http://informahealthcare.com/ddi ISSN: 0363-9045 (print), 1520-5762 (electronic) Drug Dev Ind Pharm, 2015; 41(1): 70–78 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2013.845843
RESEARCH ARTICLE
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The effect of HPMC particle size on the drug release rate and the percolation threshold in extended-release mini-tablets Faiezah A. A. Mohamed1, Matthew Roberts1, Linda Seton1, James L. Ford1, Marina Levina2, and Ali R. Rajabi-Siahboomi2 1
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK and 2Colorcon Ltd, Dartford, UK
Abstract
Keywords
The particle size of HPMC is a critical factor that can influence drug release rate from hydrophilic matrix systems. Percolation theory is a statistical tool which is used to study the disorder of particles in a lattice of a sample. The percolation threshold is the point at which a component is dominant in a cluster resulting in significant changes in drug release rates. Mini-tablets are compact dosage forms of 1.5–4 mm diameter, which have potential benefits in the delivery of drug to some patient groups such as pediatrics. In this study, the effect of HPMC particle size on hydrocortisone release and its associated percolation threshold for mini-tablets and tablets was assessed. For both mini-tablets and tablets, large polymer particles reduced tensile strength, but increased the drug release rate and the percolation threshold. Upon hydration, compacts with 45–125 mm HPMC particles formed a strong gel layer with low porosity, reducing hydrocortisone release rates. In comparison, faster drug release rates were obtained when 125–355 mm HPMC particles were used, due to the greater pore sizes that resulted in the formation of a weaker gel. Using 125–355 mm HPMC particles increased the percolation threshold for tablets and to a greater extent for mini-tablets. This work has demonstrated the importance of HPMC particle size in ER matrices, the effects of which are even more obvious for mini-tablets.
ER, hydrocortisone, hypromellose, matrix, pediatric
Introduction Hypromellose (HPMC), specifically the high viscosity grades, is the most popular hydrophilic polymer used in extended release (ER) matrix tablets1. HPMC is regarded as safe, easy to handle and is compatible with most drugs1. HPMC has a low potential risk of dose dumping2, is compressible and can accommodate high drug levels3. The rate of drug release from matrix tablets containing HPMC is influenced by factors such as the amount and grade of polymer, the drug, polymer/drug ratio, polymer and drug particle size and filler type used4. When HPMC ER tablets are placed in aqueous media, water penetrates into the matrix through microscopic pores and a gel is formed by hydration of the polymer5. The size of HPMC particles can have a significant impact on gel formation, and therefore, drug release rate6,7. Extended drug release is difficult or even impossible to achieve when relatively large (125–355 mm) HPMC particles are used at low polymer concentrations6. Matrix systems made with
Address for correspondence: Matthew Roberts, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK. Tel: 00 44 (0)151 231 2036. E-mail: [email protected]
History Received 15 July 2013 Revised 13 September 2013 Accepted 15 September 2013 Published online 17 October 2013
large HPMC particles tend to be porous, and they take a long time to hydrate and form a gel6. Small particles of the polymer, on the other hand, allow a rapid formation of a stabilised gel, permitting extended drug release6,7. Heng et al.8 estimated the particle size threshold (the level at which reducing polymer particle size has no effect on drug release rate) for HPMC (K15M) to be 113 mm. At HPMC concentrations of less than 10%, tablets disintegrate rapidly due to an insufficient level of the polymer; thus, the effect of particle size is difficult to observe. At high HPMC concentrations the effect of particle size is negligible6, since the whole tablet is occupied by HPMC particles, masking any particle size effects9. Percolation is a statistical theory that is used to study the behavior of disorder in a system. The theory was first described in 1957 by Broadbent and Hammersley10, while Leuenberger and co-workers introduced the percolation theory to the pharmaceutics field11. A tablet can be considered as a heterogeneous binary system, which consists of a drug and an excipient7. Within a tablet, the sites of a lattice which exists underlying the binary system can be occupied by particles or pores12. Percolation theory assumes that in a binary tablet, the sites of the lattice are occupied randomly by either particles of component A or B or pores13,14, where A is the drug and B is the excipient (polymer)15. A percolating cluster is established when particles of one component are in contact with each other throughout the tablet, resulting in the formation of a continuous phase.
HPMC percolation threshold in extended-release mini-tablets
DOI: 10.3109/03639045.2013.845843
The concentration at which the maximum occurrence of this continuous phase is reached is described as the percolation threshold7,16. The percolation threshold is a critical point where a rapid change in tablet characteristics, such as drug release rate or matrix mechanical properties occurs12,17. Below the percolation threshold, HPMC is not percolating the whole system. Therefore, a strong gel does not form, due to porosity and rapid gel erosion7. According to the fundamental equation of percolation theory (Equation (1)), if the Kinetic parameter (Higuchi’s slope ‘‘b’’) with respect to the volumetric fraction behaves as a critical property, it is expected that:
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X / Sðp pcÞq
ð1Þ
where X is the studied property; S is a constant; (p pc) is the distance to the percolation threshold and q is a critical exponent18. Previous studies demonstrated a straight line relationship between the percolation threshold and the particle size of drug and excipients in a swelling binary system16. Small particles facilitate the formation of a coherent, infinite cluster14. The percolation threshold increases when the particle size of excipients increases. Mini-tablets, also known as micro-tablets or miniature tablets19 are small tablets, previously reported20–24 to be 2–3 mm or 2–5 mm or smaller in diameter25,26. However, they have recently been defined as being 1.5–4 mm in diameter by the WHO27. ER minitablets are potentially advantageous multi-particulate dosage forms. Previously, we have evaluated the effects of HPMC concentration and mini-tablet size on the release of drugs with different solubilities28 and the manufacture of ER mini-tablets using directly compressible grades of HPMC under simulated rotary press production conditions29. The aims of this study were to investigate the influence of HPMC particle size on the mechanical strength and the drug release rate from mini-tablets and to estimate the percolation threshold of HPMC in mini-tablets.
Materials and methods Materials Hydrocortisone (Courtin and Warner Ltd, Lewes, UK), HPMC (METHOCELÔ K15M, Colorcon Inc, Harleysville, PA), lactose (agglomerated a-lactose monohydrate, Tablettose 80, Meggle, Wasserburg, Germany), colloidal silicon dioxide (Aerosil 200, Evonik, Essen, Germany) and magnesium stearate (BDH, UK) were all used as supplied. Particle size analysis The particle size distribution of the bulk HPMC was determined by sieve analysis using a mechanical shaker for 10 min and standard laboratory sieves (Endecotts Ltd., London, UK) with 500, 355, 250, 180, 125, 90, 63 and 45 mm aperture sizes. The weight of each size fraction was calculated as a percentage of the bulk weight and used to determine the particle size distribution. Samples of the 45–125 mm and 125–355 mm size fractions were subsequently separated and used for further work. Formulations Formulations (each of a total weight of 100 g) were developed comprising: 16.67%w/w hydrocortisone as a model drug, 20, 30, 40, 50, 60, 70 or 80%w/w HPMC (un-sieved, 45–125 mm or 125–355 mm particles), 2.33, 12.33, 22.33, 32.33, 42.33, 52.33 or 62.33%w/w lactose, 0.5%w/w colloidal silicon dioxide and 0.5%w/w magnesium stearate. Materials were blended using a Turbula mixer (Type 2C, WAB, Switzerland) at 42 rpm for
71
5 min prior to screening (500 mm sieve) and subsequently blended with magnesium stearate for 2 min. Tablet and mini-tablet manufacture The model hydrocortisone formulations were used in the manufacture of 3 mm mini-tablets and 7 mm tablets (drug doses were 0.67 and 33.34 mg, respectively). Tablets and mini-tablets were produced by direct compression using a Stylcam 100R rotary press simulator (Medel’Pharm, Beynost, France) fitted with flatfaced tooling at a speed of 20 rpm. The compression pressure was maintained between 260 and 480 MPa and the aspect ratio (ratio of the tablet thickness to diameter) was in the range of 0.5–0.6. Tensile strength The crushing strengths, F (kp) of tablets and mini-tablets were determined using a model 6D tablet tester (Dr Schleuniger Pharmatron, Thun, Germany). Tensile strength, t, (MPa) was calculated according to Equation (2)30 where D ¼ tablet diameter (mm) and H ¼ tablet thickness (mm). t ¼ 2F=DH
ð2Þ
Drug release Drug release, from six different mini-tablets was evaluated individually using USP Apparatus 2 at 50 rpm in 900 mL water at 37 C over a period of 12 h using a Varian VK 7000 dissolution tester and a Cary 50 UV spectrophotometer at 248 nm. Data analysis The MinitabÔ 15 software package was used for statistical analysis. Analysis of variance (ANOVA) and post hoc test (Tukey’s) was used to determine any significant difference in the tensile strength of mini-tablets and tablets. Values with p 0.05 were considered to be significantly different. Dissolution profiles were compared by calculating the similarity factor (f2, Equation (3))31. A high degree of similarity is indicated by values in the range of 50 f2 100. (" #)0:5 X 2 f2 ¼ 50 þ log 1 þ ð1=nÞ nðRt Tt Þ 100 ð3Þ t¼1
where Rt Tt are the cumulative percentage drug dissolved at each time point (n) of the two profiles being compared. Calculations of f2 values were based on the dissolution profiles of bulk HPMC as the reference (R). Drug release from hydrophilic matrices was analysed using Equation (4)32. This equation assumes that the drug release occurs as soon as the dosage form is placed in the dissolution medium. Q ¼ K1 tn
ð4Þ
The Korsmeyer equation was modified by Ford et al. (1991) and a lag period was included (Equation (5)). The lag period is the time taken to hydrate the edge of the matrix, reaching equilibrium and subsequent erosion33. This phase usually occurs as a result of the poor wettability of poorly water soluble drugs34. Q ¼ K2 ðt lÞn
ð5Þ
where Q is the fraction of drug release, K1 and K2 are kinetic constants, t is the drug release time and l is the lag time34. n is the release exponent indicative of the mechanism of release and depends the shape of the matrix tested (a cylinder is studied in this case). The drug dissolution mechanism is dictated from the value
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of the diffusional release exponent, so when n ¼ 0.45 the system follows the Fick rule (Fickian diffusion), when 0.455n50.89, non-Fickian diffusion or anomalous diffusion occurs and when 0.895n51.0 the system has zero-order drug release. The modified Korsmeyer equation (Equation (5)) was used to analyze the release kinetics from the different tablet sizes at different HPMC levels using data in the range of 5–70% drug released and the time taken for 50% drug release to occur (t50%). The n values were only calculated for extended release profiles where the t50% was 42 h. Percolation theory
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The Higuchi model is used to describe the drug release rate from matrix tablets35. The Higuchi’s constant was determined using Equation (6). Q ¼ KH t0:5
ð6Þ
where Q is the fraction of the drug released, KH is the Higuchi rate constant and t is time. The initial porosity ("0) of tablets and mini-tablets was calculated using Equation (7). ð"0 Þ ¼ ðVreal Vtheor Þ=Vreal
ð7Þ
Vreal is the real tablet volume and Vtheor is the theoretical tablet volume. Theoretical volume is the sum of the volume of each excipient derived by dividing the mass of the excipient by its true density. In order to calculate the percolation threshold it was essential to calculate the volume of the tablet and the volume fraction using Equations (8) and (9), respectively, Vreal ¼ H ðD=2Þ2
ð8Þ
where Vreal is the volume, H is the thickness and D is the diameter of a tablet. Volume fractionð%v=vÞ ¼ ðVolume of HPMC=Vreal Þ 100 ð9Þ The volumes of excipients and drug were calculated using Equation (10). Volume ¼ weight=true density
ð10Þ
The true density of the materials was determined using a helium pycnometer (Multipycnometer, Quantachrome, Hook, UK). Figure 1. The particle size distribution of bulk HPMC K15M (mean SD, n ¼ 3).
The Higuchi release rate (b) was obtained by plotting drug release versus square root of time with the slope of the graph being equal to the release rate. The normalised Higuchi release rate was derived by dividing the Higuchi slope by volumetric fraction of HPMC ((b)/%v/v).
Results and discussion Particle size and tensile strength The majority of the particles in the bulk HPMC powder were below 125 mm and almost no particles were above 355 mm (Figure 1). The two particle size fractions separated from the bulk material accounted for approximately 56% (45–125 mm) and 33% (125–355 mm) of the bulk material. The particle size of materials is a critical factor which can drastically influence the mechanical strength of a compact. As demonstrated in Figures 2 and 3, decreasing the size of HPMC particles resulted in a significant increase (p50.05) in the tensile strengths of tablets and mini-tablets. Tablets and mini-tablets containing bulk material expressed tensile strengths that were significantly (p50.05) lower than those containing small particles, but insignificantly different (p40.05) to those containing large particles. This indicates that removal of fine particles leads to a significant reduction in strength, perhaps as a result of reduced surface area and subsequent inter-particulate bonding. Similar findings were reported by Nokhodchi et al.36 and Velasco et al.37. Nokhodchi et al.36 suggested that the agglomeration of small particles contributed to an increase in tablet mechanical strength, whereas large particles fractured during compression and had a low compressibility index. Therefore, large particles have low interparticulate frictional cohesive forces. Overall, increasing the level of HPMC increased tensile strength regardless of the size of the particles. Mini-tablets were stronger in comparison to larger tablets at all HPMC concentrations. High levels of HPMC did not mask the differences in tensile strength between tablets and minitablets with different particle size fractions even at 80%w/w of the polymer. Drug release Figures 4 and 5 show the release profiles of hydrocortisone from mini-tablets and tablets (data for the formulations comprising 20, 40, 60 and 80%w/w HPMC are shown). Overall, the HPMC concentration required to extend hydrocortisone release from mini-tablets was higher than that needed for larger tablets in agreement with previous findings28. The size of HPMC particles
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DOI: 10.3109/03639045.2013.845843
HPMC percolation threshold in extended-release mini-tablets
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Figure 2. The tensile strength of 7 mm tablets containing g bulk, g 45–125 mm and œ125–355 mm HPMC particles at different polymer concentrations (mean SD, n ¼ 5).
Figure 3. The tensile strength of 3 mm mini-tablets containing g bulk, g 45–125 mm and œ 125–355 mm HPMC particles at different polymer concentrations (mean values SD, n ¼ 5).
Figure 4. Hydrocortisone release from 3 mm mini-tablets containing bulk, - - - - 45–125 mm and —125–355 mm HPMC particles at (a) 20, (b) 40, (c) 60 and (d) 80%w/w polymer concentrations (mean SD, n ¼ 6).
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Figure 5. Hydrocortisone release from 7 mm tablets containing bulk, - - - - 45–125 mm and — 125–355 mm HPMC particles at (a) 20, (b) 40, (c) 60 and (d) 80%w/w polymer concentrations (mean SD, n ¼ 6).
Table 1. The t50% values (hours:minutes) for hydrocortisone release profiles from tablets and mini-tablets containing different HPMC particle fractions at different concentrations (mean SD, n ¼ 6). HPMC concentration (%w/w) Tablet diameter 7 mm
3 mm
HPMC fraction
20
30
40
50
60
70
80
bulk 45–125 mm 125–355 mm bulk 45–125 mm 125–355 mm
00:37 0:11 00:46 0:13 00:15 0:02 00:09 0:04 00:07 0:02 00:09 0:02
– 10:30 0:00 00:29 0:04 02:03 1:12 00:19 0.00 00:09 0.00
– – 00:22 0:06 05:20 0:29 05:15 0:41 00:09 0:01
– – – 06:21 0:35 06:10 0:52 00:51 0:26
– – – 05:47 0:32 06:39 0:42 05:38 0:26
– – – 03:40 0:21 06:33 1:00 06:55 1:18
– – – 06:58 0:22 06:53 0:18 06:33 1:19
Table 2. The similarity factor (f2) values for hydrocortisone release profiles from tablets and mini-tablets containing different HPMC particle size fractions at different concentrations, where the drug release rate for the un-sieved HPMC was taken as the reference. HPMC concentration (%w/w) Tablet diameter 7 mm 3 mm
HPMC fraction
20
30
40
50
60
70
80
45–125 mm 125–355 mm 45–125 mm 125–355 mm
47 71 59 65
63 9 31 30
100 9 65 14
98 61 84 19
93 87 77 50
97 98 96 73
91 96 83 75
played a crucial role in controlling the rate at which hydrocortisone was released. This was clearly illustrated by the drug release profiles, the t50% and the f2 values (Tables 1 and 2). The impact of particle size was greater in mini-tablets and the requirement of high HPMC levels to extend release was clear, in particular, when large HPMC particles were used. Despite the equal percentages of HPMC in mini-tablets and tablets, the larger tablets contain a six-fold higher weight of HPMC. In addition, due to the lower surface area to volume ratio of tablets in comparison to mini-tablets, the diffusion pathway of the dissolution media to the matrix core is longer. Therefore, the size of the tablets is a factor affecting drug release from and ER matrix system, which is as important as HPMC concentration. Tablets and mini-tablets containing bulk or 45–125 mm HPMC particles released the drug in a controlled manner at HPMC concentrations of 30 and 40%w/w, respectively. Due to the high level of fine particles in the
bulk powder, the drug release rates were similar at most concentrations (Figures 4 and 5). When larger (125–355 mm) HPMC particles were used, the entire quantity of drug was released from mini-tablets within 2 h, even at 50%w/w HPMC where the t50% value was less than 1 h compared to more than 6 h for mini-tablets containing un-sieved or 45–125 mm HPMC particles at the same concentration (Table 1). The drug release rate from mini-tablets with large HPMC particles was controlled only at polymer concentrations of 60%w/ w or greater (Figure 4 and Table 2). The f2 values for drug release profiles of mini-tablets containing large HPMC particles were less than 50 at 30, 40 and 50%w/w HPMC concentrations (Table 2), indicating more than a 10% difference in drug release rate38. For mini-tablets containing small HPMC particles, with the exception of the 30%w/w HPMC release profile, all f2 values were
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DOI: 10.3109/03639045.2013.845843
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Table 3. The release exponent, n, kinetic constant, k, (% minn) and linear regression, r2, values for 3 mm hydrocortisone mini-tablets. HPMC fraction 45–125 mm
Bulk HPMC concentration (%w/w) 20 30 40 50 60 70 80
2
n – – 0.64 0.83 1.01 0.87 0.87
n
k
r
– – 0.78 0.93 0.90 0.87 0.89
– – 2.75 2.35 2.27 2.43 2.28
– – 0.994 0.999 0.996 0.997 0.996
125–355 mm
k
r
2
n
k
r2
– – 3.06 2.54 2.17 2.42 2.35
– – 0.989 0.998 0.999 0.996 0.990
– – – – 0.75 1.14 0.81
– – – – 2.77 1.9 2.51
– – – – 0.989 0.998 0.985
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Table 4. The release exponent, n, kinetic constant, k, (% minn) and linear regression, r2, values for 7 mm hydrocortisone tablets. HPMC fraction 45–125 mm
Bulk HPMC concentration (%w/w) 20 30 40 50 60 70 80
2
n – 0.48 0.94 1.01 0.97 0.98 0.91
n
k
r
– 0.56 0.95 0.98 0.98 0.99 1.06
– 2.32 1.20 1.05 0.90 0.88 0.56
– 0.963 0.998 0.999 0.998 0.997 0.999
450 (Table 2) indicating similarity. At these concentrations the t50% values were45 h. However, the similarity (high f2 values values) at 20%w/w HPMC concentrations was due to rapid drug release in the presence of insufficient levels of the polymer, meaning that particle size effects were negligible. Similar trends were observed for 7 mm tablets (Table 2, Figure 5). However, the influence of particle size was eliminated at a lower HPMC concentration of 50%w/w. Unlike mini-tablets, where 480% of the drug was released within 12 h at all HPMC levels irrespective of particle size fraction (Figure 4), less than 50 % of the drug was released from 7 mm tablets at high HPMC concentrations (40–80%w/w bulk or 45–125 mm particles and 50–80%w/w 125–355 mm particles) (Figure 5). Therefore, it was not possible to calculate the t50% values at such concentrations (Table 1). At low HPMC levels, the t50% values clearly indicated the influence of polymer particle size on drug release rate from 7 mm tablets (Table 1). For tablets containing 40%w/w 125–355 mm HPMC particles, the t50% value was 22 min, while the t50% value for tablets containing 30%w/w 45–125 mm HPMC particles was 10 h 30 min. The f2 values were also 550 for tablets containing 45–125 mm HPMC particles at 20%w/w and 125– 355 mm particles at 30 and 40% w/w polymer (Table 2). The rapid drug release rates from tablets containing 125–355 mm HPMC particles can be explained by the fact that large polymer particles do not occupy the whole system at low concentrations, leaving some parts void of HPMC37,39. In comparison, a high number of fine particles and the associated larger surface area, which can be up to three times greater than for large particles, allow HPMC to spread through the whole system efficiently. In addition, 45–125 mm HPMC particles permitted a limited amount of water to ingress into the tablet due to the reduced porosity and increased tortuosity8,9. Formulations comprising 125–355 mm HPMC particles tend to have high proportions of inter-particulate pores compared to those containing fine particles. The number of pores is very important as the rate of liquid diffusion is proportional to the number of pores. Through these pores water can ingress into the core of the
125–355 mm
k
r
2
n
k
r2
– 2.74 1.23 0.94 1.06 0.77 0.69
– 0.963 0.997 0.998 0.998 0.998 0.999
– – – 0.49 0.84 1.05 1.07
– – – 2.33 1.31 0.77 0.96
– – – 0.954 0.991 0.999 0.997
system8,9. Due to their size, large particles hydrate at a slow rate6, and as a result, they do not bind with neighbouring particles. Thus, water imbibes to the core of the system causing rapid drug release rate and it has been reported that at low concentrations, large HPMC particles (4180 mm) can function as a disintegrant rather than a release retarding agent8. Increasing HPMC concentration eliminated any effects that could occur due to polymer particle size, as illustrated by the high f2 values (Table 2). At high HPMC levels the particles are in close proximity and thus, there are a limited number of pores available for water to penetrate into the system. However, the concentrations at which the particle size has a negligible effect on drug release rate varied with tablet size (50%w/w for 7 mm tablets and 60%w/w for 3 mm mini-tablets). Once extended release was achieved there was little or no change in the release mechanism as the content of HPMC increased, evidenced by the consistent n values (Tables 3 and 4). This was also apparent in the drug release profiles (Figures 4 and 5). For mini-tablets and tablets, n values obtained indicated that the drug was released by diffusion and erosion of the gel. Percolation threshold The trends for the percolation threshold were estimated by plotting two linear regressions of Higuchi slope/% v/v of HPMC plus initial porosity versus volume fraction plus porosity of each HPMC concentration for each tablet size (Figures 6 and 7). One of the two linear regressions represented the HPMC concentrations above the percolation threshold, while the other regression represented the HPMC concentrations below the percolation threshold. In previous studies15,17 the percolation threshold was estimated by the intersection point of two linear regressions. However, in this study most of the graphs presented only one point for one of the two regressions which made this method of estimation unreliable. Therefore, the percolation threshold was determined as a range between the nearest points to the intersection point (the points above and below it).
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Figure 6. Normalized Higuchi slope versus %v/v of HPMC plus initial porosity for 7 mm tablets containing (a) bulk (b) 45–125 mm (c) 125–355 mm HPMC particles: œ HPMC concentrations below the percolation threshold and g HPMC concentrations above the percolation threshold.
Figure 7. Normalized Higuchi slope versus %v/v of HPMC plus initial porosity for 3 mm mini-tablets containing (a) bulk (b) 45–125 mm (c) 125–355 mm HPMC particles: œ HPMC concentrations below the percolation threshold and g HPMC concentrations above the percolation threshold.
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Table 5. Real volume (Vreal), theoretical volume (Vtheor) and porosity ("0) for 3 mm mini-tablets and 7 mm tablets. 7 mm tablets HPMC (%w/w)
3
Vtheor (cm )
"0 (%)
Vreal (cm )
Vtheor (cm3)
"0 (%)
0.1348 0.1348 0.1348 0.1348 0.1348 0.1348 0.1348
0.1302 0.1282 0.1262 0.1241 0.1220 0.1200 0.1180
3.35 4.87 6.38 7.89 9.40 10.91 12.42
0.0106 0.0106 0.0106 0.0106 0.0106 0.0106 0.0106
0.0097 0.0096 0.0095 0.0093 0.0092 0.0090 0.0089
7.92 9.36 10.80 12.24 13.68 15.12 16.56
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Table 6. The percolation threshold (critical point) (%w/w) for 3 mm minitablets and 7 mm tablets derived from Figures 6 and 7. HPMC percolation threshold (%w/w) HPMC fraction bulk 45–125 mm 125–355 mm
3 mm mini-Tablets
Vreal (cm )
20 30 40 50 60 70 80
3
7 mm tablets
3 mm mini-tablets
20–30 20–30 50–60
20–30 20–30 60–70
Although HPMC particle size influenced the percolation threshold in tablets and mini-tablets (Figures 6 and 7) the effect was more apparent in mini-tablets, due to their smaller size and higher porosity (Table 5). When 125–355 mm HPMC particles were used an increase in the percolation threshold was recorded at 50–60%w/w and 60–70%w/w, for tablets and mini-tablets, respectively (Table 6). Similar percolation thresholds of 20–30 %w/w were obtained for tablets and mini-tablets with either bulk or 45–125 mm HPMC particles (Table 6). According to the percolation threshold theory, in the presence of large particles, several lattice points are occupied by one large particle and the volume of small particles identifies the volume of the lattice point40. Consequently, a large particle is recognised to be a cluster that occupies s lattice sites and its density is considered to be 100%, since all the sites are occupied by the same cluster. A high density particle is an indication of its poor ability to percolate the whole system. The density value must be low (less than 50%) in order to obtain an effective percolation, with a random mixture of the same size particles40. In principle, the percolation threshold should not be affected by the size of the compacts, as long as they are manufactured from the same batch. The results show, however, that the percolation threshold was found to be influenced by the tablet size, suggesting that both the size of HPMC particles and the matrix influence the percolation threshold. This is a significant consideration in the successful development of ER matrix mini-tablets. In order to reach the percolation threshold, HPMC particles must percolate the whole system, but the number of pores in the system must also be limited. Therefore, the amount of HPMC that might be adequate to achieve extended release in large tablets will not be necessarily adequate for mini-tablets. The amount of HPMC must be high, so that the probability of finding sufficient number of HPMC particles even in a small quantity of the blend is high. This will ensure that parts lacking HPMC, which can form pores during hydration, are limited. Large tablets can prevent rapid ingress of liquid into the core because they have high tortuosity. Therefore, even if parts of the outer tablet layer do not contain a sufficient quantity of HPMC particles, there will be additional HPMC particles in the lower layers. Consequently, if the water is absorbed rapidly by the upper part of the tablet, its diffusion into the core will be delayed, due to the presence of HPMC in the lower layers. Mini-tablets, however, have a short diffusion pathway, which means that a small pore
3
might be enough to permit water ingress into the core causing disintegration of the whole mini-tablet. Therefore, a pore which might be regarded to be small in large tablets may present a high proportion of the overall volume within a mini-tablet and so a higher proportion of HPMC in the formulation is necessary to achieve extended release.
Conclusions In this study, the effect of HPMC particle size on drug release rate from mini-tablets was evaluated and the percolation threshold was estimated for the bulk material and two different HPMC particle size fractions. The results were compared to conventional size tablets. Due to the high surface area of mini-tablets, a high HPMC content of at least 60%w/w was required to obtain extended drug release rates. This requirement increased as the size of HPMC particles increased. At low concentrations, large HPMC particles failed to form a strong gel layer to provide extended drug release. The same trends were found for larger tablets, yet the effect of particle size was more apparent in mini-tablets. Knowledge of the percolation threshold helps determine the polymer concentration at which extended drug release can be achieved. Tablet size and particle size were found to be critical factors that can impact the percolation threshold. HPMC particle size must be controlled to guarantee extended drug release at appropriate polymer concentrations, especially when formulating mini-tablets.
Declaration of interest A. R. Rajabi-Siahboomi is VP and Chief Scientific Officer at Colorcon Inc.; F. Mohamed, M. Roberts, J. L. Ford, M. Levina and L. Seton report no declarations of interest.
References 1. Ghimire M, Hodges LA, Band J, et al. In-vitro and in-vivo erosion profiles of hydroxypropylmethylcellulose (HPMC) matrix tablets. J Control Release 2010;147:70–5. 2. Moin A, Shivakumar H. Formulation of sustained-release diltiazem matrix tablets using hydrophilic gum blends. Tropical J Pharm Res 2010;9:283–91. 3. Fu XC, Wang GP, Liang WQ, Chow MSS. Prediction of drug release from HPMC matrices: effect of physicochemical properties of drug and polymer concentration. J Control Rel 2004;95:209–16. 4. Levina M, Rajabi-Siahboomi AR. The influence of excipients on drug release from hydroxypropyl methylcellulose matrices. J Pharm Sci 2004;93:2746–54. 5. Wan LSC, Heng PWS, Wong LF. The effect of hydroxypropyl methylcellulose on water penetration into a matrix system. Int J Pharm 1991;73:111–16. 6. Campos-Aldrete M, Villafuerte-Robles L. Influence of the viscosity grade and the particle size of HPMC on metronidazole release from matrix tablets. Eur J Pharm Biopharm 1997;43:173–8.
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7. Mitchell SA, Balwinski KM. Investigation of hypromellose particle size effects on drug release from sustained release hydrophilic matrix tablets. Drug Dev Ind Pharm 2007;33:952–8. 8. Heng PWS, Chan LW, Easterbrook MG, Li X. Investigation of the influence of mean HPMC particle size and number of polymer particles on the release of aspirin from swellable hydrophilic matrix tablets. J Control Release 2001;76:39–49. 9. Mitchell K, Ford JL, Armstrong DJ, et al. The influence of concentration on the release of drugs from gels and matrices containing Methocel . Int J Pharm 1993;100:155–63. 10. Broadbent SR, Hammersley JM. Percolation processes. I. Crystals and mazes. Proc Cambridge Philosophical Soc 1957;3:629–41. 11. Leuenberger H, Rohera BD, Haas C. Percolation theory – a novel approach to solid dosage form design. Int J Pharm 1987; 38:109–15. 12. Castellanos GE, Iraizoz CA, Bataille B, et al. Estimation of the percolation thresholds in ternary lobenzarit disodium– dextran–HPMC hydrophilic matrices tablets: effects of initial porosity. Eur J Pharm Sci 2009;38:312–19. 13. Caraballo I, Ferna´ndez-Are´valo M, Milla´n M, et al. Study of percolation thresholds in ternary tablets. Int J Pharm 1996;139: 177–86. 14. Caraballo I, Ferna´ndez-Are´valo M, Holgado MA, Rabasco AM. Percolation theory: application to the study of the release behaviour from inert matrix systems. Int J Pharm 1993;96:175–81. 15. Fuertes I, Miranda A, Milla´n M, Caraballo I. Estimation of the percolation thresholds in acyclovir hydrophilic matrix tablets. Eur J Pharm Biopharm 2006;64:336–42. 16. Gonc¸alves-Arau´jo T, Rajabi-Siahboomi AR, Caraballo I. Application of percolation theory in the study of an extended release Verapamil hydrochloride formulation. Int J Pharm 2008;361: 112–17. 17. Miranda A, Milla´n M, Caraballo I. Study of the critical points of HPMC hydrophilic matrices for controlled drug delivery. Int J Pharm 2006;311:75–81. 18. Maghsoodi M, Barghi L. Polymer percolation threshold in multi-component HPMC matrices tablets. Adv Pharm Bull 2011;1: 27–33. 19. Hersbberg EB. Apparatus for punching miniature tablets. United States Patent Office 3 175 521, 30 March 1965. 20. de Brabander C, Vervaet C, Go¨rtz JP, et al. Bioavailability of ibuprofen from matrix mini-tablets based on a mixture of starch and microcrystalline wax. Int J Pharm 2000;208:81–6. 21. Tissen C, Woertz K, Breitkreutz J, Kleinebudde P. Development of mini-tablets with 1 mm and 2 mm diameter. Int J Pharm 2011;416: 164–70. 22. Lennartz P, Mielck JB. Minitabletting: improving the compactability of paracetamol powder mixtures. Int J Pharm 1998;173:75–85. 23. Lopes CM, Lobo JMlS, Pinto JF, Costa P. Compressed mini-tablets as a biphasic delivery system. Int J Pharm 2006;323:93–100.
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24. Lopes CM, Sousa Lobo JM, Costa P, Pinto JF. Directly compressed mini matrix tablets containing ibuprofen: preparation and evaluation of sustained release. Drug Dev Ind Pharm 2006;32:95–106. 25. Thomson SA, Tuleu C, Wong ICK, et al. Minitablets: new modality to deliver medicines to preschool-aged children. Pediatrics 2009; 123:235–8. 26. Allenspach CT, Zannou EA. Compaction of combination products. Chapter 11. In: Celik M, ed. Pharmaceutical powder compaction technology. 2nd ed., Vol. 197. London, UK: Informa Health care; 2011: 253–79. 27. WHO. Development of paediatric medicines – points to consider in pharmaceutical development. Geneva, Switzerland: WHO; 2012. 28. Mohamed F, Roberts M, Ford JL, et al. The influence of HPMC concentration on release of theophylline or hydrocortisone from extended-release mini-tablets. Drug Dev Ind Pharm 2013;39: 1167–74. 29. Mohamed FAA, Roberts M, Seton L, et al. Production of extended release mini-tablets using directly compressible grades of HPMC. Drug Dev Ind Pharm (Early Online) 2013:1–8. doi: 10.3109/ 03639045.2012.730524. 30. Fell JT, Newton JM. The tensile strength of lactose tablets. J Pharm Pharmacol 1968;8:657–9. 31. Moore JW, Flanner HH. Mathematical comparison of curves with an emphasis on dissolution profiles. Pharm Tech 1996;20:64–74. 32. Korsmeyer RW, Gurny R, Doelker E, et al. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm 1983;15: 25–35. 33. Ford JL, Mitchell K, Rowe P, et al. Mathematical modelling of drug release from hydroxypropyl methylcellulose matrices: effect of temperature. Int J Pharm 1991;71:95–104. 34. Ford JL, Rubinstein MH, McCaul F, et al. Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxypropyl methylcellulose matrix tablets. Int J Pharm 1987;40: 223–34. 35. Grassi M, Grassi G. Mathematical modelling and controlled drug delivery: matrix systems. Curr Drug Deliv 2005;2:97–116. 36. Nokhodchi A, Rubinstein MH, Ford JL. The effect of particle size and viscosity grade on the compaction properties of hydroxypropylmethylcellulose 2208. Int J Pharm 1995;126:189–97. 37. Velasco MV, Ford JL, Rowe P, Rajabi-Siahboomi AR. Influence of drug:hydroxypropylmethylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC tablets. J Control Release 1999;57:75–85. 38. Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Sci 2005;8:76–93. 39. Mitchell K, Ford JL, Armstrong DJ, et al. The influence of the particle size of hydroxypropylmethylcellulose K15M on its hydration and performance in matrix tablets. Int J Pharm 1993;100:175–9. 40. Miranda A, Milla´n M, Caraballo I. Investigation of the influence of particle size on the excipient percolation thresholds of HPMC hydrophilic matrix tablets. J Pharm Sci 2007;96:2746–56.
RESEARCH ARTICLE
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The effect of HPMC particle size on the drug release rate and the percolation threshold in extended-release mini-tablets Faiezah A. A. Mohamed1, Matthew Roberts1, Linda Seton1, James L. Ford1, Marina Levina2, and Ali R. Rajabi-Siahboomi2 1
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK and 2Colorcon Ltd, Dartford, UK
Abstract
Keywords
The particle size of HPMC is a critical factor that can influence drug release rate from hydrophilic matrix systems. Percolation theory is a statistical tool which is used to study the disorder of particles in a lattice of a sample. The percolation threshold is the point at which a component is dominant in a cluster resulting in significant changes in drug release rates. Mini-tablets are compact dosage forms of 1.5–4 mm diameter, which have potential benefits in the delivery of drug to some patient groups such as pediatrics. In this study, the effect of HPMC particle size on hydrocortisone release and its associated percolation threshold for mini-tablets and tablets was assessed. For both mini-tablets and tablets, large polymer particles reduced tensile strength, but increased the drug release rate and the percolation threshold. Upon hydration, compacts with 45–125 mm HPMC particles formed a strong gel layer with low porosity, reducing hydrocortisone release rates. In comparison, faster drug release rates were obtained when 125–355 mm HPMC particles were used, due to the greater pore sizes that resulted in the formation of a weaker gel. Using 125–355 mm HPMC particles increased the percolation threshold for tablets and to a greater extent for mini-tablets. This work has demonstrated the importance of HPMC particle size in ER matrices, the effects of which are even more obvious for mini-tablets.
ER, hydrocortisone, hypromellose, matrix, pediatric
Introduction Hypromellose (HPMC), specifically the high viscosity grades, is the most popular hydrophilic polymer used in extended release (ER) matrix tablets1. HPMC is regarded as safe, easy to handle and is compatible with most drugs1. HPMC has a low potential risk of dose dumping2, is compressible and can accommodate high drug levels3. The rate of drug release from matrix tablets containing HPMC is influenced by factors such as the amount and grade of polymer, the drug, polymer/drug ratio, polymer and drug particle size and filler type used4. When HPMC ER tablets are placed in aqueous media, water penetrates into the matrix through microscopic pores and a gel is formed by hydration of the polymer5. The size of HPMC particles can have a significant impact on gel formation, and therefore, drug release rate6,7. Extended drug release is difficult or even impossible to achieve when relatively large (125–355 mm) HPMC particles are used at low polymer concentrations6. Matrix systems made with
Address for correspondence: Matthew Roberts, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK. Tel: 00 44 (0)151 231 2036. E-mail: [email protected]
History Received 15 July 2013 Revised 13 September 2013 Accepted 15 September 2013 Published online 17 October 2013
large HPMC particles tend to be porous, and they take a long time to hydrate and form a gel6. Small particles of the polymer, on the other hand, allow a rapid formation of a stabilised gel, permitting extended drug release6,7. Heng et al.8 estimated the particle size threshold (the level at which reducing polymer particle size has no effect on drug release rate) for HPMC (K15M) to be 113 mm. At HPMC concentrations of less than 10%, tablets disintegrate rapidly due to an insufficient level of the polymer; thus, the effect of particle size is difficult to observe. At high HPMC concentrations the effect of particle size is negligible6, since the whole tablet is occupied by HPMC particles, masking any particle size effects9. Percolation is a statistical theory that is used to study the behavior of disorder in a system. The theory was first described in 1957 by Broadbent and Hammersley10, while Leuenberger and co-workers introduced the percolation theory to the pharmaceutics field11. A tablet can be considered as a heterogeneous binary system, which consists of a drug and an excipient7. Within a tablet, the sites of a lattice which exists underlying the binary system can be occupied by particles or pores12. Percolation theory assumes that in a binary tablet, the sites of the lattice are occupied randomly by either particles of component A or B or pores13,14, where A is the drug and B is the excipient (polymer)15. A percolating cluster is established when particles of one component are in contact with each other throughout the tablet, resulting in the formation of a continuous phase.
HPMC percolation threshold in extended-release mini-tablets
DOI: 10.3109/03639045.2013.845843
The concentration at which the maximum occurrence of this continuous phase is reached is described as the percolation threshold7,16. The percolation threshold is a critical point where a rapid change in tablet characteristics, such as drug release rate or matrix mechanical properties occurs12,17. Below the percolation threshold, HPMC is not percolating the whole system. Therefore, a strong gel does not form, due to porosity and rapid gel erosion7. According to the fundamental equation of percolation theory (Equation (1)), if the Kinetic parameter (Higuchi’s slope ‘‘b’’) with respect to the volumetric fraction behaves as a critical property, it is expected that:
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X / Sðp pcÞq
ð1Þ
where X is the studied property; S is a constant; (p pc) is the distance to the percolation threshold and q is a critical exponent18. Previous studies demonstrated a straight line relationship between the percolation threshold and the particle size of drug and excipients in a swelling binary system16. Small particles facilitate the formation of a coherent, infinite cluster14. The percolation threshold increases when the particle size of excipients increases. Mini-tablets, also known as micro-tablets or miniature tablets19 are small tablets, previously reported20–24 to be 2–3 mm or 2–5 mm or smaller in diameter25,26. However, they have recently been defined as being 1.5–4 mm in diameter by the WHO27. ER minitablets are potentially advantageous multi-particulate dosage forms. Previously, we have evaluated the effects of HPMC concentration and mini-tablet size on the release of drugs with different solubilities28 and the manufacture of ER mini-tablets using directly compressible grades of HPMC under simulated rotary press production conditions29. The aims of this study were to investigate the influence of HPMC particle size on the mechanical strength and the drug release rate from mini-tablets and to estimate the percolation threshold of HPMC in mini-tablets.
Materials and methods Materials Hydrocortisone (Courtin and Warner Ltd, Lewes, UK), HPMC (METHOCELÔ K15M, Colorcon Inc, Harleysville, PA), lactose (agglomerated a-lactose monohydrate, Tablettose 80, Meggle, Wasserburg, Germany), colloidal silicon dioxide (Aerosil 200, Evonik, Essen, Germany) and magnesium stearate (BDH, UK) were all used as supplied. Particle size analysis The particle size distribution of the bulk HPMC was determined by sieve analysis using a mechanical shaker for 10 min and standard laboratory sieves (Endecotts Ltd., London, UK) with 500, 355, 250, 180, 125, 90, 63 and 45 mm aperture sizes. The weight of each size fraction was calculated as a percentage of the bulk weight and used to determine the particle size distribution. Samples of the 45–125 mm and 125–355 mm size fractions were subsequently separated and used for further work. Formulations Formulations (each of a total weight of 100 g) were developed comprising: 16.67%w/w hydrocortisone as a model drug, 20, 30, 40, 50, 60, 70 or 80%w/w HPMC (un-sieved, 45–125 mm or 125–355 mm particles), 2.33, 12.33, 22.33, 32.33, 42.33, 52.33 or 62.33%w/w lactose, 0.5%w/w colloidal silicon dioxide and 0.5%w/w magnesium stearate. Materials were blended using a Turbula mixer (Type 2C, WAB, Switzerland) at 42 rpm for
71
5 min prior to screening (500 mm sieve) and subsequently blended with magnesium stearate for 2 min. Tablet and mini-tablet manufacture The model hydrocortisone formulations were used in the manufacture of 3 mm mini-tablets and 7 mm tablets (drug doses were 0.67 and 33.34 mg, respectively). Tablets and mini-tablets were produced by direct compression using a Stylcam 100R rotary press simulator (Medel’Pharm, Beynost, France) fitted with flatfaced tooling at a speed of 20 rpm. The compression pressure was maintained between 260 and 480 MPa and the aspect ratio (ratio of the tablet thickness to diameter) was in the range of 0.5–0.6. Tensile strength The crushing strengths, F (kp) of tablets and mini-tablets were determined using a model 6D tablet tester (Dr Schleuniger Pharmatron, Thun, Germany). Tensile strength, t, (MPa) was calculated according to Equation (2)30 where D ¼ tablet diameter (mm) and H ¼ tablet thickness (mm). t ¼ 2F=DH
ð2Þ
Drug release Drug release, from six different mini-tablets was evaluated individually using USP Apparatus 2 at 50 rpm in 900 mL water at 37 C over a period of 12 h using a Varian VK 7000 dissolution tester and a Cary 50 UV spectrophotometer at 248 nm. Data analysis The MinitabÔ 15 software package was used for statistical analysis. Analysis of variance (ANOVA) and post hoc test (Tukey’s) was used to determine any significant difference in the tensile strength of mini-tablets and tablets. Values with p 0.05 were considered to be significantly different. Dissolution profiles were compared by calculating the similarity factor (f2, Equation (3))31. A high degree of similarity is indicated by values in the range of 50 f2 100. (" #)0:5 X 2 f2 ¼ 50 þ log 1 þ ð1=nÞ nðRt Tt Þ 100 ð3Þ t¼1
where Rt Tt are the cumulative percentage drug dissolved at each time point (n) of the two profiles being compared. Calculations of f2 values were based on the dissolution profiles of bulk HPMC as the reference (R). Drug release from hydrophilic matrices was analysed using Equation (4)32. This equation assumes that the drug release occurs as soon as the dosage form is placed in the dissolution medium. Q ¼ K1 tn
ð4Þ
The Korsmeyer equation was modified by Ford et al. (1991) and a lag period was included (Equation (5)). The lag period is the time taken to hydrate the edge of the matrix, reaching equilibrium and subsequent erosion33. This phase usually occurs as a result of the poor wettability of poorly water soluble drugs34. Q ¼ K2 ðt lÞn
ð5Þ
where Q is the fraction of drug release, K1 and K2 are kinetic constants, t is the drug release time and l is the lag time34. n is the release exponent indicative of the mechanism of release and depends the shape of the matrix tested (a cylinder is studied in this case). The drug dissolution mechanism is dictated from the value
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of the diffusional release exponent, so when n ¼ 0.45 the system follows the Fick rule (Fickian diffusion), when 0.455n50.89, non-Fickian diffusion or anomalous diffusion occurs and when 0.895n51.0 the system has zero-order drug release. The modified Korsmeyer equation (Equation (5)) was used to analyze the release kinetics from the different tablet sizes at different HPMC levels using data in the range of 5–70% drug released and the time taken for 50% drug release to occur (t50%). The n values were only calculated for extended release profiles where the t50% was 42 h. Percolation theory
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The Higuchi model is used to describe the drug release rate from matrix tablets35. The Higuchi’s constant was determined using Equation (6). Q ¼ KH t0:5
ð6Þ
where Q is the fraction of the drug released, KH is the Higuchi rate constant and t is time. The initial porosity ("0) of tablets and mini-tablets was calculated using Equation (7). ð"0 Þ ¼ ðVreal Vtheor Þ=Vreal
ð7Þ
Vreal is the real tablet volume and Vtheor is the theoretical tablet volume. Theoretical volume is the sum of the volume of each excipient derived by dividing the mass of the excipient by its true density. In order to calculate the percolation threshold it was essential to calculate the volume of the tablet and the volume fraction using Equations (8) and (9), respectively, Vreal ¼ H ðD=2Þ2
ð8Þ
where Vreal is the volume, H is the thickness and D is the diameter of a tablet. Volume fractionð%v=vÞ ¼ ðVolume of HPMC=Vreal Þ 100 ð9Þ The volumes of excipients and drug were calculated using Equation (10). Volume ¼ weight=true density
ð10Þ
The true density of the materials was determined using a helium pycnometer (Multipycnometer, Quantachrome, Hook, UK). Figure 1. The particle size distribution of bulk HPMC K15M (mean SD, n ¼ 3).
The Higuchi release rate (b) was obtained by plotting drug release versus square root of time with the slope of the graph being equal to the release rate. The normalised Higuchi release rate was derived by dividing the Higuchi slope by volumetric fraction of HPMC ((b)/%v/v).
Results and discussion Particle size and tensile strength The majority of the particles in the bulk HPMC powder were below 125 mm and almost no particles were above 355 mm (Figure 1). The two particle size fractions separated from the bulk material accounted for approximately 56% (45–125 mm) and 33% (125–355 mm) of the bulk material. The particle size of materials is a critical factor which can drastically influence the mechanical strength of a compact. As demonstrated in Figures 2 and 3, decreasing the size of HPMC particles resulted in a significant increase (p50.05) in the tensile strengths of tablets and mini-tablets. Tablets and mini-tablets containing bulk material expressed tensile strengths that were significantly (p50.05) lower than those containing small particles, but insignificantly different (p40.05) to those containing large particles. This indicates that removal of fine particles leads to a significant reduction in strength, perhaps as a result of reduced surface area and subsequent inter-particulate bonding. Similar findings were reported by Nokhodchi et al.36 and Velasco et al.37. Nokhodchi et al.36 suggested that the agglomeration of small particles contributed to an increase in tablet mechanical strength, whereas large particles fractured during compression and had a low compressibility index. Therefore, large particles have low interparticulate frictional cohesive forces. Overall, increasing the level of HPMC increased tensile strength regardless of the size of the particles. Mini-tablets were stronger in comparison to larger tablets at all HPMC concentrations. High levels of HPMC did not mask the differences in tensile strength between tablets and minitablets with different particle size fractions even at 80%w/w of the polymer. Drug release Figures 4 and 5 show the release profiles of hydrocortisone from mini-tablets and tablets (data for the formulations comprising 20, 40, 60 and 80%w/w HPMC are shown). Overall, the HPMC concentration required to extend hydrocortisone release from mini-tablets was higher than that needed for larger tablets in agreement with previous findings28. The size of HPMC particles
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DOI: 10.3109/03639045.2013.845843
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Figure 2. The tensile strength of 7 mm tablets containing g bulk, g 45–125 mm and œ125–355 mm HPMC particles at different polymer concentrations (mean SD, n ¼ 5).
Figure 3. The tensile strength of 3 mm mini-tablets containing g bulk, g 45–125 mm and œ 125–355 mm HPMC particles at different polymer concentrations (mean values SD, n ¼ 5).
Figure 4. Hydrocortisone release from 3 mm mini-tablets containing bulk, - - - - 45–125 mm and —125–355 mm HPMC particles at (a) 20, (b) 40, (c) 60 and (d) 80%w/w polymer concentrations (mean SD, n ¼ 6).
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Figure 5. Hydrocortisone release from 7 mm tablets containing bulk, - - - - 45–125 mm and — 125–355 mm HPMC particles at (a) 20, (b) 40, (c) 60 and (d) 80%w/w polymer concentrations (mean SD, n ¼ 6).
Table 1. The t50% values (hours:minutes) for hydrocortisone release profiles from tablets and mini-tablets containing different HPMC particle fractions at different concentrations (mean SD, n ¼ 6). HPMC concentration (%w/w) Tablet diameter 7 mm
3 mm
HPMC fraction
20
30
40
50
60
70
80
bulk 45–125 mm 125–355 mm bulk 45–125 mm 125–355 mm
00:37 0:11 00:46 0:13 00:15 0:02 00:09 0:04 00:07 0:02 00:09 0:02
– 10:30 0:00 00:29 0:04 02:03 1:12 00:19 0.00 00:09 0.00
– – 00:22 0:06 05:20 0:29 05:15 0:41 00:09 0:01
– – – 06:21 0:35 06:10 0:52 00:51 0:26
– – – 05:47 0:32 06:39 0:42 05:38 0:26
– – – 03:40 0:21 06:33 1:00 06:55 1:18
– – – 06:58 0:22 06:53 0:18 06:33 1:19
Table 2. The similarity factor (f2) values for hydrocortisone release profiles from tablets and mini-tablets containing different HPMC particle size fractions at different concentrations, where the drug release rate for the un-sieved HPMC was taken as the reference. HPMC concentration (%w/w) Tablet diameter 7 mm 3 mm
HPMC fraction
20
30
40
50
60
70
80
45–125 mm 125–355 mm 45–125 mm 125–355 mm
47 71 59 65
63 9 31 30
100 9 65 14
98 61 84 19
93 87 77 50
97 98 96 73
91 96 83 75
played a crucial role in controlling the rate at which hydrocortisone was released. This was clearly illustrated by the drug release profiles, the t50% and the f2 values (Tables 1 and 2). The impact of particle size was greater in mini-tablets and the requirement of high HPMC levels to extend release was clear, in particular, when large HPMC particles were used. Despite the equal percentages of HPMC in mini-tablets and tablets, the larger tablets contain a six-fold higher weight of HPMC. In addition, due to the lower surface area to volume ratio of tablets in comparison to mini-tablets, the diffusion pathway of the dissolution media to the matrix core is longer. Therefore, the size of the tablets is a factor affecting drug release from and ER matrix system, which is as important as HPMC concentration. Tablets and mini-tablets containing bulk or 45–125 mm HPMC particles released the drug in a controlled manner at HPMC concentrations of 30 and 40%w/w, respectively. Due to the high level of fine particles in the
bulk powder, the drug release rates were similar at most concentrations (Figures 4 and 5). When larger (125–355 mm) HPMC particles were used, the entire quantity of drug was released from mini-tablets within 2 h, even at 50%w/w HPMC where the t50% value was less than 1 h compared to more than 6 h for mini-tablets containing un-sieved or 45–125 mm HPMC particles at the same concentration (Table 1). The drug release rate from mini-tablets with large HPMC particles was controlled only at polymer concentrations of 60%w/ w or greater (Figure 4 and Table 2). The f2 values for drug release profiles of mini-tablets containing large HPMC particles were less than 50 at 30, 40 and 50%w/w HPMC concentrations (Table 2), indicating more than a 10% difference in drug release rate38. For mini-tablets containing small HPMC particles, with the exception of the 30%w/w HPMC release profile, all f2 values were
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DOI: 10.3109/03639045.2013.845843
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Table 3. The release exponent, n, kinetic constant, k, (% minn) and linear regression, r2, values for 3 mm hydrocortisone mini-tablets. HPMC fraction 45–125 mm
Bulk HPMC concentration (%w/w) 20 30 40 50 60 70 80
2
n – – 0.64 0.83 1.01 0.87 0.87
n
k
r
– – 0.78 0.93 0.90 0.87 0.89
– – 2.75 2.35 2.27 2.43 2.28
– – 0.994 0.999 0.996 0.997 0.996
125–355 mm
k
r
2
n
k
r2
– – 3.06 2.54 2.17 2.42 2.35
– – 0.989 0.998 0.999 0.996 0.990
– – – – 0.75 1.14 0.81
– – – – 2.77 1.9 2.51
– – – – 0.989 0.998 0.985
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Table 4. The release exponent, n, kinetic constant, k, (% minn) and linear regression, r2, values for 7 mm hydrocortisone tablets. HPMC fraction 45–125 mm
Bulk HPMC concentration (%w/w) 20 30 40 50 60 70 80
2
n – 0.48 0.94 1.01 0.97 0.98 0.91
n
k
r
– 0.56 0.95 0.98 0.98 0.99 1.06
– 2.32 1.20 1.05 0.90 0.88 0.56
– 0.963 0.998 0.999 0.998 0.997 0.999
450 (Table 2) indicating similarity. At these concentrations the t50% values were45 h. However, the similarity (high f2 values values) at 20%w/w HPMC concentrations was due to rapid drug release in the presence of insufficient levels of the polymer, meaning that particle size effects were negligible. Similar trends were observed for 7 mm tablets (Table 2, Figure 5). However, the influence of particle size was eliminated at a lower HPMC concentration of 50%w/w. Unlike mini-tablets, where 480% of the drug was released within 12 h at all HPMC levels irrespective of particle size fraction (Figure 4), less than 50 % of the drug was released from 7 mm tablets at high HPMC concentrations (40–80%w/w bulk or 45–125 mm particles and 50–80%w/w 125–355 mm particles) (Figure 5). Therefore, it was not possible to calculate the t50% values at such concentrations (Table 1). At low HPMC levels, the t50% values clearly indicated the influence of polymer particle size on drug release rate from 7 mm tablets (Table 1). For tablets containing 40%w/w 125–355 mm HPMC particles, the t50% value was 22 min, while the t50% value for tablets containing 30%w/w 45–125 mm HPMC particles was 10 h 30 min. The f2 values were also 550 for tablets containing 45–125 mm HPMC particles at 20%w/w and 125– 355 mm particles at 30 and 40% w/w polymer (Table 2). The rapid drug release rates from tablets containing 125–355 mm HPMC particles can be explained by the fact that large polymer particles do not occupy the whole system at low concentrations, leaving some parts void of HPMC37,39. In comparison, a high number of fine particles and the associated larger surface area, which can be up to three times greater than for large particles, allow HPMC to spread through the whole system efficiently. In addition, 45–125 mm HPMC particles permitted a limited amount of water to ingress into the tablet due to the reduced porosity and increased tortuosity8,9. Formulations comprising 125–355 mm HPMC particles tend to have high proportions of inter-particulate pores compared to those containing fine particles. The number of pores is very important as the rate of liquid diffusion is proportional to the number of pores. Through these pores water can ingress into the core of the
125–355 mm
k
r
2
n
k
r2
– 2.74 1.23 0.94 1.06 0.77 0.69
– 0.963 0.997 0.998 0.998 0.998 0.999
– – – 0.49 0.84 1.05 1.07
– – – 2.33 1.31 0.77 0.96
– – – 0.954 0.991 0.999 0.997
system8,9. Due to their size, large particles hydrate at a slow rate6, and as a result, they do not bind with neighbouring particles. Thus, water imbibes to the core of the system causing rapid drug release rate and it has been reported that at low concentrations, large HPMC particles (4180 mm) can function as a disintegrant rather than a release retarding agent8. Increasing HPMC concentration eliminated any effects that could occur due to polymer particle size, as illustrated by the high f2 values (Table 2). At high HPMC levels the particles are in close proximity and thus, there are a limited number of pores available for water to penetrate into the system. However, the concentrations at which the particle size has a negligible effect on drug release rate varied with tablet size (50%w/w for 7 mm tablets and 60%w/w for 3 mm mini-tablets). Once extended release was achieved there was little or no change in the release mechanism as the content of HPMC increased, evidenced by the consistent n values (Tables 3 and 4). This was also apparent in the drug release profiles (Figures 4 and 5). For mini-tablets and tablets, n values obtained indicated that the drug was released by diffusion and erosion of the gel. Percolation threshold The trends for the percolation threshold were estimated by plotting two linear regressions of Higuchi slope/% v/v of HPMC plus initial porosity versus volume fraction plus porosity of each HPMC concentration for each tablet size (Figures 6 and 7). One of the two linear regressions represented the HPMC concentrations above the percolation threshold, while the other regression represented the HPMC concentrations below the percolation threshold. In previous studies15,17 the percolation threshold was estimated by the intersection point of two linear regressions. However, in this study most of the graphs presented only one point for one of the two regressions which made this method of estimation unreliable. Therefore, the percolation threshold was determined as a range between the nearest points to the intersection point (the points above and below it).
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Figure 6. Normalized Higuchi slope versus %v/v of HPMC plus initial porosity for 7 mm tablets containing (a) bulk (b) 45–125 mm (c) 125–355 mm HPMC particles: œ HPMC concentrations below the percolation threshold and g HPMC concentrations above the percolation threshold.
Figure 7. Normalized Higuchi slope versus %v/v of HPMC plus initial porosity for 3 mm mini-tablets containing (a) bulk (b) 45–125 mm (c) 125–355 mm HPMC particles: œ HPMC concentrations below the percolation threshold and g HPMC concentrations above the percolation threshold.
HPMC percolation threshold in extended-release mini-tablets
DOI: 10.3109/03639045.2013.845843
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Table 5. Real volume (Vreal), theoretical volume (Vtheor) and porosity ("0) for 3 mm mini-tablets and 7 mm tablets. 7 mm tablets HPMC (%w/w)
3
Vtheor (cm )
"0 (%)
Vreal (cm )
Vtheor (cm3)
"0 (%)
0.1348 0.1348 0.1348 0.1348 0.1348 0.1348 0.1348
0.1302 0.1282 0.1262 0.1241 0.1220 0.1200 0.1180
3.35 4.87 6.38 7.89 9.40 10.91 12.42
0.0106 0.0106 0.0106 0.0106 0.0106 0.0106 0.0106
0.0097 0.0096 0.0095 0.0093 0.0092 0.0090 0.0089
7.92 9.36 10.80 12.24 13.68 15.12 16.56
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Table 6. The percolation threshold (critical point) (%w/w) for 3 mm minitablets and 7 mm tablets derived from Figures 6 and 7. HPMC percolation threshold (%w/w) HPMC fraction bulk 45–125 mm 125–355 mm
3 mm mini-Tablets
Vreal (cm )
20 30 40 50 60 70 80
3
7 mm tablets
3 mm mini-tablets
20–30 20–30 50–60
20–30 20–30 60–70
Although HPMC particle size influenced the percolation threshold in tablets and mini-tablets (Figures 6 and 7) the effect was more apparent in mini-tablets, due to their smaller size and higher porosity (Table 5). When 125–355 mm HPMC particles were used an increase in the percolation threshold was recorded at 50–60%w/w and 60–70%w/w, for tablets and mini-tablets, respectively (Table 6). Similar percolation thresholds of 20–30 %w/w were obtained for tablets and mini-tablets with either bulk or 45–125 mm HPMC particles (Table 6). According to the percolation threshold theory, in the presence of large particles, several lattice points are occupied by one large particle and the volume of small particles identifies the volume of the lattice point40. Consequently, a large particle is recognised to be a cluster that occupies s lattice sites and its density is considered to be 100%, since all the sites are occupied by the same cluster. A high density particle is an indication of its poor ability to percolate the whole system. The density value must be low (less than 50%) in order to obtain an effective percolation, with a random mixture of the same size particles40. In principle, the percolation threshold should not be affected by the size of the compacts, as long as they are manufactured from the same batch. The results show, however, that the percolation threshold was found to be influenced by the tablet size, suggesting that both the size of HPMC particles and the matrix influence the percolation threshold. This is a significant consideration in the successful development of ER matrix mini-tablets. In order to reach the percolation threshold, HPMC particles must percolate the whole system, but the number of pores in the system must also be limited. Therefore, the amount of HPMC that might be adequate to achieve extended release in large tablets will not be necessarily adequate for mini-tablets. The amount of HPMC must be high, so that the probability of finding sufficient number of HPMC particles even in a small quantity of the blend is high. This will ensure that parts lacking HPMC, which can form pores during hydration, are limited. Large tablets can prevent rapid ingress of liquid into the core because they have high tortuosity. Therefore, even if parts of the outer tablet layer do not contain a sufficient quantity of HPMC particles, there will be additional HPMC particles in the lower layers. Consequently, if the water is absorbed rapidly by the upper part of the tablet, its diffusion into the core will be delayed, due to the presence of HPMC in the lower layers. Mini-tablets, however, have a short diffusion pathway, which means that a small pore
3
might be enough to permit water ingress into the core causing disintegration of the whole mini-tablet. Therefore, a pore which might be regarded to be small in large tablets may present a high proportion of the overall volume within a mini-tablet and so a higher proportion of HPMC in the formulation is necessary to achieve extended release.
Conclusions In this study, the effect of HPMC particle size on drug release rate from mini-tablets was evaluated and the percolation threshold was estimated for the bulk material and two different HPMC particle size fractions. The results were compared to conventional size tablets. Due to the high surface area of mini-tablets, a high HPMC content of at least 60%w/w was required to obtain extended drug release rates. This requirement increased as the size of HPMC particles increased. At low concentrations, large HPMC particles failed to form a strong gel layer to provide extended drug release. The same trends were found for larger tablets, yet the effect of particle size was more apparent in mini-tablets. Knowledge of the percolation threshold helps determine the polymer concentration at which extended drug release can be achieved. Tablet size and particle size were found to be critical factors that can impact the percolation threshold. HPMC particle size must be controlled to guarantee extended drug release at appropriate polymer concentrations, especially when formulating mini-tablets.
Declaration of interest A. R. Rajabi-Siahboomi is VP and Chief Scientific Officer at Colorcon Inc.; F. Mohamed, M. Roberts, J. L. Ford, M. Levina and L. Seton report no declarations of interest.
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