Preparation and <i>in Vitro</i> Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets

doi:10.4236/pp.2012.34064

Paper Menu >>

Journal Menu >>

Pharmacology & Pharmacy, 2012, 3, 468-473

http://dx.doi.org/10.4236/pp.2012.34064 Published Online October 2012 (http://www.SciRP.org/journal/pp)

Preparation and in Vitro Drug Release Evaluation of

Once-Daily Metformin Hydrochloride Sustained-Release

Tablets

Ling Zhao1, Yumeng Wei1*, Yong Mei2, Li Yang2, Yuan You2, Xufeng Yang2, Yanhong Jiang2

1Department of Pharmaceutics, School of Pharmacy, Luzhou Medical College, Luzhou, China; 2Chongqing Conquor Pharmaceutical

Co., Chongqing, China.

Email: *[email protected]

Received June 24th, 2012; revised July 25th, 2012; accepted August 11th, 2012

ABSTRACT

The objective of this study was to develop once-daily metformin hydrochloride sustained-release tablets (MHSRT) and

evaluate their in vitro release behavior. MHSRT were prepared by the film coating method. The in vitro drug release

rate of MHSRT and the commercial tablets Fortamet® made in the United States of America in water was fitted with

zero order kinetic equation, and Ritger-Peppas kinetic equation in 0.1 M HCl and pH 6.8-phosphate buffer, respectively.

The similarity factor f2 values of MHSRT in three different dissolution medium were 82, 80 and 74, respectively in

comparison with imported Fortamet®, which were all greater than 50. The results of storage-stability showed that

MHSRT were stable for at least 6 months under stress condition (40˚C ± 2˚C, RH 75% ± 5%). Therefore, in this study,

MHSRT were successfully prepared using optimized formulation technologies that meet mass produce. The in vitro

release behavior of MHSRT was almost similar to that of imported Fortamet®.

Keywords: Sustained-Release Tablets; Metformin Hydrochloride; In Vitro Release Rate; Similarity Factor; Kinetic

Model

1. Introduction

Metformin hydrochloride (MH) is a biguanide oral anti-

diabetic drug which is widely used to treat non-insulin

dependent diabetes mellitus (type 2 diabets). Its mode of

action is thought to be multifactoral and includes de-

layed uptake of glucose from the intestinal tract, in-

creased peripheral glucose utilisation mediated by in-

creased insulin sensitivity and decreased hepatic and renal

gluconeogenesis. In clinical treatment, there are many

advantages of MH such as the tendency to weight reduc-

tion and the ability to reduce blood glucose to normal

level without significant hypoglycaemia [1]. However,

because of its relative low bioavailability (40% - 60%)

and short biological half-life (0.9 - 2.6 h) [2-5], the im-

mediate release dosage forms of MH such as conven-

tional tablets and capsules, have to be administered three

times a day [3], which results in a significant fluctuation

in the plasma drug concentration and poor patient com-

pliance. In order to overcome these problems, sustained-

release drug delivery systems of MH including sustained-

release matrix tablets [2,6-8], sustained-release pellets

[3,9], sustained-release microparticles [10], prolonged

release microspheres [11], gastroretentive drug delivery

preparation [12], pH-controlled peroral delivery formula-

tion [13] have been developed in recent years. Though

sustained release formulations of MH have been reported to

prolong drug release, formulation and technologies used in

these studies were complicated and costly, which influence

industrial scale and market expansion. At present, MHSRT

produced by Bristol-Myers Squibb Company (USA)

capture a major market share in China. However, many

patients in our developing country could not accept it due to

its high cost. Therefore, development of sustained release

dosage form of MH that is similar to imported drug is to

save pharmacy cost and improve clinical outcomes.

Therefore, in this study, MHSRT were prepared using

optimized formulation technologies that meet mass pro-

duce. The in vitro drug release behavior of MHSRT was

studied in water, 0.1 M HCl and pH 6.8-phosphate buffer

as release medium and compared with the commercial

tablets Fortamet® made in the United States of America.

2. Materials and Methods

2.1. Materials

Metformin hydrochloride (purity: 99.86%) was purchased

*Corresponding autho

Preparation and in Vitro Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets 469

from Huainan Jiameng Pharmaceutical Co., Ltd (China).

Carboxymethyl cellulose sodium (CMC) and pregelati-

nized Starch was obtained from Anhui Shanhe Pharma-

ceutical Excipient Co., Ltd (China). Ethyl cellulose was

purchased from Shandong Heda Co., Ltd (China). PEG-

6000 was supplied by Liaoyang Aoke Nano Meterial Co.,

Ltd. (China). Hexadecanol was purchased from Hunan

Erkang Pharmaceutical Co., Ltd (China). Magnesium

stearate was purchased from Chongqing Chemical Re-

agent Co. Ltd. (China). Fortamet® (batch number: 4602094;

expiry date: 20121102) were obtained from Watson La-

boratories—Florida Ft. Lauderdale, FL 33314 (USA).

were obtained from the United States of America. All

chemicals and reagents used were of analytical grade.

Water used in this study was double distilled water.

2.2. Preparation of MHSRT

Firstly, MH core tablets were prepared by wet granula-

tion method. MH and CMC were mixed and the mixture

was passed through a 100-mesh sieve. Granulation was

done using water. The wet mass was passed through

fourteen meshes using the pendular granulator and the

wet granules were air dried for about 2 h. The granules

were then sized by fourteen mesh sieve and mixed with

pregelatinized starch and magnesium stearate. The core

tablets were compressed on a tablet compression ma-

chine equipped with 12 mm convex punches. Secondly,

the film coat suspension was prepared by dissolving and

dispersing EC, PEG-6000 and hexadecanol in 95 %

ethanol. In brief, the above core tablets were placed into

a fluid-bed spray coater and prewarmed to 35˚C - 40˚C

for 3 - 5 min. The coating solution was delivered using

peristaltic pump with a flow rate of 1.8 mL/min. Coating

was carried out at 50˚C inlet air temperature and 45˚C

outlet air temperature. The resulted MHSRT were dried

at 40˚C for 12 h and then were further performed quality

evaluation.

2.3. Determination of Drug Content

According to the Chinese Pharmacopoeia (2010 version)

about the determination of MH content, the samples (20

tablets) were taken and ground to fine powder. Then

about 20 mg powder was accurately weighed and placed

in a 100 mL volumetric flask containing 75 mL water.

After it was dissolved using ultrasonication at room

temperature for 20 min, this solution was diluted with

water to 100 mL and mixed well, then filtered through a

0.45 µm hydrophilic membrane. 2.5 mL of the solution

was accurately taken and transferred to a 100 mL volu-

metric flask, and then was diluted with water to 100 mL

and mixed well. The drug content was measured using

an UV-visible spectrophotometer at a wavelength of

233 nm.

2.4. Weight Variation Test

To study weight variation, 20 tablets of each batch sam-

ples were weighed using an electronic balance (BT214D,

Germany Sartorius), and the test was carried out ac-

cording to the Chinese Pharmacopoeia (2010 version)

method.

2.5. Hardness and Friability Test

For each batch of MHSRT, the hardness and friability of

12 tablets was determined using tablet with four measur-

ing instrument (78X-6A).

2.6. In Vitro Release Test

In vitro release studies of MHSRT was carried out by the

rotating basket methods of Chinese Pharmacopoeia

(2010 version) appendix XD No.1. Six tablets of each

batch of MHSRT were taken and placed in rotating bas-

ket, respectively. Then the rotating basket was introduced

into 900 mL of each dissolution medium (water, 0.1 M

HCl and pH 6.8 phosphate buffer) at 37˚C ± 0.5˚C with a

rotation speed of 100 rpm. 5 mL of sample solution was

collected at different time intervals (2, 4, 6, 8, 10, 12 h)

and filtered through a 0.45 µm hydrophilic membrane.

1.0 mL of subsequent filtrate was taken accurately to add

into a 100 mL volumetric flask and diluted with the cor-

responding dissolution medium to 100 mL and mixed

well. The amount of drug dissolved in the dissolution

medium was measured using an UV-visible spectropho-

tometer at 233 nm. The same volume of fresh dissolution

medium at the same temperature was added to replace

the amount withdrawn after each sampling.

The drug amount of cumulative release from the

MHSRT was calculated with a standard curve prepared

using bracketed concentration of MH each dissolution

medium solution in a range from 15 to 125% of a theo-

retical concentration of 5.5 µg/mL. The standard curve:

Y = 0.0746X − 0.0031 for distilled water; Y = 0.0758X −

0.0034 for 0.1 M HCl and Y = 0.0798X − 0.0037 for pH

6.8 phosphate buffer were obtained with coefficient of

correlation (r = 0.9999).

2.7. Data Analysis

In order to evaluate the drug release kinetic model of the

MHSRT, four kinetic models including the zero-order

release equation, first-order release equation, Higuchi’s

equation and Ritger-Peppas ((1)-(4), respectively) were

chosen to process the in vitro drug release data.

tktb



 (1)





Ln 1002

tktb





(2)

Preparation and in Vitr o Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets

470

In order to validate whether the optimized formulation

technologies of MHSRT can be suitable for mass pro-

duce, the three batches of MHSRT (100000 tablets/batch)

were produced by Chongqing Conquor Pharmaceutical

Co., Ltd. and the results were shown in Table 1 and

Figures 1-3. Drug content was found to be uniform

among the three batches of MHSRT and ranged from

97.85% ± 0.09% to 99.36% ± 0.07%. The mean percent-

age weight variation of 20 tablets of each batch was less

tkt b (3)

Ln 4Ln

tk tb (4)

where Mt is the cumulative release percentage at time t,

the k1, k2, k3 and k4 are the rate constant of the above

kinetic equation, respectively.

In order to compare the difference of in vitro drug re-

lease behavior between the MHSRT, the similarity factor

f2 is used in this study and defined by the following

equation (5).





0.5

250 log11100fn





 

 (5)

024681012

100

120

MH released (%)

Time (h)

111105

111106

111107

where n is the number of time point, Rt and Tt are the

mean cumulative percentage drug dissolved at each time

point, t. MHSRT developed in this study and imported

Fortamet® made in the United States of America were

chosen as test samples and reference preparation, respec-

tively.

2.8. Stability Test of MHSRT

The accelerate stability testing was carried out according

to the Technical Standard of Drug Stability Test of Chi-

nese Pharmacopoeia (2010 version). The MHSRT sam-

ples were stored at 40˚C ± 2˚C, RH 75% ± 5% for 6

months and the in vitro release was measured after 1, 2, 3

and 6 months of storage.

Figure 1. Drug release profiles of the three batches (111105,

111106, and 111107) of MHSRT in water as dissolution

medium.

3. Results and Discussion

024681012

100

120

MH released (%)

Time (h)

111105

111106

111107

3.1. Development of MHSRT

In the preliminary study, MH, CMC, pregelatinized

starch and magnesium stearate were chosen to prepare

the core tablets as formulation composition. In addition,

the film coating formulation was composed of EC,

PEG-6000 and hexadecanol. On the basis of single factor

experiments, we have confirmed the dosage range of the

formulation composition. Then an orthogonal array was

used to investigate the key influence on preparation. In

the current research, the optimal formation of the core

tablets was MH (500 g), CMC (40 g), pregelatinized

starch (30 g) and magnesium stearate (9 g), the optimal

formulation of the film coating was composed of EC (15

g), PEG-6000 (6 g) and hexadecanol (6 g) dissolved or

dispersed in 95% ethanol resulting in 300 mL coating

suspensions.

Figure 2. Drug release profiles of the three batches (111105,

111106, and 111107) of MHSRT in 0.1 M HCl as dissolution

medium.

Table 1. Properties of the three batches of MHSRT prepared in this study.

Batch Drug content (%) Deviation in weight variation (%) Hardness (kg/cm2) Friability (%)

111105 98.55 ± 0.05 3.26 ± 0.02 6.8 ± 0.22 0.72 ± 0.04

111106 99.36 ± 0.07 2.90 ± 0.04 6.1 ± 0.17 0.79 ± 0.05

111107 97.85 ± 0.09 3.86 ± 0.03 7.4 ± 0.26 0.55 ± 0.04

Preparation and in Vitro Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets 471

than 5.0%. The hardness and percentage friability of the

tablets of all batches ranged from 6.1 ± 0.17 kg/cm2 to

7.4 ± 0.26 kg/cm2 and 0.55% ± 0.04% to 0.79% ± 0.05%,

respectively. The in vitro drug release behaviors of the

three batches of MHSRT in three different dissolution

medium were almost similar. Therefore, the optimized for-

mulation technologies possess good reproduction, which

are suitable for mass produce.

3.2. Evaluation of in Vitro Drug Release

The dissolution profiles of MHSRT developed in this

study and imported Fortamet® made in the United States

of America in water, 0.1 M HCl and pH 6.8 phosphate

buffer as release medium are shown in Figure 4. It was

found from Figure 4 that the release rate of MHSRT was

similar to that of Fortamet®. In the first 2 h, the cumula-

tive release percentages of MHSRT and Fortamet® were

25% and 27% in water; 25% and 22% in 0.1 M HCl;

22% and 20% in pH 6.8 phosphate buffer, respectively.

After 6 h, the cumulative release percentages of MHSRT

and Fortamet® were 59% and 56% in water; 64% and

62% in 0.1 M HCl; 58% and 51% in pH 6.8 phosphate

buffer, respectively.

As we all know, the different release kinetic models

are assumed to reflect different release mechanisms [14].

Therefore, in this study, zero-order release equation,

first-order release equation, Higuchi’s equation and Rit-

ger-Peppas were used to analyze the in vitro released

data. Correlation coefficients of Zero-order, First-order,

Higuchi’s equation and Ritger-Peppas kinetic models

used in this study were shown in Tables 2-4. It can be

seen that the in vitro drug release rate of MHSRT and

Fortamet® in water showed a zero order approximately

kinetic model and could be described by the following

equation: Mt = 7.915t + 8.934 (R = 0.996) and Mt =

7.843t + 9.934 (R = 0.996). However, the release rate of

MHSRT and Fortamet® in 0.1 M HCl and pH 6.8 phos-

phate buffer was fitted with Ritger-Peppas kinetic models

024681012

100

120

MH released (%)

Time (h)

111105

111106

111107

Figure 3. Drug release profiles of the three batches (111105,

111106, and 111107) of MHSRT in pH 6.8 phosphate buffer

as dissolution medium.

024681012

100

120

MH released (%)

Time (h)

MHSRT in water

Fortamet(R)in water

MHSRT in 0.1 M HCl

Fortamet(R)in 0.1 M HCl

MHSRT in pH 6.8 phosphate buffer

Fortamet(R)in pH 6.8 phosphate buffer

Figure 4. Drug release profiles of MHSRT develope d in this

study and imported Fortamet® in water, 0. 1 M HCl and pH

6.8 phosphate buffer as dissolution medium.

Table 2. Correlation coefficients of kinetic models used for evaluate the in vitro release behavior of MHSRT and Fortamet® in

water as dissolution medium.

Sample Zero-order First-order Higuchi’s equation Ritger-peppas

MHSRT 0.996 0.893 0.991 0.993

Fortamet® 0.996 0.910 0.989 0.991

Table 3. Correlation coefficients of kinetic models used for evaluate the in vitro release behavior of MHSRT and Fortamet® in

0.1 M HCl as dissolution medium.

Sample Zero-order First-order Higuchi’s equation Ritger-peppas

MHSRT 0.987 0.853 0.996 0.998

Fortamet® 0.988 0.865 0.993 0.997

Preparation and in Vitr o Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets

472

Table 4. Correlation coefficients of kinetic models used for evaluate the in vitro release behavior of MHSRT and Fortamet® in

pH 6.8 phosphate buffer as dissolution medium.

Sample Zero-order First-order Higuchi’s equation Ritger-peppas

MHSRT 0.995 0.827 0.993 0.999

Fortamet® 0.994 0.834 0.982 0.996

and could be described by the following equation: LnMt =

0.801Lnt + 2.665 (R = 0.998) and LnMt = 0.857Lnt +

2.551 (R = 0.997); LnMt = 0.875Lnt + 2.471 (R = 0.999)

and LnMt = 0.922Lnt + 2.354 (R = 0.996), respectively,

which indicated that the drug release mechanisms of

MHSRT and Fortamet® were similar in gastrointestinal

tract. According the formulation composition MHSRT, it

was obvious that drug diffusion and erosion were the

main factor in controlling the drug release rate from

MHSRT. This was also evidenced by the value of the

release exponent n of 0.801 and 0.875, because when n

ranged from 0.45 to 0.89, indicating that drug is released

by the combination of diffusion and erosion mechanisms

[15-16].

On the other hand, the similarity factor f2 value be-

tween 50 and 100 shows that two release profiles are

similar [17]. Therefore, in order to evaluate the in vitro

release difference of MHSRT, when imported Fortamet®

were chosen as reference, f2 value was calculated. It was

found that the dissolution profile of only MHSRT pre-

pared in this study was similar to that of Fortamet®, be-

cause the f2 values in water, 0.1 M HCl and pH 6.8

phosphate buffer were 82, 80 and 74, respectively, which

were all greater than 50.

3.3. Test for Stability

It was known that the stability of preparation is an im-

portant factor to estimate the quality of pharmaceutical

formulation. Thus, the acceleration stability test was

performed to study the stability of MHSRT. It can be

seen from Figures 5-7 that good storage stability was ob-

served and the in vitro release profiles had little change.

And no significant difference in cumulative release per-

centage of drug in water, 0.1 M HCl and pH 6.8 phos-

phate buffer after 1, 2, 3 and 6 months was observed in

comparison with MHSRT samples before storage (n = 3;

P > 0.05). Therefore, MHSRT developed in this study

were stable at least for 6 months under stress conditions.

4. Conclusion

In this study, once-daily metformin hydrochloride sus-

tained-release tables (MHSRT) were successfully devel-

oped by the optimized formulation technologies that are

suitable for mass produce at Chongqing Conquor Phar-

maceutical Co., Ltd. The in vitro release behavior of

MHSRT was almost similar to that of imported For-

024681012

100

120

MH released (%)

Time (h)

0 month

1 month

2 month

3 month

6 month

Figure 5. Drug release profiles of MHSRT develope d in this

study in water before and after 1, 2, 3 and 6 months of

storage under stress conditions (40˚C ± 2˚C, RH 75% ±

5%).

024681012

100

120

ease

(%)

Time (h)

0 month

1 month

2 month

3 month

6 month

Figure 6. Drug release profiles of MHSRT develope d in this

study in 0.1 M HCl before and after 1, 2, 3 and 6 months of

storage under stress conditions (40˚C ± 2˚C, RH 75% ±

5%).

tamet®. Furthermore, MHSRT developed in this study

were stable at least for 6 months under stress conditions.

5. Acknowledgements

This research was supported of by the National Natural

Science Foundation of China (81101678), the Key Pro-

gram of the Scientific Research Foundation of the Edu-

Preparation and in Vitro Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets 473

024681012

100

120

MH released (%)

Time (h)

0 month

1 month

2 month

3 month

6 month

Figure 7. Drug release profiles of MHSRT develope d in this

study in pH 6.8 phosphate buffer before and after 1, 2, 3

and 6 months of storage under stress conditions (40˚C ± 2˚C,

RH 75% ± 5%).

cation Department of Sichuan Province [09ZA049;

11ZZ024], the Scientific Research Foundation of the

Health Bureau of Sichuan Province [100215; 100214]and

the Key Program of the Scientific Research Foundation

of Bureau of Science and Technology of luzhou Munici-

pality [2011-S-32(1/4)].

REFERENCES

[1] X.-X. Yin, Y.-D. Zhang, H.-T. Zhuo, J.-P. Shen, L.-M. Li

and Q. Jun, “Pharmacokinetics and Relative Bioavailabil-

ity of Metformin Hydrochloride Sustained Release Tab-

lets in Healthy Chinese Volunteers,” Asian Journal of

Drug Metabolism and Pharmacokinetics, Vol. 4, No. 2,

2004, pp.137-142.

[2] G. Corti, M. Cirri, F. Maestrelli, N. Mennini and P. Mura,

“Sustained-Release Matrix Tablets of Metformin Hydro-

chloride in Combination with Triacetyl-Beta-Cyclodex-

trin,” European Journal of Pharmaceutics and Biophar-

maceutics, Vol. 68, No. 2, 2008, pp. 303-309.

doi:10.1016/j.ejpb.2007.06.004

[3] L. D. Hu, Y. Liu, X. Tang and Q. Zhang, “Preparation

and in Vitro/in Vivo Evaluation of Sustained-Release Met-

formin Hydrochloride Pellets,” European Journal of P har -

maceutics and Biopharmaceutics, Vol. 64, No. 2, 2006,

pp. 185-192. doi:10.1016/j.ejpb.2006.04.004

[4] P. J. Pentikäinen, P. J. Neuvonen and A. Penttilä, “Phar-

macokinetics of Metformin after Intravenous and Oral

Administration to Man,” European Journal of Clinical

Pharmacology, Vol. 16, No. 3, 1979, pp. 195-202.

doi:10.1007/BF00562061

[5] G. T. Tucker, C. Casey, P. J. Phillips, H. Connor, J. D.

Ward and H. F. Woods, “Metformin Kinetics in Healthy

Subjects and in Patients with Diabetes Mellitus,” British

Journal of Clinical Pharmacology, Vol. 12, No. 2, 1981,

pp. 235-246.

[6] P. K. Bhoyar and D. M. Biyani, “Formulation and in Vitro

Evaluation of Sustained Release Dosage Form with Taste

Masking of Metformin Hydrochloride,” Indian Journal of

Pharmaceutical Sciences, Vol. 72, No. 2, 2010, pp. 184-

190. doi:10.4103/0250-474X.65031

[7] O. Defang, N. Shufang, L. Wei, G. Hong, L. Hui and P.

Weisan, “In Vitro and in Vivo Evaluation of Two Ex-

tended Release Preparations of Combination Metformin

and Glipizide,” Drug Development and Industrial Phar-

macy, Vol. 31, No. 7, 2005, pp. 677-685.

doi:10.1080/03639040500216410

[8] A. Ghosh, A. Bose and U. Bhaumik, “Application of

Response Surface Methodology in the Formulation of

Sustained Release Matrix Tablets of Metformin Hydro-

chloride,” Asian Journal of Chemistry, Vol. 20, No. 7,

2008, pp. 5541-5556.

[9] J. Piao, J. E. Lee, K. Y. Weon, D. W. Kim, J. S. Lee, J. D.

Park, Y. Nishiyama, I. Fukui and J. S. Kim, “Develop-

ment of Novel Mucoadhesive Pellets of Metformin Hy-

drochloride,” Archives of Pharmacal Research, Vol. 32,

No. 3, 2009, pp. 391-397.

doi:10.1007/s12272-009-1312-0

[10] P. Subhedar, J. B. Naik and D. N. Muley, “Effect of

Polymer Concentration on Sustained Release Microparti-

cles of Metformin Hydrochloride Prepared by Using Spray

Dryer,” Polymer-Plastics Technology and Engineering,

Vol. 49, No. 3, 2010, pp. 267-271.

[11] H. F. Liu, X. Y. Su, X. Li, X. Zhao, L. Zang and W. S.

Pan, “Development of Prolonged Release Microspheres

of Metformin Hydrochloride Using Ion Exchange Res-

ins,” Journal of Chinese Pharmaceutical Sciences, Vol.

15, No. 3, 2006, pp. 155-161.

[12] S. P. Boldhane and B. S. Kuchekar, “Gastroretentive

Drug Delivery of Metformin Hydrochloride: Formulation

and in Vitro Evaluation Using 32 Full Factorial Design,”

Current Drug Deliver, Vol. 6, No. 5, 2009, pp. 477-485.

[13] G. Di Colo, S. Falchi and Y. Zambito, “In Vitro Evalua-

tion of a System for pH-Controlled Peroral Delivery of

Metformin,” Journal of Controlled Release, Vol. 80, No.

1-3, 2002, pp. 119-128.

doi:10.1016/S0168-3659(02)00022-6

[14] P. C. Wu, M. J. Tsai, Y. B. Huang, J. S. Chang and Y. H.

Tsai, “In Vitro and in Vivo Evaluation of Potassium Chlo-

ride Sustained Release Formulation Prepared with Satu-

rated Polyglycolyed Glycerides Matrices,” International

Journal of Pharmaceutics, Vol. 243, No. 1-2, 2002, pp.

119-124. doi:10.1016/S0378-5173(02)00264-8

[15] J. E. Polli, G. S. Rekhi, L. L. Augsburger and V. P. Shah,

“Methods to Compare Dissolution Profiles and a Ration-

ale for Wide Dissolution Specifications for Metoprolol

Tartrate Tablets,” Journal of Pharmaceutical Sciences,

Vol. 86, No. 6, 1997, pp. 690-700. doi:10.1021/js960473x

[16] S. G. Wang, L. Wang, Z. Z. Shao, X. P. Lu and X. Q.

Hang, “Study on the Release Rate of Niacin in Different

Media for the Compound Niacin Extended-Release and

Simvastatin Tablets,” Chinese Journal of Pharmacology

and Toxicology, Vol. 8, No. 10, 2011, pp. 581-584.

[17] N. A. Peppas, “Analysis of Fickian and Non-Fickian Drug

Release from Polymers,” Pharmaceutica Acta Helvetiae,

Vol. 60, No. 4, 1985, pp. 110-111.