Int J Pharm Pharm Sci, Vol 7, Issue 4, 369-375Original Article
DEVELOPMENT OF HYDROPHILIC MATRIX TABLET OF CARBAMAZEPINE USING 33 FULL FACTORIAL EXPERIMENTAL DESIGNS
SHASHIKANT BARHATE1, MARIA HUSAIN2
1Department of Pharmaceutics, Shri Suresh Dada Jain Institute of Pharmaceutical Education and Research, Jamner, Maharashtra, 2Department of Pharmaceutics, Dr. Rafiq Zakaria Campus, Y. B. Chavan College of Pharmacy, Aurangabad, Maharashtra.
Email: saifeemaria@gmail.com
Received: 06 Feb 2015 Revised and Accepted: 20 Feb 2015
ABSTRACT
Objective: The study aims at developing the hydrophilic matrix tablet of carbamazepine (CBZ) using an optimization technique. The purpose of the study was to develop the hydrophilic matrix dosage form using the combination of different viscosity grades of hydroxypropyl methylcellulose (HPMC) to get the release within the desired target dissolution profile (TDP).
Methods: A full factorial design was employed to develop once a day matrix tablet using hydrophilic matrix polymers like HPMC K4M (X1), HPMC K15M (X2) and HPMC K100M (X3) as independent variables and the percent drug release at 1h (Y1), 8h (Y2) and 20h (Y3) was considered as dependent variables. The optimization and the design space were obtained using response surface methodology and multiple response optimization using the polynomial equation.
Results: The result indicates that concentration of all the three polymers plays an important role in the release of the drug for 24h. The formulated tablets have good physical properties and the optimized formulation prepared using design space showed the release within the target dissolution profile and followed zero order release pattern.
Conclusion: The results demonstrated that design of an experiment can be used to develop hydrophilic matrix dosage form with the desired drug release properties.
Keywords: Design of experiment, Hydroxypropyl methycellulose, Full factorial design, Design space, Targeted dissolution profile.
INTRODUCTION
Hydrophilic matrices are simple to formulate, easy to produce, in expensive and have valid invitro-invivo correlation beside that it has good regulatory acceptability [1]. HPMC is one of the most frequently used hydrophilic polymer for matrix dosage form because of its approval as an excipient by Food and Drug administration of United States [2-4]. It is a water-soluble polymer and study have shown that the drug release from the HPMC matrices occurs either by diffusion through the gel layer or through surface erosion of this gel layer [3, 5, 6]. Matrix dosage forms prepared using HPMC generally show pH-independent release profiles when the drug solubility is pH independent but may produce pH-dependent release profiles for drugs having pH dependent solubility [7-9]. CBZ a dibenzapine derivative with a structure resembling the tricyclic antidepressants [10], is an effective anti-epileptic drug and specific analgesic for trigeminal neuralgia. It is poorly water soluble drug belonging to BCS class II [11, 12] and its absorption is dissolution rate-limited. As CBZ shows the narrow therapeutic window and diurnal variations in plasma concentration, the conventional tablets needs to be administered 3-4 times a day [13]. Thus preparing sustained release matrix helps in reducing side effects and improving patient compliance [14]. Several studies have been done to prepare CBZ extended release tablets by using different techniques viz. using a combination of eudragit RS PO and RL PO [13], HPMC K4M [15], ethyl cellulose [16] and compritol 888ATO and HPMC K15M [17]. The purpose of the study was to examine the effect of combination of different viscosity grades of HPMC namely K4M, K15M and K100M on the release of CBZ from the hydrophilic matrices and to obtain a design space for formulation wherein the drug release from the hydrophilic matrix will always be within Targetted Dissolution Profile (TDP). To achieve this aim the design of experiment (DOE) was used. A full factorial design was proposed for the development of hydrophilic matrix tablet based on the combination of three polymers. The independent variables include the percentage amount of HPMC K4M (X1). HPMC K15M (X2) and HPMC K100M. The dependent variables were selected as percent release of drug at 1h (Y1), percent release of drug at 8h (Y2) and percent drug release at 20h (Y3). These responses were selected with the view that release at 1h is indicative whether dose dumping will occur from the formulation or not. The release of the drug at 8h from the matrix tablets indicates whether the drug release could be sustained until 12 h or 24h and release of the drug from the matrix tablets at 20h is indicative of the complete release of the drug from the dosage form. All the response variables were fitted to linear, cubic and quadratic model and regression analysis were carried out to get a quantitative relationship between dependent and independent variables.
MATERIALS AND METHODS
Materials
CBZ (MW= 236.269 g/mol) was purchased from EMCO Industries Hyderabad Ltd. HPMC (K4M. K15M and K100M) were received as gift samples from Dow Chemicals, India. Microcrystalline cellulose (Avicel PH 102) was obtained from FMC. Magnesium stearate was procured from Ferro USA. Colloidal silicon dioxide (Aerosil 200 Pharma) was received as gift sample from Evonik Technical Centre India. All other reagents used for analysis were of analytical grade and procured from Merck India. Purified water IP was used wherever indicated.
Table 1: Variables in 33 Factorial design
Independent variable |
Level |
||
Low |
Medium |
High |
|
X1 Percentage of HPMC K4M |
10 |
12.5 |
15 |
X2 Percentage of K15M |
10 |
12.5 |
15 |
X3 Percentage of K100M |
10 |
12.5 |
15 |
Transformed Value |
-1 |
0 |
+1 |
Preparation of matrix tablets
33Full factorial design was employed to study the effect of combination of HPMC (K4M, K15M and K100M) polymer on the release of the CBZ from the matrix tablet. Higher and lower levels of each factor were coded as+1 and −1 respectively, and the mean value as 0. The selected factor levels are summarized in table 1.
Twenty seven batches (F1 to F27) were prepared as per full factorial design for optimization of HPMC (K4M, K15M and K100M) concentrations to obtain the drug release profile similar to targeted dissolution profile (TDP). Compositions of the factorial batches are shown in table 2. For each batch, tablets of 500 mg were prepared using direct compression method. In brief, the manufacturing process can be described as previously weighed CBZ was mixed with the weighed quantity of HPMC (HPMC K4M, K15M and K100M) and passed through 30# sieve. This mixture was mixed with Avicel PH102 formerly passed through 30# and finally the whole blend was mixed with aerosil and magnesium stearate earlier passed through 60 #. The mixed blend was directly compressed on 12.5 mm circular biconvex die/punch set using Rimex Mini Press rotary compression machine. The compression force was set in such a way that all formulations were having the hardness of 4 to 6 kg/cm2.
Table 2: Composition of hydrophilic matrix tablet of CBZ
| Formulations | HPMC K4M | HPMC K15M | HPMC K100M | Avicel PH 102 |
| F1 | 75 | 75 | 75 | 155 |
| F2 | 75 | 75 | 62.5 | 177.5 |
| F3 | 75 | 75 | 50 | 190 |
| F4 | 75 | 62.5 | 75 | 177.5 |
| F5 | 75 | 62.5 | 50 | 202.5 |
| F6 | 75 | 62.5 | 50 | 190 |
| F7 | 75 | 50 | 75 | 190 |
| F8 | 75 | 50 | 62.5 | 202.5 |
| F9 | 75 | 50 | 50 | 215 |
| F10 | 62.5 | 75 | 75 | 177.5 |
| F11 | 62.5 | 75 | 62.5 | 190 |
| F12 | 62.5 | 75 | 50 | 202.5 |
| F13 | 62.5 | 62.5 | 75 | 190 |
| F14 | 62.5 | 62.5 | 62.5 | 202.5 |
| F15 | 62.5 | 62.5 | 50 | 215 |
| F16 | 62.5 | 50 | 75 | 202.5 |
| F17 | 62.5 | 50 | 62.5 | 215 |
| F18 | 62.5 | 50 | 50 | 227.5 |
| F19 | 50 | 75 | 75 | 190 |
| F20 | 50 | 75 | 62.5 | 202.5 |
| F21 | 50 | 75 | 50 | 215 |
| F22 | 50 | 62.5 | 75 | 202.5 |
| F23 | 50 | 62.5 | 62.5 | 215 |
| F24 | 50 | 62.5 | 50 | 227.5 |
| F25 | 50 | 50 | 75 | 215 |
| F26 | 50 | 50 | 62.5 | 227.5 |
| F27 | 50 | 50 | 50 | 240 |
Each tablets contained 100 mg of CBZ and proper amount of magnesium stearate and talc.
In vitro release of CBZ from prepared hydrophilic matrix tablets
The in vitro drug release from CBZ matrix tablets was evaluated using USP type I dissolution test apparatus. The dissolution test was carried out for a total period of 24 hours. The dissolution medium comprised of 900 ml of distilled water maintained at 37o±0.5 °C. The dissolution test was carried out at 100 revolutions per minute. Aliquot samples (10 ml) were withdrawn and replaced by fresh medium to maintain constant volume at 1,2,4,8, 12 and 20 h. The samples were filtered and analyzed at 285.5 nm by UV Spectrophotometer. The drug concentration was calculated using the standard calibration curve. The percent drug releases were compared to the target dissolution profile (TDP). The values of the TDP were based on an average dissolution rate of 4% to 6.5 % per hour in order to achieve a 24h in-vitro release profile.
Drug release kinetic studies
The drug release mechanism from CBZ hyrdrophilic matrix tablets was determined using zero order (Eq. 1) [18], First order (Eq2), Korsmeyer Peppas (Eq. 3) [19], and Higuchi release models (Eq. 40) [20].
Mt = M0 + k0t Eq.1
Mt = amount of drug released at time ‘t’, M0 = amount of drug in the solution at t= 0, k0 = zero-order release constant
lnMt = lnM0 + k1t Eq.2
Where Mt and M0 are described as above and k1 is first order release rate constant.
Where Mt/M∞ = Fraction of drug released at time t, k
Mt = is amount of drug release at time t '√t ', kH = Higuchi release constant.
Data analysis
All responses were fitted to linear, interaction or quadratic models using Design Expert 9.0.3.1 Stat-Ease Minneapollis USA trial version and analyzed statistically using analysis of variance (ANOVA) and those having p-value<0.05 was included in the analysis. The data were also subjected to 3-D response surface methodology to study the interaction of polymers and their effect on dependent variables. Thus from the DOE data the design space was constructed within which the dissolution profile for formulation shall always be within the TDP.
RESULTS AND DISCUSSION
Initially, the preliminary formulation trials were done to evaluate the effect of individual polymer on the release of CBZ from hydrophilic matrix tablets prepared using different viscosity grades of HPMC. Initial studies indicated that to control the percent drug release of CBZ from the matrix tablet, the minimum concentration of HPMC K4M individually required was 30% of the tablet weight and 15% of HPMC K100M was required for controlling the drug release when used alone. However, the drug release was within the TDP only for the formulations containing 45% of HPMC K4M and 30% of HPMC K15M individually. Rest of the formulations failed to meet the TDP. Thus based on these early experiments, the overall level of the three polymers in combination for the DOE experiment was finalized as 30% low, 37.5% middle and 45% of the tablet weight as the highest level. The preliminary study indicated that for each polymer, the level of polymer in DOE study should be+1 =15%, 0= 12.5% and-1 should be equal to 10% of the tablet weight.
The factorial batches prepared using DOE was evaluated for tablet characteristics, and all batches showed uniformity in tablet weight. The weights of matrix tablet for all 27 batches were found to be in between 500±15 mg indicating good uniformity in weight and less variation in the filling of the powder in the die cavity. Thickness for all the factorial batches was found to 7.6±0.39 mm, the hardness of the tablets of all the factroial batches were between 6 to 8 kg/cm2 and the friability all the batches were within the pharmacopoeial limits and have friability less than 0.5 % w/w. The drug contents of each formulation batch were determined using the UV spectroscopic method, and all formulations complies the official requirement of the pharmacopoeia and showed % assay between 97.52 to 98.64%.
In vitro release of CBZ from the hydrophilic matrix tablet
The TDP of the drug release from 24 h matrix tablets based on the average dissolution rate of 4 to 6.5% per hour is shown in table 3.
Table 3: Target dissolution profile for 24h drug release
| Time (h) | TDP low (%) | TDP high (%) |
| 0 | 0 | 0 |
| 1 | 0 | 10 |
| 2 | 5 | 15 |
| 4 | 15 | 35 |
| 8 | 40 | 70 |
| 12 | 65 | 85 |
| 20 | 80 | 100 |
The percent drug releases of factorial batches of hydrophilic matrix tablets of CBZ were compared with the TDP, and it was found that except formulation F15, F24 and F26 none of the formulations showed the percent drug release within the TDP. The graphs of percent drug release of CBZ at various time intervals are shown in fig. 1,2 and 3. The factorial batch F27 containing low levels of the three polymers that is HPMC K4M, K15 M and K100M, showed the faster drug release than the TDP. In this formulation, almost 20.52% of drug got released in 1st hour and more than 95% of the drug got released in the 8 h. This formulation was not able to control the release of the drug for 24 h. The reason for higher drug release from the formulation could be the low levels of hydrophilic polymer, which was not able to form a strong coherent matrix. Moreover, the presence of high amount of microcrystalline cellulose (Avicel PH 102) could be acting as channeling agent by absorbing water to some extent, and allowing faster permeation of the drug from the weak matrices [16].
Rest of all the formulations except F15, F24 and F26 showed a less percent drug release when compared with target dissolution profile. The reason of the slow drug release from the maximum formulations could be because of low solubility of carbamazepine in the dissolution medium [21]. The percent drug release of CBZ was found to be minimum with the formulation F1 containing the highest concentration of the total polymer that is 45% w/w. The reason of slower drug release from the formulation could be that with an increase in concentration and viscosity of HPMC could have led to increase tortuosity or gel strength of polymer. Literature has reported that use of hydrophilic polymer like HPMC is preferred in formulation of CBZ matrix tablets because they inhibit the polymorphic transition of carbamazepine to carbamzepine dihydrate. This result in the more amorphous and less crystalline form of carbamazepine present in the polymeric matrix. The literature indicates that such hydrophilic polymers like HPMC serves as templates or micro substrate for nucleation in the crystallization process. The interaction between the drug and polymer appears to occur by hydrogen bonding. The hydroxyl groups of the polymer apparently attach to the drug at the site of water binding, and thus its transformation to the dihydrate form, is inhibited [22].
Fig. 1: Release of CBZ from factorial batches (F1-F9) (n=3)
Fig. 2: Release of CBZ from factorial batches (F10-F18) (n=3)
Fig. 3: Release of CBZ from factorial batches (F19-F27) (n=3)
Drug release kinetic studies
In this study, different mathematical models like zero order, first order, Higuchi, Hixon Crowell and Korsmeyer Peppas model were applied to understand the dissolution profile of CBZ from the hydrophilic matrix prepared using different viscosity grades of HPMC. The R2 values obtained from different mathematical models were evaluated. According to Korsmeyer Peppas model, CBZ release during 24 h of the test was mainly by anomalous transport. The n value obtained for formulations F1 to F27 was 0.0.453<n<0.85 in which both Fickian diffusion and non-Fickian mechanism occur. Anomalous diffusion of drug release mechanism signifies a coupling of the diffusion and erosion mechanism which indicate that the drug release is controlled by more than one process [23]. During first 2 h of dissolution differences in drug release was observed for formulations F15, F24 and F26, which fitted the targeted dissolution profile. The R2 values obtained for these formulations are listed in table 4. The drug release during first, 2h in all the three formulations was predominantly by diffusion (n values were between 0.362-0.457). During the remaining 22h the drug release was mainly by zero order release. The formulations did not have good fit for first order release mechanism, indicating that the CBZ release from the hydrophilic matrix tablets was not dependent on the drug remaining in the HPMC matrix tablet.
Statistical analysis of the data
All responses were fitted to linear, interaction or quadratic models using Design Expert 9.0.3.1. The regression coefficients for each term to the regression model are summarized in table 5 and table 6, describing the model parameters affecting the response variable's Y1, Y2 and Y3.
Table 4: Mathematical fit for drug release model for CBZ hydrophilic matrix tablets
Formula-tion |
Zero Order |
First order |
Higuchi |
Korsmeyer-peppas |
|||||||||||
|
0-2h |
2-24h |
0-24h |
0-2h |
2-24h |
0-24h |
0-2h |
2-24h |
0-24h |
0-2h |
2-24h |
0-24h |
0-2h |
2-24h |
0-24h |
F15 |
0.9175 |
0.9847 |
0.9898 |
0.9246 |
0.9483 |
0.9525 |
0.9968 |
0.9584 |
0.9254 |
1 |
0.9644 |
0,970 |
0.397 |
0.859 |
0.763 |
F24 |
0.9064 |
0.9805 |
0.9815 |
0.9133 |
0.9372 |
0.9204 |
0.9942 |
0.9468 |
0.8796 |
1 |
0.9318 |
0.911 |
0.362 |
1.013 |
0.803 |
F26 |
0.9349 |
0.9921 |
0.9914 |
0.9410 |
0.9596 |
0.9304 |
0.9995 |
0.9430 |
0.8920 |
1 |
0.9856 |
0.967 |
0.457 |
1.027 |
0.863 |
Fig. 4: Surface response plot showing the effect of X1 and on drug release at 1h
Table 5: Regression coefficient for the response variables
| Y1= 3.97-0.56 X1-0.47X2-0.57X3 |
| Y2 = 33.34-7.68 X1-4.14 X2-5.95X3+5.95 X1X2+4.89 X1X3+6.85 X2X3 |
| Y3= 91.66-9.49X1-4.07X2-8.28X3+2.05X1X2-2.32 X1X3+7.95X2X3-7.14 X12-8.30X22-8.44 X32 |
The release of drug at 1h was affected by the concentrations of X1, X2 and X3 as the concentrations of HPMC K4M, K15M and K100M increased in the matrix tablets the percent drug release decreased as was evident in formulation F1, F2, F3 and F4. They showed the percent release between 3.16 to 4.92% and with the lowest concentration of all the formulations in matrix tablet that is F27 the release was 20.52% at 1h. There was no significant interaction between X1, X2 and X3 polymer, which would influence the drug release at 1h, which was evident from surface response plot shown in fig. 5.
The concentration of HPMC K4M, K15M and K100M has the negative influence on the percent release of drug at 8 h as seen from the equation listed in table 5. The interaction between HPMC K4M, K15M and K100M can be elucidated by using surface response and interaction plots shown in fig. 4. When HPMC K100M was kept constant at mid level and HPMC K4M and K15M was kept to the lowest level the percent drug release was 41.56% but when the concentration of HPMC K4M and K15M was increased to the high level (+1) the percent drug release of CBZ drastically decreased to 25.62% indicating a stronger matrix formation which retarded the release of already poorly soluble drug due to more hindrances for drug diffusion.
Table 6: Model parameters for the studied response variables
| Source | df | SS | MS | F value | p |
| Release at 1h (%) | |||||
| X1 | 1 | 5.62 | 5.62 | 7.55 | 0.0115 |
| X2 | 1 | 4.04 | 4.04 | 5.43 | 0.0290 |
| X3 | 1 | 5.86 | 5.86 | 7.87 | 0.0101 |
| Release at 8h (%) | |||||
| X1 | 1 | 1062.1 | 1062.1 | 11.66 | 0.0027 |
| X2 | 1 | 308.60 | 308.60 | 3.39 | 0.0807 |
| X3 | 1 | 638.08 | 638.08 | 7 | 0.0155 |
| X1X2 | 1 | 424.59 | 424.59 | 4.66 | 0.0432 |
| X1X3 | 1 | 286.95 | 286.95 | 3.15 | 0.0912 |
| X2X3 | 1 | 562.66 | 562.66 | 6.17 | 0.0219 |
| Release at 20h (%) | |||||
| X1 | 1 | 1620.51 | 1620.51 | 6.98 | 0.0003 |
| X2 | 1 | 297.84 | 297.84 | 3.62 | 0.0004 |
| X3 | 1 | 1233.06 | 1233.06 | 14.98 | 0.0742 |
| X1X2 | 1 | 50.51 | 50.51 | 0.61 | 0.4442 |
| X1X3 | 1 | 64.36 | 64.36 | 0.78 | 0.3889 |
| X2X3 | 1 | 64.36 | 64.36 | 0.78 | 0.3889 |
| X12 | 1 | 305.54 | 305.54 | 3.71 | 0.0709 |
| X22 | 1 | 413.12 | 413.12 | 5.02 | 0.0387 |
| X32 | 1 | 427.85 | 427.85 | 5.20 | 0.0358 |
Fig. 5: Surface response plot showing the effect of X1 and X2 on drug release at 8h. and the interaction plots between the three polymers
Fig. 6: Surface Response Plot showing the effect of X1 and X2 on drug release at 20h
In case of percent drug release at 20h (Y3) the factor X1, X2, X3 and its quadratic effect were found to be significant as the concentrations of all the three polymers in the matrix tablet increases the percent drug release decreases. The interaction between the three polymers can be elucidated using surface response plot shown in fig. 6. The result indicates that when X1 is kept at the high level (+1) and the concentration of X2 is varied from lower level to higher level (i.e. from-1 to+1) the percent drug release decreased from 78.29% to 63.36%. Similarly when X1 was kept at the lowest level (-1), and the X2 was varied from the lowest level (-1) to highest level (+1) the drug release decreased from 100% to 74.03%. The probable explanation of this behavior could be due to polymer relaxation and disentanglement leading to erosion of the polymer at 20h of dissolution study.
From the DOE data, the design space was created with the help of the contour plots of Y1, Y8 and Y20. The contour plots are shown in the fig. 7 and 8 for the various responses. The design space constructed within which the dissolution profile for formulation shall always be within the Target Dissolution profile (TDP). The optimized levels low and high for the three grades of HPMC are given in table 7.
Table 7: Optimized range of polymer concentrations for Carbamazepine hydrophilic matrix tablets
| HPMC grade | Low level (%) | High level (%) |
| K4M | 10 | 10.6 |
| K15M | 10.2 | 10.6 |
| K100M | 10 | 10.27 |
Fig. 7: Contour plot showing the effect of HPMC K4M, K15M and K100M on the percent drug release at 1h and 8h
Fig. 8: Contour plot showing the effect of HPMC K4M, K15M and K100M on the percent drug release at 20h
The optimized formulation was prepared by keeping the levels of different viscosity grades of HPMC as obtained in design space mentioned in table 7. The formulation was compressed and all compression parameters were kept same as that of factorial batches and the formulation obtained showed the dissolution profile within TDP and the release of CBZ from the matrix followed zero order release kinetic.
CONCLUSION
CBZ hydrophilic matrix tablets were successfully prepared using a combination of different viscosity grades of HPMC. A full factorial design was employed to study the effect of polymer concentrations on the release of the drug at various time points. Amount of HPMC K4M, K15M and K100M was significant in maintaining the drug release within TDP. The DOE approach for formulation optimization is a useful tool in obtaining a design space within which the formulations will always show the desired dissolution profile.
CONFLICT OF INTERESTS
Declared None
REFERENCES
- Alderman DA. A review of cellulose ethers in hydrophilic matrices for oral controlled-release dosage forms. Int J Pharm Tech Prod Mfr 1984;5:1-9.
- Colombo P. Swelling-controlled release in hydrogel matrices for oral route. Adv Drug Deliv Rev 1993;11:37–57.
- Siepmann J, Peppas NA. Modelling of drug release from delivery systems based on hydroxylpropyl methylcellulose (HPMC). Adv Drug Deliv Rev 2001;48:139-57.
- Jamzad S, Fassihi R. Development of a controlled release low dose class II drug-Glipizide. Int J Pharm 2006;312:24-32.
- Ford JL, Rubinstein MH, McCaul F, Hogan JE, Edgar PJ. Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxylpropyl methylcellulose matrix tablets. Int J Pharm 1987;40:223-34.
- Rao KVR, Padmalatha DK, Buri P. Influence of molecular size and water solubility of the solute on its release from swelling and erosion controlled polymeric matrices. J Control Rel 1990;12:133-41.
- Badshah A, Subhan F, Rauf K. Controlled release matrix tablets of olanzapine: influence of polymers on the in vitro release and bioavailability. AAPS Pharm sci Tech 2010;11:1397-04.
- Kranz H, Wagner T. Effects of formulation and process variables on the release of a weakly basic drug from single unit extended release formulations. Eur J Pharm Biopharm 2006;62:70-6.
- Streubel A, Siepmann J, Dashevsky A, Bodmeier R. pH-independent release of a weakly basic drug from water-insoluble and soluble matrix tablets. J Control Release 2000;67:101-10.
- Reynolds JEF. Martindale, The extra pharmacopoeia. London, The Royal Pharmaceutical Society of Great Britain; 1993. p. 295.
- Löbenberg R, Amidon GL. Modern bioavailability, bioequivalence and biopharmaceutics classification system; new scientific approaches to international regulatory standards. Eur J Pharm Biopharm 2000;50:3-12.
- Rinaki E, Valsami G, Macheras P. Quantitative biopharmaceutics classification system: The central role of dose/solubility ratio. Pharm Res 2003;20:1917-25.
- Apu AS, Pathan AH, Shrestha D, Kibria G, Jalil R. Investigation of in vitro release kinetics of carbamazepine from eudragit® RS PO and RL PO matrix tablets. Trop J Pharm Res April 2009;8(2):145-52.
- Sivenius J, Heinonen E, Lehto H, Jaarvensivu P, Anttila M, Ylinen A, et al. Reduction of dosing frequency of carbamazepine with a slow release preparation. Epilepsy Res 1988;2:32-6.
- Mohammed FA, Aarunachalam A, Reddy VG, Pallavi V, Sk Moulali, Rama Raju TVT. Formulation and evaluation of carbamazepine extended release tablets USP 200 mg. IJBPR 2012;3(1):145-53.
- Aziz SH, Abdulrasool AA, Hussein AA. Factors affecting the formulation of carbamazepine extended release tablet. Iraqi J Pharm Sci 2008;17(1):55-63.
- Barakat NS, Elbagory IM, Almurshedi AS. Controlled-release carbamazepine matrix granules and tablets comprising lipophilic and hydrophilic components. Drug Delivery 2009;16(1):57–65.
- Lee PI. Novel zero order drug delivery via immobilized nonuniformed drug distribution in glassy hydrogels. J Pharm Sci 1984;7:1344-7.
- Korsmeyer RW, Doelker GEP, Peppas NA. Mechanisms of potassium chloride from compressed hydrophilic polymeric matrices: Effect of entrapped air. J Pharm Sci 1983;72:1189-91.
- Higuchi T. Mechanism of sustained action medication: theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 1963;52:1145-9.
- Moneghini M, Voinovich D, Perissutti B, Princivalle F. Action of carriers on carbamazepine dissolution. Pharm Dev Technol 2002;7:289-96.
- Katzhendler I, Azoury R, Friedman M. Crystalline properties of carbamazepine in sustained release hydrophilic matrix tablets based on hydroxypropyl methylcellulose. J Control Release 1998;54(1):69-85.
- Pani NR, Nath LK. Development of controlled release tablet by optimizing HPMC: Consideration of theoretical release and RSM. Carbohydr Polym 2014;104:238–45.