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Investigation of the impact of insoluble diluents on the compression and release properties of matrix based sustained release tablets
Powder Technology 214 (2011) 375–381
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Powder Technology journal homepage: www.elsevier.com/locate/powtec
Investigation of the impact of insoluble diluents on the compression and release properties of matrix based sustained release tablets M.P. Vaidya, A.M. Avachat ⁎ Sinhgad College of Pharmacy, Vadgaon (Bk), Pune-411 041 (MS), India
a r t i c l e
i n f o
Article history: Received 27 January 2011 Received in revised form 19 July 2011 Accepted 28 August 2011 Available online 3 September 2011 Keywords: Microcrystalline cellulose Dibasic calcium phosphate Sustained release Heckel's equation Kawakita equation Compression force
a b s t r a c t In the present study the effect of insoluble diluents such as microcrystalline cellulose (MCC) and dibasic calcium phosphate (DCP) on the compression characteristics and release profile of sustained release tablets containing Hydroxypropylmethylcellulose (HPMC) matrices was investigated. The effect of diluents on the compression characteristics was studied using Heckel and Kawakita equations. The effect of compression forces on the release profile was also investigated. Diclofenac Sodium (DS) was used as a model drug. Tablets were prepared using wet granulation method. It was found that there is a decrease in the drug release as the concentration of these insoluble diluents is increased. From the Heckel and Kawakita analysis it was concluded that the compressed granules of formulations containing microcrystalline cellulose showed higher plastic deformation, densification and granule fragmentation as compared to DCP. Also a relationship was evaluated between the compression force and the release profile i.e. an increase in compression force causes decrease in the release rate of the drug from the formulation irrespective of change in the diluent. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Diluents are fillers designed to make up the required bulk of the tablet when the drug dosage itself is inadequate to produce this bulk. Diluents can also be used in tablet formulation for following purpose. ➣ To provide better tablet properties such as improved cohesiveness ➣ To permit use of direct-compression manufacturing ➣ To promote flow of the powder or granules [1] As the diluents used for the preparation of tablets are of different types, they are responsible for change in the physical properties and the performance of the formulation with respect to each diluent. Also concentration of diluent in the formulation is important, which may cause change in the properties of the final formulation especially with reference to the release and compressional characteristics of tablets. Microcrystalline cellulose (MCC) is an organic diluent while dicalcium phosphate (DCP) is an inorganic diluent and both are water insoluble. Nonionic cellulose ethers, and most frequently hydroxypropyl methylcellulose (HPMC, hypromellose) have been widely studied
⁎ Corresponding author at: Sinhgad College of Pharmacy, 44/1, Vadgaon (Bk.), Pune411 041, Maharshtra, India. Tel.: +91 98224 56636. E-mail address: [email protected] (A.M. Avachat). 0032-5910/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2011.08.035
for their applications in oral sustained release (SR) systems. When in contact with water, HPMC hydrates rapidly and forms a gelatinous barrier layer around the tablet. The rate of drug release from HPMC matrix is dependent on various factors such as type of polymer, drug, polymer/drug ratio, particle size of drug and polymer, and the type and amount of fillers used in the formulation [2]. Work has been done to see the effect of Carbopol 934P concentration and granulation technique on the release of poorly water-soluble drug (Ibuprofen) [3]. Also the influence of commonly used excipients, spray-dried lactose (SDL), MCC, and partially pregelatinized maize starch (Starch 1500) on drug release from HPMC matrix tablets prepared by direct compression has been studied [2]. Some authors studied the relationship and influence of different levels of MCC, starch, and lactose, in order to achieve a zero-order release of Diclofenac Sodium [4]. Investigation of the influence of the concentration of the matrix material (carbopol 974P) and several co-excipients (lactose, microcrystalline cellulose, and starch) on the release rate of the drug has also been reported [5]. To measure the flowability and compressibility of the granules of different formulations Kawakita analysis was done. The Kawakita relationship is employed to determine the tensile strength of agglomerates provided that the influence of the friction at the die wall has been taken into account since it is well known that wall friction significantly increases resistance to deformation. The Kawakita equation is as follows [6]
P=C ¼ P=a þ 1=ab
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Where P is the applied pressure, C is the degree of volume reduction and is calculated from the initial volume V0 and tapped volume V as: C ¼ ðV0 −VÞ=V ‘a’ and ‘b’ are constants. ‘a’ describes the degree of volume reduction at the limit of tapping and is called compactibility; 1/b is considered to be a constant related to cohesion and is called cohesiveness. Kawakita constants ‘a’ and ‘b’ were obtained from the slope and intercept of the plots for each formulation, where ‘a’ represents the minimum porosity of the bed prior to compression while ‘b’, which is termed the coefficient of compression is related to the plasticity of the material. The reciprocal of ‘b’ is a pressure term designated as Pk, which is the pressure required to reduce the powder bed by 50%. The value of Pk gives an inverse relation with the plastic deformation during compression process. The lower the value of Pk, higher is the degree of plastic deformation occurring during compression. The study of the mechanical properties of cylindrical compacts of lactose and microcrystalline cellulose with the help of tensile and compressive strength has been reported [7]. Some authors studied the relationship between the material properties of various αlactose monohydrate grades (αLM), process parameters (punch velocity, lubricant fraction) and the tablet tensile strength (TS) using Heckel and Kawakita analysis, as well as, used it for studying compaction properties of three types of starches and the mechanical properties of their tablets [8,9]. Compression behaviors of spray dried rice starch (SDRS), as well as pregelatinized starch (PS), and MCC were characterized using Heckel analysis was also reported in the literature [10]. However a detailed investigation of the effect of insoluble diluents on the compressional behavior characteristics of a tablet containing a retardant material and the release profile has not been reported. The objectives of this study were: i) To investigate the effect of concentration and type of insoluble diluents on the release profile of tablets containing HPMC matrices. ii) To characterize the compression behavior of the tablets containing insoluble diluents namely MCC and DCP using Heckel and Kawakita equations. iii) To investigate the effect of compression forces on the release. 2. Materials and methods 2.1. Materials Diclofenac Sodium was received as a gift sample from Lupin Research Park, Pune (India). HPMC K4M (Viscosity—4000 cps) and HPMC K100M (Viscosity—100,000 cps) were received as gift samples from Colorcon Asia Pvt. Ltd., Mumbai (India). Avicel 101 (MCC PH-101) was received as gift sample from Ran Q Pharmaceuticals, Nashik (India). All other ingredients like DCP, PVP K-30, magnesium stearate and talc were procured from Loba Chemie Pvt. Ltd., Mumbai (India) and were of analytical grade. Table 1 Formulation of DS tablets containing microcrystalline cellulose as diluent.
2.2. Preparation of DS granules and tablets Granules of formulations A0–A6 and D0–D6 shown in Tables 1–3 of DS were prepared by wet granulation method. DS was passed through sieve no. 40 and mixed with all other excipients (except magnesium stearate and talc) which were previously passed through sieve no. 60 via geometric mixing. The blend was mixed for 10 min in a polybag. The mixture was then granulated using isopropyl alcohol (IPA) and the resulting wet mass was passed through sieve no. 14 to obtain granules of uniform size. The granules were then dried at 50 °C approximately for 15–20 min, after which they were passed through sieve no. 22. These sized granules were then blended with magnesium stearate and talc as lubricant and glidant respectively, mixed and were compressed into tablets using a 6 station rotary tablet punching machine fitted with round standard 10 mm flat punch. Tablets were then evaluated for thickness, diameter, hardness, friability and in-vitro release study. The granules of different formulations containing MCC and DCP as diluents were prepared using formulae as given in Tables 1 and 2 respectively. 2.3. Evaluation of granules Angle of repose, Bulk density and tapped density, Carr's Compressibility Index and Hausner's ratio of granules of each formulation were determined. 2.4. Evaluation of tablets 2.4.1. Physical characterization of tablets [11,12] Tablet thickness and diameter was measured using vernier calipers. Tablet hardness was measured by Monsanto hardness tester in terms of kg/cm 2. Roche friabilator was used for testing the friability of the tablets using following formula. % loss ¼ 100ðInitial wt:of tablets−Final wt:of tabletsÞ=Initial wt:of tablets
2.4.2. In vitro dissolution studies The dissolution test of DS tablets was performed in 900 ml of phosphate buffer pH 6.8 I.P., at 37 ± 0.5 °C and 50 rpm using USP dissolution testing apparatus II (Paddle type). A 10 ml sample solution was withdrawn from the dissolution apparatus at 30 min, 1 h and there after every hour for 8 h. Samples were replaced by its equivalent volume of dissolution medium. The samples were filtered through 0.45 μ Millipore filter (Cellulose acetate membrane) and analyzed at 276 nm by UV Spectrophotometer (Shimadzu, 1800, Japan). Cumulative percentage of drug release was calculated [13]. 2.5. Evaluation of compression properties 2.5.1. Tablet tensile strength Tensile strength (T) of the tablet was measured by compressing granules of formulation of DS containing different diluents at a Table 2 Formulation of DS tablets containing dibasic calcium phosphate as diluent.
Ingredientsa
A1
A2
A3
A4
A5
A6
Ingredientsa
A1
A2
A3
A4
A5
A6
DS HPMC K4M HPMC K100M Avicel 101 PVP K-30 Mg. Stearate Talc
45.45 22.73 – 20 6.36 1.82 3.64
41.67 20.83 – 30 2.50 1.67 3.33
34.48 17.24 – 40 4.14 1.38 2.76
45.45 – 22.73 20 6.36 1.82 3.64
41.67 – 20.83 30 2.50 1.67 3.33
34.48 – 17.24 40 4.14 1.38 2.76
DS HPMC K4M HPMC K100M DCP PVP K-30 Mg. Stearate Talc
45.45 22.73 – 20 6.36 1.82 3.64
41.67 20.83 – 30 2.50 1.67 3.33
34.48 17.24 – 40 4.14 1.38 2.76
45.45 – 22.73 20 6.36 1.82 3.64
41.67 – 20.83 30 2.50 1.67 3.33
34.48 – 17.24 40 4.14 1.38 2.76
a
All are in % with respect to total weight of tablet.
a
All are in % with respect to total weight of tablet.
M.P. Vaidya, A.M. Avachat / Powder Technology 214 (2011) 375–381 Table 3 Formulation of DS tablets without sustained release polymer.
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Table 4 Evaluation of granules of formulations of DS containing different diluents.
Ingredientsa
A0
D0
Parameter
A0–A6
D0–D6
DS Diluent PVP K-30 Mg. Stearate Talc
40 46.4 4.8 1.6 3.2
40 46.4 4.8 1.6 3.2
Angle of repose (°) Bulk density (g/cm3) Tapped density (g/cm3) Carr's Compressibility Index Hausner's ratio
24–26 0.26–0.28 0.28–0.30 6.80–7.10 1.07–1.08
29–31 0.35–0.38 0.39–0.42 8.90–9.20 1.09–1.10
A0—Formulation containing MCC as diluent. D0—Formulation containing DCP as diluent. a All are in % with respect to total weight of tablet.
constant pressure using 10 mm flat punch by adjusting total weight of each formulation, on a 6 station Rotary Tablet Compression Machine. Tablets were stored in airtight vials for 24 h and then their final thickness Tt and diameter Dt were measured using vernier calipers. Tablet hardness was measured using Erweka Hardness Tester in terms of N. The tablet tensile strength (T) was calculated using following formula T ¼ 2H=ΠDt Tt where H = Hardness Diameter of the tablet Thickness of the tablet
Dt Tt
A0–A60—Formulations containing MCC as diluent. D0–D60—Formulations containing DCP as diluent.
slope, 1/a and the intercept, 1/ab, of plots of P/C against applied pressure P. 2.5.2.5. Heckel's analysis [6]. The compaction characteristics of the powders were also studied using Heckel equation ln1=1−Dr ¼ KP þ A The Heckel's plot was plotted using ln 1 / 1 − Dr versus applied pressure P. From the plot K (the slope of the straight line portion) is obtained which is the reciprocal of the yield pressure, Py, of the material. From the intercept A, the relative density DA, can be calculated using the following Eq. −A
DA ¼ 1−e 2.5.2. Heckel's and Kawakita analysis 2.5.2.1. Determination of particle density [6]. The particle densities of the granules of optimized formulations were determined by the liquid displacement method using immiscible solvent (xylene) and the particle density (Dp) was computed according to the equation:
The relative density, D0, of the powder at the point when the applied pressure equals zero is obtained from. D0 = Bulk density/particle density DB is obtained from the difference between DA and D0. DB ¼ DA −D0
Dp ¼ W1 = W2þ W1 −W3 SG 2.6. Effect of diluent alone on drug release Where W1 is the weight of powder, SG is the specific gravity of the solvent, W2 is the weight of bottle + solvent and W3 is the weight of bottle + solvent + powder. 2.5.2.2. Preparation of compacts at different pressures. Compacts containing granules of optimized formulations were made using different compression pressure using tablet compression machine. Compression pressures were used in the range of 17.5 kN to 30 kN. Three compacts were made at each compression level. The compacts were stored over silica gel for 24 h (to allow for elastic recovery, hardening and prevent falsely low yield values) before evaluations. 2.5.2.3. Determination of relative density. The dimensions (thickness and diameter) of three compacts were determined. The relative density Dr was calculated as the ratio of apparent density D of the compact to the particle density Dp, of the granules. Dr = Density of the compact (D)/Particle density (Dp,) The data obtained was used for drawing the Heckel plots. 2.5.2.4. Kawakita analysis [14]. The flowability and compressibility of the granules of different formulations was studied by Kawakita equation P=C ¼ P=a þ 1=ab The Kawakita plot was plotted using P/C versus applied pressure P. Numerical values for constants ‘a’ and 1/b are obtained from the
To study the effect of diluent alone on drug release, granules of DS containing all ingredients except sustained release polymer were prepared by wet granulation. The procedure used for preparation of granules was the same as given in Section 2.2. The formula used for preparation of tablets is given in Table 3. The dissolution profile of these tablets was done using procedure given in Section 2.4.2 for 90 min. 2.7. Influence of compression force on in vitro release The dissolution profile of the tablets compressed at different compression forces ranging from 17.5 kN to 30 kN was studied. The procedure used for dissolution test of tablets was the same as given in Section 2.4.2. 3. Results and discussion 3.1. Evaluation of granules Various granule evaluation parameters like angle of repose, bulk and tapped density, Carr's Compressibility Index and Hausner's ratio were obtained as shown in Table 4. Granules of formulation containing MCC as diluent showed good flowabity and compressibility as compared to granules containing DCP. The Carr's Index and Hausner's ratio are measures of Propensity of powder to be compressed and Angle of repose is a characteristic related to interparticulate friction or resistance to movement between particles. The angle of repose is
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3.2.2. In vitro dissolution studies
Table 5 Tablet evaluation parameters. Parameter
A0–A6
D0–D6
Thickness (mm) Diameter (mm) Hardness (Kg/cm2) Friability (%)
3.70–4.30 10.00 ± 0.05 5–6 b1
3.30–3.70 10.00 ± 0.05 4–5 b1
A0–A60—Formulations containing MCC as diluent. D0–D60—Formulations containing DCP as diluent.
3.2.2.1. Effect of type of diluent on release profile. Fig. 1 shows the effect of type of diluent (40% concentration) on the release of drug containing 50% HPMC (with respect to drug) of two grades i.e. HPMC K4M and HPMC K100M. Tablets containing DCP as water insoluble and inorganic diluent showed slowest drug release with respect to formulations containing MCC which is insoluble and organic in nature. This might be due to its
Fig. 1. Effect of type of diluents on the release tablets containing HPMC K4M and HPMC K100M respectively.
not more than 30° as well as the Carr's index is below 10%, both indicating the flow properties and compressibility to be good. A table showing relationship between angle of repose, Carr's compressibility index, Hausner's ratio and flowability is given in USP 30 NF-25 which clearly shows that granules of all the formulations has good flowability and compressibility [15].
3.2. Evalutaion of tablets 3.2.1. Physical characterization of tablets Tablet dimensions, hardness and friability were determined for each formulations and which is shown in Table 5. The thickness of tablets containing MCC is different from that containing DCP. This showed that there is an effect of change in diluent on tablet thickness. The change in tablet thickness may also be due to a change in the compressibility of the diluent used. The hardness of formulations with DCP is less which may be due to poor compressibility of DCP as compared to MCC.
insoluble nature or hydrophobicity which was not overcome by the ability of swelling due to HPMC. This caused a retardation of the dissolution fluid to penetrate into the matrix. It indicates that it has imparted hydrophobicity to the entire matrix and has decreased the water ingress and hence release of drug. From Fig. 1, it is clear that there is great difference in the drug release from tablets containing MCC and DCP as diluents. After 8 h dissolution study tablets containing MCC showed 55% drug release while that of DCP showed only 18% release for HPMC K4M matrices. Similarly for HPMC K100M matrices tablets of MCC showed 48% release while tablets of DCP showed 17% release. From this it can be concluded that DCP has very high release retardant property as compared to MCC.
3.2.2.2. Effect of diluent concentration on drug release. To check the effect of diluent concentration on release, each diluent was used in 20, 30 and 40% concentration of formulation containing a constant concentration of 2 different grades of HPMC as sustained release polymer.
Fig. 2. Effect of concentration of MCC on DS release containing HPMC K4M and HPMC K100M respectively (Formulations A1–A6).
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Fig. 3. Effect of concentration of DCP on DS release HPMC K4M and HPMC K100M respectively (Formulations D1–D6).
Effect of concentration of MCC on the release of DS from tablets containing different grades of HPMC is shown in Fig. 2. Effect of concentration of DCP on the release of DS from tablets containing different grades of HPMC is shown in Fig. 3. The results showed that there is a decrease in the release of DS as the concentration of MCC or DCP is increased in the formulation. This might be due to the insoluble nature of MCC and DCP which may retard the penetration of dissolution fluid into the tablets which causes retardation in the drug release. Also there may be a synergistic effect between MCC and HPMC as both are cellulose derivatives, which causes decrease in the release as concentration of MCC was increased. While in the case of DCP it may be due to its hydrophobic nature as discussed earlier. The results also show that irrespective of the grade or concentration of HPMC, the effect of MCC or DCP concentration remains the same i.e. release decreases with increase in diluent concentration. 3.3. Evaluation of compression properties Compression represents one of the most important unit operations because the shape, strength and other important properties of the tablets are determined at this time. The compression properties of the formulation may change as the constituents in the formulation changes due to the differences in properties of the excipients. This is evaluated using simple techniques like determination of particle density, relative density, tensile strength and complex mathematical equations like Kawakita and Heckel's equation. 3.3.1. Tablet tensile strength A practical approach and the simplest way to quantify the compactibility is the tensile strength, where minimum pressure is needed to make a compact of a given strength. Tablets must retain their mechanical integrity until administration. Tensile strength is one of the most important mechanical properties. It has been generally recognized that tablet tensile strength is influenced by the number of contact points between the powder particles and the inter-particle binding force, such as the surface molecular interaction and mechan-
Table 6 Tensile strength of formulations of DS containing different diluents. Formulation
A6
D6
Tensile strength (MN/m2)
5.011 ± 0.05
3.0764 ± 0.05
All values are mean ± SD (n = 5).
Table 7 Particle density of granules of formulation of each diluent. Formulation
A6
D6
Particle density (g/cm3)
4.7267
8.3173
ical interlocking. The tensile strength of formulations is given in Table 6. The tensile strength of tablets containing MCC is 5.011 MN/m 2 and that of DCP is 3.0764 MN/m 2. Thus it can be observed that the tablets containing MCC as diluent showed good tensile strength as compared to tablets containing DCP, which might be due to the good compressibility of MCC with HPMC. MCC has free hydroxyl groups; hence there is stronger interaction force due to hydrogen bonding in hydroxyl groups resulting in increased compressibility [14]. Hence the tablets of MCC were hard and robust while tablets of DCP were soft in nature. 3.3.2. Heckel's and Kawakita analysis 3.3.2.1. Particle density. The particle density of granules of formulation of each diluent was determined and is given in Table 7. High particle density favors free flow of powders. Granules of DCP showed higher particle density (8.3173 g/cm 3) than the granules of MCC (4.7267 g/cm 3). This means that formulations containing DCP has good flowability but poor compressibility as compared to MCC. 3.3.2.2. Kawakita analysis. The Kawakita plots for formulations plotted using P/C versus P are shown in Fig. 4 and parameters obtained are shown in Table 8. As discussed earlier less the ‘a’ value least is the densification. From this it can be concluded that granules of MCC showed good densification during the compression process as compared to DCP. Also the value of Pk gives an inverse relation with the plastic deformation during compression process. From this it can be concluded that degree of plastic deformation for granules of MCC is significantly greater as compared granules of DCP [16]. 3.3.2.3. Heckel's analysis. The compaction characteristics of the powders were studied using Heckel equation, ln1=1−Dr ¼ KP þ A Where Dr is the density of the compact relative to the particle density of the material being compacted i.e. relative density of the compact, P is the applied pressure, K is constant. The Heckel's plot was plotted using ln 1 / 1 − Dr versus applied pressure P and is shown in Fig. 5. Parameters obtained from Heckel's plot are shown in Table 8. The mean yield pressure Py is inversely related to the formulations ability to deform plastically under pressure. Low values of Py indicate faster onset of plastic deformation [17]. The Py value for granules of formulation containing MCC is less as compared to DCP. This indicates that MCC showed faster onset of plastic deformation during compression than DCP. The D0 and DA values represent the initial rearrangement phase of densification as a result of die filling at low pressure [18]. The formulation containing MCC showed higher D0 and DA values than formulations containing DCP. This indicates that formulation containing MCC exhibited higher degree of densification at zero and low pressure, while formulation
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Fig. 6. Effect of diluents alone on release profile of DS.
Fig. 4. Kawakita plots for granules of formulations.
Table 8 Parameters obtained from Kawakita plots and Heckel's plots. Sr. no.
Parameters
A6
D6
1 2 3 4 5 6 7 8
1/a Compactibility (%) (a) Cohesiveness (Pk = 1/b) K A Py (kN) DA D0
1.25 0.8 0.332 0.0017 0.282 588.2353 0.2457 0.058
1.2970 0.771 0.6584 0.0006 0.1704 1666.667 0.1567 0.0471
containing DCP showed less degree of densification at zero and low pressure [19,20]. The DB value represents the particle rearrangement phase in the early compression stages. Decrease in DB value causes decrease in granule fragmentation [16]. Again formulations containing MCC showed higher DB value and formulation containing DCP showed lower value. This indicates that the granule fragmentation for MCC is high while that of DCP is low. From the compression study (Tensile strength, Heckel's and Kawakita analysis) it can be concluded that granules of MCC have better compactibility than the granules of DCP.
Fig. 7. Effect of compression force on release of formulation containing MCC as diluent.
hydrophobic nature. There is a large difference of about 40% in the drug release from both the formulations after 5 h. Hence it can be concluded that DCP may have its own release retardant property which is independent of presence of sustained release polymer or that it can be a good additive to enhance the retardant property of sustained release agent like HPMC.
3.4. Effect of diluent alone on drug release
3.5. Influence of compression force on in vitro release
The effect of diluents without sustained release polymers on release of the drug was studied to check whether diluent alone affects the release characteristics of the drug. Fig. 6 shows the effect of diluent alone on the release of DS. The tablets containing MCC disintegrated within 15 min because of its own disintegrant property, resulting in increased release of DS as compared to tablets containing DCP. However tablets containing DCP were unable to disintegrate because of lack of inherent disintegrant property of DCP and its
The release of tablets containing MCC and DCP as diluents at different compression forces is shown in Figs. 7 and 8 respectively. The results showed that there is a slight decrease in the release from tablets of each formulation as the compression force goes on increasing. This might be due to reduction in the porosity of the matrices with
Fig. 5. Heckel's plot for granules of formulations.
Fig. 8. Effect of compression force on release of formulation containing DCP as diluent.
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increasing compression force, leading to slower water uptake and water front movement into the matrix, which in turn, may lead to slower drug release [2]. From this it can be concluded that though compression force affects the drug release from sustained release tablets, it is not to a large extent. It is the difference in the properties of the diluents which has a higher impact on the drug release. 4. Conclusion From the compression characteristics it can be concluded that tablets containing MCC have good tensile strength as compared to DCP. From the Kawakita and Heckel's analysis it can be concluded that granules of MCC showed higher densification, higher degree of plastic deformation, as well as, higher granule fragmentation as compared to DCP. However, the in vitro dissolution studies revealed that DCP which is a more hydrophobic excipient affects the release characteristics to a larger extent than MCC even when combined with cellulose based retardant material like HPMC. The overall dissolution study reveals that insoluble diluents inherently have some release retardant property in sustained release matrices and one can use less amounts of the sustained release polymers which are generally expensive to achieve control release by using an insoluble diluent. Acknowledgments The authors are grateful to Lupin Research Park, Pune, India and Colorcon Asia Private Ltd, Goa, India for the gift samples of Diclofenac Sodium and hydroxypropyl methylcellulose respectively. References [1] G.S. Bankar, N.R. Anderson, Tablets, in: L. Lachman, H.A. Lieberman, J.L. Kanig (Eds.), The Theory and Practice of Industrial Pharmacy, Third ed., Varghese publishing house, Mumbai, 1990, p. 325. [2] M. Levina, A.R. Rajabi-Siahboomi, The influence of excipients on drug release from hydroxypropyl methylcellulose matrices, Journal of Pharmaceutical Sciences 93 (11) (2004) 2746–2754. [3] P. Thapa, M. Ghimire, A.B. Mullen, H.N.E. Stevens, Controlled release oral delivery system containing water insoluble drug, Kathmandu University Journal of Science, Engineering Technology I (1) (2005) 1–10.
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Investigation of the impact of insoluble diluents on the compression and release properties of matrix based sustained release tablets M.P. Vaidya, A.M. Avachat ⁎ Sinhgad College of Pharmacy, Vadgaon (Bk), Pune-411 041 (MS), India
a r t i c l e
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Article history: Received 27 January 2011 Received in revised form 19 July 2011 Accepted 28 August 2011 Available online 3 September 2011 Keywords: Microcrystalline cellulose Dibasic calcium phosphate Sustained release Heckel's equation Kawakita equation Compression force
a b s t r a c t In the present study the effect of insoluble diluents such as microcrystalline cellulose (MCC) and dibasic calcium phosphate (DCP) on the compression characteristics and release profile of sustained release tablets containing Hydroxypropylmethylcellulose (HPMC) matrices was investigated. The effect of diluents on the compression characteristics was studied using Heckel and Kawakita equations. The effect of compression forces on the release profile was also investigated. Diclofenac Sodium (DS) was used as a model drug. Tablets were prepared using wet granulation method. It was found that there is a decrease in the drug release as the concentration of these insoluble diluents is increased. From the Heckel and Kawakita analysis it was concluded that the compressed granules of formulations containing microcrystalline cellulose showed higher plastic deformation, densification and granule fragmentation as compared to DCP. Also a relationship was evaluated between the compression force and the release profile i.e. an increase in compression force causes decrease in the release rate of the drug from the formulation irrespective of change in the diluent. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Diluents are fillers designed to make up the required bulk of the tablet when the drug dosage itself is inadequate to produce this bulk. Diluents can also be used in tablet formulation for following purpose. ➣ To provide better tablet properties such as improved cohesiveness ➣ To permit use of direct-compression manufacturing ➣ To promote flow of the powder or granules [1] As the diluents used for the preparation of tablets are of different types, they are responsible for change in the physical properties and the performance of the formulation with respect to each diluent. Also concentration of diluent in the formulation is important, which may cause change in the properties of the final formulation especially with reference to the release and compressional characteristics of tablets. Microcrystalline cellulose (MCC) is an organic diluent while dicalcium phosphate (DCP) is an inorganic diluent and both are water insoluble. Nonionic cellulose ethers, and most frequently hydroxypropyl methylcellulose (HPMC, hypromellose) have been widely studied
⁎ Corresponding author at: Sinhgad College of Pharmacy, 44/1, Vadgaon (Bk.), Pune411 041, Maharshtra, India. Tel.: +91 98224 56636. E-mail address: [email protected] (A.M. Avachat). 0032-5910/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2011.08.035
for their applications in oral sustained release (SR) systems. When in contact with water, HPMC hydrates rapidly and forms a gelatinous barrier layer around the tablet. The rate of drug release from HPMC matrix is dependent on various factors such as type of polymer, drug, polymer/drug ratio, particle size of drug and polymer, and the type and amount of fillers used in the formulation [2]. Work has been done to see the effect of Carbopol 934P concentration and granulation technique on the release of poorly water-soluble drug (Ibuprofen) [3]. Also the influence of commonly used excipients, spray-dried lactose (SDL), MCC, and partially pregelatinized maize starch (Starch 1500) on drug release from HPMC matrix tablets prepared by direct compression has been studied [2]. Some authors studied the relationship and influence of different levels of MCC, starch, and lactose, in order to achieve a zero-order release of Diclofenac Sodium [4]. Investigation of the influence of the concentration of the matrix material (carbopol 974P) and several co-excipients (lactose, microcrystalline cellulose, and starch) on the release rate of the drug has also been reported [5]. To measure the flowability and compressibility of the granules of different formulations Kawakita analysis was done. The Kawakita relationship is employed to determine the tensile strength of agglomerates provided that the influence of the friction at the die wall has been taken into account since it is well known that wall friction significantly increases resistance to deformation. The Kawakita equation is as follows [6]
P=C ¼ P=a þ 1=ab
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Where P is the applied pressure, C is the degree of volume reduction and is calculated from the initial volume V0 and tapped volume V as: C ¼ ðV0 −VÞ=V ‘a’ and ‘b’ are constants. ‘a’ describes the degree of volume reduction at the limit of tapping and is called compactibility; 1/b is considered to be a constant related to cohesion and is called cohesiveness. Kawakita constants ‘a’ and ‘b’ were obtained from the slope and intercept of the plots for each formulation, where ‘a’ represents the minimum porosity of the bed prior to compression while ‘b’, which is termed the coefficient of compression is related to the plasticity of the material. The reciprocal of ‘b’ is a pressure term designated as Pk, which is the pressure required to reduce the powder bed by 50%. The value of Pk gives an inverse relation with the plastic deformation during compression process. The lower the value of Pk, higher is the degree of plastic deformation occurring during compression. The study of the mechanical properties of cylindrical compacts of lactose and microcrystalline cellulose with the help of tensile and compressive strength has been reported [7]. Some authors studied the relationship between the material properties of various αlactose monohydrate grades (αLM), process parameters (punch velocity, lubricant fraction) and the tablet tensile strength (TS) using Heckel and Kawakita analysis, as well as, used it for studying compaction properties of three types of starches and the mechanical properties of their tablets [8,9]. Compression behaviors of spray dried rice starch (SDRS), as well as pregelatinized starch (PS), and MCC were characterized using Heckel analysis was also reported in the literature [10]. However a detailed investigation of the effect of insoluble diluents on the compressional behavior characteristics of a tablet containing a retardant material and the release profile has not been reported. The objectives of this study were: i) To investigate the effect of concentration and type of insoluble diluents on the release profile of tablets containing HPMC matrices. ii) To characterize the compression behavior of the tablets containing insoluble diluents namely MCC and DCP using Heckel and Kawakita equations. iii) To investigate the effect of compression forces on the release. 2. Materials and methods 2.1. Materials Diclofenac Sodium was received as a gift sample from Lupin Research Park, Pune (India). HPMC K4M (Viscosity—4000 cps) and HPMC K100M (Viscosity—100,000 cps) were received as gift samples from Colorcon Asia Pvt. Ltd., Mumbai (India). Avicel 101 (MCC PH-101) was received as gift sample from Ran Q Pharmaceuticals, Nashik (India). All other ingredients like DCP, PVP K-30, magnesium stearate and talc were procured from Loba Chemie Pvt. Ltd., Mumbai (India) and were of analytical grade. Table 1 Formulation of DS tablets containing microcrystalline cellulose as diluent.
2.2. Preparation of DS granules and tablets Granules of formulations A0–A6 and D0–D6 shown in Tables 1–3 of DS were prepared by wet granulation method. DS was passed through sieve no. 40 and mixed with all other excipients (except magnesium stearate and talc) which were previously passed through sieve no. 60 via geometric mixing. The blend was mixed for 10 min in a polybag. The mixture was then granulated using isopropyl alcohol (IPA) and the resulting wet mass was passed through sieve no. 14 to obtain granules of uniform size. The granules were then dried at 50 °C approximately for 15–20 min, after which they were passed through sieve no. 22. These sized granules were then blended with magnesium stearate and talc as lubricant and glidant respectively, mixed and were compressed into tablets using a 6 station rotary tablet punching machine fitted with round standard 10 mm flat punch. Tablets were then evaluated for thickness, diameter, hardness, friability and in-vitro release study. The granules of different formulations containing MCC and DCP as diluents were prepared using formulae as given in Tables 1 and 2 respectively. 2.3. Evaluation of granules Angle of repose, Bulk density and tapped density, Carr's Compressibility Index and Hausner's ratio of granules of each formulation were determined. 2.4. Evaluation of tablets 2.4.1. Physical characterization of tablets [11,12] Tablet thickness and diameter was measured using vernier calipers. Tablet hardness was measured by Monsanto hardness tester in terms of kg/cm 2. Roche friabilator was used for testing the friability of the tablets using following formula. % loss ¼ 100ðInitial wt:of tablets−Final wt:of tabletsÞ=Initial wt:of tablets
2.4.2. In vitro dissolution studies The dissolution test of DS tablets was performed in 900 ml of phosphate buffer pH 6.8 I.P., at 37 ± 0.5 °C and 50 rpm using USP dissolution testing apparatus II (Paddle type). A 10 ml sample solution was withdrawn from the dissolution apparatus at 30 min, 1 h and there after every hour for 8 h. Samples were replaced by its equivalent volume of dissolution medium. The samples were filtered through 0.45 μ Millipore filter (Cellulose acetate membrane) and analyzed at 276 nm by UV Spectrophotometer (Shimadzu, 1800, Japan). Cumulative percentage of drug release was calculated [13]. 2.5. Evaluation of compression properties 2.5.1. Tablet tensile strength Tensile strength (T) of the tablet was measured by compressing granules of formulation of DS containing different diluents at a Table 2 Formulation of DS tablets containing dibasic calcium phosphate as diluent.
Ingredientsa
A1
A2
A3
A4
A5
A6
Ingredientsa
A1
A2
A3
A4
A5
A6
DS HPMC K4M HPMC K100M Avicel 101 PVP K-30 Mg. Stearate Talc
45.45 22.73 – 20 6.36 1.82 3.64
41.67 20.83 – 30 2.50 1.67 3.33
34.48 17.24 – 40 4.14 1.38 2.76
45.45 – 22.73 20 6.36 1.82 3.64
41.67 – 20.83 30 2.50 1.67 3.33
34.48 – 17.24 40 4.14 1.38 2.76
DS HPMC K4M HPMC K100M DCP PVP K-30 Mg. Stearate Talc
45.45 22.73 – 20 6.36 1.82 3.64
41.67 20.83 – 30 2.50 1.67 3.33
34.48 17.24 – 40 4.14 1.38 2.76
45.45 – 22.73 20 6.36 1.82 3.64
41.67 – 20.83 30 2.50 1.67 3.33
34.48 – 17.24 40 4.14 1.38 2.76
a
All are in % with respect to total weight of tablet.
a
All are in % with respect to total weight of tablet.
M.P. Vaidya, A.M. Avachat / Powder Technology 214 (2011) 375–381 Table 3 Formulation of DS tablets without sustained release polymer.
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Table 4 Evaluation of granules of formulations of DS containing different diluents.
Ingredientsa
A0
D0
Parameter
A0–A6
D0–D6
DS Diluent PVP K-30 Mg. Stearate Talc
40 46.4 4.8 1.6 3.2
40 46.4 4.8 1.6 3.2
Angle of repose (°) Bulk density (g/cm3) Tapped density (g/cm3) Carr's Compressibility Index Hausner's ratio
24–26 0.26–0.28 0.28–0.30 6.80–7.10 1.07–1.08
29–31 0.35–0.38 0.39–0.42 8.90–9.20 1.09–1.10
A0—Formulation containing MCC as diluent. D0—Formulation containing DCP as diluent. a All are in % with respect to total weight of tablet.
constant pressure using 10 mm flat punch by adjusting total weight of each formulation, on a 6 station Rotary Tablet Compression Machine. Tablets were stored in airtight vials for 24 h and then their final thickness Tt and diameter Dt were measured using vernier calipers. Tablet hardness was measured using Erweka Hardness Tester in terms of N. The tablet tensile strength (T) was calculated using following formula T ¼ 2H=ΠDt Tt where H = Hardness Diameter of the tablet Thickness of the tablet
Dt Tt
A0–A60—Formulations containing MCC as diluent. D0–D60—Formulations containing DCP as diluent.
slope, 1/a and the intercept, 1/ab, of plots of P/C against applied pressure P. 2.5.2.5. Heckel's analysis [6]. The compaction characteristics of the powders were also studied using Heckel equation ln1=1−Dr ¼ KP þ A The Heckel's plot was plotted using ln 1 / 1 − Dr versus applied pressure P. From the plot K (the slope of the straight line portion) is obtained which is the reciprocal of the yield pressure, Py, of the material. From the intercept A, the relative density DA, can be calculated using the following Eq. −A
DA ¼ 1−e 2.5.2. Heckel's and Kawakita analysis 2.5.2.1. Determination of particle density [6]. The particle densities of the granules of optimized formulations were determined by the liquid displacement method using immiscible solvent (xylene) and the particle density (Dp) was computed according to the equation:
The relative density, D0, of the powder at the point when the applied pressure equals zero is obtained from. D0 = Bulk density/particle density DB is obtained from the difference between DA and D0. DB ¼ DA −D0
Dp ¼ W1 = W2þ W1 −W3 SG 2.6. Effect of diluent alone on drug release Where W1 is the weight of powder, SG is the specific gravity of the solvent, W2 is the weight of bottle + solvent and W3 is the weight of bottle + solvent + powder. 2.5.2.2. Preparation of compacts at different pressures. Compacts containing granules of optimized formulations were made using different compression pressure using tablet compression machine. Compression pressures were used in the range of 17.5 kN to 30 kN. Three compacts were made at each compression level. The compacts were stored over silica gel for 24 h (to allow for elastic recovery, hardening and prevent falsely low yield values) before evaluations. 2.5.2.3. Determination of relative density. The dimensions (thickness and diameter) of three compacts were determined. The relative density Dr was calculated as the ratio of apparent density D of the compact to the particle density Dp, of the granules. Dr = Density of the compact (D)/Particle density (Dp,) The data obtained was used for drawing the Heckel plots. 2.5.2.4. Kawakita analysis [14]. The flowability and compressibility of the granules of different formulations was studied by Kawakita equation P=C ¼ P=a þ 1=ab The Kawakita plot was plotted using P/C versus applied pressure P. Numerical values for constants ‘a’ and 1/b are obtained from the
To study the effect of diluent alone on drug release, granules of DS containing all ingredients except sustained release polymer were prepared by wet granulation. The procedure used for preparation of granules was the same as given in Section 2.2. The formula used for preparation of tablets is given in Table 3. The dissolution profile of these tablets was done using procedure given in Section 2.4.2 for 90 min. 2.7. Influence of compression force on in vitro release The dissolution profile of the tablets compressed at different compression forces ranging from 17.5 kN to 30 kN was studied. The procedure used for dissolution test of tablets was the same as given in Section 2.4.2. 3. Results and discussion 3.1. Evaluation of granules Various granule evaluation parameters like angle of repose, bulk and tapped density, Carr's Compressibility Index and Hausner's ratio were obtained as shown in Table 4. Granules of formulation containing MCC as diluent showed good flowabity and compressibility as compared to granules containing DCP. The Carr's Index and Hausner's ratio are measures of Propensity of powder to be compressed and Angle of repose is a characteristic related to interparticulate friction or resistance to movement between particles. The angle of repose is
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3.2.2. In vitro dissolution studies
Table 5 Tablet evaluation parameters. Parameter
A0–A6
D0–D6
Thickness (mm) Diameter (mm) Hardness (Kg/cm2) Friability (%)
3.70–4.30 10.00 ± 0.05 5–6 b1
3.30–3.70 10.00 ± 0.05 4–5 b1
A0–A60—Formulations containing MCC as diluent. D0–D60—Formulations containing DCP as diluent.
3.2.2.1. Effect of type of diluent on release profile. Fig. 1 shows the effect of type of diluent (40% concentration) on the release of drug containing 50% HPMC (with respect to drug) of two grades i.e. HPMC K4M and HPMC K100M. Tablets containing DCP as water insoluble and inorganic diluent showed slowest drug release with respect to formulations containing MCC which is insoluble and organic in nature. This might be due to its
Fig. 1. Effect of type of diluents on the release tablets containing HPMC K4M and HPMC K100M respectively.
not more than 30° as well as the Carr's index is below 10%, both indicating the flow properties and compressibility to be good. A table showing relationship between angle of repose, Carr's compressibility index, Hausner's ratio and flowability is given in USP 30 NF-25 which clearly shows that granules of all the formulations has good flowability and compressibility [15].
3.2. Evalutaion of tablets 3.2.1. Physical characterization of tablets Tablet dimensions, hardness and friability were determined for each formulations and which is shown in Table 5. The thickness of tablets containing MCC is different from that containing DCP. This showed that there is an effect of change in diluent on tablet thickness. The change in tablet thickness may also be due to a change in the compressibility of the diluent used. The hardness of formulations with DCP is less which may be due to poor compressibility of DCP as compared to MCC.
insoluble nature or hydrophobicity which was not overcome by the ability of swelling due to HPMC. This caused a retardation of the dissolution fluid to penetrate into the matrix. It indicates that it has imparted hydrophobicity to the entire matrix and has decreased the water ingress and hence release of drug. From Fig. 1, it is clear that there is great difference in the drug release from tablets containing MCC and DCP as diluents. After 8 h dissolution study tablets containing MCC showed 55% drug release while that of DCP showed only 18% release for HPMC K4M matrices. Similarly for HPMC K100M matrices tablets of MCC showed 48% release while tablets of DCP showed 17% release. From this it can be concluded that DCP has very high release retardant property as compared to MCC.
3.2.2.2. Effect of diluent concentration on drug release. To check the effect of diluent concentration on release, each diluent was used in 20, 30 and 40% concentration of formulation containing a constant concentration of 2 different grades of HPMC as sustained release polymer.
Fig. 2. Effect of concentration of MCC on DS release containing HPMC K4M and HPMC K100M respectively (Formulations A1–A6).
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Fig. 3. Effect of concentration of DCP on DS release HPMC K4M and HPMC K100M respectively (Formulations D1–D6).
Effect of concentration of MCC on the release of DS from tablets containing different grades of HPMC is shown in Fig. 2. Effect of concentration of DCP on the release of DS from tablets containing different grades of HPMC is shown in Fig. 3. The results showed that there is a decrease in the release of DS as the concentration of MCC or DCP is increased in the formulation. This might be due to the insoluble nature of MCC and DCP which may retard the penetration of dissolution fluid into the tablets which causes retardation in the drug release. Also there may be a synergistic effect between MCC and HPMC as both are cellulose derivatives, which causes decrease in the release as concentration of MCC was increased. While in the case of DCP it may be due to its hydrophobic nature as discussed earlier. The results also show that irrespective of the grade or concentration of HPMC, the effect of MCC or DCP concentration remains the same i.e. release decreases with increase in diluent concentration. 3.3. Evaluation of compression properties Compression represents one of the most important unit operations because the shape, strength and other important properties of the tablets are determined at this time. The compression properties of the formulation may change as the constituents in the formulation changes due to the differences in properties of the excipients. This is evaluated using simple techniques like determination of particle density, relative density, tensile strength and complex mathematical equations like Kawakita and Heckel's equation. 3.3.1. Tablet tensile strength A practical approach and the simplest way to quantify the compactibility is the tensile strength, where minimum pressure is needed to make a compact of a given strength. Tablets must retain their mechanical integrity until administration. Tensile strength is one of the most important mechanical properties. It has been generally recognized that tablet tensile strength is influenced by the number of contact points between the powder particles and the inter-particle binding force, such as the surface molecular interaction and mechan-
Table 6 Tensile strength of formulations of DS containing different diluents. Formulation
A6
D6
Tensile strength (MN/m2)
5.011 ± 0.05
3.0764 ± 0.05
All values are mean ± SD (n = 5).
Table 7 Particle density of granules of formulation of each diluent. Formulation
A6
D6
Particle density (g/cm3)
4.7267
8.3173
ical interlocking. The tensile strength of formulations is given in Table 6. The tensile strength of tablets containing MCC is 5.011 MN/m 2 and that of DCP is 3.0764 MN/m 2. Thus it can be observed that the tablets containing MCC as diluent showed good tensile strength as compared to tablets containing DCP, which might be due to the good compressibility of MCC with HPMC. MCC has free hydroxyl groups; hence there is stronger interaction force due to hydrogen bonding in hydroxyl groups resulting in increased compressibility [14]. Hence the tablets of MCC were hard and robust while tablets of DCP were soft in nature. 3.3.2. Heckel's and Kawakita analysis 3.3.2.1. Particle density. The particle density of granules of formulation of each diluent was determined and is given in Table 7. High particle density favors free flow of powders. Granules of DCP showed higher particle density (8.3173 g/cm 3) than the granules of MCC (4.7267 g/cm 3). This means that formulations containing DCP has good flowability but poor compressibility as compared to MCC. 3.3.2.2. Kawakita analysis. The Kawakita plots for formulations plotted using P/C versus P are shown in Fig. 4 and parameters obtained are shown in Table 8. As discussed earlier less the ‘a’ value least is the densification. From this it can be concluded that granules of MCC showed good densification during the compression process as compared to DCP. Also the value of Pk gives an inverse relation with the plastic deformation during compression process. From this it can be concluded that degree of plastic deformation for granules of MCC is significantly greater as compared granules of DCP [16]. 3.3.2.3. Heckel's analysis. The compaction characteristics of the powders were studied using Heckel equation, ln1=1−Dr ¼ KP þ A Where Dr is the density of the compact relative to the particle density of the material being compacted i.e. relative density of the compact, P is the applied pressure, K is constant. The Heckel's plot was plotted using ln 1 / 1 − Dr versus applied pressure P and is shown in Fig. 5. Parameters obtained from Heckel's plot are shown in Table 8. The mean yield pressure Py is inversely related to the formulations ability to deform plastically under pressure. Low values of Py indicate faster onset of plastic deformation [17]. The Py value for granules of formulation containing MCC is less as compared to DCP. This indicates that MCC showed faster onset of plastic deformation during compression than DCP. The D0 and DA values represent the initial rearrangement phase of densification as a result of die filling at low pressure [18]. The formulation containing MCC showed higher D0 and DA values than formulations containing DCP. This indicates that formulation containing MCC exhibited higher degree of densification at zero and low pressure, while formulation
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Fig. 6. Effect of diluents alone on release profile of DS.
Fig. 4. Kawakita plots for granules of formulations.
Table 8 Parameters obtained from Kawakita plots and Heckel's plots. Sr. no.
Parameters
A6
D6
1 2 3 4 5 6 7 8
1/a Compactibility (%) (a) Cohesiveness (Pk = 1/b) K A Py (kN) DA D0
1.25 0.8 0.332 0.0017 0.282 588.2353 0.2457 0.058
1.2970 0.771 0.6584 0.0006 0.1704 1666.667 0.1567 0.0471
containing DCP showed less degree of densification at zero and low pressure [19,20]. The DB value represents the particle rearrangement phase in the early compression stages. Decrease in DB value causes decrease in granule fragmentation [16]. Again formulations containing MCC showed higher DB value and formulation containing DCP showed lower value. This indicates that the granule fragmentation for MCC is high while that of DCP is low. From the compression study (Tensile strength, Heckel's and Kawakita analysis) it can be concluded that granules of MCC have better compactibility than the granules of DCP.
Fig. 7. Effect of compression force on release of formulation containing MCC as diluent.
hydrophobic nature. There is a large difference of about 40% in the drug release from both the formulations after 5 h. Hence it can be concluded that DCP may have its own release retardant property which is independent of presence of sustained release polymer or that it can be a good additive to enhance the retardant property of sustained release agent like HPMC.
3.4. Effect of diluent alone on drug release
3.5. Influence of compression force on in vitro release
The effect of diluents without sustained release polymers on release of the drug was studied to check whether diluent alone affects the release characteristics of the drug. Fig. 6 shows the effect of diluent alone on the release of DS. The tablets containing MCC disintegrated within 15 min because of its own disintegrant property, resulting in increased release of DS as compared to tablets containing DCP. However tablets containing DCP were unable to disintegrate because of lack of inherent disintegrant property of DCP and its
The release of tablets containing MCC and DCP as diluents at different compression forces is shown in Figs. 7 and 8 respectively. The results showed that there is a slight decrease in the release from tablets of each formulation as the compression force goes on increasing. This might be due to reduction in the porosity of the matrices with
Fig. 5. Heckel's plot for granules of formulations.
Fig. 8. Effect of compression force on release of formulation containing DCP as diluent.
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increasing compression force, leading to slower water uptake and water front movement into the matrix, which in turn, may lead to slower drug release [2]. From this it can be concluded that though compression force affects the drug release from sustained release tablets, it is not to a large extent. It is the difference in the properties of the diluents which has a higher impact on the drug release. 4. Conclusion From the compression characteristics it can be concluded that tablets containing MCC have good tensile strength as compared to DCP. From the Kawakita and Heckel's analysis it can be concluded that granules of MCC showed higher densification, higher degree of plastic deformation, as well as, higher granule fragmentation as compared to DCP. However, the in vitro dissolution studies revealed that DCP which is a more hydrophobic excipient affects the release characteristics to a larger extent than MCC even when combined with cellulose based retardant material like HPMC. The overall dissolution study reveals that insoluble diluents inherently have some release retardant property in sustained release matrices and one can use less amounts of the sustained release polymers which are generally expensive to achieve control release by using an insoluble diluent. Acknowledgments The authors are grateful to Lupin Research Park, Pune, India and Colorcon Asia Private Ltd, Goa, India for the gift samples of Diclofenac Sodium and hydroxypropyl methylcellulose respectively. References [1] G.S. Bankar, N.R. Anderson, Tablets, in: L. Lachman, H.A. Lieberman, J.L. Kanig (Eds.), The Theory and Practice of Industrial Pharmacy, Third ed., Varghese publishing house, Mumbai, 1990, p. 325. [2] M. Levina, A.R. Rajabi-Siahboomi, The influence of excipients on drug release from hydroxypropyl methylcellulose matrices, Journal of Pharmaceutical Sciences 93 (11) (2004) 2746–2754. [3] P. Thapa, M. Ghimire, A.B. Mullen, H.N.E. Stevens, Controlled release oral delivery system containing water insoluble drug, Kathmandu University Journal of Science, Engineering Technology I (1) (2005) 1–10.
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