Calculation of predominant drug release mechanism using Peppas-Sahlin model, Part-I (substitution method): A linear regression approach

 

Ravindra Babu Baggi1*,  Dr. Naveen Babu Kilaru2

1Department of Pharmaceutics, Sri Siddhartha Pharmacy College, Nuzvid, 521201, India.

2Department of Pharmaceutical Biotechnology, KVSR Siddhartha Pharmacy College, Vijayawada, 520010, India.

*Corresponding Author E-mail: baggi.ravi39@gmail.com

ABSTRACT:

The objective of this study was to develop Nicorandil controlled release floating tablets using combination of hydrophilic and hydrophobic polymers by melt granulation technique. The in vitro drug release characteristics were determined using USP XXII type 2 (paddle type) apparatus, in a medium of 0.1N HCL. The dissolution profile of all the batches were extended up to 24 hrs. To study and model the drug delivery from polymeric floating tablets, the dissolution data was fitted to a pioneered method Korsmeyer-Peppas equation. The results indicate that, all the formulations followed super Case-II release mechanism, except MCS4 which followed non-Fickian or anomalous release mechanism. In order to determine the predominant mechanism (diffusion/ relaxation model), drug release data was incorporated into Peppas-Sahlin model. The results revealed that, Fickian release contribution was preponderance than corresponding Case-II relaxational contribution in all the formulations. In addition to this, the relaxational contribution was observed with negative sign in all the formulations but, only at specific time intervals. Relaxational contribution with negative values indicates the Fickian release mechanism was more pronounced than relaxation i.e. almost the relaxational mechanism was absent.

 

KEY WORDS: Controlled release, Nicorandil, Diffusion, Relaxation, Fickian diffusion.

 

INTRODUCTION:

The quantitative analysis of data and study of drug release kinetics calculated from dissolution data was easier when mathematical formulae/ models were used to describe the process[1]. The kinetic release study was very important, since it allows constant calculations and provide a useful quantitative value to compare the behaviour of these systems in terms of its strength and ultimately help to predict the effect of device design parameters on the release kinetic of the formulation optimize and also useful to design a therapeutic device to yield information on the efficacy of various release models. The drug release phenomenon in relation to specific mathematical formulae revealed the information related to surface properties, liquid uptake behaviour, swelling and erosion of matrix tablets and drug release mechanisms[2,3,4].

 

 

However, a special attention has to pay in the selection of best mathematical model/ appropriate model depends on the desired or required predictive ability to obtain a good fit to the geometry as well as characteristics of the matrix and the drug released[5]. The study of drug release mechanism was pre-requisite step for improvement of the safety of the formulation and for effective trouble shouting during production.

 

The objective of the present study was to develop gastroretentive floating tablets of Nicorandil as model drug prepared by melt granulation method and evaluate the drug release mechanism using Korsmeyer-Peppas model and Peppas-Sahlin model. As the drug (Nicorandil) is freely soluble in water[6], combination of hydrophilic, swellable and retarding polymer (Almond Gum, AG) and hydrophobic retarding polymer/wax/lipid (cetosteryl alcohol, CSA) are used to prepare Nicorandil gastroretentive floating tablets.

 

MATERIALS AND METHODS:

Materials:

Nicorandil was obtained as a gift sample from Torrent Pharmaceuticals (P) Ltd., Gujarat, India; Cetosteryl alcohol obtained from Loba Chemical, Mumbai, India; Sodium bicarbonate, Citric acid and Lactose were purchased from SD fine chemicals, Mumbai, India. All other chemicals and reagents used were analytical grade.

 

Preparation of effervescent floating tablets by melt granulation technique:

Nicorandil effervescent floating tablets were prepared by direct compression technique using combination of AG and lipid/ wax polymer (Table 1). All the ingredients except wax were passed through sieve 60(#). As per each formulation of batch code, required quantity of wax was weighed and melted separately in a large china dish on hot plate and drug was added to it with stirring. To this mixture, other sieved ingredients except talc were added and stirred well to mix. Then mass was removed from the hot plate and subjected to scrapping until it attained room temperature. The coherent mass was passed through 22 mesh (#), and the resulting granules were resifted over 44 mesh(#) to separate granules and fines. The granules were lubricated by adding talc extra granularly and compressed into a tablet using 10 mm standard flat-face punches on 6 station tabletting machine.


 

 

Table 1: Composition of Nicorandil floating tablets using different amounts of AG and CSA

Ingredients

Quantity per tablet (mg)

MCS

1

MCS

2

MCS

3

MCS

4

MCS

5

MCS

6

MCS

7

MCS

8

MCS

9

MCS

10

MCS

11

MCS

12

NCRD

21

21

21

21

21

21

21

21

21

21

21

21

AG

100

90

80

70

60

50

70

70

70

80

90

100

CSA

50

60

70

80

90

100

90

100

110

80

80

80

NaHCO3

30

30

30

30

30

30

30

30

30

30

30

30

CA

10

10

10

10

10

10

10

10

10

10

10

10

SA

5

5

5

5

5

5

5

5

5

5

5

5

Lactose

78

78

78

78

78

78

68

58

48

68

58

48

Talc

6

6

6

6

6

6

6

6

6

6

6

6

NCRD = Nicorandil, AG = Almond gum, CSA = Cetosteryl alcohol, NaHCO3 = Sodium bicarbonate, CA = Citric acid, SA = Stearic acid

 

 

In vitro release studies:[7]

In vitro drug release studies of all prepared floating matrix tablets were conducted for a period of 24 hrs using an eight station USP XXII type 2 (paddle type) apparatus. The dissolution medium consisted of 0.1N HCl (900 ml), equilibrate the dissolution medium to 37 ± 0.5°C, and rotating the paddle at 50 rpm. At specified time interval, samples of 5 ml of specimen and replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution medium at 37°C to maintain sink condition and to maintain the volume constant. After filtration and appropriate dilution (if necessary), the absorbance of sample preparations was measured in 1cm cell on UV spectrophotometer at 272 nm using 0.1N hydrochloric acid as blank. Triplicate runs were carried out and the results were averaged.

 

MATHEMATICAL ANALYSIS OF THE DRUG TRANSPORT MECHANISM:

Calculation of drug release mechanism by Korsmeyer-Peppas equation:[8,9]

The dissolution data was fitted to semi-empirical equation Korsmeyer-Peppas model to the first 60% of drug release (Mt/M∞ ≤ 0.6; log(Mt/M∞) ≤ -0.22).

 

 

Where, Mt = absolute cumulative amount of drug released at time t, M∞ = absolute cumulative amount of drug release after infinite time, Mt /M∞ = fraction of drug released at time t, kKP = release rate constant at the elapsed time t (time-n), and n = time  exponent or diffusional exponent characteristic of the release mechanism of the system. According to Korsmeyer-Peppas equation, mechanism of drug release from various swellable controlled release systems, a value of diffusional exponent (n) may be distinguished in several classes based on solvent diffusion rate (Rdiff) and polymer chain relaxation rate (Rrelax). For a planar geometry, the value of n = 0.45 indicated Case-I diffusion (Fickian diffusion controlled drug release) in which the rate of solvent penetration was much smaller than the rate of polymer chain relaxation and the system controlled by diffusion (Rdiff << Rrelax). If the value of n lies in a range of 0.45 to 0.89 ( i.e. 0.45 < n < 0.89) indicates anomalous (non- Fickian) diffusion mechanism where the diffusion and relaxation rates were comparable to each other (Rdiff ≈ Rrelax). Otherwise, the value of n = 0.89 indicated Case-II transport/ zero order (swelling controlled drug release) which describes the diffusion process was much faster than the relaxation process and the system controlled by relaxation (Rdiff >> Rrelax,). Occasionally, the values of n > 0.89 have been observed, describes super Case-II transport of drug release mechanism and indicated that the drug release by both diffusion (Rdiff) and relaxation of polymer chain (Rrelax). Sometimes, the solvent diffusion rate was much below the polymer chain relaxation rate, where the n value can be observed below 0.5. This situation was also classified as Fickian diffusion, specially called as ‘Less Fickian’ behaviour.

 

Calculation of drug release contribution by peppas-sahlin equation:[10]

Calculation of the approximate contribution and coupled effect of the Fickian diffusion and polymer relaxation mechanism to an anomalous release process based on logic concepts was carried out by fitting the data to the heuristic approach proposed by Peppas and Sahlin (1989) for quantify and materialize the amount of drug released by the two phenomena controlling the drug release from swellable matrix.

 

 

Where, k1 =  kinetic constant for Fickian contribution of drug release, k2 = kinetic constant for Case-II contribution and m = diffusional exponent. The first term of right hand-side was Fickian contribution and the second term being the Case-II relaxational contribution i.e. this equation accounts for the coupled effects of Fickian diffusion and Case- II transport.

 

The percentage of drug release due to Fickian mechanism (F) was calculated by,

 

 

Ratio of relaxational over Fickian contribution calculated by,

 

 

Calculation of kinetic constants using substitution method:

In order to determine the kinetic constants in Peppas-Sahlin model (k1 and k2), at first diffusional exponent (m) value has to be fixed. According to the literature[10] with comparison of Korsmeyer-Peppas and Peppas-Sahlin equations, it was concluded that m = n when the relaxational mechanism was negligible. Based on this assumption m value was fixed which was equivalent to n value from Korsmeyer-Peppas equation. After that the kinetic constants (k1 and k2) has to be determined. There were several methods available to calculate the constants from a system of linear or nonlinear equations namely graphical method, elimination method, substitution method and matrix method. Systems of two equations in two variables could be solved graphically since their solutions were the points at which the graphs of the equations intersect.  However, the graphical method tends to give inaccurate results.  Therefore, graphing was not an acceptable solution method.  Another method was elimination method which involved to remove the variables until only a single last variable was left, i.e. until there was one equation with one unknown. This equation was then solved for this unknown there by the other unknown can also be deduced. But this method was practically difficult. Instead, It was possible to calculate the kinetic constants using substitution method and matrix method. In this work substitution method was used in order to describe the predominant drug release mechanism.

 

The kinetic constants of the systems of two equations in two variables can be calculate using substitution method or addition method. The substitution method works extremely well for finding solutions of systems containing at least one non-linear equation.  The addition method was often used for linear systems, but cannot always be used for systems containing non-linear equations. In order to calculate the constants from Peppas-Sahlin equation, it was essential to use the fraction of drug release say f1 and f2 at two measured time points say t1 and t2. The fraction of drug released (f1) at t1 can be written as the following:

 

 

And the fraction of drug released (f2) at t2 can be written as the following:

 

Rearrangement of Eq.(5) to calculate k1 as follows,

 

Substitution of k1 value in Eq.(5) or Eq.(6) to get the value of k2 as follows,

 

 

Substitution of f1 and f2 values in Eq.(7) and Eq.(8) at different time intervals one can get the values of k1 and k2, thereby it was possible to calculate the Fickian and relaxational contribution.

 

RESULTS AND DISCUSSION:

Drug release profile of all the batches were extended up to 24 hrs by the use of combination of hydrophilic and hydrophobic polymers but showed a variation in drug release along with AG and CSA concentration (Figure 1A and 1B).  Based on the drug release profile it can be observed that, as the concentration of hydrophobic wax polymer was increased, greater retardation of both rate and extent of drug release was observed. The fact can be reasoned in the way that, an increase in the hydrophobic polymer content results in decrease the drug release rate due to  decrease in the total porosity (initial porosity plus porosity due to the dissolution of the drug) of the matrices. Also increases the tortuosity of the matrix along with drug diffusion path-length which in turn slows down diffusion and erosion from/of the matrix. These behaviour can be explained in terms of release mechanism suggested that, because of the high hydrophobicity of lipid materials, penetration of dissolution fluid was hindered through the matrix and can progress in the dosage form by dissolving the grains of drug in contact with polymer and leading to diminished drug release over an extended period. Further, the dissolution of the drug particles on the surface of the matrix allows the formation of channels, from which the drug was slowly released followed by formation of a denser gel and slower erosion.

 

For Korsmeyer-Peppas model of all the formulations, square of correlation coefficient (R2), adjusted R2, k and n- values calculated by Microsoft Excel-2007 showed ranged from 0.9720 to 0.9975, 0.9680 to 0.9971, 3.2774 to 5.1041 and 0.8720 to 0.9989, respectively. The highest values of R2 and adjusted R2 were indicates that the drug release data was good linearity with Korsmeyer-Peppas equation. The drug release mechanism from tablet matrices containing swellable polymers was complex and not completely understood. Some polymeric systems may be classified as either purely diffusion or erosion controlled, while most of the systems exhibits a combination of these systems. All the formulations showed good linearity with slope (n) values greater than 0.89, except for MCS4 (n=0.87). This indicated that, all the formulations followed super Case-II transport of drug release mechanism, in which the formulation MCS4 exploited by non-Fickian or anomalous release mechanism. The formulations which showed the n value >0.89 indicated that the drug release by both diffusion (Rdiff) and relaxation of polymer chain (Rrelax) and revealed the fact that, possibly owing to chain distanglement and swelling of hydrophilic polymer. Whereas the formulation MCS4 showed the n value of 0.87, indicated Case-II transport/ zero order (swelling controlled drug release) which describes the solvent diffusion process was much faster than the polymer chain relaxation process and the system controlled (rate controlling step) by relaxation (Rdiff » Rrelax).

 

 

 

 

Figure 1A and 1B: In vitro release profiles of Nicorandil floating tablets

According to the literature[11], Case-II transport (zero order) of swellable cylinder was defined by n = 0.89±0.02 (i.e. ranged from 0.87 to 0.91). From the above statement, the drug release mechanism for the formulation MCS4 (n = 0.87) also critically appears to indicate a coupling of diffusion and erosion mechanisms -so called Case-II transport which lie either in or very close to the theoretical value. Analogously, Case-II (relaxational) transport mechanism was associated with initial linear time dependence of the fractional release from all geometries and followed zero order release from dosage form in which the release was independent of time regardless of the geometry and the drug transport mechanism associated with stress and state-transition in hydrophilic glassy polymers which swell in water or biological fluids. This transport mechanism indicating combined effect of chain disentanglement, erosion and swelling of hydrophilic polymer for drug release. Case-II transport/ zero order (swelling controlled drug release) also describes the diffusion process was much faster than the relaxation process and the system controlled by relaxation (Rdiff » Rrelax). From the aforementioned possible phenomena it was obvious that the drug release patterns of both anomalous diffusion and Case-II transport were associated for drug release from the formulation MCS4. These two release mechanisms were demonstrated to be valid due to the good agreement between experimental data and the equation. The value of 'n' from MCS4 were the characteristic of anomalous kinetics (non-Fickian) and Case-II transport, suggesting that more than one mechanism may be involved in release kinetics, referring to combination of polymer relaxation, swelling, diffusion or erosion based drug release mechanism[12]. In case of formulation MCS4, immediate synchronization of the movement of swelling and erosion (constant gel layer thickness) was observed. It was very interesting to observed that the release profiles was not only linear, but also that the linear part of the curve showed the identical slope at different time intervals.

 

               In order to determine the predominant mechanism among drug diffusion and polymer relaxation, the drug release profile of all the formulation were fitted to Peppas-Sahlin equation using the concept[10] of m = n, where n was obtained from Korsmeyer-Peppas equations. Here substitution method was used to calculated k1 and k2. Accordingly, Peppas-Sahlin model constants (k1 and k2) were calculated followed by respective contribution of release mechanisms (diffusion/ relaxation model) was also calculated by incorporating in respective equation. An Excel (Microsoft Corporation, Redmond, WA,USA) worksheet was used to calculate all the data in which the nonlinear data were first transformed to create a linear relationship and then were analysed with linear regression. The higher value of k1 than k2, indicates that Fickian diffusion was predominant mechanism of drug release from the matrices than polymer relaxation and swelling in such matrix. Otherwise, when the values of k2 was found to be higher than k1 indicates some level of polymer relaxation and swelling in such matrix and supports its tendency to release drug by Non-Fickian kinetics. The extreme negative values of  k1 indicates that there was an insignificant effect of Fickian diffusion mechanism in the drug release process but it was only a pure polymer chain relaxation predominant mechanism. In general, for water soluble drugs diffusional mechanism was predominant than polymer relaxation.

              

               Substitution method of a system for linear or nonlinear equations involves expressing one variable in terms of another until there was a single equation in one unknown and this equation was used to solve second unknown. According to the equations (1) and (2), it was possible to calculate the k1 and k2 at all time intervals and further used to calculate the release mechanism contributions and related parameters. Several parameters (Table 2A, 2B and 2C) were calculated using substitution method by Microsoft Office Excel like fraction of drug release with time in hr (f), kinetic constant for Fickian contribution of drug release (k1), kinetic constant for Case-II contribution (k2), Fickian contribution (F),  Case-II relaxational contribution (R), ratio of relaxational over Fickian contribution (R/F) and  percentage fraction of drug release due to Fickian mechanism (%f(F)). From the Table 2A, 2B and 2C, it was observed that, diffusional kinetic constant (k1) was far greater than relaxational kinetic constant (k2) with all the formulations except for formulation MCS5 only at 5th hour. The average values of kinetic constants (k1, k2) were found to be (0.0334, -0.0011), (0.0383, -0.0009), (0.0436, -0.0017), (0.0539,  -0.0006), (0.0479, -0.000033) and (0.0376, -0.0007) for MCS1, MCS2, MCS3, MCS4, MCS5 and MCS6, respectively. Whereas the average values of (k1, k2) were found to be (0.0453, -0.0003), (0.0407, 0.0004), (0.0317, -0.001), (0.0496, 0.0003), (0.0465, 0.0005) and (0.0332, -0.0009) for MCS7, MCS8, MCS9, MCS10, MCS11 and MCS12, respectively.  The average values of release contribution (Fickian release contribution, Case-II relaxational contribution) were found to be (0.19, 0.053), (0.2098, 0.0532), (0.2199, 0.008), (0.2787, 0.016), (0.3067, -0.0105) and (0.2228, 0.0264)  for MCS1, MCS2, MCS3, MCS4, MCS5 and MCS6, respectively. Whereas the average values of release contribution (Fickian release contribution, Case-II relaxational contribution) were found to be (0.2728, 0.0118), (0.2493, 0.0223), (0.1952, 0.0388), (0.2798, -0.0065), (0.2927, 0.0071) and (0.2086, 0.0397) for MCS7, MCS8, MCS9, MCS10, MCS11 and MCS12, respectively.


 

              

Table 2A: Calculation of drug release by diffusion, relaxational contribution with time and related parameters from Peppas-Sahlin equation

 

 

 

 

 

MCS1

 

Time (hr)

f

k1 (hr-0.87)

k2 (hr-1.74)

F

R

R/F

% f (F)

0

0

-

-

-

-

-

-

1

0.0479

0

0

-

-

-

-

2

0.0685

0.0612

-0.0133

0.1186

-0.0501

-0.4221

173.0494

3

0.0909

0.0428

-0.0038

0.1222

-0.0313

-0.2563

134.4647

4

0.1187

0.0326

-0.0003

0.1223

-0.0036

-0.0298

103.0686

5

0.1546

0.0246

0.0019

0.1142

0.0404

0.3540

73.8561

6

0.2044

0.0139

0.0042

0.0768

0.1275

1.6603

37.5904

9

0.3055

0.0358

0.0002

0.2911

0.0144

0.0494

95.2896

12

0.4326

0.0285

0.0011

0.3055

0.1271

0.4162

70.6137

15

0.5746

0.0279

0.0012

0.3692

0.2054

0.5563

64.2567

     Average

0.0334

-0.0011

0.1900

0.0537

0.2910

94.0236

 

 

 

 

 

MCS2

0

0

-

-

-

-

-

-

1

0.0512

0

0

-

-

-

-

2

0.0787

0.0621

-0.0110

0.1187

-0.0401

-0.3374

150.9319

3

0.1021

0.0511

-0.0052

0.1425

-0.0404

-0.2833

139.5356

4

0.1379

0.0328

0.0013

0.1199

0.0179

0.1494

87.0025

5

0.1769

0.0310

0.0019

0.1393

0.0376

0.2698

78.7523

6

0.2215

0.0275

0.0026

0.1467

0.0748

0.5097

66.2400

9

0.3266

0.0406

0.0002

0.3166

0.0099

0.0314

96.9538

12

0.4537

0.0335

0.0011

0.3417

0.1120

0.3277

75.3171

15

0.6066

0.0281

0.0016

0.3530

0.2535

0.7182

58.1996

      Average

0.0383

-0.0009

0.2098

0.0532

0.1732

94.1248

 

 

 

 

 

MCS3

0

0

-

-

-

-

-

-

1

0.0536

0

0

-

-

-

-

2

0.0827

0.0656

-0.0118

0.1275

-0.0447

-0.3509

154.0616

3

0.1114

0.0507

-0.0041

0.1455

-0.0340

-0.2340

130.5557

4

0.1547

0.0318

0.0024

0.1203

0.0344

0.2856

77.7867

5

0.1954

0.0372

0.0010

0.1741

0.0213

0.1224

89.0980

6

0.2316

0.0429

-0.0002

0.2393

-0.0078

-0.0324

103.3537

9

0.3474

0.0399

0.0003

0.3282

0.0192

0.0586

94.4653

12

0.4727

0.0373

0.0006

0.4045

0.0682

0.1687

85.5685

     Average

0.0436

-0.0017

0.2199

0.0081

0.0025

104.9835

 

 

 

 

 

MCS4

0

0

-

-

-

-

-

-

1

0.0581

0

0

-

-

-

-

2

0.0972

0.0641

-0.0060

0.1172

-0.0200

-0.1705

120.5502

3

0.1399

0.0517

0.0008

0.1344

0.0055

0.0407

96.0936

4

0.1782

0.0554

-0.0006

0.1849

-0.0067

-0.0364

103.7733

5

0.2161

0.0537

-0.0001

0.2177

-0.0015

-0.0071

100.7166

6

0.2502

0.0570

-0.0009

0.2711

-0.0209

-0.0769

108.3360

9

0.3602

0.0512

0.0003

0.3463

0.0139

0.0401

96.1464

12

0.4962

0.0396

0.0020

0.3444

0.1518

0.4408

69.4082

15

0.6002

0.0582

-0.0001

0.6135

-0.0134

-0.0218

102.2266

              Average

0.0539

-0.0006

0.2787

0.0136

0.0261

99.6619

 

 

 

Table 2B: Calculation of drug release by diffusion, relaxational contribution with time and related parameters from Peppas-Sahlin equation

 

 

 

 

 

 

MCS5

Time (hr)

f

k1 (hr-0.87)

k2 (hr-1.74)

F

R

R/F

% f (F)

0

0

-

-

-

-

-

-

1

0.0522

0

0

-

-

-

-

2

0.0818

0.0624

-0.0102

0.1190

-0.0372

-0.3125

145.4609

3

0.1379

0.0284

0.0076

0.0792

0.0587

0.7411

57.4343

4

0.1839

0.0464

0.0011

0.1690

0.0148

0.0878

91.9325

5

0.2038

0.0722

-0.0060

0.3240

-0.1202

-0.3710

158.9729

6

0.2863

0.0001

0.0101

0.0004

0.2859

747.5705

0.1336

9

0.3773

0.0652

-0.0021

0.5059

-0.1286

-0.2542

134.0796

12

0.5128

0.0424

0.0008

0.4307

0.0820

0.1905

83.9983

15

0.5864

0.0661

-0.0015

0.8257

-0.2393

-0.2898

140.7997

Average

0.0479

-0.000033

0.3067

-0.0105

93.4203

101.6039

 

 

 

 

 

MCS6

0

0

-

-

-

-

-

-

1

0.0453

0

0

-

-

-

-

2

0.0694

0.0553

-0.0100

0.1067

-0.0374

-0.3500

153.8505

3

0.1028

0.0353

0.0003

0.1002

0.0026

0.0258

97.4873

4

0.1363

0.0351

0.0004

0.1309

0.0053

0.0408

96.0830

5

0.1853

0.0210

0.0042

0.0968

0.0885

0.9140

52.2479

6

0.2086

0.0516

-0.0025

0.2825

-0.0739

-0.2617

135.4393

9

0.3252

0.0331

0.0009

0.2664

0.0588

0.2208

81.9143

12

0.4128

0.0448

-0.0005

0.4738

-0.0611

-0.1289

114.7926

15

0.5537

0.0249

0.0013

0.3252

0.2285

0.7027

58.7301

Average

0.0376

-0.0007

0.2228

0.0264

0.1454

98.8240

 

 

 

 

 

MCS7

0

0

-

-

-

-

-

-

1

0.0543

0

0

-

-

-

-

2

0.0865

0.0640

-0.0096

0.1208

-0.0343

-0.2842

139.7054

3

0.1157

0.0536

-0.0042

0.1470

-0.0313

-0.2129

127.0479

4

0.1566

0.0367

0.0020

0.1311

0.0255

0.1944

83.7220

5

0.2087

0.0273

0.0046

0.1197

0.0890

0.7434

57.3597

6

0.2744

0.0183

0.0067

0.0950

0.1793

1.8874

34.6330

9

0.3653

0.0627

-0.0019

0.4707

-0.1055

-0.2240

128.8703

12

0.4866

0.0449

0.0005

0.4395

0.0470

0.1070

90.3355

15

0.5833

0.0548

-0.0005

0.6584

-0.0751

-0.1141

112.8764

Average

0.0453

-0.0003

0.2728

0.0118

0.2621

96.8232

 

 

 

 

 

 

MCS8

0

0

-

-

-

-

-

-

1

0.0486

0

0

-

-

-

-

2

0.0797

0.0573

-0.0075

0.1094

-0.0273

-0.2495

133.2438

3

0.1237

0.0350

0.0030

0.0975

0.0230

0.2361

80.8987

4

0.1427

0.0652

-0.0060

0.2377

-0.0805

-0.3385

151.1765

5

0.2286

-0.0239

0.0137

-0.1075

0.2771

-2.5785

-63.3514

6

0.2852

0.0329

0.0031

0.1753

0.0887

0.5060

66.4001

9

0.3525

0.0789

-0.0033

0.6131

-0.2002

-0.3266

148.4997

12

0.4331

0.0580

-0.0011

0.5902

-0.1166

-0.1976

124.6189

15

0.5747

0.0223

0.0014

0.2789

0.2138

0.7666

56.6072

Average

0.0407

0.0004

0.2493

0.0223

-0.2727

87.2624

 

 

 

 

Table 2C: Calculation of drug release by diffusion, relaxational contribution with time and related parameters from Peppas-Sahlin equation

 

 

 

 

 

 

MCS9

Time (hr)

f

k1 (hr-0.87)

k2 (hr-1.74)

FC

RC

R/F

% f (F)

0

0

-

-

-

-

-

-

1

0.0399

0

0

-

-

-

-

2

0.0612

0.0491

-0.0093

0.0980

-0.0368

-0.3759

160.2366

3

0.0898

0.0319

-0.0006

0.0953

-0.0055

-0.0581

106.1725

4

0.1265

0.0248

0.0018

0.0985

0.0280

0.2842

77.8724

5

0.1426

0.0443

-0.0031

0.2201

-0.0775

-0.3522

154.3692

6

0.1690

0.0304

-0.0003

0.1811

-0.0122

-0.0672

107.2036

9

0.3346

0.0100

0.0031

0.0892

0.2454

2.7510

26.6598

12

0.3854

0.0528

-0.0017

0.6274

-0.2421

-0.3858

162.8137

15

0.5633

0.0103

0.0019

0.1523

0.4110

2.6992

27.0332

Average

0.0317

-0.0010

0.1952

0.0388

0.5619

102.8015

 

 

 

 

 

MCS10

 

 

0

0

-

-

-

-

-

-

1

0.0565

0

0

-

-

-

-

2

0.0922

0.0657

-0.0091

0.1256

-0.0335

-0.2664

136.3140

3

0.1237

0.0567

-0.0045

0.1585

-0.0348

-0.2195

128.1158

4

0.1748

0.0328

0.0041

0.1199

0.0549

0.4578

68.5952

5

0.2717

-0.0060

0.0147

-0.0268

0.2985

-11.1230

-9.8785

6

0.3325

0.0499

0.0023

0.2667

0.0658

0.2465

80.2229

9

0.4153

0.0818

-0.0037

0.6388

-0.2236

-0.3500

153.8390

12

0.5027

0.0661

-0.0017

0.6756

-0.1729

-0.2559

134.3909

Average

0.0496

0.0003

0.2798

-0.0065

-1.6443

98.8021

 

 

 

 

 

MCS11

 

 

0

0

-

-

-

-

-

-

1

0.0512

0

0

-

-

-

-

2

0.0843

0.0590

-0.0078

0.1128

-0.0285

-0.2527

133.8124

3

0.1353

0.0346

0.0049

0.0967

0.0385

0.3983

71.5137

4

0.1658

0.0584

-0.0036

0.2136

-0.0478

-0.2240

128.8640

5

0.2535

-0.0018

0.0129

-0.0081

0.2616

-32.2683

-3.1981

6

0.3056

0.0513

0.0011

0.2741

0.0315

0.1149

89.6981

9

0.3762

0.0767

-0.0037

0.5989

-0.2226

-0.3717

159.1696

12

0.4742

0.0540

-0.0007

0.5515

-0.0773

-0.1402

116.3084

15

0.6033

0.0399

0.0006

0.5021

0.1011

0.2014

83.2393

Average

0.0465

0.0005

0.2927

0.0071

-4.0678

98.0143

 

 

 

 

 

 

MCS12

0

0

-

-

-

-

-

-

1

0.0416

0

0

-

-

-

-

2

0.0647

0.0508

-0.0092

0.1015

-0.0368

-0.3626

156.8932

3

0.0963

0.0329

-0.0003

0.0986

-0.0023

-0.0231

102.3599

4

0.1338

0.0281

0.0014

0.1121

0.0217

0.1936

83.7834

5

0.1574

0.0413

-0.0020

0.2061

-0.0487

-0.2364

130.9575

6

0.1877

0.0325

-0.0002

0.1948

-0.0072

-0.0368

103.8218

9

0.3266

0.0213

0.0017

0.1908

0.1358

0.7115

58.4274

12

0.4283

0.0381

-0.0002

0.4565

-0.0282

-0.0619

106.5933

15

0.5917

0.0206

0.0013

0.3087

0.2830

0.9168

52.1704

Average

0.0332

-0.0009

0.2086

0.0397

0.1376

99.3859

 

              


From these values, for all the formulations it can be noticed that Peppas-Sahlin model showed higher values for the diffusional constant with respect to the relaxation constant, meaning that the principal mechanism for the drug release was Fickian diffusion than relaxation or erosion of the polymer chains. The dominant release mechanism was further confirmed by calculating their respective release mechanism contributions. Fickian release contribution was preponderance than corresponding Case-II relaxational contribution in all the formulations since the value of  diffusional contribution was much higher than the relaxational contribution. In addition to this, the relaxational contribution was observed with negative sign in all the formulations only at specific time intervals. The situation where the negative values were observed at particular time interval indicates the Fickian release mechanism was more pronounced than relaxation i.e. almost the relaxational mechanism was absent. The above statement was further confirmed by calculating the ratios of relaxation to diffusional contributions (R/F) value, in which R/F >1 indicates that  relaxational contribution was predominant than  diffusional contribution and vice versa.

 

Regarding drug release mechanism, the results obtained by Korsmeyer-Peppas model was in agreement with that obtained from the application of Peppas-Sahlin equation at fixed m value at 0.87. The release mechanism for all the formulations except for MCS4 obtained from Korsmeyer-Peppas model reveals to follow super Case-II transport mechanism in which the drug release was facilitated by both diffusion (Rdiff) and relaxation of polymer chain (Rrelax). And the drug release mechanism from Peppas-Sahlin model revealed that the drug release mechanism was facilitated by contribution of both Fickian diffusion and polymer chain relaxation.

 

CONCLUSION:

Controlled drug release attained in present study indicates that the floating matrix tablets of Nicorandil, prepared by combination of AG and CSA as retarding polymers, can successfully be employed as a once-a-day oral controlled release drug delivery system. The drug release profile of all the formulations were fitted to well known Korsmeyer-Pappas equation. The diffusional exponent of all the formulations revealed to follow super Case-II transportation except MCS4 which showed to follow non-Fickian drug release mechanism. In order to determine the exact release mechanism with respect to time, the release data was further fitted to the heuristic model proposed by Peppas-Sahlin equation. From the study it was revealed that, Fickian release was more prevalence than relaxation mechanism. At particular time interval the relaxational contribution mechanism was presented with negative value, which indicates that the relaxation was insignificant.

 

ACKNOWLEDGMENT:

The authors wish to thank Torrent Pharmaceuticals (P) Ltd., Gujarat, for the supply of Nicorandil as gift sample. The authors also like to thank management of SSPC, for providing facilities used in the research.

 

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Received on 21.07.2016   Accepted on 27.10.2016             

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2016; 6(4): 223-230.

DOI: 10.5958/2231-5713.2016.00033.7