International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 • Issue 1 • April – June 2010
Research Paper Effect of Tablet Surface Area and Surface Area/Volume on Drug Release from Lamivudine Extended Release Matrix Tablets P. Narayana Raju*, K. Prakash, T. Rama Rao, B.C.S. Reddy, V. Sreenivasulu and M. Lakshmi Narasu KLR Pharmacy College, Khammam, India.
ABSTRACT: The purpose of this study was to investigate the influence of tablet surface area/ volume (SA/Vol) on drug release from extended-release matrix tablets of lamivudine prepared with hydroxy propyl methylcellulose (HPMC). Highly soluble drug such as lamivudine was utilized in this study to give predominantly diffusion-controlled release. Drug release from HPMC matrix tablets with similar values of SA/Vol was comparable within the same tablet shaped tablet. Tablets having the same surface area but different SA/Vol values did not result in similar drug release, tablets with larger SA/Vol values had faster release profiles. Utility of SA/Vol to affect drug release was demonstrated by changing drug doses, and altering tablet shape to adjust SA/Vol. When SA/Vol was held constant, similar release profiles were obtained. Thus, surface area/volume is one of the key variables in controlling drug release from HPMC matrix tablets. Proper use of this variable has practical application by formulators who may need to duplicate drug release profiles from tablets of different sizes and different shapes.
KEYWORDS: Controlled release; Lamivudine matrix tablets; HPMC; Surface area; Surface area/volume ratio 1966., Lapidus etal 1966., Alderman etal 1984., Ford etal 1984, 1987) and molecular weight (Huber etal 1968), drug level and solubility (Colombo etal., 1996) , type of excipient (Ford etal 1987), and tablet shape and size (Skoug etal., 1991, Laicher etal., 1995, Cheng etal., 1999, Karusulu et al., 2000, Siepmnan etal., 2000). Matrix geometry such as shape and size, affects the drug release for controlled-release dosage forms and several researchers reported the same (Karusulu et al., 2000). Specifically, the effect of matrix geometry on drug release for HPMC matrix tablets has been studied in detail (Siepmann., 2000, Skoug., 1991). Siepmann et al. developed a mathematical model for diffusional drug release from HPMC matrices. In another study, Siepmann et al. examined the effect of the aspect ratio (radius/ height) and the size of cylindrical matrices on drug release for diffusion-controlled systems. They stated that since small cylindrical tablets have a higher relative surface area, i.e., absolute surface area/ absolute volume, the release from small tablets is faster than from large cylindrical tablets. Skoug et al. 16 also reported that two halves of a sustained release tablet had an increase in the surface area to volume ratio (SA/Vol) of about 16% relative to whole tablets. This study demonstrated the effete of SA and SA/Vol on drug release of lamivudine form HPMC matrix tablets as a part of an ongoing project on the development of extended release formulations of lamivudine.
Introduction In the formulation development, it is necessary to change the size, or shape of an existing product while maintaining the same release profile and also it is necessary to develop new strengths of the same dosage form. One method to develop a new strength is by incorporating the excipients with increased or decreased concentration. Most of the formulations will be developed as dose proportional by increasing or decreasing the weight of the tablets. Even though it is dose proportional it is often difficult to maintain the similar release profiles in all the strengths. Similar release profile in all the strengths is a mandatory for USFDA to file ANDA. This is very difficult in case of developing the controlled release formulation. To overcome such problem it is always necessary to maintain some parameters such as shape, size, surface area and surface area/ volume as constant so that the optimum release profiles will be achieved. Hydrophilic polymers, such as hydroxypropyl methylcellulose (HPMC), are commonly used as ratecontrolling polymers for controlled drug release from matrix-type dosage forms. Controlled drug release from HPMC matrix tablets may be affected by several formulation variables, such as polymer level (Huber et al * For correspondence: P Narayana Raju, E-mail:
[email protected]
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Where r is the radius of the tablet and t is the band thickness of the tablet. The matrix tablets prepared with HPMC K 100 M were used in this study.
Materials and Methods Materials Lamivudine (LAMI) was obtained as a gift sample from Alkem laboratories Ltd (Mumbai, India). Hydroxypropyl methylcellulose of two grades (HPMC K 100 M and HPMC 874) were obtained from Colorcon Asia Private Ltd, lactose (Pharmatose DCL 21) was obtained form DMV International, Netherlands, Micro crystalline cellulose (Avicel PH 200) was obtained form FMC Biopolymers, USA, colloidal silicon dioxide (Aerosil) was obtained form Degussa, Germany, talc was obtained form Luzenac, France and magnesium stearate was obtained form Ferro Industrial Chemicals USA. All other chemicals and reagents used in the study were of analytical grade.
Table 1 Formulation components of Lamivudine HPMC K100M matrix tablets. Lamivudine
200
HPMC K 100 M
50
Pharmatose DCL 21
15
Micro crystalline cellulose (AVICEL PH 200)
20
Aerosil
6
Talc
4
Magnesium stearate
5
Analytical method
Drug content (% )
A validated UV Spectrophotometric method was used for the determination of lamivudine using Schimadzu, UV1700 E 23 in pH 6.8 phosphate buffer at 271 nm.
Hardness (kg/cm2)
Formulation of Lamivudine matrix tablets In the present study the matrix tablets were prepared using HPMC as the release retarding polymer. The tablets were manufactured by the direct compression. The drug, polymer(s) and all other excipients were sifted through 425 µm sieve (ASTM mesh no 40) and mixed uniformly. The dry mix blend was then pre lubricated with aerosil and talc. The pre lubricated blend then lubricated with magnesium stearate. The lubricated blend was characterized for drug content. The lubricated blend was directly compressed on 16-station tablet compression machine using different punches. (Cadmach Machinery Co, Ahmedabad, India). Three batches were prepared for each formulation and compressed 100 tablets form each batch for the characterization study.
Surface area and Volume calculations The formulation in the present study was selected based on the in vitro dissolution study of ongoing project. The tablets were compressed with different size round flat faced punches. The formulation components summarized in the table 1 Tablet surface area (SA) and volume (Vol) were determined for each tablet by measuring tablet band thickness. The measured tablet thickness was used in tooling specific equations to calculate the tablet surface area and volume. The following equations were used to calculate the surface area and volume for the flat faced round tablets (46) SA = 2 π r (r + t)
…..(1)
SA/Vol = 2 (r + t) / r t
…..(2)
Thickness (mm) Friability (%)
99.5 7.2 (±0.3) 3.6 < 0.1
In vitro drug release studies The in vitro dissolution studies were performed up to 14 hours using USP type I dissolution apparatus (LABINDIA, DISSO-2000, Mumbai, India) at 100 rpm. The dissolution medium consisted of phosphate buffer pH 6.8 (900 mL), maintained at 37°C ± °C. An aliquot (5 mL) was withdrawn at specific time intervals and filtered through 0.45 µ (Millipore) filter. After appropriate dilution the samples were analyzed and cumulative percentage of the drug released was calculated. The mean of 6 tablets from 3 different batches was used in data analysis.
Statistical Comparison of Dissolution Profiles Dissolution profiles were constructed and the similarity factor (f2 factor) was used to compare the dissolution profile of different formulations. The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent dissolution between the two curves. The following equation defines a similarity factor (f2).
where f2 is the similarity factor, log is logarithm to base 10, P is number of sampling time points, Σ is the summation of over all time points, µti is the dissolution measurement (in mean percent labeled amount) at time point t of the first batch (test batch) profile, µri is the dissolution measurement (in mean percent labeled amount) at time point t of the second batch (reference batch) profile.
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International Journal of Pharmaceutical Sciences and Nanotechnology
greater impact on release from hydrophilic matrices than the tablet surface area (SA). Even though the surface area was held constant for these two sets of tablets, the actual order of relative release followed the order of tablet SA/Vol values. The similarity factor of these two sets of tablets was found around “38” which clearly indicates that the dissolution of these tablets were not similar.
Results and discussion Effect of Increasing SA/Vol on Release Effect of increasing SA/Vol on release matrix tablets containing HPMC with the same tablet diameter (11mm FFR) and increasing tablet weight resulted in tablets with decreasing SA/ Vol. Tablet dimensions for HPMC matrix tablets with Lamivudine are shown in Table 2 As seen in Figure. 1 release rate of Lamivudine increased with increasing SA/vol. The release rate was expected to be directly proportional to the SA/Vol. There is also an increase in SA with the increased tablet weight and thickness. Even though there is an increase in surface area, the order of release was based on the increase in SA/Vol.
Effect of Constant SA/Vol on Release In the case of tablets having the same shape, i.e. all FFR, but increasing tablet diameter, the surface area to volume ratio was held constant by adjusting the tablet thickness through changing the tablet weight (Table 4). The release profiles vs. time for the lamivudine tablets are shown in Fig 3. As a result of maintaining SA/Vol for the tablets relatively constant, the release profiles for the various tablets were very similar. The practical applicability of SA/Vol as a formulation variable is apparent, especially since the utility of this variable appears to hold for tablets of different shapes and dimensions. Good similarity factor (f-2) with a value of “77” was observed between these tablets further confirms that the release was almost similar.
Effect of Constant Surface Area on Release Two different sets of FFR tablets (diameters of 8 and 11.5 mm) of relatively constant surface area were tested to examine the effect of surface area on release. Tablet dimensions for HPMC matrices with Lamivudine are given in Table 3. The Lamivudine release profiles in Figure 2 show that the surface area to volume ratio (SA/Vol) has a
Table 2 Tablet dimensions for 11 mm flat faced round HPMCK100M matrix tablets with increasing surface area/volume values. Tablet weight (mg) 150 300 450
Proportion of Lamivudine in mg 100 200 300
Tablet thickness (mm) 1.36 3.56 5.76
SA (mm2) 237.1 313.1 389.3
SA/Vol (mm2/ mm3) 1.83 0.93 0.71
100
Cumulative percent released
80
60
40
F-5 SA/Vol-1.834 20
F-5 SA/Vol-0.925 F-5 SA/Vol-0.710
0 0
2
4
6
8
10
12
14
Time (hrs)
Fig. 1 Percentage lamivudine released vs. time demonstrating the effect of increasing SA/Vol for FFR tablets, 11 mm diameter. (n=6).
P Narayana Raju et al.: Effect of Tablet Area and Surface Area/ Volume on Drug Release from …
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Table 3 Tablet dimensions for flat faced round HPMCK100M matrix tablets with constant surface area values. Tablet diameter (mm)
Tablet weight (mg)
Proportion of Lamivudine in mg
Tablet thickness (mm)
SA (mm2)
SA/Vol (mm2/ mm3)
8
150
100
1.36
237.1
1.834
11.5
450
300
4.1
240
0.868
100
Cumulativepercent released
80
60
40
F-5 SA-237.08 F-5 SA-240
20
0 0
2
4
6
8
10
12
14
Time (hrs)
Fig. 2 Percentage lamivudine released vs. time demonstrating the effect of constant surface area for FFR tablets with different dimensions 8 mm and 11.5 mm diameter. (n=6). Table 4 Tablet dimensions for flat faced round HPMC K100M matrix tablets with constant surface area/volume values. Tablet diameter (mm)
Tablet weight (mg)
Proportion of Lamivudine in mg
Tablet thickness (mm)
SA (mm2)
SA/Vol (mm2/ mm3)
8
300
100
5.3
233.76
0.877
11
350
116
3.96
326.95
0.869
100
Cumulativepercent released
80
60
40
F-5 SA/Vol-0.8770
20
F-5 SA/Vol-0.8686
0 0
2
4
6
8
10
12
14
Time (hrs)
Fig. 3 Percentage lamivudine released vs. time demonstrating the effect of constant SA/Vol for FFR tablets with different dimensions 8 mm and 11 mm diameter. (n=6).
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Conclusion The study clearly indicates the matrix geometry will alter the drug release profile. This study clearly demonstrated that the release profiles of the matrix tablets increase with increase in tablet SA/Vol and decreases with the decrease in the surface area volume. To get a constant drug release profiles in different strengths, it always essential to keep the SA/Vol constant. Constant surface area could not give the similar release profiles in all the strenghts. The order of relative release mainly depends on the change in the SA/Vol. This study is applicable for the tablet dosage forms prepared with hydrophilic polymers. This study is very useful for extended release formulation with multiple strengths, having different shapes and sizes.
References Huber HE, Dale LB, Christenson GL. Utilization of Hydrophilic Gums for the Control of Drug Release from Tablet Formulations: Disintegration and Dissolution Behavior. J. Pharm. Sci., 55 : 974–976, (1966). Lapidus H, Lordi NG. Some Factors Affecting the Release of a Water-Soluble Drug from a Compressed hydrophilic Matrix. J. Pharm. Sci. 55: 840–843, (1966). Alderman DA, A Review of Cellulose Ethers in Hydrophilic Matrices for Oral Controlled-Release Dosage Forms. Int. J. Pharm. Technol. Prod. Manuf. 5 : 1–9, (1984). Ford JL, Rubinstein MH, Hogan JE, Formulation of Sustained Release Promethazine Hydrochloride Tablets Using Hydroxypropylmethylcellulose Matrixes. Int. J. Pharm. 24 : 327–338, (1985). Ford JL, Rubinstein MH, McCaul F, Hogan JE, Edgar PJ. Importance of Drug Type, Tablet Shape and Added Diluents on Drug Release Kinetics from Hydroxypropylmethylcellulose Matrix Tablets. Int. J. Pharm. 40:223–234, (1987). Huber HE, Christenson GL. Utilization of Hydrophilic Gums for the Control of Drug Substance Release from Tablet
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Formulations. II. Influence of Tablet Hardness and Density on Dissolution Behavior. J. Pharm. Sci. 57: 164–166.( 1968). Colombo P, Bettini R, Santi P, DeAscentiis A, Peppas NA. Analysis of the Swelling and Release Mechanisms from Drug Delivery Systems with Emphasis on Drug Solubility and Water Transport. J. Contr. Rel., 39: 231–237,( 1996). Skoug JW, Borin MT, Fleishaker JC, Cooper AM. In Vitro and In Vivo Evaluation of Whole and Half Tablets of SustainedRelease Adinazolam Mesylate. Pharm. Res., 8 , 1482–1488, ( 1991). Laicher A, Profitlich T. Influence of Tablet Formulation and Size on the In Vitro Sustained- Release Behavior of metoprolol Tartrate from Hydrophilic Matrices. Drug Dev. Ind. Pharm. 21: 1929–1939, (1995). Cheng K, Zhu J, Song X, Sun L. Studies of Hydroxypropylmethylcellulose Donut-Shaped Tablets. Drug Dev. Ind. Pharm. 25: 1067–1071, (1999). Karasulu HY, Ertan G, Kose T. Modeling of Theophylline Release from Different Geometrical Erodible Tablets. Eur. J. Pharm. Biopharm.49: 177–182, (2000). Siepmann J, Kranz H, Peppas NA, Bodmeier R. Calculation of the Required Size and Shape of Hydroxypropyl Methylcellulose Matrices to Achieve Desired Drug Release Profiles. Int. J. Pharm. 201: 151–164, (2000). Siepmann J, Podual K, Sriwongjanya M, Peppas NA, Bodmeier R. A New Model Describing the Swelling and Drug Release Kinetics from Hydroxypropyl Methylcellulose Tablets. J. Pharm. Sci. 88: 65–72, (1999). Siepmann J, Kranz H, Peppas NA, Bodmeier R. Calculation of the Required Size and Shape of Hydroxypropyl Methylcellulose Matrices to Achieve Desired Drug Release Profiles. Int. J. Pharm. 201: 151–164, (2000). Skoug JW, Borin, M T, Fleishaker JC, Cooper AM. In Vitro and In Vivo Evaluation of Whole and Half Tablets of SustainedRelease Adinazolam Mesylate. Pharm. Res, 8 : 1482–1488, (1991)
