Abstract
Introduction:
Present investigation describes an influence of ratio of Gelucire 43/01(hydrophobic) to hydroxypropyl methylcellulose K4M (HPMC K4M) (hydrophilic) and different fillers on release of famotidine from gastro-retentive tablets using 32 full factorial design. Ratio of Gelucire 43/01 to HPMC K4M (X1) and the type of filler (X2) were selected as independent variables while buoyancy lag time (BLT), drug release at 1h (Q1), 6h (Q6), and the 12h (Q12) were selected as dependent variables.
Materials and Methods:
Gastro-retentive tablets of famotidine were prepared by a solvent free melt granulation technique using Gelucire 43/01 as a hydrophobic meltable binder. HPMC K4M and sodium bicarbonate were used as matrixing agent and gas-generating agent, respectively. Prepared tablets were evaluated for in vitro dissolution, in vitro buoyancy, friability, hardness, drug content and weight variation. Dissolution data were fitted to various models to ascertain kinetics of drug release. The data were analyzed using regression analysis and analysis of variance.
Results:
All formulations (F1-F9) showed floating within 3min and had total floating time of more than 12h. It was observed that a type of filler and the ratio of Gelucire 43/01 to HPMC K4M had significant influence on buoyancy lag time (P = 0.037) and Q6 (P = 0.011), respectively without significant influence on Q1 and Q12.
Conclusion:
Formulation F5 was selected as an optimum formulation as it showed more similarity in dissolution profile with theoretical profile (Similarity factor, f2 = 83.01). The dissolution of batch F5 can be described by zero order kinetics (r2 = 0.9914) with anomalous (non-Fickian) diffusion as a release mechanism (n = 0.559). The difference observed in in vitro release profile after temperature sensitivity study at 40°C for 1 month was insignificant.
Keywords: Buoyancy lag time, full factorial design, Gelucire 43/01, melt granulation
INTRODUCTION
Frequency of drug administration in a conventional dosage form depends upon the elimination half-life of drug (t1/2).[1] Controlled release dosage form reduces a frequency of drug administration and the fluctuations in plasma drug concentration. A gastro-retentive drug delivery system that can be retained in the stomach is useful for controlled release and for site specific drug absorption. There are number of approaches used to prolong gastric retention time, such as floating drug delivery system, swelling and expanding system, polymeric bioadhesive systems, modified shape systems, high density system and raft formation.[2–4]
Famotidine is histamine receptor (H2) antagonist used in a treatment of zollinger ellision syndrome, gastro esophageal reflux disease and peptic ulcer in the dose ranging from 10 to 80 mg.[5] Half life of a drug is about 2.5–3.5 h and the oral bioavailability is 45 ± 14% indicating its promising candidature for sustained release formulation.[6] Oral treatment of gastric disorders with H2 receptor antagonist such as famotidine or ranitidine in combination with antacids promotes local delivery of these drugs to the receptor of parietal cell wall. Local delivery also increases a bioavailability and the efficacy of drug to reduce acid secretion.[7]
Hydrophilic matrices are widely used and accepted for sustained release but a drug release from such matrices is time dependent with very less possibility of zero order drug release.[8] Initially, a drug present at surface of the matrix is released quickly, yielding a burst effect, then with time, as the diffusion path length increases the release rate is progressively reduced. Several authors have described various approaches to limit the burst effect from monolithic matrix systems in order to obtain zero order drug release.[9–13] Conte and co-workers designed a multilayered hydrophilic matrix system (GeomatrixR) to obtain zero order drug delivery by coating one or both sides of the matrix tablet with HPMC based barrier.[14–16] Krogel and Bodmeier invented a system composed of hydrophilic matrix tablet placed in impermeable polypropylene cylinder, reducing drug release to the open ends of the cylinder.[17] Colombo et al. described a modulation of drug release by physically restricting matrix swelling through partial coating of the matrix with impermeable cellulose acetate propionate film.[18] Danckwerts developed a core-in-cup tablet consisting of inert cup of ethylcellulose and carnauba wax into which drug-containing matrix layer was compressed, thus leading to matrix with only one side in contact with the surrounding medium.[19] Although these devices are able to reduce drug release, they have in common that their production process is complicated and time-consuming. Hydrophobic polymers are most suitable matrix formers to limit the burst effect from monolithic matrix system containing hydrophilic polymers.[20]
So the purpose of this research was to prepare a mixed matrix gastroretentive tablet of famotidine using Gelucire 43/01 and hydroxylpropyl methylcellulose K4M (HPMC K4M). A 32 full factorial design was employed to investigate effect of two independent variables, i.e. a ratio of Gelucire 43/01 to hydroxypropyl methylcellulose (HPMC K4M) and the type of filler (lactose, dicalcium phosphate, microcrystalline cellulose) on the dependent variables, i.e. buoyancy lag time (BLT), Q1, Q6 and Q12 (% drug release after 1, 6, 12 hr, respectively).
MATERIALS AND METHODS
Materials
Famotidine was received as a gift sample from Mann Pharmaceuticals Ltd, Mehsana, India. Hydroxypropyl methylcellulose K4M (HPMC K4M) was obtained from Yarrow Chem. Products, Mumbai, India. Gelucire 43/01 was obtained from Gattefosse, France. Sodium bicarbonate and magnesium stearate were obtained from Shakti Chemicals, Mehsana, India. Lactose and talc were obtained from Chemdyes Corporation, Ahmedabad, India. All other materials and chemicals used were of either pharmaceutical or analytical grade.
Methods
Preparation of famotidine floating tablets by melt granulation
Gelucire 43/01 was melted in a large petridish at 50°C and the required quantity of famotidine was added to melted mass. Previously prepared geometric mixture of HPMC K4M and sodium bicarbonate was added to famotidine - Gelucire 43/01 mixture and stirred well to mix. This mass was removed from a 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 using 44 meshes to separate fines. The granules were collected and mixed with talc (2%) and magnesium stearate (1%). The lubricated blend was compressed using round tooling on Rimek-I rotary tablet machine (Karnavati Engineering, Kadi, India). Compression pressure was adjusted to obtain tablets with hardness in a range of 2–3 kg/cm2.
In vitro buoyancy studies
The in vitro buoyancy of the tablets was studied at 37 ± 0.5°C in 100 ml of simulated gastric fluid (SGF) at pH 1.2 without pepsin (USP). The duration of tablet floatation was observed visually.[21]
In vitro dissolution study
The in vitro dissolution study of famotidine tablets was performed using USP apparatus (model TDT-08T, Electrolab, Mumbai, India) fitted with paddle (50 rpm) at 37 ± 0.5°C using SGF (pH 1.2; 900 mL) as a dissolution medium. At predetermined time intervals, 10-mL samples were withdrawn, filtered through a 0.45μm membrane filter, diluted and assayed at 265 nm using Shimadzu UV 1800 double-beam spectrophotometer (Shimadzu, Kyoto, Japan). Cumulative percentage drug release was calculated using an equation obtained from calibration curve.
Preliminary screening
Preliminary screening was performed to optimize amount of sodium bicarbonate and total amount of polymer in a formulation. Tablets were prepared by melt granulation method using 40% of total concentration of polymers (Gelucire 43/01 and HPMC K4M in ratio of 3:5) and varying amount of sodium bicarbonate (5%, 10%, 15%) as shown in Table 1. Prepared tablets were tested for in vitro buoyancy studies and intactness. Tablets were prepared using 10% of sodium bicarbonate and varying amount (30%, 40%, 50%) of polymer (Gelucire 43/01 and HPMC K4M in ratio of 3:5) as shown in Table 2. Tablets prepared with varying amount of polymer were tested for in vitro buoyancy studies, intactness and in vitro drug release.
Table 1.
Formulation of famotidine floating tablets using different amount of sodium bicarbonate
Table 2.
Formulation of famotidine floating tablets using different amount of polymers
Optimization of variables using full factorial design
A 32 randomized full factorial design was used in present study. In this design 2 factors were evaluated, each at 3 levels, and experimental trials were performed for all 9 possible combinations. Ratio of Gelucire 43/01 to HPMC K4M (X1) and type of filler (lactose, microcrystalline cellulose, dicalcium phosphate) (X2) were chosen as independent variables while BLT, percentage drug release in 1 h (Q1), 6 h (Q6), and 12 h (Q12) were taken as dependent variables. The formulation layout for the factorial design batches (F1–F9) is shown in Table 3. Prepared formulations were evaluated for assay, friability and hardness in addition to in vitro buoyancy and release study. Results of this evaluation are shown in Table 4.
Table 3.
Formulation and evaluation of batches in 32 full factorial design
Table 4.
Results of factorial design batches (F1–F9)
Kinetic modeling of dissolution data
Dissolution profile of all batches were fitted to various models such as zero order, first order, Higuchi,[22] Hixon Crowell,[23] Korsemeyer, and Peppas[24] to ascertain kinetics of drug release. The method described by Korsemeyer and Peppas was used to describe mechanism of drug release.
Comparison of dissolution profiles for selection of optimum batch
The similarity factor (f2) given by SUPAC guidelines for modified release dosage forms was used to compare dissolution profiles. The dissolution profiles are considered to be similar when f2 is between 50 and 100. The dissolution profile of products were compared using f2, which is calculated from following formula,
Where, n is the dissolution time and Rt and Tt are the reference (here it is theoretical dissolution profile of famotidine) and test dissolution value at time t.[25]
Fourier transform infrared spectroscopy
Fourier transform infrared (FTIR) spectra of famotidine, HPMC K4M, Gelucire 43/01 and a physical mixture of these ingredients were recorded using KBr mixing method on FTIR instrument available at central instrument laboratory of the institute (FTIR-1700, Shimadzu, Kyoto, Japan).
Temperature sensitivity study
To determine change in in vitro release profile and buoyancy behavior on storage, a temperature sensitivity study of the optimal batch was performed at 40°C in humidity jar with 75% relative humidity (RH). Samples were withdrawn at 1 month interval and evaluated for any change in in vitro drug release pattern and buoyancy behavior.
RESULTS AND DISCUSSION
Results of preliminary screening
Gelucire 43/01 was selected as a hydrophobic meltable material to impart sufficient integrity to the tablets. HPMC K4M (hydrophilic) was selected as a matrixing agent considering its widespread applicability and excellent gelling activity in sustained release formulations. Sodium bicarbonate generates CO2 gas in a presence of hydrochloric acid present in dissolution medium. Generated gas is trapped and protected within a gel formed by hydration of HPMC K4M, thereby decreasing the density of tablet. As a density of tablet fall below 1 (density of water), the tablet becomes buoyant. Three batches (CO1, CO2, CO3) as shown in Table 1, were prepared using same amount of polymer Gelucire 43/01 and HPMC K4M while different amount of sodium bicarbonate (5%, 10%, 15%). From the evaluation results [Table 1] it was observed that as the amount of sodium bicarbonate increased from 5% to 15%, BLT was decreased. At higher amount of sodium bicarbonate, a tablet remained intact only for 10h and lost the matrix integrity. Batch containing 10% sodium bicarbonate remained buoyant and intact for 24h. Hence 10% of sodium bicarbonate was considered to be optimum. Three batches (PO1, PO2, PO3) as shown in Table 2, were prepared using 10%of sodium bicarbonate and different amount of polymer (30%, 40%, 50%). Formulations PO1, PO2, and PO3 were subjected to in vitro dissolution study. All formulations exhibited buoyancy lag time of less than 100 sec. Tablets of batch PO2 retained integrity throughout a study and released the drug in controlled manner (100.8 CPR in 11 h as shown in Figure 1. Tablets of batch PO1 did not maintain integrity) and released more than 90% of a drug in 6 h. Tablets of batch PO3 released only 80.2% drug in 12 h, which may be due to higher amount of polymer. Hence it was decided to keep total polymer concentration at 40% for acceptable formulation in further study.
Figure 1.
In vitro dissolution profile of batch PO1, PO2, and PO3
Full factorial design
A statistical model incorporating interactive and poly nominal terms was used to evaluate the responses.
Y = b0 + b1X1 + b2X2 + b12X1X2 + b11X12 + b22X22
Where Y is the dependent variable, b0 is the arithmetic mean response of the 9 runs, and b1 is the estimated coefficient for the factor Xi. The main effects (X1 and X2) represent the average result of changing one factor at a time from its low to high values. The interaction terms (X1X2) show how the response changes when two factors are simultaneously changed. The polynomial terms (X12 and X22) are included to investigate nonlinearity. Dissolution profile for 9 batches showed a wide variation (i.e., initial 1 h release ranging from 14.78 % to 64.37 % and drug released after 12 h ranging from 90.28 % to 101.44%) [Figure 2]. Dissolution data indicated that drug release is strongly dependent on the selected independent variables. The coefficients for fitted equations (full and reduced) relating the responses, BLT, Q1, Q6 and Q12 to the transformed factors are shown in Table 3. These polynomial equations can be used to draw conclusion after considering a magnitude of coefficient and the mathematical sign it carries (i.e., negative or positive). Table 5 shows the results of analysis of variance (ANOVA), which was performed to identify insignificant factors. The data were analyzed using Microsoft Excel.
Figure 2.
In vitro dissolution profile of formulation F1-F9
Table 5.
Summary of results of regression analysis
R2 value for BLT, Q1, and Q6 are 0.9082, 0.8637, 0.9331, respectively indicating good correlation between dependent and independent variables. Low R2 value for Q12 (0.485) indicates that drug release at 12h is less dependent on selected variables. Reduced models were developed for response variables by omitting the insignificant terms with P > 0.05. The terms with P < 0.05 were considered statistically significance and retained in the reduced model. The coefficients for full and reduced models for response variables are shown in Table 5. The coefficients of independent variables for Q1 and Q12 were found - insignificance at P > 0.05 with out any contribution in prediction of Q1 and Q12.
Full and reduced model for BLT
Significance levels of coefficients b1, b12 and b11 were found to be P = 0.153, 0.597, and 0.639, respectively, hence they were omitted from a full model to generate the reduced model. Results of statistical analysis are shown in Table 5. Coefficients b0, b2, and b22 were found to be significant at P < 0.05; hence they were retained in a reduced model. Reduced model was tested in proportion to determine whether coefficients b1, b12 and b11 contribute significance information in a prediction of BLT or not.[26] The results of model testing are shown in Table 6. The critical value of F for α = 0.05 is equal to 9.28 (df = 3,3). Since a calculated value (Fcal = 1.41) is less than the critical value (Fcri = 9.28), it was concluded that coefficients b1, b12, and b11 did not contribute significantly in the prediction of BLT and could be omitted from full model to generate-reduced model.
Table 6.
Calculations for testing the model in portions
Full and reduced model for Q6
Significance levels of coefficients b2, b12, and b22 were found to be P = 0.890, 0.776, and 0.402, respectively, hence they were omitted from a full model to generate the reduced model. Results of statistical analysis are shown in Table 5. Coefficients b0, b1, and b11 were found to be significant at P < 0.05; hence they were retained in a reduced model. Reduced model was tested in proportion to determine whether coefficients b2, b12, and b22 contribute significance information in a prediction of Q6 or not. The results of model testing are shown in Table 6. The critical value of F for α = 0.05 is equal to 9.28 (df = 3,3). Since a calculated value (Fcal = 0.355) is less than the critical value (Fcri = 9.28), it was concluded that coefficients b2, b12, and b22 did not contribute significantly in a prediction of Q6 and could be omitted from full model to generate-reduced model.
Kinetic modeling of dissolution data
Kinetics of dissolution data were well fitted to zero order, Higuchi model, and Korsemeyer-Peppas model as evident from regression coefficients [Table 7]. In a case of -controlled or sustained release formulation, diffusion, swelling and erosion are the three most important rate controlling mechanisms. Formulation containing swelling polymers shows swelling as well as diffusion mechanism because a kinetic of swelling includes relaxation of polymer chains and imbibitions of water, causing the polymer to swell and changing it from glassy to rubbery state. Diffusion exponent n is an indicative of mechanism of drug release from the formulation. For a swellable cylindrical (tablet) drug delivery system, the n value of 0.45 is indicative of Fickian diffusion controlled drug release. Value of n between 0.5 and 0.85 signifies anomalous (non-Fickian) transport, n value of 0.85 indicates case II transport, and n value greater than 0.85 indicates super case II transport.[27,28] Value of diffusion exponent n for most factorial formulations is between 0.5 and 0.85 [Table 7] indicating non-Fickian drug release from the formulations.
Table 7.
Kinetic treatment of dissolution data
Comparison of dissolution profiles for selection of optimum batch
Values of similarity factor (f2) for batches F1 to F6 were greater than 50 compared with theoretical dissolution profile [Table 4] indicating good similarity in dissolution. Tablets of batch F5 showed maximum value of f2 (83.01), hence was selected as optimum batch. The tablets of batch F5 were subjected to the temperature sensitivity study.
Fourier transform infrared spectroscopy
Drug excipients interactions play a vital role in the release of drug from formulation. Fourier transform infrared spectroscopy has been used to study physical and chemical interactions between a drug and the excipients used. The pure famotidine and its mixture with Gelucire 43/01 and HPMC K4M was mixed separately with IR grade KBr and were scanned over a range of 400-4500 cm-1 using FTIR instrument (FTIR-1700, Shimadzu, Kyoto, Japan). The drug exhibits peak due to primary amine and alkene group. It was observed that there were no changes in these main peaks in IR spectra of a mixture of drug and polymers [Figures 3–6]. The FTIR study revealed no physical or chemical interactions of famotidine with Gelucire 43/01 and HPMC K4M as evident from Figure 6.
Figure 3.
FTIR spectra of Famotidine
Figure 6.
FTIR spectra of physical mixture (Famotidine, Gelucire 43/01 and HPMC K4M)
Figure 4.
FTIR spectra of Gelucire 43/01
Figure 5.
FTIR spectra of HPMC K4M
Results of temperature sensitivity study
To determine any change in in vitro release profile on storage, a temperature sensitivity study of the optimal batch F5 was performed at 40°C in humidity jar with 75% RH. Sample withdrawn after 1 month showed no significant change in in vitro buoyancy and in vitro drug release pattern.
CONCLUSION
From present investigation it was concluded that a combined matrix system containing hydrophobic and hydrophilic polymer minimized bust release of drug from tablet and achieved drug release by zero order kinetic, which is practically difficult with only hydrophilic matrix.
ACKNOWLEDGMENTS
The authors thank Gattefosse for a gift sample of Gelucire 43/01, Mann Pharmaceuticals Limited, Mehsana, for a gift sample of famotidine. Authors also thank Shri Sarvajanik Pharmacy College, Mehsana, for providing all other ingredients and the required infrastructure for conducting this research work.
Footnotes
Source of Support: Nil.
Conflict of Interest: None declared.
REFERENCES
- 1.Sood A, Panchagnula R. Design of controlled release delivery systems using a modified pharmacokinetic approach: A case study for drugs having a short elimination half-life and a narrow therapeutic index. Int J Pharm. 2003;261:27–41. doi: 10.1016/s0378-5173(03)00267-9. [DOI] [PubMed] [Google Scholar]
- 2.Kim KH, Singh BN. Floating drug delivery system an approach to oral controlled drug delivery via gastric retention. J Control Release. 2000;63:235–359. doi: 10.1016/s0168-3659(99)00204-7. [DOI] [PubMed] [Google Scholar]
- 3.Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F. Gastroretentive dosage forms: Overview and special case of Helicobacter pylori. J Control Release. 2006;111:1–18. doi: 10.1016/j.jconrel.2005.10.031. [DOI] [PubMed] [Google Scholar]
- 4.Klausner EA, Lavy E, Friedman M, Hoffman A. Expandable gastroretentive dosage form. J Control Release. 2003;90:143–62. doi: 10.1016/s0168-3659(03)00203-7. [DOI] [PubMed] [Google Scholar]
- 5.Reynolds JE. Gastro-intestinal agents. In: Parfitt Kathleen., editor. Martindale, the extra pharmacopoeia. 31st ed. London: The Royal Pharmaceutical Society; 1996. pp. 1218–20. [Google Scholar]
- 6.Willemjntje A, Hoogerwerf, Pasrich PJ. Agents for control of gastric acidity and treatment of peptic ulcers and gastrooesophageal reflux disease. In: Hardman J, editor. Goodman and Gilman's “The Pharmacological Basis of Therapeutics”. 10th ed. New York: The MC Graw Hill; 2001. p. 1741. [Google Scholar]
- 7.Chien YW. Fundamentals of controlled drug administration. In: Swarbrick J, editor. Novel drug delivery system. 2nd ed. New York, Basel: Marcel Dekker. Inc; 1982. pp. 465–574. [Google Scholar]
- 8.Conte U, Maggi L, Colombo P, Manna AL. Multilayered hydrophilic matrices as constant release devices. J Control Release. 1993;26:39–47. [Google Scholar]
- 9.Behzad S, Taybeh J, Fakher R, Mohmmad R. Multiple unite sustained released floating of sodium diclofenac: Formulation and evaluation using factorial design. Int J Drug Deliv. 2010;2:344–51. [Google Scholar]
- 10.Thakkar VT, Shah PA, Soni TG, Parmar MY, Gohel MC, Gandhi TR. Fabrication and evaluation of levofloxacin hemihydrates floating tablet. Res In Pharma Sci. 2008;3:1–8. [Google Scholar]
- 11.Lakade SH, Bhalekar MR. Formulation and evaluation of sustained release matrix tablet of anti-anginal Drug: Influence of combination of hydrophobic and hydrophlic matrix former. Res J Pharm Tech. 2008;1:410–3. [Google Scholar]
- 12.Kar RK, Mohapatra S, Barik BB. Design and characterization of controlled release matrix tablets of zidovudine. Asian J Pharm Clin Res. 2009;2:54–61. [Google Scholar]
- 13.Ravisankar V, Reddy YD, Rao AN, Dhachinamoorthy D, Chandrasekhar KB. Effect of hydrophilic and hydrophobic polymers on losartan potassium matrix tablet. J Pharm Res. 2010;3:2195–7. [Google Scholar]
- 14.Conte U, Maggi L. Modulation of the dissolution profiles from GeomatrixR multilayer matrix tablets containing drugs of different solubility. Biomaterials. 1996;17:889–96. doi: 10.1016/0142-9612(96)83284-4. [DOI] [PubMed] [Google Scholar]
- 15.Conte U, Maggi L. A flexible technology for the linear, pulsatile release of drugs, allowing for easy accommodation of difficult in vitro targets. J Control Release. 2000;64:263–8. doi: 10.1016/s0168-3659(99)00147-9. [DOI] [PubMed] [Google Scholar]
- 16.Conte U, Maggi L. Multilayer tablets as drug delivery devices. Pharm Tech Int. 1998;10:174–82. [Google Scholar]
- 17.Krögel I, Bodmeier R. Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder. J Control Release. 1999;61:43–50. doi: 10.1016/s0168-3659(99)00096-6. [DOI] [PubMed] [Google Scholar]
- 18.Colombo P, Conte U, Gazzaniga A, Maggi L, Sangalli ME, Manna AL, et al. Drug release modulation by physical restrictions of matrix swelling. Int J Pharm. 1990;63:43–8. [Google Scholar]
- 19.Danckwerts MP. Optimization and development of a core-incup tablet for modulated release of theophylline in simulated gastrointestinal fluids. Drug Dev Ind Pharm. 2000;26:767–72. doi: 10.1081/ddc-100101296. [DOI] [PubMed] [Google Scholar]
- 20.Tiwari SB, Pai MR, Mehta PR, Chaudhary PB, Murhty TK. Controlled release formulation of tramadolol hydrochloride using hydrophilic hydrophobic mixture. AAPS PharmSciTech. 2003;4:31. doi: 10.1208/pt040331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Xu X, Sun M, Zhi F, Hu Y. Floating matrix dosage form for phenoporlamine hydrochloride based on gas forming agent: In vitro and in vivo evaluation in healthy volunteers. Int J Pharm. 2006;310:139–45. doi: 10.1016/j.ijpharm.2005.12.003. [DOI] [PubMed] [Google Scholar]
- 22.Higuchi T. Mechanism of sustained action mediation, theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52:1145–49. doi: 10.1002/jps.2600521210. [DOI] [PubMed] [Google Scholar]
- 23.Hixon AW, Crowell JH. Dependence of reaction velocity upon surface and agitation. Ind Engg Chem. 1931;23:923–31. [Google Scholar]
- 24.Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanism of solute release from porous hydrophillic polymers. Int J Pharm. 1983;15:25–35. doi: 10.1002/jps.2600721021. [DOI] [PubMed] [Google Scholar]
- 25.Coasta P, Manuel J, Labao S. Modelling and comparision of dissolution profiles. Eur J Pharm Sci. 2002;13:123–33. doi: 10.1016/s0928-0987(01)00095-1. [DOI] [PubMed] [Google Scholar]
- 26.Mendenhall W, Sincich T. A second course in Business statasticals, Regression analysis. 3rd ed. San Francisco, CA: Dellen Publishing Co; 1989. Multiple regression; pp. 141–226. [Google Scholar]
- 27.Siepmam J, Peppas NA. Modelling of drug release from delivery system based on hydroxylpropyl methylcellulose. Adv Drug Deliv Rev. 2001;48:139–57. doi: 10.1016/s0169-409x(01)00112-0. [DOI] [PubMed] [Google Scholar]
- 28.Ritger PL, Peppas NA. A simple equation for description of solute release from swellable device. J Control Release. 1987;5:7–42. [PubMed] [Google Scholar]