at the wavelength of 429nm 6 times within one day, calculate
the concentrations, RSD=0.065%. The results showed that the precision of the instrument was good.
Stability Test
According to the determination method of dissolution, take one piece of curcumin tablet into a
dissolution cup, sample 60ml at 45min, filter, take the successive filtrate, and the filtrate was divided
into 7 parts. Take the dissolution medium used as the blank control and determinate the absorbance at
the wavelength of 429nm at 0, 1, 2, 3, 4, 5 and 6h, respectively,then calculate the concentrations,
RSD=0.320%. The results showed that the stability of solution was good within 6 hours.
Excipients Interference Test
According to the preparation process and the amount of the prescription, make blank tablets without
drugs. Take 20mg of blank tablet and grind them into fine, take about 10mg of fine powder, with
precise metage, place it in a 25ml brown volumetric flask, with 95% ethanol and diluted to the scale,
ultrasonic 5min, chilling, take 2ml into a 10ml volumetric flask, diluted to the scale with dissolution
medium, shake, filter, take the successive filtrate. Take dissolution medium containing geometric
ethanol (V/V) as blank control and determine the absorbance at the wavelength of 429nm, and scan in
the wavelength range of 300~500nm. The results showed no absorption peak at 429nm, which
indicated no interference from excipients.
Recovery Test
Take 3 copies of standard solutions of 2.5, 4, 5ml respectively into 10ml brown volumetric flask, add
fine powder of the blank tablets with amount of prescription, dilute with dissolution medium to the
sample solutions containing 50%,80%,100% Cur, Filter the above solution, take successive filtrate,
and use dissolution medium of corresponding concentration of ethanol as blank control to
determinate the absorbance at the wavelength of 429nm. Result showed that the average recovery rate
was 98.08%, RSD=0.610%, which was in line with the requirements.
In Vitro Dissolution Test
Take this product, according to the dissolution test method (Appendix X C second), with
hydrochloric acid solution (containing 0.2% SDS and 0.2% NaCl, w/v) as the dissolution medium at
the speeding rate of 50, According to the operation, sample 10ml at 45, 60, 90 and 120min, then
supplement fresh medium of the same temperature and volume, filter, take successive filtrate, take
precisely moderate amount of successive filtrate, diluted quantitatively with dissolution medium to
obtain the Cur concentration of 3μg.ml-1. According to UV-VIS spectrophotometry (Appendix IV A),
the absorbance is determinated at the wavelength of 429nm. And then take another Cur standard
solution, dilute it to 3μg•ml-1. The absorbance was determined by the same method, and the
dissolution amount of each table was calculated.
Preparation of Curcumin Tablets
Prescription amount of L-HPC, lactose and MCC were weighed and screened through No.5 mesh
sieve respectively, and then mixed equably and standby. Prescribed amount of Poloxamer 188 was
added into an appropriate amount of acetone, stirred until completely dissolved. Add prescriptions
amount of Cur, and mix well. Then add Gremophor RH40, stir until Cur was completely dissolved.
Prescription amount of PVPP and SiO2 were added to the above solution with stirring. The backup
mixture flour was added to the system, and soft material was prepared and screened a No.2 mesh
sieve to granulate. The granules were dried at 40 ℃ to a control the moisture content at 3~6%, over a
NO.2 mesh sieve. a prescription amount of lubricant (0.4% MS calculated by particles (W / W), 0.6%
SiO2 calculated by particles (W / W)) was added and mixed well. Measure content and prepare tablets.
The weight of every tablet is about 200mg.
Preparation Process Optimization of Curcumin Tablets
Previous studies found that a certain amount of Poloxamer 188 and Gremophor RH40 caused
tableting process sticking phenomenon, and affected the disintegration and dissolution of the tablets.

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Therefore, Poloxamer 188 and Gremophor RH40 were as main factors to the dissolution of the
indexes, selecting the best prescription with RSM.
Gremophor RH40 Single Factor
Based on the of preliminary experiments tablet were granulated and prepared followed by the method
under ”3.2” using the ratio of Cur: Poloxamer 188: Gremophor RH40 with 1: 5: 0.5, 1: 5: 1 and 1: 5:
1.5, respectively. When the amount of Gremophor RH40 was 0.5 times of Cur, the granules could be
screened, but still caused tablets sticking phenomenon. When the amount of Gremophor RH40 was
1.0 and 1.5 times of Cur, it sieves difficultly and sticks seriously. The results showed that with the
increase of the proportion of Gremophor RH40, it was more difficult to screen and illustrated more
serious to stick. The amount of Gremophor RH40 in this preparation should be less than half of Cur.
Poloxamer188 Single Factor Test
On the basis of preliminary experiments, according to the method under “3.2” to granulate and
prepare tablets, when Cur: Poloxamer188: Gremophor RH40 ratio were 1: 1: 0.4, 1: 3: 0.4, 1: 5: 0.4
and 1: 7: 0.4, respectively. The dissolution was used as the indicator and tablet sticking situation was
compared. When the amount of Poloxamer188 was 3, 5 and 7 times of prescription amount of Cur,
the dissolution at 45min were 69.40%, 64.63%, 87.43% and 97.86% , respectively; While at 120min,
the in vitro dissolution was 85.34%, 80.22%, 89.71 % and 99.43%, respectively. Dissolution of the
ratio 1: 5 and 1: 7 indicated better, but the phenomenon of sticking became more serious with the
increase of the amount of Poloxamer188. Therefore, through the prescription optimization the
amount of Poloxamer188 should be less than five times of Cur's.
Response Surface Methodology
Design-Expert 8 software is used to statistically optimize the formulation to improve in vitro
dissolution with RSM. According to the principle of 3-Level design, ratio of P188 to Cur (x1) and
Gremophor RH40 to Cur (x2) were selected as the variables and in vitro dissolution at 120min (y) as
the dependent variable tested in a 13-run experiment to determine the optimum levels (As shown in
Table 1). As shown in Figure 1, response surfaces at 45, 60, 90 and 120min were obtained， which
reflected the increasing of y as x1 and x2 were growing. Because of the hydrotropy of P188 and
Gremophor RH40, as x1 and x2 increased, y increased accordingly, but when the amount of the two
came to a certain value, it would affect the viscosity of the tablets, which affected the disintegration
and dissolution. The analysis of variance in 120min was shown in Table 2. The variance analysis
results of Table 2 showed that experimental models had significant differences, quadratic term x12 has
a significant influence on dissolution. The least squares method was used to calculate the optimum
ratio of Cur: P188: Gremophor RH40= 1: 2.52: 0.4.

Table 1 Response Surface Methodology Analysis

Gremophor Dissolution(%) at
Experiment P188/Cur
RH40/Cur 120[min]
No.
（x1） （x2） (y)
1 4.0 0.4 59.79
2 2.5 0.4 94.04
3 2.5 0.4 96.84
4 2.5 0.3 87.36
5 2.5 0.4 90.78
6 4.0 0.5 71.17
7 2.5 0.5 72.80
8 1.0 0.3 56.37
9 1.0 0.4 74.60
10 1.0 0.5 65.61
11 2.5 0.4 90.53
12 2.5 0.4 90.53
13 4.0 0.3 68.94

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Fig. 1. Response surface renderings (top to bottom are 45, 60, 90 and 120min response surface
map)

Table 2 ANALYSIS of VARIANCE IN 120[min]

Source Sum of df Mean F Value p-value
Squares Square >F
Modle 1521.81 5 304.36 4.11 0.0462
x1 1.84 1 1.84 0.025 0.8792
x2 1.59 1 1.59 0.021 0.8876
x1x2 12.31 1 12.31 0.17 0.6956
x1 2 965.66 1 965.66 13.04 0.0086
x2 2 93.233 1 93.23 1.26 0.2989
Residual 518.38 7 74.05
Lack of Fit 371.46 3 123.82 3.37 0.1355
Pure Error 146.93 4 36.73
Cor Total 2040.19 12

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Verification Test
Press optimal formulation, In accordance with the method under "3.2", three batches of curcumin
tablets were prepared. The in vitro dissolution results remained the same, the average dissolution was
64.85% at 45min and 95.12% at 120min.
The Dissolution of Different Formulations
Cur pharmaceutical raw materials by count of 10mg/cup, prescriptions Cur raw materials mixture
with the 200mg, capsules of Cur powders and a commercial operator by 10mg Cur were accurately
weighed respectively. The dissolution was measured according to the dissolution procedure. The
dissolution of Cur substance, raw materials and accessories prescriptions Cur mixture, capsule
powder were 28.31%, 29.30%, 77.49% at 45min and 46.88%, 41.92%, 89.21% at 120min. The
dissolution of Cur tablets by the response surface design of optimal prescription obtained was 64.85%
at 45min, and 95.12% at 120min. The results showed that the tablets prepared along the optimal
prescription had higher dissolution compared with raw Cur and physical mixtures, capsule powder.

Conclusions
Microporous membranes used in this experiment is a polyether sulfone material, curcumin has certain
adsorption, membrane adsorption in the experiment, and the filtrate was discarded early 2ml~3ml,
membrane adsorption amount is less than the average 2%, but the beginning of the filtrate was
discarded 3mL adsorption filters less experimental error is smaller, so this was chosen 3ml beginning
of the filtrate was discarded.
The study found Gremophor RH40 sample order of dissolution Cur sheet impact, will Gremophor
RH40 was adjusted to Cur added prepared curcumin tablets dissolution repeatable, and the
corresponding dissolution also increased. Another of the experiment the amount of PVPP screening
results show that, PVPP dosage of curcumin on in vitro dissolution of little effect.
Curcumin poorly soluble drugs, for poorly soluble drugs, its dissolution time than the body of drug
absorption time, and the dissolution rate is the rate-limiting step of drug absorption. So, dissolution
rate and bioavailability have a high correlation [9]. This insoluble drug Cur solubility is not high in
ethanol, and much higher in acetone. Thus, acetone was used in the experiment. In order to improve
the bioavailability of the drug, this experiment optimized formulation and technology to improve
dissolution in vitro of Cur. The preparation process for equipment less demanding, simple operation,
eliminating the solid dispersion is heated to melt and freeze-dried preparation to join the cumbersome
extra step adhesives and the like, easy to implement industrial production.

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